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: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:17514", "collection": "thesis", "collection_id": "17514", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:07052025-063244748", "type": "thesis", "title": "Expanding the Chemical Space of Nitrene Transferases: Biocatalytic Construction of C\u2013N Bonds", "author": [ { "family_name": "Qin", "given_name": "Ziyang", "orcid": "0000-0001-7356-6927", "clpid": "Qin-Ziyang" } ], "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": "Shapiro", "given_name": "Mikhail G.", "orcid": "0000-0002-0291-4215", "clpid": "Shapiro-M-G" }, { "family_name": "Wei", "given_name": "Lu", "orcid": "0000-0001-9170-2283", "clpid": "Wei-Lu" }, { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The construction of carbon\u2013nitrogen (C\u2013N) bonds is pivotal to the development of pharmaceuticals, agrochemicals, and advanced materials. While traditional synthetic methods offer robust and efficient solutions, biocatalysis has emerged as a powerful, sustainable alternative for constructing these bonds with precise stereochemical control. Yet, the enzymatic repertoire for C\u2013N bond formation remains limited compared to its chemical counterpart. By leveraging directed evolution and enzyme promiscuity, we have traversed beyond natural enzymatic functions and explored the new-to-nature catalytic landscape of enzymes.
\r\n\r\nThis thesis outlines a suite of strategies that expand the enzymatic toolbox for stereoselective C\u2013N bond construction in two main avenues: the functionalization of more challenging C\u2013H bonds and the development of novel nitrene species. Chapter I reviews contemporary chemical and biocatalytic approaches, highlighting how directed evolution can transcend native enzymatic functions to unlock new reactivities.
\r\n\r\nChapter II presents engineered serine-ligated cytochrome P411 variants capable of catalyzing enantioselective propargylic C(sp3)\u2013H amination, granting streamlined access to chiral propargylamines. Chapter III addresses the long-standing challenge of differentiating minimally distinct alkyl groups, methyl and ethyl substituents, by evolving P411 enzymes that perform enantiospecific functionalization of tertiary C\u2013H bonds to construct methyl-ethyl stereocenters with high selectivity.
\r\n\r\n\r\nChapter IV expands the scope of enzymatic nitrene transfer, enabling intramolecular alkyl and aryl nitrene C\u2013H insertions to synthesize chiral pyrrolidines and methyl indolines. Subsequent biocatalytic derivatization of these products affords complex molecules bearing multiple chiral centers, showcasing the potential of biocatalysis to rapidly build molecular complexity. Chapter V introduces engineered protoglobins capable of mediating intermolecular methylnitrene transfer using a simple and stable N-methyl hydroxylamine recursor. This process uniquely achieves the stereoconvergent conversion of both (Z)- and (E)-silyl enol ether isomers, affording enantiopure N-methyl-a-aminoketones, which defies conventional limitations of enzyme specificity.
\r\n\r\nTogether, these efforts address critical gaps in biocatalytic C\u2013N bond formation, establishing broadly applicable platforms for sustainable and stereoselective synthesis of N-containing molecules. The strategies developed herein not only deepen our understanding of heme-dependent enzymes but also lay the foundation for future innovations in biocatalysis and synthetic biology.
", "doi": "10.7907/5pv2-nr39", "publication_date": "2026", "thesis_type": "phd", "thesis_year": "2026" }, { "id": "thesis:17707", "collection": "thesis", "collection_id": "17707", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09292025-144555882", "primary_object_url": { "basename": "Skylar Osler_Thesis_Revised_09302025.pdf", "content": "final", "filesize": 60257130, "license": "other", "mime_type": "application/pdf", "url": "/17707/1/Skylar Osler_Thesis_Revised_09302025.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Elucidating Fundamental Structure-Property Relationships of Naphthopyran Mechanophores", "author": [ { "family_name": "Osler", "given_name": "Skylar Kathleen", "orcid": "0000-0003-1021-7011", "clpid": "Osler-Skylar-Kathleen" } ], "thesis_advisor": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "orcid": "0000-0003-1464-2461", "clpid": "Dougherty-D-A" }, { "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": "Naphthopyran mechanophores have been identified as a privileged class of molecules due to their synthetic accessibility and structural modularity. In response to mechanical force, naphthopyran mechanophores undergo a ring-opening reaction to generate highly colored merocyanine dyes. Force is transduced to naphthopyran small molecules by covalently attached polymer chains, and naphthopyrans that are incorporated into polymeric materials visually report on macroscopic stress and/or strain. The properties of merocyanine dyes produced under mechanical force have been effectively tuned through straightforward structural modifications on various naphthopyran scaffolds. Additionally, the sensitivity of naphthopyran mechanophores toward mechanochemical ring-opening has been modified through targeted molecular design. The studies discussed herein provide insight into the fundamental relationship between the structure of naphthopyran mechanophores and their mechanochromic properties.", "doi": "10.7907/bsm6-p620", "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:17881", "collection": "thesis", "collection_id": "17881", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02112026-184323225", "primary_object_url": { "basename": "PhD_Thesis_Final_B_Gross.pdf", "content": "final", "filesize": 22184981, "license": "other", "mime_type": "application/pdf", "url": "/17881/6/PhD_Thesis_Final_B_Gross.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "The Total Synthesis of (+)-Ineleganolide, the Lycojapomine Alkaloids, and a New Strategy for Radical Deoxygenation", "author": [ { "family_name": "Gross", "given_name": "Benjamin Martin", "orcid": "0000-0002-9124-2317", "clpid": "Gross-Benjamin-Martin" } ], "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": "Semlow", "given_name": "Daniel R.", "orcid": "0000-0001-6538-9713", "clpid": "Semlow-D-R" }, { "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": "Organic chemistry is an enabling science, that has given scientist the ability to construct and manipulate small molecules. The relationship that bridges the classic study of chemical reactivity and synthesis at the molecular level with the broader field of the life sciences continues to flourish and has expanded its impact tremendously. The study of complex, bioactive small molecules, their synthesis, and the development of new reactions has laid the foundation for many of these advancements to build upon. The contents of this thesis contribute to this goal and hope to be of use for future generations and the development of the field.
\r\n\r\nThe first chapter describes the total synthesis of the furanobutenolide-derived norcembranoid diterpenoid ineleganolide, a secondary metabolite produced by sinularia soft corals. Displaying cytotoxic bioactivity, the chemical structure has intrigued chemists for several decades. We describe a successful synthesis of the natural product in 14 steps, enabled by several unique cascade reactions.
\r\n\r\nThe second chapter details the total synthesis of Lycojapomine A and B, two members of the lycopodium alkaloids. To achieve a practical and concise synthetic route, we developed a photoreaction for the stepwise dearomatization of a pyrrole heterocycle. Building off the simple and easily accessible starting material, we can synthesize each of the complex target molecule in 13 steps.
\r\n\r\nInspired by the previously utilized photochemistry, the third chapter details a new catalytic method for the generation of alkyl radicals directly from alcohols. We achieved this transformation by photo irradiation of a titanium porphyrin catalyst and showcase its ability to deoxygenate several different alcohols, by generation of the carbon-centered radical.
