Natural product total synthesis continues to serve as a driving force for inventions in organic chemistry, and is an essential paradigm in the Stoltz group. The content of this thesis reflects this central objective. Chapter 1 focuses on the total synthesis of aleutianamine\u2014 a new pyrroloiminoquinone alkaloid natural product that possesses an unprecedented structure and potent anti-tumor activity. Herein is described a non-biomimetic synthesis that hinges upon the development of a dearomative thiophene arylation to construct the unique [3.3.1] ring system of the natural product. An unconventional ketone installation was then developed to install the alkenyl bromide, and finally, an oxidative amination/thioaminal formation protocol was developed to complete the synthesis. Additionally, a novel Larock/Buchwald\u2013Hartwig annulation/cyclization was developed to access the core of the natural product.
\r\n\t\t\r\nChapter 2 focuses on leveraging the Larock/Buchwald\u2013Hartwig annulation/cyclization developed en route to aleutianamine to access several pyrroloiminoquinone alkaloids in a divergent manner. This strategy led to the shortest synthetic sequences at the time of four pyrroloiminoquinone alkaloids, and the first synthesis of another.
\r\n\t\t\r\nChapter 3 describes the progress toward the total synthesis of atkamine, another pyrroloiminoquinone that has yet to be synthesized, by further leveraging of the Larock/Buchwald\u2013Hartwig annulation/cyclization. The development of additional reaction methodologies were investigated to try and rapidly access the complex bicyclic ring system of this natural product.
\r\n\t\t\r\nFinally, Chapter 4 describes the synthesis of authentic standards to enable investigations of pinene secondary organic aerosols. Access to these standards allowed for the identification and formation mechanism of dimer esters in pinene organic aerosols, which has been a long-standing challenge in the field.
", "doi": "10.7907/xmbz-by61", "publication_date": "2026", "thesis_type": "phd", "thesis_year": "2026" }, { "id": "thesis:17492", "collection": "thesis", "collection_id": "17492", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06262025-215200160", "type": "thesis", "title": "Transition Metal-Catalyzed Methodologies for the Synthesis of Complex Amide Building Blocks", "author": [ { "family_name": "Barbor", "given_name": "Jay Park", "orcid": "0000-0003-2787-4923", "clpid": "Barbor-Jay-Park" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Amides are ubiquitous functional groups that play a critical role in the composition and function of many biologically active molecules. Herein, this thesis presents three novel methodologies toward the construction of small molecules bearing amide functionality. In the first chapter, a convergent Ni-catalyzed N\u2013N cross-coupling for the synthesis of hydrazides is described. This reaction constitutes the first example of a transition metal-catalyzed N\u2013N bond forming reaction compatible with a wide array of aliphatic amine nucleophiles. In the second chapter, an enantioselective \u03b1-vinylation of \u03b3-lactams is presented. In the third chapter, a novel, enantioselective spirocyclization of Pd-enolates intercepted under decarboxylative allylic alkylation conditions is disclosed. Finally, in the last appendices, we present a revised and expedient route toward the bis-THIQ natural product scaffold and describe the synthesis of some non-natural analogs.", "doi": "10.7907/hqt6-e038", "publication_date": "2026", "thesis_type": "phd", "thesis_year": "2026" }, { "id": "thesis:17799", "collection": "thesis", "collection_id": "17799", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12152025-191624055", "primary_object_url": { "basename": "2025-Thesis_JKT_final.pdf", "content": "final", "filesize": 37414738, "license": "other", "mime_type": "application/pdf", "url": "/17799/1/2025-Thesis_JKT_final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Development of a Convergent Fragment Coupling Strategy Toward Grayanane Diterpenoids: Enantioselective Synthesis of (+)-Auriculatol A", "author": [ { "family_name": "Thompson", "given_name": "Jordan Kenji", "orcid": "0009-0007-6395-7087", "clpid": "Thompson-Jordan-Kenji" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Total synthesis is a cornerstone of organic chemistry, serving not only as a demonstration of synthetic strategy and innovation but also as a gateway to accessing biologically active natural products that are often scarce or inaccessible from natural sources. Among such natural products, the grayanane diterpenoids represent a structurally complex and medicinally intriguing family of compounds. These molecules, first identified as the active agents in \u201cmad honey,\u201d have a rich history of traditional use and a modern resurgence in medicinal interest due to their activity as sodium channel modulators, carbonic anhydrase inhibitors, and potential analgesics. Grayanotoxin III, in particular, exhibits great pain-relieving properties, positioning it and its analogs as compelling targets for chemical synthesis. Despite their early isolation and full structural elucidation by the early 1960s, the grayananes remain difficult to access in the realm of total synthesis, a testament to their dense stereochemical architecture and unusual [5-7-6-5] fused tetracyclic core.
\r\n\r\nThis work explores synthetic strategies toward the construction of these challenging natural products, with the aim of enabling broader access to their biological potential and deepening our understanding of chemical tools to use in their synthesis. This work introduces complex bond-forming strategies and methods development, with a particular emphasis on nickel catalysis to advance the total synthesis of grayanane diterpenoids. A convergent approach was designed to maximize efficiency at each stage, beginning with the development of a model system to rapidly evaluate \u03b3-functionalization strategies of butenolides or masked butenolide equivalents using siloxyfuran intermediates as a polarity reversal tactic. Key advances include the synthesis of a 5,5-fused butenolide fragment and the discovery and optimization of a unique vinylogous Mukaiyama aldol reaction. Early studies on the diastereoselective 1,4-reduction of butenolides and the development of a nickel-catalyzed \u03b1-enolate arylation reaction are highlighted. Subsequent chapters explore the construction of the 3.2.1 bicycle through a range of innovative transformations, including a Snider radical cascade, palladium-catalyzed decarboxylative Tsuji-Stoltz allylation, and a nickel catalyzed intramolecular carbonyl 1,2-addition. The result of these efforts is a rapid fragment coupling strategy that enables access to the pentacyclic core of auriculatol A through the use of a nickel catalyzed \u03b1-enolate alkenylation reaction using a unique olefin-supported nickel catalyst. In addition to discovering that low-valent olefin-supported nickel catalysts are privileged for \u03b1-enolate arylation and alkenylation, an unexpected 6-membered ring-containing side product was isolated in these reactions, which could have unique mechanistic implications in the area of dehydrogenative catalysis. To follow, detailed investigations into late-stage olefin functionalization and hydrogenation ultimately culminate in the first synthesis of (+)- auriculatol A along with its epimer (+)-9-epi-auriculatol A. Collectively, these studies offer a blueprint for future synthetic approaches to the broader grayanane diterpenoid family and stand as a hallmark achievement for the synthesis of grayanane natural products containing an embedded e ring in an uncommon pentacyclic scaffold.
", "doi": "10.7907/8sth-7196", "publication_date": "2026", "thesis_type": "phd", "thesis_year": "2026" }, { "id": "thesis:17796", "collection": "thesis", "collection_id": "17796", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12112025-115800167", "type": "thesis", "title": "Strategies and Tactics in Alkaloid Synthesis: Total Synthesis of Strempeliopidine via a Non-Directed Petasis Reaction and Progress Toward the Synthesis of Mitomycin B", "author": [ { "family_name": "Gonzalez", "given_name": "Kevin Jaime", "orcid": "0000-0002-4904-590X", "clpid": "Gonzalez-Kevin-Jaime" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Shapiro", "given_name": "Mikhail G.", "orcid": "0000-0002-0291-4215", "clpid": "Shapiro-M-G" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis describes research toward total synthesis of bioactive alkaloids with complex architectures that have demanded for the invention of methodology. Chapter 1 comprehensively reviews the semi-, partial, and total synthesis of heterodimeric monoterpenoid bisindole alkaloid natural products. Chapter 2 describes the enantioselective total synthesis of the bisindole alkaloid strempeliopidine. A convergent strategy featuring a diastereoselective Petasis reaction enabled the synthesis of the natural product and several stereoisomeric analogs. Chapter 3 details the development of a non-directed Petasis reaction inspired by the key step in the synthesis of strempeliopidine. This methodology couples hydroxyindoles with trifluoroborate salts under mild conditions, thereby enabling the synthesis of non-natural heterodimeric bisindole alkaloids. Chapter 4 explores ongoing efforts toward the asymmetric total synthesis of mitomycin B. Chapter 5 covers the development of an enantioselective 1,3-dipolar cycloaddition for the construction of nitrogen-rich spirocycles. A chiral magnesium Lewis acid catalyst facilitated the asymmetric [3+2] cycloaddition between alpha-methylene lactams and diazoacetates or nitrile oxides.", "doi": "10.7907/hakn-7h25", "publication_date": "2026", "thesis_type": "phd", "thesis_year": "2026" }, { "id": "thesis:17830", "collection": "thesis", "collection_id": "17830", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:01212026-163903186", "type": "thesis", "title": "Polymer Mechanochemistry Using Ultrasound: From Fundamental Reactivity to Controlled Drug Delivery", "author": [ { "family_name": "Luo", "given_name": "Meng (Stella)", "orcid": "0000-0003-4003-7468", "clpid": "Luo-Meng-Stella" } ], "thesis_advisor": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" }, { "family_name": "Shapiro", "given_name": "Mikhail G.", "orcid": "0000-0002-0291-4215", "clpid": "Shapiro-M-G" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Polymer mechanochemistry harnesses mechanical force to drive specific chemical transformations in stress-sensitive molecules known as mechanophores. Through judicious chemical design, these force-driven reactions have enabled functional polymeric materials capable of sensing, self-healing, and catalysis. Research in this field encompasses expanding the mechanophore repertoire, elucidating the fundamental principles governing mechanically induced reactivity, and translating force-responsive systems into practical applications.
\r\n \r\nThis thesis advances the field by contributing both fundamental insight and applied functionality in mechanophore activation under ultrasonication, with a particular focus on controlled drug release in biological environments. First, we develop an improved methodology for characterizing mechanophore reactivity, addressing sensitivity limitations in sonication experiments and, combined with computational modeling, revealing underlying principles that govern force-induced bond activation. Separately, we establish a synergistic platform that couples cargo-releasing mechanophores with biocompatible focused ultrasound, enabling controlled release of a fluorophore and a chemotherapeutic agent under physiological conditions. Finally, we demonstrate mechanochemically triggered drug delivery in vivo and validate this process using an inducible protein-expression system as a biological readout, achieving the first constructive modulation of cellular function enabled by covalent polymer mechanochemistry. Together, these studies deepen the fundamental understanding of mechanophore reactivity and illustrate the substantial biomedical potential of mechanochemical approaches using ultrasound activation.
", "doi": "10.7907/mnbj-xq97", "publication_date": "2026", "thesis_type": "phd", "thesis_year": "2026" }, { "id": "thesis:17441", "collection": "thesis", "collection_id": "17441", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06102025-162952847", "type": "thesis", "title": "Stereoselective Synthesis of \u03b1- and \u03b2-Functionalized Carbonyl Derivatives: Allylic Alkylation of Dialkyl Malonates, Total Synthesis of Hunterine A, and Progress Toward the Synthesis of Kuroshine A", "author": [ { "family_name": "Hicks", "given_name": "Elliot Frederick", "orcid": "0009-0004-8965-0460", "clpid": "Hicks-Elliot-Frederick" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Research in the Stoltz group generally focuses on the synthesis of complex molecules enabled by the discovery and application of new synthetic methodologies. The majority of the research described in this thesis encompasses variations on this unifying central theme.
\r\n \r\nChapter 1 focuses on the development of new asymmetric methodology for the synthesis of stereogenic all-carbon quaternary centers through the application of iridium catalysis. A key advance was the use of malonate nucleophiles and bis-alkyl substituted electrophiles, two inputs commonly employed in allylic alkylation chemistry that had yet to be utilized for the synthesis of quaternary carbon centers.
\r\n \r\nChapter 2 describes the development and execution of a synthetic strategy for the asymmetric construction of a rearranged monoterpene indole alkaloid, hunterine A. Key to the assembly of this molecule were an enantioselective desymmetrization, aza-Cope/Mannich rearrangement, azide-alkene dipolar cycloaddition, and regioselective aziridine opening.
\r\n \r\nChapter 3 details an investigation born out of an observation of a regioselective aziridine opening during the course of the synthesis of hunterine A. This research focuses on the synthesis of sterically unbiased fused bicyclic N-aryl aziridines and their reactivity in a variety of ring opening reactions.
\r\n\r\nChapter 4 and Appendix 7 describe ongoing efforts toward the synthesis of Kuroshine A and other highly oxidized zoanthamine alkaloids. The synthetic strategies described focus on evaluating formation of the ABC ring system of the molecule via a masked ortho-benzoquinone cycloaddition.
", "doi": "10.7907/fs03-xy64", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:17264", "collection": "thesis", "collection_id": "17264", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05222025-165729471", "primary_object_url": { "basename": "pham_kim_2024_thesis-final.pdf", "content": "final", "filesize": 41860246, "license": "other", "mime_type": "application/pdf", "url": "/17264/1/pham_kim_2024_thesis-final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Application of Ultrafast Spectroscopy Techniques to Probe Correlated Ion Hopping Mechanisms in Solid-State Ion Conductors", "author": [ { "family_name": "Pham", "given_name": "Kim Hoang", "orcid": "0000-0003-4053-6363", "clpid": "Pham-Kim-Hoang" } ], "thesis_advisor": [ { "family_name": "Cushing", "given_name": "Scott K.", "orcid": "0000-0003-3538-2259", "clpid": "Cushing-Scott-K" }, { "family_name": "See", "given_name": "Kimberly", "orcid": "0000-0002-0133-9693", "clpid": "See-Kimberly" } ], "thesis_committee": [ { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Faber", "given_name": "Katherine T.", "orcid": "0000-0001-6585-2536", "clpid": "Faber-K-T" }, { "family_name": "See", "given_name": "Kimberly", "orcid": "0000-0002-0133-9693", "clpid": "See-Kimberly" }, { "family_name": "Cushing", "given_name": "Scott K.", "orcid": "0000-0003-3538-2259", "clpid": "Cushing-Scott-K" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Superionic conductors, or solid-state ion conductors that surpass the ionic con- ductivity of its liquid counterpart, can enable more energy dense batteries, robust artificial ion pumps, and optimized fuel cells. The mechanisms enabling superionic conductivity still remain elusive, though many-body correlations between the mi- grating ions, lattice vibrational modes, and charge screening clouds have all been posited to greatly enhance ionic conduction. Most spectroscopic techniques cannot directly probe and validate the role of such correlations due to their inability to transiently resolve these ultrafast dynamics occurring at picosecond timescales. In this work, we develop an ultrafast technique that measures the time-resolved change in impedance while a light source ranging from UV to THz frequencies selectively excites an ion-coupled correlation. The technique is used to compare the relative changes in impedance of a solid-state Li\u207a conductor Li0.5La0.5TiO3 (LLTO) before and after light excitation to elucidate the role of charge screening clouds, optical phonons, and acoustic phonons on ion migration. From our techniques, we deter- mine that electronic screening and rocking phonon-mode interactions significantly dominate the ion migration pathway of LLTO compared to acoustic phonons. Al- though we only present one case study, our technique can extend to O\u00b2\u207b, H\u207a, or other charge carrier transport phenomena where ultrafast correlations control transport. Furthermore, the temporal relaxation of the measured impedance can distinguish ion transport effects caused by many-body correlations, optical heating, correlation, and memory behavior.", "doi": "10.7907/825x-r459", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:17221", "collection": "thesis", "collection_id": "17221", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05122025-153409748", "primary_object_url": { "basename": "Flesch Thesis.pdf", "content": "final", "filesize": 48300552, "license": "other", "mime_type": "application/pdf", "url": "/17221/1/Flesch Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Asymmetric Transformations from Palladium Enolates and Progress Toward the Total Synthesis of Hypermoin A", "author": [ { "family_name": "Flesch", "given_name": "Kaylin Nicole", "orcid": "0000-0002-8582-2614", "clpid": "Flesch-Kaylin-Nicole" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Research in the Stoltz group is centered around developing new methodologies for the asymmetric formation of stereocenters and the application of these technologies in complex natural product total synthesis. Herein we describe the development of new enantioselective transformations from Pd enolate intermediates and efforts toward the total synthesis of hypermoin A. Chapter 1 reports the development of an asymmetric intramolecular decarboxylative [4+2] cycloaddition from a catalytically generated chiral Pd enolate, forging four contiguous stereocenters in a single transformation. Mechanistic studies including quantum mechanics calculations, Eyring analysis, and KIE studies offer insight into the reaction mechanism. Appendix 2 discloses efforts toward the development of an asymmetric intermolecular decarboxylative double Michael addition. Chapter 2 describes an enantioselective cyclization of Pd enolates and isocyanates to form spirocyclic \u03b3-lactams. This reaction proceeds under mild reaction conditions and utilizes a novel Meldrum\u2019s acid derivative to achieve catalyst turnover, delivering enantioenriched products in up to 97% yield and 96% ee. Chapter 3 outlines the ongoing progress toward the total synthesis of hypermoin A. A [4+2] cycloaddition and ring expansion strategy has been developed in a model system to form the key [3.2.2] bicycle and current efforts are dedicated to the application of this sequence in a more complex setting.", "doi": "10.7907/jfcn-4r24", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:17340", "collection": "thesis", "collection_id": "17340", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06012025-173559572", "type": "thesis", "title": "Design and Application of Complexity Generating Strategies and Transformations in Natural Product Synthesis", "author": [ { "family_name": "Stegner", "given_name": "Andrea Anna Therese", "orcid": "0000-0001-9408-3967", "clpid": "Stegner-Andrea-Anna-Therese" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "https://orcid.org/0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Rapid and efficient chemical synthesis of complex molecules is critical for enabling studies of their biological function and therapeutic potential. Complexity generation can be achieved by: (1) the development of selective transformations that rapidly construct complex scaffolds from simple precursors, and (2) the application of strategic retrosynthetic disconnections that maximize the efficiency of a synthesis i.e., via convergent fragment coupling strategies. We disclose efforts to address these aims by combining reaction design with the identification of strategic disconnections.
\r\n\r\nToward the first aim, a diastereoselective dearomative pyridine cyclization that forges the tetracyclic core of the matrine-type lupin alkaloids in a single step from commodity feedstocks was developed. This reaction, paired with a C15-selective oxidation cascade and late-stage isomerization, enabled the first total synthesis of (\u2013)-sophoridine and the shortest syntheses to date of (+)-matrine, (+)-isomatrine, (+)-allomatrine, and (+)- isosophoridine.
\r\n\r\nTo address the second aim, a convergent strategy for the synthesis of 6,7-seco-ent- kauranoids via strategic, transition metal-catalyzed C-C bond formation was developed. Both a Ni-catalyzed sp\u00b2\u2013sp\u00b3 and a dual Ni/Pd-catalyzed sp\u00b2\u2013sp\u00b2 coupling were developed and enabled efficient union of complex fragments, the latter yielding 1,3 dienes that underwent divergent annulation reactions to form various complex ring systems. These transformations provided the complete skeleton of isorosthin A and advanced intermediates en route to isodocarpin and secoexertifolin A.
", "doi": "10.7907/w4xa-hy67", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:16579", "collection": "thesis", "collection_id": "16579", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:07222024-161123922", "primary_object_url": { "basename": "Thesis-Zhenqi Zhao.pdf", "content": "final", "filesize": 10312697, "license": "other", "mime_type": "application/pdf", "url": "/16579/1/Thesis-Zhenqi Zhao.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Synthesis of Strained Systems via Vinyl Carbocation Intermediates", "author": [ { "family_name": "Zhao", "given_name": "Zhenqi (Steven)", "orcid": "0000-0002-6848-2689", "clpid": "Zhao-Zhenqi-Steven" } ], "thesis_advisor": [ { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Vinyl carbocations are a class of dicoordinated carbocations. Due to their challenging generation, they have been less studied compared to tricoordinated carbocations. This thesis reports multiple novel reactivities involving vinyl carbocation intermediates.
\r\n\r\nThe first chapter reviews methods for generating vinyl carbocations and past reports of vinyl carbocation C\u2013H insertion. It then introduces a field guide to assist researchers in using vinyl carbocation C\u2013H insertion in their synthesis, providing detailed information and optimal reaction conditions developed in our laboratory.
\r\n\r\nThe second chapter describes a catalytic method for forming medium-sized rings via intramolecular Friedel-Crafts reactions of vinyl carbocation intermediates. These reactive species are catalytically generated through the ionization of vinyl toluenesulfonates by a Lewis acidic lithium cation/weakly coordinating anion salt.
\r\n\r\nThe third chapter details selective [2+2] cycloadditions between vinyl carbocations and terminal alkenes, using a LiHMDS-mediated approach. This method allows for the efficient synthesis of strained cyclobutene-containing bicycles under mild conditions, demonstrating the versatile application of vinyl carbocations in constructing complex strained organic structures.
", "doi": "10.7907/xcmv-0060", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:16364", "collection": "thesis", "collection_id": "16364", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04292024-194607461", "primary_object_url": { "basename": "Allison Stanko PhD Thesis FINAL.pdf", "content": "final", "filesize": 20735784, "license": "other", "mime_type": "application/pdf", "url": "/16364/1/Allison Stanko PhD Thesis FINAL.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Assembly of Complex Carbocyclic Architectures via Palladium and Nickel-Catalyzed Cyclizations", "author": [ { "family_name": "Stanko", "given_name": "Allison Michelle", "orcid": "0000-0003-0576-3739", "clpid": "Stanko-Allison-Michelle" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" }, { "family_name": "See", "given_name": "Kimberly", "orcid": "0000-0002-0133-9693", "clpid": "See-Kimberly" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Transition metal catalysis can be leveraged to construct challenging chemical bonds with excellent chemo- and stereoselectivity. Herein we describe the discovery of a novel palladium-catalyzed cascade cyclization and a nickel-catalyzed spirocyclization, enabling the assembly of complex carbocyclic architectures. We begin with an introduction describing notable applications of palladium-catalyzed cascade cyclizations in natural product synthesis, enabling the concurrent formation of C\u2013C and C\u2013N bonds in a single synthetic step.
\r\n\r\nNext, the development of a palladium-catalyzed oxidative Heck/aza-Wacker cascade cyclization is described. This cascade reaction enabled the construction of an all-carbon quaternary center, a C\u2013C bond, and a C\u2013N bond in a single synthetic step. Furthermore, it was employed to build the carbocyclic core of the natural product noraugustamine.
\r\n\r\nThen, we outline the discovery and optimization of an enantioselective nickel-catalyzed \u03b1-spirocyclization of lactones. The established method efficiently and enantioselectively forges 5-, 6-, and 7-membered rings containing all-carbon quaternary centers. This discovery represents an expansion of the synthetic toolkit for enantioselective spirocyclization, providing access to chiral, pharmaceutically relevant spirocyclic products.
\r\n\r\nFinally, we describe a collaborative project with the Su lab at the University of Arizona in the area of polymer synthesis and gas sensing, where we designed a sensor for the selective detection of gaseous nitric oxide. The sensor\u2019s excellent specificity and part-per-trillion level sensitivity was enabled by novel ferrocene-containing polymeric coatings.
", "doi": "10.7907/xx1b-9262", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16362", "collection": "thesis", "collection_id": "16362", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04292024-055507772", "type": "thesis", "title": "Altering Framework Topology and Heteroatom Distributions of Molecular Sieves by Designed Organic Structure-Directing Agents", "author": [ { "family_name": "Park", "given_name": "Youngkyu", "orcid": "0000-0001-7328-7565", "clpid": "Park-Youngkyu" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Flagan", "given_name": "Richard C.", "orcid": "0000-0001-5690-770X", "clpid": "Flagan-R-C" }, { "family_name": "Manthiram", "given_name": "Karthish", "orcid": "0000-0001-9260-3391", "clpid": "Manthiram-Karthish" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The growing demand for chemical production combined with the urgent need to mitigate the accelerated climate and environmental changes motivates efforts to create highly efficient and selective catalysts and adsorbents. Zeolites and molecular sieves are a key class of materials for addressing these needs because of their high activity and selectivity with catalytic reactions. Additionally, they can show superior adsorption properties because of their structure and surface polarity that can also give shape selectivity with molecules smaller than ca. 1 nanometer. Further advancements in molecular sieve properties will rely on advancements in preparation methods. To this end, the research results presented here explore synthetic approaches for controlling the framework topology and the heteroatom incorporation within silicate-based molecular sieves by means of the strategic design of their organic structure-directing agents (OSDAs).
\r\n\r\nPart I presents the synthesis of STW-type germanosilicate molecular sieves with high-silica framework compositions and the enrichment of chirality. A chiral OSDA is computationally designed based on the predicted stabilization energy toward the pure-silica STW framework. An improved synthesis route for both enantiomers of the OSDA is developed. The enantiopure OSDA is capable of crystallizing a high-silica STW-type germanosilicate molecular sieve that shows distinct framework compositions from previously reported germanium-rich STW. The enantiomeric enrichment of powdered samples without occluded enantiopure OSDAs is characterized by the dynamical refinement of microcrystal electron diffraction data. The high-silica, enantiomerically enriched STW exhibits the framework stability upon thermal treatment and the enantioselective adsorption of 2-butanol. The results in Part I demonstrate the design strategy of OSDAs for crystallizing stable, enantio-enriched molecular sieves for enantioselective chemical separations and catalysis.
\r\n\r\nIn Part II, the distribution of heteroatoms incorporated within borosilicate molecular sieves is studied with regard to its control by cationic OSDAs. To aid in the characterization of the heteroatom sites within borosilicate molecular sieves, the relationship between the 11B NMR chemical shift and the local geometry of boron within tetrahedrally coordinated silicate frameworks is first investigated. From crystalline borosilicate minerals with highly ordered, tetrahedrally coordinated boron atoms, it is revealed that the chemical shifts from 11B NMR linearly correlate with the local geometric parameters. Further studies on the borosilicate molecular sieves that possess more open space and wider angles suggest that the correlation between the average bond angles and 11B NMR chemical shifts can be employed for the entire class of three-dimensional, crystalline borosilicates. Two structurally similar quaternary ammonium OSDAs with different locations of positive charge are designed and synthesized. MWW-type borosilicate molecular sieves are crystallized by both OSDAs, and the quaternary ammonium moieties in the two OSDAs are found to interact with boron species with significantly different 11B NMR chemical shifts. Using the correlation developed here, the characterization results demonstrate that the heteroatom siting within the molecular sieve framework can be selectively altered by tailoring the OSDA structure in terms of the position of positive charge.
", "doi": "10.7907/d1xj-kn25", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16165", "collection": "thesis", "collection_id": "16165", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08242023-170135027", "primary_object_url": { "basename": "Shilong_Gao_Thesis_08242023.pdf", "content": "final", "filesize": 50904166, "license": "other", "mime_type": "application/pdf", "url": "/16165/1/Shilong_Gao_Thesis_08242023.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Engineering Heme Proteins for C(sp\u00b3)\u2013H Primary Amination", "author": [ { "family_name": "Gao", "given_name": "Shilong", "orcid": "0000-0003-2808-6283", "clpid": "Gao-Shilong" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Hadt", "given_name": "Ryan G.", "orcid": "0000-0001-6026-1358", "clpid": "Hadt-Ryan-G" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Primary amine is one of the most prevalent moieties in synthetic intermediates and pharmaceutical compounds. The preparation of aliphatic primary amines via C\u2212H functionalization would provide direct access to the nitrogen-containing compounds from hydrocarbon substrates. While the enzymatic oxyfunctionalization of C\u2013H bonds is well established, the analogous strategy for nitrogen incorporation is unknown in Nature. Likewise, a synthetic method for selective primary amination of aliphatic C\u2013H bonds remains elusive. Combining chemical intuition and inspiration from Nature, chemists and protein engineers have created new heme-containing enzymes for the C(sp\u00b3)\u2013H primary amination via directed evolution. This thesis describes some of the efforts in the continued pursuit of these new-to-nature reactions. Chapter I discusses directed evolution in the context of biocatalysis, the strategies for introducing new-to-nature chemistry in enzymes, the discovery of nitrene transferases from the cytochrome P450 monooxygenase, and finally, the development of C(sp\u00b3)\u2013H primary aminases. Chapter II details the discovery and engineering of serine-ligated cytochrome P411 enzymes that catalyze the first primary amination of C(sp\u00b3)\u2013H bonds with excellent selectivity, affording a broad scope of enantioenriched primary amines. Chapter III demonstrates that these new-to-nature nitrene transferases were engineered to aminate and amidate unactivated, unbiased C(sp\u00b3)\u2013H bonds with unprecedented selectivity. In Chapter IV, engineered protoglobins are shown to utilize hydroxylamine (NH\u2082OH) for nitrene transfer reactions, including benzylic C\u2013H primary amination and styrene aminohydroxylation. Overall, these new-to-nature reactions can be considered the nitrogen analogs to the C\u2013H oxidation chemistry performed by monooxygenases and peroxygenases. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds. Finally, this work hints at the possible future discovery of natural enzymes that use hydroxylamine precursors for amination chemistry.
", "doi": "10.7907/gsmr-b827", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16161", "collection": "thesis", "collection_id": "16161", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08212023-202451948", "primary_object_url": { "basename": "Zhang_Caltech_Thesis_Final.pdf", "content": "final", "filesize": 45557113, "license": "other", "mime_type": "application/pdf", "url": "/16161/1/Zhang_Caltech_Thesis_Final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Efforts Towards C-C Bond Formations: From Ni Catalysis to Transition-Metal Free Electrolysis", "author": [ { "family_name": "Zhang", "given_name": "Wanji Wendy", "orcid": "0000-0002-6895-9598", "clpid": "Zhang-Wanji-Wendy" } ], "thesis_advisor": [ { "family_name": "See", "given_name": "Kimberly", "orcid": "0000-0002-0133-9693", "clpid": "See-Kimberly" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "See", "given_name": "Kimberly", "orcid": "0000-0002-0133-9693", "clpid": "See-Kimberly" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The selective construction of C-C bonds has been a critical challenge in modern synthetic organic chemistry. Among the numerous methodologies developed, cross-coupling remains an attractive strategy for direct C-C bond formation. Herein, a diverse range of cross-coupling reactions for C-C bond formations are investigated from different perspectives. First, the mechanism of a Ni/cyano-box-catalyzed asymmetric Suzuki alkynylation is studied. The existing data is consistent with a radical chain pathway that is previously proposed for other Ni-catalyzed enantioselective cross-coupling reactions. Next, moving on from the traditional electrophile-nucleophile cross-couplings, we explore Ni-catalyzed reductive coupling of alkyl halides with internal olefins in the presence of a hydrosilane. With judicious choice of the directing group, hydroalkylation of internal olefins can be achieved with high regio- and enantioselectivity. Following that, an electrochemically driven, transition-metal free cross-electrophile coupling reaction is explored as a greener alternative to constructive C(sp\u00b3)-C(sp\u00b3) bonds. Specifically, we focus on improving the Mg sacrificial anode performance in these electroreductive systems. By carefully choosing the electrolyte composition, we are able to manipulate the metal electrode interfaces for a more effective counter electrode. Finally, Al stripping in ethereal solvents is investigated for its application as a sacrificial anode in reductive electrosynthesis. Inspired by Al corrosion chemistry, we are able to achieve bulk Al stripping in THF-based electrolyte by incorporating halide co-supporting electrolytes.
", "doi": "10.7907/czam-9x35", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16343", "collection": "thesis", "collection_id": "16343", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03302024-040656026", "primary_object_url": { "basename": "HeimGavinThesis.pdf", "content": "final", "filesize": 78661523, "license": "other", "mime_type": "application/pdf", "url": "/16343/1/HeimGavinThesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Molecular Tuning of Electrocatalysts for Generation of Commodity Chemicals", "author": [ { "family_name": "Heim", "given_name": "Gavin Paul", "orcid": "0000-0002-9244-6565", "clpid": "Heim-Gavin-Paul" } ], "thesis_advisor": [ { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" } ], "thesis_committee": [ { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Manthiram", "given_name": "Karthish", "orcid": "0000-0001-9260-3391", "clpid": "Manthiram-Karthish" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Improving our understanding of electrocatalytic transformations is envisioned to facilitate society\u2019s implementation of technologies that achieve a net zero carbon footprint. Carbon dioxide is one of the most emitted greenhouse gases, and improvement in CO\u2082 capture technologies along with decreasing costs of renewable energy provide an opportunity to convert this species to value-added chemicals using electrochemical processes. Tuning homogeneous and heterogeneous electrocatalyst performance with well-defined molecular species can render systems more selective and active while also allowing us to readily predict variables crucial in achieving these transformations. This thesis investigates 1) molecular and polymeric species as electrode coatings for enhanced generation of carbon-coupled products and 2) discrete electrocatalyst active sites for formation CO\u2082 reduction products at low overpotentials; generation of highly reduced liquid fuels is observed with molecular electrocatalysts supported on electrodes.\r\nChapter I provides context and background to the contents of this thesis.
\r\n\r\nChapter II discusses novel, polyaromatic molecular additives utilized for low pH CO\u2082 reduction on Cu electrodes. N-phenyl isoquinolinium triflate film facilitates high selectivity for C\u2082+ products in 0.1 M H\u2083PO\u2084/KH\u2082PO\u2084, suggesting enhancement in CO\u2082 mass transport rather than limiting proton carrier diffusion. Improvement in long-term stability and tolerance to lower pH compared to previous films is observed.
\r\n\r\nChapter III reports on a series of polystyrene-based ionomers to probe the effect of local [K\u207a] in the Cu electrode microenvironment on CO\u2082R performance. Partial current density towards C\u2082\u208a products (|jC\u2082\u208a|) increases monotonically with [K\u207a] in ionomer, up to 225 mA cm\u207b\u00b2. Replacing K\u207a with [Me4N]\u207a lowers performance to the level of bare Cu, highlighting the crucial role of K\u207a in improving C\u2082\u208a product selectivity. Molecular dynamics simulations and partial pressure CO\u2082 electrolysis experiments are consistent with enhanced CO\u2082 mass transport due to K\u207a in the film.
\r\n\r\nChapter IV discusses variation of ionomer/polymer structures to maximize CO\u2082R performance. Incorporation of neutral comonomers bearing cross-linking units rich in biphenyl and terphenyl motifs result in high current densities (~270 mA cm\u207b\u00b2) towards C\u2082\u208a products with 82% Faradaic efficiency. The analogous neutral variants (i.e., those lacking the charged comonomer) show comparable |jC\u2082\u208a| to the K\u207a-containing polymers, suggesting a non-innocent role of the aryl-rich polymers in boosting performance.
\r\n\r\nChapter V presents novel four-coordinate, dicationic Co complexes supported on carbon nanotubes capable of generating MeOH from CO\u2082. Electrolysis with CO also leads to formation of MeOH, suggesting a CO-bound complex to be a crucial intermediate in CO\u2082R to MeOH. This work highlights rare examples of molecular systems facilitating multi-electron electrochemical transformations to highly demanded commodity chemicals.
\r\n\r\nChapter VI presents work on molecular electrocatalysts bearing novel polyaromatic ligands that lower the electrocatalytic potential (Ecat) of CO\u2082R by ~310 mV compared to state-of-the-art complexes as determined via cyclic voltammetry. The extended \u03c0 system motif is more proximal to the metal center relative to previously reported nanographene-containing electrocatalysts. Well-defined characterization was obtained via single-crystal X-ray diffraction in addition to solution-state techniques. Density functional theory calculations reveal significant ligand contributions in the frontier orbitals of relevant CO\u2082R intermediates.
\r\n\r\nChapter VII highlights a polycyclic aromatic hydrocarbon (PAH) bearing twelve edge nitrogen atoms. Spectroscopy, electrochemistry, and computational results suggest a significant narrowing of the HOMO-LUMO gap compared to the N-free analogue owing to the electron-deficient extended \u03c0 system imposed by the nitrogen dopants. Changes to absorption and emission spectra from titration of the PAH with metal salts suggest that coordination chemistry provides an additional degree of freedom towards tuning electronic structure. Dramatic changes from addition of trifluoromethanesulfonic acid suggest this material to be a possible pH sensor. This approach in judiciously tuning the band gap of bulk graphene materials via saturation of the nanographene edge sites with nitrogen atoms gives rise to a novel compound with intriguing electronic properties.
\r\n\r\nAppendix A describes systematic attempts in demonstrating cascade electrocatalysis between molecular CO\u2082-to-CO complexes and pyridinium film-modified Cu towards enhanced rates of C\u2082\u208a products formation.
\r\n\r\nAppendix B provides results coupling electrodeposited imidazolium-derived films with pyridinium towards enhanced CO\u2082R to C\u2082\u208a on Cu. While promising performance is achieved, the difficulty in characterizing the films limits the tractability of these systems with respect to their impacts on the microenvironment.
\r\n\r\nAppendix C discusses developing coordination complexes of heteroatom containing polyaromatic hydrocarbons. Several examples characterized via X-ray crystallography are reported.
\r\n\r\nAppendix D shows CO\u2082R data on K\u207a ionomer-coated Au. Elevation in |jCO| is demonstrated as a function of potassium content in the electrode-electrolyte interface provided by the film.
\r\n\r\nAppendix E discusses attempts to determine and CO\u2082 uptake by K\u207a ionomers via solid state NMR spectroscopy.
", "doi": "10.7907/dm95-6856", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16249", "collection": "thesis", "collection_id": "16249", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11172023-202811116", "type": "thesis", "title": "Development of Microcrystal Electron Diffraction Techniques for the Characterization of Small Molecules and Novel Materials", "author": [ { "family_name": "Jones", "given_name": "Christopher Glenn", "orcid": "0000-0003-4308-1368", "clpid": "Jones-Christopher-Glenn" } ], "thesis_advisor": [ { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" }, { "family_name": "Manthiram", "given_name": "Karthish", "orcid": "0000-0001-9260-3391", "clpid": "Manthiram-Karthish" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Traditional techniques for structural analysis, such as X-ray crystallography and Nuclear Magnetic Resonance (NMR), have been invaluable in understanding the composition of various substances. However, these methods often encounter challenges when applied to the analysis of small molecules and certain novel materials, particularly those that cannot form large, high-quality crystals. The research presented here focuses on the evolution and applications of Microcrystal Electron Diffraction (MicroED), a transformative technique that has expanded the boundaries of structural analysis. We trace the developmental trajectory of MicroED, exploring its underlying principles, technological advancements, and comparative advantages over conventional methods. A variety of data from several key studies was collected through a series of experiments utilizing MicroED to analyze a range of substances, from small organic molecules to complex novel materials and innovative inorganic complexes. MicroED offers unprecedented resolution and sensitivity, capable of structural elucidation where other methods fail. In particular, MicroED has been successful in determining the structures of several novel materials and small molecules with applications in areas such as renewable energy, advanced manufacturing, and pharmaceuticals. Furthermore, this technique is highly amenable to integration with other analytical and computational methods, including machine learning algorithms for data interpretation, enhancing its applicability and efficiency. This research contends that MicroED is not merely an alternative but a substantial upgrade to existing methodologies, holding the potential to revolutionize fields as diverse as materials science, chemistry, and medicine.", "doi": "10.7907/cfnr-f362", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16236", "collection": "thesis", "collection_id": "16236", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11032023-041429778", "primary_object_url": { "basename": "Jiajun Du Thesis 110323.pdf", "content": "final", "filesize": 33583941, "license": "other", "mime_type": "application/pdf", "url": "/16236/6/Jiajun Du Thesis 110323.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Vibrational Imaging for Chemical Biology: from Label-Free to Molecular probes", "author": [ { "family_name": "Du", "given_name": "Jiajun", "orcid": "0000-0003-2693-834X", "clpid": "Du-Jiajun" } ], "thesis_advisor": [ { "family_name": "Wei", "given_name": "Lu", "orcid": "0000-0001-9170-2283", "clpid": "Wei-Lu" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Wei", "given_name": "Lu", "orcid": "0000-0001-9170-2283", "clpid": "Wei-Lu" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Since the invention of stimulated Raman scattering (SRS) microscopy in 2008, vibrational imaging is increasingly recognized as a powerful tool for biological investigation. As the most suitable far field vibrational imaging modality for live biological studies, SRS microscopy is taking the lead role within its vibrational counterparts with desired sensitivity and image quality. The totally different mechanism of generating vibration signals from fluorescence signals determines the special features of vibrational imaging. Bond vibration originating signals provide inherent optical contrast for every molecule and the quantitative manner allows straightforward quantification. Since the inception, SRS microscopy has achieved large success in label-free imaging. Label-free imaging avoids tedious labeling step and has the least perturbation to the biological samples but with limited sensitivity and specificity. The introducing of labeling starting about 10 years ago opens up a new avenue for SRS microscopy to tackle the fundamental limitations of label-free approaches. Whether to use label-free or molecular probes for SRS microscopy depends on the specific studies. This thesis aims to utilize SRS microscopy (both label-free and minimally labeling) for metabolic study and develop new molecular probes for SRS microscopy.
\r\n\r\nWe start from comparing different vibrational imaging modality and fluorescence imaging and conclude that SRS is the best vibrational imaging technique for biological samples. Then we discuss the features of label-free, bioorthogonal labeling and super-multiplexed SRS imaging. The minimally perturbative triple bond tagging and isotope labeling makes SRS especially suitable for tracking metabolites and accessing metabolic pathways. Furthermore, we also summarize the design principles for functional Raman imaging probe development based on their spectroscopic signatures. (Chapter 1).
\r\n\r\nNon-invasively probing metabolites within single live cells is highly desired but challenging. We explored Raman spectro-microscopy towards spatially-resolved single cell metabolomics, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. The chemical composition analysis of single cell and single organelle lipid droplets identified the fatty acid synthesis pathway and lipid mono-unsaturation as druggable susceptibility. More importantly we revealed that inhibiting lipid mono-unsaturation leads to cellular apoptosis accompanied by the formation of phase-separated intracellular membrane domains. (Chapter 2).
\r\n\r\nNext, we established a first-in-class design of multi-color photoactivatable Raman probes for subcellular imaging and tracking. The fast photochemically generated alkynes from cyclopropenones enable background-free Raman imaging with desired photocontrollable features. After necessary molecule engineering to improve the biocompatibility and sensitivity, we generated organelle-specific probes for targeting mitochondria, lipid droplets, endoplasmic reticulum, and lysosomes. Multiplexed photoactivated imaging and tracking at both subcellular and single-cell levels was also demonstrated to monitor the dynamic migration and interactions of the cellular contents. (Chapter 3).
\r\n\r\nFurther improvement of the Raman signal with molecular probes is a central topic for Raman imaging. Recently developed electronic preresonance (epr) probes boost Raman signals and pushed SRS sensitivity close to that offered by confocal fluorescence microscopy. To guide the development of even stronger Raman probes and fill the final gap between epr-SRS probes and single molecule imaging, the structure-function relationship of epr-SRS probes is indispensable. We therefore used ab initio approach employing the displaced harmonic oscillator (DHO) model for calculating the epr-SRS signals, which proves to provide a consistent agreement between simulated and experimental SRS intensities of various triple-bond bearing epr-SRS probes. The theory also allows us to illustrate how the observed intensity differences between molecular scaffolds stem from the coupling strength between the electronic excitation and the targeted vibrational mode. Utilizing the discovered structure-function relationship of epr-SRS probes, we engineered MARS palette for higher sensitivity. With chemical modification to improve Raman mode displacement or enhance transition dipole moment or adjust detuning, we enhance the signal of alkynyl pyronins and nitrile pyronins, setting the current sensitivity records for small molecule far-field Raman probes. (Chapter 4 and 5).
", "doi": "10.7907/dm1y-r078", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16131", "collection": "thesis", "collection_id": "16131", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06222023-231753197", "primary_object_url": { "basename": "AQC_Thesis_Final.pdf", "content": "final", "filesize": 81763761, "license": "other", "mime_type": "application/pdf", "url": "/16131/1/AQC_Thesis_Final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Asymmetric Pericyclic Transformations from Reactive Palladium Intermediates", "author": [ { "family_name": "Cusumano", "given_name": "Alexander Quinn", "orcid": "0000-0002-2914-2008", "clpid": "Cusumano-Alexander-Quinn" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Pd-catalyzed decarboxylative asymmetric allylic alkylation of enolate nucleophiles is a cornerstone of our groups\u2019 efforts to develop methodologies that directly facilitate the synthesis of stereochemically complex molecular building blocks. This thesis first focuses on our efforts to deepen our mechanistic understanding of these transformations. We then employ our insights as a base from which we expand the scope of the decarboxylative asymmetric allylic alkylation reaction, as well as develop entirely novel reaction paradigms.", "doi": "10.7907/b0wn-wt67", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16131", "collection": "thesis", "collection_id": "16131", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06222023-231753197", "primary_object_url": { "basename": "AQC_Thesis_Final.pdf", "content": "final", "filesize": 81763761, "license": "other", "mime_type": "application/pdf", "url": "/16131/1/AQC_Thesis_Final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Asymmetric Pericyclic Transformations from Reactive Palladium Intermediates", "author": [ { "family_name": "Cusumano", "given_name": "Alexander Quinn", "orcid": "0000-0002-2914-2008", "clpid": "Cusumano-Alexander-Quinn" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Pd-catalyzed decarboxylative asymmetric allylic alkylation of enolate nucleophiles is a cornerstone of our groups\u2019 efforts to develop methodologies that directly facilitate the synthesis of stereochemically complex molecular building blocks. This thesis first focuses on our efforts to deepen our mechanistic understanding of these transformations. We then employ our insights as a base from which we expand the scope of the decarboxylative asymmetric allylic alkylation reaction, as well as develop entirely novel reaction paradigms.", "doi": "10.7907/b0wn-wt67", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16480", "collection": "thesis", "collection_id": "16480", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06032024-082931807", "type": "thesis", "title": "Asymmetric Total Synthesis of Havellockate and Investigation into Chiral Palladium Enolate: Synthesis, Reactivity, and Applications", "author": [ { "family_name": "Chan", "given_name": "Tsam Mang Melinda", "orcid": "0000-0002-2495-0110", "clpid": "Chan-Tsam-Mang-Melinda" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Research in the Stoltz group focuses on the synergy of complex natural product synthesis and method development in that we strive to invent new and efficient methodologies that have great synthetic potential in the use for pharmaceuticals and natural products. Herein we describe an asymmetric total synthesis of Havellockate, a polycyclic furanobutenolide-derived cembranoid diterpenoid that exhibits biological activities such as anti-inflammatory, anti-microbial, and cytotoxic. The strategy for this synthesis is highlighted by a convergent Julia\u2013Kocienski olefination, followed by an acylation/intramolecular [4+2] cycloaddition cascade, which furnishes the main core of the natural product in high efficiency.
\r\n\r\nAnother synthetic route toward the total synthesis of Havellocate is presented, using a propargyl ether as a key intermediate. Though the route was unfruitful in compleing the synthesis, the Diels\u2013Alder cascade had significant improvement of yield and stability with this route, and it constitutes tremendous value for the synthesis of other targets within the furanobutenolide-derived natural product family.
\r\n\r\nNext, the synthesis, isolation, and reactivity of a chiral Pd enolate is described. The Pd enolate is arose by an alpha bromo acetophenone oxidative addition complex with Pd2(dba)3 and PHOX ligand. A crystal structure is obtained to show that the enolate is C- bound and highly regioselective. The novelty of this isolation can shine light on the applications of such Pd enolate for future developments.
\r\n\r\nThen, we outlined a Pd-catalyzed asymmetric vinylation of \u03b3-lactams to construct all-carbon quaternary stereocenters. The use of canonically inactive vinyl chloride electrophiles afforded the highest yields and levels of stereoselectivity, and a range of tri-substituted vinyl chlorides were found to be proficient in promoting this transformation. These stereogenically congested products could be further elaborated to functionally rich scaffolds, proving the synthetic utility of this transformation.
\r\n\r\nLastly, we describe the work of organizing the inaugural Day of Inclusion event of CCE. The event was orchestrated by the Diversity in Chemistry Initiative (DICI), aimed to foster cohesion and to inspire concerted efforts towards Diversity, Equity, and Inclusivity (DEI) within the Chemistry and Chemical Engineering (CCE) division at Caltech.
", "doi": "10.7907/kb44-n573", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16455", "collection": "thesis", "collection_id": "16455", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05312024-185929614", "primary_object_url": { "basename": "Csernica Thesis_FINAL.pdf", "content": "final", "filesize": 8140672, "license": "other", "mime_type": "application/pdf", "url": "/16455/1/Csernica Thesis_FINAL.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Exploring Nature\u2019s Fingerprints with Isotopic Distributions", "author": [ { "family_name": "Csernica", "given_name": "Timothy Andrew", "orcid": "0000-0002-5273-0721", "clpid": "Csernica-Timothy-Andrew" } ], "thesis_advisor": [ { "family_name": "Eiler", "given_name": "John M.", "orcid": "0000-0001-5768-7593", "clpid": "Eiler-J-M" } ], "thesis_committee": [ { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Marcus", "given_name": "Rudolph A.", "orcid": "0000-0001-6547-1469", "clpid": "Marcus-R-A" }, { "family_name": "Eiler", "given_name": "John M.", "orcid": "0000-0001-5768-7593", "clpid": "Eiler-J-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis examines the measurement and interpretation of isotopic distributions and the application of these techniques to forensic questions. Stable isotope abundances are a powerful tool for examining a compound\u2019s history. However, their use is complicated by the fact that 1) isotope substitutions can occur at many positions of a molecule, resulting in a combinatorial increase in possible combinations of isotopes (or isotopologues) with molecule size, and 2) it is difficult to experimentally distinguish between isotopologues, so observational data averages over many isotopologues with distinct properties and histories. We here develop experimental and theoretical strategies to address these questions via observations of the isotopic distributions of small organic compounds obtained by Orbitrap mass spectrometry. In Chapter II, we develop mathematical procedures for manipulating and tracking isotopologues through various experimental designs, allowing us to make precise statements about how observable quantities are affected by underlying physical and chemical processes. Chapters III and IV explore corresponding experimental methods: Chapter III presents a sample introduction technique for the long duration observations required to measure rare, multiply substituted isotopologues, while Chapter IV applies these to observe 146 isotopic properties of methionine, a model analyte. We then explore the use of these Orbitrap methods to applied science problems. In Chapter V, we characterize the 13C and 2H enrichment of methylphosphonic acid, a breakdown product of sarin precursors, and examine the signatures of its synthesis methods. In Chapter VI, we apply these techniques to extraterrestrial, abiotic syntheses of nucleobases, focusing on the chemistry of adenine. These results are interpreted in the context of proposed extraterrestrial syntheses of adenine and other purine nucleobases and used to predict the isotopic distributions of these compounds.
", "doi": "10.7907/zt08-jh39", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16385", "collection": "thesis", "collection_id": "16385", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05152024-205420698", "type": "thesis", "title": "Novel Reactivity and Applications of Transition Metal-Catalyzed Nucleophilic Substitution Reactions", "author": [ { "family_name": "Tong", "given_name": "Xiaoyu", "orcid": "0000-0002-1343-6335", "clpid": "Tong-Xiaoyu" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "For more than 20 years, the Fu lab has explored the use of transition metal catalysts to enable novel nucleophilic substitution reactions. However, deficiencies in both fundamental reactivity and useful applications persist in this area. The research detailed in this thesis focuses on the development of reactivity and applications of transition metal-catalyzed nucleophilic substitution reactions.", "doi": "10.7907/nqkk-2x98", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16378", "collection": "thesis", "collection_id": "16378", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05092024-225449838", "type": "thesis", "title": "Exploring the Photophysics and Reactivity of Nickel\u2013Bipyridine Cross-Coupling Catalysts", "author": [ { "family_name": "Cagan", "given_name": "David Abraham", "orcid": "0000-0002-4719-2789", "clpid": "Cagan-David-Abraham" } ], "thesis_advisor": [ { "family_name": "Hadt", "given_name": "Ryan G.", "orcid": "0000-0001-6026-1358", "clpid": "Hadt-Ryan-G" } ], "thesis_committee": [ { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Hadt", "given_name": "Ryan G.", "orcid": "0000-0001-6026-1358", "clpid": "Hadt-Ryan-G" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Ni(II)\u2013bipyridine (bpy) aryl halide complexes have been prized for nearly a decade for their catalytic potency to facilitate cross-coupling reactions. To achieve these transformations, the energy from light is leveraged to drive the key catalytic processes. Thus, Ni-mediated photoredox catalysis provides an attractive and sustainable means to replace precious metal catalysts. However, precise mechanistic information regarding how these transformations occur is limited. This thesis thus focuses on a dual experimental and computational analysis of Ni(II)\u2013bpy aryl halide complexes and their photoproducts to provide insight into the specific photophysical and chemical pathways that these catalysts undertake for cross-coupling reactions. The first chapter is a review of the proposed mechanisms presented for Ni-mediated photoredox catalysis. Therein, certain portions of this work are also summarized. The second chapter provides a computational description of the Ni(II) excited states. The third chapter expands on this analysis with experiment, elucidating the photophysical pathway that grants entry into dark Ni(I)/Ni(III) catalytic cycles. Together, chapters two and three show that Ni(II)\u2013bpy aryl halide complexes form low-valent Ni(I)\u2013bpy halide species by an aryl-to-Ni ligand-to-metal charge transfer. Chapter four outlines a method to generate and study these reactive Ni(I)\u2013bpy halide intermediates, identifying their mechanism of C(sp2)\u2013Cl bond activation as nucleophilic aromatic substitution, tunable via the energies of the 3d-orbitals and the effective nuclear charge of Ni. The final chapter finds that these low-valent Ni species are competitive light-absorbers, and it presents a study into their ultrafast photophysics, marking the first of its kind on any Ni(I) complex. The excited-state relaxation dynamics of Ni(I)\u2013bpy halide complexes are well described by vibronic Marcus theory, spanning the normal and inverted regions as a result of simple changes to the bpy substituents. Altogether, these studies have provided a framework to gain electronic structural control over Ni-meditated photoredox catalysis and, thus, guides the use of photonic energy as a sustainable alternative to precious metal catalysis.
", "doi": "10.7907/n3xz-6v34", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:15148", "collection": "thesis", "collection_id": "15148", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04282023-211208336", "type": "thesis", "title": "Development of Oxidation and Transition Metal-Mediated Reactions and Application to Natural Product Synthesis", "author": [ { "family_name": "Dibrell", "given_name": "Sara Elise", "orcid": "0000-0003-0332-1101", "clpid": "Dibrell-Sara-Elise" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Expedient access to complex molecules via chemical synthesis is important for assessing their biological activity and medicinal properties. In one approach, convergent joining of fragments of similar size and complexity is followed by minimal scaffold tailoring steps to rapidly access natural products. This strategy hinges on the ability to (1) tailor peripheral oxidation, ideally via creative redox transformations, and (2) forge strategic bonds within a complex scaffold through C\u2013C bond formation. We disclose efforts to address these aims by developing broadly useful chemical tools and applying them to the preparation of bioactive natural products.
\r\n\r\nToward the first aim, we investigated unusual oxidative reactivity mediated by selenium dioxide. To address the second aim, we developed nickel-catalyzed reductive cross-coupling reactions to study: catalyst-controlled enantioselectivity in the preparation of medicinally relevant small molecules, substrate-controlled stereoselectivity, and selectivity for ring formation. The latter studies enabled the exploration of transition metal-mediated cyclization as a convergent annulation strategy toward the rearranged isoryanodane diterpene (+)-cassiabudanol A, as well as the formal synthesis of the macrocyclic cytotoxin (\u2013)-cylindrocyclophane F.
", "doi": "10.7907/ve4j-tw63", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:16092", "collection": "thesis", "collection_id": "16092", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06072023-204031343", "primary_object_url": { "basename": "Sepand Nistanaki Thesis - 6-7-23.pdf", "content": "final", "filesize": 27322606, "license": "other", "mime_type": "application/pdf", "url": "/16092/1/Sepand Nistanaki Thesis - 6-7-23.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Application of Dewar Heterocycles and Vinyl Carbocations in Organic Synthesis", "author": [ { "family_name": "Nistanaki", "given_name": "Sepand K.", "orcid": "0000-0002-5252-803X", "clpid": "Nistanaki-Sepand-K" } ], "thesis_advisor": [ { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "High-energy molecules are frequently employed in the construction of organic molecules and materials in both academic and industrial settings. This thesis describes the application of two distinct classes of reactive molecules in organic synthesis: (1) Dewar heterocycles, which contain a highly strained bicyclic structure; (2) vinyl cations, a class of dicoordinated carbocations containing an electron-deficient carbon center bound to only two atoms. A description of our experimental work relevant to this thesis commences with the exploration of Dewar pyrone in the total synthesis of (\u00b1)-vibralactone. Next, the application of Dewar heterocycles to the synthesis of new strained-ring polymers will be discussed, including examples of post-polymerization strategies to access soluble poly(acetylene) derivatives and \u03b2-amino acid type polymers. Finally, the development of a catalytic asymmetric C\u2013H insertion reaction of vinyl carbocations will be described, with an emphasis on reaction development, scope, and mechanism.
", "doi": "10.7907/m1t7-tm48", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:16084", "collection": "thesis", "collection_id": "16084", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06052023-155701672", "type": "thesis", "title": "Development of Selective Carbon\u2013Carbon Bond-Forming Reactions of Vinyl Carbocations", "author": [ { "family_name": "Williams", "given_name": "Chloe Gabrielle", "orcid": "0000-0001-5090-8146", "clpid": "Williams-Chloe-Gabrielle" } ], "thesis_advisor": [ { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "See", "given_name": "Kimberly", "orcid": "0000-0002-0133-9693", "clpid": "See-Kimberly" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Carbocationic intermediates play an important role in the construction of complex molecules, from biosynthetic pathways in nature to the synthesis of natural products by organic chemists. Herein, a brief introduction that surveys C\u2013C bond forming reactions of vinyl carbocations is highlighted. The discussion of experimental work commences with the development of a main group-catalyzed approach towards accessing vinylated esters through the trapping of vinyl carbocations with silyl ketene acetals. Next, a Claisen-type rearrangement is discussed, which is a result of trapping vinyl carbocations with allyl ethers to form an allyl vinyl oxonium intermediate in situ that can subsequently rearrange. Finally, the last method that is highlighted includes the development of an asymmetric C\u2013H insertion reaction of vinyl carbocations to forge bicyclic products in a highly enantioselective fashion.", "doi": "10.7907/rkge-pz74", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:16059", "collection": "thesis", "collection_id": "16059", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06022023-191413115", "primary_object_url": { "basename": "TC_Thesis_Final.pdf", "content": "final", "filesize": 36686682, "license": "other", "mime_type": "application/pdf", "url": "/16059/1/TC_Thesis_Final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Unveiling Incipient Reactivity via Tandem Hydrosilylation Reaction Cascades and the Progress Toward the Total Synthesis of (\u2013)-Cylindrocyclophane A", "author": [ { "family_name": "Casselman", "given_name": "Tyler Daniel", "orcid": "0000-0002-1691-3969", "clpid": "Casselman-Tyler-Daniel" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The two pillars of synthetic organic chemistry, reaction methodology development and total synthesis of complex natural products, has remained the focus of chemical research for synthetic chemists since their fundamental inception. In particular, harnessing the reactivity of unstable, but useful, chemical intermediates through telescoping reaction conditions is emerging as an attractive approach to rapidly access complex molecular architecture from readily available building blocks. Herein is described two unique reaction methodologies relying on tandem hydrosilylation reaction cascades to synthesis saturated N-heterocyclic products in a stereoselective manner. We have developed a diastereoselective Mannich reaction combining \u03b1-substituted-\u03b3-lactam pronucleophiles with N-silyl imine electrophiles generated in situ via catalytic hydrosilylation of aryl nitriles. Additionally, we have developed a tandem hydrosilylation, enantioselective allylic alkylation reaction of substituted pyridines to yield chiral tetrahydropyridine products. This serves as the first example of using hydrosilylation of pyridines to generate enamine nucleophiles that can undergo an asymmetric allylic alkylation reaction. The final portion of this thesis describes the progress toward a total synthesis of (\u2013)-cylindrocyclophane using C\u2013H functionalization logic. We were able to access the necessary [7.7]-paracyclophane core in 8 steps from a feedstock aryl diazoacetate compound and n-hexene. Through functional group manipulations, we were able to advance this paracyclophane core to an intermediate possessing the exact stereocenters and carbon framework in (\u2013)-cylindrocyclophane A. We are currently modeling the necessary deoxygenation needed to advance this intermediate and complete the total synthesis.