", "doi": "10.7907/4sc5-0e50", "publication_date": "2026", "thesis_type": "phd", "thesis_year": "2026" }, { "id": "thesis:17764", "collection": "thesis", "collection_id": "17764", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11172025-045827404", "type": "thesis", "title": "Methodological Development and Computational Investigations of Metal-Catalyzed Coupling Reactions", "author": [ { "family_name": "Anderson", "given_name": "Robert Lon", "orcid": "0009-0000-5568-7768", "clpid": "Anderson-Robert-Lon" } ], "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": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Chapter One describes the computational study of the asymmetric arylation of propargylic electrophiles. While previous mechanistic experiments have verified the general scheme of the catalytic cycle, it was still not known what the enantiodetermining step is, or how factors of the ligand and substrate influence reactivity. To answer these questions, a computational study to emulate the entire catalytic cycle was performed. It was determined that radical addition to the nickel catalyst was likely the enantiodetermining step. While the standard substrate and ligand combinations result was well predicted, the computational method was not widely applicable to different ligands. This implies that the catalytic cycle may not go through a discrete radical capture and reductive elimination step, but instead a more concerted process may be operating.
\r\n\r\nChapter Two details the development of the asymmetric cross-coupling between tertiary nucleophiles and secondary electrophiles. Specifically, \u03b1-zincated benzylic nitriles are asymmetrically coupling with secondary alkyl iodides under the influence of a nickel catalyst and iminopyrox ligand. This study represents the first report of such a ligand being use for any asymmetric nickel-catalyzed cross-couplings.
\r\n\r\nChapter Three describes computational work on three separate projects published by coworkers in the Fu lab.
\r\n1) The first section details work on the nickel-catalyzed asymmetric coupling of enynes with secondary racemic electrophiles to accomplish for the first time the simultaneous control of axial and point chirality. The computational work probed the possible steps of rearrangement of the putative nickel-propargyl species into nickel allenyl species, as well as rationalized the different reactivity of the catalyst towards different electrophiles.
\r\n2) The second project was investigations into the photocatalytic coupling of secondary and tertiary electrophiles with secondary amines by copper and a dual-ligand system. The computations shed light on possible C\u2014N coupling mechanisms, as well as rationalized the differing photoactivity of the two CuI complexes present in the system.
\r\n3) The final work supported mechanistic studies into the photocatalytic asymmetric azidation of \u03b1-bromoamides by a copper-phosphine complex. DFT studies were performed to predict EPR spectra which were used to disambiguate the possible CuII species present in solution.
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:16536", "collection": "thesis", "collection_id": "16536", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:07052024-225058837", "type": "thesis", "title": "Development of Photoinduced Copper-Catalyzed Amination of Alkyl Electrophiles: Synthesis and Mechanism", "author": [ { "family_name": "Cho", "given_name": "Hyungdo", "orcid": "0000-0001-6109-5742", "clpid": "Cho-Hyungdo" } ], "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": "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": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The formation of carbon-nitrogen (C\u2013N) bonds is crucial in organic chemistry due to the importance of nitrogen-containing functional groups. While traditional nucleophilic substitution reactions, such as SN1, SN2, and SNAr, are limited in scope and efficiency, transition metal-catalyzed versions of these reactions, particularly involving copper, offer a more versatile approach by activating electrophiles and facilitating C\u2013N bond formation via oxidative addition and reductive elimination.
\r\n\r\nCopper-catalyzed C\u2013N couplings have been extensively developed but are primarily effective for aryl electrophiles rather than alkyl electrophiles due to the need for thermal activation, which often leads to undesired side reactions in alkyl electrophiles. The development of photoinduced copper-catalyzed reactions by Fu and Peters addresses these challenges, enabling the activation of alkyl electrophiles without thermal activation.
\r\n\r\nOver the past decade, the Fu group has focused on expanding the scope of this novel approach. The research detailed in this thesis focuses on developing photoinduced copper-catalyzed C\u2013N coupling reactions for more challenging substrates, such as sterically hindered alkyl electrophiles and amines.
\r\n\r\nChapter 2 discusses the photoinduced, enantio-convergent coupling of racemic tertiary alkyl electrophiles with aniline nucleophiles, catalyzed by bisphosphine-copper complexes. The mechanism of this reaction was elucidated using various tools, identifying key copper-based intermediates, including a chiral copper(II)\u2013anilido complex that couples with a tertiary organic radical to form the C\u2013N bond with good enantioselectivity.
\r\n\r\nChapter 3 presents the photoinduced, copper-catalyzed coupling of secondary alkyl amines with secondary or tertiary alkyl bromides to synthesize N-tertiary alkyl amines under mild conditions. This novel reaction provides unique stereoselectivity and compatibility with strained electrophiles, contributing valuable methodologies to the synthesis of bioisosteres and other complex amine structures.
\r\n\r\nOverall, this work broadens the understanding and application of photoinduced copper-catalyzed reactions, offering new pathways for the synthesis of sterically hindered amines.
", "doi": "10.7907/1008-m865", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:17282", "collection": "thesis", "collection_id": "17282", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05282025-142549821", "type": "thesis", "title": "Catalytic Proton-Coupled Reductions of Dinitrogen and Cyanide", "author": [ { "family_name": "Johansen", "given_name": "Christian Marinelli", "orcid": "0000-0003-0066-4424", "clpid": "Johansen-Christian-Marinelli" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "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": "Manthiram", "given_name": "Karthish", "orcid": "0000-0001-9260-3391", "clpid": "Manthiram-Karthish" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis, directly and indirectly, focuses on mechanisms and strategies for the 6H\u207a/6e\u207b reduction of N\u2082 to NH\u2083 (nitrogen reduction; N\u2082R) using well-defined molecular catalysts. In nature, nitrogenases reduce N\u2082 to NH\u2083, but nitrogenases can also reduce cyanide to CH\u2084 and NH\u2083, making CN\u207b and N\u2082 reduction interesting to compare. We describe the highly selective catalytic reduction of CN\u207b to NH\u2083 and CH\u2084 by a mononuclear Fe-catalyst related to Fe-based N\u2082R systems. Mechanistic studies suggest several intermediates, including iron isocyanides (FeCNH), aminocarbynes (FeCNH\u2082), and aminocarbenes (FeC(H)NH\u2082\u207a), allowing a comparison to N\u2082R. We then show the 2H\u207a/2e\u207b equilibration of iron cyanide to the iron aminocarbyne complexes of these early intermediates of catalysis. Such reversible triple bond activations are rare. We show that key to this transformation is the H-bond facilitated multisite proton-coupled electron transfer (MS-PCET).