", "doi": "10.7907/92b3-2d90", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:16058", "collection": "thesis", "collection_id": "16058", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06022023-190747966", "type": "thesis", "title": "Enantioselective Syntheses of Tetrahydroisoquinolines (THIQs) via Iridium-Catalyzed Asymmetric Hydrogenation and Progress Toward the Total Synthesis of (+)-Cyanocycline A", "author": [ { "family_name": "Kim", "given_name": "Alexia Nahyun", "orcid": "0000-0002-4060-8892", "clpid": "Kim-Alexia-Nahyun" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Described herein are two reviews and three projects related to the asymmetric syntheses of tetrahydroisoquinoline (THIQs) alkaloids, and the progress toward the total synthesis of (+)-cyanocycline A. In Chapter 1, a review of the development of asymmetric methodologies for the preparation of enantioenriched N-heteroarenes is detailed. In Chapter 2, the development of an iridium-catalyzed enantio- and diastereoselective hydrogenation of 1,3-disubstituted isoquinolines to achieve cis-THIQs is reported. Chapter 3 describes the iridium-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines that can afford trans-THIQs in a single transformation. Preliminary mechanistic insights to the iridium-catalyzed asymmetric hydrogenation method using deuterium experiments are detailed.
\r\n\r\nChapter 4 details a comprehensive review of the advances in the total syntheses of complex THIQ alkaloids from 2000 \u2013 2020, ranging from simple benzyl THIQ natural products to complex THIQ alkaloids such as Ecteinascidin-743. In Chapter 5, efforts toward the total synthesis of (+)-cyanocycline A are described, harnessing a non- biomimetic synthetic route through a convergent cross-coupling of two heterocyclic fragments followed by a global hydrogenation event.
", "doi": "10.7907/4xty-8711", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15258", "collection": "thesis", "collection_id": "15258", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06012023-171716967", "primary_object_url": { "basename": "Jeff Kerkovius Thesis with Redacted Chapter 4.pdf", "content": "final", "filesize": 23845140, "license": "other", "mime_type": "application/pdf", "url": "/15258/8/Jeff Kerkovius Thesis with Redacted Chapter 4.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Total Synthesis of Lupin Alkaloids, Diterpenoid Alkaloids, and Progress Towards the Myrsinane Diterpenes", "author": [ { "family_name": "Kerkovius", "given_name": "Jeffrey Kevan", "orcid": "0000-0001-5692-0285", "clpid": "Kerkovius-Jeffrey-Kevan" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "Resnick Sustainability Institute" }, { "literal": "div_chem" } ], "abstract": "The interplay between total synthesis and methodology is a driver of innovation in organic synthesis. Challenging bond formations in complex systems necessitate the development ever more robust new reactions, which intern can enable more efficient syntheses. The need for powerful synthetic organic chemistry can\u2019t be understated because of its utility in applications such as medicine, petrochemicals, plastics, and agrichemicals.
\r\n\r\nHerein, we present how total synthesis drives innovation in organic chemistry. First, a novel cyclization reaction between pyridine and glutaryl chloride is discussed, which has enabled the synthesis of seven lupin alkaloids. Next, the development of a convergent fragment coupling tactic based upon the semi-pinacol rearrangement is evaluated for its generality inspired by the total synthesis of several C19 diterpenoid alkaloids. Lastly, a convergent fragment coupling approach is applied to the total synthesis of falcatin A based upon a Mukaiyama Michael tandem Mukaiyama aldol reaction.
", "doi": "10.7907/y6rd-nm97", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15243", "collection": "thesis", "collection_id": "15243", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05312023-172947562", "primary_object_url": { "basename": "RFT_compiled thesis.pdf", "content": "final", "filesize": 79149124, "license": "other", "mime_type": "application/pdf", "url": "/15243/1/RFT_compiled thesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Mechanistic Investigations and Development of Ni-Catalyzed Cross- Electrophile Coupling Reactions", "author": [ { "family_name": "Turro", "given_name": "Raymond Farnon", "orcid": "0000-0001-9774-4556", "clpid": "Turro-Raymond-Farnon" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Transition metal-catalyzed cross-coupling reactions have proven to be a powerful technology for the modular construction of carbon-carbon and carbon-heteroatom bonds over the last half century. More recently, reductive cross-coupling catalyzed by nickel has emerged as a complementary synthetic approach that couples electrophilic fragments and is rendered catalytic by the inclusion of a terminal reductant. These reactions are advantageous because the use electrophiles as coupling partners which display greater stability, functional group tolerance, and commercial availability over the corresponding nucleophilic coupling partners. Additionally, Ni catalysts are less prone to \u03b2-hydride elimination compared to later transition metals which enables C(sp\u00b3)\u2013C(sp\u207f) couplings. The challenge with using coupling partners of the same polarity is developing a catalyst that can activate each electrophile in a mechanistically distinct way in order to get high levels off cross-selectivity, over statistical mixtures of cross- and homocoupled products.
\r\n\r\nHerein, we describe a mechanistic investigation on Ni-catalyzed cross-electrophile couplings developed in our lab; specifically, the asymmetric reductive alkenylation of N-hydroxyphthalimide (NHP) esters and benzylic chlorides. Investigations of the redox properties of the Ni-bis(oxazoline) catalyst, the reaction kinetics, and mode of electrophile activation show divergent mechanisms for these two related transformations. Notably, the mechanism of C(sp\u00b3) activation changes from a Ni-mediated process when benzyl chlorides and Mn\u2070 are used to a reductant-mediated process that is gated by a Lewis acid when NHP esters and tetrakis(dimethylamino)ethylene is used. Kinetic experiments show that changing the identity of the Lewis acid can be used to tune the rate of NHP ester reduction. Spectroscopic studies support a Ni^(\u026a\u026a)\u2013alkenyl oxidative addition complex as the catalyst resting state. DFT calculations suggest an enantiodetermining radical capture step and elucidate the origin of enantioinduction for this Ni-BOX catalyst.
\r\n\r\nEfforts to expand the scope of coupling partners in XEC reactions to include novel classes of electrophiles, such as N-alkyl imines, are also described. The preparation of heterobenzylic amines by a Ni-catalyzed reductive cross-coupling between heteroaryl imines and C(sp\u00b3) electrophiles is reported. This umpolung-type alkylation proceeds under mild conditions, avoids the pre-generation of organometallic reagents, and exhibits good functional group tolerance. Mechanistic studies are consistent with the imine substrate acting as a redox-active ligand upon coordination to a low-valent Ni center. The resulting bis(2-imino)heterocycle\u00b7Ni complexes can engage in alkylation reactions with a variety of C(sp\u00b3) electrophiles, giving heterobenzylic amine products in good yields.
", "doi": "10.7907/na61-ed84", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15242", "collection": "thesis", "collection_id": "15242", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05312023-053933898", "primary_object_url": { "basename": "Sercel Thesis.pdf", "content": "final", "filesize": 49258358, "license": "other", "mime_type": "application/pdf", "url": "/15242/7/Sercel Thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Synthesis of Organic Building Blocks and Synthetic Strategies Toward Aleutianamine", "author": [ { "family_name": "Sercel", "given_name": "Zachary Patrick", "orcid": "0000-0001-7977-8509", "clpid": "Sercel-Zachary-Patrick" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Described herein are the development of the palladium-catalyzed decarboxylative asymmetric allylic alkylation of medicinally relevant 5- and 7-membered diazaheterocycles and efforts toward the total synthesis of the cytotoxic pyrroloiminoquinone marine alkaloid aleutianamine. The former methodology provides a new tactic to incorporate Csp3 structural complexity into future lead compounds containing diazepane and imidazolidine moieties. The latter project is ongoing.
\r\n\r\nAdditionally, Chapter 3 discusses preliminary attempts to improve the synthetic accessibility of minimally substituted corroles, which were conducted during a research internship in the laboratory of Prof. Zeev Gross at the Technion. During the course of this research, the first example of a \u03b2-unsubstituted free base monoazaporphyrin was isolated, and its cobalt complex was characterized by x-ray crystallography.
\r\n\r\nFinally, Appendix 8 presents a series of cationic and radical-mediated fragmentations of a derivative of (+)-3-Carene, a chiral pool material. These experiments led to the observation and mechanistic study of an unexpected rearrangement.
", "doi": "10.7907/3ezw-2h57", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15200", "collection": "thesis", "collection_id": "15200", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05222023-030948313", "primary_object_url": { "basename": "Breunig_thesis.pdf", "content": "final", "filesize": 15344648, "license": "other", "mime_type": "application/pdf", "url": "/15200/83/Breunig_thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Incorporation of Non-Canonical Proline Residues into Proteins Expressed in Escherichia coli", "author": [ { "family_name": "Breunig", "given_name": "Stephanie Lynne", "orcid": "0000-0002-8665-6363", "clpid": "Breunig-Stephanie-Lynne" } ], "thesis_advisor": [ { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "orcid": "0000-0003-1464-2461", "clpid": "Dougherty-D-A" }, { "family_name": "Mayo", "given_name": "Stephen L.", "orcid": "0000-0002-9785-5018", "clpid": "Mayo-S-L" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Non-canonical proline residues expand the chemical space about proline, while maintaining some conformational properties of the canonical residue. The translational machinery of Escherichia coli can accommodate close structural analogs of proline, which has enabled the production of recombinant proteins that contain non-canonical residues at proline positions. However, proline mutagenesis in E. coli is restricted to a relatively small set of proline variants, and protein science and engineering efforts utilizing non-canonical proline residues are limited.
\r\n\r\nThis thesis aims to expand the scope of proline analogs that can be accepted by E. coli, and demonstrate the utility of proline mutagenesis in modifying and studying protein behavior. In Chapter II, we describe the incorporation of three aliphatic proline residues into recombinantly-produced insulin, and find that these modest modifications at ProB28 alter the biophysical properties of the therapeutic protein. In particular, the addition of an exocyclic olefin at B28 accelerated insulin fibril formation, while 4-methyl substituents increased the rate of dissociation from the pharmaceutically-formulated insulin hexamer. We expand our proline mutagenesis approach to monomeric insulins in Chapter III. 4-fluorinated proline analogs replaced ProB29 of the fast-acting insulin lispro; 4S-fluorination of ProB29 slowed fibril formation. Chapter IV describes the incorporation of the photo-activatable proline analog \"photo-proline\" into proteins expressed in E. coli, and Chapter V discusses our efforts to engineer the E. coli prolyl-tRNA synthetase to accommodate more diverse proline substrates. Together, this work expands the proline analogs accessible to recombinant expression in E. coli, and demonstrates their use in probing and engineering the biophysical properties of proteins.
", "doi": "10.7907/8nj2-v152", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15189", "collection": "thesis", "collection_id": "15189", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05182023-054024067", "type": "thesis", "title": "Synthetic Studies Toward the Total Synthesis of Enterocin", "author": [ { "family_name": "Tao", "given_name": "Yujia", "orcid": "0000-0003-4615-6409", "clpid": "Tao-Yujia" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "As part of a broader program aimed at the synthesis of complex and highly oxygenated natural products, we initiated a chemical synthesis of the natural polyketide enterocin. This dissertation will disclose our efforts to bridge that gap through the development of synthetic strategies for the total synthesis of the enterocin. The studies herein will address three unique strategies to access the tactical difficulties in the rich oxygenation patterns and caged core structure of enterocin. The program was first inspired by a SeO2 multioxidation reaction, and the methodology has been successfully applied to install bridgehead oxygenation patterns in enterocin. A strategy featuring a radical-polar crossover reaction as an annulation step to quickly construct the [3.2.1] bicyclic core of enterocin is detailed. Initial studies have successfully achieved the radical-polar crossover annulation reaction to forge [3.2.1]bicycles with bridgehead hydroxyl groups, and will guide the future development toward the total synthesis of enterocin. An intermolecular aldol approach will be discussed to address the challenge on pyrone installation and core structure synthesis. In summary, the development of an efficient and general approach will allow the development of novel reactions and a comprehensive evaluation of the potential of caged polyketides to serve as medicinally interesting molecules.", "doi": "10.7907/jdhq-sb66", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15055", "collection": "thesis", "collection_id": "15055", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11032022-004822338", "type": "thesis", "title": "The Development of Ni-Catalyzed Methods for Application in Total Synthesis", "author": [ { "family_name": "Shimozono", "given_name": "Alexander Mitsuo", "orcid": "0000-0001-7164-4741", "clpid": "Shimozono-Alexander-Mitsuo" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The total synthesis of complex natural products often requires the development of mild, selective transformations. Once developed, these methods can serve as starting points for related methodologies, fundamental mechanistic studies, or applied in other total syntheses. Herein, a series of projects that embody this relationship are described. Inspired by unexpected challenges in the synthesis of complex diterpenoid alkaloid talatisamine, a Ni-catalyzed enol-triflate-halogen exchange reaction was developed. In addition to finding application toward the synthesis of talatisamine, this reaction found further use in an attempted route toward enmein-type ent-kauranoid natural products. En route to the synthesis of these natural products, a need for meso-anhydride functionalization was identified which inspired a research program dedicated to Ni-catalyzed reductive functionalization of anhydrides.
", "doi": "10.7907/h0w0-1d25", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15156", "collection": "thesis", "collection_id": "15156", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05092023-013609857", "primary_object_url": { "basename": "Ross Barber 2023 Thesis.pdf", "content": "final", "filesize": 5924873, "license": "other", "mime_type": "application/pdf", "url": "/15156/3/Ross Barber 2023 Thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Mechanophore Strategies for the Development of Polymers with Mechanically Gated Responsive Behavior", "author": [ { "family_name": "Barber", "given_name": "Ross William", "orcid": "0000-0003-0434-847X", "clpid": "Barber-Ross-William" } ], "thesis_advisor": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of mechanically sensitive molecules has recently enabled mechanical force to induce specific changes in polymeric materials. This document details efforts in the development of such mechanophores in which mechanical activation is used to gate the desired functional responses.
\r\n\r\nChapter 1 is an introduction to polymer mechanochemistry and delineates the state of the field as it relates to color changing mechanophores used for damage detection. Special emphasis is placed on a system developed by our lab in which mechanical force gates the photoresponsive behavior of a diarylethene molecular switch.
\r\n\r\nChapter 2 details the design of a new mechanically gated photoswitch whose synthesis and activity are improved from the previous iteration. The modular design enables a late-stage synthetic intermediate to be differentiated into a small library of masked photoswitches that produce unique colors following mechanical activation and ultraviolet irradiation. Notably, these mechanophores show activity in solution phase experiments as well as in bulk polymeric materials.
", "doi": "10.7907/wgnw-zq30", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15146", "collection": "thesis", "collection_id": "15146", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04272023-220317123", "primary_object_url": { "basename": "230425_Versaw_Brooke_thesis_VOR.pdf", "content": "final", "filesize": 14253370, "license": "other", "mime_type": "application/pdf", "url": "/15146/1/230425_Versaw_Brooke_thesis_VOR.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "Thermally and Mechanically Responsive Platforms for Functional Polymeric Materials", "author": [ { "family_name": "Versaw", "given_name": "Brooke Ann", "orcid": "0000-0002-6200-7203", "clpid": "Versaw-Brooke-Ann" } ], "thesis_advisor": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "local_group": [ { "literal": "Resnick Sustainability Institute" }, { "literal": "div_chem" } ], "abstract": "Connecting a polymer\u2019s reactivity or properties to its working environment is a grand challenge in polymer chemistry. Research towards this goal is driven both by a fundamental interest in mimicking nature\u2019s ability to create surfaces that adapt to their surroundings and a practical desire to tailor the properties of materials to the wide-ranging contexts where they find use. This thesis investigates the development of polymers that exhibit productive changes in physical properties or chemical reactivity under an applied environmental stimulus.", "doi": "10.7907/2hwm-af78", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:14563", "collection": "thesis", "collection_id": "14563", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04272022-163740814", "primary_object_url": { "basename": "DeLano_Thesis_Final.pdf", "content": "final", "filesize": 39397720, "license": "other", "mime_type": "application/pdf", "url": "/14563/1/DeLano_Thesis_Final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Development of Nickel-Catalyzed Asymmetric Cross-Coupling Reactions", "author": [ { "family_name": "DeLano", "given_name": "Travis Jon", "orcid": "0000-0002-2052-611X", "clpid": "DeLano-Travis-Jon" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "See", "given_name": "Kimberly", "orcid": "0000-0002-0133-9693", "clpid": "See-Kimberly" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Asymmetric cross-coupling reactions have emerged in recent decades as powerful tools for the formation of valuable carbon\u2013carbon bonds in the synthesis of enantioenriched small molecules. Nickel catalysis in particular has proven to be an especially powerful tool for the formation of C(sp\u00b2)\u2013C(sp\u00b3) bonds in part due to the propensity of nickel catalysts to access odd oxidation states and interact with radical intermediates. Application of asymmetric nickel catalysis to a variety of radical precursors has resulted in the development of a broad range of stereoconvergent reductive and redox-neutral cross coupling reactions, allowing for the highly enantioselective formation of many synthetically useful and biologically relevant molecules.
\r\n\r\nHerein we describe our recent efforts in the development of new nickel-catalyzed enantioselective cross-coupling reactions. First, an enantioselective reductive cross- coupling of alkenyl and benzyl halides was rendered electroreductive. Careful electrochemical cell design proved critical for this reaction, which represents the first report of an enantioselective nickel-catalyzed electroreductive cross coupling reaction. We next discuss our development of an enantioselective reductive cross coupling of \u237a-chloroesters with aryl iodides. This reaction proceeds with especially high ee when \u03b2-branched substrates are employed, prompting the development of a multivariate linear regression model to probe the origin of the observed enantioselectivity trends. Finally, a redox-neutral nickel/photoredox co-catalyzed coupling of \u237a-N-heterocyclic potassium alkyl trifluoroborates and aryl bromides is reported. This reaction, developed in collaboration with researchers at Merck, provides rapid enantioselective access to motifs commonly found in bioactive molecules.
", "doi": "10.7907/pzfp-ad90", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14419", "collection": "thesis", "collection_id": "14419", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11062021-003540914", "type": "thesis", "title": "Development of a Synthetic Strategy Toward Falcatin A. Development of an Asymmetric Diels\u2013Alder Reaction of \u03b1-Acyloxy Enones", "author": [ { "family_name": "Mendoza", "given_name": "Skyler Dakota", "orcid": "0000-0003-1939-1884", "clpid": "Mendoza-Skyler-Dakota" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Accessing natural products via de novo synthetic methods is important for the discovery of new medicines, antibiotics, agrochemicals, and more. Design and investigation of efficient strategies is of interest to many pharmaceutical industries.
\r\n\r\nHerein, we discuss several strategies geared towards the synthesis of the natural product falcatin A. First, a general discussion of the class of natural products is discussed. Secondly, we discuss our first generation photoredox cascade cyclization approach toward the synthesis of falcatin A. This strategy allows for the efficient and convergent synthesis of two halves of falcatin. Next, a transition metal-catalyzed cascade cyclization approach is discussed in which we were able to successfully synthesize the core of the natural product on a model system. Efforts are ongoing to elaborate to more advanced fragments for the synthesis of falcatin A. Lasty, we discuss our work on the yttrium-catalyzed asymmetric Diels\u2013Alder reaction of \u03b1-acyloxy enone dienophiles, performed in collaboration with BASF. We demonstrate that this methodology can be utilized to access enantioenriched natural product T-4-ol.
", "doi": "10.7907/v3ys-kj69", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14428", "collection": "thesis", "collection_id": "14428", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11182021-220809412", "primary_object_url": { "basename": "dfreas_thesis_final.pdf", "content": "final", "filesize": 8999194, "license": "other", "mime_type": "application/pdf", "url": "/14428/1/dfreas_thesis_final.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "The Synthesis of Diverse Families of Organic Compounds via Nickel-Catalyzed Nucleophilic Substitution Reactions", "author": [ { "family_name": "Freas", "given_name": "Dylan Joshua", "orcid": "0000-0003-0611-7907", "clpid": "Freas-Dylan-Joshua" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Transition metal-catalyzed cross-coupling has provided an exceptionally powerful approach to carbon\u2013carbon bond formation, allowing chemists to solve a number of important problems in organic synthesis. However, by the early 2000s, its application to the formation of alkyl\u2013alkyl bonds had been limited by the slow oxidative addition of palladium catalysts toward alkyl halides and the tendency of transition-metal-alkyls to undergo \u03b2-hydride elimination. Since then, complexes based on nickel, an earth-abundant metal, have emerged as efficient catalysts for the nucleophilic substitution of alkyl electrophiles. The propensity for nickel to access a range of oxidation states allows it to react via one-electron pathways to generate radical intermediates, opening the door to couplings of sterically-hindered electrophiles and offering a ready mechanism for enantioconvergence.
\r\n\r\nOur group has applied nickel catalysts to substitution reactions of activated and unactivated 2o and 3o alkyl electrophiles by carbon\u2013 as well as by heteroatom-based nucleophiles, including a number of enantioconvergent processes. However, given the enormous range of conceivable coupling partners, many interesting challenges have yet to be addressed. The application of nickel-catalyzed substitution reactions to the synthesis of diverse families of compounds, particularly those with frequent uses in organic synthesis and pharmaceutical science, is described in this thesis. While reaction development is the primary focus of this work, a variety of synthetic applications and mechanistic investigations are also detailed within.
\r\n\r\nChapter 2 describes two methods for the catalytic enantioconvergent synthesis of amines, which involve the coupling of an alkylzinc reagent with a racemic electrophile (specifically, an \u03b1-phthalimido alkyl chloride and an N-hydroxyphthalimide ester of a protected \u03b1-amino acid). A one-pot variant of this transformation is possible, enabling the efficient enantioselective synthesis of a range of interesting target molecules. Several mechanistic insights are also detailed.
\r\n\r\nChapter 3 outlines the nickel-catalyzed alkylation of racemic \u03b1-haloglycine derivatives, a class of electrophile previously unemployed in metal-catalyzed asymmetric cross-coupling reactions, with alkylzinc reagents to generate protected unnatural \u03b1-amino acids. This method is applied to the generation of several enantioenriched unnatural \u03b1-amino acids that have previously been shown to serve as useful intermediates in the synthesis of bioactive compounds.
\r\n\r\nChapter 4 details the development of a nickel-catalyzed cross-coupling for the asymmetric synthesis of protected thiols. The synthesis of an N-hydroxyphthalimide ester containing a geminal thioester (a previously unreported class of molecule with no applications to cross-coupling) is described, along with its reactivity toward alkylzinc reagents and other classes of organometallic nucleophiles.
\r\n\r\nChapter 5 examines the ability of nickel to catalyze the nucleophilic fluorination of unactivated alkyl halides, a transformation whose application to the synthesis of alkyl fluorides has been impeded by the low nucleophilicity and high basicity of fluoride. The reactivities of unactivated 1o, 2o, and 3o alkyl bromides, as well as several preliminary mechanistic investigations, are presented.
", "doi": "10.7907/e76h-vh27", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14355", "collection": "thesis", "collection_id": "14355", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09072021-162545226", "primary_object_url": { "basename": "CRL_Thesis_Short.pdf", "content": "final", "filesize": 13889808, "license": "other", "mime_type": "application/pdf", "url": "/14355/1/CRL_Thesis_Short.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "The Modular Synthesis and Functionalization of Cyclic Compounds Using Modern Methods", "author": [ { "family_name": "Lacker", "given_name": "Caitlin Rebecca", "orcid": "0000-0003-2531-2636", "clpid": "Lacker-Caitlin-Rebecca" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Accessing libraries of similar compounds quickly is important in the pharmaceutical industry, as it allows for the expedient investigation of a wide variety of parameters. An efficient strategy to access compounds of interest is to start from a single intermediate containing an interesting or pharmaceutically active structure and decorating it with varying functionality to generate a library of related compounds. Cross-coupling is a powerful tool for this type of divergent, modular approach.
\r\n\r\nHerein, we discuss several strategies geared towards the synthesis of small libraries of compounds of interest. First, a modular approach towards a library of enantioenriched trans cyclobutanes is discussed. This strategy allows for the synthesis of diverse substrates from a single enantioenriched intermediate, and this approach was applied to the synthesis of the small molecule (+)-rumphellaone A. Finally, the development of an enantioselective nickel-catalyzed photoredox cross-coupling to form N-(hetero)benzylic azoles in collaboration with researchers at Merck is discussed.
", "doi": "10.7907/61ky-5w83", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14940", "collection": "thesis", "collection_id": "14940", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06032022-194915019", "primary_object_url": { "basename": "NJHThesisFinal.pdf", "content": "final", "filesize": 20013089, "license": "other", "mime_type": "application/pdf", "url": "/14940/1/NJHThesisFinal.pdf", "version": "v9.0.0" }, "type": "thesis", "title": "Synthesis and Applications of Terpenoid Natural Products: Total Synthesis of Scabrolide A and Havellockate, and Synthesis of Pinene Oxidation Products for Atmospheric Investigations", "author": [ { "family_name": "Hafeman", "given_name": "Nicholas Joseph", "orcid": "0000-0001-7525-7597", "clpid": "Hafeman-Nicholas-Joseph" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Wennberg", "given_name": "Paul O.", "orcid": "0000-0002-6126-3854", "clpid": "Wennberg-P-O" }, { "family_name": "Nelson", "given_name": "Hosea M.", "orcid": "0000-0002-4666-2793", "clpid": "Nelson-H-M" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The total synthesis of complex natural products remains one of the enduring challenges in organic chemistry. Whether motivated by the biological activity of the target, or its structural complexity, total synthesis continues to serve as a proving ground for synthetic methodology as well as strategic planning. Herein is described the first total synthesis of the polycyclic furanobutenolide-derived (nor)cembranoid diterpenoids scabrolide A and havellockate. Our total synthesis of scabrolide A involves an intramolecular [4+2] cycloaddition, which forges a fused [5\u20135\u20136] tricycle possessing two of the three carbocycles that characterize the natural product. Next, a photocycloaddition/fragementation sequence is employed to forge the final seven-membered ring and complete the total synthesis. Using a similar strategy, we could forge the [5\u20135\u20136] tricyclic core of the related diterpenoid havellockate with an intramolecular [4+2] cycloaddition. This is followed by a challenging enone allylation which installs the final carbon atoms of the target. Finally, elaboration of the allyl group, followed by a Cu/TEMPO-catalyzed oxidative lactonization furnishes havellockate. The final chapter of this thesis describes the synthesis and characterization of several pinene oxidation products and their dimers, which have been observed in pinene-derived secondary organic aerosol samples, as standards for atmospheric studies. This research uses the power of chemical synthesis to confirm (and in some cases reassign) the structures of naturally occurring, yet difficult to characterize chemical species found in the atmosphere.
", "doi": "10.7907/3st9-6a73", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14488", "collection": "thesis", "collection_id": "14488", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02022022-183557614", "primary_object_url": { "basename": "2022-02_Michael_Maser_phd_thesis.pdf", "content": "final", "filesize": 69533936, "license": "other", "mime_type": "application/pdf", "url": "/14488/1/2022-02_Michael_Maser_phd_thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Machine Learning Methods Inspired by Challenges in Total Synthesis", "author": [ { "family_name": "Maser", "given_name": "Michael Robert", "orcid": "0000-0001-7895-7804", "clpid": "Maser-Michael-Robert" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Yue", "given_name": "Yisong", "orcid": "0000-0001-9127-1989", "clpid": "Yue-Yisong" }, { "family_name": "Listgarten", "given_name": "Jennifer", "orcid": "0000-0002-6600-1431", "clpid": "Listgarten-Jennifer" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Synthetic organic chemists face a dearth of challenges in the efficient construction of functional molecules, particularly bioactive compounds. Predictive approaches offer reductions to research timelines and resource costs and allow chemists to devote their expertise where it is most valuable. Promising machine learning (ML) methods have evolved for uncovering patterns in chemical data that are beyond the grasp of expert humans, but a number of grand challenges in molecular ML remain. First, the learning of chemical structure representations rooted in physical first principles has yet to be robustly demonstrated. Second, the practical task of predicting successful \"over-the-arrow\" reaction conditions remains elusive. Finally, the demonstration of such solutions in the context of complex synthesis has yet to be realized.
\r\n\r\nHerein, approaches to these grand challenges are developed and described. Inspiration is derived from the successful synthesis of the anticancer marine natural product ritterazine B. Reaction condition prediction is approached first, where a novel graph neural network architecture is developed under a multilabel classification framework. The resulting model is successfully demonstrated on datasets of four high-value reaction types in modern synthesis. Next, 3D-to-1D representation learning is approached by development of a volumetric neural architecture based on inception networks. Such voxel models are demonstrated for the prediction of expensive quantum mechanical properties from space-filled data alone.
\r\n\r\nThe merging of these approaches for reaction condition optimization and utility in complex settings is discussed and forecasted for future works, which are currently underway.
", "doi": "10.7907/ffjk-g059", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14946", "collection": "thesis", "collection_id": "14946", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06062022-012944875", "type": "thesis", "title": "Asymmetric Total Synthesis of (\u2013)-Myrifabral A and B, Havellockate, and New Strategies for Acyclic Stereocontrol", "author": [ { "family_name": "Fulton", "given_name": "Tyler James", "orcid": "0000-0002-9343-2456", "clpid": "Fulton-Tyler-James" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Research in the Stoltz group aims, generally, to develop novel technologies for the preparation of stereochemically rich molecules and, further, to apply these technologies in the context of complex natural product total synthesis. Chapter 1 of this thesis describes the strategic utilization of a Pd-catalyzed asymmetric allylic allylation and N-acyl iminium ion cyclization to accomplish short, enantioselective total syntheses of (\u2013)-myrifabral A and (\u2013)-myrifabral B. Chapter 2 describes the development of a Pd-catalyzed asymmetric allylic alkylation to generate acyclic \u03b1-quaternary carboxylic acid derivatives from geometrically defined fully substituted N-acyl indole-derived allyl enol carbonates. While ester-derived enol carbonates could be prepared with a high degree of enolate geometry control, they were ineffective in the asymmetric allylic alkylation reaction. Thus, N-acyl indole substrates served as excellent carboxylic ester equivalents. Chapter 3 discusses an unusual Pd-catalyzed decarboxylative \u03b1,\u03b2-dehydrogenation reaction of N-acyl indole-derived enol carbonates enabled by a novel, highly electron-deficient phosphinooxazoline ligand. Research presented in Chapter 4 delineates a globally diastereoconvergent approach to the Ireland\u2013Claisen rearrangement for the synthesis of \u03b1-tetrasubstituted amino acids bearing vicinal tertiary stereogenic centers. Computational investigation of the diastereoconvergence in Ireland\u2013Claisen rearrangement revealed key intramolecular interactions which enable the reaction to proceed in exceptional diastereoselectivity without the need for a selective enolization protocol. Additionally, a diastereodivergent approach for the Ireland\u2013Claisen rearrangement in acyclic systems to generate vicinal quaternary/tertiary and quaternary/quaternary stereogenic centers in good to high diastereoselectivity is discussed. Enolate geometry control and substrate design are critical for achieving high diastereoselectivity in these transformations.
", "doi": "10.7907/qb9s-xj38", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14528", "collection": "thesis", "collection_id": "14528", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03242022-211905773", "primary_object_url": { "basename": "KensethChristopher_2022_Thesis.pdf", "content": "final", "filesize": 46922631, "license": "other", "mime_type": "application/pdf", "url": "/14528/1/KensethChristopher_2022_Thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Formation, Abundance, and Evolution of Molecular Products in \u03b1-Pinene and \u03b2-Pinene Secondary Organic Aerosol", "author": [ { "family_name": "Kenseth", "given_name": "Christopher M.", "orcid": "0000-0003-3188-2336", "clpid": "Kenseth-Christopher-M" } ], "thesis_advisor": [ { "family_name": "Seinfeld", "given_name": "John H.", "orcid": "0000-0003-1344-4068", "clpid": "Seinfeld-J-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Wennberg", "given_name": "Paul O.", "orcid": "0000-0002-6126-3854", "clpid": "Wennberg-P-O" } ], "thesis_committee": [ { "family_name": "Flagan", "given_name": "Richard C.", "orcid": "0000-0001-5690-770X", "clpid": "Flagan-R-C" }, { "family_name": "Seinfeld", "given_name": "John H.", "orcid": "0000-0003-1344-4068", "clpid": "Seinfeld-J-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Wennberg", "given_name": "Paul O.", "orcid": "0000-0002-6126-3854", "clpid": "Wennberg-P-O" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The atmospheric oxidation of \u03b1-pinene and \u03b2-pinene (C10H16), emitted in appreciable quantities from forested regions (~85 Tg y\u20131), contributes significantly to the global burden of secondary organic aerosol (SOA), a substantial component (15\u201380% by mass) of atmospheric fine particulate matter (PM2.5), which exerts large but uncertain effects on climate as well as adverse impacts on air quality and human health. Deciphering the molecular composition, and in turn formation and aging mechanisms, of \u03b1-pinene and \u03b2-pinene SOA is essential to reducing uncertainty in assessment of their environmental and health impacts. However, molecular characterization of \u03b1-pinene and \u03b2-pinene SOA is significantly hindered by their chemical complexity. In this work, we constrain the formation, abundance, and evolution of molecular products in SOA derived from ozonolysis and photooxidation of \u03b1-pinene and \u03b2-pinene using a combination of laboratory experiments, liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS), and organic synthesis. Through detailed MS/MS analysis, coupled with 13C isotopic labeling and OH scavenging, we identify a suite of dimeric compounds (C15\u201319H24\u201332O5\u201311) formed from synergistic O3 + OH oxidation of \u03b2-pinene (i.e., accretion of O3- and OH-derived products/intermediates). Informed by these structural analyses, together with 18O isotopic labeling and H/D exchange, we synthesize the first authentic standards of several major dimer esters identified in SOA from ozonolysis of \u03b1-pinene and \u03b2-pinene and elucidate their formation mechanism from targeted environmental chamber experiments. Additionally, we synthesize a series of pinene-derived carboxylic acid and dimer ester homologues and find that the ESI efficiencies of the dimer esters are 19\u201336 times higher than that of commercial cis-pinonic acid, a common quantification surrogate. Finally, we investigate the aqueous (photo)chemistry (kinetics, products, and mechanisms) of the carboxylic acid and dimer ester homologues at cloudwater-relevant concentrations as a function of pH.
", "doi": "10.7907/bj1b-1441", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14534", "collection": "thesis", "collection_id": "14534", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03292022-234015177", "type": "thesis", "title": "Path Space Markov Chain Monte Carlo Methods for Molecular Simulation", "author": [ { "family_name": "Rosa-Ra\u00edces", "given_name": "Jorge Luis", "orcid": "0000-0003-2311-2948", "clpid": "Rosa-Ra\u00edces-Jorge-Luis" } ], "thesis_advisor": [ { "family_name": "Miller", "given_name": "Thomas F.", "orcid": "0000-0002-1882-5380", "clpid": "Miller-T-F" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Wang", "given_name": "Zhen-Gang", "orcid": "0000-0002-3361-6114", "clpid": "Wang-Zhen-Gang" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" }, { "family_name": "Miller", "given_name": "Thomas F.", "orcid": "0000-0002-1882-5380", "clpid": "Miller-T-F" }, { "family_name": "Stuart", "given_name": "Andrew M.", "orcid": "0000-0001-9091-7266", "clpid": "Stuart-Andrew-M" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Path space Markov-chain Monte Carlo (McMC) provides a versatile framework for simulating the structure and dynamics of condensed-phase systems aptly described by classical and quantum Boltzmann statistics. This thesis comprises our efforts to design, analyze and improve path space McMC algorithms to achieve numerically advantageous, and physically accurate, simulation of molecular processes across a range of scales. To improve molecular dynamics (MD) simulations of atomically resolved systems exhibiting pronounced nuclear quantum effects, we introduce a family of integrators for non-preconditioned path-integral MD exhibiting dimension-free statistical accuracy and efficiency, and enabling a many-fold increase in time-step stability relative to conventional approaches at no additional computational cost or implementation complexity. The integrators come with robust performance guarantees that are borne out in thermostatted ring-polymer MD simulations of realistic condensed-phase models. Concurrently, toward extending the range of accessible timescales in stochastic MD simulations of mesoscale coarse-grained molecular systems, we introduce a parallel-in-time integrator for the overdamped Langevin equation based on McMC evaluation of a path-integral representation of the many time-step stochastic MD transition kernel. The parallel-in-time integrator achieves simultaneous integration of multiple stochastic MD time-steps at no greater wall-time cost and with no lesser accuracy than a standard Euler--Maruyama integrator does in serial, and thus instantiates new opportunities to accelerate stochastic dynamics simulations on massively parallel computer architectures. Our work along these two methodological avenues extends the utility of path space McMC across applications in molecular simulation and has broader implications in other disciplines that require accurate and efficient simulations of Markov diffusion processes in state spaces or path spaces.
", "doi": "10.7907/10jr-hg67", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14566", "collection": "thesis", "collection_id": "14566", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04292022-203100439", "type": "thesis", "title": "Palladium-Catalyzed Cascade Cyclizations in Natural Product Synthesis: Synthetic Studies of Noraugustamine and Falcatin A", "author": [ { "family_name": "Holman", "given_name": "Karli Rose", "orcid": "0000-0001-6424-9479", "clpid": "Holman-Karli-Rose" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Palladium-catalyzed cascade cyclizations present a powerful strategy for the rapid assembly of polycyclic skeletal frameworks, enabling the efficient synthesis of bioactive and structurally complex natural products. Herein, we review the field of palladium-catalyzed cascade cyclizations in natural product synthesis and describe our application of these transformations toward the total syntheses of noraugustamine and falcatin A.
\r\n\r\nOur approach to the Amaryllidaceae alkaloid noraugustamine was driven by the simultaneous disconnection of a C\u2013C and a C\u2013N bond, with the aim of forming both bonds and two of the target\u2019s six rings in a single step. A radical cascade cyclization delivered noraugustamine but displayed poor regioselectivity for 6-exo-trig versus 7-endo-trig cyclization. Improved regioselectivity was achieved using a palladium-catalyzed Heck cyclization, leading to the development of a novel oxidative Heck/aza-Wacker cascade forming both of the desired bonds with good yield and selectivity. This transformation and the general lessons taken from this work should find broad utility in the design of cascade cyclizations toward alkaloids of similar complexity.
\r\n\r\nWe also investigated a palladium-catalyzed carboetherification cascade toward the synthesis of the central five- and seven-membered rings of the myrsinane diterpene falcatin A. In this case, competitive C\u2013O coupling, olefin insertion, and cyclopropanation hindered our efforts to develop the proposed transformation in a simplified model system. A stereoselective bromoetherification and a nickel-catalyzed Nozaki\u2013Hiyama\u2013Kishi reaction were ultimately successful, forming the targeted rings. Efforts to synthesize a fully elaborated cyclization substrate, translate the key steps from the model system, and complete the synthesis of falcatin A are ongoing.
", "doi": "10.7907/9r6z-tw08", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14650", "collection": "thesis", "collection_id": "14650", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05292022-214045444", "primary_object_url": { "basename": "Fastuca_NJ_Thesis2022.pdf", "content": "final", "filesize": 18163287, "license": "other", "mime_type": "application/pdf", "url": "/14650/1/Fastuca_NJ_Thesis2022.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Fragment Coupling Approach To C\u2081\u2089- AND C\u2082\u2080-Diterpenoid Alkaloids: Total Synthesis of (\u2013)-Talatisamine, (\u2013)-Liljestrandisine, and (\u2013)-Liljestrandinine", "author": [ { "family_name": "Fastuca", "given_name": "Nicholas James", "orcid": "0000-0003-4081-6031", "clpid": "Fastuca-Nicholas-James" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "A unified, convergent fragment coupling approach to the C\u2081\u2089- and C\u2082\u2080-diterpenoid alkaloid natural products is presented. The highly-caged aconitine, denudatine, and napelline cores are disconnected through the central B-ring cyclohexane to an A/E/F-ring fragment common to the structures all three subfamilies. 1,2-addition of an appropriate organometallic C/D-bicycle to an A/F-ring hydrindane epoxy ketone fragment followed by a Lewis acid-catalyzed semipinacol reaction couples the two fragments together and sets a key all-carbon quaternary center at C11. This strategy is realized in the synthesis of the C\u2081\u2089-aconitine core by using a [3.2.1]-bicyclooctene C/D-fragment as the nucleophile in the 1,2-addition. This C/D-fragment is prepared using a meta-photocycloaddition; this represents an alternative approach to the commonly employed biomimetic Wagner-Meerwein rearrangement of a [2.2.2]-bicyclooctane.
\r\n\r\nTo complete the aconitine core, a radical cyclization cascade to form the E-ring piperidine and B-ring cyclohexane in a single step is investigated. N-centered radicals were evaluated to initiate the cascade via a 6-exo-trig cyclization. A neutral aminyl radical gave rise to an unexpected Hoffman-L\u00f6ffler-Freytag type product resulting from 1,5-hydrogen atom transfer. Employing Lewis-acidic single electron reducing metal catalyst led to formation of the E-ring cyclized product, however the second cyclization to close the B-ring did not occur.
\r\n\r\nAs an alternative approach, the E-ring was closed via an intramolecular aziridination. Treatment of this aziridine with acetyl bromide results in an aziridine-opened alkyl bromide product. This alkyl bromide is used as a functional group handle to form the final ring of the aconitine core. From there, the total synteheses of the C\u2081\u2089-diterpenoid alkaloids (\u2013)-talatisamine, (\u2013)-liljestrandisine, and (\u2013)-liljestrandinine were completed in short order. These synthetic efforts led to revision of the proposed structure of (\u2013)-liljestrandisine.
", "doi": "10.7907/vf11-jy04", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:14004", "collection": "thesis", "collection_id": "14004", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11192020-190811434", "type": "thesis", "title": "Transition Metal-Catalyzed Enantioselective Alpha Functionalization of Nitrogen and Oxygen-Containing Heterocycles", "author": [ { "family_name": "Jette", "given_name": "Carina Ivonne", "orcid": "0000-0002-8476-6032", "clpid": "Jette-Carina-Ivonne" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "orcid": "0000-0002-0057-7817", "clpid": "Grubbs-R-H" }, { "family_name": "Clemons", "given_name": "William M.", "orcid": "0000-0002-0021-889X", "clpid": "Clemons-W-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Research in the Stoltz group is focused on the development of synthetic methods for the preparation of stereochemically rich molecules and the total synthesis of complex natural products. One major theme of our group\u2019s methods development is transition-metal catalyzed \u03b1-functionalization of carbonyl derivatives, with a particular focus on the development of allylic alkylation protocols. Although the \u03b1-functionalization of carbonyl derivatives such as enolates, has been extensively studied, the use of nitrogen and oxygen- containing heterocycles, such as lactams and lactones, remains under- developed. These types of nucleophiles are significantly more reactive, and in the case of the \u03b3-butyrolactones and \u03b3-lactams, may be smaller in size. Because of these differences, the conditions that have been developed for the functionalization of carbonyl derivatives such as ketones does not translate well to these nucleophiles. Furthermore, within the context of enantioselective functionalization, the unique characteristics of these nucleophiles necessitates the development of large, bulky ligands that enable the formation of a very well-defined chiral environment around the transition metal catalyst. This thesis mainly describes strategies that have been developed for the enantioselective \u03b1-functionalization of nitrogen and oxygen-containing heterocycles, with a particular focus on the \u03b3-lactams and \u03b3-butyrolactones.
", "doi": "10.7907/qs4z-3803", "publication_date": "2021", "thesis_type": "phd", "thesis_year": "2021" }, { "id": "thesis:14221", "collection": "thesis", "collection_id": "14221", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06012021-172201123", "primary_object_url": { "basename": "Allen_Hannah_2021.pdf", "content": "final", "filesize": 8409021, "license": "other", "mime_type": "application/pdf", "url": "/14221/2/Allen_Hannah_2021.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Constraining the Formation and Fate of Hydroperoxides in the Remote Atmosphere", "author": [ { "family_name": "Allen", "given_name": "Hannah Marie", "orcid": "0000-0002-4218-5133", "clpid": "Allen-Hannah-Marie" } ], "thesis_advisor": [ { "family_name": "Wennberg", "given_name": "Paul O.", "orcid": "0000-0002-6126-3854", "clpid": "Wennberg-P-O" } ], "thesis_committee": [ { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" }, { "family_name": "Seinfeld", "given_name": "John H.", "orcid": "0000-0003-1344-4068", "clpid": "Seinfeld-J-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Wennberg", "given_name": "Paul O.", "orcid": "0000-0002-6126-3854", "clpid": "Wennberg-P-O" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Atmospheric hydroperoxides form as second generation products in the atmospheric oxidation of many volatile organic compounds (VOCs) during reactions of these VOCs with OH and HO2 (i.e. HOx), where HOx are among the atmosphere's main oxidants and thus drivers of the majority of atmospheric chemistry. Once formed, the lifetime and ultimate fate of hydroperoxides are set by a variety of potential chemical and physical pathways that have different impacts on the atmosphere's oxidizing capacity, including either recycling HOx or removing HOx. This dissertation explores the role of hydroperoxides with several different structures through field and laboratory studies using CF3O- chemical ionization mass spectrometry (CIMS) to understand the role of these hydroperoxides in the oxidation chemistry of the remote atmosphere.
\r\n\r\nHydrogen peroxide (H2O2) and methyl hydroperoxide (MHP, CH3OOH) are two of the most abundant hydroperoxides found in oceanic environments. Both hydroperoxides were measured using time of flight and tandem quadrupole CIMS aboard the NASA DC-8 aircraft during the Atmospheric Tomography Mission, enabling a seasonal investigation into their global distribution with near pole-to-pole coverage across the Pacific and Atlantic Oceans and ranging in altitude from the marine boundary layer to the upper troposphere and lower stratosphere. Hydroxymethyl hydroperoxide (HMHP, HOCH2OOH) and isoprene hydroxy hydroperoxides (ISOPOOH, HOC5H8OOH) are organic hydroperoxides derived from the oxidation of isoprene, one of the dominant biogenic VOCs in forested environments. The loss of HMHP from the atmosphere via reaction with OH is investigated in the laboratory using time of flight CIMS and laser induced fluorescence along with theoretical chemical modeling methods. To better distinguish the varying roles of structurally complex hydroperoxides, a novel field-deployable gas chromatograph integrated with a high resolution time of flight CIMS is developed that sensitively detects hydroperoxides along with a number of other oxidation products. This instrument is deployed at a rural forested site in northern Michigan during the PROPHET field campaign to probe the relative contribution of different ISOPOOH isomers to the oxidation pathways of isoprene.
", "doi": "10.7907/1108-c936", "publication_date": "2021", "thesis_type": "phd", "thesis_year": "2021" }, { "id": "thesis:14008", "collection": "thesis", "collection_id": "14008", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12022020-190300132", "primary_object_url": { "basename": "Messinger_Thesis_Final.pdf", "content": "final", "filesize": 2576650, "license": "other", "mime_type": "application/pdf", "url": "/14008/1/Messinger_Thesis_Final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Spectroscopy and Kinetics of Atmospheric and Astrochemical Reactions", "author": [ { "family_name": "Messinger", "given_name": "Joseph Peter Herman", "orcid": "0000-0001-7305-3945", "clpid": "Messinger-Joseph-Peter-Herman" } ], "thesis_advisor": [ { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" } ], "thesis_committee": [ { "family_name": "Seinfeld", "given_name": "John H.", "orcid": "0000-0003-1344-4068", "clpid": "Seinfeld-J-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The reactions between reactive radicals and other neutral compounds have long been known to be important in atmospheric chemistry and astrochemistry. This work uses pulsed-laser photolysis cavity ringdown spectroscopy and laser-induced fluorescence to measure the rate constants and branching ratios of chemical reactions over a wide range of temperatures and pressures relevant to both polluted atmospheres, and the interstellar medium. This includes studying the OH + NO\u2082 reaction in the 253 \u2013 333 K range, the reaction of CN with benzene (C\u2086H\u2086) and toluene (C\u2087H\u2088) down to 16 K, and the OH + CO reaction down to 30 K.
", "doi": "10.7907/ak7w-w439", "publication_date": "2021", "thesis_type": "phd", "thesis_year": "2021" }, { "id": "thesis:13863", "collection": "thesis", "collection_id": "13863", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09042020-064530373", "primary_object_url": { "basename": "ArnettCHThesisFinal.pdf", "content": "final", "filesize": 25510727, "license": "other", "mime_type": "application/pdf", "url": "/13863/30/ArnettCHThesisFinal.pdf", "version": "v11.0.0" }, "type": "thesis", "title": "Multimetallic Models of the Nitrogenase Active Site", "author": [ { "family_name": "Arnett", "given_name": "Charles Haden", "orcid": "0000-0002-1272-3797", "clpid": "Arnett-Charles-Haden" } ], "thesis_advisor": [ { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" } ], "thesis_committee": [ { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Motivated by the lack of an atomic-level understanding of the reduction of small molecule substrates by nitrogenase, this dissertation describes the synthesis, characterization and reactivity of well-defined model clusters of the enzyme active site.
\r\n\r\nChapter 2 describes a series of site-differentiated, high spin iron clusters which reversibly bind carbon monoxide in redox states FeII\u2084 through FeIIFeIII\u2083. Detailed spectroscopic and thermochemical studies reveal that this remarkable reactivity can be attributed to the ability of remote metal centers to shuttle reducing equivalents to the small molecule binding site.
\r\n\r\nChapter 3 further explores the consequences of internal electron transfer events on the thermodynamics of small molecule binding by site-differentiated, tetranuclear iron clusters. To systematically tune the electronic properties of the cluster, a Hammett series was prepared. Counterintuitively, introduction of electron-donating substituents suppresses the first CO binding event but enhances the second. Detailed spectroscopic studies revealed that the origin of this behavior can be traced to the effect of the substituents on the redox reorganization energy associated with internal electron transfer.
\r\n\r\nChapter 4 presents the synthesis and characterization of the first open-shell diiron \u00b5-carbyne complex, which also features a biologically relevant Fe(\u00b5-C)(\u00b5-H)Fe core. This electronically unusual species could be activated toward binding of N\u2082 upon addition of H\u207a/e, which initially involves an iron-carbene intermediate.
\r\n\r\nChapter 5 describes the synthesis and spectroscopic investigation of the first carbonbridged, bimetallic complexes featuring odd numbers of valence electrons as spectroscopic models of the critical E\u2084(4H) intermediate of nitrogenase. Detailed pulse EPR studies revealed the effects of electronic localization on the spectroscopic signatures of the \u00b5-hydride motif and provide insight into the electronic distribution in a reduced state of FeMoco.
\r\n\r\nChapter 6 describes the synthesis and characterization of terminal iron-carbene complexes, including EPR characterization of open-shell variants.
\r\n\r\nAppendix A describes unpublished efforts to prepared site-differentiated models of FeMoco featuring carbon- or sulfur-based donors.
\r\n\r\nAppendix B presents unpublished work towards modelling the cooperative activation and reduction of N\u2082 by diiron complexes featuring carbon-based bridging ligands.
", "doi": "10.7907/fgje-ns05", "publication_date": "2021", "thesis_type": "phd", "thesis_year": "2021" }, { "id": "thesis:13847", "collection": "thesis", "collection_id": "13847", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08052020-191152340", "primary_object_url": { "basename": "CER Thesis Final with Revisions.pdf", "content": "final", "filesize": 53065561, "license": "other", "mime_type": "application/pdf", "url": "/13847/13/CER Thesis Final with Revisions.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Convergent Synthetic Strategies toward Heterodimeric Bisindole Alkaloids and Polyoxygenated Diterpenoids", "author": [ { "family_name": "Reimann", "given_name": "Christopher Elias", "orcid": "0000-0003-3274-7590", "clpid": "Reimann-Christopher-Elias" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Ondrus", "given_name": "Alison E.", "orcid": "0000-0002-6023-3290", "clpid": "Ondrus-A-E" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Described herein are two projects in the field of natural product synthesis unified by their use of convergent strategies. An introduction into a relevant subclass of natural products, the bis(monoterpenoid) indole alkaloids, precedes our synthetic efforts. The molecules in this class are comprised of two monoterpenoid indole alkaloids conjoined by at least one carbon\u2013carbon bond, and we review efforts to construct these dimers using semi-, partial, and total synthesis.
\r\n\r\nThe account of our synthetic work begins with a detailed approach to the bis(monoterpenoid) indole alkaloid leucophyllidine. An enantioselective Pd-catalyzed decarboxylative allylic alkylation generates an \u03b1-quaternary-substituted lactam, which serves as a building block for both monomeric subunits. The northern fragment, eburnamonine, is constructed through a five-step sequence comprised of Fischer indole synthesis, Bischler\u2013Napieralski cyclization, and diastereoselective hydrogenation. The southern fragment, eucophylline, is constructed through a ten-step formal synthesis comprised of a Friedla\u0308nder quinoline synthesis, followed by two orthogonal C\u2013H functionalizations that each displayed unexpected reactivity.
\r\n\r\nWe then describe the evolution of a convergent coupling strategy to unify the two polycyclic fragments. While the \"biomimetic\" Friedel\u2013Crafts and \"bio-inspired\" organometallic addition approaches failed, a Pd-catalyzed cross-coupling was ultimately successful in forging the key C\u2013C bond. Extensive efforts to install the final stereogenic center with a variety of reducing agents were unsuccessful, and DFT modeling was utilized to probe the recalcitrant nature of the trisubstituted alkene. Preliminary investigations of a directed hydrogenation are then discussed.
\r\n\r\nFinally, we report an approach to the first total synthesis of the polyoxygenated diterpenoid (\u2013)-scabrolide A. The route begins with the synthesis of an enantioenriched cyclopentendiol building block and an acyclic diyne from (R)-linalool and (R)-carvone, respectively. A Stieglich esterification and thermal [4+2] cycloaddition affords a tricylic intermediate bearing all 19 carbons observed in the natural product. The cycloheptenoid motif is installed through a photochemical [2+2]/fragmentation sequence, exploiting an unusual alkene protecting group strategy to counteract unexpected reactivity.
", "doi": "10.7907/j1y9-g269", "publication_date": "2021", "thesis_type": "phd", "thesis_year": "2021" }, { "id": "thesis:14104", "collection": "thesis", "collection_id": "14104", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03122021-181842560", "primary_object_url": { "basename": "FN-thesis-final-ORCID.pdf", "content": "final", "filesize": 79313878, "license": "other", "mime_type": "application/pdf", "url": "/14104/1/FN-thesis-final-ORCID.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "I. Development of Nickel- and Palladium-Catalyzed Asymmetric Allylic Alkylation Reactions. II. Enantioselective Syntheses of Tetrahydroisoquinoline\u2013Based Natural Products and Unnatural Analogs", "author": [ { "family_name": "Ngamnithiporn", "given_name": "Aurapat Fa", "orcid": "0000-0002-5389-8171", "clpid": "Ngamnithiporn-Aurapat-Fa" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "orcid": "0000-0002-0057-7817", "clpid": "Grubbs-R-H" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Described in this thesis are four projects related to the development of synthetic methodologies for the preparation of enantioenriched building blocks, and the total syntheses of complex tetrahydroisoquinoline natural products. In Chapter 1, the development of nickel-catalyzed asymmetric allylic alkylation of lactones and lactams with allylic alcohols is presented. In Chapter 2, the development of palladium-catalyzed enantioselective decarboxylative allylic alkylation of silicon-containing heterocycles is detailed. In these chapters, the utilization of prochiral enolates as nucleophiles has enabled access to enantioenriched all-carbon quaternary stereocenters.
\r\n\r\nChapter 3 describes the total syntheses of bis-tetrahydroisoquinoline alkaloids, \r\n(\u2013)-jorumycin and (\u2013)-jorunnamycin A. A general synthetic strategy, which exploits the tandem cross-coupling/hydrogenation approach, represents the first non-biomimetic synthetic route and allows for an efficient construction of the pentacyclic core in a highly modular fashion. Additional bis-tetrahydroisoquinoline analogs were prepared, and preliminary studies to probe their cytotoxicity against cancer cell lines were conducted. Finally, an extension of the enantioselective and diastereoselective hydrogenation technology to include simple 1,3-disubstituted isoquinolines is described in Chapter 4.
", "doi": "10.7907/999q-qm11", "publication_date": "2021", "thesis_type": "phd", "thesis_year": "2021" }, { "id": "thesis:13674", "collection": "thesis", "collection_id": "13674", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04132020-174738338", "primary_object_url": { "basename": "DPS Thesis Draft 2.pdf", "content": "final", "filesize": 32739606, "license": "other", "mime_type": "application/pdf", "url": "/13674/1/DPS Thesis Draft 2.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Development and Mechanistic Investigation of Potassium Tert-Butoxide Catalyzed C\u2013H Silylation", "author": [ { "family_name": "Schuman", "given_name": "David Phillip", "clpid": "Schuman-David-Phillip" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The synthetic organic community has a long history of concurrent development of new methods, total syntheses, and mechanistic investigations. For example, new methods may allow the synthesis of previously inaccessible synthetic targets or a challenging transformation in a total synthesis may lead to the development of new reaction methods. Understanding the mechanism of a reaction may lead to the development of new methods or application in total synthesis. Historically, the Stoltz group has found great success focusing on the synergistic development of reaction methods, total synthesis, and mechanistic investigation. This thesis focuses on the mechanistic investigation of a novel method developed by our group and a number of new methods inspired by this better understanding of the reaction mechanism.
\r\n\r\nInitially, an overview of transition-metal-free, catalytic C\u2013H silylation reactions is presented. Next, a detailed mechanistic investigation into the KOt-Bu-catalyzed C\u2013H silylation reaction of aromatic heterocycles is presented. This investigation covers a series of experimental, computational, and analytic techniques to probe possible radical or ionic reaction mechanisms. The development of a number of new methods is presented including the catalytic trimethylsilylation of aromatic heterocycles and catalytic silylation of terminal alkynes.
\r\n\r\nFinally, the current progress of our efforts toward the total synthesis of the natural product illisimonin A are presented.
", "doi": "10.7907/248y-cp18", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:13665", "collection": "thesis", "collection_id": "13665", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03272020-105741489", "primary_object_url": { "basename": "THESIS TOC.pdf", "content": "final", "filesize": 196018, "license": "other", "mime_type": "application/pdf", "url": "/13665/15/THESIS TOC.pdf", "version": "v12.0.0" }, "type": "thesis", "title": "Evolving Strategies Toward the Synthesis of Curcusone C", "author": [ { "family_name": "Wright", "given_name": "Austin Cameron", "clpid": "Wright-Austin-Cameron" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Ondrus", "given_name": "Alison E.", "clpid": "Ondrus-A-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Curcusone C is a tricyclic diterpenoid natural product possessing potent anti-cancer activities as well as a structurally unusual 2,3,7,8-tetrahydroazulene-1,4-dione skeleton. Herein, we report our evolving synthetic efforts toward the divergent total syntheses of ent-curcusone C and several structural congeners, which commenced with a Suzuki coupling of the peripheral carbon-based rings. Whereas the boronate partner was constructed from cyclopentenone, the halide partner could be elaborated from (S)-perillaldehyde. The alcohol coupling product was next esterified, then subjected to diazo transfer and cyclopropanation to produce a lactone. The resulting vinyl cyclopropane moiety was exposed to Kauffmann olefination conditions in order to form a divinylcyclopropane, which upon reductive lactone opening smoothly underwent a Cope rearrangement to establish the essential tricyclic core embedded in the curcusones.
\r\n\r\nDue to ongoing issues of scalability as well as unsatisfactory yields for the key cyclopropanation step, this route was ultimately abandoned, and an alternative strategy was devised which instead relied on a cross-electrophile coupling to join the peripheral rings. We further found that a central ring could be constructed via either Stetter annulation or ring-closing metathesis (RCM), accessing the tricyclic core of the curcusones in only 9 steps. Potential end-game strategies are further described.
\r\n\r\nWe additionally report our experimental research into the acyl-amination of in situ-generated arynes using symmetrical imides. The difunctionalized aryl products could be further derivatized to synthetically useful indoles and quinolones via McMurray coupling and Camps cyclization, respectively.
\r\n", "doi": "10.7907/6FET-N212", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:13697", "collection": "thesis", "collection_id": "13697", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05052020-172131873", "primary_object_url": { "basename": "[FINAL]SSFThesis_Compiled.pdf", "content": "final", "filesize": 11556184, "license": "other", "mime_type": "application/pdf", "url": "/13697/1/[FINAL]SSFThesis_Compiled.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Development of a Modular Strategy Towards the Total Synthesis of (+)-Pleuromutilin and Progress Towards the Synthesis of (\u2013)-Merrilactone A", "author": [ { "family_name": "Feng", "given_name": "Sean S. L.", "orcid": "0000-0002-8095-6402", "clpid": "Feng-Sean-S-L" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Natural products have long stood as a rich source of biologically relevant molecules bearing highly functionalized and complex architectures. On one hand, they are a focal point for the development of new therapeutic agents owing to their inherent biological activities. On the other, they serve as an exciting testing ground for existing synthetic methodologies and provide opportunities for the development of new reactions.
\r\n\r\nHerein, we describe a modular strategy that was employed for the total synthesis of the antibiotic (+)-pleuromutilin. Key features of our synthesis include (1) the development of a highly stereoselective SmI\u2082-mediated ketyl radical cyclization to establish the central eight-membered ring and (2) a modular crotylation reaction to install the eight-membered ring\u2019s backbone that permits full control over the stereochemistry at C12 as desired. During our synthetic studies, a transannular [1,5]-hydrogen atom transfer reaction that affects a stereospecific redox relay to set the C10 stereocenter was serendipitously uncovered. This strategy enabled the completion of a concise total synthesis of (+)-pleuromutilin, proceeding in 18 steps. To demonstrate the modularity of our synthetic approach, the same strategy was readily applied to the synthesis of (+)-12-epi-pleuromutilin with no reoptimization, providing a new platform for the preparation of fully synthetic derivatives that may hold promise as broad-spectrum antibiotics.
\r\n\r\nThis report also highlights the work we have conducted in the development of a synthetic strategy towards (\u2013)-merrilactone A. We detail our investigation of a Pd-catalyzed asymmetric allylic alkylation reaction that rapidly constructs the D-ring bearing the C5 and C6 vicinal quaternary centers. Potential paths forward to complete the synthesis of this neurotropic natural product leveraging this advanced intermediate will also be discussed.
", "doi": "10.7907/chfe-0q83", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:11757", "collection": "thesis", "collection_id": "11757", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08012019-192629717", "type": "thesis", "title": "Investigation of Ethylene Tetramerization Catalysis from Structurally-Defined Organochromium Compounds", "author": [ { "family_name": "Hirscher", "given_name": "Nathanael Allen", "clpid": "Hirscher-Nathanael-Allen" } ], "thesis_advisor": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" } ], "thesis_committee": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Chapter 1 is a general introduction to the topic of ethylene tetramerization catalysis.
\r\n\r\nChapter 2 presents the synthesis and catalytic utility of chromium multi-aryl complexes that were the first examples of ethylene tetramerization catalysts that could be produced without excess alkyl aluminum reagents.
\r\n\r\nChapter 3 describes the mechanistic analysis of the ethylene tetramerization reaction using isotopically labelled ethylene. Co-production of 1-hexene along with 1-octene was determined to be intrinsic to the reaction mechanism. This is due to the intermediacy of a chromacyclic species that can either eliminate 1-hexene or insert a fourth ethylene.
\r\n\r\nChapter 4 presents the synthesis of additional Cr tris(aryl) complexes, which are coordinatively saturated, and were used to generate a crystallographically-characterized Cr(III) cationic species. This was the first reported single-component precatalyst for ethylene tetramerization.
\r\n\r\nChapter 5 describes the isotopic labelling of a well-defined ethylene tetramerization precatalyst with a deuteriomethyl group. This label was tracked following protonation of the neutral Cr complex via pulse EPR. Successful detection of deuterium on Cr-alkyl ligands led to in situ analysis of the catalytic mixture. A low-spin species derived from deuterated ethylene was observed.
\r\n\r\nAppendix 1 describes the synthesis of various Cr aryl amine complexes. Appendix 2 provides the results of additional catalytic experiments for ethylene tetramerization, including those with a more soluble precatalyst, and those at higher ethylene pressure. Appendix 3 details the synthesis of a molecular Re catalyst for CO2 electroreduction which was used to modify electrodes. Appendix 4 lists various X-ray crystal structures that were obtained, but not related elsewhere in the thesis.
", "doi": "10.7907/GVYR-MV95", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:13779", "collection": "thesis", "collection_id": "13779", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06042020-213305750", "type": "thesis", "title": "Synthesis of Enantioenriched (Poly)Fluorinated Building Blocks, 2,2-Disubstituted Pyrrolidines and [7,7]Paracyclophanes", "author": [ { "family_name": "Goldstein", "given_name": "Elizabeth Lee", "orcid": "0000-0002-2208-6090", "clpid": "Goldstein-Elizabeth-Lee" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Stoltz group, and moreover the synthetic community at large, has long been interested in the synthesis of enantioenriched compounds with interesting biological activities. This thesis presents three projects unified in an attempt to access compounds with relevance to the medicinal chemistry and natural products communities, encompassing reaction development, synthetic strategy and natural product synthesis.
\r\n\r\nA general method for the enantioselective synthesis of carbo- and heterocyclic carbonyl compounds bearing fluorinated \u03b1-tetrasubstituted stereocenters using palladium-catalyzed allylic alkylation is described. These fluorinated, stereochemically rich building blocks hold potential value in medicinal chemistry and are prepared using an orthogonal and enantioselective approach into such chiral moieties compared to traditional approaches, often without the use of electrophilic fluorinating reagents.
\r\n\r\nThe synthesis of a variety of enantioenriched 2,2-disubstituted pyrrolidines is described. A stereogenic quaternary center is first formed utilizing an asymmetric allylic alkylation reaction of a benzyloxy imide, which can then be reduced to a chiral hydroxamic acid. This compound can then undergo a thermal \"Spino\" ring contraction to afford a carbamate protected 2,2-disubstituted pyrrolidine stereospecifically, allowing access to new molecules that could be useful in the medicinal chemistry community.
\r\n\r\nFinally, we have developed a synthesis of an enaptioenriched [7,7]paracyclophane compound using sequential C-H functionalization reactions, including selective Rh-catalyzed C-H insertion reactions developed by the Davies group at Emory University. Investigations are currently ongoing into potential antimicrobial activity of different [7,7]paracyclophanes and the total synthesis of naturally occurring [7,7]paracyclophanes.
", "doi": "10.7907/hks0-tg22", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:13760", "collection": "thesis", "collection_id": "13760", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06012020-135910044", "primary_object_url": { "basename": "ZAS-Full_Thesis-FinalVersion.pdf", "content": "final", "filesize": 13719154, "license": "other", "mime_type": "application/pdf", "url": "/13760/22/ZAS-Full_Thesis-FinalVersion.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "C(sp\u00b3)\u2013H Activation via Dehydrogenation of Cyclic and Heterocyclic Alkanes by Single-Site Iridium Pincer Ligated Complexes", "author": [ { "family_name": "Al-Saihati", "given_name": "Zainab Ahmed", "orcid": "0000-0002-3837-9736", "clpid": "Al-Saihati-Zainab-Ahmed" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The direct dehydroaromatization of C(sp\u00b3)\u2013H alkanes may seem conceptually simple but in fact is a challenging transformation. Industrially practiced methods utilize energy intensive processes operating at high pressures and temperatures due to the requirement of such conditions to overcome the endergonic and unreactive nature of alkanes. Chapter 1 briefly discusses early and recent achievements in the field of alkanes dehydrogenation by Ir pincer ligated complexes. While there has been great advancement in the dehydrogenation transformation recently, the direct dehydroaromatization of heterocyclic substrates generating functionalized aromatics is significantly underdeveloped. In Chapter 2, we successfully extended the applicability of Ir catalyzed dehydrogenation systems using pincer ligated complexes on a diverse collection of heterocyclic alkanes with functionalities known to be strongly coordinating and poorly compatible with (PCP)\u2013Ir type catalysts. Carbo- and heteroarenes containing oxygen and nitrogen can be synthesized in moderate to excellent yields up to 99%, and the reaction tolerates functional groups such as bromides and fluorides. In Chapter 3, we demonstrate the efficient disproportionation of cycloalkenes to the corresponding arenes and cycloalkanes with up to 100% conversion, which has been a long-standing challenge in the field of pincer-ligated Ir-catalyzed dehydrogenation studies. For example, 1-cyclohexene was disproportionated to benzene and cyclohexane and 1-4-vinyl-1-cyclohexene was disproportionated to ethylbenzene and ethylcyclohexane. We also demonstrate that a key mechanistic feature of our system is a lack of catalyst inhibition by arenes. In addition, our method is advantageous to previous reports as no sacrificial olefin is used, thereby circumventing the requirement for exogeneous hydrogen acceptors. Our studies presented in Chapter 2 and Chapter 3 provides a novel and a complementary pathway to access important aromatic building blocks and may help create alternative routes to complex molecules via late stage dehydrogenation without the need of stoichiometric oxidants.", "doi": "10.7907/tsge-5m91", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:13716", "collection": "thesis", "collection_id": "13716", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05222020-215559562", "primary_object_url": { "basename": "Alexy thesis v3.pdf", "content": "final", "filesize": 112044799, "license": "other", "mime_type": "application/pdf", "url": "/13716/1/Alexy thesis v3.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Development of Enantioselective Transition-Metal Catalyzed Allylic Alkylation Methodologies", "author": [ { "family_name": "Alexy", "given_name": "Eric John", "orcid": "0000-0002-2971-9698", "clpid": "Alexy-Eric-John" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Research in the Stoltz group is directed, generally, at the development of synthetic methods for the preparation of stereochemically rich molecules, and the total synthesis of complex natural products. One major theme of our group\u2019s methods development is transition-metal catalyzed allylic alkylation, of which we have reported Pd, Ir, Cu, and Ni catalyzed strategies. Described in this thesis are projects related to these interests, primarily focused on new approaches toward acyclic stereocenters via palladium catalysis; however also include an iridium-catalyzed formal \u03b3-alkylation of malonates and \u03b2-ketoesters, as well as an Overman rearrangement strategy for synthesizing \u03b1-amino ketones. A majority of asymmetric enolate functionalization methods, developed by our group and others, pertain to cyclic systems in which only one enolate geometry isomer is possible due to the constrained ring. In acyclic systems, however, this issue of enolate geometry becomes a major challenge that must be addressed. When one seeks to prepare a tetrasubstituted acyclic enolate, which would lead to a fully-substituted stereocenter following functionalization, one must contend with the issue of non-selective formation of a mixture of enolates which generally leads toward less selective transformations. Strategies toward overcoming this issue, as well as new insights gained regarding the palladium-catalyzed alkylation of acyclic enolates, are described in the subsequent chapters.
", "doi": "10.7907/41nh-wb31", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:13581", "collection": "thesis", "collection_id": "13581", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11202019-023320724", "primary_object_url": { "basename": "Jiaming-Li-Thesis-2019-Final.pdf", "content": "final", "filesize": 13929327, "license": "other", "mime_type": "application/pdf", "url": "/13581/1/Jiaming-Li-Thesis-2019-Final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Concise Total Syntheses of \u2206\u00b9\u00b2-Prostaglandin J Natural Products Using Stereoretentive Metathesis", "author": [ { "family_name": "Li", "given_name": "Jiaming", "orcid": "0000-0001-6646-5693", "clpid": "Li-Jiaming" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "\u2206\u00b9\u00b2-Prostaglandin J family is a type of secondary metabolite isolated in cell culture, and is recently discovered to have potent anticancer activity. Concise syntheses of four \u2206\u00b9\u00b2-prostaglandin J natural products (7\u20138 steps in the longest linear sequences) are developed, enabled by convergent stereoretentive cross-metathesis by Ru-based metathesis catalyst. Exceptional control of alkene geometry was achieved through stereoretention.
", "doi": "10.7907/Q78K-7R18", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:11594", "collection": "thesis", "collection_id": "11594", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06012019-034543690", "primary_object_url": { "basename": "Hofstra_Thesis_2019_Final.pdf", "content": "final", "filesize": 30604704, "license": "other", "mime_type": "application/pdf", "url": "/11594/1/Hofstra_Thesis_2019_Final.pdf", "version": "v9.0.0" }, "type": "thesis", "title": "Development and Mechanistic Studies of Ni-Catalyzed Asymmetric Reductive Cross-Coupling Reactions", "author": [ { "family_name": "Hofstra", "given_name": "Julie Lyn", "orcid": "0000-0001-9558-4317", "clpid": "Hofstra-Julie-Lyn" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Cross-coupling reactions have emerged as powerful methods to form carbon-carbon and carbon-heteroatom bonds in a vast array of synthetic contexts. Nickel-catalyzed reductive cross-coupling reactions have opened up a new mode of reactivity, allowing for the cross-coupling of bench-stable electrophiles as both coupling partners. Asymmetric variants, which use a chiral ligand, increase molecular complexity by introducing stereocenters with high levels of enantioselectivity. Application of this methodology to an array of electrophiles has led to the development of a number of transformations incorporating both C(sp2)-hybridized electrophiles (aryl iodides, alkenyl bromides, and acyl chlorides) and C(sp3)-hybridized electrophiles (benzyl chlorides and \u03b1-chloronitriles).
\r\n\r\nHerein we discuss our most recent efforts in the development and application of Ni-catalyzed asymmetric cross-coupling reactions with alkenyl electrophiles. First, the expansion of our previously developed methodology has allowed for bulky trimethylsilyl groups on the benzyl chloride electrophile, providing chiral allylic silane products in good yield and enantioselectivity. The utility of these products with both traditional and newly developed methodology is highlighted. Following this, we describe the development of reaction conditions that proceed with benzyl N-hydroxyphthalimide esters. This approach proceeds through a decarboxylative strategy, generates previously accessible radical intermediates, and proceeds with the use of a homogenous reductant. Our investigations into the mechanism on the cross-coupling of alkenyl bromides and benzyl chlorides is also disclosed, where we first identified the formation of alkenyl chloride and alkenyl iodide intermediates under the reaction conditions. This inspired us to develop a Ni-catalyzed alkenyl triflate halogenation in order to prepare alkenyl halide synthetic intermediates.
", "doi": "10.7907/G8M3-CQ05", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11419", "collection": "thesis", "collection_id": "11419", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03102019-234035587", "type": "thesis", "title": "Engineering Heme Proteins for Olefin and Carbon\u2212Hydrogen Bond Functionalization Reactions", "author": [ { "family_name": "Zhang", "given_name": "Ruijie", "orcid": "0000-0002-7251-5527", "clpid": "Zhang-Ruijie" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Shan", "given_name": "Shu-ou", "orcid": "0000-0002-6526-1733", "clpid": "Shan-Shu-ou" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "local_group": [ { "literal": "Rosen Bioengineering Center" }, { "literal": "div_chem" } ], "abstract": "One of the most important challenges in chemistry is the creation of new catalysts. Nature excels at this: constructed from biologically available elements, enzymes are versatile catalysts which adapt quickly to changing environments in order to sustain life. The combination of adaptable proteins with abiological reagents from synthetic chemistry affords a new direction for catalyst development. This thesis describes new enzymes, derived from a cytochrome P450 monooxygenase, which catalyze nitrogen and carbon atom transfer reactions to olefins and carbon\u2212hydrogen bonds. Chapter 1 introduces directed evolution, a strategy for the laboratory optimization of proteins, in the context of improving metalloproteins for their native catalysis or for new reactions. Chapter 2 details the development of an enzyme-catalyzed transformation of olefins to aziridines, a valuable motif which is both present in bioactive molecules and used as a versatile building block for synthesis. This study establishes that when provided the appropriate reagents (e.g. styrenes and tosyl azide), heme proteins can adopt a nitrene transfer catalytic cycle to form aziridine products and that the turnover and selectivity of the catalyst can be optimized through mutation of its amino acid sequence. The activity of heme protein catalysts is extended to the functionalization of sp3 hybridized C\u2212H bonds for carbon\u2013nitrogen and carbon\u2013carbon bond formation through nitrene and carbene insertion respectively (Chapters 3 and 4). With the exception of C\u2212H oxygenation chemistry, iron complexes are under-utilized for sp3 C\u2212H functionalization reactions, despite iron being readily available and non-toxic. Combining previously engineered heme proteins with suitable substrates led to initial reaction discovery. Directed evolution of these enzymes significantly improved their C\u2212H functionalization activity (by 140-fold in Chapter 4). Characterization of evolved enzymes, including the attainment of an X-ray crystal structure (Chapter 3) and substrate scope studies (Chapters 3 and 4), were pursued. In sum, the thesis work addresses both the biological question of expanding the catalytic capabilities of existing enzymes through mutation and expands the chemistry of iron-porphyrin catalysts.", "doi": "10.7907/2076-CX23", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11342", "collection": "thesis", "collection_id": "11342", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:01152019-115519988", "primary_object_url": { "basename": "Grunenfelder_Denise_Thesis.pdf", "content": "final", "filesize": 55618042, "license": "other", "mime_type": "application/pdf", "url": "/11342/1/Grunenfelder_Denise_Thesis.pdf", "version": "v12.0.0" }, "type": "thesis", "title": "Synthetic Strategies for the Total Synthesis of Acutumine Alkaloids and the Development of Radical Deoxychlorination Reactions", "author": [ { "family_name": "Gr\u00fcnenfelder", "given_name": "Denise Christine", "orcid": "0000-0002-0334-2167", "clpid": "Gr\u00fcnenfelder-Denise-Christine" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The acutumine alkaloids are a family of architecturally complex propellane natural products with promising medicinal properties. Herein, we disclose the continued development of a synthetic strategy toward the asymmetric total synthesis of acutumine alkaloids. The spirocyclic scaffold was synthesized in two new series, which follow our successful access to the dechloroacutumine core in 2013. Central to the synthetic design is the retro-aldol/Dieckmann cyclization of a cyclobutyl lactone to install the spirocycle. The key cyclobutane intermediate is obtained via a photo-mediated [2+2]-cycloaddition of a furanyl dihydroindolone, which is accessible via a stereoselective 1,2-addition/reductive cyclization sequence of a benzoquinone-derived imine. Installation of the dimethoxyenone motif is accomplished via a late-stage elimination of a dimethoxyketal, which furnished the requisite vinylogous ester after methylation. Overall, these efforts have culminated in the synthesis of the complete carbocyclic core and oxidation pattern of the natural product (\u2013)-acutuminine, with a C10 neopentyl alcohol in place of the neopentyl chloride.
\r\n\r\nTen of the known acutumine alkaloids contain a neopentyl chloride; this motif provided underlying motivation for the development of novel radical deoxychlorination reactions, including the chlorination of cesium oxalates. This reaction allows access to hindered 2\u00b0 and 3\u00b0 alkyl chlorides, provides complementary reactivity to standard heterolytic conditions, and is performed under mild conditions using visible light and ethyl trichloroacetate as a Cl\u2022 source. Application to deoxybromination and deoxyfluorination is also demonstrated, showcasing the versatility of the discovered halogenation. This method should find broad utility in the deoxyhalogenation of hindered alcohols, particularly in the pharmaceutical industry where selective installation of fluorides is a common challenge.
", "doi": "10.7907/FS86-HB55", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11513", "collection": "thesis", "collection_id": "11513", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05132019-140157302", "type": "thesis", "title": "Stereoselective Synthesis of Diazaheterocycles by Decarboxylative Asymmetric Allylic Alkylation", "author": [ { "family_name": "Sun", "given_name": "Alexander Wang", "orcid": "0000-0001-6639-4469", "clpid": "Sun-Alexander-Wang" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Stoltz group has developed transition-metal catalyzed methods to synthesize quaternary and tetrasubstituted stereocenters over the past fourteen years. Using iridium, palladium, copper, and nickel, the group has synthesized a myriad cyclic and acylic quaternary motifs of incredible synthetic and medicinal utility. This thesis presents several projects that further expand the scope of Pd-catalyzed decarboxylative allylic alkylation and examine its applications to the synthesis of medicinally important small molecules. The synthesis of chiral gem-disubstituted five-, six-, and seven-membered diazaheterocycles is presented. Their utility as building blocks for complex medicinal compounds is highlighted. Then, we explore the utility of gem-disubstituted heterocycles in the context of medicinal chemistry.
", "doi": "10.7907/E2YS-GJ06", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11510", "collection": "thesis", "collection_id": "11510", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05132019-092701701", "type": "thesis", "title": "Applications of the Enantioselective Allylic Alkylation Toward the Synthesis of Complex Natural Products", "author": [ { "family_name": "Loskot", "given_name": "Steven Anthony", "clpid": "Loskot-Steven-Anthony" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Stoltz group, and moreover the synthetic community at large, has long been interested in the development of methods for the synthesis of enantioenriched all-carbon quaternary stereocenters. This thesis present three projects all unified by the development and use of the palladium-catalyzed decarboxylative allylic alkylation to synthesize enantioenriched all-carbon quaternary stereocenter containing cyclopentanones as well as the natural product total synthesis.
", "doi": "10.7907/TZHG-9B35", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11692", "collection": "thesis", "collection_id": "11692", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06052019-172451535", "primary_object_url": { "basename": "Rusty_Thesis_Final.pdf", "content": "final", "filesize": 21140108, "license": "other", "mime_type": "application/pdf", "url": "/11692/1/Rusty_Thesis_Final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Evolution and Characterization of Carbene Transferases for Cyclopropanation and Carbon\u2013Silicon Bond Formation", "author": [ { "family_name": "Lewis", "given_name": "Russell DeRieux", "orcid": "0000-0002-5776-7347", "clpid": "Lewis-Russell-DeRieux" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Shapiro", "given_name": "Mikhail G.", "orcid": "0000-0002-0291-4215", "clpid": "Shapiro-M-G" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "orcid": "0000-0003-1464-2461", "clpid": "Dougherty-D-A" }, { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "local_group": [ { "literal": "div_bbe" } ], "abstract": "Heme proteins have recently been demonstrated to catalyze cyclopropanation reactions via a putative carbene transfer mechanism. Carbene transfer reactions are not known to occur in natural biological systems, but are highly useful synthetic reactions. There is growing interest in developing new \"carbene transferases\" that bring new chemical reactions into the realm of biology, and growing interest in engineering these enzymes for use in organic synthesis. Additionally, the mechanistic details of iron porphyrin-catalyzed carbene transfer reactions are largely unknown, especially with regards to how the enzyme environment influences the outcome of a carbene transfer reaction. This thesis details both the engineering of carbene transferases with novel catalytic capabilities and investigations into how these enzymes catalyze carbene transfer reactions. Chapter 1 introduces heme protein-catalyzed carbene transfer reactions and describes the directed evolution of new enzymes that allow access to a range of useful cyclopropane products. Chapter 2 describes the evolution of an enzyme that performs carbene transfer to silicon\u2013hydrogen bonds, resulting in a highly efficient and selective carbon\u2013silicon bond-forming enzyme, the first of its kind. Chapter 3 focuses on the characterization of a key reactive intermediate, the iron-porphyrin carbene, in the active site of the evolved carbon\u2013silicon bond-forming enzyme. This study provides an explanation of the remarkable enantioselectivity of the enzyme and provides a foundation from which to investigate the enzyme reaction mechanism. The mechanism of carbon\u2013 silicon bond formation is elucidated in Chapter 4, and the is then used to explain how the enzyme achieves chemoselectivity, which in turn guides the evolution of enzyme variants with altered chemoselectivity. Finally, two off-cycle catalytic pathways that cause inactivation of the carbene transferase are characterized, and methods to prevent and/or circumvent inactivation are investigated (Chapter 5). Overall, the work presented here expands the repertoire of enzyme-catalyzed reactions and facilitates the continuing development of new carbene transferases by developing our mechanistic understanding of this novel class of enzymes.
", "doi": "10.7907/RMEX-Q134", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11606", "collection": "thesis", "collection_id": "11606", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06022019-233820328", "type": "thesis", "title": "The Development of a Synthetic Strategy Toward Oxazine-Containing Natural Products Enabled by Novel Copper Catalysis", "author": [ { "family_name": "Cowper", "given_name": "Nicholas Glenn William", "clpid": "Cowper-Nicholas-Glenn-William" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "1,2-oxazine natural products are a small closely related family of highly oxidized compounds. Herein, the development of a synthetic strategy toward gliovirin and the trichodermamides is described which enabled the synthesis of the western fragments of gliovirin and trichodermamide B. To that end, we developed two novel copper-catalyzed transformations:the asymmetric propargylation of an oxime and the diasteroeselective oxidative cyclization of hydroxamic acid with a diene.
\r\n\r\nThe challenge of working with tetrahydro-1,2-oxazines is their sensitivity to a variety of reaction conditions and purification methods. Extensive optimization of each transformation was accomplished, bringing to bear the state-of-the-art in oxidative modifications, including a palladium-catalyzed direct desaturation of an epoxy ketone. As well as this work led to the rare observation of a vinylogous Payne rearrangement.
\r\n\r\nThe successful synthesis of the fully functionalized western and eastern fragments of gliovirin are described toward a late-stage diketopiperazine formation and thiolation. Interrogation of our late-stage strategy with these fragments demonstrates that the coupling of the fully functionalized western and eastern fragments is not an effective strategy toward gliovirin proof-of-concept experiments suggest this chemistry could be used toward the synthesis of the trichodermamides.
", "doi": "10.7907/Y9WZ-TZ31", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11745", "collection": "thesis", "collection_id": "11745", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:07202019-210018604", "type": "thesis", "title": "Coupled Cluster Green's Functions for Periodic Systems: Ab-Inito Computation and Applications", "author": [ { "family_name": "Yu", "given_name": "Jason Miao", "orcid": "0000-0002-2270-6798", "clpid": "Yu-Jason-Miao" } ], "thesis_advisor": [ { "family_name": "Chan", "given_name": "Garnet K.", "orcid": "0000-0001-8009-6038", "clpid": "Chan-Garnet-K-L" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Chan", "given_name": "Garnet K.", "orcid": "0000-0001-8009-6038", "clpid": "Chan-Garnet-K-L" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Coupled Cluster Green\u2019s function method is expanded to periodic systems and preliminary results of the spectral function for diamond and graphene are shown. Future improvements and potential applications are discussed.
", "doi": "10.7907/0P9H-ZQ15", "publication_date": "2019", "thesis_type": "masters", "thesis_year": "2019" }, { "id": "thesis:11732", "collection": "thesis", "collection_id": "11732", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06102019-013016109", "primary_object_url": { "basename": "SmarteMatthewDavid_thesis2019.pdf", "content": "final", "filesize": 11302764, "license": "other", "mime_type": "application/pdf", "url": "/11732/1/SmarteMatthewDavid_thesis2019.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Kinetic and Spectroscopic Studies of Atmospheric Intermediates", "author": [ { "family_name": "Smarte", "given_name": "Matthew David", "orcid": "0000-0002-4835-7880", "clpid": "Smarte-Matthew-David" } ], "thesis_advisor": [ { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" } ], "thesis_committee": [ { "family_name": "Marcus", "given_name": "Rudolph A.", "clpid": "Marcus-R-A" }, { "family_name": "Wennberg", "given_name": "Paul O.", "clpid": "Wennberg-P-O" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Atmospheric chemistry investigates the chemical transformations of atmospheric trace constituents through three complementary approaches: field observations, laboratory experiments, and computational modeling. This thesis used the laboratory experiment approach to explore persistent unknowns associated with free radical chemistry in the troposphere and stratosphere. Studies were conducted using two powerful techniques for the study of chemical kinetics: multiplexed synchrotron photoionization mass spectrometry and cavity ringdown spectroscopy.
\r\n\r\nIn the first part of this thesis, we describe experiments measuring of the absolute photoionization cross sections of chlorine monoxide (ClO) and chlorine dioxide (ClOOCl). The cross sections of ClO were found to be at least a factor of three greater than a prior determination and those of ClOOCl were measured for the first time. ClO and ClOOCl play important roles in the catalytic destruction of polar stratospheric ozone and yet values of the parameters controlling the rate of atmospheric ClOOCl photolysis are uncertain. Our results show that photoionization spectroscopy is highly sensitive to the ClO radical and may be ideally suited for future experiments constraining the quantum yields of ClOOCl photolysis at wavelengths of relevance to the polar stratosphere.
\r\n\r\nWe next discuss experiments investigating the kinetics of chlorine-substituted peroxy radicals (ClRO2). These species are formed in the troposphere upon oxidation of alkenes by chlorine atoms. We present rate constants for the formation and loss pathways of the simplest intermediate in this class: the \u03b2\u2013chloroethyl peroxy radical. We also discuss measurements of the rate constants between NO and the ClRO2 formed upon oxidation of ethene, propene, 1-butene, 2-butene, 1,3-butadiene, and isoprene.
\r\n\r\nFinally, we present results exploring the impact of temperature and humidity on the chemistry of hydroxyl-substituted peroxy radicals (HORO2). In particular, the self reaction of the \u03b2\u2013hydroxyethyl peroxy radical was investigated and found to be significantly enhanced by water vapor at cold temperatures. The product branching ratio was also studied and found to shift in favor of radical suppression. Given the prevalence of water vapor throughout the troposphere, altered reactivity of HORO2\u2013H2O complexes likely plays an important role in atmospheric oxidation mechanisms.
", "doi": "10.7907/E3W5-QR05", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11728", "collection": "thesis", "collection_id": "11728", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06082019-154532666", "primary_object_url": { "basename": "ARWTHESIS_compiled.pdf", "content": "final", "filesize": 52266648, "license": "other", "mime_type": "application/pdf", "url": "/11728/1/ARWTHESIS_compiled.pdf", "version": "v19.0.0" }, "type": "thesis", "title": "Total Syntheses of the C19 Diterpenoid Alkaloids (\u2013)-Liljestrandisine and (\u2013)-Liljestrandinine", "author": [ { "family_name": "Wong", "given_name": "Alice Rose", "clpid": "Wong-Alice-Rose" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "A unified synthetic strategy to access diterpenoid alkaloid natural products is presented. The highly bridged hexacyclic natural products are characterized as having a hydrindane bridged piperidyl motif that is common to the C19 aconitine type diterpenoid alkaloids and the C20 napelline and denudatine type diterpenoid alkaloids. A unified strategy to the C19 and C20 diterpenoid alkaloids is developed. An asymmetric synthesis of an epoxy-hydrindane fragment enables the development of the key unified strategy, involving a 1,2-addition followed by a semipinacol rearrangement in a key fragment coupling process. The fragment coupling is demonstrated generally with a variety of substrates, including an aromatic substrate that is advanced to a key bicyclo[2.2.1]heptane intermediate towards the C20 diterpenoid alkaloids.
\r\n\r\nThe developed 1,2-addition/semipinacol-rearrangement strategy is ultimately leveraged in the total synthesis of two different C19 aconitine type diterpenoid alkaloids. An asymmetric synthesis of a bridged bicyclo[3.2.1]octane fragment is presented. The bridged bicyclo[3.2.1]octane fragment is advanced through the developed 1,2-addition/semipinacol rearrangement fragment coupling strategy affording a key tetracyclic intermediate. This work ultimately culminates in the total syntheses of two natural products (\u2013)-liljestrandisine and (\u2013)-liljestrandinine. Key steps for the completion of the total syntheses include advancement of the key tetracyclic intermediate from the fragment coupling through a series of C\u2013N and C\u2013C bond forming reactions, including an intramolecular aziridination reaction and a radical cyclization.
", "doi": "10.7907/0KR7-PP68", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11531", "collection": "thesis", "collection_id": "11531", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05222019-135022700", "primary_object_url": { "basename": "KEP_final_thesis.pdf", "content": "final", "filesize": 136922636, "license": "other", "mime_type": "application/pdf", "url": "/11531/61/KEP_final_thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Development of Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Reactions", "author": [ { "family_name": "Poremba", "given_name": "Kelsey Elizabeth", "orcid": "0000-0002-7446-257X", "clpid": "Poremba-Kelsey-Elizabeth" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Asymmetric reductive cross-electrophile coupling is a powerful method to forge C\u2013C bonds and access enantioenriched small molecules, which can be further functionalized to access scaffolds present in natural products and bioactive pharmaceutical agents. However, an innate challenge of this methodology is identifying a chiral catalyst that achieves optimal cross-selectivity and stereocontrol. Herein, we report studies on the asymmetric cross-coupling of C(sp3) electrophiles, such as benzyl chlorides, \u03b1-chloroesters, and N-hydroxyphthalimide esters, with several classes of C(sp2) electrophiles.
\r\n\r\nWe describe the asymmetric Ni-catalyzed reductive cross-coupling of (hetero)aryl iodides and benzyl chlorides to prepare enantioenriched 1,1-diarylalkanes. As part of these studies, a new chiral bi(oxazoline) ligand, 4-HeptylBiOX, was developed to obtain products in synthetically useful yield and enantioselectivity. This novel ligand is demonstrated to expand the substrate scope of these stereoconvergent reductive cross- couplings to include the asymmetric cross-coupling of \u03b1-chloroesters with aryl iodides, and sterically hindered N-hydroxyphthalimide esters with alkenyl bromides. Model studies have been initiated to study the application of these reactions toward the total synthesis of cylindrocyclophane natural products.
", "doi": "10.7907/ZW64-GJ97", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11209", "collection": "thesis", "collection_id": "11209", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09292018-211645714", "type": "thesis", "title": "Synthetic Strategies for the Total Synthesis of the Ryanoid and Isoryanoid Diterpenes", "author": [ { "family_name": "Han", "given_name": "Arthur", "orcid": "0000-0001-8691-699X", "clpid": "Han-Arthur" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Highly oxygenated, polycyclic terpenoids provide a rich source of biologically active natural products, yet the translation of their activity to lead candidate analogs and useful biological probes requires concise solutions to address, at once, accessibility and diversification. This dissertation will disclose our efforts to bridge that gap through the development of synthetic strategies for the total synthesis of the ryanoid and isoryanoid diterpenes. The studies herein will address the strategy and logic that rendered the success of a challenging C3 acylation to directly incorporate a pyrrole-2-carboxylate ester, ultimately resulting in an 18-step total synthesis of (+)-ryanodine. The versatility of the route was demonstrated by the preparation of the related ryanoid diterpene (+)-20-deoxyspiganthine. Enabling the success of both syntheses was the development of robust conditions to induce late-stage reductive ring closure and forge the C1\u2013C15 bond.
\r\n\r\nThe lessons learned from these synthetic efforts drew us thereafter to the complex, polycyclic structure of the isoryanoid diterpene (+)-perseanol. The evaluation of several different approaches culminated in the discovery of a successful fragment coupling approach, hinging on a 2-step sequence involving (1) 1,2-addition to induce convergent union of two fragments of equal complexity and (2) Heck-Stille cyclization/cross-coupling cascade to complete the preparation of the ABC tricyclic core. Emphasis will be placed on the strategic use of our fragment coupling approach to overcome the inherent stereochemical bias presented by late-stage intermediates, thereby enabling an 18-step total synthesis. The oxidation tactics developed herein should find broad utility in the preparation of other ryanoid, isoryanoid, and highly oxidized diterpenoids.
", "doi": "10.7907/JDZV-P010", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11382", "collection": "thesis", "collection_id": "11382", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02012019-134839099", "type": "thesis", "title": "General Strategies for Visible-Light Decaging Based on Quinone Photochemistry", "author": [ { "family_name": "Walton", "given_name": "David Paul", "orcid": "0000-0002-9557-6461", "clpid": "Walton-David-Paul" } ], "thesis_advisor": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The design, synthesis, and photochemistry of several quinone based photoremovable protecting groups is reported. A visible light (400-600 nm) intramolecular photoreduction of 1,4-benzoquinones and 1,4-naphthoquinones mediated by amine and sulfide substituents was employed to launch a fast thermal lactonization step. Both the trimethyl lock and o-coumarinic acid lactonizations were incorporated into these designs. Quantum yields in air equilibrated solvents are moderate (\u03a6 = 0.01-0.10), and chemical yields are generally quantitative. Detailed mechanistic studies reveal a mechanism distinct from typical n,\u03c0* quinone photochemistry. Biological applications and longer wavelength derivatives were further explored.
", "doi": "10.7907/0793-KJ34", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11527", "collection": "thesis", "collection_id": "11527", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05222019-121353860", "primary_object_url": { "basename": "Thesis_catenated.pdf", "content": "final", "filesize": 7732354, "license": "other", "mime_type": "application/pdf", "url": "/11527/20/Thesis_catenated.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "Hemilabile, Non-Innocent (Poly)arylene Donors for Accessing Novel Reactivity at Transition Metal Centers", "author": [ { "family_name": "Low", "given_name": "Choon Heng (Marcus)", "orcid": "0000-0002-9219-3377", "clpid": "Low-Choon-Heng-Marcus" } ], "thesis_advisor": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" } ], "thesis_committee": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Understanding the effects that ligands have on the coordination environment and reactivity of metal complexes is an endeavor that drives much of the field of inorganic chemistry. The use of ligands capable of flexible binding modes and redox states further enriches the chemistry of these complexes. This dissertation describes studies on metal complexes bearing pendant (poly)arylene donors that demonstrate hemilability and redox non-innocence. Within this context, conditions that result in coordination mode change and the multi-electron bond transformation that is made possible by the hemilability and/or non-innocence of the ligand are discussed.
\r\n\r\nChapter 2 investigates the meta-terphenyl diphosphine framework bearing a central phenolate donor as an anionic POP pincer on a variety of first-row transition metals. The circumstances under which coordination mode change from the phenolate donor to the arene face are investigated. Reduction of the cobalt and nickel complexes induced a coordination mode change from phenolate oxygen to metal-arene binding, while Lewis acid additives induced a coordination mode change in some iron POP complexes. Additionally, it was found that iron chloride POP complex initially not amendable to two-electron reduction was cleanly reduced in the presence of Lewis acids, suggesting a role the Lewis acid plays in quenching the negatively charged phenolate and stabilizing the overall transformation.
\r\n\r\nChapter 3 discusses reactivity on 1,4-naphthalenediyl diphosphine molybdenum complexes in the context of carbon monoxide (CO) coupling. Similar to the previously studied phenylene system, the reductive coupling of CO can be carried out. However, the naphthalene system showed a distinct and exclusive selectivity for the two-electron reductive CO coupling to a bis(siloxy)acetylene motif, without C\u2013O bond cleavage. This difference in selectivity is proposed to be a result of accessible \u03b74-arene binding modes previously not observed in the phenylene variant. Additionally, the bis(siloxy)acetylene complex also displays \u03b74-binding to the central arene. Further CO catenation can be effected from this species, providing a metallacyclobutenone complex that bears a C3 fragment derived completely from CO.
\r\n\r\nIn Chapter 4, the reactivity of 9,10-anthracenediyl bis(phenoxide) zirconium complexes is presented. The more expanded polyaromatic system with a milder reduction potential allowed the anthracene motif to function as a non-innocent ligand. This enabled facile reductive elimination of ancillary benzyl ligands on the metal center without the use of harsh reductants. This reduced complex was then able to oxidatively couple alkynes, and alkynes with nitriles. Furthermore, further insertion of an additional nitrile followed by reductive elimination, likely facilitated by the non-innocent anthracene motif, allowed for the catalytic synthesis of pyridines and pyrimidines with high yields and selectivities. This reactivity was further leveraged in the final Chapter of this dissertation. Chapter 5 presents the development of a new methodology towards the synthesis of pyridine or pyrimidine-containing polycyclic aromatic hydrocarbons (PAHs) using polyaromatic alkyne and nitrile building blocks. Because conventional methods of oxidative cyclodehydrogenation towards N-doped nanographenes proved ineffective with these PAHs, a new reductive cyclization route was developed offering a complementary method towards the challenging synthesis of these N-doped nanographenes.
\r\n\r\nAppendix A briefly explores additional reactivity on the 1,4-naphthalenediyl diphosphine complexes with regard to nitrile activation. Appendix B explores the synthesis of iron complexes supported by a benzene tris(thiophenolate) ligand towards potential model compounds for the iron molybdenum cofactor in nitrogenase. Appendix C presents preliminary studies on the 9,10-anthracenediyl bis(phenoxide) zirconium complex towards oxidative coupling of alkynes with CO2.
", "doi": "10.7907/BQJM-BN49", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11519", "collection": "thesis", "collection_id": "11519", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05142019-181954795", "primary_object_url": { "basename": "JCB_Thesis_Compiled.pdf", "content": "final", "filesize": 24161328, "license": "other", "mime_type": "application/pdf", "url": "/11519/67/JCB_Thesis_Compiled.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Reaction Development for the Total Syntheses of the Terpenoid Natural Products (+)-Psiguadial B, (+)-Rumphellaone A, and (\u2013)-Isodocarpin", "author": [ { "family_name": "Beck", "given_name": "Jordan Casey", "orcid": "0000-0003-0898-5644", "clpid": "Beck-Jordan-Casey" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "orcid": "0000-0001-9883-1600", "clpid": "Barton-J-K" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" }, { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The de novo synthesis of bioactive natural products provides an opportunity to learn more about the mechanism of bioactivity and to develop novel chemistry that is of interest to the synthetic community. Herein, we describe our strategy for the total synthesis of the trans-fused cyclobutane containing meroterpenoid (+)-psiguadial B. Key to this strategy was the development of a photochemical Wolff Rearrangement with asymmetric ketene aminolysis. A palladium-catalyzed C\u2013H alkenylation is used to build structural complexity, and we use two different epimerization strategies to perform an enantiodivergent synthesis of (+)-psiguadial B.
\r\n \r\nThis strategy was explored further and applied to the synthesis of chiral cyclobutanes through a 1,2-difunctionalization strategy, wherein a C\u2013H arylation forges one carbon-carbon bond and a subsequent decarboxylative cross-coupling enables functionalization at the adjacent carbon. This strategy enabled the asymmetric total synthesis of (+)-rumphellaone A in 9 steps.
\r\n \r\nThis report also highlights the work we have conducted in the development of a unified strategy for the enmein-type ent-kauranoid natural product, (\u2013)-isodocarpin. We detail our investigation of a convergent cross-electrophile coupling as a means to build the core of (\u2013)-isodocarpin. We also discuss our development of a 1,2-addition/semi-Pinacol rearrangement strategy for the preparation of all-carbon quaternary centers, which can be elaborated to enmein-type ent-kauranoid natural product scaffolds.
\r\n", "doi": "10.7907/78A5-K715", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11516", "collection": "thesis", "collection_id": "11516", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05142019-145414091", "type": "thesis", "title": "Copper and Nickel Catalysis for the Construction of Novel C\u2212N and C\u2212C Bonds", "author": [ { "family_name": "Matier", "given_name": "Carson Douglas", "orcid": "0000-0002-1618-7944", "clpid": "Matier-Carson-Douglas" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "First-row transition-metals such as nickel and copper have revolutionized cross-coupling chemistry. Their propensity to form radical intermediates from alkyl electrophiles has greatly expanded the scope of traditional cross-coupling reactions. Alkyl radicals can be recaptured by a chiral transition-metal catalyst allowing for enantioselective bond formation. In general, alkyl radicals rapidly epimerize, and thus both enantiomers of a racemic mixture of an alkyl electrophile can be processed into the same enantiomer of product, rendering the overall process enantioconvergent. Herein, the development of basic bond constructions and the development of asymmetric reactions leveraging alkyl radical intermediates for carbon-nitrogen and carbon-carbon bond formations are discussed. Reaction development is the primary focus of this work, though mechanistic insights discovered along the way are also detailed within.
\r\n\r\nChapter 2 describes the development of an enantioconvergent alkylation of amine nucleophiles with alkyl electrophiles. Carbazole and indole derivatives are employed as nucleophiles to undergo copper-catalyzed cross-coupling with tertiary \u03b1-chloroamide electrophiles under visible light irradiation. Reaction optimization, scope of reactivity, inorganic synthesis, and mechanistic insights are described within.
\r\n\r\nChapter 3 details the development of a non-asymmetric copper-catalyzed alkylation of aliphatic amines with unactivated alkyl electrophiles under visible light irradiation. The development of a novel catalytic system to circumvent the issues with the photophysical properties of aliphatic amine-copper complexes is discussed. Scope of reactivity and mechanistic investigations are detailed within. Additionally, our efforts to develop an asymmetric variant of this reaction are enclosed.
\r\n\r\nChapter 4 discusses the development of a copper-catalyzed alkylation of N-heterocycles with \u03b1-halolactams in the absence of light. The scope of the reactivity is detailed within. Mechanistic studies contained in this section suggest a unique and interesting reaction pathway\u2014one that does not proceed through a radical intermediate.
\r\n\r\nChapter 5 presents a novel class of organosilane electrophiles employed in an enantioconvergent nickel-catalyzed cross-coupling reaction. Here, the development of the reaction, scope of reactivity, and initial mechanistic insights are discussed.
\r\n\r\n", "doi": "10.7907/G3Q9-8F81", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:10938", "collection": "thesis", "collection_id": "10938", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05252018-104854693", "primary_object_url": { "basename": "Dissertation - Final.pdf", "content": "final", "filesize": 7373482, "license": "other", "mime_type": "application/pdf", "url": "/10938/66/Dissertation - Final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Cyclic Polyolefins via Ring-Expansion Metathesis Polymerization", "author": [ { "family_name": "Edwards", "given_name": "Julian Peter", "orcid": "0000-0001-9243-8197", "clpid": "Edwards-Julian-Peter" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The synthesis of cyclic polyolefins prepared using a supported, molecular ring-expansion metathesis polymerization catalyst is described. The synthesis of the catalysts, themselves, is described in detail. Additionally, thorough physical characterization of cyclic polymers with comparison to linear polymer analogues is reported.
", "doi": "10.7907/kmh1-y153", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:10956", "collection": "thesis", "collection_id": "10956", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05282018-184138570", "type": "thesis", "title": "Copper Carbazolides in Photoinduced C\u2013N Couplings", "author": [ { "family_name": "Ahn", "given_name": "Jun Myun", "orcid": "0000-0002-8181-908X", "clpid": "Ahn-Jun-Myun" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Photoinduced, copper-catalyzed reactions of organohalides have emerged in recent years as a powerful tool to construct a wide array of C\u2013N bonds, which are prevalent in organic materials and polymers, pharmaceuticals, natural products, and ligands in transition metal catalysts. Described herein is the study and applications of copper complexes ligated by carbazole and its derivatives in photoinduced, copper-catalyzed C\u2013N bond-constructing transformations. Various areas of synthetic inorganic and organic chemistry are explored, including in-depth mechanistic elucidation, ligand and catalyst design, reaction development, as well as spectroscopic and structural characterization of reactive copper complexes.\r\nChapter 2 describes the mechanistic investigation on photoinduced, copper-catalyzed couplings of carbazoles with unactivated alkyl halides. A wide array of mechanistic tools suggests the viability of an out-of-cage C(sp\u00b3)\u2013N coupling pathway. Spectroscopic and structural characterization data of the key intermediates are detailed.\r\nChapter 3 outlines the design and preparation of a new copper-based photoredox catalyst supported by a tridentate bis(phosphino)carbazole ligands. The ground- and excited-state properties of the new photocatalyst are examined.\r\nChapter 4 details the development of photoinduced, copper-catalyzed C(sp\u00b3)\u2013N couplings of carbamates with unactivated alkyl bromides using the new copper photoredox system. The scope with respect to the nucleophile and the electrophile and mechanistic investigations are communicated.\r\nChapter 5 illustrates the chemistry of copper complexes supported by bidentate (phosphino)carbazole ligands. A diverse array of copper complexes in both the S = 0 and S = 1/2 states are reported, including a rare, paramagnetic copper\u2013phosphine complex that may serve as a structural model for key copper intermediates of the enantioselective C(sp\u00b3)\u2013N couplings of carbazoles.", "doi": "10.7907/H8AP-G249", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:10364", "collection": "thesis", "collection_id": "10364", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08042017-162439257", "primary_object_url": { "basename": "MakVictor_Thesis2017_FINAL.pdf", "content": "final", "filesize": 70506194, "license": "other", "mime_type": "application/pdf", "url": "/10364/85/MakVictor_Thesis2017_FINAL.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Development of Synthetic Strategies for the Total Synthesis of Ent-Kauranoid and Diterpenoid Alkaloid Natural Products", "author": [ { "family_name": "Mak", "given_name": "Victor Wei-Dek", "clpid": "Mak-Victor-Wei-Dek" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "As part of an ongoing synthetic effort directed towards biologically active ent-kauranoid natural products, the preparation of two structurally unique natural products, (\u2013)-trichorabdal A and (\u2013)-longikaurin E, is presented. The syntheses intercept an early intermediate from the synthetic route towards the rearranged natural product (\u2013)-maoecrystal Z, and thus, represents a unified synthetic strategy to access structurally unique ent-kauranoids. Specifically, the syntheses are enabled by a palladium-mediated oxidative cyclization of a silyl ketene acetal to install a key quaternary center within the bicyclo[3.2.1]octane unit, as well as a reductive cyclization of an aldehyde-lactone to construct the oxabicyclo[2.2.2]octane motif of (\u2013)-longikaurin E.
\r\n\r\nA synthetic strategy to access C19-diterpenoid alkaloids, specifically of the aconitine type, is presented. These highly bridged polycyclic natural products are generally characterized by a substituted piperidyl ring bridging a hydrindane framework that is further attached to a bicyclo[3.2.1]octane. The synthetic strategy relies on the enantioselective synthesis of two bicyclic fragments, which are coupled in a convergent fashion through a 1,2-addition/semipinacol rearrangement sequence to forge a sterically hindered quaternary center. Efficient access to late stage intermediates has enabled the synthesis of the aconitine carbocyclic core, with appropriate functionality for advancement to a selective voltage-gated K+ channel blocker, talatisamine. Additionally, the synthetic strategy described herein is well applicable to the synthesis of related denudatine and napelline type C20-diterpenoid alkaloids.
", "doi": "10.7907/Z9ST7N04", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:10974", "collection": "thesis", "collection_id": "10974", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05302018-124410879", "type": "thesis", "title": "Development of Stereoselective Iridium-Catalyzed Allylic Alkylation Methods", "author": [ { "family_name": "Shockley", "given_name": "Samantha Elizabeth", "orcid": "0000-0001-5682-8569", "clpid": "Shockley-Samantha-Elizabeth" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Stoltz group, and moreover the synthetic community at large, has long been interested in the development of methods for the synthesis of enantioenriched all-carbon quaternary stereocenters. Historically, our group\u2019s interest has centered on palladium-catalyzed allylic alkylation, though recently effort has moved to include the study of iridium catalysts. This thesis presents four related projects, all unified by the use of enantioselective iridium-catalyzed allylic alkylation to construct highly-congested C\u2013C bonds.
\r\n\r\nFirst, the development of the first diastereo-, enantio-, and regioselective iridium-catalyzed allylic alkylation reaction of prochiral enolates to form vicinal tertiary and all-carbon quaternary stereodyads with alkyl-substituted allylic electrophiles is described. Next, the first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) nucleophile is presented, representing a rare example of umpolung strategy in iridium-catalyzed allylic alkylation. Additionally, the application of a MAC reagent in the first highly enantioselective iridium-catalyzed allylic alkylation to provide access to products bearing an allylic all-carbon quaternary stereocenter is detailed. The use of the MAC nucleophile enables the one-pot preparation of \u03b1-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. Finally, the first enantioselective transition metal-catalyzed allylic alkylation providing access to acyclic products bearing vicinal all-carbon quaternary centers is presented.
\r\n", "doi": "10.7907/S93J-6P85", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:10233", "collection": "thesis", "collection_id": "10233", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05312017-144547085", "primary_object_url": { "basename": "Bates_Kelvin_2017.pdf", "content": "final", "filesize": 58551554, "license": "other", "mime_type": "application/pdf", "url": "/10233/103/Bates_Kelvin_2017.pdf", "version": "v23.0.0" }, "type": "thesis", "title": "Isoprene Oxidation Mechanisms and Secondary Organic Aerosol Formation Under HO2-Dominated Conditions", "author": [ { "family_name": "Bates", "given_name": "Kelvin Hamilton", "orcid": "0000-0001-7544-9580", "clpid": "Bates-Kelvin-Hamilton" } ], "thesis_advisor": [ { "family_name": "Seinfeld", "given_name": "John H.", "clpid": "Seinfeld-J-H" }, { "family_name": "Wennberg", "given_name": "Paul O.", "clpid": "Wennberg-P-O" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" }, { "family_name": "Seinfeld", "given_name": "John H.", "clpid": "Seinfeld-J-H" }, { "family_name": "Wennberg", "given_name": "Paul O.", "clpid": "Wennberg-P-O" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Isoprene, a volatile hydrocarbon emitted by plants, represents the single most abundant source of non-methane organic carbon to the atmosphere. After its rapid oxidation by OH radicals in the troposphere, isoprene may follow any of a number of complex reaction mechanisms to form more highly functionalized products, depending in large part on the relative abundance of reactive radicals such as HO2 and NO; some of these products can be sufficiently water-soluble, non-volatile, and/or reactive to partition into atmospheric particles and contribute to the creation of secondary organic aerosol (SOA). In this work, I explore the gas-phase oxidation mechanisms and SOA formation potential of second- and later-generation products formed in the HO2-dominated reaction cascade, which predominates in remote regions and is estimated to account for over >40% of isoprene oxidation. Pure standards of significant isoprene products, such as isoprene epoxydiols (IEPOX) and C4 dihydroxycarbonyl compounds, are synthesized, and the rates and product yields of their gas-phase reactions with OH are measured by CF3O- chemical ionization mass spectrometry in environmental chamber experiments. Results are compared to field observations from the Southern Oxidant and Aerosol Study in the Southeastern United States, where significant concentrations of these compounds were detected, and are integrated into a global chemical transport model to investigate their effects throughout the atmosphere. Further, the results from these and other gas-phase kinetic and product studies are incorporated into an explicit isoprene oxidation mechanism, designed to simulate the effects of isoprene chemistry on oxidant concentrations and to produce accurate representations of products known to be involved in condensed phase processes, including IEPOX. Finally, additional chamber experiments with synthetic IEPOX and inorganic seed aerosol are performed to derive particle uptake coefficients and examine the effects of particle pH, liquid water content, and chemical composition on IEPOX-SOA formation, using aerosol mass spectrometry and differential mobility analysis. The gas- and particle-phase reaction rates and product yields reported herein, along with the explicit model, provide important constraints on the fate of isoprene-derived carbon in the atmosphere and on the influence the HO2-dominated isoprene oxidation pathway exerts on SOA and oxidant budgets.
", "doi": "10.7907/Z9930R6T", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10019", "collection": "thesis", "collection_id": "10019", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:01202017-173233936", "primary_object_url": { "basename": "KEK Full Thesis - FINAL - library.pdf", "content": "final", "filesize": 34182498, "license": "other", "mime_type": "application/pdf", "url": "/10019/163/KEK Full Thesis - FINAL - library.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "The Synthesis and Late-Stage Diversification of the Cyanthiwigin Natural Product Core and Synthetic Insights Derived Therein", "author": [ { "family_name": "Kim", "given_name": "Kelly Eun-Jung", "orcid": "0000-0002-4132-2474", "clpid": "Kim-Kelly-Eun-Jung" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Inspired by the therapeutic properties of many natural products and the ever-growing need for novel medicines, research programs for the late-stage diversification of complex molecular scaffolds have risen in popularity over the past few decades. In addition to generating a wide range of non-natural compounds for biological evaluation, these research efforts provide valuable synthetic insights into the preapration and reactivity of structurally intricate molecules. After a brief summary of the various strategies for late-stage diversification, examples of previous studies toward the derivatization of natural product-inspired scaffolds are highlighted.
\r\n\r\nA second-generation synthesis of the cyanthiwigin natural product core employing recently developed technologies is described. Re-optimization of the key double asymmetric catalytic alkylation transformation facilitates large-scale operations, and application of the aldehyde-selective Tsuji\u2013Wacker oxidation enables productive recycling of an advanced intermediate. Together, these modifications expedite the preparation of the tricyclic cyanthiwigin framework on multi-gram scale.
\r\n\r\nThe aldehyde-selective Tsuji\u2013Wacker reaction is demonstrated to be effective for the oxidation of terminal alkenes bearing quaternary carbons at the allylic or homoallylic position. The synthetic utility of this method is extended through further transformation of the crude aldehyde products, permitting catalytic conversion of hindered terminal olefins to a variety of other synthetically useful functional groups.
\r\n\r\nWith access to large quantities of the cyanthiwigin natural product core, a comparative study of various methods for intermolecular C\u2013H oxidation was conducted. Examination of the reactivity of the cyanthiwigin framework under established conditions for allylic C\u2013H acetoxylation, C\u2013H hydroxylation, C\u2013H amination, C\u2013H azidation, and C\u2013H chlorination reveals significant steric and electronic influences and suggests that functionalization is guided by innate reactivity within the substrate.
\r\n\r\nFinally, the preparation of several non-natural cyanthiwigin\u2013gagunin hybrid molecules from the cyanthiwigin core is described. Preliminary studies toward the biological activities of synthetic intermediates are presented, and future directions for the synthesis of novel cyanthiwigin\u2013gagunin hybrids are outlined.
", "doi": "10.7907/Z9KP8046", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:9942", "collection": "thesis", "collection_id": "9942", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10172016-133616811", "primary_object_url": { "basename": "Thesis_Toutov-A-A.pdf", "content": "final", "filesize": 29068087, "license": "other", "mime_type": "application/pdf", "url": "/9942/12/Thesis_Toutov-A-A.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Alkaline Salts of Sodium and Potassium: from C\u2013X Reduction to C\u2013H Functionalization and Beyond", "author": [ { "family_name": "Toutov", "given_name": "Anton Alexandrovich", "orcid": "0000-0002-6561-0462", "clpid": "Toutov-Anton-Alexandrovich" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Virgil", "given_name": "Scott C.", "clpid": "Virgil-S-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "Resnick Sustainability Institute" }, { "literal": "3MT Competition (Caltech)" }, { "literal": "div_chem" } ], "abstract": "The discovery and contemplations of Gilbert N. Lewis (1875\u20131946) regarding the concept of electron pair acceptors has led to an improved fundamental understanding of molecular interactions. Lewis\u2019s recognition that acidic character can exist in substances not containing hydrogen (i.e.,\r\nBr\u00f8nsted acids) led to the classification of a new group of reagents and catalysts for organic synthesis: Lewis acids. Over the last half-century, the application of these reagents and catalysts has in turn led to the discovery of a plethora of new chemical reactions, enabling previously unknown\r\ntransformations. It has also been appreciated that electron pair donors (i.e., Lewis bases) are characterized by analogous and opposite behavior. Perhaps most intriguing is that in certain cases Lewis bases are capable of modifying simultaneously the electrophilic and nucleophilic character of\r\nthe substance to which they are coordinated. It is also known that neutral tetravalent silicon can act as a Lewis acid for a variety of nucleophiles (i.e., Lewis bases) generating pentavalent Si species; these adducts are observed to have enhanced electrophilicity at Si and enhanced electron density at the ligands bound to silicon. In the case of organosilanes wherein at least one of the groups on silicon is a hydrogen (i.e., a hydrosilane), the reaction with Lewis bases can lead to pentavalent adducts with weakened Si\u2013H bonds wherein the H has enhanced hydridic character. This property has been exploited by researchers in a number of ways, perhaps most prevalently in the development of hydrosilanes as mild reducing agents for the reduction of carbonyl compounds or for the mechanistically-related carbonyl hydrosilylation reaction.
\r\n\r\nThis thesis details the discovery and development of fundamentally new chemical reactivity of silanes enabled by their interaction with basic salts of certain alkali metals (and includes some, but certainly not all of the work that I have performed in this area). First, it was found that specific combinations of hydrosilanes with basic alkali metal salts \u2013 in particular KOt-Bu \u2013 under certain conditions form exceptionally powerful reductive couples capable of selectively cleaving strong aromatic C\u2013O and C\u2013S bonds with exceptional effectiveness and novel selectivity. Second, I found that certain modifications and elaborations of this chemical system lead to dramatic changes in the operative reaction manifold: from C\u2013X bond cleavage to E\u2013Si bond formation. I determined that this concept of activating hydrosilanes with alkaline salts of the alkali metals can be harnessed for the mild and efficient construction of a wide array of E\u2013Si bond classes by catalytic crossdehydrogenative coupling. Surprisingly, these challenging chemistries all occur in the absence of transition metal species, providing new horizons and opportunities for investigating Earth-abundant elements as catalysts and reagents for a host of applications.
", "doi": "10.7907/Z9VM499F", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10287", "collection": "thesis", "collection_id": "10287", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06052017-155930157", "primary_object_url": { "basename": "Thesis_Chu_finalversion_2.pdf", "content": "final", "filesize": 8023429, "license": "other", "mime_type": "application/pdf", "url": "/10287/79/Thesis_Chu_finalversion_2.pdf", "version": "v9.0.0" }, "type": "thesis", "title": "Advances in Selectivity and Reactivity in Transition Metal Catalysis: Carbon\u2013Silicon Bond Formation, Wacker Oxidation, and Olefin Metathesis", "author": [ { "family_name": "Chu", "given_name": "Crystal Kitying", "clpid": "Chu-Crystal-Kitying" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of reaction methodology and catalysts that promote challenging transformations with high yields and selectivities is presented in Chapters 2\u20134 of this thesis. The three projects discussed address challenges in cross-coupling, olefin oxidation, and olefin metathesis.
\r\n\r\nChapter 2 describes a nickel-catalyzed cross-coupling strategy for the formation of C\u2013Si bonds using unactivated alkyl halides as substrates. Reaction optimization, exploration of the substrate scope, and mechanistic studies are described. This method is unique in its compatibility with not only secondary alkyl bromides, but tertiary alkyl bromides as well. Low loadings of the nickel catalyst, the absence of an added ligand, and relative tolerance of air and moisture contribute to the efficiency and robustness of this reaction. Mechanistic studies suggest that oxidative addition proceeds through a radical intermediate, consistent with previous studies of C\u2013C bond formation.