\r\n\r\nNext, seeking alternative ways to drive N\u2082R, a photodriven approach is explored. The Hantzsch ester (HEH\u2082), a dihydropyridine, is utilized as a 2H\u207a/2e\u207b photoreductant, and when partnered with a suitable catalyst (Mo) and an organic buffer (collidine/collidinium; Col/ColH\u207a) under blue light irradiation allows for photodriven N\u2082R. Catalysis is enhanced by addition of a photoredox catalyst (Ir). This photodriven N\u2082R is thermodynamically comparable to the industrial hydrogenation of N\u2082, but light is used to drive the reaction. Mechanistic studies of the Ir-free conditions show that Col-buffer is essential for transferring H\u207a/e\u207b from HEH\u2082 to N\u2082. An H-bonded pre-association can form between [ColH]\u207a and HEH\u2082, allowing for rapid oxidative quenching of the excited HEH\u2082. Subsequently, the base deprotonates HEH\u2082\u2022\u207a, circumventing back electron transfer. In net ColH\u2022 and HEH\u2022, two potent H-atom donors are generated. This reagent combination is competent for the photoreduction of organic substrates as well. Lessons from this mechanistic study drove the development of photodriven methods for SmIII-to-SmII reduction, an appealing prospect given SmI\u2082 being a potent and selective reductant, including for N\u2082R. HEH\u2082 can serve either as a direct photoreductant or as the reductive quencher for an Ir photoredox catalyst. Both methods for SmI\u2082 generation translate to proof-of-concept photodriven, Sm-catalyzed reductive cross-coupling reactions.
", "doi": "10.7907/jrh7-2a15", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:17265", "collection": "thesis", "collection_id": "17265", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05222025-205440915", "type": "thesis", "title": "Reductive Samarium Catalysis Enabled By A Thermochemical Roadmap", "author": [ { "family_name": "Boyd", "given_name": "Emily A.", "orcid": "0000-0003-0150-5396", "clpid": "Boyd-Emily-A" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "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" }, { "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" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Samarium diiodide is a versatile single-electron reductant. Its reactivity is modulated by recruitment of a wide range of additives to its large coordination sphere. Binding of strong Lewis bases produces more potent Sm(II) reductants, while polar protic donors promote net proton-coupled electron transfer to a variety of unsaturated substrates including intermediates of molybdenum-catalyzed nitrogen reduction. However, samarium(II) reagents are used (super)stoichiometrically in all but a few select cases because mild, tunable methods for selective reduction of oxidized samarium(III) products back to the active samarium(III) state were unavailable at the outset of the following studies. Chapter 1 frames the challenge of catalytic samarium turnover in the context of nitrogen fixation. Proton-coupled electron transfer and inner-sphere electron transfer are introduced as two potential catalytic roles for samarium(II), and a strategy for proton-coupled reduction of problematic samarium(III)-alkoxide intermediates to achieve turnover is outlined. Chapter 2 describes a well-defined model system used to construct extended quantitative thermochemical cycles mapping proton transfer, electron transfer, and ligand association at samarium. The samarium(II) complex binds a secondary amide to generate a remarkably potent net hydrogen atom donor. In Chapter 2, this driving force is leveraged in iron-catalyzed nitrogen reduction; the strongly reducing, weakly acidic nature of the samarium reagent leads to selective generation of hydrazine over ammonia (99:1). In Chapter 3, the benchmarked samarium(III)-alkoxide protonolysis thermodynamics inform selection of Br\u00f8nsted acids that can be coupled with a mild reductant (zinc powder or an applied electrochemical potential) to achieve catalytic samarium turnover in reductive coupling of ketones and acrylates to form \u03b3-lactones. Photodriven methods for this samarium-catalyzed transformation are reported in Chapter 5. Finally, in Chapter 6, the hypothesis that samarium(II) might serve as an inner-sphere reductant in nitrogen reduction with transition metal catalysts guides design of conditions for tandem samarium/molybdenum catalysis in electrocatalytic nitrogen reduction to ammonia with the lowest driving force and highest Faradaic efficiency (82%) reported to date for a nonaqueous system at atmospheric pressure.", "doi": "10.7907/7f8x-qg41", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:16955", "collection": "thesis", "collection_id": "16955", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:01212025-074800688", "type": "thesis", "title": "Spectroscopic Investigation, Kinetic Analysis, and Ligand Field Theory Rationalization of Catalytic Reactivity for Data-Driven Methodology Development", "author": [ { "family_name": "Tong", "given_name": "Zhengjia Jaron", "orcid": "0000-0001-9329-8034", "clpid": "Tong-Zhengjia-Jaron" } ], "thesis_advisor": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" } ], "thesis_committee": [ { "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" }, { "family_name": "Hadt", "given_name": "Ryan G.", "orcid": "0000-0001-6026-1358", "clpid": "Hadt-Ryan-G" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "First-row transition metal catalysis can leverage one or two-electron redox chemistry to catalyze selective C\u2013C bond formation between two stereoelectronically differentiated substrates. Owing to this redox flexibility, many competing reaction pathways could occur, leading to the formation of both desired and undesired products. The electronic structure of the catalytic intermediates and reaction conditions are empirically recognized to modulate product distributions, but identifying the underlying design principle is often challenging. Mechanistic elucidation of the catalytic cycle and spectroscopic elucidation of important factors that influence catalytic reactivity could be beneficial to this endeavor. With the aid of ligand field theory and molecular orbital theory, a direct relationship may be established between the electronic structures of the metal catalysts and the thermodynamic or kinetic parameters of the elementary transformation they catalyze. To this end, this thesis describes the effort of combining spectroscopy, reactivity interpretation, and reaction kinetics to understand Ni-catalyzed reductive alkenylation and acylation of benzylic electrophiles and Cu-catalyzed allylic alkylation of \u03b3-butyric lactone. The research approach and the results described herein are anticipated to aid the emergent effort of data-driven reaction development.", "doi": "10.7907/7r55-2431", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "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: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:16311", "collection": "thesis", "collection_id": "16311", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03012024-065205159", "type": "thesis", "title": "Masked 2-Furylcarbinol Derivatives: A Modular and General Platform for Mechanically Triggered Molecular Release", "author": [ { "family_name": "Zeng", "given_name": "Tian", "orcid": "0000-0001-5957-3442", "clpid": "Zeng-Tian" } ], "thesis_advisor": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "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": "Wei", "given_name": "Lu", "orcid": "0000-0001-9170-2283", "clpid": "Wei-Lu" }, { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Stimuli-responsive polymers that undergo chemical transformations when exposed to external stimuli are attractive materials for a wide range of applications, such as targeted drug delivery, sensing, and catalysis. Within the emerging field of polymer mechanochemistry, mechanical force is harnessed to promote productive chemical transformations in stress-responsive molecules known as mechanophores. My research over the past several years has focused on the development of a modular and general mechanophore platform capable of releasing covalently-bound payloads in response to mechanical force. I envision that the further advancement of this design will not only aid in a deeper understanding of the design principles of mechanophores, but also enable new technologies, including non-invasive spatiotemporal delivery of bioactivate small molecules and self-healing materials.