\r\n\r\nChapter 3 describes the application of an aldehyde-selective Wacker oxidation to allylic fluoride substrates to produce beta-fluorinated aldehydes with remarkably high regioselectivities. Efficient anti-Markovnikov oxidation of allylic fluorides bearing a variety of functional groups was possible with reduced loadings of palladium, copper, and nitrite catalysts. In order to highlight the utility of this methodology, further derivatization of the aldehyde products to diverse fluorinated products is described. Mechanistic studies demonstrate the role of inductive effects in enhancing the regioselectivity of oxidation.
\r\n\r\nChapter 4 investigates the synthesis, characterization, and reactivity studies of a new class of second-generation ruthenium olefin metathesis catalysts bearing aminophosphine ligands. The incorporation of P\u2013N bonds into the dissociating phosphine ligand results in trends in catalyst initiation rates and catalyst activity that reveal important considerations for ligand design. The results from kinetics experiments correlate well with computational studies, which indicate that there are significant effects derived from sterics, electronic induction, orbital overlap from the nitrogen (aminophosphine) lone pair, and ligand distortion energies that contribute to trends in phosphine dissociation.
", "doi": "10.7907/Z90C4SV7", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10274", "collection": "thesis", "collection_id": "10274", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06052017-010024254", "primary_object_url": { "basename": "Chapman_Lauren_M_2017_Thesis.pdf", "content": "final", "filesize": 35683896, "license": "other", "mime_type": "application/pdf", "url": "/10274/13/Chapman_Lauren_M_2017_Thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Development of a Synthetic Strategy Toward Trans-Cyclobutane-Containing Natural Products: Enantioselective Total Synthesis of (+)-Psiguadial B", "author": [ { "family_name": "Chapman", "given_name": "Lauren Marie", "clpid": "Chapman-Lauren-Marie" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Virgil", "given_name": "Scott C.", "clpid": "Virgil-S-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Trans-cyclobutane-containing meroterpenoids are a structurally intriguing class of natural products with a diverse array of pharmacologically interesting properties. Herein, the development of a synthetic strategy for de novo construction of the trans-cyclobutane motif is described, which has enabled the first enantioselective total synthesis of the cytotoxic natural product, (+)-psiguadial B. Specifically, we have developed a photochemical Wolff rearrangement with tandem catalytic, asymmetric addition to a ketene generated in situ. To our knowledge, this work represents the first example of this methodology used to prepare enantioenriched amides. A palladium-catalyzed, directed C(sp3)\u2013H alkenylation reaction is used to quickly build molecular complexity, and two distinct epimerization strategies permit access to either enantiomer of the natural product from a single enantiomer of organocatalyst.
\r\n\r\nIn the course of this work, three different synthetic routes toward (+)-psiguadial B were investigated and each is discussed. These studies have led to the execution of several challenging key transformations, including an ortho-quinone methide hetero\u2013Diels\u2013Alder cycloaddition with a cyclohexanone-derived enol ether, a vinyl sulfide-mediated Prins cyclization, and a modified Norrish\u2013Yang cyclization. Ultimately, the successful synthetic strategy was realized by employing a ring-closing metathesis to form the strained, 7-membered terpene framework, and a late-stage benzylic oxidation/arylation strategy to complete the core of the natural product. Finally, in an effort to apply these key strategy concepts in the context of other bioactive trans-cyclobutane-containing natural products, initial results toward a concise total synthesis of (+)-rumphellaone A are presented.
\r\n", "doi": "10.7907/Z90G3H5M", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10271", "collection": "thesis", "collection_id": "10271", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06042017-233801526", "primary_object_url": { "basename": "SB Thesis final.pdf", "content": "final", "filesize": 18168470, "license": "other", "mime_type": "application/pdf", "url": "/10271/49/SB Thesis final.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Development of Cu- and Ni-Catalyzed C\u2013C and C\u2013N Bond Forming Reactions", "author": [ { "family_name": "Bachman", "given_name": "Shoshana", "clpid": "Bachman-Shoshana" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Chapters 1 and 2 describe the development of photoinduced, Cu-catalyzed coupling reactions of unactivated secondary alkyl halides with amide and cyanide nucleophiles. These reactions may be conducted at room temperature under operationally simple conditions. Mechanistic studies are consistent with the intermediacy of alkyl radicals in these processes.
\r\n\r\nChapter 3 describes progress toward the development of the first enantioselective Ni-catalyzed cross coupling of racemic alkyl halides and heteroatom nucleophiles. Borylation of secondary benzylic chlorides with B2(pin)2 may be achieved in good yield and promising levels of enantioselectivity.
\r\n\r\nChapter 4 describes enantioselective Ni-catalyzed couplings of \u03b1-substituted lactam enolates with benzonitrile derivatives resulting in formal intermolecular C- acylation via in situ hydrolysis of an imine intermediate.
", "doi": "10.7907/Z99S1P2G", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10195", "collection": "thesis", "collection_id": "10195", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05232017-150306598", "type": "thesis", "title": "Studies in Palladium-Catalyzed Allylic Alkylation: Enantioselective Total Syntheses of Structurally Diverse Alkaloids", "author": [ { "family_name": "Pritchett", "given_name": "Beau Patrick", "orcid": "0000-0001-9922-9160", "clpid": "Pritchett-Beau-Patrick" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Presented herein are three projects, all unified by the use of palladium-catalyzed, enantioconvergent, decarboxylative allylic alkylations to synthesize stereochemically rich, nitrogen-containing small molecules. The ubiquity of nitrogen in biologically active natural products and pharmaceutical ingredients necessitates perpetual exploration and development of relevant small molecules. Highly robust palladium-catalyzed allylic alkylation reactions of non-stabilized enolates enable the construction of sterically encumbered all-carbon quaternary and tetrasubstituted tertiary stereocenters present within such targets.
\r\n\r\nThe successful development of a novel substrate class for palladium-catalyzed allylic alkylation, namely dihydropyrido[1,2-a]indolones (DHPIs), has enabled divergent syntheses of multiple monoterpene indole alkaloids. By setting the C20 quaternary stereocenter present within these alkaloids at an early stage in the synthesis, the remaining stereocenters can be forged with exquisite levels of control. Critical to the success of this work was the identification of highly tunable and predictable cyclizations between an indole and a C2-tethered iminium moiety. Regiodivergent cyclizations were used to complete the first catalytic enantioselective total synthesis of (\u2013)-goniomitine, along with efficient formal syntheses of (+)-aspidospermidine and (\u2013)-quebrachamine. Stereodivergent cyclization strategies were then employed in total syntheses of (+)-limaspermidine and (+)-kopsihainanine A. Synthetic efforts toward the highly caged Kopsia alkaloids (\u2013)-kopsinine, (\u2013)-kopsinilam, and (\u2013)-kopsifoline G are also discussed.
\r\n\r\nLastly, the synthesis of challenging alpha-quaternary Mannich-type products was accomplished through a simple, elegant inversion of strategy. The chiral building blocks made available by this technology bear significant potential in the realm of medicinal chemistry. Furthermore, this work enabled rapid total syntheses of (\u2013)-isonitramine and (+)-sibirinine.
", "doi": "10.7907/Z9ZG6Q9Q", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10088", "collection": "thesis", "collection_id": "10088", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03072017-164212272", "type": "thesis", "title": "Methodological Developments and Synthetic Applications of Strained Rings and Allylic C-H Functionalization of Hindered Substrates", "author": [ { "family_name": "O'Connor", "given_name": "Nicholas R.", "clpid": "O'Connor-Nicholas-R" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Formal dipolar cycloadditions of cyclopropanes and aziridines are useful methods for the formation of carbo- and heterocycles. Given our group\u2019s previous interest in this area, we sought to expand the scope of strained ring cycloadditions by employing heterocumulenes as dipolarophiles. This thesis describes our development of Lewis acid catalyzed formal (3 + 2) cycloadditions between donor\u2013acceptor cyclopropanes and isocyanates, isothiocyanates, and carbodiimides to furnish various five-membered heterocycles. Enantioenriched cycloadducts can be accessed through a stereospecific reaction if enantiopure substrates are employed. We also present a method to access more highly nitrogenated heterocycles by replacing donor\u2013acceptor cyclopropanes with activated aziridines. These aziridines react smoothly with isothiocyanates and carbodiimides in the presence of zinc Lewis acids to afford iminothiazolidine and iminoimidazolidine products in good yields. Our efforts to apply a cyclopropane cycloaddition toward the total synthesis of the indole alkaloid calophyline A are also described.
\r\n\r\nIn addition, a method for the activation of sterically hindered allylic C\u2013H bonds is presented. Despite numerous recent advances in the functionalization of allylic C\u2013H bonds and the general utility of these transformations, reactions of sterically hindered substrates remain challenging. In this thesis we describe the development of a novel system for the palladium(II)-catalyzed allylic C\u2013H acetoxylation of \u03b1-allyl lactams. We believe the lactam moiety may act as a directing group to aid in the palladation of these generally unreactive substrates. During optimization, we also discovered enal products were formed if water was added. These conditions represent the first example of a transition metal catalyzed C\u2013H oxidation system with tunable selectivity over the extent of oxidation.
\r\n", "doi": "10.7907/Z9JS9NF6", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10155", "collection": "thesis", "collection_id": "10155", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05042017-104254217", "type": "thesis", "title": "Highly Enantioselective Palladium-Catalyzed Allylic Alkylation Reactions of Carbocyclic Enaminones and Acyclic Substrates", "author": [ { "family_name": "Duquette", "given_name": "Douglas Charles", "clpid": "Duquette-Douglas-Charles" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This report details the studies of the palladium-catalyzed asymmetric allylic alkylation reactions of carbocyclic substrates, specifically of vinylogous amides and enaminones, resulting in the discovery of a new substrate class (enaminones) with the highest enantioselectivies observed for this catalytic system to date. Moreover, conditions were discovered and developed for the asymmetric allylic alkylation of acyclic substrates by the selective formation of fully substituted enolates and application of a novel C2-symmetric Pd ligand.
", "doi": "10.7907/Z9S46Q0P", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:9865", "collection": "thesis", "collection_id": "9865", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06082016-142725994", "primary_object_url": { "basename": "KVC-Thesis.pdf", "content": "final", "filesize": 9094795, "license": "other", "mime_type": "application/pdf", "url": "/9865/1/KVC-Thesis.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "A Total Synthesis of (+)-Ryanodol", "author": [ { "family_name": "Chuang", "given_name": "Kangway V.", "orcid": "0000-0002-0652-8071", "clpid": "Chuang-Kangway-V" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Highly oxygenated, architecturally complex terpenoids constitute a biologically important class of natural products, yet their development into medicinally relevant analogs and effective biological probes are obstructed by their synthetic accessibility. Ryanodine is a unique diterpenoid that exhibits high affinity to a class of intracellular calcium ion channels bearing its name: ryanodine receptors. Structure-activity relationship studies have demonstrated how peripheral structural modifications affect binding affinity and selectivity among receptor isoforms, but to date have been limited to analogs prepared via chemical derivatization of natural material due to the intractability of total chemical synthesis.
\r\n\r\nThis thesis details synthetic efforts culminating in a total synthesis of ryanodol that proceeds in only 15-steps from commercially available (\u2013)-pulegone. Early stage oxygen atom incorporation is strategically implemented to facilitate key, stereoselective carbon-carbon bond formation. In particular, a rhodium-catalyzed, intramolecular Pauson\u2013Khand reaction is utilized to rapidly assemble the tetracyclic ABCD-ring system that constitutes the anhydroryanodol core. A novel, selenium-dioxide mediated oxidation to install three oxidation states and three oxygen atoms was discovered, enabling the rapid oxidative functionalization of the ryanodol A-ring. The modular route described herein allows for the preparation of synthetic structural analogs not readily accessible via chemical degradation, and is anticipated to enable rapid construction and evaluation of biologically active ryanodine analogs.
\r\n", "doi": "10.7907/Z95X26ZV", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9717", "collection": "thesis", "collection_id": "9717", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05122016-112417957", "primary_object_url": { "basename": "dodson_leah_2016_thesis_final-2.pdf", "content": "final", "filesize": 7128196, "license": "other", "mime_type": "application/pdf", "url": "/9717/19/dodson_leah_2016_thesis_final-2.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Gas Phase Spectroscopy and Kinetics of Atmospheric Radicals", "author": [ { "family_name": "Dodson", "given_name": "Leah G.", "orcid": "0000-0001-5960-056X", "clpid": "Dodson-Leah-G" } ], "thesis_advisor": [ { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" } ], "thesis_committee": [ { "family_name": "Blake", "given_name": "Geoffrey A.", "clpid": "Blake-G-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Wennberg", "given_name": "Paul O.", "clpid": "Wennberg-P-O" }, { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "An important goal for atmospheric and combustion chemists is continued improvement in our understanding of the gas phase reactivity of free radical intermediates formed during hydrocarbon oxidation. The primary focus of this thesis was to measure gas phase kinetics of prototypical free radicals relevant to atmospheric and combustion chemistry, a goal that requires spectroscopy, quantitative product detection, and computational chemistry in order to address these complex chemical systems.
\r\n\r\nNear-infrared cavity ringdown spectroscopy was used to study the peroxy radicals (RO2) formed from chlorine-initiated oxidation of isoprene and other unsaturated hydrocarbons. Isoprene is one of the most important hydrocarbons in the atmosphere; detection of RO2 formed directly from isoprene oxidation will aid in understanding the initial steps of its fate in the atmosphere. As expected, the near-infrared chloro-isoprenyl peroxy radical spectrum has many features; each spectral feature corresponds to a different isomer and conformer, indicating that several RO2 structures are formed. In small RO2, it was possible to identify the molecular structure of the absorber by comparing the experimental spectrum with the vibrationally-resolved electronic spectrum generated by computational chemistry. Identification of each feature then enabled preliminary isomer-specific kinetics measurements.
\r\n\r\nPhotoionization mass spectrometry is another useful method for selective detection of radicals, with the added bonus of detecting many of the other species of interest, leading to a comprehensive understanding of the reaction mechanism. The yields of radical chain-propagating product channels of prototypical RO2 reactions (self- and cross-reactions) are important in understanding radical chemistry in gas phase hydrocarbon oxidation. We obtained branching ratio information for reactions of acetyl peroxy radicals with HO2, with particular focus on OH-regenerating reactions. Along the way, we observed unexpected product formation from low-pressure reactions of acetyl radicals and oxygen. Using the same techniques, we also looked at the self-reaction of ethyl peroxy radicals, confirming past measurements of the radical-propagating channel for this reaction, and investigated interesting product formation, like what may be the dialkyl peroxide. These studies were supported by measurements of VUV photoionization cross sections for several radical species. The utility of this instrumentation was also extended by the development of a low-temperature (200\u2013300 K) flow reactor.
\r\n\r\nFinally, using time-resolved broadband cavity-enhanced absorption spectroscopy, we measured the rate coefficient of reactions of the smallest Criegee intermediate, CH2OO with ozone. We observed that this reaction is rather fast, which could have significant implications for experimental ozonolysis studies that are carried out under high initial reactant concentrations.
", "doi": "10.7907/Z9XD0ZP8", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9869", "collection": "thesis", "collection_id": "9869", "cite_using_url": "https://resolver.caltech.edu/CaltechThesis:06082016-214138510", "primary_object_url": { "basename": "Henthorn_Final_Thesis.pdf", "content": "final", "filesize": 15762164, "license": "other", "mime_type": "application/pdf", "url": "/9869/1/Henthorn_Final_Thesis.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Molybdenum Quinonoid Complexes: Synthesis, Characterization, and Reactivity", "author": [ { "family_name": "Henthorn", "given_name": "Justin Travis", "orcid": "0000-0003-4876-2680", "clpid": "Henthorn-Justin-Travis" } ], "thesis_advisor": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" } ], "thesis_committee": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Pi-bound Molybdenum-quinonoid complexes supported by pendant phosphines were prepared and investigated for metal-ligand cooperative reactivity and access to multiple equivalents of protons and electrons within a single transition metal complex. Chapters 3, 4, and 5 of this dissertation describe the synthesis, characterization, and reactivity of these complexes in the context of multiproton, multielectron chemistry and small molecule activation.
\r\n\r\nChapter 2 presents the synthesis of an unprecedented bis-borane supported peroxide dianion, prepared from a mixture of ferrocenes, borane, and dioxygen. The peculiarity of such a structure is emphasized, and reactivity explored. While ferrocenes of varying reduction potential were found to lead to the peroxide, only tris(pentafluorophenyl)borane was found to yield isolable peroxide, with other boranes leading to oxygenation or borate formation.
\r\n\r\nChapter 3 describes the synthesis of a series of \u03c0-bound Molybdenum-quinonoid complexes and explores their reactivity with dioxygen. The Mo-quinonoid interaction is probed and elucidated through a number of reactions and experiments, highlighting the importance of the electronic coupling of the metal center with the organic fragment on overall reactivity with O2.
\r\n\r\nChapter 4 further explores the \u03c0-bound Molybdenum-quinonoid complexes in various protonation and oxidation states, totaling four electrons and two protons accessible to the system. Proton-coupled electron transfer was demonstrated in two different oxidation states, and the effects of the metal-quinonoid interaction on the transfer of protons and electrons investigated thermochemically.
\r\n\r\nChapter 5 explores the potential for \u03c0-bound Molybdenum-quinonoid complexes to access inner-sphere reactivity. The activation of E\u2013X bonds, including H2 and PhSiH3, is demonstrated, as well as catalytic hydrosilylation of aldehydes.
\r\n\r\nAppendix A describes initial investigations into the preparation of heterobimetallic complexes supported by the catechol-diphosphine ligand framework. The synthesis of heterobimetallic MoCu complexes is presented and their structural parameters discussed.
\r\n\r\nAppendix B outlines the synthesis of multinucleating ligand platforms based off bipyridine frameworks, for the preparation of biologically inspired multimetallic complexes. Dioxygen reactivity of a dicopper system is also briefly presented.
\r\n\r\nAppendix C contains relevant NMR spectra for the compounds presented in the preceding sections.
", "doi": "10.7907/Z9V40S53", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9860", "collection": "thesis", "collection_id": "9860", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06082016-025813806", "type": "thesis", "title": "Photochemical Strategies to Decage Organic Compounds", "author": [ { "family_name": "Regan", "given_name": "Clinton Joseph", "clpid": "Regan-Clinton-Joseph" } ], "thesis_advisor": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This dissertation primarily describes new photochemical decaging systems that are activated by visible light. Such systems are expected to be useful as chemical biology tools or as drug delivery systems in a therapeutic context. A primary motivation for the development of these systems is for the treatment of traumatic brain injury, where a decaging strategy would require activation by low energy near-infrared light. Since most photochemical reactions are initiated using ultraviolet light, a primary challenge in developing these systems is overcoming the low energy efficiency of typical photochemical processes. Initial model systems are designed to address this challenge through use of the photoacidic effect. While many hydroxyaromatic compounds are known to become much more acidic in their excited state, the effect has never been utilized to accelerate an acid-catalyzed chemical reaction. Investigations are carried out in Chapter 2 to probe for the possibility of this unprecedented photochemistry. Ultimately, the results suggest that the acid-catalyzed decaging processes are too slow to be useful in a photochemical context. This finding led to the development of decaging strategies that utilize a phototriggered approach. In Chapter 2, a system is described where decaging occurs through rapid lactonization of a photogenerated hydroquinone. Formation of the hydroquinone results from an intramolecular photoreduction of the benzoquinone due to activation by violet light. Detailed mechanistic studies carried out on this system ultimately establish the importance of the triplet state in the overall reaction. While most benzoquinones form the triplet with unit efficiency, the system studied here forms the triplet in less than 10% yield. However, when the triplet is formed, it proceeds cleanly to products with high efficiency. Although the benzoquinone system has been useful for mechanistic studies, its application as a therapeutic decaging strategy has been challenging. Efforts to extend the wavelength toward the near-infrared have led to loss in photochemical reactivity. Ultimately, this challenge was overcome through the use of methylene blue. Methylene blue is a common organic dye that is activated by red light and undergoes photoreduction to a colorless form, similar to the benzoquinone systems. In Chapter 4, derivatives of methylene blue that are capable of undergoing photoreductive cyclization are designed and synthesized. Ultimately, these systems are found to be capable of rapidly decaging alcohols using red light.", "doi": "10.7907/Z9C53HTF", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9839", "collection": "thesis", "collection_id": "9839", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06032016-162550993", "primary_object_url": { "basename": "NTK-Thesis_Final.pdf", "content": "final", "filesize": 36485675, "license": "other", "mime_type": "application/pdf", "url": "/9839/91/NTK-Thesis_Final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Development of Ni-Catalyzed Asymmetric Reductive Cross-Coupling Reactions", "author": [ { "family_name": "Kadunce", "given_name": "Nathaniel Thomas", "clpid": "Kadunce-Nathaniel-Thomas" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Over the last half century, the development of metal-catalyzed cross-coupling reactions has transformed the toolkit of transformations available to synthetic chemists. From the very beginning of this effort, researchers have studied the application of these reactions to afford enantioenriched products via asymmetric catalysis. A great deal of success has been achieved in this arena, giving rise to an ever-growing number of chiral catalysts for a wide range of transformations. Despite these efforts, inherent difficulties in the reactivity of C(sp3) electrophiles with the most common noble metal catalysts have limited the development of these substrates until more recently. A resurgence of interest in Ni-catalysis has enabled the stereoconvergent cross-coupling of C(sp3) electrophiles with many partners, opening doors to access these challenging chiral products.
\r\n\r\nReductive cross-coupling, involving the union of two different electrophiles, has emerged still more recently, and had previously not been employed asymmetrically. Herein we describe our efforts to develop the first Ni-catalyzed asymmetric reductive cross-couplings of C(sp3) halides to afford highly enantioenriched products. In the first such reaction, the coupling of acyl chlorides with benzylic chlorides affords acyclic \u03b1-tertiary ketone products. Following this, we describe the coupling of new C(sp3) partners, \u03b1-chloronitriles, with challenging Lewis-basic heteroaryl iodides, enabled by the development of a novel PHOX ligand scaffold. Finally, we report the extension of a more general dioxane/TMSCl solvent condition to new asymmetric reductive couplings, including that of heteroaryl iodides with benzylic chlorides, as well as additional preliminary results with new substrate classes.
\r\n", "doi": "10.7907/Z9JS9NDR", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9596", "collection": "thesis", "collection_id": "9596", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03012016-104838419", "primary_object_url": { "basename": "Yufan Liang_Thesis_2016.pdf", "content": "final", "filesize": 23804153, "license": "other", "mime_type": "application/pdf", "url": "/9596/1/Yufan Liang_Thesis_2016.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Applications of Nickel-Catalyzed Cross-Coupling Methods in the Synthesis of Organofluorine Compounds", "author": [ { "family_name": "Liang", "given_name": "Yufan", "orcid": "0000-0002-0533-2982", "clpid": "Liang-Yufan" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The applications of nickel-catalyzed cross-coupling strategy to the synthesis of organofluorine compounds are explored in this thesis.
\r\n\r\nChapter 2 describes the development of the first enantioselective cross-coupling method using secondary geminal dihalides as electrophiles. This method provides a unique approach for the generation of enantioenriched tertiary alkyl fluorides. These cross-coupling products can be further transformed into a variety of potentially valuable chiral building blocks.
\r\n\r\nChapter 3 describes the development of a practical and versatile Negishi alkylation method employing \u03b1-halo-\u03b1-perfluoroalkyl secondary electrophiles. Target molecules bearing perfluoroalkyl-substituted (including trifluoromethyl-substituted) tertiary carbons can be easily generated from fluorinated electrophiles. Competition experiments and mechanistic studies have been performed to reveal the unique properties of these electrophiles and also prove the existence of alkyl radicals.
\r\n\r\nChapter 4 describes the development of an asymmetric Negishi arylation protocol with \u03b1-halo-\u03b1-trifluoromethyl secondary electrophiles. This study provides a unique approach to construct trifluoromethyl-substituted tertiary stereocenters. The optimized condition can also be directly applied to substrates bearing an array of fluoroalkyl groups.
\r\n\r\nChapter 5 details the progress towards the development of an asymmetric alkynylation method employing \u03b1-halo-\u03b1-trifluoromethyl secondary electrophiles. Preliminary studies also demonstrate that the protocol we developed has the potential to be used for other non-fluorinated secondary electrophiles.
\r\n", "doi": "10.7907/Z9CF9N45", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9727", "collection": "thesis", "collection_id": "9727", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05172016-222905476", "primary_object_url": { "basename": "SeojungHan2016thesis.pdf", "content": "final", "filesize": 37861723, "license": "other", "mime_type": "application/pdf", "url": "/9727/1/SeojungHan2016thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "I. Synthetic Studies Toward the Total Synthesis of Polycyclic Natural Products \u2013 Communesin F, Perophoramidine and Ineleganolide. II. Nickel Catalyzed Intramolecular C\u2013O Bond Formation", "author": [ { "family_name": "Han", "given_name": "Seojung", "clpid": "Han-Seojung" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Finally, a previously unknown mild and efficient deprotection protocol for the o-nitrobenzyl group is disclosed \u2013 this serendipitous discovery permitted a concise endgame for the formal syntheses of both communesin F and perophoramidine.
\r\n\r\nIn addition, the atroposelective synthesis of PINAP ligands has been accomplished via a palladium-catalyzed C\u2013P coupling process through dynamic kinetic resolution. These catalytic conditions allow access to a wide variety of alkoxy- and benzyloxy-substituted PINAP ligands in high enantiomeric excess.
\r\n\r\nAn efficient and exceptionally mild intramolecular nickel-catalyzed carbon\u2013oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step.
\r\n\r\nFinally, synthetic studies toward polycyclic ineleganolide are described. The entire fragmented carbon framework has been constructed from this work. Highly (Z)-selective olefination was achieved by the method by the Ando group.
", "doi": "10.7907/Z9NV9G6M", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9760", "collection": "thesis", "collection_id": "9760", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05252016-185612554", "primary_object_url": { "basename": "Christopher K. Haley Thesis.pdf", "content": "final", "filesize": 6798059, "license": "other", "mime_type": "application/pdf", "url": "/9760/1/Christopher K. Haley Thesis.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Aryne Reactions in the Synthesis of Heterocyclic Molecules", "author": [ { "family_name": "Haley", "given_name": "Christopher Keating", "clpid": "Haley-Christopher-Keating" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Reactive intermediates play an important the within the realm of chemical synthesis. Their high energy and transient nature make them difficult to observe and characterize, but it is these same properties that empower them to form bonds traditionally seen as difficult to prepare and unusual architectures quickly and efficiently. Herein, two reactive intermediates, arynes and transitient (2azaaryl)-cuprates, are exploited for their abilities to prepare important chemical motifs. Both serve as an avenue into the functionalization of arenes to provide products which hold value in a variety of fields including natural product total syntethis, pharmaseuticals and ligand design. ", "doi": "10.7907/Z9QN64P5", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:8869", "collection": "thesis", "collection_id": "8869", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05192015-131629900", "primary_object_url": { "basename": "Corey-Reeves-2015-FullThesis.pdf", "content": "final", "filesize": 33285414, "license": "other", "mime_type": "application/pdf", "url": "/8869/134/Corey-Reeves-2015-FullThesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Strategies for the Stereoselective Synthesis of Carbon Quaternary Centers via Transition Metal-Catalyzed Alkylation of Enolate Compounds", "author": [ { "family_name": "Reeves", "given_name": "Corey Michael", "clpid": "Reeves-Corey-Michael" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Notwithstanding advances in modern chemical methods, the selective installation of sterically encumbered carbon stereocenters, in particular all-carbon quaternary centers, remains an unsolved problem in organic chemistry. The prevalence of all-carbon quaternary centers in biologically active natural products and pharmaceutical compounds provides a strong impetus to address current limitations in the state of the art of their generation. This thesis presents four related projects, all of which share in the goal of constructing highly-congested carbon centers in a stereoselective manner, and in the use of transition-metal catalyzed alkylation as a means to address that goal.
\r\n\r\nThe first research described is an extension of allylic alkylation methodology previously developed in the Stoltz group to small, strained rings. This research constitutes the first transition metal-catalyzed enantioselective \u03b1-alkylation of cyclobutanones. Under Pd-catalysis, this chemistry affords all\u2013carbon \u03b1-quaternary cyclobutanones in good to excellent yields and enantioselectivities.
\r\n\r\nNext is described our development of a (trimethylsilyl)ethyl \u03b2-ketoester class of enolate precursors, and their application in palladium\u2013catalyzed asymmetric allylic alkylation to yield a variety of \u03b1-quaternary ketones and lactams. Independent coupling partner synthesis engenders enhanced allyl substrate scope relative to allyl \u03b2-ketoester substrates; highly functionalized \u03b1-quaternary ketones generated by the union of our fluoride-triggered \u03b2-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this method for complex fragment coupling.
\r\n\r\nLastly, our development of an Ir-catalyzed asymmetric allylic alkylation of cyclic \u03b2-ketoesters to afford highly congested, vicinal stereocenters comprised of tertiary and all-carbon quaternary centers with outstanding regio-, diastereo-, and enantiocontrol is detailed. Implementation of a subsequent Pd-catalyzed alkylation affords dialkylated products with pinpoint stereochemical control of both chiral centers. The chemistry is then extended to include acyclic \u03b2-ketoesters and similar levels of selective and functional group tolerance are observed. Critical to the successful development of this method was the employment of iridium catalysis in concert with N-aryl-phosphoramidite ligands.
\r\n", "doi": "10.7907/Z9VX0DGH", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:9010", "collection": "thesis", "collection_id": "9010", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06082015-101231805", "primary_object_url": { "basename": "WickensThesisFinalPDF2015June.pdf", "content": "final", "filesize": 18358938, "license": "other", "mime_type": "application/pdf", "url": "/9010/1/WickensThesisFinalPDF2015June.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Manipulating Selectivity and Reactivity in Palladium-Catalyzed Oxidation Reactions", "author": [ { "family_name": "Wickens", "given_name": "Zachary Kimble", "clpid": "Wickens-Zachary-Kimble" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Since the initial discovery of the Wacker process over half a century ago, the Wacker oxidation has become a premier reaction for the oxidation of terminal alkenes to methyl ketones. This thesis describes strategies for manipulating selectivity and reactivity in Wacker-type oxidations to provide synthetically useful transformations.
\r\n\r\nChapter 2 describes how nitrite co-catalysts can be exploited in Wacker oxidations to reverse their typically high Markovnikov selectivity. Using these aerobic oxidation conditions, alkenes can be oxidized to aldehydes in high yield and selectivity. Preliminary mechanistic experiments are presented that are consistent with oxygen atom transfer from the nitrite catalyst to the substrate. The influence of proximal functionality on the new reaction is explored, yielding both synthetically useful transformations and further mechanistic insight.
\r\n\r\nChapter 3 investigates how minor modifications to the nitrite-modified Wacker can interrupt the Wacker oxidation pathway, providing dioxygenated products using molecular oxygen as the terminal oxidant. A variety of functional groups are tolerated and high yields of 1,2-diacetoxylated products are obtained with a range of substrates. Mechanistic experiments are presented that demonstrate the kinetic competency of nitrogen dioxide to mediate the reaction and probe the nature of the reductive elimination event.
\r\n\r\nChapter 4 details the development of a highly active Wacker-type oxidation capable of efficiently oxidizing internal alkenes, which are unreactive under\r\nclassical conditions. Under these simple and mild reaction conditions, a wide range of functional groups are tolerated and molecular oxygen can be employed as the terminal oxidant. Furthermore, the regioselectivity in unsymmetrical internal alkenes is investigated.
\r\n\r\nChapter 5 explores the origins of innate regioselectivity in Wacker oxidations. Systematic investigations of both internal and terminal alkenes illustrate that inductive effects are sufficient to dramatically influence Wacker regioselectivity. These observations lead to the development of a simple set of reactions conditions that strongly enforces Markovnikov's rule, even with substrates that provide mixtures of aldehydes and ketones under classical conditions.
", "doi": "10.7907/Z97S7KS9", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8935", "collection": "thesis", "collection_id": "8935", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05292015-170352881", "primary_object_url": { "basename": "YL2015Thesis.pdf", "content": "final", "filesize": 44626274, "license": "other", "mime_type": "application/pdf", "url": "/8935/109/YL2015Thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Palladium-Catalyzed Decarboxylative and Decarbonylative Transformations in the Synthesis of Fine and Commodity Chemicals", "author": [ { "family_name": "Liu", "given_name": "Yiyang", "clpid": "Liu-Yiyang" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "Resnick Sustainability Institute" }, { "literal": "div_chem" } ], "abstract": "Decarboxylation and decarbonylation are important reactions in synthetic organic chemistry, transforming readily available carboxylic acids and their derivatives into various products through loss of carbon dioxide or carbon monoxide. In the past few decades, palladium-catalyzed decarboxylative and decarbonylative reactions experienced tremendous growth due to the excellent catalytic activity of palladium. Development of new reactions in this category for fine and commodity chemical synthesis continues to draw attention from the chemistry community.
\r\n\r\nThe Stoltz laboratory has established a palladium-catalyzed enantioselective decarboxylative allylic alkylation of \u03b2-keto esters for the synthesis of \u03b1-quaternary ketones since 2005. Recently, we extended this chemistry to lactams due to the ubiquity and importance of nitrogen-containing heterocycles. A wide variety of \u03b1-quaternary and tetrasubstituted \u03b1-tertiary lactams were obtained in excellent yields and exceptional enantioselectivities using our palladium-catalyzed decarboxylative allylic alkylation chemistry. Enantioenriched \u03b1-quaternary carbonyl compounds are versatile building blocks that can be further elaborated to intercept synthetic intermediates en route to many classical natural products. Thus our chemistry enables catalytic asymmetric formal synthesis of these complex molecules.
\r\n\r\nIn addition to fine chemicals, we became interested in commodity chemical synthesis using renewable feedstocks. In collaboration with the Grubbs group, we developed a palladium-catalyzed decarbonylative dehydration reaction that converts abundant and inexpensive fatty acids into value-added linear alpha olefins. The chemistry proceeds under relatively mild conditions, requires very low catalyst loading, tolerates a variety of functional groups, and is easily performed on a large scale. An additional advantage of this chemistry is that it provides access to expensive odd-numbered alpha olefins.
\r\n\r\nFinally, combining features of both projects, we applied a small-scale decarbonylative dehydration reaction to the synthesis of \u03b1-vinyl carbonyl compounds. Direct \u03b1-vinylation is challenging, and asymmetric vinylations are rare. Taking advantage of our decarbonylative dehydration chemistry, we were able to transform enantioenriched \u03b4-oxocarboxylic acids into quaternary \u03b1-vinyl carbonyl compounds in good yields with complete retention of stereochemistry. Our explorations culminated in the catalytic enantioselective total synthesis of (\u2013)-aspewentin B, a terpenoid natural product featuring a quaternary \u03b1-vinyl ketone. Both decarboxylative and decarbonylative chemistries found application in the late stage of the total synthesis.
", "doi": "10.7907/Z9NZ85NC", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8884", "collection": "thesis", "collection_id": "8884", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05242015-134810426", "primary_object_url": { "basename": "Craig-II-Thesis-COMPLETE-Vols_1_and_2-FINAL.pdf", "content": "final", "filesize": 71567268, "license": "other", "mime_type": "application/pdf", "url": "/8884/20/Craig-II-Thesis-COMPLETE-Vols_1_and_2-FINAL.pdf", "version": "v9.0.0" }, "type": "thesis", "title": "Progress Toward the Enantioselective Total Synthesis of Ineleganolide and the Polycyclic Norcembranoid Diterpenes and Construction of the Ineleganoloids", "author": [ { "family_name": "Craig", "given_name": "Robert Allen, II", "clpid": "Craig-Robert-Allen-II" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Ineleganolide, horiolide, kavaranolide, sinulochmodin C, scabrolide A, scabrolide B, and yonarolide are related polycyclic furanobutenolide norcembranoid natural products that exhibit potent biological activity, and feature highly oxygenate carbocyclic scaffolds with complex stereochemical frameworks. Herein, we describe a unified synthetic approach toward ineleganolide and the related furanobutenolide norcembranoids. Assembly of the tetracyclic scaffold of ineleganolide is accomplished in a convergent manner from (R)-carvone and an enantioenriched cis-1,3-cyclopentenediol fragment, which is constructed by a key enantioselective allylic alkylation. From the combined product of the two major fragments, we employ a tandem intramolecular cyclopropanation/Cope rearrangement to furnish the cycloheptene carbocyclic core characteristic of ineleganolide.
\r\n \r\nSynthetic manipulations of this carbocyclic core are extensively investigated; several constitutional isomers of ineleganolide are synthesized through these studies. Many approaches are explored to assist in the completion of the synthesis. Computational studies inform our understanding of the conformational bias of late-stage intermediates. The retroaldol-aldol carbocyclic isomerization from the core of ineleganolide to the core of sinulochmodin C is also investigated.
\r\n\r\nAdditionally, our work on the (3 + 2) cycloadditions of heterocumulenes with donor\u2013acceptor cyclopropanes and with N\u2013H- and N\u2013sulfonyl aziridines is disclosed. The exploration of substrate scope, reaction mechanism, and the enantiospecific formation of heterocyclic products in investigated.
", "doi": "10.7907/Z92B8VZ6", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8817", "collection": "thesis", "collection_id": "8817", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04082015-185228801", "primary_object_url": { "basename": "JonnyThesisFinal.pdf", "content": "final", "filesize": 13567908, "license": "other", "mime_type": "application/pdf", "url": "/8817/1/JonnyThesisFinal.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Applications of a Concise and General Strategy for the Syntheses of Transtaganolide and Basiliolide Natural Products", "author": [ { "family_name": "Gordon", "given_name": "Jonny Robert", "clpid": "Gordon-Jonny-Robert" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Virgil", "given_name": "Scott C.", "clpid": "Virgil-S-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Herein are described the total syntheses of all members of the transtaganolide and basiliolide natural product family. Utilitzation of an Ireland\u2013Claisen rearrangement/Diels\u2013Alder cycloaddition cascade (ICR/DA) allowed for rapid assembly of the transtaganolide and basiliolide oxabicyclo[2.2.2]octane core. This methodology is general and was applicable to all members of the natural product family.
\r\n\r\nA brief introduction outlines all the synthetic progress previously disclosed by Lee, Dudley, and Johansson. This also includes the initial syntheses of transtaganolides C and D, as well as basiliolide B and epi-basiliolide B accomplished by Stoltz in 2011. Lastly, we discuss our racemic synthesis of basililide C and epi-basiliolide C, which utilized an ICR/DA cascade to constuct the oxabicyclo[2.2.2]octane core and formal [5+2] annulation to form the ketene-acetal containing 7-membered C-ring.
\r\n\r\nNext, we describe a strategy for an asymmetric ICR/DA cascade, by incorporation of a chiral silane directing group. This allowed for enantioselective construction of the C8 all-carbon quaternary center formed in the Ireland\u2013Claisen rearrangement. Furthermore, a single hydride reduction and subsequent translactonization of a C4 methylester bearing oxabicyclo[2.2.2]octane core demonstrated a viable strategy for the desired skeletal rearrangement to obtain pentacyclic transtaganolides A and B. Application of the asymmetric strategy culminated in the total syntheses of (\u2013)-transtaganolide A, (+)-transtaganolide B, (+)-transtaganolide C, and (\u2013)-transtaganolide D. Comparison of the optical rotation data of the synthetically derived transtaganolides to that from the isolated counterparts has overarching biosynthetic implications which are discussed.
\r\n\r\nLastly, improvement to the formal [5+2] annulation strategy is described. Negishi cross-coupling of methoxyethynyl zinc chloride using a palladium Xantphos catalyst is optimized for iodo-cyclohexene. Application of this technology to an iodo-pyrone geranyl ester allowed for formation and isolation of the eneyne product. Hydration of the enenye product forms natural metabolite basiliopyrone. Furthermore, the eneyne product can undergo an ICR/DA cascade and form transtaganolides C and D in a single step from an achiral monocyclic precursor.
\r\n", "doi": "10.7907/Z99021P4", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8952", "collection": "thesis", "collection_id": "8952", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06012015-102412340", "primary_object_url": { "basename": "Cherney_Alan_2015_Thesis.pdf", "content": "final", "filesize": 62145142, "license": "other", "mime_type": "application/pdf", "url": "/8952/43/Cherney_Alan_2015_Thesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Development of Nickel-Catalyzed Asymmetric Reductive Cross-Coupling of Benzylic Electrophiles", "author": [ { "family_name": "Cherney", "given_name": "Alan Hayden", "orcid": "0000-0001-7440-6634", "clpid": "Cherney-Alan-Hayden" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Over the last forty years, the advent of transition metal-catalyzed cross-coupling has revolutionized the synthetic chemist\u2019s ability to generate C\u2013C bonds. Since the 1970s, a parallel effort to control the stereochemical outcome of such transformations has yielded a variety of chiral catalyst complexes that deliver enantioenriched cross-coupled products. Nonetheless, challenges in the use of C(sp3)-hybridized coupling partners have limited asymmetric variants to a narrow fraction of the total number of cross-coupling methodologies published each year.
\r\n\r\nHerein, we report studies on the asymmetric cross-coupling of benzylic groups under either Pd or Ni catalysis. We have developed a Pd-catalyzed Fukuyama cross-coupling of thioesters and secondary benzylzinc halides to deliver racemic ketones under mild conditions. Investigations with chiral catalysts revealed that a promising asymmetric transformation could be achieved to give modestly enantioenriched ketones.
\r\n\r\nReductive cross-coupling, involving the union of two different electrophiles, has the added advantage of avoiding harsh or expensive organometallic reagents. We have discovered the first highly enantioselective Ni-catalyzed reductive cross-couplings of two organohalide electrophiles. Treatment of an acid chloride and a secondary benzyl chloride with a chiral nickel/bis(oxazoline) complex and Mn(0) as the stoichiometric reductant furnishes ketone products in good yield and high enantioselectivity. Expanding on this result, we have demonstrated that vinyl bromides and secondary benzyl chlorides can be cross-coupled using a different chiral nickel/bis(oxazoline) complex, illustrating the generality of an asymmetric reductive coupling platform. Preliminary studies directed toward other coupling partners are also disclosed.
", "doi": "10.7907/Z99W0CDW", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8658", "collection": "thesis", "collection_id": "8658", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09152014-112952177", "primary_object_url": { "basename": "NiJane2015thesis.pdf", "content": "final", "filesize": 20875984, "license": "other", "mime_type": "application/pdf", "url": "/8658/72/NiJane2015thesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Development of Asymmetric Protonation Reactions for the Synthesis of Indoline Alkaloids", "author": [ { "family_name": "Ni", "given_name": "Jane", "clpid": "Ni-Jane" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Nitrogen-containing heterocycles, such as indolines and pyrroloindolines, are prevalent in a variety of diverse natural products, many of which exhibit remarkable biological activities. These frameworks have inspired innovative research aimed at discovering novel methods for their stereoselective preparation.
\r\n\r\nWe have developed an enantioselective synthesis of pyrroloindolines based on a formal (3 + 2) cycloaddition of indoles and 2-amidoacrylates. This reaction is promoted by (R)-BINOL\u2022SnCl4; this complex is a Lewis acid-assisted Br\u00f8nsted acid that effects a highly face-selective catalyst-controlled protonation of an enolate. Mechanistic studies also determined that the initial product of this reaction is an indolinium ion, which upon aqueous workup undergoes cyclization to the pyrroloindoline.
\r\n\r\nBased on this result, we investigated alternative nucleophiles to trap the indolinium ion. First, addition of sodium borohydride to the optimized reaction conditions yields indoline-containing amino acid derivatives.
\r\n\r\nNext, carbon nucleophiles were explored. Indole substrates incorporating a tethered alkene were exposed to the conditions for the formal (3 + 2) cycloaddition, resulting in a conjugate addition/asymmetric protonation/Prins cyclization cascade. In this transformation, the indolinium ion is attacked by the olefin, and the resulting carbocation is quenched by a chloride ion. Zirconium tetrachloride was found to be the optimal Lewis acid. Stoichiometric proton and chloride sources were also found to be crucial for reactivity.
\r\n", "doi": "10.7907/Z95B00C4", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8999", "collection": "thesis", "collection_id": "8999", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06052015-132556787", "primary_object_url": { "basename": "MEK_Thesis_Final.pdf", "content": "final", "filesize": 36866169, "license": "other", "mime_type": "application/pdf", "url": "/8999/1/MEK_Thesis_Final.pdf", "version": "v13.0.0" }, "type": "thesis", "title": "New Catalytic Methods for the Preparation of Tryptophans and Pyrroloindolines: Total Synthesis of (+)-Naseseazines A and B and (\u2013)-Aspergilazine A\r ", "author": [ { "family_name": "Kieffer", "given_name": "Madeleine Eileen", "clpid": "Kieffer-Madeleine-Eileen" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Tryptophan and unnatural tryptophan derivatives are important building blocks for the total synthesis of natural products, as well as the development of new drugs, biological probes, and chiral small molecule catalysts. This thesis describes various catalytic methods for the preparation of tryptophan derivatives as well as their functionalization and use in natural product total synthesis.
\r\n\r\nHerein, the tandem Friedel\u2013Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate to provide enantioenriched trytophans is reported. This method inspired further work in the area of transition metal catalyzed arylation reactions. We report the development of the coppercatalyzed arylation of tryptamine and tryptophan derivatives. The utility of these transformations is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B. Further work on the development of a mild and general Larock indolization protocol to access unnatural tryptophans is also discussed.
", "doi": "10.7907/Z9X0650X", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8968", "collection": "thesis", "collection_id": "8968", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06022015-104348919", "primary_object_url": { "basename": "AGWeidmannThesisCompiled.pdf", "content": "final", "filesize": 47094104, "license": "other", "mime_type": "application/pdf", "url": "/8968/1/AGWeidmannThesisCompiled.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Biological Activity of Rhodium Metalloinsertors and the Design of Bifunctional Conjugates", "author": [ { "family_name": "Weidmann", "given_name": "Alyson Gloria", "orcid": "0000-0003-3876-2847", "clpid": "Weidmann-Alyson-Gloria" } ], "thesis_advisor": [ { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Barton laboratory has established that octahedral rhodium complexes bearing the sterically expansive 5,6-chrysene diimine ligand can target thermodynamically destabilized sites, such as base pair mismatches, in DNA with high affinity and selectivity. These complexes approach DNA from the minor groove, ejecting the mismatched base pairs from the duplex in a binding mode termed metalloinsertion. In recent years, we have shown that these metalloinsertor complexes also exhibit cytotoxicity preferentially in cancer cells that are deficient in the mismatch repair (MMR) machinery.
\r\n\r\nHere, we establish that a sensitive structure-activity relationship exists for rhodium metalloinsertors. We studied the relationship between the chemical structures of metalloinsertors and their effect on biological activity for ten complexes with similar DNA binding affinities, but wide variation in their lipophilicity. Drastic differences were observed in the selectivities of the complexes for MMR-deficient cells. Compounds with hydrophilic ligands were highly selective, exhibiting preferential cytotoxicity in MMR-deficient cells at low concentrations and short incubation periods, whereas complexes with lipophilic ligands displayed poor cell-selectivity. It was discovered that all of the complexes localized to the nucleus in concentrations sufficient for mismatch binding; however, highly lipophilic complexes also exhibited high mitochondrial uptake. Significantly, these results support the notion that mitochondrial DNA is not the desired target for our metalloinsertor complexes; instead, selectivity stems from targeting mismatches in genomic DNA.
\r\n\r\nWe have also explored the potential for metalloinsertors to be developed into more complex structures with multiple functionalities that could either enhance their overall potency or impart mismatch selectivity onto other therapeutic cargo. We have constructed a family of bifunctional metalloinsertor conjugates incorporating cis-platinum, each unique in its chemical structure, DNA binding interactions, and biological activity. The study of these complexes in MMR-deficient cells has established that the cell-selective biological activity of rhodium metalloinsertors proceeds through a critical cellular pathway leading to necrosis.
\r\n\r\nWe further explored the underlying mechanisms surrounding the biological response to mismatch recognition by metalloinsertors in the genome. Immunofluorescence assays of MMR-deficient and MMR-proficient cells revealed that a critical biomarker for DNA damage, phosphorylation of histone H2AX (\u03b3H2AX) rapidly accumulates in response to metalloinsertor treatment, signifying the induction of double strand breaks in the genome. Significantly, we have discovered that our metalloinsertor complexes selectively inhibit transcription in MMR-deficient cells, which may be a crucial checkpoint in the eventual breakdown of the cell via necrosis. Additionally, preliminary in vivo studies have revealed the capability of these compounds to traverse the complex environments of multicellular organisms and accumulate in MMR-deficient tumors. Our ever-increasing understanding of metalloinsertors, as well as the development of new generations of complexes both monofunctional and bifunctional, enables their continued progress into the clinic as promising new chemotherapeutic agents.
", "doi": "10.7907/Z9RX991X", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8926", "collection": "thesis", "collection_id": "8926", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05292015-143832701", "primary_object_url": { "basename": "CWL.pdf", "content": "final", "filesize": 11367646, "license": "other", "mime_type": "application/pdf", "url": "/8926/1/CWL.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "Progress Toward the Total Synthesis of Curcusone C and Mechanistic Elucidation of an Unexpected Rearrangement", "author": [ { "family_name": "Lee", "given_name": "Chung Whan", "clpid": "Lee-Chung-Whan" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Curcusone C is tricyclic diterpenoid natural product isolated from Jatropha curcas that exhibits potent biological activity and features a 2,3,7,8- tetrahydroazulene-1,4-dione moiety. Herein, we describe a synthetic approach toward ent-curcusone C. Construction of the tricyclic scaffold of ent-curcusone C is achieved from a cyclopentenol boronate and a vinyl bromide, which was synthesized from (S)-perillaldehyde. Suzuki coupling of the two precursors furnished a dieneol, which was converted to a diazoester via transesterification followed by diazo transfer reaction. A divinylcyclopropane was synthesized from the diazoester by intramolecular cyclopropanation and subsequent Kauffmann olefination. The tricyclic core of ent-curcusone C was accomplished by divinylcyclopropane rearrangement, which was initiated by reduction of the lactone moiety.
\r\n\r\nWe discovered an unexpected rearrangement during the course of our investigation toward the synthesis of curcusone C. Surprisingly, a silyl enol ether was converted to a complex tetracyclic compound under mild heating conditions. The transformation was elucidated as a unique reaction cascade of [3,3] Cope rearrangement, [1,5] silyl migration, Ireland\u2013Claisen rearrangement, retro Claisen rearrangement, and [1,5] silyl migration by computational and experimental efforts.
\r\n\r\nAdditionally, our work on the development of a bis(phosphine) copper catalyst for the asymmetric alkylation of 3-Bromooxindoles with \u03b1-arylated malonate esters is described. Versatile copper sources and chiral bis(phosphine) ligands were investigated.
", "doi": "10.7907/Z9J964C4", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:9000", "collection": "thesis", "collection_id": "9000", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06052015-143010623", "primary_object_url": { "basename": "Haoxuan Wang-2015Thesis.pdf", "content": "final", "filesize": 21565855, "license": "other", "mime_type": "application/pdf", "url": "/9000/56/Haoxuan Wang-2015Thesis.pdf", "version": "v11.0.0" }, "type": "thesis", "title": "Enantioselective Total Synthesis of Diketopiperazinecontaining Natural Products: (\u2013)-Lansai B, (+)-Nocardioazines A and B, and (\u2013)-Acetylapoaranotin", "author": [ { "family_name": "Wang", "given_name": "Haoxuan", "orcid": "0000-0002-8663-3073", "clpid": "Wang-Haoxuan" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Diketopiperazine (DKP) motif is found in a wide range of biologically active natural products. This work details our efforts toward two classes of DKP-containing natural products.
\r\n\r\nClass one features the pyrroloindoline structure, derived from tryptophans. Our group developed a highly enantioselective (3 + 2) formal cycloaddition between indoles and acrylates to provide pyrroloindoline products possessing three stereocenters. Utilizing this methodology, we accomplished asymmetric total synthesis of three natural products: (\u2013)-lansai B, (+)-nocardioazines A and B. Total synthesis of (\u2013)-lansai B was realized in six steps, and featured an amino acid dimerization strategy. The total synthesis of (+)-nocardioazine B was also successfully completed in ten steps. Challenges were met in approaching (+)-nocardioazine A, where a seemingly easy last-step epoxidization did not prove successful. After re-examining our synthetic strategy, an early-stage epoxidation strategy was pursued, which eventually yielded a nine-step total synthesis of (+)-nocardioazine A.
\r\n\r\nClass two is the epidithiodiketopiperazine (ETP) natural products, which possesses an additional episulfide bridge in the DKP core. With the goal of accessing ETPs with different peripheral structures for structure-activity relationship studies, a highly divergent route was successfully developed, which was showcased in the formal synthesis of (\u2013)-emethallicin E and (\u2013)-haematocin, and the first asymmetric synthesis of (\u2013)-acetylapoaranotin.
", "doi": "10.7907/Z92V2D3H", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:7961", "collection": "thesis", "collection_id": "7961", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09242013-191401866", "primary_object_url": { "basename": "Lenton_T_Thesis.pdf", "content": "final", "filesize": 2741708, "license": "other", "mime_type": "application/pdf", "url": "/7961/1/Lenton_T_Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Bis(thiophenolate)pyridine Pincer Ligands and Trivalent Zirconocene Complexes Relevant to Earlv Transition Metal Polymerization Catalysts", "author": [ { "family_name": "Lenton", "given_name": "Taylor Nichole Baker", "clpid": "Lenton-Taylor-Nichole-Baker" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Two major topics are covered: the first chapter is focused on the development of post-metallocene complexes for propylene polymerization. The second and third chapters investigate the consequences of diisobutylaluminum hydride (HAliBu2) additives in zirconocene based polymerization systems.
\r\n\r\nThe synthesis, structure, and solution behavior of early metal complexes with a new tridentate LX2 type ligand, bis(thiophenolate)pyridine ((SNS) = (2-C6H4S)2-2,6-C5H3N) are investigated. SNS complexes of Ti, Zr, and Ta having dialkylamido coligands were synthesized and structurally characterized. The zirconium complex, (SNS)Zr(NMe2)2, displays C2 symmetry in the solid state. Solid-state structures of tantalum complexes (SNS)Ta(NMe2)3 and (SNS)TaCl(NEt2)2 also display pronounced C2 twisting of the SNS ligand. 1D and 2D NMR experiments show that (SNS)Ta(NMe2)3 is fluxional with rotation about the Ta N(amide) bonds occurring on the NMR timescale. The fluxional behavior of (SNS)TaCl(NEt2)2 in solution was also studied by variable temperature 1H NMR. Observation of separate signals for the diastereotopic protons of the methylene unit of the diethylamide indicates that the complex remains locked on the NMR timescale in one diastereomeric conformation at temperatures below -50 \u00b0C.
\r\n\r\nReduction of Zr(IV) metallocenium cations with sodium amalgam (NaHg) produces EPR signals assignable to Zr(III) metallocene complexes. Thus, chloro-bridged heterobinuclear ansa-zirconocenium cation [((SBI))Zr(μ-Cl)2AlMe2]+B(C6F5)4¯ (SBI = rac-dimethylsilylbis(1-indenyl)), gives rise to an EPR signal assignable to the complex (SBI)ZrIII(μ-Cl)2AlMe2, while (SBI)ZrIII-Me and (SBI)ZrIII(-H)2AliBu2 are formed by reduction of [(SBI)Zr(μ-Me)2AlMe2]+B(C6F5)4¯ and [(SBI)Zr(μ-H)3(AliBu2)2]+B(C6F5)4¯, respectively. These products are also formed, along with (SBI)ZrIII-iBu and [(SBI)ZrIII]+ AlR4¯ when (SBI)ZrMe2 reacts with HAliBu2, eliminating isobutane en route to the Zr(III) complex. Studies concerning the interconversion reactions between these and other (SBI)Zr(III) complexes and reaction mechanisms involved in their formation are also reported.
\r\n\r\nThe addition of HAliBu2 to precatalyst [(SBI)Zr(\u00b5-H)3(AliBu2)2]+ significantly slows the polymerization of propylene and changes the kinetics of polymerization from 1st to 2nd order with respect to propylene. This is likely due to competitive inhibition by HAliBu2. When the same reaction is investigated using [(nBuCp)2Zr(μ-H)3(AliBu2)2]+, hydroalumination between propylene and HAliBu2 is observed instead of propylene polymerization.
\r\n", "doi": "10.7907/FPP5-0461", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:7929", "collection": "thesis", "collection_id": "7929", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08192013-205304543", "primary_object_url": { "basename": "Repka_LindsayM_Thesis.pdf", "content": "final", "filesize": 28186690, "license": "other", "mime_type": "application/pdf", "url": "/7929/123/Repka_LindsayM_Thesis.pdf", "version": "v9.0.0" }, "type": "thesis", "title": "Enantiosclective Synthesis of Pyrroloindolines and Tryptophan Derivatives by an Asvmmetric Protonation Reaction", "author": [ { "family_name": "Repka", "given_name": "Lindsay Michelle", "clpid": "Repka-Lindsay-Michelle" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Pyrroloindoline and unnatural tryptophan motifs are important targets for synthesis based on their incorporation into a diverse array of biologically active natural products. Both types of alkaloids have also found applications as chiral catalysts and tryptophan derivatives are commonly employed as biological probes. On account of their applications, these frameworks have inspired the development of numerous enantioselective, catalytic reactions. In particular, the past few years have witnessed an impressive number of novel approaches for pyrroloindoline formation.
\r\n\r\nThe first project described herein involves our contribution to pyrroloindoline research. We have developed an (R)-BINOL\u2022SnCl4-catalyzed formal (3 + 2) cycloaddition reaction between 3-substituted indoles and 2-amidoacrylates that affords pyrroloindoline-2-carboxylates bearing an all-carbon quaternary center. Mechanistic studies have elucidated that the enantiodetermining step is a highly face-selective catalyst-controlled protonation reaction.
\r\n\r\nSecond, application of this asymmetric protonation strategy to the synthesis of a variety of enantioenriched tryptophan derivatives is discussed. Finally, we found that these derivatives could undergo selective functionalization. More specifically, we were able to prepare novel hydroxypyrroloindolines that are currently the subject of a collaboration project with the Dougherty lab aimed at identifying novel positive allosteric modulators of ligand-gated ion channels.
\r\n", "doi": "10.7907/Y8MS-J286", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8231", "collection": "thesis", "collection_id": "8231", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05132014-111254056", "primary_object_url": { "basename": "Holder_Jeffrey_2014_Thesis.pdf", "content": "final", "filesize": 39800147, "license": "other", "mime_type": "application/pdf", "url": "/8231/1/Holder_Jeffrey_2014_Thesis.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "The Development of an Asymmetric Palladium-Catalyzed Conjugate Addition and Its Application Toward the Total Syntheses of Taiwaniaquinoid Natural Products", "author": [ { "family_name": "Holder", "given_name": "Jeffrey Clinton", "clpid": "Holder-J-C" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The asymmetric synthesis of quaternary stereocenters remains a challenging problem in organic synthesis. Past work from the Stoltz laboratory has resulted in methodology to install quaternary stereocenters \u03b1- or \u03b3- to carbonyl compounds. Thus, the asymmetric synthesis of \u03b2-quaternary stereocenters was a desirable objective, and was accomplished by engineering the palladium-catalyzed addition of arylmetal organometallic reagents to \u03b1,\u03b2-unsaturated conjugate acceptors.
\r\n\r\nHerein, we described the rational design of a palladium-catalyzed conjugate addition reactions utilizing a catalyst derived from palladium(II) trifluoroacetate and pyridinooxazole ligands. This reaction is highly tolerant of protic solvents and oxygen atmosphere, making it a practical and operationally simple reaction. The mild conditions facilitate a remarkably high functional group tolerance, including carbonyls, halogens, and fluorinated functional groups. Furthermore, the reaction catalyzed conjugate additions with high enantioselectivity with conjugate acceptors of 5-, 6-, and 7-membered ring sizes. Extension of the methodology toward the asymmetric synthesis of flavanone products is presented, as well.
\r\n \r\nA computational and experimental investigation into the reaction mechanism provided a stereochemical model for enantioinduction, whereby the \u03b1-methylene protons adjacent the enone carbonyl clashes with the tert-butyl groups of the chiral ligand. Additionally, it was found that the addition of water and ammonium hexafluorophosphate significantly increases the reaction rate without sacrificing enantioselectivity. The synergistic effects of these additives allowed for the reaction to proceed at a lower temperature, and thus facilitated expansion of the substrate scope to sensitive functional groups such as protic amides and aryl bromides. Investigations into a scale-up synthesis of the chiral ligand (S)-tert-butylPyOx are also presented. This three-step synthetic route allowed for synthesis of the target compound of greater than 10 g scale.
\r\n\r\nFinally, the application of the newly developed conjugate addition reaction toward the synthesis of the taiwaniaquinoid class of terpenoid natural products is discussed. The conjugate addition reaction formed the key benzylic quaternary stereocenter in high enantioselectivity, joining together the majority of the carbons in the taiwaniaquinoid scaffold. Efforts toward the synthesis of the B-ring are presented.
\r\n", "doi": "10.7907/EW6K-2D88", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:7958", "collection": "thesis", "collection_id": "7958", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09172013-192454898", "primary_object_url": { "basename": "CodelliThesisFINAL.pdf", "content": "final", "filesize": 24570444, "license": "other", "mime_type": "application/pdf", "url": "/7958/1/CodelliThesisFINAL.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "The Development of a Synthetic Strategy Toward Dihydrooxepine-Containing Epipolythiodiketopiperazines: Enantioselective Total Synthesis of (-)-Acetylaranotin and Related Investigations", "author": [ { "family_name": "Codelli", "given_name": "Julian Andrew", "clpid": "Codelli-Julian-Andrew" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "To the chemist, the epipolythiodiketopiperazine (ETP) fungal metabolites represent a fascinating family of natural products, not only for their unique structural elements, but also for the unusual modes by which they are hypothesized to exert their biological activities. Though efforts at the total synthesis of these molecules have led to an evolution of innovative synthetic methodologies and strategies, challenges remain\u2014particularly with respect to acid-sensitive and highly oxygenated ETP structures, such as those containing one or more dihydrooxepine ring. As part of a broad research program targeting ETP natural products, we have developed a synthetic strategy towards dihydrooxepine-containing ETPs.
\r\n\t\r\nHerein, the enantioselective total synthesis of (\u2013)-acetylaranotin is described. This represents the first total synthesis of any dihydrooxepine-containing ETP natural product. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide.
\r\n\t\r\nOur strategy was extended to the synthesis of a small panel of epitetrathiodiketopiperazines, including the natural products SCH64877 and emethallicin C as well as analogs, which are currently being evaluated for biological activity. Furthermore, preliminary investigations into the synthesis of dihydrooxepine-containing macrocycles have been conducted, with a particular focus on the preparation of bis(ortho-methoxyaryl) ethers.
\r\n\t\r\nFinally, as part of our efforts to further explore interesting side reactions observed during synthetic studies toward acetylaranotin, a catalytic asymmetric double (1,3)-dipolar cycloaddition reaction was developed. This reaction provides access to highly substituted, enantioenriched pyrrolidizines from inexpensive, commercially available starting materials. Furthermore, the reactivity of diketopiperazine intermediates prepared en route to acetylaranotin toward aerobic oxidation was briefly explored.
", "doi": "10.7907/Z9CR5RC4", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:7959", "collection": "thesis", "collection_id": "7959", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09182013-164526961", "primary_object_url": { "basename": "Anderson_John_Thesis2014.pdf", "content": "final", "filesize": 6614671, "license": "other", "mime_type": "application/pdf", "url": "/7959/1/Anderson_John_Thesis2014.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Catalytic Conversion of Nitrogen to Ammonia by an Iron Model Complex", "author": [ { "family_name": "Anderson", "given_name": "John Stuart", "clpid": "Anderson-John-Stuart" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Threefold symmetric Fe phosphine complexes have been used to model the structural and functional aspects of biological N2 fixation by nitrogenases. Low-valent bridging Fe-S-Fe complexes in the formal oxidation states Fe(II)Fe(II), Fe(II)/Fe(I), and Fe(I)/Fe(I) have been synthesized which display rich spectroscopic and magnetic behavior. A series of cationic tris-phosphine borane (TPB) ligated Fe complexes have been synthesized and been shown to bind a variety of nitrogenous ligands including N2H4, NH3, and NH2
Treatment of an anionic FeN2 complex with excess acid also results in the formation of some NH3, suggesting the possibility of a catalytic cycle for the conversion of N2 to NH3 mediated by Fe. Indeed, use of excess acid and reductant results in the formation of seven equivalents of NH3 per Fe center, demonstrating Fe mediated catalytic N2 fixation with acids and protons for the first time. Numerous control experiments indicate that this catalysis is likely being mediated by a molecular species.
\r\n\r\nA number of other phosphine ligated Fe complexes have also been tested for catalysis and suggest that a hemi-labile Fe-B interaction may be critical for catalysis. Additionally, various conditions for the catalysis have been investigated. These studies further support the assignment of a molecular species and delineate some of the conditions required for catalysis.
\r\n\r\nFinally, combined spectroscopic studies have been performed on a putative intermediate for catalysis. These studies converge on an assignment of this new species as a hydrazido(2-) complex. Such species have been known on group 6 metals for some time, but this represents the first characterization of this ligand on Fe. Further spectroscopic studies suggest that this species is present in catalytic mixtures, which suggests that the first steps of a distal mechanism for N2 fixation are feasible in this system.
", "doi": "10.7907/NS23-B474", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8034", "collection": "thesis", "collection_id": "8034", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12022013-141841545", "primary_object_url": { "basename": "NavarroRaul_FullThesis_2014.pdf", "content": "final", "filesize": 16823427, "license": "other", "mime_type": "application/pdf", "url": "/8034/205/NavarroRaul_FullThesis_2014.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "New Strategies for the Total Synthesis of Aza-Propellane Natural Products", "author": [ { "family_name": "Navarro", "given_name": "Raul", "clpid": "Navarro-Raul" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The propellane alkaloids comprise a large class of natural products that possess varying degrees of structural complexity and biological activity. The earliest of these to be isolated was acutumine, a chlorinated alkaloid that has been shown to exhibit selective T-cell cytotoxicity and antiamnesic properties. Alternatively, the hasubanan family of natural products has garnered considerable attention from the synthetic community in part due to its structural similarities to morphine. While these alkaloids have been the subject of numerous synthetic studies over the last forty years, very few enantioselective total syntheses have been reported to date.
\r\n\r\nAs part of a research program directed towards the synthesis of various alkaloid natural products, we have developed a unified strategy for the preparation of the hasubanan and acutumine alkaloids. Specifically, a highly diastereoselective 1,2-addition of organometallic reagents to benzoquinone-derived tert-butanesulfinimines was established, which provides access to enantioenriched 4-aminocyclohexadienone products. This methodology enabled the enantioselective construction of functionalized dihydroindolones, which were found to undergo intramolecular Friedel-Crafts conjugate additions to furnish the propellane cores of several hasubanan alkaloids. As a result of these studies, the first enantioselective total syntheses of 8-demethoxyrunanine and cepharatines A, C, and D were accomplished in 9-11 steps from commercially available starting materials.
\r\n\r\nMore recent efforts have focused on applying the sulfinimine methodology to the synthesis of a more structurally complex propellane alkaloid, acutumine. Extensive studies have determined that a properly functionalized dihydroindolone undergoes a photochemical [2+2] cycloaddition followed by a lactone fragmentation/Dieckmann cyclization to establish the carbocyclic framework of the natural product. The preparation of more appropriately oxidized propellane intermediates is currently under investigation, and is anticipated to facilitate our synthetic endeavors toward acutumine.
\r\n\r\n", "doi": "10.7907/XQ0M-NT53", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8170", "collection": "thesis", "collection_id": "8170", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03252014-222127174", "primary_object_url": { "basename": "Yeoman-John-2014-FullThesis-Final.pdf", "content": "final", "filesize": 23014759, "license": "other", "mime_type": "application/pdf", "url": "/8170/44/Yeoman-John-2014-FullThesis-Final.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "A Unified Strategy to Ent-Kauranoid Natural Products: Total Syntheses of (-)-Maoecrystal Z, (-)-Trichorabdal A, and (-)-Longikaurin E", "author": [ { "family_name": "Yeoman", "given_name": "John Thomas Schafer", "clpid": "Yeoman-John-Thomas-Schafer" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The diterpenoid constituents of the Isodon plants have attracted reasearchers interested in both their chemical structures and biological properties for more than a half-century. In recent years, the isolations of new members displaying previously unprecedented ring systems and highly selective biological properties have piqued interest from the synthetic community in this class of natural products.
\r\n\r\nReported herein is the first total synthesis of such a recently isolated diterpenoid, (\u2013)-maoecrystal Z. The principal transformations implemented in this synthesis include two highly diastereoselective radical cyclization reactions: a Sm(II)-mediated reductive cascade cyclization, which forms two rings and establishes four new stereocenters in a single step, and a Ti(III)-mediated reductive epoxide-acrylate coupling that yields a functionalized spirolactone product, which forms a core bicycle of maoecrystal Z.
\r\n\r\nThe preparation of two additional ent-kauranoid natural products, (\u2013)-trichorabdal A and (\u2013)-longikaurin E, is also described from a derivative of this key spirolactone. These syntheses are additionally enabled by the palladium-mediated oxidative cyclization reaction of a silyl ketene acetal precursor that is used to install the bridgehead all-carbon quaternary stereocenter and bicyclo[3.2.1]octane present in each natural product. These studies have established a synthetic relationship among three architecturally distinct ent-kaurane diterpenoids and have forged a path for the preparation of interesting unnatural ent-kauranoid structural analogs for more thorough biological study.
", "doi": "10.7907/5TDN-7M11", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8220", "collection": "thesis", "collection_id": "8220", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05062014-151417635", "primary_object_url": { "basename": "NHD THESIS Full.pdf", "content": "final", "filesize": 13805012, "license": "other", "mime_type": "application/pdf", "url": "/8220/1/NHD THESIS Full.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Studies of the Serotonin Type 3A Receptor and the Chemical Preparation of tRNA", "author": [ { "family_name": "Duffy", "given_name": "Noah Hanville", "clpid": "Duffy-Noah-Hanville" } ], "thesis_advisor": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "thesis_committee": [ { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis describes studies surrounding a ligand-gated ion channel (LGIC): the serotonin type 3A receptor (5-HT3AR). Structure-function experiments using unnatural amino acid mutagenesis are described, as well as experiments on the methodology of unnatural amino acid mutagenesis. Chapter 1 introduces LGICs, experimental methods, and an overview of the unnatural amino acid mutagenesis.
\r\n\r\nIn Chapter 2, the binding orientation of the clinically available drugs ondansetron and granisetron within 5-HT3A is determined through a combination of unnatural amino acid mutagenesis and an inhibition based assay. A cation-\u03c0 interaction is found for both ondansetron and granisetron with a specific tryptophan residue (Trp183, TrpB) of the mouse 5-HT3AR, which establishes a binding orientation for these drugs.
\r\n\r\nIn Chapter 3, further studies were performed with ondansetron and granisetron with 5-HT3A. The primary determinant of binding for these drugs was determined to not include interactions with a specific tyrosine residue (Tyr234, TyrC2). In completing these studies, evidence supporting a cation-\u03c0 interaction of a synthetic agonist, meta-chlorophenylbiguanide, was found with TyrC2.
\r\n\r\nIn Chapter 4, a direct chemical acylation strategy was implemented to prepare full-length suppressor tRNA mediated by lanthanum(III) and amino acid phosphate esters. The derived aminoacyl-tRNA is shown to be translationally competent in Xenopus oocytes.
\r\n\r\nAppendix A.1 gives details of a pharmacological method for determining the equilibrium dissociation constant, KB, of a competitive antagonist with a receptor, known as Schild analysis. Appendix A.2 describes an examination of the inhibitory activity of new chemical analogs of the 5-HT3A antagonist ondansetron. Appendix A.3 reports an organic synthesis of an intermediate for a new unnatural amino acid. Appendix A.4 covers an additional methodological examination for the preparation of amino-acyl tRNA.
", "doi": "10.7907/X1YA-DM13", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:7487", "collection": "thesis", "collection_id": "7487", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02202013-172928174", "primary_object_url": { "basename": "COMPLETE_FINAL.pdf", "content": "final", "filesize": 33013983, "license": "other", "mime_type": "application/pdf", "url": "/7487/85/COMPLETE_FINAL.pdf", "version": "v9.0.0" }, "type": "thesis", "title": "Synthetic Applications and Methodological Developments of Donor-Acceptor Cyclopropanes", "author": [ { "family_name": "Goldberg", "given_name": "Alexander F. G.", "clpid": "Goldberg-Alexander-F-G" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Donor\u2013acceptor cyclopropanes are a versatile class of synthetic intermediates, compatible in a broad range of ring-opening reactions and formal cycloadditions, and employed in numerous natural product syntheses. We have developed new Lewis acid mediated cycloadditions for the synthesis of five-membered heterocycles, and applied existing a transition metal catalyzed cyclopropane cycloaddition method toward the synthesis of complex alkaloids.
\r\n\r\nFirst, described is the development of a Lewis acid mediated (3 + 2) cycloaddition of donor\u2013acceptor cyclopropanes with isocyanates, isothiocyanates and carbodiimides. This reaction was found in certain cases to proceed with excellent stereochemical fidelity, providing access to an array of enantioenriched thioimidates and amidines.
\r\n\r\nSecond, we targeted the Melodinus alkaloids for total synthesis due to their unique structural features. Synthetic efforts toward scandine, the parent of the natural product family, are detailed herein. Our approach features a palladium catalyzed formal (3 + 2) cycloaddition of a vinyl cyclopropane and a \u03b2-nitrostyrene to rapidly assemble the central cyclopentane core of the natural product. Initial efforts focused on the synthesis and application of a 1,1-divinylcyclopropane to the formal (3 + 2) cycloaddition reaction, whereas later work entailed the use of a mono-vinylcyclopropane with the goal of installing the second requisite vinyl group at a later stage using modern C\u2013H functionalization technologies.
\r\n", "doi": "10.7907/Z9W9576V", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7496", "collection": "thesis", "collection_id": "7496", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02282013-171348639", "primary_object_url": { "basename": "BenLi Thesis Final Edit.pdf", "content": "final", "filesize": 10711126, "license": "other", "mime_type": "application/pdf", "url": "/7496/1/BenLi Thesis Final Edit.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Synthesis and Biological Studies of DNA-binding Cyclic Py-Im Polyamides", "author": [ { "family_name": "Li", "given_name": "Benjamin Chun Yeung", "clpid": "Li-Benjamin-Chun-Yeung" } ], "thesis_advisor": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Rees", "given_name": "Douglas C.", "clpid": "Rees-D-C" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Pyrrole-imidazole (Py-Im) polyamides are programmable oligomers that bind to the minor groove of DNA in a sequence-specific manner at affinities comparable to natural DNA-binding proteins. Hairpin polyamides have been shown to localize within the nucleus of live cells, disrupt protein-DNA interactions, and modulate endogenous gene expression. Cyclic polyamides display further enhanced DNA binding affinities and exhibit similar gene regulatory effects, but investigations into their biological activity have been limited by the lack of effective synthetic methods. Herein, we demonstrate the efficient synthesis of a focused library of cyclic polyamide utilizing a novel microwave-assisted solid-phase technique. The orthogonal protection strategy allowed for selective turn modifications, and the mild cleavage conditions gave access to polyamide cores beginning with a C-terminal imidazole. In addition to expanding our synthetic repertoire, we further examined the cytotoxicity and cell uptake profiles of the cyclic polyamide variants, which highlighted the significant changes in biological activity resulting from minor structural modifications. Molecular recognition of the polyamide turn unit was also explored by installing heteroatom substituents at the \u03b1-position. Interestingly, while none of the fluoro, hydroxyl, or amino derivatives increased turn specificity, the (S)-fluoro turn exhibited better tolerance for binding a C\u2022G pair. Finally, we optimized the synthesis of several biologically active hairpin polyamides on a 50-mg scale and examined their antitumor activity in mice xenograft models.", "doi": "10.7907/82YX-QB29", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7342", "collection": "thesis", "collection_id": "7342", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12192012-071010744", "primary_object_url": { "basename": "AYH-FullThesis 1-15.pdf", "content": "updated", "filesize": 91891131, "license": "other", "mime_type": "application/pdf", "url": "/7342/14/AYH-FullThesis 1-15.pdf", "version": "v12.0.0" }, "type": "thesis", "title": "Development of a Novel Ring Contraction Strategy and Application to the Total Synthesis of Presilphiperfolanol Natural Products", "author": [ { "family_name": "Hong", "given_name": "Allen Yu", "orcid": "0000-0002-4691-548X", "clpid": "Hong-Allen-Yu" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Virgil", "given_name": "Scott C.", "clpid": "Virgil-S-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Biologically active and structurally complex natural products provide a powerful driving force for the development of novel reaction methodology. Major advances can reshape the way chemists approach the construction of challenging chemical bonds.
\r\n\r\nIn this work, we begin by describing the development of a catalytic asymmetric synthesis of five and seven-membered rings containing all-carbon quaternary stereocenters. Enantioselective Pd-catalyzed decarboxylative allylic alkylation reactions of \u03b2-ketoester substrates afforded a variety of chiral seven-membered \u03b1-quaternary vinylogous esters. Initial attempts to convert these compounds to \u03b3-quaternary cycloheptenones led to the discovery of a two-carbon ring contraction reaction, which provided isomeric \u03b3-quaternary acylcyclopentenes. Subsequent adjustment of reaction parameters provided divergent access to the originally targeted cycloheptenones. Numerous synthetic applications of the two versatile product types are demonstrated. The methodology expands on our previous investigations of six-membered ring scaffolds and provides additional chiral building blocks for asymmetric total synthesis.
\r\n \r\nThe ring contraction approach to acylcyclopentenes was further developed in the total synthesis of the presilphiperfolanols, which are important intermediates in sesquiterpene biosynthesis. Key to our synthetic route to the tricyclic core was the application of intramolecular Diels\u2013Alder and Ni-catalyzed 1,4-hydroboration reactions. From these efforts, the enantioselective total synthesis of presilphiperfolan-1\u03b2-ol was achieved. Future research efforts seek to extend the synthetic route to presilphiperfolan-9\u03b1-ol and study the synthetic compounds in biomimetic carbocation rearrangement processes.
", "doi": "10.7907/Z9WW7FMB", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7181", "collection": "thesis", "collection_id": "7181", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:07312012-134600191", "primary_object_url": { "basename": "Keitz_Ben_Thesis_2013.pdf", "content": "final", "filesize": 5289537, "license": "other", "mime_type": "application/pdf", "url": "/7181/1/Keitz_Ben_Thesis_2013.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Selectivity in Ruthenium Catalyzed Olefin Metathesis: Applications and Origins", "author": [ { "family_name": "Keitz", "given_name": "Benjamin Keith", "clpid": "Keitz-Benjamin-Keith" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Ruthenium-based catalysts for olefin metathesis display high activity in the presence of common functional groups and have been utilized in a variety of chemical disciplines. This thesis describes the development of new catalysts with superior properties and mechanistic studies directed at understanding the factors governing catalyst activity and selectivity.
\r\n\tChapter 2 describes the preparation of acid-activated olefin metathesis catalysts containing acetylacetonate (acac)-type ligands. The effect of ligand structure and the exogenous acid on catalytic activity was examined. The acid-activated catalysts were also combined with a photoacid generator (PAG), which resulted in a highly active system for photo-activated olefin metathesis.
\r\n\tChapter 3 details the incorporation of mesoionic carbenes (MICs) into ruthenium metathesis catalysts. The activity of these catalysts in several metathesis assays was measured and correlated to their initiation rates. The protonolysis of a Ru-MIC bond and the incorporation of this reaction into an acid-activated catalyst are also described. \t
\r\n\tChapter 4 explores the relationship between catalyst structure and degenerate metathesis. A ring-closing metathesis assay was used to measure the preference of different catalysts for productive or degenerate metathesis. The relationship between degenerate metathesis and reactions such as ethenolysis is also discussed.
\r\n\tChapter 5 describes the study of ruthenacyclobutanes formed from the degenerate metathesis selective catalysts presented in Chapter 4. The rates of various chemical exchange processes were measured and correlated to catalyst structure. Kinetic parameters for the rate-limiting step in ring-closing metathesis were also measured and used to rationalize the differences in productive/degenerate selectivity for various catalysts.
\t\r\n\tChapter 6 details the preparation and study of C-H-activated ruthenium catalysts for Z-selective olefin metathesis. Ligand effects on catalyst activity and selectivity are explored along with the application of these catalysts in Z-selective cross-metathesis and ring-opening metathesis polymerization.
", "doi": "10.7907/01TJ-QC10", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7215", "collection": "thesis", "collection_id": "7215", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09282012-144447840", "primary_object_url": { "basename": "Nelson-Hosea-Martin-2013.pdf", "content": "final", "filesize": 18012457, "license": "other", "mime_type": "application/pdf", "url": "/7215/1/Nelson-Hosea-Martin-2013.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "A Unified Synthetic Approach to the Transtaganolide and Basiliolide Natural Products", "author": [ { "family_name": "Nelson", "given_name": "Hosea Martin", "clpid": "Nelson-Hosea-Martin" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Herein are described the first total syntheses of several members of the transtaganolide and basiliolide natural product family. A general strategy, hinging upon the use of a biomimetic Ireland\u2013Claisen rearrangement/Diels\u2013Alder cycloaddition cascade, was developed. It allowed for the rapid assembly of the most structurally complex, and biologically active members of the family.
\r\n\r\nA brief introduction that surveys the use of the pyrone Diels\u2013Alder cycloaddition in total synthesis precedes details of our synthetic efforts. The diversity of structural motifs accessible through this reaction manifold is described through literature examples.
\r\n\r\nThe account of our experimental work begins with details of extensive model studies. First, a simple system was prepared which probed the ability to construct basiliolide B via an intramolecular pyrone Diels\u2013Alder reaction. It was demonstrated that the sterically congested core could be constructed in a highly diastereoselective fashion using this technology. Second, a simple prenylated pyrone was constructed, and shown to undergo a facile Ireland\u2013Claisen rearrangement under a variety of conditions. Subsequently, the utilization of these two methods within a cascade allowed for the rapid construction of racemic transtaganolide C, transtaganolide D, basiliolide B, and epi-8-basiliolide B. Furthermore, a novel Pd-catalyzed [5+2] annulation technology is utilized to construct the venerable, carboxy-ketene-acetal containing C-ring present in most of the metabolites.
\r\n\r\nIntegration of asymmetry into our general strategy is also described. Utilization of a chiral silane directing group allowed for the successful and rare application of an enantioselective Ireland\u2013Claisen rearrangement, culminating in the total syntheses of (+)- transtaganolide C, (\u2013)-transtaganolide D, (+)-transtaganolide B, and (\u2013)-transtaganolide A. Furthermore, the impact of this work on existing biosynthetic hypotheses is discussed.
\r\n", "doi": "10.7907/09DW-P586", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7892", "collection": "thesis", "collection_id": "7892", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06112013-202017350", "primary_object_url": { "basename": "Heather R Williamson Thesis library.pdf", "content": "final", "filesize": 4523391, "license": "other", "mime_type": "application/pdf", "url": "/7892/1/Heather R Williamson Thesis library.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Engineering Multi Step Electron Tunneling Systems in Proteins", "author": [ { "family_name": "Williamson", "given_name": "Heather R.", "clpid": "Williamson-Heather-R" } ], "thesis_advisor": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" } ], "thesis_committee": [ { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Multi-step electron tunneling, or \u201chopping,\u201d has become a fast-developing research field with studies ranging from theoretical modeling systems, inorganic complexes, to biological systems. In particular, the field is exploring hopping mechanisms in new proteins and protein complexes, as well as further understanding the classical biological hopping systems such as ribonuclease reductase, DNA photolyases, and photosystem II. Despite the plethora of natural systems, only a few biologically engineered systems exist. Engineered hopping systems can provide valuable information on key structural and electronic features, just like other kinds of biological model systems. Also, engineered systems can harness common biologic processes and utilize them for alternative reactions. In this thesis, two new hopping systems are engineered and characterized.
\r\n\r\nThe protein Pseudomonas aeruginosa azurin is used as a building block to create the two new hopping systems. Besides being well studied and amenable to mutation, azurin already has been used to successfully engineer a hopping system. The two hopping systems presented in this thesis have a histidine-attached high potential rhenium 4,7-dimethyl-1,10-phenanthroline tricarbonyl [Re(dmp)(CO)3] + label which, when excited, acts as the initial electron acceptor. The metal donor is the type I copper of the azurin protein. The hopping intermediates are all tryptophan, an amino acid mutated into the azurin at select sites between the photoactive metal label and the protein metal site. One system exhibits an inter-molecular hopping through a protein dimer interface; the other system undergoes intra-molecular multi-hopping utilizing a tryptophan \u201cwire.\u201d The electron transfer reactions are triggered by excitation of the rhenium label and monitored by UV-Visible transient absorption, luminescence decays measurements, and time-resolved Infrared spectroscopy (TRIR). Both systems were structurally characterized by protein X-ray crystallography.
", "doi": "10.7907/BRZJ-YZ76", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7883", "collection": "thesis", "collection_id": "7883", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06102013-121027424", "primary_object_url": { "basename": "Bennett-N-BThesis.pdf", "content": "final", "filesize": 118366833, "license": "other", "mime_type": "application/pdf", "url": "/7883/79/Bennett-N-BThesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Palladium-Catalyzed Asymmetric Allylic Alkylation: Insights, Application Toward Cyclopentanoid and Cycloheptanoid Molecules, and the Total Synthesis of Several Daucane Sesquiterpenes ", "author": [ { "family_name": "Bennett", "given_name": "Nathan Bruce", "clpid": "Bennett-Nathan-Bruce" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Virgil", "given_name": "Scott C.", "clpid": "Virgil-S-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The asymmetric construction of quaternary stereocenters is a topic of great interest in the organic chemistry community given their prevalence in natural products and biologically active molecules. Over the last decade, the Stoltz group has pursued the synthesis of this challenging motif via a palladium-catalyzed allylic alkylation using chiral phosphinooxazoline (PHOX) ligands. Recent results indicate that the alkylation of lactams and imides consistently proceeds with enantioselectivities substantially higher than any other substrate class previously examined in this system. This observation prompted exploration of the characteristics that distinguish these molecules as superior alkylation substrates, resulting in newfound insights and marked improvements in the allylic alkylation of carbocyclic compounds.
\r\n\r\nGeneral routes to cyclopentanoid and cycloheptanoid core structures have been developed that incorporate the palladium-catalyzed allylic alkylation as a key transformation. The unique reactivity of \u03b1-quaternary vinylogous esters upon addition of hydride or organometallic reagents enables divergent access to \u03b3-quaternary acylcyclopentenes or cycloheptenones through respective ring contraction or carbonyl transposition pathways. Derivatization of the resulting molecules provides a series of mono-, bi-, and tricyclic systems that can serve as valuable intermediates for the total synthesis of complex natural products.
\r\n\r\nThe allylic alkylation and ring contraction methodology has been employed to prepare variably functionalized bicyclo[5.3.0]decane molecules and enables the enantioselective total syntheses of daucene, daucenal, epoxydaucenal B, and 14-p-anisoyloxydauc-4,8-diene. This route overcomes the challenge of accessing \u03b2-substituted acylcyclopentenes by employing a siloxyenone to effect the Grignard addition and ring opening in a single step. Subsequent ring-closing metathesis and aldol reactions form the hydroazulene core of these targets. Derivatization of a key enone intermediate allows access to either the daucane sesquiterpene or sphenobolane diterpene carbon skeletons, as well as other oxygenated scaffolds.
\r\n", "doi": "10.7907/ZP3K-A474", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7847", "collection": "thesis", "collection_id": "7847", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06062013-031825238", "primary_object_url": { "basename": "Nani-R-R-2013thesis.pdf", "content": "final", "filesize": 23539137, "license": "other", "mime_type": "application/pdf", "url": "/7847/1/Nani-R-R-2013thesis.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "The Intramolecular Buchner Reaction of \u03b1-Diazo-\u03b2-Ketonitriles: Development and Application to the Total Synthesis of (+)-Salvileucalin B", "author": [ { "family_name": "Nani", "given_name": "Roger Rauhauser", "clpid": "Nani-Roger-Rauhauser" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Since its discovery in 1896, the Buchner reaction has fascinated chemists for more than a century. The highly reactive nature of the carbene intermediates allows for facile dearomatization of stable aromatic rings, and provides access to a diverse array of cyclopropane and seven-membered ring architectures. The power inherent in this transformation has been exploited in the context of a natural product total synthesis and methodology studies.
\r\n\r\nThe total synthesis work details efforts employed in the enantioselective total synthesis of (+)-salvileucalin B. The fully-substituted cyclopropane within the core of the molecule arises from an unprecedented intramolecular Buchner reaction involving a highly functionalized arene and an \u03b1-diazo-\u03b2-ketonitrile. An unusual retro-Claisen rearrangement of a complex late-stage intermediate was discovered on route to the natural product.
\r\n\r\nThe unique reactivity of \u03b1-diazo-\u03b2-ketonitriles toward arene cyclopropanation was then investigated in a broader methodological study. This specific di-substituted diazo moiety possesses hitherto unreported selectivity in intramolecular Buchner reactions. This technology was enables the preparation of highly functionalized norcaradienes and cyclopropanes, which themselves undergo various ring opening transformations to afford complex polycyclic structures.
\r\n\r\nFinally, an enantioselective variant of the intramolecular Buchner reaction is described. Various chiral copper and dirhodium catalysts afforded moderate stereoinduction in the cyclization event.
\r\n", "doi": "10.7907/2KGP-7X92", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:6755", "collection": "thesis", "collection_id": "6755", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12192011-112528810", "primary_object_url": { "basename": "Tonks_Thesis_Corrected.pdf", "content": "final", "filesize": 10940169, "license": "other", "mime_type": "application/pdf", "url": "/6755/1/Tonks_Thesis_Corrected.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Fundamental Studies of Early Transition Metal-Ligand Multiple Bonds: Structure, Electronics, and Catalysis", "author": [ { "family_name": "Tonks", "given_name": "Ian Albert", "clpid": "Tonks-Ian-Albert" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Two major topics are covered: the first section is focused on the structure, electronics, stoichiometric reactivity and catalysis of nonmetallocene early transition metal complexes that often contain metal-ligand multiple bonds (Chapters 2-4); the second section is dedicated to the development of hydrazide(2-) ligands for group 5 elements, which were heretofore unexplored as ligands for group 5 (Chapters 5-6).
\r\n\r\nA series of tantalum imido and amido complexes supported by a pyridine linked bis(phenolate) (ONO) ligand has been synthesized. Characterization of these complexes via X ray crystallography reveals both Cs and C2 binding modes of the bis(phenolate)pyridine ligand. DFT calculations and molecular orbital analyses of the complexes have revealed that the preference for Cs symmetric ligand binding is a result of Ta-O \u03c0 bonding: in cases where Ta-O \u03c0 bonding is overridden by stronger Ta N \u03c0 bonding, C2 symmetric ligand binding is preferred because this is the lowest energy geometric conformation.
\r\n\r\nTitanium and zirconium complexes supported by a related pyridine bis(anilide) ligand (NNN = pyridine 2,6 bis(N-mesitylanilide)) have been synthesized. The ligand geometry of these complexes is dictated solely by chelate ring strain rather than metal-ligand \u03c0-bonding. These complexes were tested as propylene polymerization precatalysts, with most complexes giving low to moderate activities (10^2-10^4 g/mol*h) for the formation of polypropylene.
\r\n\r\n(ONO)TiX2 complexes are highly active precatalysts for the intermolecular hydroamination of internal alkynes with primary arylamines and some alkylamines. (ONO)TiBn2 also cyclotrimerizes dimethylacetylene. During the cyclotrimerization reaction the Ti(IV) precatalyst is reduced to Ti(II), which is the active species for catalysis. The mechanism of formation of TiII has been investigated and an (ONO)Ti(II) species has been trapped by ethylene and crystallographically characterized.
\r\n\r\nHydrazide complexes (dme)TaCl3(NNPh2) and (dme)NbCl3(NNPh2) (dme = 1,2 dimethoxyethane) were synthesized. Unlike the corresponding imido derivatives, (dme)TaCl3(NNPh2) is dark blue due to an LMCT that has been lowered in energy as a result of an N\u03b1-N\u03b2 antibonding interaction that raises the HOMO. Reaction of (dme)TaCl3(NNPh2) with a variety of neutral, mono and dianionic ligands generates the corresponding ligated complexes retaining the k-1 bound [TaNNPh2] moiety.
\r\n\r\nFurthermore, a series of colorful terminal hydrazide complexes of the type (dme)MCl3(NNR2) (M = Nb, Ta; R = alkyl or aryl) or (MeCN)WCl4(NNR2) have been synthesized. Perturbing the electronic environment of the \u03b2 nitrogen significantly impacts the lowest-energy charge transition in these complexes, and in the W complexes leads to metal based reduction. The photophysics of these complexes highlights the importance of the difference in reduction potential between metal centers, and could lead to differences in ligand- and/or metal-based redox chemistry in early transition metal hydrazidos, especially in the context of N2 fixation.
\r\n\r\nFinally, the hydroxy-bridged dimer [(COD)IrOH]2 (COD = 1,5-cyclooctadiene) cleanly C-H activates indene and cyclopentadiene to form (COD)Ir(\u03b73-indenyl) and (COD)Ir(\u03b75-C5H5), respectively. The kinetics of the formation of (COD)Ir(\u03b73-indenyl) has been investigated, and the mechanism involves coordination of indene to the dimeric [(COD)IrOH]2 followed by rate determining C-H activation from the dimer-indene unit.
\r\n", "doi": "10.7907/FYGA-KK18", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:6859", "collection": "thesis", "collection_id": "6859", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03212012-034245395", "primary_object_url": { "basename": "01_-_Intro_-_FINAL.pdf", "content": "final", "filesize": 334443, "license": "other", "mime_type": "application/pdf", "url": "/6859/1/01_-_Intro_-_FINAL.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Aryne Annulation Reactions Toward the Synthesis of Heterocyclic Molecules", "author": [ { "family_name": "Gilmore", "given_name": "Christopher Dennis", "clpid": "Gilmore-Christopher-Dennis" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The last decade has seen an outgrowth in the development of synthetic methodologies exploiting benzyne. The unique ability of this reactive intermediate to directly furnish ortho-difuntionalized aromatic systems first stoked interest in this research group as a possible partner in asymmetric arylation reactions. Since our initial forays, we have expanded our synthetic strategies to include bond insertions, cycloadditions, condensations, and multicomponent reactions. The first project discussed in this volume is the development of an aryne annulation strategy for constructing common, synthetically useful heterocyclic structures in a convergent manner. We have developed a convergent approach to indoles and indolines. Likewise, through an orthogonal functional group intallation upon an enamine substrate, isoquinolines, quinolines, and isoquinolones can all be accessed as well. In this manner, we have been able to generate an array of functionalized heterocycles, including some that are prohibited by traditional means of synthesis. We have also begun to understand some of the reactivity trends in this context for the elusive aryne reaction partner. The development of the aryne annulation strategy for the synthesis of isoquinolines directly led to the shortest reported total synthesis of the opiate alkaloid papaverine, and the tetrahydroisoquinoline anticancer antibiotic quinocarcin. Our more recent, ongoing efforts toward the synthesis of the bis-tetrahydroisoquinoline antitumor molecule jorumycin and its many structural relatives are detailed herein. Jorumycin has been targeted through a combination of aryne annulation and acyl-alkylation/condensation methodologies aimed at the synthesis of a functionalized bis-isoquinoline intermediate. Reduction of this key bis-isoquinoline to a bis-tetrahydroisoquinoline and subsequent lactamization will provide the pentacyclic core of jorumycin and related natural products in only three steps from simple isoquinoline building blocks. The final project described is the development of several different aryne multicomponent reactions to form novel carbo- and heterocyclic scaffolds, including iminoisobenzfurans, iminoindenones, dibenzoketocaprolactams, and 2-quinolones.\r\n", "doi": "10.7907/C8F7-DQ34", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:7010", "collection": "thesis", "collection_id": "7010", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05082012-070058810", "primary_object_url": { "basename": "Thomas_Renee_M_Thesis.pdf", "content": "final", "filesize": 2307476, "license": "other", "mime_type": "application/pdf", "url": "/7010/1/Thomas_Renee_M_Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "The Design, Synthesis, and Application of Ruthenium Metathesis Catalysts for the Preparation of Small Molecules and Polymers", "author": [ { "family_name": "Thomas", "given_name": "Renee Michelle", "clpid": "Thomas-Renee-Michelle" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Olefin metathesis is a widely used method for constructing carbon\u2013carbon double bonds. This methodology has broad applications in organic and polymer chemistry, and the continued design of highly efficient catalysts has been critical to the success of this reaction. The main goal of this thesis was to design and synthesize new catalysts for better selectivity and for improved properties for targeted applications, as well as to explore different ligand structures for optimal catalyst performance in olefin metathesis.
\r\n\r\nThe application of ruthenium catalysts for the ring-opening metathesis polymerization of challenging monomer 1,5-dimethyl-1,5-cyclooctadiene in the presence of a chain transfer agent is discussed in chapter 2. A variety of complexes were explored to find the ideal catalyst for this transformation, enabling the synthesis of telechelic polyisoprene, which has extensive applications in block copolymerization.
\r\n\r\nChiral N-alkyl, N-aryl NHC ruthenium catalysts were designed and synthesized to improve the enantioselectivity during asymmetric ring-opening cross-metathesis. Mechanistic studies of these catalysts revealed a preference for methylidene propagation compared to previous NHC catalysts. Chapter 3 describes these studies, in addition to the screening of a variety of chiral ligands for optimal enantioselectivity. Some of these catalysts gave very high enantioselectivity, comparable to the best reported ruthenium catalysts. Insights into the stability of these complexes as a propagating methylidene led to investigating them in applications where propagation as a methylidene is desirable.
\r\n\r\nN-aryl, N-alkyl NHC ruthenium catalysts were designed and synthesized for improved selectivity during ethenolysis reactions, which require a ruthenium methylidene species to react with an internal olefin to yield a terminal olefin and a ruthenium alkylidene species. Subsequent reaction of this ruthenium alkylidene species with ethylene gives the other terminal olefin. This reaction can be applied to the internal olefin of seed oils to generate valuable products that are typically derived from petroleum sources, thus providing an environmentally friendly route to the same products. An important component of ethenolysis catalysts is stability to existing as a methylidene, a property of the N-aryl, N-alkyl NHC ruthenium catalysts described in chapter 4.
\r\n \r\nChapter 5 describes the design and synthesis of sterically hindered N-aryl, N-alkyl NHC ruthenium catalysts for application in latent metathesis. These complexes also show excellent stability at elevated temperatures for extended periods of time.
\r\n\r\nAppendix A contains NMR spectra for catalysts described in chapter 4, as well as X-ray crystal structures for two of the catalysts.
\r\n\r\nAppendix B contains NMR spectra for catalysts described in chapter 5, as well as X-ray crystal structures for two of those catalysts.
\r\n", "doi": "10.7907/VTAR-5J81", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:6732", "collection": "thesis", "collection_id": "6732", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11092011-100634353", "primary_object_url": { "basename": "PMT_Thesis_2012_Open_File.pdf", "content": "final", "filesize": 64438814, "license": "other", "mime_type": "application/pdf", "url": "/6732/1/PMT_Thesis_2012_Open_File.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Exploiting the Reactivity of Arynes in the Total Synthesis of Natural Products", "author": [ { "family_name": "Tadross", "given_name": "Pamela Michele", "clpid": "Tadross-Pamela-Michele" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" }, { "family_name": "Virgil", "given_name": "Scott C.", "clpid": "Virgil-S-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Within 14 years of the seminal experiments of J. D. Roberts leading to the first proposal of the structure of benzyne, synthetic organic chemists recognized the potential to exploit this highly reactive intermediate (and its substituted variants) in the synthesis of natural products. More specifically, it was recognized that arynes offered the strategic advantage of rapidly functionalizing an aromatic ring by forming multiple carbon\u2013carbon or carbon\u2013heteroatom bonds in a single operation, often in a regioselective manner. Herein are reported three separate efforts aimed at constructing natural products by aryne-based methodologies. In each of the studies described in the following chapters, the implementation of new aryne technologies developed in our group to natural product synthesis has resulted in concise, convergent, and general strategies to our targets.
\r\n\r\nThe first project discussed in this work is the enantioselective total synthesis of (\u2013)-curvularin by an acyl-alkylation reaction of a protected resorcinylic silyl aryl triflate aryne precursor with a \u03b2-ketolactone. Application of this strategic disconnection resulted in a six-step convergent synthesis of the polyketide natural product, the shortest to date. These efforts also resulted in the syntheses of curvulin and diplodialide C.
\r\n\r\nIn our efforts toward the total synthesis of two naturally occurring HIV integrase inhibitors, integrastatins A and B, we attempted to utilize a sequence involving an acyl-alkylation followed by an ortho-Fries-type rearrangement to access the tetracyclic core of the natural products. However, this proved to be a significant challenge and led to the development of an alternative route to the tetracyclic integrastatin core by a Wacker cyclization of a diol onto a pendant olefin.
\r\n\r\nFinally, ongoing progress toward the synthesis of the bis-tetrahydroisoquinoline natural product jorumycin is detailed. In a departure from the efforts toward curvularin and the integrastatins, jorumycin has been targeted through the application of a combination of aryne annulation and acyl-alkylation/condensation methodologies aimed at the synthesis of a functionalized bis-isoquinoline intermediate. Reduction of this key bis-isoquinoline to a bis-tetrahydroisoquinoline and subsequent lactamization provided the pentacyclic core of jorumycin and related natural products in only two steps from simple isoquinoline building blocks.
", "doi": "10.7907/0HAZ-QF41", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:6716", "collection": "thesis", "collection_id": "6716", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10162011-170949582", "primary_object_url": { "basename": "ThesisTotal.pdf", "content": "final", "filesize": 7916440, "license": "other", "mime_type": "application/pdf", "url": "/6716/1/ThesisTotal.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Improving Selectivity in Olefin Metathesis for Small Molecule Synthesis and Materials Applications", "author": [ { "family_name": "Li", "given_name": "Jean", "clpid": "Li-Jean" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The olefin metathesis reaction has been studied extensively from the perspective of catalyst design and synthesis, as well as from that of reaction control and application in a variety of fields. Beginning with the design of enantioselective catalysts based on the \u201cgeared\u201d C2-symmetric N-heterocyclic carbene (NHC) containing ruthenium catalysts, architectural modifications were envisioned and implemented in order to control the N-bound arene tilt angle (Chapter 2). From there, the asymmetric class of olefin metathesis reactions were explored and trends in enantioselectivities were obtained and reapplied in the further design of novel, chiral catalysts. These asymmetric catalysts were developed not only for their useful application in a range of asymmetric metathesis reactions, but also to provide insight into the spatial arrangement of the NHC ligand during the catalytic cycle.
\r\n\r\nAmidst this overall cyclical process, mechanistic understandings of the ruthenium-based olefin metathesis catalysts were garnered and integrated; and the concept of a covalentlylinked NHC ligand was born. In Chapter 3, both the cis-fused and trans-fused versions of this linked NHC were constructed, with each independent synthesis hinging on a key ringclosing metathesis reaction mediated by ruthenium catalysts. These novel NHCs were then translated into rhodium-bound complexes and their unique structural conformations were studied with X-Ray crystallography.
\r\n\r\nChapter 4 explores the forefront of control and selectivity in olefin metathesis, specifically, in the selective reactivity of dienes in cross-metathesis reactions. The desire to synthesize conjugated dienes, thus limiting reactivity to one of two potentially reactive olefins, is both mechanistically intriguing and contains practical applications for the synthesis of linear pheromone natural products. These pheromones show great utility as a green, biorational pesticide with few ecological and biological side-effects. Thus, exploration of the general diene cross-metathesis reaction was focused on the actual synthesis of codlemone, one of the world\u2019s most sought-after insecticides.
\r\n\r\nThe potential of the olefin metathesis reaction for biomedical applications was further explored in the application of peptide-containing polynorbornenes formed from ringopening metathesis polymerization (ROMP). In order to apply synthetic materials made from ROMP in biological applications, a route towards ruthenium removal to the FDAapproved levels of 10 parts per million (ppm) was developed. Once low ppm remnant ruthenium content was obtained, the synthesis of varying monomers for crosslinking to bulk materials was explored.
", "doi": "10.7907/JVC6-7A52", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:6710", "collection": "thesis", "collection_id": "6710", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10112011-135016656", "primary_object_url": { "basename": "Kedrowski_Thesis.pdf", "content": "final", "filesize": 54132836, "license": "other", "mime_type": "application/pdf", "url": "/6710/1/Kedrowski_Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "I. Chemical-Scale Studies of Ligand-Gated Ion Channels, and II. Novel Methods for Phosphonate Synthesis", "author": [ { "family_name": "Kedrowski", "given_name": "Sean M. A.", "clpid": "Kedrowski-Sean-M-A" } ], "thesis_advisor": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Clemons", "given_name": "William M.", "clpid": "Clemons-W-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Section 1: Chemical-Scale Studies of Ligand-Gated Ion Channels : Ligand-gated ion channels are amazing molecular machines that respond to specific small-molecule agonists by opening a central pore to enable ions to flow through them. In the aggregate, they transduce chemical signals into electrical currents, and they have numerous critical physiological functions. The tools of pharmacology and unnatural amino acid (and hydroxy acid) mutagenesis enable us to study these receptors on an atomic level. Two such projects are presented here. First, the synthesis of a new 5-HT3 receptor agonist helps to map the receptor\u2019s binding site. Second, mutant cycle analysis in the nicotinic acetylcholine receptor with the novel unnatural residue \u03b1-hydroxyserine (Sah) enables the identification of a crucial hydrogen bond whose formation is part of the pathway leading from acetylcholine binding to pore opening.
\r\nSection 2: Novel Methods for Phosphonate Synthesis : Phosphonates are a key functional group in both organic synthesis and biological chemistry. The Arbuzov reaction stands as dominant method available for synthesizing this important class of compounds. Two new methods for phosphonate synthesis are presented here. The first method enables room-temperature phosphonate synthesis from carboxylic acids, taking advantage of a novel Wolff-Kishner-type reductive deoxygenation of an intermediate acyl phosphonate. The second method enables phosphonate synthesis through the reductive coupling of ketones/aldehydes with dialkyl phosphites, mediated by a tosylhydrazone derivative. The latter method requires only mild heating (60 \u00b0C) and enables access to phosphonates containing azides, benzyl halides, and other functional groups poorly tolerated by the Arbuzov onditions.
", "doi": "10.7907/RQ16-6C44", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:6579", "collection": "thesis", "collection_id": "6579", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08112011-151147364", "primary_object_url": { "basename": "ECW_Thesis_Chapter1_Through_Chapter4.pdf", "content": "final", "filesize": 1693397, "license": "other", "mime_type": "application/pdf", "url": "/6579/1/ECW_Thesis_Chapter1_Through_Chapter4.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Synthesis, Characterization, and Reactivity Studies of Pyridine Bis(anilide) Iron Complexes", "author": [ { "family_name": "Weintrob", "given_name": "Edward Charles", "clpid": "Weintrob-Edward-Charles" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The unifying concept within this thesis is the investigation of pyridine bis(anilide) (NNN) iron complexes. Within this topic, chapter 1 speaks to the motivation behind studying these complexes, and how they relate to problems within iron catalysis in general. Chapter 2 introduces the general ligand design and the features which are thought to give unique and desirable properties to the complexes derived from it. The mesityl susbstituted ligand [MesNNN]H2 and subsequently ferrous ([MesNNN]Fe(THF)) and ferric ([MesNNN]FeI and ([MesNNN]Fe)2O) complexes are synthesized. The properties of the complexes are investigated using a variety of characterization techniques. Such techniques include paramagnetic 1H NMR spectroscopy, X-ray crystallography, Evans method, cyclic voltammetry, DFT calculations, and UV-vis spectrscopy. A detailed explanation of the challenges and solutions involved in using paramagnetic NMR are discussed. Crystallographic data indicate that the ligand framework confers a quite unusual geometry about the iron center, especially for the ferrous derivative [MesNNN]Fe(THF). The factors involved in this geometry are discussed, and DFT calculations supplement this discussion. Chapter 3 focuses on the reactivity of the iron complexes. Various oxidants and reductants were employed which interconvert the iron derivatives in chapter 2. Organometallic derivatives [MesNNN]FeR (R = hydride, alkyl, aryl) were not accessible, likely due to homolytic processes. L ligand exchange for [MesNNN]Fe(THF) was investigated. Ethylene reversibly binds, while cyclohexene does not. Trimethylphosphonium methylidene displaces THF to generate [MesNNN]FeCH2PMe3. Although the I oxidation state was accessible for [MesNNN]Fe(THF) electrochemically, attempts to chemically produce Fe I complexes based on the NNN ligand led to multiple products. Chapter 4 focuses on the intramolecular C-H activation of [MesNNN]Fe(THF) with RN3 to afford [MesNNN-NHR]Fe (R = SiMe3, adamantyl). The kinetics of the reaction with Me3SiN3 was investigated in detail, and a mechanism was proposed. Iron complexes based on the pincer ligands [tBuNNN] and [ONO] were investigated. ", "doi": "10.7907/M1Y4-RM69", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:6197", "collection": "thesis", "collection_id": "6197", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12072010-151616905", "primary_object_url": { "basename": "AJMM_Thesis_Final_Corrected.pdf", "content": "final", "filesize": 26416759, "license": "other", "mime_type": "application/pdf", "url": "/6197/4/AJMM_Thesis_Final_Corrected.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Emissive Monocopper Amidophosphine Complexes and Lewis Acid-Assisted Reductive Coupling of Carbon Monoxide", "author": [ { "family_name": "Miller", "given_name": "Alexander James Minden", "clpid": "Miller-Alexander-James-Minden" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Two major themes are presented, in roughly chronological order: the synthesis and characterization of photoluminescent copper complexes are described, followed by studies on the selective conversion of synthesis gas (CO and H2) to oxygenates. With the latter comprising the majority of the work, it is the subject of the introductory Chapter 1. In Chapter 2, the photoluminescent copper chemistry is introduced, and the synthesis and photophysics of monomeric amidophosphine complexes of copper is presented. The copper complexes are exceptional luminophores, with quantum efficiency up to 70% and lifetimes up to 150 \u03bcs. In Chapter 3, homogeneous CO hydrogenation is pursued using a strategy reliant on the incorporation of pendent Lewis acidic groups into the secondary coordination sphere of a metal carbonyl complex. This design feature promotes facile C\u2013H and C\u2013C bond formation, with transition metal hydrides as the hydrogen source. A structure-function study investigating the specific role of the Lewis acid determined that thefirst C\u2013H bond formation is not particularly sensitive to the acid, whereas the second C\u2013H bond formation and C\u2013C coupling are both highly sensitive to the length of the tether between the metal and the borane. In Chapter 4, this chemistry is extended to utilize dihydrogen directly as a reductant, in a \"frustrated Lewis pair\" (FLP) mechanism. A strong phosphazene base is too bulky to interact with the pendent borane, but can heterolytically cleave dihydrogen in concert with the borane to generate a borohydride that transforms the carbonyl ligands into a metal-bound C2 organic fragment. In Chapter 5, Lewis acidic boranes are again employed as promoters of reductive chemistry, this time for CO2 reduction. The same late transition metal hydrides that were employed for CO reduction, such as [HNi(dmpe)2][BF4] (dmpe = 1,2-bis(dimethylphosphino)ethane), are able to reduce CO2 gas when used in concert with the appropriate borane, affording a borane-formate adduct. In Chapter 6, the \"frustrated Lewis pair\" concept is extended to a different problem: the dehydrogenation of amine-boranes, which are candidates for hydrogen storage applications. Treatment of amine-boranes with the FLP tBu3P/B(C6F5)3 effects rapid and quantitative transfer of H2 from the amine-borane, forming cyclic aminoborane products along with [tBu3PH][HB(C6F5)3]. Appendices are provided, including early work on Br\u00f8nsted acid-assisted CO reduction, speciation of trialkylborohydrides, tabulating NMR impurities in deuterated solvents of interest to the organometallic chemist, and crystallographic tables.\r\n", "doi": "10.7907/SPH6-R695", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6476", "collection": "thesis", "collection_id": "6476", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05312011-072858726", "primary_object_url": { "basename": "thesis.pdf", "content": "final", "filesize": 22584816, "license": "other", "mime_type": "application/pdf", "url": "/6476/1/thesis.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Mechanistic Investigations into the Palladium-Catalyzed Decarboxylative Allylic Alkylation of Ketone Enolates Using the PHOX Ligand Architecture\r ", "author": [ { "family_name": "Sherden", "given_name": "Nathaniel Haynes", "clpid": "Sherden-Nathaniel-Haynes" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Palladium-catalyzed asymmetric allylic alkylation has become a large and important field for chemical synthesis. Many methodologies in this field offer mild conditions under which challenging and important molecular features can be reliably synthesized, including chiral all-carbon quaternary stereocenters. As a result, palladium- catalyzed asymmetric allylic alkylation has found significant use in total synthesis, and growing use in industry. While the general process of palladium-catalyzed asymmetric allylic alkylation has been studied for decades, there have been a number of recent modifications and developments, such as asymmetric versions of decarboxylative allylic alkylation procedures that are not yet well understood. The development of future implementations and improvements to palladium-catalyzed asymmetric allylic alkylation and related methodologies is expected to be facilitated by a better understanding of these more recent developments, and thus further mechanistic investigation is warranted.
\r\n\r\nReported herein is a set of investigations into the palladium-catalyzed decarboxylative asymmetric allylic alkylation of ketone enolates using the PHOX ligand architecture. By monitoring the reaction via 31P NMR, a series of previously unidentified key intermediates is discovered. Two representatives of these key intermediates are isolated and characterized. The solution behavior of these species under reaction-like conditions is studied along with a few novel and related complexes. The role of these intermediates and their impact on the behavior of the reaction and product formation is discussed.\tPreviously confounding experimentally observed behavior for this methodology is rationalized via the properties elucidated for these discovered intermediates.
", "doi": "10.7907/QEAX-9N40", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:5986", "collection": "thesis", "collection_id": "5986", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08042010-151446303", "primary_object_url": { "basename": "Thesis_final2.pdf", "content": "final", "filesize": 14207405, "license": "other", "mime_type": "application/pdf", "url": "/5986/7/Thesis_final2.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Palladium(II)-Catalyzed Oxidation Reactions in Natural Product Synthesis: Efforts toward Bielschowskysin and Phalarine", "author": [ { "family_name": "Meyer", "given_name": "Michael Elliott", "clpid": "Meyer-Michael-Elliott" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Two types of oxidative transformations, an oxidative kinetic resolution and an oxidative heterocyclization, have been developed by several laboratories using palladium(II)-catalysis to provide enantioenriched products. The main drawback of these asymmetric transformations is the limited substrate scope for each set of conditions. To address this, the Stoltz laboratory developed a unique platform utilizing palladium(II)-catalysis that provides a highly effective oxidative kinetic resolution of secondary alcohols and an asymmetric oxidative heterocyclization of phenols. Key to this platform is the use of (\u2013)-sparteine as the chiral ligand and O2 as the stoichiometric oxidant. Both of these methodologies will be featured in this thesis as they were applied toward the total synthesis of complex natural products.
\t\r\n\r\nOur palladium(II)-catalyzed oxidative kinetic resolution was used to access an enantioenriched intermediate in our efforts toward the synthesis of bielschowskysin, a polycyclic diterpenoid. A key disconnection in our strategy was formation of the cyclobutane core of bielschowskysin from a cyclopropane intermediate. After considerable experimentation, we were able to synthesize a cyclopropane intermediate that could be used for future research.
\r\n\r\nIn separate work, we hoped to use two palladium(II)-catalyzed oxidative heterocyclization reactions to provide the core of phalarine, a polycyclic alkaloid. The synthesis of a key intermediate relied on a Stille coupling reaction of a complex 4,5,7-substituted indole and a nitro-arene. Model cyclization studies on an aniline substrate gave inconclusive results, while a model of a phenolic substrate has shown that cyclization onto styrenyl olefins is possible.
\r\n", "doi": "10.7907/J3YQ-SP42", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6243", "collection": "thesis", "collection_id": "6243", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02152011-145456588", "primary_object_url": { "basename": "Thesis_Full.pdf", "content": "final", "filesize": 7250128, "license": "other", "mime_type": "application/pdf", "url": "/6243/9/Thesis_Full.pdf", "version": "v11.0.0" }, "type": "thesis", "title": "Iridium Corroles: Synthesis, Properties, and Electronic Structure", "author": [ { "family_name": "Palmer", "given_name": "Joshua Henry", "clpid": "Palmer-Joshua-Henry" } ], "thesis_advisor": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The synthesis, properties, and electronic structures of a family of iridium corrole complexes are discussed in detail. These compounds represent the first well-characterized examples of third-row metals being inserted successfully into the small corrole binding pocket; they possess a planar macrocycle, which neither saddles nor ruffles upon bromination, and are bound at the axial positions by either two amine ligands or one phosphine. Unlike their well-studied cobalt and rhodium analogues, whose redox activity is restricted primarily to the corrole ring, iridium corroles can be oxidized to produce an electron paramagnetic resonance spectrum that has extremely anisotropic g tensor components, implying mixing of the 5d orbitals into the oxidized ground state and opening the door to possible higher-valent iridium complexes. Detailed experimental and computational studies are presented showing that this oxidized ground state is actually mostly corrole-based, as has been found in the past for numerous other supposedly high-valent corrole compounds, but the percentage of iridium character varies from 10 to 18% and tracks with the electron-donating ability of the ligand. Additionally, the unique (among corrole complexes) near-IR phosphorescence of Ir(III) corroles is presented and discussed. Iridium(III) corroles phosphoresce with lifetimes ranging from hundreds of nanoseconds to a few microseconds at room temperature, with slightly longer lifetimes at low temperature. Unfortunately, the quantum yields of phosphorescence are low, 1% or less, and this appears to be due to an exceptionally slow set of radiative rates for the corroles. An examination of the reactivity of ammine-ligated Ir(III) corroles is also described. These compounds can be oxidized in the presence of an ammonia source to form novel six-coordinate iridium(III) azaporphyrins in an unprecedented chemical transformation. The characterization and properties of these iridium azaporphyrin complexes are detailed as well, with a focus on nuclear magnetic resonance characterization techniques and a discussion of the red phosphorescence of the azaporphyrins. ", "doi": "10.7907/7CAD-6P44", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6257", "collection": "thesis", "collection_id": "6257", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02272011-102614437", "primary_object_url": { "basename": "VJS-Thesis.pdf", "content": "final", "filesize": 4696579, "license": "other", "mime_type": "application/pdf", "url": "/6257/1/VJS-Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Investigations of C-H Activation and the Conversion of Methanol to Triptane", "author": [ { "family_name": "Scott", "given_name": "Valerie J.", "clpid": "Scott-Valerie-J" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Broadly speaking, this thesis represents research towards understanding the mechanisms and important species related to small molecule conversion, namely methane to methanol and methanol to higher hydrocarbons. The first section is on understanding the catalytic formation of methanol from methane, with specific interest in using gold (Au). While this transformation is known to occur catalytically, very little is understood about how it happens. To study this reaction, well-defined Au-complexes were synthesized and reactions relevant to the possible catalytic cycles were examined. In doing so, the first simple Au(III)-monoalkyl complex was generated and characterized: (Idipp)AuI2Me, where Idipp = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). Kinetics experiments demonstrated that the complex reductively eliminates methyl iodide, which is relevant to the functionalization step in CH activation. At low concentrations of iodide, the reductive elimination happens faster, from an unobserved 3-coordinate intermediate. However, at high iodide concentrations, the pathway is still consistent with reductive elimination, but from a 5-coordinate intermediate. This is in contrast to the related platinum-system, as well as to density functional theory calculations done on the Au-system.
\r\n \r\nThe second section studies the C-H activation step alone by close examination of the microscopic reverse: protonation of a metal-alkyl. It had previously been noted that the observed kinetic isotope effects (KIEs) were unusually high for the protonolysis of a few Pd complexes and one Pt complex. It was hypothesized that these high KIEs and involvement of quantum mechanical tunneling may indicate a change in the mechanism of the protonolysis reaction, from protonation at the metal center and reductive coupling to direct protonation of the M-Me bond. The experiments described here were designed to explicitly test this theory and demonstrated that no correlation can be made between mechanism and tunneling.
\r\n\r\nThe third section is focused on the study of the conversion of methanol to highly branched alkanes that make good fuel additives, namely 2,2,3-trimethylbutane (triptane), amidst other alkanes, olefins, and aromatics. Catalyzed by ZnI2 or InI3 at high temperatures, the reaction is hydrogen deficient: aromatics are formed as unsaturated by-products necessary for alkane generation. While the product distributions are somewhat different for the two different catalysts, the general mechanism is the same. While typical InI3 reactions generate more alkanes, more aromatics, and fewer olefins than ZnI2 reactions, longer reaction times and higher temperatures make the ZnI2 reaction look like the InI3 profile. Furthermore, InI3 can activate alkanes; it was found that InI3 can \u201cupgrade\u201d other alkanes with methanol. Notably, a 1:1 mixture of 2,3-dimethylbutane and methanol can be converted into triptane with good selectivity and little aromatic formation; ZnI2 can carry out similar chemistry at higher temperatures. Quantification of the iodine-containing products in each reaction mixture was attempted because of its relevance to the system\u2019s industrial viability and found that these concentrations were significantly higher than would be acceptable in an industrial setting.