\r\n\r\nChapter 1 reviews the recent process of the development of small molecule-releasing mechanophores and provide an overview of the masked 2-furylcarbinol derivatives we developed that enables a mechanically gated release cascade. Chapter 2 describes our initial demonstration of mechanically gated small molecule release from our mechanophore and the subsequent structural-property investigation to optimize for faster release rates. In Chapter 3, an alternative mechanophore design is introduced that has a shortened synthetic sequence while maintaining a fast release kinetics. In Chapter 4, we address the challenge of low release capacity from previous designs with a novel mechanophore that can be incorporated into multimechanophore polymers. Finally, Chapter 5 demonstrates the use of our modular and general release platform to trigger the depolymerization of a self-immolative polymer.
", "doi": "10.7907/2vm9-5415", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16489", "collection": "thesis", "collection_id": "16489", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06032024-222310291", "type": "thesis", "title": "Applications of Synthesis in Copolymer Upcycling, Reduction of CO\u2082, Ligand Non-Innocence, and New Weakly-Coordinating Anions", "author": [ { "family_name": "Bruening", "given_name": "Meaghan Ann", "orcid": "0000-0001-8132-9497", "clpid": "Bruening-Meaghan-Ann" } ], "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": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "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": "This dissertation focuses on a very diverse series of studies with synthetic applications to organometallic systems supported by a redox non-innocent ligand architecture, \u03b1,\u03c9 diene generation, ionomers for tuning performance of electrochemical CO2 reduction, and design of new weakly coordinating anions.
\r\n\r\nChapter 2 discusses the reactivity of a 9,10-anthracenediyl bis(phenoxide) titanium complex, where the polyaromatic anthracene motif functions as a non-innocent ligand. This enables access to a reduced Ti complex which is competent for oxidative coupling of alkyne and nitrile substrates, and pyrimidines and substituted benzenes can be accessed catalytically. Additional reactivity with oximes and oxidative coupling of alkynes and CO2 is explored.
\r\n\r\nChapter 3 reports a two-step method for generation of a distribution of \u03b1,\u03c9-dienes from ethylene and butadiene. Copolymers are prepared with variable butadiene content, where 1,4-butadiene incorporation ensures the double bonds are in the polymer backbone. Subsequent ethenolysis of the copolymers produces \u03b1,\u03c9-dienes in the C10-C20 range. The conditions can be modified to control product selectivity.
\r\n\r\nChapter 4 presents a series of polystyrene-based ionomers to probe the impact of local [K+] in the Cu electrode microenvironment on CO2R performance (Part A). Partial current density towards C2+ products (|jC2+|) increases with [K+] in ionomer, up to 225 mA cm\u20132. When K+ is replaced with [Me4N]+, performance lowers to the level of bare Cu, highlighting the crucial role of K+ in improving C2+ product selectivity. Molecular dynamics simulations and partial pressure CO2 experiments support enhanced CO2 mass transport with the ionomers. An expanded series of ionomers is presented (Part B), where the incorporation of different neutral comonomers (vinyl biphenyl) and cross-linking monomers (biphenyl and terphenyl) dramatically boosts performance. Direct tends between K+ content and CO2R performance are not observed with the expanded series, highlighting the non-innocent role of the neutral monomer and polymer structure.
\r\n\r\nChapter 5 presents a new, Si-based weakly-coordinating anion. A library of anions bearing a variety of R groups is prepared, enabling facile tuning of sterics and solubility. A range of cations employed in chemical reactivity is supported by these anions, including ether-free alkali cations, Ph3C+, and an ethylene/CO copolymerization catalyst [Pd(dppe)(NCMe)Me]+ (generated by salt metathesis or protonation of a metal-alkyl bond). Electrochemical studies on the [Bu4N]+ variant show an exceptionally wide stability window for the [MeSiF]- anion of 7.5 V in MeCN. The [C6F5SiF]- variant can be readily modified to access additional diverse and/or dianionic variants.
\r\n\r\nChapter 6 discusses the electrochemical performance of a new class of magnesium electrolytes for next-generation batteries. [Mg(DME)3][MeSiF]2 demonstrates remarkable performance with good stability, moderate conditioning, high coulombic efficiency ( > 96%), and high current density ( ~100 mA cm-2). However, the sensitivity of the experiments requires careful study of many parameters including impact of MgR2 additives (identity and concentration), cycling protocol, synthetic route, and the Pt working electrode to understand how the electrochemical performance is impacted. While addition of MgMe2 improves electrochemical performance, it is not inherently required for reversible Mg deposition and stripping. Following an extensive investigation of the cyclic voltammetry (CV) performance of [Mg(DME)3][MeSiF]2, preliminary screening of additional [Mg(DME)3][RSiF]2 variants is discussed.
\r\n\r\nAppendix I discusses the characterization of ethylene/\u03b1-olefin copolymers generated from monometallic and bimetallic Zr catalysts. The decreased polar monomer incorporation for the bimetallic vs. monometallic catalysts is attributed to the steric clash of larger comonomers with the distal metal site in bimetallic catalysts.
\r\n\r\nAppendix II discusses the preparation of bulky anthracene phenoxide ligands for Ti and Ta.
\r\n\r\nAppendix III discusses the preparation of mixed aryl/hydride borates as electrolytes for next-generation Mg batteries.