\r\n", "doi": "10.7907/P0A0-JV28", "publication_date": "2011-02-14", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6133", "collection": "thesis", "collection_id": "6133", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10122010-101531793", "primary_object_url": { "basename": "JAE_Thesis_Complete.pdf", "content": "final", "filesize": 47659223, "license": "other", "mime_type": "application/pdf", "url": "/6133/1/JAE_Thesis_Complete.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Total Synthesis of Cyanthiwigin Natural Products via Double Asymmetric Catalytic Alkylation and Investigations into the Nature of Double Asymmetric Processes", "author": [ { "family_name": "Enquist", "given_name": "John Andrew", "clpid": "Enquist-John-Andrew" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Since the initial isolation of the cyathane molecules in 1970, considerable synthetic interest has been invested into the preparation of these diterpenoid natural products. Owing to the biological activity and intriguing molecular architecture of these compounds, the members of the cyathane family of natural products have emerged as appealing targets for total synthesis. After a brief summary of the isolation and bioactivity properties of these diterpene compounds, previous synthetic efforts toward these molecules are reviewed.
\r\n\r\nA concise and versatile approach toward the preparation of the cyanthiwigin family of cyathane natural products is described. By leveraging a unique double asymmetric catalytic alkylation procedure it is possible to quickly establish two of the most critical stereocenters of the cyanthiwigin framework with high levels of selectivity and expediency. The synthesis additionally employs a tandem ring-opening and cross-metathesis reaction, and an aldehyde-olefin radical cyclization process, to rapidly arrive at the tricyclic cyathane core of the cyanthiwigin molecules. From this unifying intermediate, the preparation of cyanthiwigins B, F, and G are attained swiftly and without the need for protecting groups.
\r\n\r\nThe nature of double asymmetric transformations is investigated from a historical, mathematical, and experimental perspective. The initial findings of Langenbeck and Horeau concerning the enantioenriching effects of scalemic duplication are described, with a specific focus on the impact of this phenomenon on total synthesis. A thorough mathematical examination, based on the work of Kagan, is then presented for situations involving double asymmetric transformations of prochiral starting materials. Expressions relating the final quantities of the stereoisomeric products to the intermediary selectivity of each stereoselective process are presented based on these formulae.
\r\n\r\nFinally, experiments designed to probe the selectivity of each stage of stereoselective bond construction in a double asymmetric process are presented. The compiled results are scrutinized in keeping with the previously derived equations, and these findings are analyzed to understand the nature of the double asymmetric processes in question.
", "doi": "10.7907/V11W-RH98", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6140", "collection": "thesis", "collection_id": "6140", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10122010-162444550", "primary_object_url": { "basename": "SM_Thesis_Full.pdf", "content": "final", "filesize": 14119026, "license": "other", "mime_type": "application/pdf", "url": "/6140/1/SM_Thesis_Full.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Progress Toward the Cortistatin A Carbocyclic Core and the Development of the Catalytic Enantioselective Alkylation of 3-Helooxindoles", "author": [ { "family_name": "Ma", "given_name": "Sandy", "clpid": "Ma-Sandy" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Biologically active natural products often contain interesting and complex structural features and functionalities that make them attractive targets for synthetic chemists. As such, these natural products can serve as inspiration for the development of new reaction methodology.
\r\n \r\nCortistatin A contains a unique rearranged steroidal core and possesses potent anti-angiogenic activity. These features have made cortistatin A the target of many synthetic efforts, including ours. The progress toward the synthesis of the cortistatin A carbocyclic core via an enyne-ene metathesis is discussed. Our studies towards the construction of the cortistatin A carbocyclic core yielded an interesting result, wherein an attempted SN2 inversion of a secondary mesylate afforded product with retention of stereochemistry.
\r\n\r\nOxindole derived motifs are also prevalent in biologically active molecules. More specifically, 3,3-disubstituted oxindoles can be used to access pyrrolidinylspirooxindole and pyrrolidinoindoline cores. Herein, the development of a catalytic enantioselective malonate alkylation of 3-halooxindoles to access enantiopure 3,3-disubstituted oxindoles is detailed. We then demonstrate that the enantiopure 3,3-disubstituted oxindoles derived from this novel transformation can be used towards the construction of pyrrolidinylspirooxindole and pyrrolidinoindoline cores.
\r\n", "doi": "10.7907/ZF1G-Y610", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6181", "collection": "thesis", "collection_id": "6181", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11182010-211348487", "primary_object_url": { "basename": "SMBThesis.pdf", "content": "final", "filesize": 4608701, "license": "other", "mime_type": "application/pdf", "url": "/6181/1/SMBThesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Investigation of the Role of Hydrides in Zirconocene Catalyzed Olefin Polymerization", "author": [ { "family_name": "Baldwin", "given_name": "Steven M.", "clpid": "Baldwin-Steven-M" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The structure and reactivity of zirconocene hydrides in the presence of aluminum alkyls is investigated for both neutral species and cationic species. Unbridged zirconocene dichlorides react with HAliBu2 to yield trihydride dialuminum clusters of the general formula (RnC5H5-n)2Zr(\u03bc-H)3(AliBu2)3(\u03bc-Cl)2. Bridged zirconocenes instead predominantly yield a dihydride monoaluminum cluster of the general form Me2E(RnC5H4-n)2Zr(Cl)(\u03bc-H)2AliBu2 where E = Si or C. For tert-butyl substituted zirconocenes the terminal Cl is replaced by a H. It is shown that steric factors dictate which hydride is formed.
\r\n\r\nA single type of cationic trihydride dialuminum cluster of general formula [(RnC5H4-n)2Zr(\u03bc-H)3(AliBu2)+] is formed for all zirconocene hydrides upon addition of [Ph3C][B(C6F5)4] regardless of which class of neutral hydride was formed. For {(SBI)Zr} and {(Me2Si)2(C5H3)2Zr} the resulting cations were crystallographically characterized where SBI stands for Me2Si(indenyl)2. [(SBI)Zr(\u03bc-H)3(AliBu2)]+ reacts with propene to make isotactic polypropene while the Me-substituted analogue [(SBI)Zr(\u03bc-H)3(AliMe2)]+ is a catalyst for hydroalumination. These trihydride cations are shown to be dormant species in polymerization reactions. [(SBI)Zr(\u03bc-H)3(AliBu2)]+ is identified as the hydride observed by Babushkin and Brintzinger (Babushkin, D. E.; Brintzinger, H. H. Chem. Eur. J. 2007, 13, 5294) upon addition of AliBu3 or HAliBu2 to a mixture of (SBI)ZrCl2 and methylaluminoxane.
\r\n", "doi": "10.7907/P2XG-AD12", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:5733", "collection": "thesis", "collection_id": "5733", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04222010-082435622", "type": "thesis", "title": "Chemical Synthesis in Elastomer-Based Integrated Microfluidics", "author": [ { "family_name": "Lee", "given_name": "Cheng-Chung", "clpid": "Lee-Cheng-Chung" } ], "thesis_advisor": [ { "family_name": "Quake", "given_name": "Stephen R.", "clpid": "Quake-S-R" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Quake", "given_name": "Stephen R.", "clpid": "Quake-S-R" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Yang", "given_name": "Changhuei", "clpid": "Yang-Changhuei" } ], "local_group": [ { "literal": "div_eng" } ], "abstract": "There is wide interest in using the unique properties of microfluidic environments for the production of fine chemicals and pharmaceuticals. Compared to bench top synthesis, microfluidic systems engender the significant advantage of superior control of chemical state functions. The ability to tune reagent concentration, reaction temperature, mixing time, and residence time allows reactions to run more efficiently thus generating products of higher yield and purity. While several microfluidic platforms are actively developed in both academic and industrial laboratories, vast majority are based in rigid materials and have only demonstrated improvements in yield for single reaction steps.
\r\n\r\nMultilayer Soft Lithography has already found much use in the biological field. For example, several complex devices based upon functional modules have been developed for protein crystallography, nucleic acid processing, FACS, enzyme screening tools, and PCR. Because of the many similarities between operations in organic synthesis and biochemistry, there is widespread interest in extending these newfound successes in the realm of biology to the realm of automated chemical synthesis.
\r\n\r\nThis thesis focuses on the application of Multilayer Soft Lithography to the development and adaptation of microfluidic tools for chemical synthesis. The first successful demonstration of multistep organic synthesis in integrated microfluidics was the production of a molecular image probe, 2-deoxy-2-[18F]fluoro-d-glucose. The nanogram level dosage for imaging probes makes them attractive candidates for small scale synthesis of microfluidics. The reduced synthesis time achieved by using a microfluidic device is especially important because of the relatively short half-life of the radioactive fluoride.
\r\n\r\nWhile PDMS remains the material of choice for devices in biological applications, its incompatibility with many nonpolar organic solvents limits the types of reactions that can be performed with it. Through collaboration with Joseph DeSimone\u2019s group at the University of North Carolina at Chapel Hill, a suitable substitute for PDMS was found in perfluoropolyethers (PFPE). A solvent-resistant integrated microfluidic device was developed for solid-phase oligonucleotide synthesis using conventional phosphoramidite chemistry. To confirm that the microfluidic platform in development can indeed become a valuable tool in the field of synthetic biology, a 16 column parallel oligonucleotide synthesizer was manufactured that is capable of producing 16 distinct sequences up to 40 bases in length to be used in gene assembly. Successful construction of a gene fragment was completed from a mixture of unpurified and unamplified oligonucleotides synthesized on the device.
", "doi": "10.7907/8603-G150", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5908", "collection": "thesis", "collection_id": "5908", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06022010-164832965", "primary_object_url": { "basename": "Thesis_master.pdf", "content": "final", "filesize": 6629180, "license": "other", "mime_type": "application/pdf", "url": "/5908/1/Thesis_master.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "The Development of Br\u00f8nsted Acid Catalysis Technologies and Mechanistic Investigations Therein", "author": [ { "family_name": "Carrera", "given_name": "Diane Elizabeth", "clpid": "Carrera-Diane-Elizabeth" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The enantioselective reductive amination of ketones with Hantzsch ester has been achieved through Br\u00f8nsted acid catalysis. A novel triphenylsilyl substituted BINOL-derived phosphoric acid catalyst has been developed for this transformation, imparting high levels of selectivity when used with methyl ketones and aromatic amines. A stereochemical model for the observed selectivity based on torsional effects has been developed through molecular modeling and is further supported by a single crystal x-ray structure of an imine-catalyst complex.
\r\n\r\nMechanistic studies have revealed the importance of catalyst buffering and drying agent on reaction efficiency while a Hammett analysis of acetophenone derivatives offers insight into the key factors involved in the enantiodetermining step. Kinetic studies have shown that imine reduction is rate-determining and follows Michaelis-Menten kinetics. Determination of the Eyring parameters for the imine reduction has also been accomplished and suggests that the phosphoric acid catalyst behaves in a bifunctional manner by activating both the imine electrophile and the Hantzsch ester nucleophile.
\r\n\r\nThe intermolecular addition of vinyl, aromatic, and heteroaromatic potassium trifluoroborate salts to non-activating imines and enamines can also be accomplished through Br\u00f8nsted acid activation. This analog of the Petasis reaction shows a wide substrate scope and is amenable to use with a variety of carbamate protected nitrogen electrophiles in the first example of metal-free 1,2-additions of trifluoroborate nucleophiles. The mechanistic underpinnings of benzyl trifluoroborate addition has also been explored and, in contrast to what is seen with \u03c0-nucleophilic species, appears to proceed through an intramolecular alkyl-transfer mechanism.
", "doi": "10.7907/ZGS8-QT92", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5925", "collection": "thesis", "collection_id": "5925", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06072010-114755605", "primary_object_url": { "basename": "Thesis_SRG.pdf", "content": "final", "filesize": 8246412, "license": "other", "mime_type": "application/pdf", "url": "/5925/1/Thesis_SRG.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Organometallic Reaction Mechanisms: Olefin Polymerization Catalysis and C-H Bond Activation by Early Transition Metal Bisphenolate Complexes and Protonolysis of Bipyrimidine Platinum Methyl Complexes ", "author": [ { "family_name": "Golisz", "given_name": "Suzanne Rose", "clpid": "Golisz-Suzanne-Rose" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Mechanistic aspects of organometallic transformations such as polymerization, C H activation, and protonolysis have been examined. Relationships between catalyst geometry and polymer microstructure were defined. The mechanism of an intramolecular C H activation process was found to involve two competing pathways. The protonolysis of platinum methyl complexes was investigated for kinetic isotope effects and observation of intermediates.
\r\n\r\nBisphenolate ligands with pyridine and benzene diyl linkers were synthesized and metalated with group 4 and 5 transition metals. The solid state structures of some of the group 4 complexes were solved. The titanium, zirconium, hafnium, and vanadium complexes were tested for propylene, 1 hexene, and ethylene/1 octene polymerization activities with methylaluminoxane as co catalyst. Titanium and zirconium (IV) precatalysts with pyridine diyl linkers provided mixtures of isotactic and atactic polypropylene while titanium (IV) precatalysts with benzene diyl linkers gave atactic polypropylene only. The hafnium (IV) precatalyst with a pyridine diyl linker generated moderately isotactic polypropylene.
\r\n\r\nA titanium dibenzyl complex featuring a ligand with two phenolates linked by a benzene diyl was found to undergo thermal decomposition to give toluene and a cyclometalated dimeric complex. The thermal decomposition followed first order kinetics and was studied at a number of temperatures to determine the activation parameters. Deuterated isotopologs were synthesized to measure the kinetic isotope effects. The complexes with deuterium in the benzyl methylene positions decomposed slower than the protio analogs. Isotopologs of toluene with multiple deuteration positions were observed in the product mixtures. These data are consistent with competing \u03b1-abstraction and \u03c3-bond metathesis.
\r\n \r\nThe protonolysis of bipyrimidine ligated platinum (II) complexes was explored. The bipyrimidine platinum dimethyl complex (bpm)PtMe\u2082 was shown to undergo protonation at the metal upon addition of trifluoroacetic acid (tfa) to give a platinum (IV) hydride intermediate which reductively eliminated methane to give (bpm)PtMe(tfa). Using a mixture of deutero and protio acid, all isotopologs of methane were observed. The protonation of (bpm)PtMe(tfa) was less straightforward as no intermediates were found, and CH\u2084, CH\u2083D, and CH\u2082D\u2082 were observed upon addition of a mixture of deutero and protio acid. The protonation of a nitrogen of the bpm ligand was also examined and determined improbable under the present conditions.
\r\n", "doi": "10.7907/BBBN-SA63", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5340", "collection": "thesis", "collection_id": "5340", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10192009-145249345", "primary_object_url": { "basename": "entire_thesis_10-30-09.pdf", "content": "final", "filesize": 36649638, "license": "other", "mime_type": "application/pdf", "url": "/5340/1/entire_thesis_10-30-09.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Structural Variations on the Turn Unit of DNA-Binding Hairpin Py-Im Polyamides", "author": [ { "family_name": "Farkas", "given_name": "Michelle Elizabeth", "clpid": "Farkas-Michelle-Elizabeth" } ], "thesis_advisor": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Campbell", "given_name": "Judith L.", "clpid": "Campbell-J-L" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Modulation of gene expression by small molecules is a challenge in the field of chemical biology. Hairpin pyrrole-imidazole polyamides are a class of programmable small molecules that bind to the minor groove of DNA, and have been shown to inhibit gene expression by interfering with transcription factor-DNA interfaces. When considering the biological implications of these molecules, improvement of sequence-specificities and binding affinities is of great interest. The work described herein focuses on modifications to the turn sub-unit of hairpin polyamides, and subsequent effects on the biophysical and biological characteristics of these molecules. The substitution of a \u03b3-2,4-diaminobutyric acid with an \u03b1-2,4-diaminobutyric acid hairpin turn moiety resulted in greater selectivity, and diminished reactivity for polyamide-alkylator conjugates. These molecules have been utilized in generating site-specific damage in histone H4 genes in cancer cells. Employment of 3,4-diaminobutyric acid in the turn unit has resulted in increased DNA affinities for polyamides targeting particular sequences. These molecules are also promising in their abilities to tolerate modifications that improve cellular uptake but would otherwise severely diminish binding.", "doi": "10.7907/RVY7-BR84", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5834", "collection": "thesis", "collection_id": "5834", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05252010-102954788", "primary_object_url": { "basename": "abf_thesis-double.pdf", "content": "final", "filesize": 3760541, "license": "other", "mime_type": "application/pdf", "url": "/5834/1/abf_thesis-double.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Investigating Molecular Size Variations in Thin Film Chemical Vapor Sensors", "author": [ { "family_name": "Folinsky", "given_name": "Anna Barr", "clpid": "Folinsky-Anna-Barr" } ], "thesis_advisor": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Vapor sensing arrays composed of broadly responsive, chemically sensitive detectors have been explored for many years. They have been used in fields ranging from good quality control, to environmental monitoring and explosives detection, to disease diagnostics. All of these tasks require high sensitivity and fine discrimination ability. As new challenges arise, the ability to understand the performance and improve the availability of array components becomes paramount.
\r\n\r\nThis work details progress in gaining greater understanding of certain chemical substrates used in sensor arrays. Specifically, arrays using insulator/carbon black composite sensors have been prepared using either polymer or non-volatile small organic molecules as the insulating, chemically sensitive component. The crystallinity of the small molecules as compared to the polymers was determined to cause the differing formulation requirements between the polymers and the small molecules.
\r\n\r\nAdditionally, arrays of sensors composed of varying molecular weights of a given polymer were examined. Very low molecular weights of polystyrene, a high glass transition temperature polymer, exhibited improved behavior and response times compared to higher molecular weights. Finally, arrays composed of varied length carboxylic and dicarboxylic acids were studied. Of these two homologous series, the arrays composed of carboxylic acids provided better discrimination than did those composed of dicarboxylic acids, suggesting the utility of sensor materials containing multiple accessible functional groups.
\r\n\r\nThese studies, taken together, suggest several new ways to increase the number of compounds and chemical functionalities available to use in chemical vapor sensors. Increased sensor choice allows construction of more broadly responsive and finely discriminating sensor arrays, thereby increasing the general utility of composite vapor sensor arrays.
", "doi": "10.7907/EGMC-C788", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5744", "collection": "thesis", "collection_id": "5744", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04272010-110655339", "primary_object_url": { "basename": "THESIS_-_Kevin_McCormack_Allan_-_CCE_2010.pdf", "content": "final", "filesize": 43706517, "license": "other", "mime_type": "application/pdf", "url": "/5744/1/THESIS_-_Kevin_McCormack_Allan_-_CCE_2010.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Development of Versatile Strategies for Aryne Annulation: Applications in Methodology and Natural Product Total Synthesis", "author": [ { "family_name": "Allan", "given_name": "Kevin McCormack", "clpid": "Allan-Kevin-McCormack" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Virgil", "given_name": "Scott C.", "clpid": "Virgil-S-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Since the elucidation of its structure in 1953, benzyne has been the focus of intense interest within the chemical community. Due to an unusually high degree of ring strain, benzyne displays reactivity uncharacteristic of common alkynes, including a tendency to react under mild metal-free conditions. This reactivity is exploited in the development of three novel methods for the synthesis of heterocyclic structures.
\r\n\r\nThe first synthetic methodology includes two orthogonal annulation reactions taking place between functionalized enamines and arynes. The substitution at the nitrogen atom of the enamine determines the path of reactivity. Carbamates undergo a formal [3 + 2] cycloaddition with arynes to give rise to indolines, while amides undergo a formal [4 + 2] cycloaddition and dehydration to form isoquinolines. The latter reaction is applied to a three-step synthesis of the antispasmotic pavine alkaloid, papaverine.
\r\n\r\nThis isoquinoline-forming aryne annulation reaction is further employed in a concise asymmetric total synthesis of the tetrahydroisoquinoline antitumor antibiotic, (\u2013)-quinocarcin. In addition to this key transformation, the synthetic route features an auxiliary-mediated diastereoselective dipolar cycloaddition to set the absolute stereochemistry and a novel two-step reduction to form the tetrahydroisoquinoline. In total, this strategy has enabled the shortest total synthesis of this important alkaloid reported to date.
\r\n\r\nThe second methodology involves the synthesis of 3-hydroxyisoquinolines and 2-hydroxy-1,4-naphthoquinones from \u03b2-ketoesters using an aryne acyl-alkylation reaction in combination with an in-situ condensation. This technology enables the preparation of highly functionalized polyaromatic ring systems in two steps from readily available carboxylic acid starting materials. As a demonstration of its utility, this method is employed in a rapid synthesis of the P,N-ligand, QUINAP.
\r\n\r\nFinally, the development of a pair of three-component coupling reactions between arynes, isocyanides, and a third relay species is described. Phenyl esters and quinones lead to iminoisobenzofurans, while alkynes furnish iminoindenones. Procedures for the subsequent hydrolysis of these products are provided, thereby giving access to synthetically useful ortho-ketobenzamide and indenone compounds.
", "doi": "10.7907/VPEN-7M75", "publication_date": "2010-06-11", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5841", "collection": "thesis", "collection_id": "5841", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05262010-053625648", "primary_object_url": { "basename": "JTM-Thesis_ds.pdf", "content": "final", "filesize": 68881309, "license": "other", "mime_type": "application/pdf", "url": "/5841/1/JTM-Thesis_ds.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Enantioselective Reactions of Palladium Enolates", "author": [ { "family_name": "Mohr", "given_name": "Justin Thomas", "orcid": "0000-0002-7005-3322", "clpid": "Mohr-Justin-Thomas" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Synthetic efforts directed at preparing certain target molecules highlight deficiencies in the synthetic technology currently available to chemists. Enolates are among the most important synthetic intermediates for synthesis, but general means for enolate functionalizations are not available for many transformations. In order to address these limitations in synthetic technology, novel enantioselective transformations are developed and applied to total syntheses of biologically active natural products.
\r\n\r\nFirst, to address the challenge of generating all-carbon quaternary stereocenters, a palladium-catalyzed allylic alkylation reaction is discovered and optimized for allyl enol carbonate and silyl enol ether substrate classes. Certain enolate precursors are not accessible using these substrates, and therefore a method employing racemic allyl \u03b2-ketoester substrates is developed. In addition to solving the problem of regiospecific enolate generation, these transformations are conceptually interesting due to the stereoablative enantioconvergent mechanism.
\r\n\r\nStudies of the mechanism of the above transformation suggest the intermediacy of a chiral palladium enolate. Since enolate functionalization reactions are valuable to synthetic chemistry and general protocols are rare, different electrophiles are explored in addition to the allyl electrophiles used in quaternary center formation. These studies lead to the discovery of enantioselective protonation reactions generating tertiary stereocenters.
\r\n\r\nTo demonstrate the importance of enantioselective enolate functionalization reactions in synthesis, the allylic alkylation reaction is applied in the total synthesis of cassiol and the formal synthesis of platencin.
\r\n", "doi": "10.7907/Z9RF5S1C", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5877", "collection": "thesis", "collection_id": "5877", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05282010-090825123", "primary_object_url": { "basename": "Krout-M-R-thesis-full.pdf", "content": "final", "filesize": 32812991, "license": "other", "mime_type": "application/pdf", "url": "/5877/109/Krout-M-R-thesis-full.pdf", "version": "v13.0.0" }, "type": "thesis", "title": "Progress Toward the Asymmetric Total Synthesis of Variecolin and Gas-Phase Studies of the Twisted Amide 2-Quinuclidone", "author": [ { "family_name": "Krout", "given_name": "Michael Raymond", "orcid": "0000-0002-0539-6986", "clpid": "Krout-Michael-Raymond" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Biologically active natural products and pharmaceuticals often present intriguing structural features that can challenge the state of the art in catalysis and synthetic methodology for their preparation. The identification of unique targets thus stimulates the development of new strategies and methods for chemical synthesis. The complex architecture representative of the variecolin family of sesterterpenes has inspired our pursuit of new tactics that has enabled the expansion of methods from our laboratory.
\r\n\r\nFirst, progress toward the asymmetric total synthesis of variecolin is discussed. Our convergent synthetic approach bisects the target into two complex fragments to address the main structural challenges. A microwave-promoted tandem Wolff/Cope rearrangement of vinyl cyclobutyl diazocarbonyls has been developed that provides access to functionalized, fused eight-membered rings and is used to construct the central B ring of variecolin. In addition, the utility of our Pd-catalyzed enantioselective alkylation method is extended to a new vinylogous ester substrate class to produce a quaternary ketone in excellent yield with high selectivity that is an exceptional substrate for an efficient ring contraction to the cyclopentene D ring system. The successful asymmetric preparation of our two devised fragments has facilitated initial studies toward their coupling and completion of variecolin.
\r\n\r\nSecond, a preliminary examination of the substrate scope for the asymmetric alkylation of the vinylogous \u03b2-ketoester substrate class is described. Derivatives that perturb substrate electronics display enhanced reactivity and selectivity, generating products with excellent selectivities and expanding the potential of this versatile class of substrates. Furthermore, their utility is underscored as the key enantioselective transformation en route to the synthesis of the sesquiterpenoid (+)-carissone.
\r\n\r\nFinally, gas-phase studies of the twisted amide 2-quinuclidone are described. Proton affinity experiments have quantified its high basicity, which is comparable to a tertiary amine. A gas-phase synthesis of 2-quinuclidione via elimination of water and subsequent fragmentation further highlight the unusual characteristics of extremely twisted amides.
\r\n", "doi": "10.7907/Z9765C9X", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5271", "collection": "thesis", "collection_id": "5271", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-07142009-090835", "primary_object_url": { "basename": "Kuhn_Thesis_Final2.pdf", "content": "final", "filesize": 4361681, "license": "other", "mime_type": "application/pdf", "url": "/5271/1/Kuhn_Thesis_Final2.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Understanding and Improving Efficiency in Ruthenium Olefin Metathesis", "author": [ { "family_name": "Kuhn", "given_name": "Kevin Michael", "clpid": "Kuhn-Kevin-Michael" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Olefin metathesis has become an increasingly important and powerful reaction. The development of the well-defined ruthenium alkylidene complexes, in particular, has broadened the scope and utility of the olefin metathesis reaction in both organic synthesis and polymer science. Despite these advances, complete control of the parameters (activity, stability, and selectivity) that affect efficiency in olefin metathesis remains a major challenge, and the development of more efficient catalysts for a variety of applications remains a very important goal. With that in mind, this thesis primarily focuses on understanding the requirements for and improving the efficiency of ruthenium-based olefin metathesis.
\r\n\r\nIn chapter two, a series of ruthenium olefin metathesis catalysts bearing N-heterocyclic carbene (NHC) ligands with varying degrees of backbone and N-aryl substitution were prepared. These complexes show greater resistance to decomposition through C-H activation of the N-aryl group, resulting in increased catalyst lifetimes. This work utilized robotic technology to examine the activity and stability of each catalyst in metathesis, providing insights into the relationship between ligand architecture and catalyst efficiency.
\r\n\r\nIn chapter three, the high-throughput assay developed in the previous chapter was utilized to screen a series of ruthenium catalysts for the ring-closing metathesis (RCM) of acyclic carbamates to form the corresponding di-, tri-, and tetrasubstituted five-, six-, and seven-membered cyclic carbamates. While disubstituted cyclic olefins were easily formed by a variety of catalysts, NHC-bearing catalysts were required to produce trisubstituted cylic olefin products at low catalyst loadings. Furthermore, only catalysts bearing small N-aryl bulk on the NHC ligands were found to effectively accomplish the RCM reaction for sterically challenging substrates, providing a reminder that more-efficient catalysts still need to be developed.
\r\n\r\nA process for the preparation of symmetric and unsymmetric imidazolinium chlorides that involves reaction of a formamidine with dichloroethane and a base is described in chapter four. This method makes it possible to obtain numerous imidazolinium chlorides under solvent-free reaction conditions and in excellent yields with purification by simple filtration.
\r\n\r\nIn chapter five, both chiral triazolylidenes and cyclic alkyl amino carbenes (CAACs) were chosen as ligands for the preparation of chiral ruthenium olefin metathesis catalysts. These C1 symmetric ligands were chosen to create non-conformationally flexible environments in proximity to the ruthenium center, potentially bringing chirality extremely close to the site of catalysis. These new motifs for ligand architecture show great promise. The moderate enantioselectivies obtained for AROCM and ARCM indicate potential utility toward both synthetic methodology and mechanistic insight.
\r\n\r\nFinally, appendix A describes the preparation of a series of ruthenium olefin metathesis catalysts bearing acenapthylene-annulated NHC ligands with varying degrees of N-aryl substitution. Initial evaluation of their performance in olefin metathesis demonstrated that these complexes show greater resistance to decomposition, resulting in increased catalyst lifetimes. While this work has significant potential, the results are preliminary.
\r\n", "doi": "10.7907/XT5J-TA64", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5378", "collection": "thesis", "collection_id": "5378", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11172009-113840501", "primary_object_url": { "basename": "(0)_Table_of_Contents.pdf", "content": "final", "filesize": 264362, "license": "other", "mime_type": "application/pdf", "url": "/5378/31/(0)_Table_of_Contents.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "Progress Toward an Enantioselective Total Synthesis of Ineleganolide", "author": [ { "family_name": "Roizen", "given_name": "Jennifer Lyn", "orcid": "0000-0002-6053-5512", "clpid": "Roizen-Jennifer-Lyn" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Investigations toward an enantioselective total synthesis of ineleganolide (1) are disclosed. These studies have driven the development of a novel asymmetric ketone alkylation to form C(\u03b1)-tetrasubstituted carbonyl compounds. Products of these alkylations have been converted to \u03b1-hydroxy ketones, acids, and esters, completing an asymmetric formal synthesis of (\u2013)-quinic acid.
\r\n\r\nAdditionally, one of these products, a chloroalkene, has been advanced in the synthesis of the [6\u20137\u20135\u20135]-fused core of ineleganolide. The chloroalkene can be converted through a mild oxidative bromination, Wittig olefination, and Luche reduction sequence to rapidly access the enantioenriched cyclopentenol fragment of ineleganolide. Two of these alcohols can be coupled with a cyclohexenone-derived carboxylic acid to append the six-membered ring fragment. These flexible vinylogous \u03b2-ketoesters can be advanced to a rigid [5\u20135\u20133]-fused cyclopropane.
\r\n\r\nAt the outset of this work, we envisioned the advancement of a [5\u20135]-fused cyclopropane through a tandem Wolff/Cope rearrangement to access the [6\u20137\u20135\u20135]-fused core of ineleganolide. Synthetic studies toward this rearrangement are described. Additionally, we explore a translactonization/Cope rearrangement and a cyclopropanation/Cope/epoxidation cascade sequence to access the [6\u20137\u20135\u20135]-fused scaffold. In the course of these efforts, a rich body of chemistry has been developed exploring translactonizations in cis-substituted cyclopentane diols, including the translactonization/Cope cascade.
\r\n", "doi": "10.7907/Z93F4MMN", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:3645", "collection": "thesis", "collection_id": "3645", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-09192008-185009", "primary_object_url": { "basename": "DCE_thesis.pdf", "content": "final", "filesize": 50124575, "license": "other", "mime_type": "application/pdf", "url": "/3645/17/DCE_thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Development and Applications of the Palladium-Catalyzed Enantioselective Oxidation of Secondary Alcohols ", "author": [ { "family_name": "Ebner", "given_name": "David Christopher", "clpid": "Ebner-David-Christopher" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of new methods for the preparation of chiral alcohols is vital due to the presence of alcohols in natural products, pharmaceuticals, and a variety of synthetic materials, as well as their versatility as synthetic intermediates. Until recently, oxidative kinetic resolution has been a relatively underdeveloped strategy for obtaining enantioenriched alcohols.
\r\n\r\nThe development of a palladium-catalyzed aerobic system for the enantioselective oxidation of secondary alcohols is described. This mild method utilizes (\u2013)-sparteine as a chiral ligand to resolve a wide range of benzylic, allylic, and cyclopropylcarbinyl alcohols to high enantiomeric excesses with excellent selectivity. The resolution of pharmaceutical intermediates and the Claisen rearrangement of resolved allylic alcohols demonstrate the utility of the method.
\r\n\r\nMechanistic insights have driven further catalyst development. Anionic ligand modification has provided more efficient catalysts for the resolution of a broader array of substrates. Neutral ligand studies have led to an enantioselective alcohol oxidation system with a diamine pseudo-enantiomeric to (\u2013)-sparteine, allowing access to enantioenriched alcohols in either enantiomeric series.
\r\n\r\nThis methodology has been applied to the enantioselective total synthesis of (\u2013)-amurensinine via a selective C\u2013H insertion, an aryne C\u2013C insertion, and an oxidative kinetic resolution with (\u2013)-sparteine. Use of an alternative diamine in the resolution results in a formal synthesis of (+)-amurensinine.
\r\n", "doi": "10.7907/2KEA-TT16", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:1536", "collection": "thesis", "collection_id": "1536", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04282009-211225", "primary_object_url": { "basename": "00CompleteThesis.pdf", "content": "final", "filesize": 21277358, "license": "other", "mime_type": "application/pdf", "url": "/1536/1/00CompleteThesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Synthesis and Structural Studies of Cyclic Py-Im Polyamides", "author": [ { "family_name": "Chenoweth", "given_name": "David Michael", "orcid": "0000-0002-0819-4669", "clpid": "Chenoweth-David-Michael" } ], "thesis_advisor": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Rees", "given_name": "Douglas C.", "clpid": "Rees-D-C" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The work presented in this thesis is focused on the molecular recognition of DNA by minor groove binding polyamides. Methods and strategies for the solution-phase synthesis of hairpin and cyclic pyrrole-imidazole polyamides are presented with optimized protocols requiring little to no chromatography. These synthetic strategies have led to the design of cyclic polyamides targeted to the androgen response element and are shown to be biologically active and cell permeable in cell culture experiments in addition their binding affinities rival that of most polyamide architectures. The structural elucidation of an \u03b1-amino-turn-linked cyclic polyamide is presented at 1.17 \u00c5 resolution providing insight into the detailed molecular recognition process and allosteric modulation responsible for the inhibition of transcription factor-DNA binding. Additionally, structural elucidation of a \u03b2-amino-turn-linked cyclic polyamide, highlighting the conformational differences compared to the \u03b1-amino-turn linked structure is presented. A structural basis for the inability of polyamides to bind dsRNA is also proposed based on biophysical, structural, and modeling data. In addition to these studies a new class of programmable oligomers targeting the DNA sequence 5\u2019-WGGGGW-3\u2019 were shown to inhibit DNA binding of the Nf-kB transcription factor by EMSA gel shift. Compounds synthesized in this study were found to possess unique fluorescent properties with the ability to modulate their fluorescence by binding their targeted dsDNA, leading to sequence specific fluorescent detection reagents. Efforts toward the templated-assembly of polyamides using higher-order DNA structure (NCP) are also reported and the development of a new pro-fluorescent class of heterocycle, which has the potential to be used as a chemical reporter of ligation events is described.\r\n", "doi": "10.7907/PZEC-VA33", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:5", "collection": "thesis", "collection_id": "5", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-01022009-165956", "primary_object_url": { "basename": "StockdillThesis_oneside.pdf", "content": "final", "filesize": 50869084, "license": "other", "mime_type": "application/pdf", "url": "/5/26/StockdillThesis_oneside.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Forays into the Synthesis of Zoanthenol: Intriguing Patterns in Reactivity and Selectivity", "author": [ { "family_name": "Stockdill", "given_name": "Jennifer Lynn", "orcid": "0000-0003-4238-6530", "clpid": "Stockdill-Jennifer-Lynn" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The zoanthamine family of alkaloids has attracted the attention of synthetic chemists for over two decades, beginning with the first report of their isolation in 1984. Not only are these stereochemically dense polycyclic compounds structurally fascinating, but they also display interesting and important biological activities. Foremost among these is the potent anti-osteoporotic effect of norzoanthamine. To date, norzoanthamine remains the only member to have succumbed to total synthesis, by Miyashita and co-workers in 2004. Our studies began by targeting zoanthenol, a structurally similar natural product that possesses the key stereochemical challenges of norzoanthamine, while offering unique opportunities for strategic development as compared to the other family members.\r\n\r\nThe synthetic work described herein focuses on approaches to the tricyclic core of zoanthenol, specifically employing an approach by which the stereochemical complexity of the C ring, marked by the challenging vicinal all-carbon quaternary centers, is addressed early in the synthesis. These functionalized C ring synthons are then tethered to an aromatic A ring synthon, and methods to form the final bond of the B ring are explored. Special attention is given to the acid-mediated Friedel-Crafts cyclization approach. In addition to the acid-mediated cyclization approach, an alternative cyclization method is discussed wherein the A ring is substituted with a halogen in order to enable generation of a radical. This radical then undergoes a 1,4-addition into a fully substituted enone to close the B ring and provide the desired stereochemistry both of the two new stereocenters that are generated in the cyclization.\r\n\r\nIn these efforts, we have learned a great deal about the factors governing selectivity and reactivity in these systems. For each case, stereochemical models are discussed and key structural requirements for future investigations are outlined.\r\n", "doi": "10.7907/WYAG-4S28", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:2181", "collection": "thesis", "collection_id": "2181", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05272009-161836", "primary_object_url": { "basename": "Thesis_Claire_Jacobs.pdf", "content": "final", "filesize": 7936312, "license": "other", "mime_type": "application/pdf", "url": "/2181/10/Thesis_Claire_Jacobs.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Structural Modifications to DNA-Binding Polyamides for Improved Biological Activity in Cell Culture", "author": [ { "family_name": "Jacobs", "given_name": "Claire Sigrid", "clpid": "Jacobs-Claire-Sigrid" } ], "thesis_advisor": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Rees", "given_name": "Douglas C.", "clpid": "Rees-D-C" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Polyamides are a class of synthetic small molecules that recognize DNA in a sequence-specific fashion through a network of hydrogen bonds formed with bonding partners in the floor of the minor groove. The binding affinity of polyamides is comparable to that of numerous DNA-binding proteins, and polyamides have been shown to displace DNA-binding proteins. As such, they present a powerful opportunity to modulate expression levels of genes vital to human health. The cellular permeability and biological activity of polyamides has presented an impediment in moving from in vitro to in vivo work that was partially removed by the discovery that fluorescein dyes facilitate cell entry. The work described here details recent advances in modifications to the C-terminal polyamide linker, linkage and tail groups that improve the endogenous inducible gene regulation activity of polyamides in cell culture.\r\n", "doi": "10.7907/HMMN-YW83", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:4398", "collection": "thesis", "collection_id": "4398", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11032008-191338", "primary_object_url": { "basename": "09_Thesis.pdf", "content": "final", "filesize": 2188603, "license": "other", "mime_type": "application/pdf", "url": "/4398/9/09_Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Completion of a Programmable DNA-Binding Small Molecule Library", "author": [ { "family_name": "Hsu", "given_name": "Carey Frank", "clpid": "Hsu-Carey- Frank" } ], "thesis_advisor": [ { "family_name": "Dervan", "given_name": "Peter B.", "orcid": "0000-0001-8852-7306", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Dervan", "given_name": "Peter B.", "orcid": "0000-0001-8852-7306", "clpid": "Dervan-P-B" }, { "family_name": "Mayo", "given_name": "Stephen L.", "orcid": "0000-0002-9785-5018", "clpid": "Mayo-S-L" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Hairpin pyrrole-imidazole (Py-Im) polyamides are programmable oligomers that bind the DNA minor groove in a sequence-specific manner with affinities comparable to those of natural DNA-binding proteins. These cell-permeable small molecules have been shown to enter the nuclei of live cells and downregulate endogenous gene expression. We complete here a library of 27 hairpin Py-Im polyamides that bind 7-base-pair sequences of the general form 5\u2019-WWGNNNW-3\u2019 (where W = A or T, N = W, G, or C). A table of binding affinities and sequence contexts for this completed 27-member library has been assembled for the benefit of the chemical biology community interested in molecular control of transcription. Quantitative fluorescence-based methods have been developed to determine the nuclear concentration of polyamide-fluorescein conjugates in cell culture. Confocal laser scanning microscopy and flow cytometry techniques are utilized to plot calibration curves, from which the nuclear concentration can be interpolated. Although confocal microscopy and flow cytometry generate disparate values, taken together these experiments suggest that the polyamide concentration inside the cell nucleus is lower than it is outside the cell. To further our understanding of C-terminal tail linkage effects on sequence specificity, the equilibrium association constants of hairpin polyamide conjugates were measured by quantitative DNase I footprint titration experiments. These results indicate that linkers and functional R groups on the tails of hairpin polyamide conjugates have recognition properties that should be considered in the design of these molecules to target DNA binding sites. Furthermore, these \u03b2-alanine-C\u2083-linked polyamide conjugates are shown to decrease hypoxia-inducible transcription of vascular endothelial growth factor (VEGF) in cultured HeLa cells. In addition, polyamide conjugates designed to target the Oct4 octamer DNA element modulate the expression levels of Oct4-driven genes in P19 mouse embryonal carcinoma cells and R1 mouse embryonic stem (ES) cells.\r\n", "doi": "10.7907/PG0R-3X44", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:5035", "collection": "thesis", "collection_id": "5035", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-12172007-134752", "primary_object_url": { "basename": "(Full)RMMThesis.pdf", "content": "final", "filesize": 45005243, "license": "other", "mime_type": "application/pdf", "url": "/5035/11/(Full)RMMThesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Applications of Palladium-Catalyzed Enantioselective Decarboxylative Alkylation in Natural Products Total Synthesis", "author": [ { "family_name": "McFadden", "given_name": "Ryan Michael", "clpid": "McFadden-Ryan-Michael" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The catalytic enantioselective preparation of all-carbon quaternary stereocenters within rings via alkylation is a major challenge in synthetic organic chemistry. Many important natural products and biologically active pharmaceuticals contain this motif. We have developed palladium-catalyzed decarboxylative alkylations capable of generating all-carbon quaternary stereocenters in good yield with high enantioselectivity.
\r\n\r\nAlkylated products are readily elaborated to synthetically useful cyclic scaffolds. The enantioselective decarboxylative alkylation is thus utilized to prepare intermediates previously reported in the total syntheses of classic natural products. Herein, we disclose modern formal syntheses of (\u2013)-Thujopsene, (-\u2013)-Dysidiolide, and (\u2013)-Aspidospermine.
\r\n\r\nThe longer-term goal was to apply this new enantioselective catalysis to the total syntheses of natural products with novel carbocyclic architectures. Our methodology is demonstrated during the first protecting group-free enantioselective total synthesis of (+)-dichroanone, a 4a-methyltetrahydrofluorene. The [6-5-6] tricyclic natural products family has members with important biological activity, and our route to (+)-dichroanone may provide general access to related compounds. During our synthetic endeavors, a novel Kumada-benzannulation approach to the aromatic portion of (+)-dichroanone was developed, along with a unique synthesis of a hydroxy-p-benzoquinone from a phenol. The absolute stereochemistry of the natural product was verified for the first time during our total synthesis.
\r\n\r\nSignificant progress has been made toward the total synthesis of the marine meroterpenoid liphagal, a potent and selective phosphatidylinositol 3-kinase alpha inhibitor. The enantioselective decarboxylative alkylation has been employed, and an acetylene [2 + 2] photoaddition / ring-opening sequence is used to construct the 7-membered ring. New understanding about the reactivity of [6-7] bicyclic scaffolds has been gathered, and the information applied during preparation of liphagal\u2019s benzofuran motif. Our efforts have led to a functionally diverse array of liphagal analogues, which may be used for structure-activity-relationship studies with phosphatidylinositol 3-kinases.
\r\n", "doi": "10.7907/GQ1E-RW28", "publication_date": "2008", "thesis_type": "phd", "thesis_year": "2008" }, { "id": "thesis:706", "collection": "thesis", "collection_id": "706", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-02212008-145524", "primary_object_url": { "basename": "Full.Thesis.Caspi.pdf", "content": "final", "filesize": 37238324, "license": "other", "mime_type": "application/pdf", "url": "/706/15/Full.Thesis.Caspi.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "The Adaptive Nature of Palladium Reactivity in Synthesis", "author": [ { "family_name": "Caspi", "given_name": "Daniel David", "clpid": "Caspi-Daniel-David" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Both Pd(0) and Pd(II) have had, and continue to have, far-reaching impacts on organic synthesis. The versatile nature of palladium, in conjunction with the mechanistic understanding and predictive models that have been elucidated, has permitted a wealth of exploration into the seemingly endless potential of this metal. The utility of palladium is described in the context of the syntheses of the pharmaceutical agents Prozac\u00ae, and Singulair\u00ae, as well as the natural products dragmacidin F and telomestatin.
\r\n\r\nFirst, the palladium-catalyzed aerobic oxidative kinetic resolution for the enantioselective preparation of a variety of pharmaceutical substances, including Prozac\u00ae, and Singulair\u00ae is described. In this regard, the versatility of this resolution is further demonstrated by the diversity of the substrates chosen for this study, and for the first time this work extends the utility of the resolution to include amino alcohol derivatives and highly functionalized benzylic alcohols.
\r\n\r\nSecondly, an enantiodivergent strategy for the total chemical synthesis of both (+)- and (\u2013)-dragmacidin F from a single enantiomer of quinic acid has been developed and successfully implemented. Although unique, the synthetic routes to these antipodes share a number of key features, including novel Pd(0) reductive isomerization reactions, Pd(II)-mediated oxidative carbocyclization reactions, halogen-selective Suzuki couplings, and high-yielding late-stage Neber rearrangements.
\r\n\r\nFinally, progress toward the total synthesis of the potent telomerase inhibitor telomestatin is described. Palladium-mediated cross-coupling reactions are employed to assemble oligooxazole intermediates from oxazole building blocks. Additionally, this strategy utilizes a minimum number of protecting groups, and proposes a unique aryl\u2013aryl macrocyclization as the last step of the synthesis. In addition to the biological relevance of the desired target, a successful total synthesis of telomestatin would also enable rapid access to the preparation of telomestatin analogs. This would allow for the investigation of key interactions between telomestatin and the G-quadruplex.
\r\n", "doi": "10.7907/N37A-5970", "publication_date": "2008", "thesis_type": "phd", "thesis_year": "2008" }, { "id": "thesis:5247", "collection": "thesis", "collection_id": "5247", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-08142007-151304", "primary_object_url": { "basename": "thesis2.pdf", "content": "final", "filesize": 7088139, "license": "other", "mime_type": "application/pdf", "url": "/5247/1/thesis2.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Ruthenium Olefin Metathesis Complexes: Catalyst Development and Mechanistic Studies", "author": [ { "family_name": "Anderson", "given_name": "Donde R.", "clpid": "Anderson-Donde-R" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The field of olefin metathesis has grown to include organometallic chemists who strive to develop more efficient catalysts and to understand their mechanism of activity and decomposition, synthetic organic chemists who construct complex molecules utilizing existing catalysts and continually find challenging reactions in need of more efficient catalysts, and polymer chemists who utilize current catalysts to synthesize polymers with an ever-widening array of functional groups and structures in a controlled manner. This thesis describes the exploration of new ligands for olefin metathesis catalysts and the investigation of the model compounds of olefin metathesis reaction intermediates.
\r\n\r\nChapter 2 describes the synthesis, characterization, activity and kinetic selectivity of ruthenium olefin metathesis complexes bearing cyclic (alkyl)(amino)carbenes (CAACs). The activity of phosphine-free CAAC-ruthenium complexes is significantly affected by steric interactions. By decreasing the steric bulk of the ligand, a new catalyst with activity comparable to that of existing NHC-ruthenium (N-heterocyclic carbene) complexes has been synthesized. Additionally, these complexes exhibit unusual E/Z-diastereoselectivity and ethenolysis selectivity relative to previously studied NHC-ruthenium complexes.
\r\n\r\nChapter 3 describes the exploration of 3- and 6-membered carbenes as ligands for ruthenium olefin metathesis complexes. Stable silver-cyclopropenylidene adducts were synthesized and utilized as carbene transfer reagents in the presence of ruthenium precursors. Although good conversions were observed, isolation of cyclopropenylidene-ruthenium complexes was unsuccessful. Ruthenium complexes of 6-membered \u2018borazine\u2019-like carbenes were isolated, characterized and evaluated for ring-closing metathesis activity.
\r\n\r\nChapter 4 describes the development of a model system to study ruthenium-olefin complexes relevant to the mechanism of olefin metathesis. Upon addition of the ligand precursor 1,2-divinylbenzene to (H\u2082IMes)(py\u2082)(Cl)\u2082Ru=CHPh (H\u2082IMes = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene), two ruthenium-olefin adducts are formed. Based on \u00b9H NMR spectroscopy experiments and X-ray crystallographic analysis, the solution phase and solid-state structure of these complexes is assigned. Exploration of the generality of these observations through variation of the N-heterocyclic carbene ligand and the ligand precursor are also presented.
\r\n\r\nAppendix 1 describes the screening of transitional-metal salts and ligands for the non-oxidative hydration of styrene. Appendix 2 describes the investigation of a prior report of intramolecular olefin hydroalkoxylation with ruthenium, copper and silver salts. Appendix 3 describes the evaluation of chiral NHCs as ligands for ruthenium and rhodium hydrosilylation catalysts. Appendix 4 describes the investigation of tin(II) halides as ligands for ruthenium olefin metathesis catalysts. Appendix 5 contains X-ray crystallographic analysis parameters of the structures presented in this thesis.
\r\n", "doi": "10.7907/6B6N-2V77", "publication_date": "2008", "thesis_type": "phd", "thesis_year": "2008" }, { "id": "thesis:5246", "collection": "thesis", "collection_id": "5246", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-08132007-171008", "primary_object_url": { "basename": "thesis-SL.pdf", "content": "final", "filesize": 5964737, "license": "other", "mime_type": "application/pdf", "url": "/5246/1/thesis-SL.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Development of Iminium-Activation Technologies and the Total Synthesis of (+)-Frondosin B", "author": [ { "family_name": "Lee", "given_name": "Sandra", "clpid": "Lee-Sandra" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The enantioselective imidazolidinone-catalyzed epoxidation of \u03b1,\u03b2-unsaturated aldehydes has been accomplished via a novel 1,4-heteroconjugate addition reaction using hypervalent iodine reagents. Development of an \u201cinternal syringe pump\u201d protocol for the slow release of iodosobenzene from an iminoiodinane source provides high levels of reaction efficiency and enantiomeric control in the asymmetric epoxidation of electron-deficient olefins. Fundamental to our studies were 15N NMR experiments that elucidated the oxidation pathways that lead to catalyst depletion, thereby providing a mechanistic rational for the utilization of iminoiodinanes, which circumvent these catalyst depletion pathways.
\r\n\r\nWe further established iminium catalysis as a valuable strategy for asymmetric synthesis in an organocatalytic addition of trifluoro(organo)borates and boronic acids to \u03b1,\u03b2-unsaturated aldehydes. Inspired by the Petasis reaction and guided by rational mechanistic considerations, we discovered a new mode of reactivity for organoboronates and a metal-free \u201ccoupling\u201d procedure for enantioselective C\u2013C bond construction. From a practical standpoint, this methodology stands to benefit from the structural diversity and wide commercial availability of several hundred organoboron reagents accessible to organic chemists. Furthermore, the low toxicity and the air and moisture stability of potassium organotrifluoroborates reagents make this powerful new organocatalytic process operationally trivial.
\r\n\r\nA five-step total synthesis of (+)-frondosin B highlights the stereoselective construction of a natural product target using an organocatalytic conjugate addition of a trilfluoro(organoboronate) reagent. This key step unambiguously established the absolute configuration of the frondosin B to be the (R)-enantiomer and led to the reassignment of naturally occurring frondosin B, thus resolving an existing discrepancy in the literature. To date, this work represents the most effective synthesis of frondosin B, which is accessible in only five steps and in a 32% overall yield.
", "doi": "10.7907/83M6-7R38", "publication_date": "2008", "thesis_type": "phd", "thesis_year": "2008" }, { "id": "thesis:1550", "collection": "thesis", "collection_id": "1550", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04292008-113738", "primary_object_url": { "basename": "jamisontuttlethesis.pdf", "content": "final", "filesize": 12094002, "license": "other", "mime_type": "application/pdf", "url": "/1550/1/jamisontuttlethesis.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Development of Enantioselective Organocatalytic Hydrogenation Methods and Progress toward the Total Synthesis of (+)-Minfiensine", "author": [ { "family_name": "Tuttle", "given_name": "Jamison Bryce", "clpid": "Tuttle-Jamison-Bryce" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of an enantioselective organocatalytic hydrogenation reaction utilizing the LUMO-lowering activation of \u03b1,\u03b2-unsaturated aldehydes has been developed. This strategy employs an imidazolidinone catalyst to activate the alkene towards conjugate reduction of the pendant \u03b2,\u03b2-disubstituted alkene by a Hantzsch dihydropyridine. This is the first general methodology that utilizes disubstituted alkenes for iminiuim activation chemistry and stereoconvergently reduces mixtures of olefin geometric isomers to favor an enantioenriched product. Furthermore, the reagents are air and moisture stable making this new process operationally trivial.
\r\n\r\nBy exploiting the aforementioned mode of reactivity, enones have been successfully reduced utilizing a privileged imidazolidinone catalyst. These studies led to the discovery of a novel Hantzsch dihydropyridine that exhibits a dramatic increase in reactivity. Further comparison of these Hantzsch derivatives provides interesting physical and structural data that may account for the observed differences.
\r\n\r\nA rapid entry into the tetracyclic framework of minfiensine utilizing our group\u2019s organocascade cyclization methodology was undertaken. This strategy demonstrates the first example of a 2,3-dialkyl substituted indole starting material successfully reacting under our pyrroloindoline-forming conditions. Various strategies for introducing an allyl silane moiety for use as a SOMOphile to furnish the final ring of the pentacycle were pursued. Numerous attempts were unsuccessful, and studies for introducing the allylsilane post-cyclization were undertaken. These experiments have led to the construction of a vicinal diol that should be two transformations away from attempting the key SOMO cyclization. If successful, the resulting intermediate will be six steps away from the final natural product.
\r\n", "doi": "10.7907/SJGJ-2K48", "publication_date": "2008", "thesis_type": "phd", "thesis_year": "2008" }, { "id": "thesis:1565", "collection": "thesis", "collection_id": "1565", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05012008-092352", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 2091246, "license": "other", "mime_type": "application/pdf", "url": "/1565/1/Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Computational Insight into Homogeneous Organopalladium Catalysis", "author": [ { "family_name": "Keith", "given_name": "John Andrew", "orcid": "0000-0002-6583-6322", "clpid": "Keith-John-A" } ], "thesis_advisor": [ { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "An investigation of modern computational simulation techniques and their results in describing two notable organopalladium reactions are discussed. First, a methodology for computational quantum chemistry simulations of homogeneous catalysis is presented. We find that through careful consideration of electronic and thermodynamic energy contributions, practical methods are available to accurately study complicated reaction mechanisms and to make educated predictions about their chemistry. We apply this technique to develop the first full analysis of the Wacker Process, olefin oxidation by PdCl2 catalysts, effectively uniting nearly 50 years of research into one mechanistic model. Key findings include the identification of competitive rate determining steps that are dependent on ion concentrations and the inaccessibility of [beta]-hydride elimination during product formation. The second analysis addresses the unique performance of the enantioselective Tsuji-allylation reaction, a reaction the great potential in the fields of asymmetric catalysis and natural product synthesis. In this reaction, calculations point towards enantioselectivity determined after the rate determining step. Intriguingly, we find that C-C coupling is facile in a variant to canonical reductive elimination containing characteristics of both reductive cheletropic and Claisen rearrangements. Lastly, a model is presented to direct improved catalyst design. In total, this dissertation presents an outline for practical quantum chemical simulation of complicated and elaborate organopalladium reactions.\r\n", "doi": "10.7907/FAS9-DV26", "publication_date": "2008", "thesis_type": "phd", "thesis_year": "2008" }, { "id": "thesis:537", "collection": "thesis", "collection_id": "537", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-02072007-103257", "primary_object_url": { "basename": "FrontMaterial.pdf", "content": "final", "filesize": 49432, "license": "other", "mime_type": "application/pdf", "url": "/537/6/FrontMaterial.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Controlling Olefin Metathesis through Catalyst and Monomer Design", "author": [ { "family_name": "Hejl", "given_name": "Andrew", "clpid": "Hejl-Andrew" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The olefin metathesis reaction has become a widely used method for the construction of new carbon-carbon double bonds. The development of well-defined, ruthenium-based catalysts with high air- and moisture-stability and functional group tolerance has allowed synthetic chemists to exploit this reaction in many areas. The main goal of this thesis was to better understand the impact of changes in catalyst and monomer structure on the olefin metathesis reaction.
\r\n\r\nThe introduction of chelating alkylidene ligands to olefin metathesis catalysts has resulted in systems with high activity and stability that, for the most part, are active at or below room temperature. However, for some applications, catalysts that react only at higher temperatures are desirable. Chapter 2 describes the synthesis of latent olefin metathesis catalysts with chelating alkylidenes with a range of donor ligands: including phosphines, pyridines, imines, amines, and thioethers. The nature of the donor ligand was found to have a large impact on the catalyst initiation rate.
\r\n\r\nChapter 3 describes mechanistic studies of the initiation of catalysts with chelating alkylidenes. In all cases, the rate-limiting step of catalyst initiation was found to be association of the incoming olefin, not dissociation of the donor ligand. Further investigations support a mechanism where dissociation of the chelated ligand occurs prior to olefin coordination, but is fast and reversible.
\r\n\r\nChapter 4 presents a detailed study of the ring-opening metathesis polymerization (ROMP) of low-strain monomers with ruthenium-based catalysts. The effects of monomer concentration and catalyst dependence are described for unsubstituted cycloolefins. The ROMP of low-strain olefins with polar substituents is also examined, and a predictive model for ROMP feasibility is proposed.
\r\n\r\nAppendix 1 introduces a set of six reactions with specific reaction conditions to establish standards for comparing olefin metathesis catalysts. The reactions were selected on the basis of their ability to provide a maximum amount of information describing catalyst activity, stability, and selectivity, while being operationally simple. Seven of the most widely used ruthenium-based olefin metathesis catalysts were evaluated using these standards. These conditions are useful tools for the comparison and evaluation of new olefin metathesis catalysts.
", "doi": "10.7907/F0HK-YQ26", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:5235", "collection": "thesis", "collection_id": "5235", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06152006-110234", "primary_object_url": { "basename": "Funk-T-W-2007-thesis.pdf", "content": "final", "filesize": 4357609, "license": "other", "mime_type": "application/pdf", "url": "/5235/29/Funk-T-W-2007-thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Chemo- and Stereoselective Olefin Metathesis in Small Molecule Synthesis", "author": [ { "family_name": "Funk", "given_name": "Timothy William", "orcid": "0000-0002-8828-1446", "clpid": "Funk-Timothy-William" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The major goals of the work described in this thesis were to expand the selectivity of ruthenium metathesis catalysts to include chemo- and stereoselective reactions and to apply those reactions to the synthesis of important organic compounds.
\r\n\r\nChapter 2 describes efforts to synthesize trisubstituted vinyl boronates using the cross-metathesis of 1,1-disubstituted vinyl pinacol boronates. The reactions with methyl-substituted substrates afforded products in modest yields (up to 60%), and the reactions were typically highly selective for the Z-alkene. As the size of the substituent increased, the yields and stereoselectivities decreased. The lack of reactivity of certain ruthenium catalysts in the formation of trisubstituted alkenes lent insight into how to develop a chemoselective reaction where a monosubstituted olefin would exclusively react in the presence of a more highly substituted olefin.
\r\n\r\nChapter 3 describes how conjugated dienes were synthesized by taking advantage of the large reactivity difference between monosubstituted alkenes and 1,1-disubstituted alkenes. The cross-metathesis reactions were highly chemo- and stereoselective, and only the E-isomer of the products was formed. Additionally, further functionalization of the diene products was shown to be possible in a one pot cross-metathesis/Suzuki coupling process.
\r\n\r\nThe research presented in chapters 4 and 5 focused on the asymmetric ring-closing metathesis of achiral trienes using chiral ruthenium catalysts. Chapter 4 describes how substitution on the chiral catalyst and the substrate affected the enantioselectivity of the ring-closing reaction. It was discovered that certain five, six, and seven membered rings could be made in up to 92% ee with the chiral ruthenium catalysts. The application of asymmetric ring-closing metathesis in the synthesis of (+)-5-epi-citreoviral is presented in chapter 5. The absolute configuration of one chiral center was set using asymmetric ring-closing metathesis, and the remaining three stereocenters were set from that chiral center.
\r\n\r\nIn addition, there are two appendices. Appendix 1 contains comments on the formation of tetrasubstituted olefins using unhindered ruthenium catalysts. The results from research directed toward the generation of a cis-selective olefin metathesis catalyst bearing a bidentate ligand are described in appendix 2.
", "doi": "10.7907/25WJ-J768", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:5258", "collection": "thesis", "collection_id": "5258", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-10312006-164725", "primary_object_url": { "basename": "DCB_Thesis_Full.pdf", "content": "final", "filesize": 40165419, "license": "other", "mime_type": "application/pdf", "url": "/5258/17/DCB_Thesis_Full.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Progress Toward the Synthesis of (+)-Zoanthenol and the Development of an Asymmetric Tsuji Allylation Reaction", "author": [ { "family_name": "Behenna", "given_name": "Douglas Carl", "clpid": "Behenna-Douglas-Carl" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The stereoselective synthesis of all carbon quaternary stereocenters is an important problem in synthetic chemistry due to their common occurrence in bioactive compounds. The zoanthamine class of marine natural products highlights the challenge in constructing such stereocenters. After a summary of the isolation, structure determination, and biological activities of the zoanthamine natural products, published approaches toward their chemical synthesis are reviewed.
\r\n\r\nSynthetic strategies toward the carbocyclic portion of zoanthenol focus on the synthesis of the three challenging quaternary stereocenters located on the central C ring. An unusual acid-mediated SN' cyclization of a nucleophilic arene with an allylic alcohol forms the B ring and diastereoselectively constructs the benzylic C(12) quaternary stereocenter. However, difficulties with late-stage installation of the remaining C(9) quaternary stereocenter compelled the use of C ring synthons containing the vicinal C(9) and C(22) stereocenters installed at an early stage in the synthesis. Desymmetrization of a meso-anhydride containing vicinal quaternary stereocenters accomplishes this goal in an enantioselective fashion. Several C ring synthons bearing the vicinal quaternary stereocenters are elaborated with A ring fragments, and several methods for the formation of the C(11)-C(12) bond in these systems are explored. Ultimately, a radical conjugate addition strategy provides the carbocyclic core of zoanthenol with the correct relative configuration of all three quaternary stereocenters.
\r\n\r\nThese efforts toward the synthesis of zoanthenol highlight the difficulty in generating enantioenriched alpha-quaternary cycloalkanones derived from ketones with multiple acidic alpha-hydrogens. The first direct catalytic enantioselective access to such products is achieved by the application of chiral bidentate phosphinooxazoline (PHOX) ligands to Tsuji\u2019s non-enantioselective allylation reactions. Cyclic allyl enol carbonates, silyl enol ethers, and allyl beta-ketoesters all provide uniformly excellent yields and high enantioselectivity in the reaction. The limitations on the substrate scope of the reaction are discussed. Preliminary studies into the mechanism of these allylation reactions with prochiral enolate fragments suggest that they occur by a different mechanism than the outer-sphere nucleophilic attack commonly proposed in the alkylation of prochiral allyl fragments.
\r\n", "doi": "10.7907/46KF-QE46", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:681", "collection": "thesis", "collection_id": "681", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-02192007-153310", "primary_object_url": { "basename": "TOCandAcknowledgements.pdf", "content": "final", "filesize": 94607, "license": "other", "mime_type": "application/pdf", "url": "/681/8/TOCandAcknowledgements.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Design Of Olefin Metathesis Catalysts: From Enantioselective Reactions To Tetrasubstituted Olefins", "author": [ { "family_name": "Berlin", "given_name": "Jacob Myar", "orcid": "0000-0001-7498-766X", "clpid": "Berlin-Jacob-Myar" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The widespread use of olefin metathesis in organic and polymer chemistry has been due in large part to the emergence of highly active stable ruthenium catalysts for this transformation. To date, the most successful catalysts for asymmetric olefin metathesis reactions are molybdenum based. It is expected that the development of more effective ruthenium-based catalysts for asymmetric olefin metathesis reactions will dramatically expand the synthetic utility of these reactions. Chapter 2 of this thesis describes the synthesis of novel chiral ruthenium-based olefin metathesis catalysts. These catalysts are applied to asymmetric ring-closing metathesis in chapter 3 and asymmetric ring-opening cross metathesis along with the first examples of asymmetric cross metathesis in chapter 4.
\r\n\r\nAnother area in which the use of ruthenium-based catalysts is limited is the preparation of very sterically encumbered olefins. One example of this limitation is ring-closing metathesis to form tetrasubstituted olefins, chapter 5 describes the synthesis of a family of ruthenium-based catalysts that demonstrate improved activity for this transformation.
", "doi": "10.7907/Q27D-HY48", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:1250", "collection": "thesis", "collection_id": "1250", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04022007-122855", "primary_object_url": { "basename": "Thesis_SHHong.pdf", "content": "final", "filesize": 3272690, "license": "other", "mime_type": "application/pdf", "url": "/1250/1/Thesis_SHHong.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Improvement of Olefin Metathesis Efficiency through Understanding Catalyst Stability", "author": [ { "family_name": "Hong", "given_name": "Soon Hyeok", "orcid": "0000-0003-0605-9735", "clpid": "Hong-Soon-Hyeok" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The recent development of ruthenium olefin metathesis catalysts, which show high activity and functional group tolerance, has expanded the scope of olefin metathesis. To improve efficiency of the ruthenium-catalyzed olefin metathesis, this dissertation describes: (1) mechanistic study to understand decomposition pathways of ruthenium olefin metathesis catalysts for the development of more stable and efficient catalysts, (2) a method to prevent an undesirable side reaction for the improvement of selectivity of ruthenium-catalyzed olefin metathesis, and (3) a novel ruthenium catalyst to increase olefin metathesis efficiency in aqueous media for potential biological applications and environmentally friendly approaches to this chemistry.
\r\n\r\nChapter 2 describes the first well-characterized decomposition products, dinuclear ruthenium hydride complex and methylphosphonium salt, from an N-heterocyclic carbene-based ruthenium catalyst under typical metathesis conditions. In Chapter 3, the decomposition study was expanded to other widely used ruthenium olefin metathesis catalysts. Phosphine-involvement in the decomposition was consistently observed whether or not an olefin was present. The presence of other decomposition modes for phosphine-free ruthenium catalysts was also described. Chapter 4 addresses another decomposition pathway of an N,N\u2019-diphenylbenzimidazol-2-ylidene-based catalyst via C--H activation. Chapter 6 describes the development of a novel poly(ethylene glycol)-supported water-soluble catalyst, which is active and stable in aqueous media. Chapter 7 describes an efficient, practical, and environmentally friendly method to remove residual ruthenium-containing byproducts by simple aqueous workup from olefin metathesis products using the poly(ethylene glycol)-supported catalyst.
", "doi": "10.7907/QMZ9-3Y05", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:1839", "collection": "thesis", "collection_id": "1839", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05162007-152948", "primary_object_url": { "basename": "JABthesisJEB053.pdf", "content": "final", "filesize": 28790779, "license": "other", "mime_type": "application/pdf", "url": "/1839/1/JABthesisJEB053.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Synthetic and Mechanistic Studies into the Kinetic Resolution of \u03b1-olefins Using C\u2081\u208b and C\u2082\u208b Symmetric Zirconocene Polymerization Catalysts", "author": [ { "family_name": "Byers", "given_name": "Jeffery Allen", "orcid": "0000-0002-8109-674X", "clpid": "Byers-Jeffery-Allen" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Mechanistic and synthetic investigations into the kinetic resolution of racemic \u03b1-olefins by polymerization catalysis using C\u2081\u208b and C\u2082\u208bsymmetric zirconocenes are reported. The importance of chain end control as a stereocontrol element was probed with ethylene and propylene copolymerizations catalyzed by the C\u2081\u208bsymmetric catalyst, {1,2-(SiMe\u2082)\u2082(\u03b7\u2075-3,5-C\u2085H\u2081(CHMe\u2082)\u2082)(\u03b7\u2075-4-C\u2085H\u2082((S)-CHMeCMe\u2083)]}ZrCl\u2082/MAO. Selectivity factors and pentad analysis of racemic \u03b1-olefin and propylene polymerizations catalyzed by a similar C\u2081\u208bsymmetric catalyst, {1,2-(SiMe\u2082)\u2082(\u03b7\u2075-3,5-C\u2085H\u2081(CHMe\u2082)\u2082)(\u03b7\u2075-4-C\u2085H\u2082((S)-CHEtCMe\u2083)]}ZrCl\u2082/MAO, indicate that site epimerization does not limit selectivity during kinetic resolution.
\r\n\r\nTo avoid some of the issues involved with the C\u2081\u208bsymmetric catalysts, a route to enantiopure C\u2082\u208bsymmetric zirconocenes was pursued. With the aid of the chiral auxiliary, (R)-N2,N2\u2019-di-p-tolyl-1,1\u2019-binaphtyl-2,2\u2019-diamine, enantiospecefic synthesis of (S,S)-{C\u2082H\u2084 -1,2-(1-indene)\u2082}ZrCl\u2082 was accomplished and its use for kinetic resolution was investigated. Although synthetically useful selectivities were not observed, it was determined that the C\u2082\u208bsymmetric catalyst does not racemize during polymerization, which substantiates a more thorough investigation of catalysts based on {C\u2082H\u2084 -1,2-(1-indene)\u2082}ZrCl\u2082.
", "doi": "10.7907/H55G-7C87", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:1598", "collection": "thesis", "collection_id": "1598", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05032007-151410", "primary_object_url": { "basename": "FinalThesis.pdf", "content": "final", "filesize": 12879814, "license": "other", "mime_type": "application/pdf", "url": "/1598/1/FinalThesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "An Electron Force Field for Simulating Large Scale Excited Electron Dynamics", "author": [ { "family_name": "Su", "given_name": "Julius Tsu-li", "clpid": "Su-Julius-Tsu-li" } ], "thesis_advisor": [ { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Marcus", "given_name": "Rudolph A.", "clpid": "Marcus-R-A" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "We introduce an electron force field (eFF) that makes simulation of large scale excited electron dynamics possible and practical. The forces acting on thousands of electrons and nuclei can be computed in less than a second on a single modern processor.
\r\n\r\nJust as conventional force fields parameterize the ground state potential between nuclei, with electrons implicitly included, electron force fields parameterize the potential between nuclei and simplified electrons, with more detailed degrees of freedom implicitly included. The electrons in an electron force field are Gaussian wave packets whose only parameters are its position and its size.
\r\n\r\nUsing a simple version of the electron force field, we compute the dissociation and ionization behavior of dense hydrogen, and obtain equations of state and shock Hugoniot curves that are in agreement with results obtained from vastly more expensive path integral Monte Carlo methods. We also compute the Auger dissociation of hydrocarbons, and observe core hole decays, valence electron ionizations, and nuclear fragmentation patterns consistent with experiment.
\r\n\r\nWe show we can describe p-like valence electrons using spherical Gaussian functions, enabling us to compute accurate ionization potentials and polarizabilities for first row atoms, and accurate dissociation energies and geometries of atom hydrides and hydrocarbons.
\r\n\r\nWe show also that we can describe delocalized electrons in a uniform electron gas using localized eFF orbitals. We reproduce the energy of a uniform electron gas, including correlation effects; and following the historical development of density functional theory, we develop a preliminary eFF that can compute accurate exchange and correlation energies of atoms and simple molecules.
", "doi": "10.7907/d8a3-e876", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:1981", "collection": "thesis", "collection_id": "1981", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05232006-210214", "primary_object_url": { "basename": "IKMthesisedit.pdf", "content": "final", "filesize": 12307070, "license": "other", "mime_type": "application/pdf", "url": "/1981/1/IKMthesisedit.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Development of Organocatalytic Direct Aldol Transformations, Total Syntheses of Brasoside and Littoralisone, and Progress Toward the Total Synthesis of Diazonamide A", "author": [ { "family_name": "Mangion", "given_name": "Ian Kyle", "clpid": "Mangion-Ian-Kyle" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The enantioselective amine-catalyzed direct aldol reaction of aldehdyes has been accomplished for the first time using an imidazolidinone organocatalyst. That imidazolidinone catalyst, initially developed for LUMO-lowering activation of alpha, beta-unsaturated aldehydes, provides new insight into amine-mediated aldol transition states. The concepts developed in this study have been applied toward the development of an unprecedented enantioselective Type II direct aldol. In the course of these studies the amino acid proline was also found to be a highly effective catalyst for this transformation. These catalyst systems form the basis for a novel approach to polyketide and polyglycolate architectures, structural motifs having broad representation amongst natural product isolates.
\r\n\r\nThis enamine catalysis strategy was then applied towards the total synthesis of the iridoid natural products brasoside and littoralisone. Direct aldol chemistry was applied towards the synthesis of a substituted carbohydrate structure, and a recently developed enantioselective oxyamination reaction installed a key stereocenter. Stereocontrolled synthesis of the bicyclic core common to the iridoid class of natural products required the development of a new, kinetically controlled organocatalytic intramolecular Michael reaction. A [2+2] photocycloaddition completed the first total synthesis of littoralisone, and demonstrated a likely biosynthetic link to brasoside, which may well be a natural precursor.
\r\n\r\nAn iminium-mediated addition-cyclization cascade reaction has been applied toward the total synthesis of the marine natural product diazonamide A. This strategy has provided stereoselective, catalytic access to the crucial C-10 quaternary carbon stereocenter for the first time. A novel intramolecular soft enolization aldol macrocyclization formed a precursor to the A-ring oxazole, which was subsequently completed in a newly discovered DAST-mediated cyclodehydration. Closure of the fourteen-membered biaryl macrocycle has been accessed through an unusual Suzuki macrocyclization, and completion of diazonamide A should be accessible in four further steps.
\r\n", "doi": "10.7907/1TPK-9277", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:4579", "collection": "thesis", "collection_id": "4579", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11152005-155011", "primary_object_url": { "basename": "ERAThesis.pdf", "content": "final", "filesize": 13588987, "license": "other", "mime_type": "application/pdf", "url": "/4579/12/ERAThesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "The First Total Synthesis of (\u2013)-Lemonomycin and Progress toward the Total Synthesis of (+)-Cyanocycline A", "author": [ { "family_name": "Ashley", "given_name": "Eric Robert", "orcid": "0000-0002-0513-3342", "clpid": "Ashley-Eric-Robert" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The first total synthesis of (\u2013)-lemonomycin has been accomplished. The synthesis features a novel, auxiliary-controlled asymmetric dipolar cycloaddition, a highly convergent Suzuki coupling, a diastereoselective enamide hydrogenation to set the C(3) stereochemistry, and a convergent, efficient, and completely diastereoselective Pictet-Spengler cyclization with a glycosyloxy acetaldehyde.
\r\n\r\nThe total synthesis of (+)-cyanocycline A has been approached along two routes. Both routes feature dipolar cycloaddition reactions with alkyne-containing substrates and completely diastereoselective hydrogenations to set the C(4) stereochemistry. Proposals for the advancement of late-stage intermediates to the natural product are included.
", "doi": "10.7907/QM4S-3B86", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:5249", "collection": "thesis", "collection_id": "5249", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-08222005-162934", "primary_object_url": { "basename": "Intro.pdf", "content": "final", "filesize": 69725, "license": "other", "mime_type": "application/pdf", "url": "/5249/1/Intro.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Application of Transition Metal Catalysis to Small Molecule Synthesis", "author": [ { "family_name": "Morrill", "given_name": "Christie", "clpid": "Morrill-Christie" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Over the past decade, transition metal catalysis has developed into a new field in organic synthesis, enabling numerous synthetic transformations that were previously not feasible. This thesis describes the application of both ruthenium and rhenium catalysis to the synthesis of several classes of small molecules. Ruthenium-catalyzed ring-opening cross-metathesis of five- through eight-membered ring cycloolefins was investigated for the synthesis of functionalized dienes (Chapter 1). Unsubstituted, trisubstituted, and allyl-substituted cycloolefins were studied. Regioselective reactions could be achieved with the use of unsymmetrical cycloolefins. Ruthenium-catalyzed cross-metathesis was explored for the synthesis of both di- and trisubstituted vinyl boronates (Chapter 2). These reactions proceeded efficiently for a wide variety of functionalized alkenes and generally exhibited high E-stereoselectivity. The resultant vinyl boronate products were stereoselectively converted into both Z-vinyl bromides and E-vinyl iodides. The rhenium-catalyzed 1,3-isomerization of allylic alcohols was employed in the synthesis of various allylic alcohols (Chapter 3). Two different strategies were developed to promote high product selectivity in these reactions: conjugated product synthesis and N,O-bis(trimethylsilyl)acetamide-promoted product trapping. These reactions enabled the synthesis of allylic alcohols with conjugated or non-conjugated, di- or trisubstituted, and electron-rich or electron-deficient alkene components. Partial chirality transfer was observed during the 1,3-isomerization of certain enantioenriched allylic alcohols. The fundamental reaction properties observed during these studies were all consistent with the operation of a mechanism involving a chair-like transition state, which contains a partially cationic allyl moiety, as the primary reaction pathway.", "doi": "10.7907/QRWG-BM33", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:5248", "collection": "thesis", "collection_id": "5248", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-08182005-120859", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 17633298, "license": "other", "mime_type": "application/pdf", "url": "/5248/15/Thesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Development of the Enantioselective Oxidation of Secondary Alcohols and Natural Products Total Synthesis", "author": [ { "family_name": "Bagdanoff", "given_name": "Jeffrey Thomas", "clpid": "Bagdanoff-Jeffrey-Thomas" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Oxidation is a fundamental process in chemistry and biology. In synthetic chemistry, there are several methods for the asymmetric oxidation of organic substrates. Classically, these methods have focused on the delivery of a heteroatom from a reagent or catalyst to a prochiral substrate. What have historically been underdeveloped are enantioselective oxidation methods that do not involve the transfer of a heteroatom, but rather are defined by the enantioselective dehydrogenation of an organic substrate. This type of oxidative transformation was investigated using a palladium(II) catalyst system.
\r\n\r\nA palladium-catalyzed oxidative kinetic resolution of secondary alcohols was developed. Key features of the catalytic system include the use of (\u2013)-sparteine as the source of chiral relay, and molecular oxygen as the sole stoicheometric oxidant. Under the described catalytic system, a number of benzylic and allylic alcohols have been oxidized in an enantioselective manner, to provide a ketone and residual alcohol in high enantiomeric excess and excellent yield.
\r\n\r\nSubsequent to the original system, the systematic investigation of a number of mechanistic hypotheses involving the role of exogenous bases and H-bonding additives prompted the discovery of new reaction conditions displaying greatly enhanced reactivity, selectivity, atom economy, and generality. The net result of these improvements was a catalytic system effective in oxidative desymmetrization of a number of complex meso-diols. Ultimately, these advances have permitted our method to be applied towards a number of synthetic endeavors, including the key step in the total synthesis of the natural product alkaloid (\u2013)-lobeline.
\r\n", "doi": "10.7907/Z94F1NQK", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:5107", "collection": "thesis", "collection_id": "5107", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-12212005-185814", "primary_object_url": { "basename": "Tambar_Complete_Thesis.pdf", "content": "final", "filesize": 15479882, "license": "other", "mime_type": "application/pdf", "url": "/5107/17/Tambar_Complete_Thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Convergent Methods for Synthesizing Rings in the Context of Natural Product Synthesis: I. Development of a Tandem Stille-Oxa-Electrocyclization Reaction, and Progress Toward the Total Synthesis of Saudin. II. Development of the Direct Acyl-Alkylation of Arynes, and Its Application Toward the Total Synthesis of Amurensinine", "author": [ { "family_name": "Tambar", "given_name": "Uttam Krishan", "orcid": "0000-0001-5659-5355", "clpid": "Tambar-Uttam-Krishan" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Cyclic molecular structures are ubiquitous in chemistry. Efficient and convergent methods to synthesize these rings are of great importance, specifically in the context of natural product synthesis. The development of two methods for the synthesis of the core structures of the natural products saudin and amurensinine are described.
\r\n\r\nFirst, the development of the tandem Stille-oxa-electrocyclization will be discussed in the context of synthetic efforts with saudin. The labdane diterpenoid saudin was isolated in 1985 by Mossa and Cassady from the leaves of the Clutia richardiana (L.) family Euphorbiaceae. The natural product was found to induce hypoglycemia in mice and therefore could be an appealing lead structure for the development of new agents to treat diabetes. A diastereoselective tandem Stille-oxa-electrocyclization reaction has been developed, which provides access to the core structure of saudin in a rapid and convergent manner. Additionally, this new reaction has been extended to the convergent preparation of related polycyclic pyran systems. Progress has been made on the advancement of these complex pyran systems toward the synthesis of saudin.
\r\n\r\nSecondly, the development of the direct acyl-alkylation of arynes will be described in the context of the total synthesis of the isopavine natural product amurensinine. The isopavine alkaloids are promising lead structures for the treatment of neuronal disorders such as as Parkinson\u2019s disease, Down\u2019s syndrome, Alzheimer\u2019s disease, amyotrophic lateral sclerosis, and Huntington\u2019s chorea. All members of this family of natural products contain a seven-membered benzannulated carbocycle. To address the challenge of synthesizing the isopavines, an efficient and mild acyl-alkylation of arynes has been developed. The method forms ortho-disubstituted aromatic products that would otherwise be difficult to synthesize. Additionally, the method is used to synthesize medium-sized benzannulated carbocycles, such as the seven-membered ring structure in the isopavine alkaloids, by the ring-expansion of cyclic beta-ketoesters. Overall, the transformation results in the formation of two new C\u2013C bonds by the net insertion of an aryne into the alpha,beta C-C sigma-bond of a beta-ketoester. This reaction has been applied in the total synthesis of amurensinine.
\r\n", "doi": "10.7907/PMHT-S093", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:2570", "collection": "thesis", "collection_id": "2570", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06132005-145346", "primary_object_url": { "basename": "Chapter00frontmaterial.pdf", "content": "final", "filesize": 220110, "license": "other", "mime_type": "application/pdf", "url": "/2570/7/Chapter00frontmaterial.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "The Development of Organocatalytic Reactions Pertaining to Indoles", "author": [ { "family_name": "Austin", "given_name": "Joel Francis", "clpid": "Austin-Joel-Francis" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Leonard", "given_name": "Nelson J.", "clpid": "Leonard-N-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "An improved imidazolidinone catalyst for the LUMO-lowering activation of [alpha],[beta]-unsaturated aldehydes has been designed, synthesized and evaluated. This new catalyst allows hitherto infeasible reactions to proceed with high fidelity.\r\n\r\nA new strategy for the synthesis of C-3 chiral indoles has been developed. This strategy employs the use of the aforementioned imidazolidinone catalyst to activate [alpha], [beta]-unsaturated aldehydes toward a Friedel-Crafts reaction with a variety of indoles. This is the first and only example in the literature were an indole is alkylated by an [alpha], [beta]-unsaturated aldehyde enantioselectively and catalytically. This methodology allows for the rapid synthesis of this priviledged pharmacophore.\r\n\r\nBy exploiting the indolium ion intermediate produced during the asymmetric Friedel-Crafts alkylation of indoles, a cascade cyclization was found to occur in the first enantioselectivive catalytic construction of the pyrroloindoline architecture. This direct route provides rapid access to this valuable core motif. This research has led to interesting observances in terms of indole facial selectivity that can be rationalized by an understanding of the cation-[pi] interaction.\r\n\r\nAfter numerous unsuccessful attempts to apply the direct pyrroloindoline construction to the synthesis of vicinally quaternary adducts, exploration of the higher reactivity of oxindoles was undertaken. This study has led to the first construction of vicinally quaternary stereogenic carbons via an organocatalyzed protocol.", "doi": "10.7907/CDXN-8R73", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:2557", "collection": "thesis", "collection_id": "2557", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06122005-180419", "primary_object_url": { "basename": "First_20_pages.pdf", "content": "final", "filesize": 113929, "license": "other", "mime_type": "application/pdf", "url": "/2557/8/First_20_pages.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "N-Heterocyclic Carbene Ligands for Nickel Ethylene Polymerization Catalysts:Toward the Incorporation of Polar Comonomers", "author": [ { "family_name": "Waltman", "given_name": "Andrew Willis", "clpid": "Waltman-Andrew-Willis" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of a catalyst capable of incorporating vinyl-functionalized polar olefins (methyl acrylate, acrylonitrile) into a linear polyethylene backbone is one of the most prominent challenges in organometallic chemistry. Recent developments in group 10 catalysts (Ni and Pd) have shown promise; however, there remains no system capable of this goal. Our group has developed a series of neutral Ni complexes which are excellent catalysts for the polymerization of ethylene but are rapidly deactivated in the presence of methyl acrylate and other polar olefins. This thesis presents our studies toward the cause of catalyst deactivation by these olefins, and describes the design of novel Ni complexes based on the findings of the deactivation study.
\r\n\r\nTo determine the cause of deactivation by polar olefins, our neutral Ni catalysts were allowed to react with methyl acrylate (MA). Examination of the products revealed that, upon coordination of MA, the catalysts form chelated enolate complexes which are susceptible to deactivating protonolysis across Ni\u2013C bonds. Furthermore, it was determined that MA itself is a potential source of hydrogen atoms for this cleavage, implying protolytic deactivation is unavoidable result whenever olefins capable of chelation are introduced to the catalysts. Therefore, it was decided that chelation should be made less favorable through the use of more electron-donating ligands. For this purpose, N-heterocyclic carbenes (NHCs) were chosen.
\r\n\r\nNHCs are stable carbenes which have found increasing use as electron-rich ligands for transition metals. In order to make viable catalysts, NHC ligands capable of chelation through a phenoxide moiety were required. An efficient synthesis of these ligands was developed, and they were successfully ligated to Pd. However, it was found that upon attempted ligation to Ni, a series of unexpected and undesired compounds were obtained, one of which is the apparent result of an unprecedented C\u2013N cleavage of the NHC heterocycle. Unfortunately, when a targeted Ni complex was finally synthesized, it proved inactive toward ethylene polymerization. Finally, it was shown that group 4 (Ti and Zr) complexes of the novel NHC ligands are good catalysts for ethylene polymerization, as well as the copolymerization of ethylene with other olefins.
\r\n", "doi": "10.7907/5G0D-JD41", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:2364", "collection": "thesis", "collection_id": "2364", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06012006-151944", "primary_object_url": { "basename": "CCL_Thesis_Corrected.pdf", "content": "final", "filesize": 3466451, "license": "other", "mime_type": "application/pdf", "url": "/2364/1/CCL_Thesis_Corrected.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "The Chemistry of Tris(phosphino)borate Manganese and Iron Platforms", "author": [ { "family_name": "Lu", "given_name": "Connie Chih", "orcid": "0000-0002-5162-9250", "clpid": "Lu-Connie-Chih" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The coordination chemistry of monovalent and divalent manganese complexes supported by the anionic tris(phosphino)borate ligand [PhBPiPr3] is presented. The halide complexes, [PhBPiPr3]MnCl and [PhBPiPr3]MnI, have been characterized by XRD, SQUID magnetometry, and EPR spectroscopy. The halide [PhBPiPr3]MnI serves as a precursor to manganese azide, alkyl, and amide species: [PhBPiPr3]Mn(N3), [PhBPiPr3]Mn(CH2Ph), [PhBPiPr3]Mn(Me), [PhBPiPr3]Mn(NH(2,6-iPr2Ph)), [PhBPiPr3]Mn(dbabh), and [PhBPiPr3]Mn(1-Ph(isoindolate)). Collectively, they represent an uncommon motif of low-coordinate polyphosphine-supported manganese species. Some of our synthetic efforts to generate [PhBPiPr3]Mn?Nx species are described, as are theoretical DFT studies that probe the electronic viability of these multiply bonded target structures.
\r\n\r\nTwo tris(phosphino)borate ligands, [PhBPter3] and [PhBPCH2Cy3] are introduced that feature terphenyl and methylcyclohexyl groups on the phosphine arms, respectively. The iron chlorides, [PhBPter3]FeCl and [PhBPCH2Cy3]FeCl, have been prepared as precursors to iron nitrides. Addition of the nitride transfer reagent Li(dbabh) to [PhBPCH2Cy3]FeCl produced the terminal nitride, [PhBPCH2Cy3]Fe(N). The 15N NMR spectrum of the labeled species, [PhBPCH2Cy3]Fe(15N), contains a peak at 929 ppm, consistent with a terminal nitride functionality. Mossbauer spectroscopy of the nitride shows a low isomer shift value of 0.34(1) mm/s and an exceptionally large quadrupole splitting of 6.01(1) mm/s.
\r\n\r\nReduction of [PhBPCH2Cy3]FeCl generates a masked iron(I) species that is highly reactive. Combustion analysis of this species is consistent with \"[PhBPCH2Cy3]Fe.\" Other physical methods including VT NMR, EPR, and IR spectroscopies suggest the presence of a paramagnetic species in equilibrium with a diamagnetic species. The paramagnetic component is postulated to be an Fe(III) hydride, wherein a ligand C-H bond has been cyclometalated at the metal center. The reactivity of \"[PhBPCH2Cy3]Fe\" is consistent with iron(I). For example, its reaction with PMe3 and 1-adamantylazide affords the phosphine adduct, [PhBPCH2Cy3]Fe(PMe3), and the iron imide, [PhBPCH2Cy3]Fe(NAd), respectively. Interestingly, \"[PhBPCH2Cy3]Fe\" undergoes redox reactions with benzene to give initially a benzene adduct, {[PhBPCH2Cy3]Fe}2(mu-eta3:eta3-C6H6), which decomposes to {[PhBPCH2Cy3]Fe}2(mu-eta5:eta5-6,6'-bicyclohexadienyl) via radical C-C bond coupling. Finally, \"[PhBPCH2Cy3]Fe\" readily reduces CO2 at rt to give as the major product {[PhBPCH2Cy3]Fe}2(mu-CO)(mu-O), wherein a C=O bond has been cleaved. The minor product has not been definitively established, but one possibility is the oxalate-bridged dimer {[PhBPCH2Cy3]Fe}2(mu-eta2:eta2-O2CCO2) that results from reductive coupling of two CO2 molecules.
\r\n", "doi": "10.7907/0DND-1J03", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:1033", "collection": "thesis", "collection_id": "1033", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-03202006-120555", "primary_object_url": { "basename": "RMT.intro.Ch1.pdf", "content": "final", "filesize": 651048, "license": "other", "mime_type": "application/pdf", "url": "/1033/5/RMT.intro.Ch1.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Concerning the Mechanism and Selectivity of Palladium(II)-Catalyzed Aerobic Oxidation Reactions", "author": [ { "family_name": "Trend", "given_name": "Raissa M.", "clpid": "Trend-Raissa-M" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Oxidation is one of the most fundamental and important processes in nature. It would be advantageous to chemically replicate the high substrate specificity and selectivity observed in oxidative enzymes. Several such synthetic processes have been developed that involve the transfer of a heteroatom to a substrate in an asymmetric fashion. Enantioselective oxidative dehydrogenations, which do not involve transfer of a heteroatom, are much less common. Reactions of this type have recently been developed for the oxidative kinetic resolution of secondary alcohols using palladium(II) catalysis, dioxygen, and the chiral ligand (\u2013)-sparteine.
\r\n\r\nThis general approach (palladium(II), dioxygen, ligand) was applied to the development of oxidative heteroatom/olefin cyclizations to form dihydrobenzofurans, cyclic ethers, lactones and lactams. The nonenantioselective reaction employs pyridine as a ligand. These conditions could be extended to the enantioselective cyclization of allyl-appended phenols through the use of (\u2013)-sparteine as a ligand.
\r\n\r\nThe mechanism of the oxidative heteroatom/olefin cyclizations was explored via stereospecifically deuterium-labeled substrates. These studies indicate that the stereochemistry of oxypalladation for primary alcohol substrates is syn, whether a mono- or bidentate ligand is used. In contrast, cyclizations of deuterium-labeled carboxylic acid substrates undergo anti oxypalladation.
\r\n\r\nThe origins of stereoselectivity in the oxidative kinetic resolution of secondary alcohols using the C1 symmetric ligand (\u2013)-sparteine were investigated through structural and reactivity studies of a variety of ((\u2013)-sparteine)palladium(II) complexes. A model for the observed selectivity was developed, and is supported by theoretical calculations. Experiments with the C2 symmetric diastereomers of (\u2013)-sparteine highlight the special properties of (\u2013)-sparteine that make it a uniquely effective ligand in the kinetic resolution.
\r\n", "doi": "10.7907/M4CC-BR50", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:889", "collection": "thesis", "collection_id": "889", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-03062006-135435", "primary_object_url": { "basename": "May_PhD_Thesis.pdf", "content": "final", "filesize": 42637429, "license": "other", "mime_type": "application/pdf", "url": "/889/1/May_PhD_Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "I. Synthesis and Utilization of Diazocompounds for Applications in Solution-Phase and Gas-Phase Chemistry. II. Progress Toward the Communesin Alkaloids", "author": [ { "family_name": "May", "given_name": "Jeremy Allen", "orcid": "0000-0003-3319-0077", "clpid": "May-Jeremy-Allen" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Beauchamp", "given_name": "Jesse L.", "clpid": "Beauchamp-J-L" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Advances in the synthesis and use of diazo compounds are first discussed. The development of non-carbonyl stabilized diazo equivalents has allowed for carbene reactivity to be localized at carbons not adjacent to carbonyls. Consequently, a new tandem sequence, the Bamford-Stevens/Claisen reaction, has been developed that incorporates selective Z-enol ether formation with a thermal- or Lewis acid-promoted Claisen reaction. Bamford-Stevens/Claisen/Carbonyl Ene and Bamford-Stevens/Claisen/Cope reactions have also been realized.
\r\n\r\nAlso discussed is the application of diazocompounds to gas-phase chemistry with peptides. Crown ethers are used for binding to primary amines, and a diazomalonate is incorporated for generation of a highly reactive carbene within a non-covalent complex. Intermolecular insertion reactions can then occur in these complexes. Electrospray ionization mass spectrometry and density functional theory (DFT) are utilized to evaluate the reactions for small molecules and peptides, as well as metal-promoted Wolff Rearrangement in the gas phase.
\r\n\r\nFinally, the biosynthesis of the calycanthaceous alkaloids is examined. The development of an approach to the alkaloid communesin B is presented. The approach is based on considerations of a possible biosynthetic sequence involving an oxidative coupling of tryptamine with a derivative of the ergot alkaloid aurantioclavine. Structure revision is also suggested for the recently isolated microfilament disrupting alkaloid nomofungin. Crystallographic evidence is presented for products from the proposed inverse-demand Diels-Alder reaction.
", "doi": "10.7907/dkek-2c97", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:4588", "collection": "thesis", "collection_id": "4588", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11162005-125732", "primary_object_url": { "basename": "SSThesis.pdf", "content": "final", "filesize": 8673088, "license": "other", "mime_type": "application/pdf", "url": "/4588/1/SSThesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Kinetic Resolution of Chiral \u221d-Olefins Using Enantiopure Ziegler-Natta Polymerization Catalysts", "author": [ { "family_name": "Min", "given_name": "Endy Yeo-Jung", "clpid": "Min-Endy-Yeo-Jung" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Towards the goal of kinetic resolution of chiral olefins, a series of enantiopure C1 symmetric metallocenes has been synthesized for use in the polymerization of chiral olefins. The new precatalysts were based on the parent precatalyst {(SiMe2)2[[eta]5-C5H(CHMe2)2][[eta]5-C5H2((S)-CHMeCMe3)]}ZrCl2, (S)-2, which has a doubly, silylene-linked ligand framework. The new precatalysts include {(SiMe2)2[[eta]5-C5H(CHEt2)2][[eta]5-C5H2((S)-CHMeCMe3)]}ZrCl2, (S)-3, {(SiMe2)2[[eta]5-C5H(CHCy2)2][[eta]5-C5H2((S)-CHMeCMe3)]}ZrCl2, (S)-4 (Cy = cyclohexyl), {(SiMe2)2[[eta]5-C5H(CHTMS2)2][[eta]5-C5H2((S)-CHMeCMe3)]}ZrCl2, (S)-5 (TMS = trimethylsilyl), and {(SiMe2)2[[eta]5-C5H(CHMe2)2][[eta]5-C5H2((S)-CHEtCMe3)]}ZrCl2, (S)-6.\r\n\r\nThe zirconocene dichlorides (S)-2, (S)-3, (S)-4, and (S)-5 have an enantiopure 3,3-dimethyl-2-butyl (\"methylneopentyl\") substituent on the \"upper\" cyclopentadienyl ligand. The zirconocene dichloride (S)-6 has an enantiopure 2,2-dimethyl-3-pentyl (\"ethylneopentyl\") substituent on the \"upper\" cyclopentadienyl ligand.\r\n\r\nWhen activated with methylaluminoxane (MAO), these metallocenes show unprecedented activity for the polymerization of racemic monomers bearing substitution at the 3- and/or 4-positions. In addition, due to the optically pure nature of these single site catalysts, polymerization of racemic monomers serves as a transition metal mediated kinetic resolution strategy. The polymeric product is enriched with the faster reacting enantiomer, while the recovered monomer is enriched with the slower reacting enantiomer. The two components are easily separated, thus affecting the resolution. A modest kinetic resolution was achieved (s = kfaster/kslower = ca. 2) with most olefins surveyed. In the case of 3,4-dimethyl-1-pentene and 3,4,4-trimethyl-1-pentene, high levels of separation were obtained (s > 12). X ray crystal structure determinations for (S)-2, (S)-3, and (S)-4 have been used to examine the prevailing steric interactions expected in the diastereomeric transition states for propagation during polymerization. In comparison to (S)-2, slight improvements in the selectivity of 3-methyl-1-hexene and 3,5,5-trimethyl-1-hexene were observed with polymerizations using (S)-3. Likewise, the polymerizations of 3-methyl-1-pentene and 3,5,5-trimethyl-1-hexene using (S)-6 showed a modest increase in selectivity, relative to (S)-2. The kinetic resolution of chiral olefins containing a polar functionality also has been attempted with (S)-2. Although the selectivity of these polymerization experiments is yet to be determined, preliminary work indicates that NMR can be used to analyze the (S)-Mosher esters of the olefins to obtain the enantiomeric excess.", "doi": "10.7907/ZD0X-9Y24", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:5252", "collection": "thesis", "collection_id": "5252", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-09302006-140602", "primary_object_url": { "basename": "thesis-c.lacenere.pdf", "content": "final", "filesize": 14263807, "license": "other", "mime_type": "application/pdf", "url": "/5252/1/thesis-c.lacenere.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Advances in Single Molecule Nucleic Acid Sequencing", "author": [ { "family_name": "Lacenere", "given_name": "Christopher J.", "clpid": "Lacenere-Christopher-J" } ], "thesis_advisor": [ { "family_name": "Quake", "given_name": "Stephen R.", "clpid": "Quake-S-R" } ], "thesis_committee": [ { "family_name": "Deshaies", "given_name": "Raymond Joseph", "clpid": "Deshaies-R-J" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Elowitz", "given_name": "Michael B.", "clpid": "Elowitz-M-B" }, { "family_name": "Quake", "given_name": "Stephen R.", "clpid": "Quake-S-R" } ], "local_group": [ { "literal": "div_biol" } ], "abstract": "The ability to quickly and accurately obtain sequence information from single molecules of DNA and RNA has far-reaching implications for our understanding of biology. In the work presented here, we have made several advances in the area of single-molecule DNA and RNA sequencing. Specifically, in attempting to increase the read length of DNA polymerase, we have assayed several custom synthesized fluorescent nucleotides containing longer dye\u2013base linkers. We have validated the efficacy of these nucleotides at both bulk and single-molecule levels. Furthermore, we have screened several commercially available DNA polymerases for their ability to incorporate these nucleotides. We also show that reverse transcriptase is able to synthesize a complimentary DNA strand of 28 bases in length from an RNA template, using solely fluorescently labeled nucleotides. Additionally, we show that reverse transcriptase is able to incorporate a fluorescently labeled nucleotide into an RNA template at the single-molecule level. Finally, we demonstrate automated reagent exchange for our single-molecule sequencing system.", "doi": "10.7907/CA4B-S389", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:1836", "collection": "thesis", "collection_id": "1836", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05162006-201134", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 2008856, "license": "other", "mime_type": "application/pdf", "url": "/1836/1/Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Novel Reactivity at Iron Centers Supported by Poly(phosphino)borate Ligands", "author": [ { "family_name": "Thomas", "given_name": "Christine Marie", "orcid": "0000-0001-5009-0479", "clpid": "Thomas-Christine-Marie" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The reactivity of the iron(II) alkyl species [PhBPiPr3]FeMe ([PhBPiPr3] = PhB(CH2PiPr2)3-) towards Si-H bonds is presented. Reaction of [PhBPiPr3]FeMe with primary aryl silanes results in the unusual \u03b73 silane adducts [PhBPiPr3]Fe(H)(\u03b73-H2SiMeR). X-ray crystallography, Mossbauer spectroscopy, and theoretical calculations confirm this structural assignment; however, solution NMR experiments suggest a degree of fluxionality in solution.
\r\n\r\nLow valent, tris(phosphino)borate iron platforms have been shown to facilitate the activation of white phosphorus, P4. The iron(I) precursors {[PhBPiPr3]Fe}2(\u03bc-N2) and [PhBPPh3]Fe(PPh3) react with P4 to quantitatively generate {[PhBPiPr3]Fe}2(\u03bc-P4) and {[PhBPPh3]Fe}2(\u03bc-P4), respectively. These unique iron(II) dimers bridged by square P42- units have been characterized structurally and spectroscopically, and their reactivity has been examined. A simplified electronic structure calculation is presented to aid in discussion of bonding within these complexes.
\r\n\r\nMotivated by the versatility of the tris(phosphino)borate ligands, a new family of tripodal hybrid bis(phosphino)pyrazolylborate ligands, [PhBPtBu2(pz')]- ([PhBPtBu2(pz')]- = PhB(CH2PtBu2)2(pz')-), has been prepared and characterized. The synthesis, spectroscopy, and solid-state structures of four-coordinate, pseudo-tetrahedral iron(II) and cobalt(II) halide complexes supported by these ligands is presented. To compare the electron-releasing ability of these ligands with their [PhBPR3] analogues, the cyclic voltammetry of these complexes is introduced. Potential routes to a terminal cobalt or iron nitride complex via extrusion of N2 from coordinated azide and metathesis with the N-atom transfer reagent Li(dbabh) are investigated.
\r\n\r\nReduction of the [PhBPtBu2(pz')]MX halide complexes in the presence of excess phosphine generates low valent [PhBPtBu2(pz')]MI(PMe3) precursors. These precursors react with organic azides to generate cobalt(III) and iron(III) imides. Initial reactivity studies indicate that these imides are more moderately more reactive than the corresponding tris(phosphino)borate complexes. The electrochemistry of the [PhBPtBu2(pz')]FeIII(NR) imides features a quasi-reversible to fully reversible oxidation event, dependent on choice of pyrazolyl substituents and scan rate. This oxidation can be achieved chemically to generate the isolable cationic iron(IV) imides, [PhBPtBu2(pz')]FeIV(NR)+. The structural and spectroscopic characterization of these highly unusual complexes is discussed.
\r\n", "doi": "10.7907/AGQC-8E07", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:3672", "collection": "thesis", "collection_id": "3672", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-09202008-110622", "primary_object_url": { "basename": "Doss_rm_2006.pdf", "content": "final", "filesize": 19448639, "license": "other", "mime_type": "application/pdf", "url": "/3672/1/Doss_rm_2006.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Programmable Oligomers for DNA Recognition", "author": [ { "family_name": "Doss", "given_name": "Raymond Michael", "clpid": "Doss-Raymond-Michael" } ], "thesis_advisor": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Rees", "given_name": "Douglas C.", "clpid": "Rees-D-C" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "As the amount of information about the genetic construct of the human body continues to grow, the ability to manipulate genes via the use of synthetic molecules becomes an increasingly attractive concept. Polyamides developed in the Dervan Lab are capable of doing just this by binding in the minor groove of DNA in a highly specific manner. Not only are polyamides able to specifically target sequences of DNA, but they are able to do so at affinities which make them competitive with endogenous transcriptional machinery.
\r\n\r\nThe complex nature of the DNA minor groove structure, however, has forced the evolution of traditional imidazole, pyrrole and hydroxypyrrole polyamides into newly developed oligomers \u2014 compounds which have been shown to bind sequences of DNA that have been traditionally difficult to target. In going from polyamides to oligomers, these compounds have seen a variety of changes brought about by the search for ring systems capable of conveying improved binding properties. Several new recognition elements have been uncovered and characterized with respect to their DNA affinity and specificity. Experiments testing the capabilities of these oligomers have shown that such compounds demonstrate great potential for targeting many new, biologically relevant sequences of DNA thus showing promise as potential 2nd generation therapeutics.
\r\n", "doi": "10.7907/F0X3-Q612", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:2053", "collection": "thesis", "collection_id": "2053", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05252005-143409", "primary_object_url": { "basename": "MMTTitle.pdf", "content": "final", "filesize": 32869, "license": "other", "mime_type": "application/pdf", "url": "/2053/13/MMTTitle.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "The Molecular Recognition of DNA by Novel Heterocycles", "author": [ { "family_name": "Marques", "given_name": "Michael Anthony", "clpid": "Marques-Michael-Anthony" } ], "thesis_advisor": [ { "family_name": "Dervan", "given_name": "Peter B.", "orcid": "0000-0001-8852-7306", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Dervan", "given_name": "Peter B.", "orcid": "0000-0001-8852-7306", "clpid": "Dervan-P-B" }, { "family_name": "Mayo", "given_name": "Stephen L.", "orcid": "0000-0002-9785-5018", "clpid": "Mayo-S-L" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "With a rapid movement toward personalized genetic medicine, tailoring treatment to individual patient needs based on their genetic code is becoming an important goal. The ability to develop small molecules capable of reprogramming the cellular machinery at the genetic level is one approach to the difficult challenge of treating diseases that result from aberrant gene expression. Inspired by the architecture of the natural products netropsin and distamycin, polyamides are capable of binding the DNA minor groove with high affinity and fidelity. Originally composed of five-membered heterocyclic carboxamides, polyamides have evolved in both form and function. A search has been initiated to develop new DNA specific oligomers that have different electronic and geometric properties. Alteration of these properties may lead to a new class of compounds, capable of targeting DNA sequences that have previously been shown to be difficult to recognize. Second-generation compounds containing novel heterocyclic recognition elements, within the context of both 5-membered heterocyclic carboxamides and fused 6-5 benzimidazole analogues, have recently been developed. These molecules have successful DNA recognition profiles as well as favorable cell uptake properties, important considerations when searching for effective pharmacophores. These new classes of rationally designed oligomers offer one approach to the challenging problem of regulating gene expression.", "doi": "10.7907/GHEJ-A648", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2457", "collection": "thesis", "collection_id": "2457", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06052005-221223", "primary_object_url": { "basename": "00Chapters123.pdf", "content": "final", "filesize": 8257006, "license": "other", "mime_type": "application/pdf", "url": "/2457/1/00Chapters123.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Computational Strategy in Catalyst Design", "author": [ { "family_name": "Nielsen", "given_name": "Robert J.", "orcid": "0000-0002-7962-0186", "clpid": "Nielsen-Robert-J" } ], "thesis_advisor": [ { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "thesis_committee": [ { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The strategy and efficacy of applying computational tools to the development of new catalytic cycles is discussed using the enantioselective palladium-catalyzed aerobic oxidation of secondary alcohols as a model case. The key interactions responsible for the unique reactivity of ((\u2013)-sparteine)PdX2 complexes (X = chloride, acetate) in kinetic resolutions of secondary alcohols are elucidated using density functional theory with the Poisson-Boltzmann polarizable continuum solvent model. Enantioselectivities in these reactions are found to follow directly from calculated energies of diastereomeric beta-hydride elimination transition states incorporating (R) and (S) substrates. This relationship reveals an important role of the anion, namely to communicate the steric interaction of the ligand on one side of the PdII square plane and the substrate on the other side. When no anion is included, no enantioselectivity is predicted. Locating these transition states in different solvents shows that higher dielectrics stabilize the charge separation between the anion and metal and draw the anion farther into solution. Thus the solvent influences the barrier height (rate) and selectivity of the oxidation.
\r\n\r\nBased on this understanding, computational assays for selectivity, reaction rate and stability are developed and used to screen possible mimics of the natural product (\u2013)-sparteine which could be synthesized in both antipodes. Derivatives of the bispidine and bispidinone structures are predicted to have high selectivity but poor stability on palladium. Experimental results verify that catalytically active (bispidine)PdX2 complexes do not form.
\r\n\r\nMechanisms by which palladium diacetate complexes of N-heterocyclic carbenes may oxidize alcohols (a reaction known to occur with no enantioselectivity) are examined computationally. The strong trans effect of the carbene distinguishes the behavior of these complexes from other palladium catalysts. No traditional beta-hydride elimination is predicted to be capable of generating the high deuterium kinetic isotope effect measured using this catalyst. Instead, the low-energy pathway consistent with previous experimental observations (KIE, activation parameters, kinetics) is a \"reductive\" beta-hydride elimination, in which the beta-hydrogen of the alcohol is transferred directly to a bound acetate ligand. Assuming that relative energies of transition states of this type will determine enantioselectivity, new, chiral carbene ligands are hypothesized and screened. Careful placement of stereocenters and steric bulk has led to ligands with high predicted enantioselectivity and stability.
\r\n\r\nRecurring factors in the induction of selectivity by asymmetric ligands are observed. Strengths and weaknesses of quantum chemistry as applied to catalytic cycles are discussed, along with the synergy of theory and experiment. Common pitfalls and areas in need of improvement are highlighted.
", "doi": "10.7907/60VH-AQ40", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2358", "collection": "thesis", "collection_id": "2358", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06012005-144620", "primary_object_url": { "basename": "SBK-THESIS.pdf", "content": "final", "filesize": 4372118, "license": "other", "mime_type": "application/pdf", "url": "/2358/1/SBK-THESIS.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Direct Examination of Initiation and Propagation Kinetics of Zirconocene-Catalyzed Alkene Polymerization", "author": [ { "family_name": "Klamo", "given_name": "Sara Bernadine", "clpid": "Klamo-Sara-Bernadine" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Zirconocene precatalysts with sterically bulky alkyl groups were designed in order to obtain models for the propagating species in zirconocene-catalyzed alkene polymerization. Alkyllithium reagents Li(CH2CEt3) and Li(CH2CMe2CH2Ph) were prepared and utilized in methyl alkylzirconocene synthesis. Dialkyl and methyl alkylzirconocenes of the form [(eta-5-C5H5) (eta-5-C5Me5)Zr(R)2], [(eta-5-C5H5)2Zr(R)(CH3)], and [(eta-5-C5H5)(eta-5-C5Me5)Zr(R)(CH3)] (where R = CH2CMe3, CH2SiMe3, CH2CEt3,CH2CMe2CH2Ph) were synthesized and fully characterized by NMR spectroscopy and in some cases X-ray diffraction. The molecular structures determined display the bent sandwich coordination mode common for zirconocenes. The observed structural parameters are slightly perturbed by the steric influence of the bulky alkyl group.
\r\n\r\nA direct examination of propagation kinetics for alkene polymerization using the zirconocenium initiator, [(eta-5-C5H5)(eta-5-C5Me5)Zr(CH2CMe3)]+[CH3B(C6F5)3]-, is reported. Propagation rate constants (kp) for the polymerization of propene and a series of 1-alkenes catalyzed by [(eta-5-C5H5)(eta-5-C5Me5)Zr(CH2CHR)nCH2CMe3)]+[CH3B(C6F5)3]- were measured by 1H NMR spectroscopy in toluene-d8 at low temperature. The kp obtained for propene and other alkenes decreases with increasing chain length and steric influence. The overall activation parameters for propagation determined from an Eyring analysis are (delta)H(activation) = 8.5(3) kcal/mol and (delta)S(activation) = -25(2) eu. The propagation rate was found to increase in the presence of [CH3B(C6F5)3]- counteranion and in a polar toluene-d8-chlorobenzene-d5 solvent system. The experimental results are most consistent with propagation mechanism that does not involve the formation of outer-sphere ions for alkene polymerization by this catalyst system.
\r\n\r\nPropene initiation kinetics have been examined for a series of alkylzirconocene initiators, [(eta-5-C5H5)(eta-5-C5Me5)Zr(R)]+[CH3B(C6F5)3]- (R = CH3 (5), CH2CMe3 (1), CH2SiMe3 (4)). Measurement of ki for the neopentyl initiator reveals that the rate of initiation is on the order of propagation for this catalyst. This initiator with a polymeryl like alkyl group serves as a model of the propagating species in propene polymerization. The catalyst initiation behavior has been investigated and the observed relative rates of propene initiation are not always predicted by ground-state (zirconium-carbon bond strength or extent of ion-pairing) considerations. The catalysts 4 and 5 are both poor initiators with ki << kp and show less than 50% initiation in the presence of excess propene at -60 C in toluene-d8.
", "doi": "10.7907/Z24R-FF38", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:5205", "collection": "thesis", "collection_id": "5205", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05272005-103515", "primary_object_url": { "basename": "0.pdf", "content": "final", "filesize": 158766, "license": "other", "mime_type": "application/pdf", "url": "/5205/1/0.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Coordination Chemistry from Trigonally Coordinated Iron Platforms: Chemistry Relevant to Dinitrogen Reduction", "author": [ { "family_name": "Betley", "given_name": "Theodore Alexander", "orcid": "0000-0001-5946-9629", "clpid": "Betley-Theodore-Alexander" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The synthesis for a sterically encumbered, strong-field tris(diisopropylphosphino)borate ligand, [PhBPiPr3] ([PhBPiPr3] = [PhB(CH2PiPr2)3]-), is reported to probe aspects of its conformational and electronic characteristics within a host of complexes. To this end, the Tl(I) complex, [PhBPiPr3]Tl, was synthesized, characterized, and used to install the [PhBPiPr3] ligand onto complexes of Fe, Co, and Ru. The spectroscopic, electrochemical, magnetic, and structural features of these complexes are compared with similar examples.
\r\n\r\nTrigonally coordinated \"[PhBPiPr3]M\" platforms (M = Fe, Co) support both pi-acidic (N2) and pi-basic (NR2-) ligands at a fourth binding site. Methylation of monomeric [M0(N2)-] species successfully derivatizes the beta-N atom of the N2 ligand and affords the diazenido product [MII(N2Me)]. Addition of RN3 to MI(N2)MI results in oxidative nitrene transfer to generate [PhBPiPr3]M\u2261NR with concomitant N2 release.
\r\n\r\nA tetrahedrally coordinated L3Fe-Nx platform that accommodates both terminal nitride (L3FeIV\u2261N) and dinitrogen (L3FeI-N2-FeIL3) functionalities is described. The diamagnetic L3FeIV\u2261N species featured has been characterized in solution under ambient conditions by multinuclear NMR (1H, 31P, and 15N) and infrared spectroscopy. The terminal nitride complex oxidatively couples to generate the previously reported L3FeI-N2-FeIL3 species.
\r\n\r\nThe [PhBPiPr3] ligand can support a single iron or cobalt center in a pseudo-tetrahedral environment in which dinitrogen is bound in the fourth coordination site. Zero-valent metal-dinitrogen complexes have the general formula, [[PhBPiPr3]M(mu-N2)]2[Mg2+], while bridging structures can also be obtained as neutral [MI]\u2014N2\u2014[MI] or as anionic [(M)2(N2)]- species. The nature of the structural distortions observed in both [M(mu-N2)]2[Mg2+] and [Mn]\u2014N2\u2014[Mn] complexes are described. Magnetic characterization of the neutral and mixed-valence dimeric complexes reveal the complexes remain ferromagnetically coupled over all temperatures investigated.
\r\n\r\nThe coordination chemistry of group VIII metals featuring the bis(8-quinolinyl)amine (HBQA) ligand is presented. The electrochemical behavior of Fe, Ru, and Os complexes bearing the BQA ligand is reported and compared to related ligand platforms. Halide and phosphine ligand exchange reactions are examined from complexes of the type (BQA)MX(PR3)2 (M = Ru, Os). Carbonyl and dinitrogen complexes of Ru and Os are prepared from halide abstraction from divalent Ru and Os precursors. The spectroscopic and structural features of these complexes are compared with similar examples.
\r\n", "doi": "10.7907/PY23-ME66", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2330", "collection": "thesis", "collection_id": "2330", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05312005-201150", "primary_object_url": { "basename": "ThesisCh0.pdf", "content": "final", "filesize": 306877, "license": "other", "mime_type": "application/pdf", "url": "/2330/1/ThesisCh0.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "The Chemistry of Tris(phosphino)borate Supported Iron-Nitrogen Multiply-Bonded Linkages", "author": [ { "family_name": "Brown", "given_name": "Steven Douglas", "clpid": "Brown-Steven-Douglas" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The metallation of FeX2 (X = Cl, Br, I) salts with the strong-field [PhBP3] ([PhBP3] = PhB(CH2PPh2)3-) ligand is presented. The resulting four-coordinate, 14-electron species, [PhBP3]FeX, have been thoroughly characterized and feature high-spin (S = 2) electronic ground-states. X-ray diffraction analysis of [PhBP3]FeCl establishes a monomeric structure in the solid state.
\r\n\r\nThe one electron reduction of [PhBP3]FeCl in the presence of a triphenylphosphine cap affords a rare example of four-coordinate iron(I). This species, [PhBP3]Fe(PPh3), serves as a synthetic surrogate to a low-valent \"[PhBP3]Fe(I)\" subunit that is readily oxidized in the presence of organic azides. The resulting S = 1/2 iron(III) imides of general formula [PhBP3]Fe\u2261NR may be subsequently reduced by one electron to yield the anionic S = 0 derivatives. Exposure of the former to an atmosphere of CO results in cleavage of the Fe\u2261NR linkage to yield [PhBP3]Fe(CO)2 and free isocyanate (O=C=N-R). Dicarbonyl [PhBP3]Fe(CO)2 is itself an imide precursor and is gradually converted back to [PhBP3]Fe\u2261NR upon exposure to excess organic azide.
\r\n\r\nTolyl imide [PhBP3]Fe?N-p-tolyl readily reacts with H2 under mild conditions to undergo a step-wise Fe-Nx bond scission process to ultimately release free p-toluidine. Initially formed is the S = 2 iron(II) anilide, [PhBP3]Fe(N(H)-p-tolyl), which has been independently prepared and shown to release p-toluidine in the presence of H2. In benzene solvent the final iron containing product of the hydrogenation process is diamagnetic [PhBP3]Fe(?5-cyclohexadienyl), which is presumably formed from benzene insertion into a low-valent iron-hydride intermediate.
\r\n\r\nReduction of the ferromagnetically coupled dimer, {[PhBP3]Fe(N3)}2, yields the bridging nitride species, [{[PhBP3]Fe}2(\u03bc-N)][Na(THF)5]. This compound features two high-spin iron(II) metal centers that are so strongly antiferromagnetically coupled that a diamagnetic S = 0 ground-state is exclusively populated at room temperature. X-ray diffraction analysis reveals a bent Fe-N-Fe linkage that quantitatively releases ammonia in the presence of excess protons. Reactivity with CO and H2 is also presented, and for the latter, complete rupture of the Fe-N-Fe manifold is not observed as the presence of an additional metal center (when compared with the iron(III) imides) favors the formation of the diamagnetic bridging imide-hydride species, [{[PhBP3]Fe}2(\u03bc-NH)(\u03bc-H)][Na(THF)5].
", "doi": "10.7907/46DN-YH09", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2819", "collection": "thesis", "collection_id": "2819", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-07072004-222212", "primary_object_url": { "basename": "cjb-thesis.pdf", "content": "final", "filesize": 2586913, "license": "other", "mime_type": "application/pdf", "url": "/2819/7/cjb-thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Investigations in Enantioselective Catalysis. Development of Novel Asymmetric Organocatalytic Reactions", "author": [ { "family_name": "Borths", "given_name": "Christopher J.", "clpid": "Borths-Christopher-J" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "A new strategy for the catalysis of organic transformations using iminium ion activation has been developed. Using this strategy, the first asymmetric organocatalytic Diels-Alder reaction has been developed. This methodology has demonstrated the possibility of an imidazolidinone salt to function as an effective asymmetric catalyst for a wide variety of chemical transformations.
\r\n\r\nThe iminium ion activation strategy has also proved successful for conjugate additions, and an asymmetric organocatalytic Mukaiyama-Michael reaction has been developed using the principles of LUMO-lowering catalysis. A more reactive and selective chiral imidazolidinone catalyst was developed, and this secondary amine has extended the range of transformations possible with iminium ion catalysis.