", "doi": "10.7907/dm7p-vv68", "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:15147", "collection": "thesis", "collection_id": "15147", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04282023-205948012", "primary_object_url": { "basename": "zott_thesis.pdf", "content": "final", "filesize": 19270979, "license": "other", "mime_type": "application/pdf", "url": "/15147/1/zott_thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Strategic Applications of Electrochemistry in Ammonia Oxidation and Alkyl Halide Reduction", "author": [ { "family_name": "Zott", "given_name": "Michael David", "orcid": "0000-0003-0535-0512", "clpid": "Zott-Michael-David" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Hadt", "given_name": "Ryan G.", "orcid": "0000-0001-6026-1358", "clpid": "Hadt-Ryan-G" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Chan", "given_name": "Garnet K.", "orcid": "0000-0001-8009-6038", "clpid": "Chan-G-K" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" } ], "local_group": [ { "literal": "Resnick Sustainability Institute" }, { "literal": "div_chem" } ], "abstract": "This thesis describes the strategic application of electrochemistry in the development of catalytic systems for two challenging processes: alkyl halide reduction and ammonia oxidation. In the case of alkyl halide reduction, the ability to precisely tune electrochemical potential favored the use of electrochemistry as compared to chemical reagents. By contrast, for ammonia oxidation, electrochemistry was specifically targeted due to motivations in the eventual development of ammonia fuel cell technology. The first chapter introduces these and other advantages of electrochemistry, as well as details regarding the thermodynamic potentials and kinetic barriers associated with alkyl halide reduction or ammonia oxidation. The second chapter details our development of photoelectrochemical methodology to employ a strongly luminescent dicopper system for outer-sphere, single-electron transfer reduction of benzyl chlorides. The third chapter marks the beginning of our work in molecular iron-mediated ammonia oxidation catalysis, in which we develop our hypothesis that catalyst structures featuring cis-labile coordination sites should mediate ammonia oxidation. We disclose the first iron electrocatalyst ([(TPA)Fe(MeCN)\u2082]\u00b2\u207a) as well as a framework for the analysis of metrics such as overpotential, catalytic rate, and catalyst stability. The fourth chapter introduces a hypothesis for catalyst improvement\u2014favoring low-spin electronic structures\u2014and a model system for testing: ([(BPM)Fe(MeCN)\u2082]\u00b2\u207a). Using this second-generation catalyst, improved stability, enhanced activity, and lowered overpotential were observed. The fifth chapter explores the validity of the cis-labile and low-spin hypotheses via Hammett-type substituent studies on both the [(TPA)Fe(MeCN)\u2082]\u00b2\u207a and the [(BPM)Fe(MeCN)\u2082]\u00b2\u207a platforms. This study resulted in the development of a further enhanced molecular electrocatalyst for ammonia oxidation and revealed mechanistic information pertinent to the development of future catalytic systems.", "doi": "10.7907/4fr8-7r78", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:14992", "collection": "thesis", "collection_id": "14992", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08042022-183527205", "primary_object_url": { "basename": "JJL_Thesis_2022.pdf", "content": "final", "filesize": 19424322, "license": "other", "mime_type": "application/pdf", "url": "/14992/1/JJL_Thesis_2022.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Computational Investigations of Organometallic Catalysis", "author": [ { "family_name": "Lawniczak", "given_name": "James Joseph", "orcid": "0000-0003-1898-9809", "clpid": "Lawniczak-James-Joseph" } ], "thesis_advisor": [ { "family_name": "Miller", "given_name": "Thomas F.", "orcid": "0000-0002-1882-5380", "clpid": "Miller-T-F" } ], "thesis_committee": [ { "family_name": "Miller", "given_name": "Thomas F.", "orcid": "0000-0002-1882-5380", "clpid": "Miller-T-F" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "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" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Organometallic catalysis facilitates the synthesis of diverse products ranging from polyolefin materials to pharmaceutical compounds, and catalyst performance depends in part on the design of the ligand scaffold. Towards computational ligand design, quantum mechanical methods more fully capture chemical reactivity in comparison to classical methods, but are more computationally demanding. Free energy calculations of key elementary steps of the catalytic cycle permit the computational prediction of catalyst performance and allow modifications of the ligand structure to be explored. In the dissertation, experimental and computational investigations of organometallic catalysis focuses on rational ligand design. Embedding techniques such as embedded mean field theory (EMFT) and quantum mechanics/molecular mechanics (QM/MM) are leveraged in free energy calculations to allow for the reduction of wall-clock times of energy calculations and trajectory sampling. The organometallic systems investigated include Group IV polyolefin catalysts capable of co-polymerization and enantioselective cross-coupling nickel catalysts. Additionally, experimental methodology development is discussed for a nickel-catalyzed cross-coupling of alkynyl nucleophiles to tertiary electrophiles.
", "doi": "10.7907/aepb-jm46", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15078", "collection": "thesis", "collection_id": "15078", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12132022-201432142", "primary_object_url": { "basename": "thesis_final.pdf", "content": "final", "filesize": 184003401, "license": "other", "mime_type": "application/pdf", "url": "/15078/3/thesis_final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Understanding the Origins of Photoexcited XUV Spectra", "author": [ { "family_name": "Klein", "given_name": "Isabel McMillan", "orcid": "0000-00016134-6732", "clpid": "Klein-Isabel-McMillan" } ], "thesis_advisor": [ { "family_name": "Cushing", "given_name": "Scott K.", "orcid": "0000-0003-3538-2259", "clpid": "Cushing-Scott-K" } ], "thesis_committee": [ { "family_name": "Hadt", "given_name": "Ryan G.", "orcid": "0000-0001-6026-1358", "clpid": "Hadt-Ryan-G" }, { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Cushing", "given_name": "Scott K.", "orcid": "0000-0003-3538-2259", "clpid": "Cushing-Scott-K" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "A full measurement of photoexcited dynamics, from excitation to recombination, is required to understand the photochemical processes at the heart of solar energy materials and devices. Measuring these complete dynamics is often unachievable with a single experimental tool. Transient X-ray spectroscopies, however, have proven to be powerful techniques as they can separately measure electron and hole dynamics, as well as vibrational and structural modes, all with elemental specificity. The interpretation of these measurements is still challenging, as the core-hole created following a core-level transition distorts the measured spectrum. This thesis aims to develop complementary experimental and computational techniques to measure and interpret transient X-ray spectra. Initially, the measured photoexcited dynamics of ZnTe and CuFeO\u2082, which reveal polaron formation and lattice coupling, as well as electron and hole kinetics and band gap dynamics, are presented. Following this experimental work, we develop an ab initio computational method for modeling transient X-ray and extreme ultraviolet (XUV) spectra. The ab initio method is a Bethe-Salpeter equation (BSE) approach based on the previously developed Obtaining Core Excitations from Ab initio electronic structure and the NIST BSE solver (OCEAN) code. Building on the foundations of the OCEAN code, we incorporate photoexcited states for a range of transition metal oxides and demonstrate the method\u2019s ability to simulate the effects of state filling, isotropic thermal expansion and polaron states on XUV absorption spectra. Importantly, our method is also able to fully decompose the calculated spectra into the constituent components of the X-ray transition Hamiltonian, providing further insight into the origins and nature of spectral features. The XUV absorption spectra for the ground, photoexcited, and polaron states of \u03b1-Fe\u2082O\u2083, as well as for the ground, photoexcited, and thermally expanded states of other first row transition metal oxides \u2013 TiO\u2082, \u03b1-Cr\u2082O\u2083, \u03b2-MnO\u2082, Co\u2083O\u2084, NiO, CuO, and ZnO \u2013 are calculated to demonstrate the accuracy of our approach. This method is easily generalized to K, L, M, and N edges to provide a general approach for analyzing transient X-ray absorption or reflection data.
", "doi": "10.7907/s8qe-4s74", "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: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:15188", "collection": "thesis", "collection_id": "15188", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05182023-034742629", "primary_object_url": { "basename": "MEM_Thesis_ProofreaderEdits.pdf", "content": "final", "filesize": 21560929, "license": "other", "mime_type": "application/pdf", "url": "/15188/1/MEM_Thesis_ProofreaderEdits.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "The Emerging Mechanochemistry of Naphthopyran", "author": [ { "family_name": "McFadden", "given_name": "Molly Elizabeth", "orcid": "0000-0003-3174-6385", "clpid": "McFadden-Molly-Elizabeth" } ], "thesis_advisor": [ { "family_name": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "orcid": "0000-0003-1464-2461", "clpid": "Dougherty-D-A" }, { "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": "Robb", "given_name": "Maxwell J.", "orcid": "0000-0002-0528-9857", "clpid": "Robb-M-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Asserting remote control over reactivity is a pervasive goal in modern chemistry. Several external stimuli can supply energy to facilitate productive chemical transformations. In recent years, that list has grown to include mechanical force. In the growing field of polymer mechanochemistry, privileged, mechanically sensitive molecules called mechanophores undergo desirable chemical reactions under force. Force is transduced to mechanophores through covalently attached polymer chains. Among many applications, mechanophores that react to produce colored species can be used for visual stress and damage detection in plastics. Naphthopyran is a highly modular molecular switch that can undergo ring-opening reaction to generates intensely colored merocyanine dyes. The studies described in this dissertation have thoroughly established the versatility and complexity of naphthopyran-based mechanochromic mechanophores.