\r\n\r\nProgress has been made towards the development of an enantioselective organocatalytic alpha-oxidation of ketones. Proline catalysis has been demonstrated to effectively catalyze the asymmetric alpha-oxidation of cyclohexanone, but extension of this methodology to other ketones has not been successful. These studies have further demonstrated the utility of proline as a catalyst, and provide a platform for the extension of HOMO-raising catalysis to other organic transformations.
\r\n", "doi": "10.7907/bhq4-ep12", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:1058", "collection": "thesis", "collection_id": "1058", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-03222005-133937", "primary_object_url": { "basename": "Garg_Thesis_Caltech_Format.pdf", "content": "final", "filesize": 18672599, "license": "other", "mime_type": "application/pdf", "url": "/1058/2/Garg_Thesis_Caltech_Format.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "The Total Synthesis of Dragmacidins D and F", "author": [ { "family_name": "Garg", "given_name": "Neil Kamal", "clpid": "Garg-Neil-Kamal" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The dragmacidins are an emerging class of bis(indole) natural products isolated from deep-water marine organisms. Although there has been a substantial effort to prepare the simple piperazine dragmacidins, little synthetic work has been done in the area of the pyrazinone-containing family members, dragmacidins D, E, and F. These compounds are particularly interesting due to their complex structures and broad range of biological activity.
\r\n\r\nA highly convergent strategy to access dragmacidin D has been developed. In this approach, sequential halogen-selective Suzuki couplings were used to assemble the carbon scaffold of the natural product. After executing a highly optimized sequence of final events, the first completed total synthesis of dragmacidin D was achieved.
\r\n\r\nAn enantiodivergent strategy for the total chemical synthesis of both (+)- and (-)-dragmacidin F from a single enantiomer of quinic acid has been developed and successfully implemented. Although unique, the synthetic routes to these antipodes share a number of key features, including novel reductive isomerization reactions, Pd(II)-mediated oxidative carbocyclization reactions, halogen-selective Suzuki couplings, and high-yielding late-stage Neber rearrangements.
\r\n\r\nThe formal total syntheses of dragmacidin B, trans-dragmacidin C, and dihydrohamacanthin A are described. In addition, preliminary studies involving a novel approach for the preparation of dragmacidin E are reported.
", "doi": "10.7907/Q4GM-9610", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:4899", "collection": "thesis", "collection_id": "4899", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-12092004-165229", "primary_object_url": { "basename": "Sanders_THESIS.pdf", "content": "final", "filesize": 16601973, "license": "other", "mime_type": "application/pdf", "url": "/4899/12/Sanders_THESIS.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Development of Fluorinated Monomers and Polymers for Advanced Photolithographic Applications", "author": [ { "family_name": "Sanders", "given_name": "Daniel Paul", "orcid": "0000-0001-5736-2801", "clpid": "Sanders-Daniel-Paul" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Collier", "given_name": "C. Patrick", "clpid": "Collier-C-P" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The incorporation of fluorine into photoresist materials imparts a variety of highly desirable properties for deep ultraviolet lithography at 193 nm and 157 nm. Chief amongst these benefits are the high optical transparency of partially fluorinated materials and the high acidity of fluorocarbinols. Yet, significant challenges remain to incorporate the large amount of fluorine necessary for high transparency into functionalized norbornene monomers without adversely affecting transition metal polymerization processes.
\r\n\r\nChapters 2 details the synthesis and characterization of a series of partially fluorinated tricyclo[4.2.1.0(2,5)]non-7-ene (TCN) monomers. The fused cyclobutane ring serves as an additional scaffold onto which additional fluorinated groups can be incorporated in order to increase transparency at 157 nm without adversely affecting the polymerization behavior of the monomer. The synthesis and imaging of TCN-based photoresist polymers is detailed in Chapter 3.
\r\n\r\nChapters 4 and 5 introduce a series of 3-oxa-tricyclonon-7-ene and 4-oxa-tricyclonon-8-ene monomers synthesized from quadricyclane and fluorinated ketones. In Chapter 5, addition and ring-opening metathesis polymers of fluorinated oxatricyclononenes are shown to offer transparencies similar to a hexafluorocarbinol-functionalized norbornene addition polymer, revealing the effect of the alicyclic backbone structure on transparency at 157 nm. 4-Oxatricyclononenes are valuable comonomers for the elevation of glass transition temperatures in ROMP polymers, while low molecular weight ROMP copolymers of 3-oxatricyclonene are being evaluated as crosslinking agents in negative tone resist formulations.
\r\n\r\nChapter 6 details the use of cross-metathesis and ring-opening cross-metathesis in the synthesis of multifunctional monomers and oligomers for 193 nm immersion and 157 nm lithography. Cross-metathesis with unsaturated hexafluorocarbinols is a facile method to generate functionalized olefins without using the hexafluoroacetone. These developments culminate in the synthesis of difunctional norbornenes containing both ester and hexafluorocarbinol functionalities which display dramatically increased transparency at 157 nm and will potentially afford unique dissolution behavior.
\r\n\r\nFinally, chapter 7 explores the synthesis of trisubstituted olefins via ruthenium-catalyzed cross-metathesis. 2-Methyl-2-butene is a convenient isobutylene surrogate in the formation of prenyl groups via cross-metathesis. Understanding of the reactivity of second-generation metathesis catalysts with 1,1-disubstituted and trisubstituted olefins has prompted the exploration of ring-opening cross-metathesis of low strain cyclic olefins and three component cross-metathesis reactions with high product selectivity.
", "doi": "10.7907/g8b9-hh25", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:5198", "collection": "thesis", "collection_id": "5198", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05252005-205358", "primary_object_url": { "basename": "totalthesis.pdf", "content": "final", "filesize": 18044146, "license": "other", "mime_type": "application/pdf", "url": "/5198/61/totalthesis.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "The Design and Development of Palladium-Catalyzed Aerobic Oxidative Transformations", "author": [ { "family_name": "Ferreira", "given_name": "Eric Matthew", "orcid": "0000-0001-9412-0713", "clpid": "Ferreira-Eric-Matthew" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Oxidation is a fundamental process in chemistry and biology. In synthetic chemistry, several developments have been made in catalytic asymmetric oxidative transformations that involve a heteroatom transfer from a reagent to a substrate (e.g., epoxidations, dihydroxylations). Enantioselective oxidations that do not involve a heteroatom transfer have been relatively less explored. These types of oxidative transformations were investigated using a general palladium(II) catalyst system.
\r\n\r\nA palladium-catalyzed oxidative kinetic resolution of secondary alcohols was developed. This catalytic system utilizes (\u2013)-sparteine as the chiral ligand and molecular oxygen as the sole stoichiometric oxidant. Benzylic and allylic alcohols can be resolved to high enantiomeric excesses in excellent yields. The same selective process has been applied to the desymmetrization of meso diols.
\r\n\r\nThis general palladium(II) oxidative system was applied to intramolecular Wacker oxidations to form a variety of heterocycles. Lactones, lactams, tetrahydrofurans, dihydrobenzofurans, and dihydrobenzopyrans were all accessed by this methodology. Importantly, this work provided entry into the development of asymmetric variants. Highly enantioselective cyclizations of phenolic substrates were realized with a palladium-sparteine catalyst, analogous to the kinetic resolution chemistry. The heterocyclization chemistry was employed in the context of the total synthesis of the Cephalotxaxus alkaloids.
\r\n\r\nOxidative annulations for the synthesis of carbocycles were developed utilizing this general palladium system. Indoles with pendant olefin tethers were oxidatively cyclized under palladium(II) catalysis to form annulated indoles. Electron-rich aromatic systems were also investigated, culminating in the syntheses of benzofurans and dihydrobenzofurans. These reactions were demonstrated to proceed by an initial C-H bond functionalization event, followed by olefin insertion and beta-hydride elimination.
\r\n\r\nEnantioselective heterocyclizations using the general oxidative system were further explored. Promising results were realized in the heterocyclizations of sulfonamide-based compounds. Key experiments allowed for a firmer understanding of how the reaction was progressing, and specifically, how enantioselectivity was being induced by the palladium catalyst.
\r\n", "doi": "10.7907/Z9K64G2R", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2387", "collection": "thesis", "collection_id": "2387", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06022005-124848", "primary_object_url": { "basename": "JSOTHESISFINAL.pdf", "content": "final", "filesize": 6850326, "license": "other", "mime_type": "application/pdf", "url": "/2387/1/JSOTHESISFINAL.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "A Study of Ligand Substitution and its Importance in the C-H Activation of Methane and Methanol", "author": [ { "family_name": "Owen", "given_name": "Jonathan Scharle", "orcid": "0000-0001-5502-3267", "clpid": "Owen-Jonathan-Scharle" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Pyridinium and indolium-derived aminocarbene complexes of platinum and palladium were prepared by oxidative addition of pyridinium and 2-chloro-indolium carbene precursors. These complexes were synthesized in order to study the degree to which aminocarbene ligands pi-bond with the transition-metals to which they are bound. X-Ray crystal structures show minimal multiple bonding in the indole examples and a measurable shortening of the pyridine-2-ylidene Pt\u2013C distance (1.959(3) A) compared with typical Pt\u2013C bonds (2.01(1) A). The kinetics of associative DMSO substitution trans to the pyridine-2-ylidene ligand indicate a stabilization of the trigonal bipyramidal transition structure that is due to pi-acidity of the carbene carbon. This pi-acidity is responsible for 4-orders of magnitude acceleration in the associative substitution rate compared with a structurally similar phenyl donor.
\r\n\r\nThe relative rates of methane, methanol and dimethylether C\u2013H activation by [(N-N)PtMe(TFE-d3)]+ ((N-N) = ArN=C(Me)-C(Me)=NAr Ar = 3,5-di-tert-butylphenyl, TFE-d3 = CF3CD2OD) were studied by 1H and 13C NMR spectroscopy. Methane activation kinetics were conducted at 300-1000 psi of methane pressure in single crystal sapphire NMR tubes (k = 1.6 \u00b1 0.4 x 10-3 M-1s-1, 330 K; k = 2.7 \u00b1 0.2 x 10-4 M-1s-1, 313 K). Deuterium scrambling studies indicate that displacement of TFE-d3 from the platinum center by methane's C\u2013H bond is slower than the subsequent C\u2013H oxidative cleavage and hence the rate-determining step in methane C\u2013H activation. The kinetics of methanol and dimethylether C\u2013H activation were studied with 1H NMR spectroscopy and shown to be inhibited by a preequilibrium binding of the substrates oxygen lone-pair to the metal center. A small kinetic isotope effect (kH/kD = 1.4 \u00b1 0.1) and the observed concentration dependence suggest that the reaction proceeds by rate determining displacement of the coordinated trifluoroethanol by the C-H bonds of methanol (k = 2.0 \u00b1 0.2 x 10-3 M-1s-1, Keq = 0.0042 \u00b1 0.0006, 330 K). A similar concentration dependence is observed in the activation of dimethylether (k = 5.5 \u00b1 0.5 x 10-4 M-1s-1, Keq = 0.020 \u00b1 0.002, 313 K). Comparison of these second order rate constants (k(Methane)/k(Methanol) = 1/1.3, 330 K; k(Methane)/k(Dimethylether) = 1/2, 313 K) shows that the selectivity of this ligand substitution step matches the selectivity previously reported by our group for oxidizing methyl and hydroxymethyl groups with aqueous tetrachloroplatinate (1/1.5). These data strongly suggest a similar rate-determining step under the Shilov conditions.
", "doi": "10.7907/1SHC-4G39", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2442", "collection": "thesis", "collection_id": "2442", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06042004-153530", "primary_object_url": { "basename": "Elizabeth_I_Mayo.pdf", "content": "final", "filesize": 7155748, "license": "other", "mime_type": "application/pdf", "url": "/2442/1/Elizabeth_I_Mayo.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Kinetics and Thermodynamics of Dye (Group VIII Metal)\u2013Sensitized Nanocrystalline Titanium Dioxide Photoelectrodes", "author": [ { "family_name": "Mayo", "given_name": "Elizabeth Idonia", "clpid": "Mayo-Elizabeth-Idonia" } ], "thesis_advisor": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" } ], "thesis_committee": [ { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis reports a comprehensive series of experiments involving complementary kinetics and thermodynamic measurements directed at isolating the important individual reactions in dye-sensitized nanocrystalline titanium dioxide solar cells (DSSCs). These experiments were done in conjunction with steady-state photoelectrochemical measurements; a combination which allowed a greater understanding of the overall mechanisms and driving forces of these systems.
\r\n\r\nAlternative two-electron redox couples were studied and efficiency increases of >40% were achieved when compared to similar systems using iodide/triiodide. Surface treatment with carboxylic acids minimized direct reduction of the redox couple by electrons in the titanium dioxide, and interestingly, the photocurrent also increased resulting in overall efficiency increases as high as 20%. Bridging ligands were used in an attempt to minimize recombination of the injected electrons with the resulting oxidized dyes, but DSSCs with these sensitizers showed poor conversion efficiencies and no distance dependence for injection or recombination was observed. The lack of distance dependence was attributed to the flexible single carboxyl anchoring group. To further investigate the effect of binding mode, a series of carboxyl-modified ruthenium bipyridyl sensitizers were studied. A single carboxyl anchoring group resulted in unstable DSSCs due to enhanced desorption as well as poor photon-to-current conversion efficiencies. These dyes injected efficiently into TiO\u2082 on the nanosecond timescale, and regeneration of the oxidized sensitizers competed effectively with recombination. Consequently, individual kinetics measurements could not explain the decreased steady-state performance. The regeneration rates of these dyes in solution were found to rapid, approaching the diffusion controlled limit. The regeneration rate was dependent on the number and electron-withdrawing nature of the pendant groups, with the rate decreasing with increasing number of electron withdrawing substituents. Iridium dyes with cyclometalating ligands were shown to be efficient sensitizers in DSSCs, with quantum yields on the order of a ruthenium analogue having similar spectral overlap. Overall, the repeated inconsistencies between the steady-state behavior and the measured individual kinetics processes indicate that the current kinetic model is insufficient to accurately predict photoelectrochemical behavior.
", "doi": "10.7907/E9WY-1N05", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:5202", "collection": "thesis", "collection_id": "5202", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05262004-173345", "primary_object_url": { "basename": "Choi-T-L-2004-thesis.pdf", "content": "final", "filesize": 2032578, "license": "other", "mime_type": "application/pdf", "url": "/5202/23/Choi-T-L-2004-thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Olefin Metathesis: a Versatile Tool for the Synthesis of Small to Large Molecules", "author": [ { "family_name": "Choi", "given_name": "Tae-Lim", "orcid": "0000-0001-9521-6450", "clpid": "Choi-Tae-Lim" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "In olefin metathesis, the designing of better catalysts has been the key to the success of its utility. Throughout the history of olefin metathesis research, the development of new and improved catalysts has brought new applications and new strucures that are accessible by olefin metathesis routes. With the developmet of highly active catalyst containing an N-heterocyclic carbene, the field of olefin metathesis is currently in a period of renaissance opening up the versatile synthesis of both small orgainc molecules to macromolecules. Following four chapters describle recent applications towards the synthesis of molecules with various sizes.\r\n", "doi": "10.7907/FD0X-D313", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:778", "collection": "thesis", "collection_id": "778", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-02272004-034648", "primary_object_url": { "basename": "oren_full_thesis.pdf", "content": "final", "filesize": 4303633, "license": "other", "mime_type": "application/pdf", "url": "/778/13/oren_full_thesis.pdf", "version": "v9.0.0" }, "type": "thesis", "title": "Enhancing Materials Through Controlled Architectures with Ring-Opening Metathesis Polymerization", "author": [ { "family_name": "Scherman", "given_name": "Oren Alexander", "orcid": "0000-0001-8032-7166", "clpid": "Scherman-Oren-Alexander" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The focus of the research presented in this thesis is the synthesis of functional polymers and construction of controlled molecular architectures through a polymerization process referred to as ring-opening metathesis polymerization (ROMP). A brief overview of polymer chemistry as well as ring-olefin metathesis polymerization is discussed in introductory Chapter 1.
\r\n\r\nChapters 2 and 3 discuss new synthetic routes to polyacetylene and polyacetylene block-copolymers from cyclooctatetraene and a new ruthenium olefin metathesis catalysts. Polyacetylene is an intractable material, as are most organic conducting polymers. Chapter 3, however, introduces a novel route to soluble telechelic polyenes and polyacetylene block-copolymers.
\r\n\r\nThe construction of organic overlayers on semiconductor surfaces is important in the area of anti-fouling coatings as well as in organic electronic applications. Chapter 4 introduces a new route to polymer-covered silicon surfaces through a covalent Si-C linkage. ROMP of norbornene from a surface-attached ruthenium catalyst produces uniform polynorbornene overlayers with controlled thickness ranging from 10 \u00c5 to 5.5 \u00b5m. The work discussed in Chapter 5 elaborates on surface-initiated ROMP by constructing thin-film top-contact field effect transistors with a polynorbornene dielectric layer.
\r\n\r\nChapter 6 explores the synthesis of polar-functionalized linear polymers from cyclopentene and cycloheptene derivatives. The challenge of polymerizing low-ring strain monomers via ROMP is also discussed. A method to a priori discern a monomer's ability to undergo ROMP is outlined in this chapter as well.
\r\n\r\nChapters 7 and 8 describe the synthesis of both regioregular and stereoregular polar-functionalized linear ethylene vinyl alcohol (EVOH) co-polymers by the ROMP of rationally designed, symmetric monomers. These polymers were made with the goal of producing materials with enhanced oxygen barrier properties. Controlling material architecture imparts a dramatic effect on both the solution and solid state morphologies of EVOH and the synthetic challenges and results are discussed.
\r\n\r\nFinally, Chapter 9 complements Chapters 7 and 8, and investigates the reason behind enhanced oxygen barrier properties of EVOH through molecular dynamics simulations. For EVOH polymers that differs only by the syn or anti orientation of neighboring diols, a clear difference is observed for the hydrogen bonding clusters. Moreover, the free volume accessible to any solute molecules is extremely low identified by a probe radius of less than 0.6 \u00c5.
", "doi": "10.7907/E1BS-HG72", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:4940", "collection": "thesis", "collection_id": "4940", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-12112003-091509", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 9467020, "license": "other", "mime_type": "application/pdf", "url": "/4940/1/Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Development of the Lewis Acid Catalyzed Allenoate-Claisen Rearrangement. Investigations of Enantioselective Catalysis of the Allenoate-Claisen Rearrangement. Studies Towards the Total Synthesis of Erythrolide E", "author": [ { "family_name": "Lambert", "given_name": "Tristan Hayes", "orcid": "0000-0002-7720-3290", "clpid": "Lambert-Tristan-Hayes" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of a new Lewis acid catalyzed sigmatropic reaction is described. This process, termed the allenoate-Claisen rearrangement, involves the metal-catalyzed condensation of an allenic ester with a tertiary allylic amine. The zwitterionic intermediate resulting from this condensation undergoes facile [3,3] bond reorganization to provide \u03b2-amino-\u03b1,\u03b2,\u03b5,\u03b6-unsaturated-\u03b3,\u03b4-disubstituted ester products. The allenoate-Claisen reaction has been demonstrated to allow for the production of a diverse range of Claisen adducts in high yield and with very high diastereoselectivities. Perhaps most notably, this process is amenable to the rapid generation of quaternary carbon stereogenicity with nearly complete stereocontrol.
\r\n\r\nInvestigations of an enantioselective catalytic variant of the allenoate-Claisen rearrangement have been initiated. Enantioselectivities of up to 49% have been achieved with the use of a titanium bis(binaphthyl) catalyst and a bidentate chelating allenic partner. The effects of solvent and method of catalyst preparation on enantioselectivity are described.
\r\n\r\nProgress towards the total synthesis of the briarane diterpene, erythrolide E, has been made. Using acyl-Claisen methodology developed in the MacMillan laboratories, both key fragments of the erythrolide framework have been prepared in racemic fashion. In addition, a highly enantioselective route to the core fragment has been developed using an enantioselective organocatalytic Diels-Alder reaction and Ireland-Claisen methodology.
", "doi": "10.7907/QVJB-E506", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:2349", "collection": "thesis", "collection_id": "2349", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06012004-115510", "primary_object_url": { "basename": "Title.pdf", "content": "final", "filesize": 384405, "license": "other", "mime_type": "application/pdf", "url": "/2349/8/Title.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Ligand Design, Coordination Chemistry, and Mechanistic Studies of (Phosphino)Borates and their Platinum, Nickel, and Copper Complexes", "author": [ { "family_name": "Thomas", "given_name": "John Christopher", "clpid": "Thomas-John-Christopher" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Synthetic methods are presented for the preparation of various substituted bis(phosphino)borates. A relatively general protocol based on the delivery of a nucleophilic phosphine-containing carbanion to a borane electrophile has been developed. Preparative methods for the synthesis of substituted diarylchloroboranes from dimethyldiaryltin reagents provide the borane electrophiles. Methyldialkyl- or methyldiarylphosphines are selectively deprotonated at the phosphine-methyl using alkyl lithium bases to form the carbanion nucleophiles. The reaction of diverse phosphine-containing carbanions with diarylchloroboranes results in bis(phosphino)borates selectively substituted at the borate, at the phosphine, or at both positions. In addition to the generated lithium salts of the bis(phosphino)borates, cation-exchange protocols provide methods for preparing ammonium and thallium bis(phosphino)borate salts. Structural data for some of these derivatives are presented.
\r\n\r\nThe electronic properties of transition metals coordinated by bis(phosphino)borates are explored through NMR and IR spectroscopies. The spectroscopic features of platinum(II) dimethyl and methyl carbonyl complexes are examined for trends based on the substitution pattern of the (phosphino)borate ligand. These trends indicate that phosphine substituents have a more significant impact than borate substituents on electronics of the metal center. Structural and spectroscopic comparisons of structurally similar platinum(II) dimethyl and methyl carbonyl complexes indicate that the anionic bis(phosphino)borate ligand renders platinum(II) more electron-rich than structurally similar neutral phosphine donors. Related spectroscopic studies of anionic and neutral molybdenum(0) tetracarbonyl complexes provide results analogous to those found when comparing neutral and cationic platinum(II) systems.
\r\n\r\nComparative studies on the ligand exchange and benzene C-H activation chemistry of structurally similar platinum(II) complexes convey the similarities and differences between zwitterionic and cationic systems. Examination of THF ligand self-exchange by magnetization transfer shows a change in mechanism between the neutral and cationic species. Both bis(phosphino)borate-ligated and neutral bis(phosphine) platinum methyl solvento complexes undergo a benzene C-H activation to form the corresponding phenyl solvento complex; however, the rates of reaction and ultimate products differ. Extensive isotopic studies indicate that the zwitterionic system forms observable intermediates prior to benzene C-H activation, some of which are attributable to ligand metalation processes.
\r\n\r\nStructural and spectroscopic studies of a phenyl-substituted tris(phosphino)borate on platinum are presented. Alkyl- and hydride-containing platinum(II) and platinum(IV) species have been synthesized. The structural and spectroscopic features of these complexes are compared to related tris(pyrazolyl)borate systems on platinum.
\r\n\r\nCoordination and reaction chemistry of an isopropyl-substituted tris(phosphino)borate on nickel are discussed. Complexes in the Ni(II), Ni(I), and Ni(0) oxidation states have been prepared. This system is compared through structural, spectroscopic, and electrochemical methods to related phenyl-substituted tris(phosphino)borate chemistry on nickel. Reactivity studies aimed at preparing Ni(III) and Ni(IV) complexes containing metal-ligand multiple bonds through group-transfer reactions are presented. Theoretical studies using density functional methods are used to probe several target species containing multiply-bonded ligands.
\r\n\r\nThe coordination chemistry of copper(I) is explored using bis(phosphino)borates. Both aryl- and alkyl-substituted bis(phosphino)borates provide access to copper(I) complexes. A tert-butyl-substituted bis(phosphino)borate is particularly useful for preparing a family of three-coordinate compounds. The spectroscopic and structural features of these complexes are compared with similar, previously described examples.
", "doi": "10.7907/GCAQ-8D59", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:4278", "collection": "thesis", "collection_id": "4278", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-10282003-135857", "primary_object_url": { "basename": "wsj_thesis.pdf", "content": "final", "filesize": 8387469, "license": "other", "mime_type": "application/pdf", "url": "/4278/1/wsj_thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Development of New Asymmetric Organocatalytic Methods and Progress Towards the Total Synthesis of Guanacastepene A", "author": [ { "family_name": "Jen", "given_name": "Wendy Sandra", "clpid": "Jen-Wendy-Sandra" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "MacMillan", "given_name": "David W. C.", "clpid": "MacMillan-D-W-C" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of a new iminium-activation approach towards asymmetric organic catalysis is described. This strategy has been successfully applied to a 1,3-dipolar cycloaddition reaction to produce the first enantioselective catalytic [3+2]cycloaddition between nitrones and a,b-unsaturated aldehydes. This methodology highlights the ability of this new organocatalytic strategy to access chemical transformations not attainable though traditional Lewis acid catalysis.
\r\n\r\nWe have also applied this iminium-activation strategy towards the successful development of an enantioselective organocatalytic intramolecular Diels-Alder (IMDA) reaction. This variant of the IMDA reaction is capable of accessing a range of stereochemically complex [4.3.0] and [4.4.0] ring systems in good yields and with excellent selectivities. Furthermore, we have successfully developed the first asymmetric Type II intramolecular Diels-Alder cyclization. Finally, the utility of this methodology was demonstrated in the efficient total synthesis of (-)-solanapyrone D where an asymmetric organocatalytic IMDA reaction comprised the pivotal bond construction.
\r\n\r\nProgress has been made towards the total synthesis of guanacastepene A. Significant efforts were directed towards a pursuing a 3-component coupling/intramolecular Diels-Alder approach towards the natural product. IMDA precursors were synthesized in an efficient and convergent manner. It was found, however, that these substrates were unable to undergo the desired cyclization. By modifying our synthetic approach towards guanacastepene A, we found that the stereochemically complex cyclohexene portion of the natural product could be synthesized via an intermolecular Diels-Alder. Therefore recent efforts have been directed towards the pursuing a more convergent intermolecular Diels-Alder/ conjugate addition/ Dieckman condensation strategy towards guanacastepene A.
", "doi": "10.7907/3PZD-1K08", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:1541", "collection": "thesis", "collection_id": "1541", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04292003-134947", "primary_object_url": { "basename": "thesis.pdf", "content": "final", "filesize": 11713721, "license": "other", "mime_type": "application/pdf", "url": "/1541/12/thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Molecular Recognition of Biomolecules in the Gas Phase", "author": [ { "family_name": "Julian", "given_name": "Ryan Roy", "orcid": "0000-0003-1580-8355", "clpid": "Julian-Ryan-Roy" } ], "thesis_advisor": [ { "family_name": "Beauchamp", "given_name": "Jesse L.", "clpid": "Beauchamp-J-L" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Beauchamp", "given_name": "Jesse L.", "clpid": "Beauchamp-J-L" }, { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The first chapter introduces the most relevant noncovalent forces for gas phase experiments. Chapters 2-5 contain work on small clusters of biologically relevant molecules. In Chapter 2, it is shown that the unusual properties of arginine lead to extensive noncovalent clustering of this amino acid, when sampled by ESI-MS. The stability of the zwitterionic form of arginine for clusters without a net charge is addressed by theoretical methods in Chapter 3.
\r\n\r\nIn Chapter 4, the properties of the unusually abundant serine octamer are examined. Experiments demonstrate that this octamer has a strong preference to be homochiral. A structure for the serine octamer is proposed that is cubic and has a zwitterionic core. The results gathered from the serine octamer demonstrate that a homochiral preference can exist for very small clusters or \"nanocrystals.\"
\r\n\r\nThe first gas phase synthesis for ATP is given in Chapter 5. ATP is easily synthesized in the gas phase from a cluster of three AMP molecules bound by a sodium salt bridge. Subsequent CAD spectra following the gas phase synthesis are identical to those obtained from an authentic sample of ATP in separate experiments.
\r\n\r\nChapters 7-9 deal with the molecular recognition of amino acid side chains in ESI-MS experiments. The ability of 18C6 to recognize and selectively attach to lysine residues is explored. Recognition of arginine side chains is accomplished in a similar manner by utilizing the larger dibenzo-30-crown-10 ether (DB30C10). The two techniques are mutually compatible, allowing for both crowns to be added to the same solution.
\r\n\r\nChapters 10-11 combine the recognition of 18C6 with various chemical functionalities in order to mediate peptide chemistry in the gas phase. In Chapter 10, a new class of molecules termed ?molecular mousetraps? is described. The mousetraps combine the recognition of 18C6 with the chemical reactivity of diazo groups. The resulting molecules are capable of noncovalently attaching to any molecule that contains a protonated primary amine. CAD can be utilized to activate the complex. In Chapter 11, the mousetraps are utilized in experiments with peptides. It is shown that covalent attachment can be achieved in a quantitative fashion.
", "doi": "10.7907/8D4X-RE68", "publication_date": "2003", "thesis_type": "phd", "thesis_year": "2003" }, { "id": "thesis:1906", "collection": "thesis", "collection_id": "1906", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05212003-130334", "primary_object_url": { "basename": "Ackerman-2003.pdf", "content": "final", "filesize": 1650148, "license": "other", "mime_type": "application/pdf", "url": "/1906/10/Ackerman-2003.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Ancillary Ligand Effects in Niobocene Olefin Hydride Complexes and Hydrocarbon Oxidation by Palladium(II) Complexes", "author": [ { "family_name": "Ackerman", "given_name": "Lily Joy", "clpid": "Ackerman-Lily-Joy" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "To examine the effects of cyclopentadienyl and olefin substitution on preferred stereochemistry, the preparation of a series of singly bridged ansa-niobocene olefin hydride complexes is described. These complexes serve as stable transition state analogues for the much more kinetically labile group 4 metallocenium cationic intermediates in metallocene-catalyzed olefin polymerization. Characterization of the thermodynamically preferred isomers of niobocene olefin hydride complexes reveals that placement of a single alkyl substituent on the cyclopentadienyl ligand array may have a moderate effect on the stereochemistry of olefin coordination.
\r\n\r\nUsing dynamic NMR methods the rates of hydrogen exchange following intramolecular ethylene insertion into the metal-hydride bond have been measured for singly and doubly bridged group 5 ansa-metallocene complexes. The singly bridged ansa-niobocenes exchange up to 3 orders of magnitude faster than unbridged complexes. However, the doubly bridged ansa-tantalocene complex exchanges at a rate comparable to that previously reported for the unlinked and much slower than a singly bridged complex. These \"ansa-effects\" were investigated by DFT calculations on model complexes. The computed exchange pathway showed the presence of an agostic ethyl intermediate. The calculated barriers for hydrogen exchange of model unbridged, singly bridged, and doubly bridged niobocenes correlate with the experimental results.
\r\n\r\nN,N'-Diaryl-diimine-ligated Pd(II) dimethyl complexes undergo protonolysis with tetrafluoroboric acid (aq) in trifluoroethanol (TFE) to form cationic monomethyl complexes and methane. The cations activate benzene C-H bonds at room temperature. Kinetic analyses reveal trends similar to those observed for the analogous Pt complexes: the C-H activation step is rate determining and is inhibited by water, which is consistent with a mechanism in which benzene substitution proceeds by a solvent- (TFE-) assisted associative pathway. After benzene C-H activation under 1 atm dioxygen, the products of the reaction are biphenyl and a dimeric hydroxide complex. The Pd(0) formed in the reaction is reoxidized by dioxygen after the oxidative C-C bond formation. Toluene and trifluorotoluene were investigated as substrates to examine the regioselectivity of arene coupling.
\r\n", "doi": "10.7907/FZMS-V955", "publication_date": "2003", "thesis_type": "phd", "thesis_year": "2003" }, { "id": "thesis:4208", "collection": "thesis", "collection_id": "4208", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-10222002-204928", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 2270596, "license": "other", "mime_type": "application/pdf", "url": "/4208/1/Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Ruthenium-Based Olefin Metathesis Catalysts Coordinated with NHeterocyclic Carbene Ligands: Synthesis and Applications", "author": [ { "family_name": "Morgan", "given_name": "John Philip", "clpid": "Morgan-John-Philip" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Myers", "given_name": "Andrew G.", "clpid": "Myers-A-G" } ], "thesis_committee": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Rees", "given_name": "Douglas C.", "clpid": "Rees-D-C" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Imperiali", "given_name": "Barbara", "clpid": "Imperiali-B" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The improved synthesis and olefin metathesis activity of N-heterocyclic carbene (NHC)-coordinated ruthenium alkylidenes of the form (NHC)(L)x(Cl)2Ru=CHR (x = 1 or 2) are reported. In order to circumvent the handling of highly sensitive free carbenes, N-heterocyclic carbene \"adducts\" were prepared in high yields by the reaction of nucleophilic bases with N,N'-diarylimidazolium salts. Most notably, the addition of trichloromethyl anion to N,N'-dimesityl-4,5-dihydroimidazolium chloride produced an air-, moisture-, and temperature-stable crystalline adduct, 2-trichloromethyl-4,5-dihydro-imidazolidine. When this species is heated above the critical temperature of 55 degrees C in the presence of (PCy3)2(Cl)2Ru=CHPh, a single, clean phosphine substitution reaction occurs to form the NHC-coordinated benzylidene (NHC)(PCy)3(Cl)2Ru=CHPh in 84% isolated yield. This procedure has been successfully scaled up to industrial production and remains the most effective catalyst synthesis to date.
\r\n\r\nThe NHC-coordinated catalysts show dramatically expanded activity relative to their bis-phosphine counterparts. The high yielding, trans-stereoselective cross metathesis of various acroyl substrates is the first example of the ruthenium-catalyzed metathesis of olefins directly substituted with electron-withdrawing functionality. Ring-opening cross metathesis of acroyl species with relatively high ring strain cyclooctadiene and norbornene monomers has also been achieved in good yields and perfect regioselectivity when the norbornene is asymmetrically substituted with a bridgehead methyl group.
\r\n\r\nFurther expansion of the substrate scope was achieved when the catalyst's phosphine ligand was replaced with more weakly bound 3-bromopyridine (3-Br-pyr) ligands. The resulting catalyst (NHC)(3-Br-pyr)2(Cl)2Ru=CHPh produced synthetically useful yields (>= 67%) in the cross metathesis of acrylonitrile and terminal olefins (as opposed to less than 30% yield with the phosphine-coordinated catalyst). NHC-coordinated catalysts therefore allow both electron-rich and electron-poor olefins to undergo metathesis in the same pot, potentially leading to synthetically valuable products containing electronically differentiated olefins.
\r\n\r\nThe lower activity of phosphine-coordinated catalysts relative to those coordinated with 3-bromopyridine can be addressed by the addition of \"phosphine scavengers\" to the former. Higher pKa carboxylic acids (such as acetic and benzoic acids) are capable of accelerating catalysis as effectively as the much stronger hydrochloric acid, without concomitant catalyst decomposition. These properties make carboxylic acids the optimal choice for use with sensitive organic substrates.
\r\n", "doi": "10.7907/JFPH-1020", "publication_date": "2003", "thesis_type": "phd", "thesis_year": "2003" }, { "id": "thesis:6996", "collection": "thesis", "collection_id": "6996", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05012012-101216772", "primary_object_url": { "basename": "Wang_ccc_2002.pdf", "content": "final", "filesize": 5350283, "license": "other", "mime_type": "application/pdf", "url": "/6996/1/Wang_ccc_2002.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Sequence Specific Trapping of Topoisomerase I by Camptothecin Polyamide Conjugates", "author": [ { "family_name": "Wang", "given_name": "Clay Chia Chun", "clpid": "Wang-Clay-Chia-Chun" } ], "thesis_advisor": [ { "family_name": "Readhead", "given_name": "Anthony C. S.", "orcid": "0000-0001-9152-961X", "clpid": "Readhead-A-C-S" }, { "family_name": "Dervan", "given_name": "Peter B.", "orcid": "0000-0001-8852-7306", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" }, { "family_name": "Readhead", "given_name": "Anthony C. S.", "orcid": "0000-0001-9152-961X", "clpid": "Readhead-A-C-S" }, { "family_name": "Dervan", "given_name": "Peter B.", "orcid": "0000-0001-8852-7306", "clpid": "Dervan-P-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Roberts", "given_name": "Richard W.", "clpid": "Roberts-R-W" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Polyamides containing N-methylpyrrole (Py)N-methylimidazole (Im) and 3-hydroxy-1-methylpyrrole (Hp) are cell permeable small molecules that bind as antiparallel pairs in the minor groove of DNA according to a set of \"pairing rules\" with affinities and specificities for predetermined sequences comparable to DNA-binding proteins. Several of these ring pairings have only been demonstrated when placed internal in a hairpin and not for the terminal position in hairpin polyamides. Several series of eight ring hairpin polyamides with modification at the N-terminal position were synthesized and characterized. We observed that at the terminal position (i) the Py/Py pair functions similar to when placed internally preferring A\u2022T and T\u2022A base pairs over O\u2022C and C\u2022O, (ii) the Hp/Py pair could not distinguish between T\u2022A over A-T possibly due to rotation of the terminal Hp to form an intramolecular hydrogen bond between the 3-hydroxyl hydrogen and the carboxamide oxygen which would orient the key hydroxyl recognition element away from the minor groove. A new aromatic pair, 2-hydroxy-6-methoxybenzamidell-methylpyrrole was designed and shown to distinguish T\u2022A from A\u2022T base pairs and both from O\u2022C/C\u2022O and (iii) the Py/Im pair in the classic eight ring hairpin motif showed no preference for C\u2022O base pair possibly due to the mispositioning of the Im residue located at the C-terminal end of the four ring polyamide subunit. Targeting of C\u2022O was accomplished by replacing a pyrrole with a flexible \u03b2-alanine and setting the imidazole back in register.
\r\n\r\nPyrrole-imidazole polyamides that target DNA sequences in the promoter have been shown to inhibit transcription of specific genes in cell culture. When bound to coding region of genes, polyamides do not appear to inhibit gene expression. A possible solution is to design molecule capable of modifying DNA when bound to the coding region. A series of polyamide-camptothecin conjugates were designed to trap the enzyme Topoisomerase I and induce cleavage at predetermined DNA sites. Cleavage yields were shown to be dependent on linker length between the DNA binding polyamide\r\nand the Topo I trapping camptothecin unit with the camptothecin unit with the longest linker showing greatest cleavage yield of over 90%.
\r\n", "doi": "10.7907/sphn-ma74", "publication_date": "2002", "thesis_type": "phd", "thesis_year": "2002" }, { "id": "thesis:5542", "collection": "thesis", "collection_id": "5542", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:01282010-153053761", "primary_object_url": { "basename": "Yoon_tp_2002.pdf", "content": "final", "filesize": 6037445, "license": "other", "mime_type": "application/pdf", "url": "/5542/1/Yoon_tp_2002.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "The Acyl-Claisen Rearrangement: Development of a Novel Metal-Catalyzed Claisen Rearrangen1ent and Enantioselective Variants of the Acyl-Claisen Rearrangement", "author": [ { "family_name": "Yoon", "given_name": "Tehshik Peter", "orcid": "0000-0002-3934-4973", "clpid": "Yoon-Tehshik-Peter" } ], "thesis_advisor": [ { "family_name": "MacMillan", "given_name": "David W. C.", "orcid": "0000-0003-3352-4532", "clpid": "MacMillan-D-W-C" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "orcid": "0000-0003-1464-2461", "clpid": "Dougherty-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "orcid": "0000-0002-0057-7817", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "MacMillan", "given_name": "David W. C.", "orcid": "0000-0003-3352-4532", "clpid": "MacMillan-D-W-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of a versatile new variant of the Claisen rearrangement is described. In this new Lewis acid-catalyzed process, the condensation of an allylic amine with a ketene (generated in situ from dehydrohaolgenation of an acid chloride) results in formation of a zwitterionic intermediate. Sigmatropic rearrangement via a highly organized cyclic transition state allows stereospecific access to a diverse range of \u03b1,\u03b2-disubstituted-\u03b3,\u03b4-unsaturated amides in excellent yields and diastereoselectivities for a range of alkyl-, aryl-, and heteroatom-substituted substrates. The ability of this new methodology to generate quaternary carbon stereocenters on both cyclic and acyclic carbon frameworks is demonstrated.
\r\n\r\nAn enantioselective variant of the acyl-Claisen rearrangement employing a chiral magnesium(II)-bis(oxazoline) Lewis acid has been developed. The use of chelating acid chlorides provides excellent organizational control over the transition state, allowing the rearrangement of a range of allyl morpholine substrates to proceed in up to 97% ee. Excellent levels of complementary diastereocontrol can be achieved in a predictable and highly selective manner from the rearrangement of the (E)- and (Z)-isomers of the allyl amine substrates. This reaction is also proficient at accessing quaternary carbon stereocenters.
\r\n\r\nThe scope of the enantioselective acyl-Claisen has been expanded by the use of a new chiral boron Lewis acid. This rearrangement does not require chelating acid chloride substrates for good enantioinduction. Thus, a range of \u03b1-alkyl-, \u03b1-alkoxy-, \u03b1-thio-, and \u03b1-halogen-substituted Claisen adducts can be produced in up to 93% ee.
", "doi": "10.7907/JNTK-2387", "publication_date": "2002", "thesis_type": "phd", "thesis_year": "2002" }, { "id": "thesis:8152", "collection": "thesis", "collection_id": "8152", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03202014-115036901", "primary_object_url": { "basename": "Rostovtsev 2001.pdf", "content": "final", "filesize": 26833972, "license": "other", "mime_type": "application/pdf", "url": "/8152/1/Rostovtsev 2001.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Reactions of Platinum(II) Complexes with Dioxygen: Progress Toward Alkane Functionalization", "author": [ { "family_name": "Rostovtsev", "given_name": "Vsevolod Vladimirovich", "orcid": "0000-0002-1226-5909", "clpid": "Rostovtsev-Vsevolod-Vladimirovich" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Anson", "given_name": "Fred C.", "clpid": "Anson-F-C" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "orcid": "0000-0002-1942-9232", "clpid": "Labinger-J-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Whereas stoichiometric activation of C-H bonds by complexes of transition metals is\r\nbecoming increasingly common, selective functionalization of alkanes remains a\r\nformidable challenge in organometallic chemistry. The recent advances in catalytic\r\nalkane functionalization by transition-metal complexes are summarized in Chapter I.
\r\n\r\nThe studies of the displacement of pentafluoropyridine in\r\n[(tmeda)Pt(CH_3)(NC_5F_5)][BAr^f_4] (1) with \u03b3- tetrafluoropicoline, a very poor nucleophile,\r\nare reported in Chapter II. The ligand substitution occurs by a dissociative interchange\r\nmechanism. This result implies that dissociative loss of pentafluoropyridine is the rate-limiting\r\nstep in the C-H activation reactions of 1.
\r\n\r\nOxidation of dimethylplatinum(II) complexes (N-N)Pt(CH_3)_2 (N-N = tmeda(1), \u03b1-diimines)\r\nby dioxygen is described in Chapter III. Mechanistic studies suggest a two-step mechanism. First, a hydroperoxoplatinum(IV) complex is formed in a reaction\r\nbetween (N-N)Pt(CH_3)_2 and dioxygen. Next, the hydroperoxy complex reacts with a\r\nsecond equivalent of (N-N)Pt(CH_3)_2 to afford the final product,\r\n(N-N)Pt(OH)(OCH_3)(CH_3)_2. The hydroperoxy intermediate,\r\n(tmeda)Pt(OOH)(OCH_3)(CH_3)_2 (2), was isolated and characterized. The reactivity of 2\r\nwith several dime thylplatinum(II) complexes is reported.
\r\n\r\nThe studies described in Chapter IV are directed toward the development of a\r\nplatinum(II)-catalyzed oxidative alkane dehydrogenation. Stoichiometric conversion of\r\nalkanes (cyclohexane, ethane) to olefins (cyclohexene, ethylene) is achieved by C-H\r\nactivation with [(N-N)Pt(CH_3)(CF_3CH_2OH)]BF_4 (1, N-N is N,N'-bis(3,5-di-t-\r\nbutylphenyl)-1,4-diazabutadiene) which results in the formation of olefin hydride\r\ncomplexes. The first step in the C-H activation reaction is formation of a platinum(II)\r\nalkyl which undergoes \u03b2-hydrogen elimination to afford the olefin hydride complex.\r\nThe cationic ethylplatinum(II) intermediate can be generated in situ by treating\r\ndiethylplatinum(II) compounds with acids. Treatment of (phen)PtEt_2 with\r\n[H(OEt_2)_2]Bar^f_4 at low temperatures resulted in the formation of a mixture of\r\n[(phen)PtEt(OEt_2)]Bar^f_4 (8) and [(phen)Pt(C_2H_4)H] Bar^f_4 (7). The cationic olefin\r\ncomplexes are unreactive toward dioxygen or hydrogen peroxide. Since the success of\r\nthe overall catalytic cycle depends on our ability to oxidize the olefin hydride\r\ncomplexes, a series of neutral olefin complexes of platinum(II) with monoanionic ligands\r\n(derivatives of pyrrole-2-carboxyaldehyde N-aryl imines) was prepared. Unfortunately,\r\nthese are also stable to oxidation.
\r\n", "doi": "10.7907/jevj-7928", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:1292", "collection": "thesis", "collection_id": "1292", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04072008-112244", "primary_object_url": { "basename": "Ihee_h_2001.pdf", "content": "final", "filesize": 24711254, "license": "other", "mime_type": "application/pdf", "url": "/1292/1/Ihee_h_2001.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Ultrafast Electron Diffraction", "author": [ { "family_name": "Ihee", "given_name": "Hyotcherl", "orcid": "0000-0003-0397-5965", "clpid": "Ihee-Hyotcherl" } ], "thesis_advisor": [ { "family_name": "Zewail", "given_name": "Ahmed H.", "clpid": "Zewail-A-H" } ], "thesis_committee": [ { "family_name": "McKoy", "given_name": "Basil Vincent", "clpid": "McKoy-B-V" }, { "family_name": "Zewail", "given_name": "Ahmed H.", "clpid": "Zewail-A-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Molecular dynamics is now routinely studied on femtosecond time scales using various spectroscopies. However, direct structural information of all nuclear coordinates involved in such dynamical processes requires resolution in time by x-ray or electron diffraction. The focus of this laboratory has been the development of ultrafast electron diffraction (UED) for recording structures in motion, which exploits the six-orders-of-magnitude higher scattering cross section of electrons compared with x-rays. Conventional electron diffraction has been developed over the last several decades to become an enormously powerful technique for determining the static structures of molecules in the gas phase; the subsequent plementation of pulsed electron sources has added a temporal dimension to such studies. In UED, a femtosecond (fs) laser pulse is used to initiate a reaction, but unlike other ultrafast spectroscopies, the subsequent laser pulses normally used to probe the progress of the reaction are replaced with ultrashort pulses of electrons. Time-resolved diffraction patterns are then recorded at fixed time delays relative to the zero-of-time. This directly reflects the changing internuclear distances in the species under study.
\r\n\r\nFor these UED studies, there exist a number of significant experimental challenges, including: (i) the problem of independently determining the temporal overlap (zero-of-time) of the pump and probe pulses in situ for clocking the change; (ii) the problem of low electron flux required to minimize space-charge induced temporal broadening of electron pulses; and (iii) the problem of low scattering and sensitivity caused by the absence of long-range order present in solids, and the low density of molecules in gases. These challenges to the realization of UED have been surmounted over the last decade, and UED now approaches the combined spatial and temporal resolution necessary for tracking all nuclear coordinates during the making and breaking of chemical bonds, thereby permitting the direct observation of molecular structural dynamics in real time. In addition, the diffraction-difference method\u2014which employs the subtraction of a reference diffraction signal from the signals recorded over the course of the reaction\u2014can be used to select the contributions resulting only from changes in structure in the species under study, thereby enhancing the sensitivity of UED to chemical change. Contributions only from the products can be also isolated by adding the appropriately scaled parent diffraction signal at negative time to the difference curves, thus canceling out the parent contribution in each curve.
\r\n\r\nThe first reaction studied by UED was the dissociation of CH2I2 into CH2I and I with fs laser pulses. The second-generation apparatus allowed us to see the amplitude change in the scattering intensity on the picosecond time scale resulting from dissociation. Since this work, UED experiments have successfully investigated the course of several prototypical chemical reactions. For example, the molecular structures and branching ratios of the final products were determined in the dissociation of Fe(CO)5 upon two-photon excitation at 310 nm. A simple intermediate, CF2, was generated by fragmentation of CF2I2 and its molecular structure was precisely determined and compared with other experiments and theoretical calculations. Furthermore, the molecular structure of the transient Fe(CO)4 species was elucidated and compared with available theoretical predictions, permitting identification of the specific electronic energy state of the intermediate and the primary reaction pathway. UED was applied to another organometallic compound, namely (C5H5)Co(CO)2 and the molecular structures of the intermediate and final products were observed. A preliminary analysis showed that either C5H5 and other species can be selectively generated depending on the excitation wavelength. Further analysis will elucidate their molecular structures. The elimination of iodine from 1,2-diiodotetrafluoroethane (C2F4I2) was also studied with the second-generation apparatus, providing early results which suggested that the molecular structure of the C2F4I radical intermediate is not bridged in nature, but instead is \"classical,\" resembling the structure of the parent species.
\r\n\r\nThe need for greater sensitivity and resolution, as well as the desire to study more complex reactions, led to the development of our third-generation UED apparatus. This new machine, with vast improvements in pulsed electron flux, repetition rate, detection sensitivity, and experimental stability, permits the direct imaging of complex chemical reactions with unprecedented spatial and temporal resolution. The spatial and temporal resolution of UED approached ~0.01 \u00c5 and ~1 ps, respectively, and we were sensitive to ~1% changes in the mole fractions of the various chemical species over the course of the reaction. In its first application, the non-concerted elimination of iodine from a haloethane (C2F4I2) was re-visited and the molecular structure of the transient (C2F4I) radical was determined for the first time. Two prototypical cyclic hydrocarbons, 1,3,5-cycloheptatriene (CHT) and 1,3-cyclohexadiene (CHD), were also studied with temporal and spatial resolution of ~5 ps and ~0.04 \u00c5 respectively. At high internal energies of ~4 eV, these molecules displayed markedly different behavior. For CHT, wherein excitation resulted in the reformation of the parent, the observed diffraction change was explained with an equipartitioned model of hot structures\u2014indicating rapid energy redistribution (within a few picoseconds). For CHD, photo-induced ring opening was shown to result in hot but highly non-equilibrium structures even up to 400 ps, with energy trapped in large-amplitude motions comprised of torsion and asymmetric stretching. These studies promise a new direction of research for studying transient structural changes both in equilibrium and non-equilibrium complex systems. The results presented here provide the new limit of improved detection sensitivity, versatility, and resolution of UED, as well as the potential for its diverse applications. The extension to even more complex systems, a process that has already begun in our laboratory, represents our next challenge in UED.
\r\n", "doi": "10.7907/AZ0P-H612", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:1292", "collection": "thesis", "collection_id": "1292", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04072008-112244", "primary_object_url": { "basename": "Ihee_h_2001.pdf", "content": "final", "filesize": 24711254, "license": "other", "mime_type": "application/pdf", "url": "/1292/1/Ihee_h_2001.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Ultrafast Electron Diffraction", "author": [ { "family_name": "Ihee", "given_name": "Hyotcherl", "orcid": "0000-0003-0397-5965", "clpid": "Ihee-Hyotcherl" } ], "thesis_advisor": [ { "family_name": "Zewail", "given_name": "Ahmed H.", "clpid": "Zewail-A-H" } ], "thesis_committee": [ { "family_name": "McKoy", "given_name": "Basil Vincent", "clpid": "McKoy-B-V" }, { "family_name": "Zewail", "given_name": "Ahmed H.", "clpid": "Zewail-A-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Molecular dynamics is now routinely studied on femtosecond time scales using various spectroscopies. However, direct structural information of all nuclear coordinates involved in such dynamical processes requires resolution in time by x-ray or electron diffraction. The focus of this laboratory has been the development of ultrafast electron diffraction (UED) for recording structures in motion, which exploits the six-orders-of-magnitude higher scattering cross section of electrons compared with x-rays. Conventional electron diffraction has been developed over the last several decades to become an enormously powerful technique for determining the static structures of molecules in the gas phase; the subsequent plementation of pulsed electron sources has added a temporal dimension to such studies. In UED, a femtosecond (fs) laser pulse is used to initiate a reaction, but unlike other ultrafast spectroscopies, the subsequent laser pulses normally used to probe the progress of the reaction are replaced with ultrashort pulses of electrons. Time-resolved diffraction patterns are then recorded at fixed time delays relative to the zero-of-time. This directly reflects the changing internuclear distances in the species under study.
\r\n\r\nFor these UED studies, there exist a number of significant experimental challenges, including: (i) the problem of independently determining the temporal overlap (zero-of-time) of the pump and probe pulses in situ for clocking the change; (ii) the problem of low electron flux required to minimize space-charge induced temporal broadening of electron pulses; and (iii) the problem of low scattering and sensitivity caused by the absence of long-range order present in solids, and the low density of molecules in gases. These challenges to the realization of UED have been surmounted over the last decade, and UED now approaches the combined spatial and temporal resolution necessary for tracking all nuclear coordinates during the making and breaking of chemical bonds, thereby permitting the direct observation of molecular structural dynamics in real time. In addition, the diffraction-difference method\u2014which employs the subtraction of a reference diffraction signal from the signals recorded over the course of the reaction\u2014can be used to select the contributions resulting only from changes in structure in the species under study, thereby enhancing the sensitivity of UED to chemical change. Contributions only from the products can be also isolated by adding the appropriately scaled parent diffraction signal at negative time to the difference curves, thus canceling out the parent contribution in each curve.
\r\n\r\nThe first reaction studied by UED was the dissociation of CH2I2 into CH2I and I with fs laser pulses. The second-generation apparatus allowed us to see the amplitude change in the scattering intensity on the picosecond time scale resulting from dissociation. Since this work, UED experiments have successfully investigated the course of several prototypical chemical reactions. For example, the molecular structures and branching ratios of the final products were determined in the dissociation of Fe(CO)5 upon two-photon excitation at 310 nm. A simple intermediate, CF2, was generated by fragmentation of CF2I2 and its molecular structure was precisely determined and compared with other experiments and theoretical calculations. Furthermore, the molecular structure of the transient Fe(CO)4 species was elucidated and compared with available theoretical predictions, permitting identification of the specific electronic energy state of the intermediate and the primary reaction pathway. UED was applied to another organometallic compound, namely (C5H5)Co(CO)2 and the molecular structures of the intermediate and final products were observed. A preliminary analysis showed that either C5H5 and other species can be selectively generated depending on the excitation wavelength. Further analysis will elucidate their molecular structures. The elimination of iodine from 1,2-diiodotetrafluoroethane (C2F4I2) was also studied with the second-generation apparatus, providing early results which suggested that the molecular structure of the C2F4I radical intermediate is not bridged in nature, but instead is \"classical,\" resembling the structure of the parent species.
\r\n\r\nThe need for greater sensitivity and resolution, as well as the desire to study more complex reactions, led to the development of our third-generation UED apparatus. This new machine, with vast improvements in pulsed electron flux, repetition rate, detection sensitivity, and experimental stability, permits the direct imaging of complex chemical reactions with unprecedented spatial and temporal resolution. The spatial and temporal resolution of UED approached ~0.01 \u00c5 and ~1 ps, respectively, and we were sensitive to ~1% changes in the mole fractions of the various chemical species over the course of the reaction. In its first application, the non-concerted elimination of iodine from a haloethane (C2F4I2) was re-visited and the molecular structure of the transient (C2F4I) radical was determined for the first time. Two prototypical cyclic hydrocarbons, 1,3,5-cycloheptatriene (CHT) and 1,3-cyclohexadiene (CHD), were also studied with temporal and spatial resolution of ~5 ps and ~0.04 \u00c5 respectively. At high internal energies of ~4 eV, these molecules displayed markedly different behavior. For CHT, wherein excitation resulted in the reformation of the parent, the observed diffraction change was explained with an equipartitioned model of hot structures\u2014indicating rapid energy redistribution (within a few picoseconds). For CHD, photo-induced ring opening was shown to result in hot but highly non-equilibrium structures even up to 400 ps, with energy trapped in large-amplitude motions comprised of torsion and asymmetric stretching. These studies promise a new direction of research for studying transient structural changes both in equilibrium and non-equilibrium complex systems. The results presented here provide the new limit of improved detection sensitivity, versatility, and resolution of UED, as well as the potential for its diverse applications. The extension to even more complex systems, a process that has already begun in our laboratory, represents our next challenge in UED.
\r\n", "doi": "10.7907/AZ0P-H612", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:8152", "collection": "thesis", "collection_id": "8152", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03202014-115036901", "primary_object_url": { "basename": "Rostovtsev 2001.pdf", "content": "final", "filesize": 26833972, "license": "other", "mime_type": "application/pdf", "url": "/8152/1/Rostovtsev 2001.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Reactions of Platinum(II) Complexes with Dioxygen: Progress Toward Alkane Functionalization", "author": [ { "family_name": "Rostovtsev", "given_name": "Vsevolod Vladimirovich", "orcid": "0000-0002-1226-5909", "clpid": "Rostovtsev-Vsevolod-Vladimirovich" } ], "thesis_advisor": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Anson", "given_name": "Fred C.", "clpid": "Anson-F-C" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "orcid": "0000-0002-1942-9232", "clpid": "Labinger-J-A" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Whereas stoichiometric activation of C-H bonds by complexes of transition metals is\r\nbecoming increasingly common, selective functionalization of alkanes remains a\r\nformidable challenge in organometallic chemistry. The recent advances in catalytic\r\nalkane functionalization by transition-metal complexes are summarized in Chapter I.
\r\n\r\nThe studies of the displacement of pentafluoropyridine in\r\n[(tmeda)Pt(CH_3)(NC_5F_5)][BAr^f_4] (1) with \u03b3- tetrafluoropicoline, a very poor nucleophile,\r\nare reported in Chapter II. The ligand substitution occurs by a dissociative interchange\r\nmechanism. This result implies that dissociative loss of pentafluoropyridine is the rate-limiting\r\nstep in the C-H activation reactions of 1.
\r\n\r\nOxidation of dimethylplatinum(II) complexes (N-N)Pt(CH_3)_2 (N-N = tmeda(1), \u03b1-diimines)\r\nby dioxygen is described in Chapter III. Mechanistic studies suggest a two-step mechanism. First, a hydroperoxoplatinum(IV) complex is formed in a reaction\r\nbetween (N-N)Pt(CH_3)_2 and dioxygen. Next, the hydroperoxy complex reacts with a\r\nsecond equivalent of (N-N)Pt(CH_3)_2 to afford the final product,\r\n(N-N)Pt(OH)(OCH_3)(CH_3)_2. The hydroperoxy intermediate,\r\n(tmeda)Pt(OOH)(OCH_3)(CH_3)_2 (2), was isolated and characterized. The reactivity of 2\r\nwith several dime thylplatinum(II) complexes is reported.
\r\n\r\nThe studies described in Chapter IV are directed toward the development of a\r\nplatinum(II)-catalyzed oxidative alkane dehydrogenation. Stoichiometric conversion of\r\nalkanes (cyclohexane, ethane) to olefins (cyclohexene, ethylene) is achieved by C-H\r\nactivation with [(N-N)Pt(CH_3)(CF_3CH_2OH)]BF_4 (1, N-N is N,N'-bis(3,5-di-t-\r\nbutylphenyl)-1,4-diazabutadiene) which results in the formation of olefin hydride\r\ncomplexes. The first step in the C-H activation reaction is formation of a platinum(II)\r\nalkyl which undergoes \u03b2-hydrogen elimination to afford the olefin hydride complex.\r\nThe cationic ethylplatinum(II) intermediate can be generated in situ by treating\r\ndiethylplatinum(II) compounds with acids. Treatment of (phen)PtEt_2 with\r\n[H(OEt_2)_2]Bar^f_4 at low temperatures resulted in the formation of a mixture of\r\n[(phen)PtEt(OEt_2)]Bar^f_4 (8) and [(phen)Pt(C_2H_4)H] Bar^f_4 (7). The cationic olefin\r\ncomplexes are unreactive toward dioxygen or hydrogen peroxide. Since the success of\r\nthe overall catalytic cycle depends on our ability to oxidize the olefin hydride\r\ncomplexes, a series of neutral olefin complexes of platinum(II) with monoanionic ligands\r\n(derivatives of pyrrole-2-carboxyaldehyde N-aryl imines) was prepared. Unfortunately,\r\nthese are also stable to oxidation.
\r\n", "doi": "10.7907/jevj-7928", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" } ]