\r\n\r\nIn Chapter 1, the history of naphthopyran molecular switches is summarized with particular emphasis on the exhaustive and generalizable merocyanine structure-property relationships established for photochromic naphthopyrans. Naphthopyran mechanochemistry is reviewed and contextualized among other mechanochromic mechanophores. Mechanochromic structure-function relationships are highlighted, as well as a series of studies using the naphthopyran platform for illustration of the unusual reaction pathways accessible under force, and studies demonstrating that multimodal naphthopyrans are an ideal platform for multicolor mechanochromism.
\r\n\r\nAs discussed extensively in Chapter 1, merocyanines are typically susceptible to thermal recyclization. However, Chapter 2 describes a scissile naphthopyran mechanophore that undergoes an unusual secondary mechanochemical ester cleavage after the ring-opening reaction. By revealing a \u03b2-hydroxy ketone group with a stable intramolecular hydrogen bonding interaction, mechanical force uniquely generates persistent merocyanine species.
\r\n\r\nThe irreversible reaction sequence described in Chapter 2 enables determination of mechanochemical reaction kinetics under solution-phase ultrasound-mediated mechanical force. However, common methods for determining reaction rate constants under these conditions are time-intensive and convoluted by the competitive side reaction of nonspecific polymer backbone scission. In Chapter 3, through model studies on the highly efficient scissile naphthopyran and a comparatively inefficient coumarin dimer mechanophore, we validate a time-efficient and accurate initial rates method for determination of selective mechanophore reaction kinetics under ultrasonication.
\r\n\r\nThe ability to colorimetrically report on the magnitude of applied stress is a grand challenge in the field of mechanochromism. Chapter 4 describes the first single mechanophore capable of such behavior. Mechanical force induces unexpectedly simultaneous ring-opening reactions from a bis-naphthopyran mechanophore, biasing a dynamic equilibrium between two distinct merocyanine states to effect gradient force-dependent multicolor mechanochromism.
\r\n\r\nIn further studies seeking multicolor mechanochromic systems, it was discovered that mechanical force facilitates the first reported dual-ring-opening reaction of naphthodipyran. Chapter 5 describes the mechanochemical generation of an unusual dimerocyanine species with near-IR absorption that is not formed photochemically.
", "doi": "10.7907/r4gk-rn51", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15141", "collection": "thesis", "collection_id": "15141", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04172023-221653165", "primary_object_url": { "basename": "Dutton_Thesis_Final.pdf", "content": "final", "filesize": 47710578, "license": "other", "mime_type": "application/pdf", "url": "/15141/1/Dutton_Thesis_Final.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Chirped Pulse Rotational Spectroscopy of Small Molecule Clusters", "author": [ { "family_name": "Dutton", "given_name": "Sarah Emily", "orcid": "0000-0002-9587-5971", "clpid": "Dutton-Sarah-Emily" } ], "thesis_advisor": [ { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" } ], "thesis_committee": [ { "family_name": "Wei", "given_name": "Lu", "orcid": "0000-0001-9170-2283", "clpid": "Wei-Lu" }, { "family_name": "Cushing", "given_name": "Scott K.", "orcid": "0000-0003-3538-2259", "clpid": "Cushing-Scott-K" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Despite the ubiquity of water and alcohol mixtures in every realm of science, the hydrogen bond network governing the unique properties of these mixtures is still under investigation. To aid in the determination of hydrogen bond energetics and dynamics in alcohol and water mixtures, herein a ground up approach studying small alcohol:water clusters is presented. Novel instrumentation for chirped pulse Fourier-transform microwave spectroscopy was developed, and subsequently benchmarked against the detection and characterization of ethanol and water trimers. From there, cluster size was gradually increased, first studying ethanol and water tetramers, then switching to methanol for larger cluster studies of pentamers and hexamers. Throughout this thesis, the over-arching questions as to microaggregation in clusters and trends in geometry and relative energy ordering were investigated, and evidence supporting the facile mixing of small alcohols and water is presented at the few-molecule cluster scale. In the final studies of methanol and water hexamers, the first `3-dimensional' bonding motifs of methanol and water clusters are observed, marking the transition from the planar conformers of small clusters to the complex and higher cooperativity bonding patterns in larger clusters and in bulk mixtures.", "doi": "10.7907/dxsp-c265", "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:15042", "collection": "thesis", "collection_id": "15042", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10172022-224813021", "type": "thesis", "title": "Noncanonical Amino Acid Synthesis by Evolved Tryptophan Synthases", "author": [ { "family_name": "Almhjell", "given_name": "Patrick James", "orcid": "0000-0003-0977-841X", "clpid": "Almhjell-Patrick-James" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Wang", "given_name": "Kaihang", "orcid": "0000-0001-7657-8755", "clpid": "Wang-Kaihang" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Mayo", "given_name": "Stephen L.", "orcid": "0000-0002-9785-5018", "clpid": "Mayo-S-L" }, { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The \u03b2-subunit of tryptophan synthase (TrpB) is responsible for the final step of \u029f-tryptophan biosynthesis in all of known biology. Recognized for this important role and its powerful chemistry, TrpB has more recently been used for the in vitro synthesis of tryptophan analogs and other noncanonical amino acids (ncAAs). This thesis describes some of these efforts as well as the application of TrpB for developing new methods in directed enzyme evolution. Chapter I first establishes important topical background. It begins with a general account of directed enzyme evolution by exploring the emergence of new catalytic functions in natural and laboratory settings, and how this information and chemical intuition can be used to create enzymes for desired reactions. This is followed by a description of the state of the field of ncAA synthesis, with a special focus on biocatalytic approaches using engineered enzymes. Chapters II and III examine targeted engineering campaigns to create enzymes that can efficiently synthesize valuable blue-fluorescent ncAAs such as 4-cyanotryptophan (Chapter II) and \u03b2-(1-azulenyl)-\u029f-alanine (AzAla, Chapter III) from accessible starting materials. In Chapter IV, the native function of TrpB for \u029f-tryptophan biosynthesis is used as a selection pressure to develop an in vivo continuous evolution system. Despite a selection pressure for only \u029f-tryptophan synthesis the orthologous TrpB variants generated by this system have varying promiscuous activities for \u029f-tryptophan analogs, paralleling the sequence-function diversity of natural enzyme homologs. Chapter V describes evSeq, an inexpensive and simple method for sequencing all protein variants generated during an engineering campaign, demonstrated by collecting ~800 TrpB sequence-function data points. Finally, in Chapter VI, directed evolution and chemical intuition are used to convert TrpB from a tryptophan synthase to a novel tyrosine synthase (TyrS). This enzyme can irreversibly and regioselectively alkylate simple phenol analogs to synthesize valuable tyrosine analogs, including the blue-fluorescent ncAA \u03b2-(1-naphthol-4-yl)-\u029f-alanine (NaphAla) and 3-methyl-\u029f-tyrosine at gram scales. Because TyrS synthesizes a primary metabolite, this transformation represents a noncanonical method for the biosynthesis of \u029f-tyrosine. This is the first example of a feasible new route for de novo aromatic amino acid biosynthesis, which occurs through a universally conserved set of chemistry across all of life. In total, the work described here expands the fields of chemical synthesis and synthetic biology by presenting new enzymes\u2014and methods for producing these enzymes\u2014that are capable of synthesizing important amino acids in vitro and in vivo.
", "doi": "10.7907/rcvq-dg51", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "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: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: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: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: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:13672", "collection": "thesis", "collection_id": "13672", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04102020-135244808", "primary_object_url": { "basename": "Gu_Nina_thesis.pdf", "content": "final", "filesize": 25088141, "license": "other", "mime_type": "application/pdf", "url": "/13672/20/Gu_Nina_thesis.pdf", "version": "v12.0.0" }, "type": "thesis", "title": "Synthesis, Characterization, and Reactivity of Thiolate-Supported Metalloradicals", "author": [ { "family_name": "Gu", "given_name": "Nina Xiao", "orcid": "0000-0002-4637-8418", "clpid": "Gu-Nina-Xiao" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "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": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Reactive metalloradical intermediates have been implicated in both biological and synthetic catalyst systems for small molecule activation processes, including proton reduction and ammonia oxidation. Towards a greater mechanistic understanding of such transformations on well-defined model complexes, this thesis explores relevant H\u2013H and N\u2013N bond-forming reactions mediated by trivalent Fe and Ni species, as well as catalytic N\u2013N bond cleavage mediated by an open-shell VFe bimetallic complex. First, a pair of thiolate-supported, S = \u00bd iron and nickel hydrides are synthesized and spectroscopically characterized at low temperatures (Chapters 2, 3). Paramagnetic iron and nickel hydrides have been proposed as catalytic intermediates of [NiFe] hydrogenase and nitrogenase, but characterization of such molecular species are limited. For both the FeIII and NiIII hydride complexes described herein, spin delocalization onto the thiolate ligand is proposed to stabilize the formal 3+ metal oxidation state. Furthermore, both the FeIII\u2013H and NiIII\u2013H species are demonstrated to undergo the bimolecular reductive elimination of dihydrogen upon warming, albeit with distinct activation parameters consistent with different proposed pathways for H\u2013H bond formation. Chapter 4 expands upon the H\u2013H bond forming chemistry demonstrated on the Ni system to demonstrate related N\u2013N bond formation from an analogous NiIII\u2013NH2 species, resulting in the formation of a NiII2(N2H4) complex. Given the diverse mechanistic possibilities for the overall 6e-/6H+ transformation to oxidize ammonia to dinitrogen, identification of the active M(NHx) intermediate and pathway for N\u2013N bond formation is a central mechanistic question. While the homocoupling of M\u2013NH2 species to form hydrazine has been hypothesized as the key N\u2013N bond forming step in ammonia oxidation systems, stoichiometric examples of this transformation from M\u2013NH2 complexes are rare. Lastly, Chapter 5 details the synthesis of a heterobimetallic VFe complex featuring a bridging thiolate, inspired by the structure of the VFe nitrogenase cofactor. This VFe species is demonstrated to be an active catalyst for the disproportionation of hydrazine to dinitrogen and ammonia. Notably, the heterobimetallic complex is appreciably more active than monometallic analogues of the individual V and Fe sites, suggesting that bimetallic cooperativity may facilitate the observed catalysis.
", "doi": "10.7907/8zwz-gh20", "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:13712", "collection": "thesis", "collection_id": "13712", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05192020-111207482", "type": "thesis", "title": "Expanding the Catalytic Repertoire of Hemeproteins as Carbene Transferases to Access Diverse Molecular Structures", "author": [ { "family_name": "Chen", "given_name": "Kai", "orcid": "0000-0002-3325-3536", "clpid": "Chen-Kai" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "orcid": "0000-0002-0057-7817", "clpid": "Grubbs-R-H" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" }, { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The efficiency, selectivity, and sustainability benefits offered by enzymes are enticing chemists to consider biocatalytic transformations to complement or even supplant more traditional synthetic routes. Increasing demands for efficient and versatile synthetic methods combined with powerful new discovery and engineering tools have prompted innovations in biocatalysis, especially the development of new enzymes for precise transformations. The past decade has witnessed impressive expansion of the catalytic repertoire of enzymes to include new and useful transformations not known (or relevant) in the biological world. The continuing discovery and improvement of these new enzyme activities is opening a floodgate that connects the chemistry of the biological world to that invented by humans over the last 100 years.
\r\n\r\nThis thesis describes a new set of enzymes, derived from a cytochrome P450 monooxygenase and a cytochrome c electron-transfer protein, which are able to function as carbene transferases to construct diverse molecular structures, including strained carbocycles and lactone derivatives. Chapter 1 illustrates different approaches researchers have utilized to explore and develop new catalytic machineries of diverse enzymes. These efforts have identified new genetically-encoded biocatalysts that can be tuned and diversified through directed evolution. Chapter 2 presents the discovery of P450 variants that catalyze the formation of highly strained carbocycles, bicyclobutanes and cyclopropenes, via carbene addition to carbon\u2012carbon triple bonds. The intrinsic strain energies of these small rigid carbocycles allow them to have broad applications in different fields, but also create challenges for their construction. Using a diazo substrate as the carbene precursor, the enzyme variants optimized by directed evolution could act on structurally diverse alkynes (aromatic or aliphatic, terminal or internal) with high efficiency and selectivity, providing an effective route to an array of chiral strained structures. The carbene transferase activity is then extended to the assembly of various lactone structures, a fundamental class of organic moieties with applications in fields varying from synthetic chemistry, to materials science, to medicinal chemistry. Chapter 3 details a strategy using lactone-based carbenes, for the transfer to different functionalities, enabling rapid access to a broad range of \u03b1-substituted and spiro-lactones with unprecedented efficiencies and selectivities. A different approach based on intramolecular carbene C\u2013H insertion is outlined in Chapter 4, which allows for the synthesis of lactones in a higher order of structural diversity. Directed evolution of a P450 variant identified a lineage of potent variants, capable of assembling lactones in different sizes (5- to 7-membered) and also with sophisticated three-dimensional structures based on fused, spiro and bridged rings. Computational tools were employed to understand the reaction mechanisms and to explain some mutational effect. In sum, the thesis work lays out how protein engineering integrated with chemical rationalization enables the expansion of the chemical space accessible to native hemeproteins, especially in building diverse molecular structures.
", "doi": "10.7907/9b3c-nr61", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:11801", "collection": "thesis", "collection_id": "11801", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09252019-210323106", "primary_object_url": { "basename": "Combined.pdf", "content": "final", "filesize": 12834161, "license": "other", "mime_type": "application/pdf", "url": "/11801/13/Combined.pdf", "version": "v11.0.0" }, "type": "thesis", "title": "Small Molecule Reactivity of Trisphosphine-Supported Iron and Cobalt Complexes", "author": [ { "family_name": "Deegan", "given_name": "Meaghan Marie", "orcid": "0000-0002-7633-2074", "clpid": "Deegan-Meaghan-Marie" } ], "thesis_advisor": [ { "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": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The work described in this thesis emphasizes accessing novel reactivity patterns in the activation of carbon monoxide, dinitrogen, and dihydrogen by leveraging phosphine-supported iron and cobalt complexes. In Chapters 2 and 3, systems that access CO and N2 reductive functionalization from highly reduced Fe-hydride precursors are described. These systems access productive C-H and N-H bond forming steps from hydride precursors that ultimately allows for the liberation of four-electron reduced products through novel chemical pathways. Chapter 4 describes an unusual example of a terminal cobalt carbyne through the O-functionalization of a carbonyl complex. Next, in Chapter 5, we consider electronically unusual examples of dihydrogen complexes and explore their propensity for accessing H-atom and hydride transfer. Finally, to conclude, Chapter 6 details our synthetic efforts targeting the synthesis of a terminal Fe-carbide complex through the cleavage of a thiocarbonyl precursor.
", "doi": "10.7907/QDAW-M003", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "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: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:11565", "collection": "thesis", "collection_id": "11565", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05302019-070503222", "primary_object_url": { "basename": "Hannoun_Thesis_Final.pdf", "content": "final", "filesize": 7315938, "license": "other", "mime_type": "application/pdf", "url": "/11565/45/Hannoun_Thesis_Final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Mechanistic Study of Cu-Mediated, Photoinduced C\u2013S Bond Formation and Demonstration of Electrochemical Ammonia Production by a Surface-Attached Iron Complex", "author": [ { "family_name": "Hannoun", "given_name": "Kareem Imad", "orcid": "0000-0003-3176-1104", "clpid": "Hannoun-Kareem-Imad" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Miller", "given_name": "Thomas F.", "clpid": "Miller-T-F" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The worldwide reliance on fossil fuels for energy and petrochemicals poses a massive environmental hazard. Furthermore, many chemical processes rely on precious metals that have low abundance on Earth and are threatened. As the world population grows rapidly, these factors pose an increasing threat to our planet and new chemical processes are needed that employ earth-abundant catalysts and alternative chemical currencies such as light and electricity derived from renewable sources.
\r\n\r\nChapter 2 discusses an in-depth mechanistic study of the photoinduced, copper-mediated cross-coupling of aryl thiols with aryl halides. This reaction employs light energy and an earth-abundant metal to achieve bond formation through a pathway distinct from that of thermal reactions. In particular, I focus on the stoichiometric photochemistry and subsequent reactivity of a [CuI(SAr)2]\u2013 complex (Ar = 2,6-dimethylphenyl). A broad array of experimental techniques furnish data consistent with a pathway in which a photoexcited [CuI(SAr)2]-* complex undergoes SET to generate a CuII species and an aryl radical, which then couple through an in-cage radical recombination.
\r\n\r\nChapter 3 discusses the surface attachment of a P3BFe complex to a carbon electrode, and the electrochemical generation of ammonia from N2 by the surface-appended species (P3BFe = tris-phosphinoborane). Ammonia production is achieved industrially by the combination of N2 and H2, the latter of which is derived from methane with concomitant production of CO2. Alternative chemical processes, such as the use of energy derived from electricity, are vital for the decreasing the carbon footprint of ammonia production. Synthetic modification of a previously-reported P3BFe complex by addition of three pyrene substituents onto the catalyst backbone allows non-covalent attachment onto a graphite surface. The resulting functionalized electrode shows good stability towards iron desorption under highly reducing conditions, and produces 1.4 equiv NH3 per iron site. The data presented provide the first demonstration of electrochemical nitrogen fixation by a molecular complex appended to an electrode.
", "doi": "10.7907/R9EJ-KX83", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "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: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: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: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: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:10732", "collection": "thesis", "collection_id": "10732", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02232018-173939270", "type": "thesis", "title": "Iron, Cobalt, and Nickel Metalloboranes: Reactivity, Catalysis, N2 Activation and Stabilization of Reactive N2Hx Ligands", "author": [ { "family_name": "Nesbit", "given_name": "Mark Allen", "orcid": "0000-0002-5642-9303", "clpid": "Nesbit-Mark-Allen" } ], "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": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The reactivity of Fe and Co compounds supported by a bisphosphinoborane (DPB) ligand ([(DPB)Fe]2(N2) and (DPB)Co(N2)) towards E-H bonds (E = C, N, S, O, Si) is reported along with the catalytic hydrosilylation of ketones and aldehydes. The Fe and Co compounds displayed a mix of 1-electron and 2-electron chemistry. In some cases [(DPB)Fe]2(N2) and (DPB)Co(N2) facilitated oxidative addition of the E-H bond across the M-B interaction, and in others evolution of H2 giving a 1-electron oxidized complex of the general form (DPB)M(E) was observed. The reaction of Ph2SiH2 with (DPB)Co(N2) was found to be reversible, similar to the previously reported related nickel complex (PhDPBMes)Ni. The reactivity of these Fe and Co compounds is compared to previously reported Ni compounds supported by a similar ligand which catalyze olefin hydrogenation and hydrosilylation of substituted benzaldehydes.
\r\n\r\nThe synthesis and metalation with nickel of two new variants of the DPB ligand (DP*BPh and DP*BMes) is described. The primary modification introduced in DP*BPh and DP*BMes is the incorporation of a tertiary amine moiety into the secondary coordination sphere. This was done with the hypothesis that the amine moiety might act as a proton shuttle and facilitate proton reduction or hydrogen oxidation electrocatalysis. The process of screening these compounds for activity as proton reduction and hydrogen oxidation catalysts is also discussed. Additionally, the stoichiometric reactivity of [(DP*BPh)Ni]2(N2) and (DP*BMes)Ni(N2) with H2 was studied. We observed that [(DP*BPh)Ni]2(N2) slowly decomposed to an unidentified mixture of products while (DP*BMes)Ni(N2) dimerized to form a phosphine bridged Ni-borohydride dimer [(DP*BMesH)Ni]2. [(DP*BPh)Ni]2(N2) and (DP*BMes)Ni(N2) were also tested as precatalysts for olefin hydrogenation and found to be less active that their previously reported counterpart (PhDPBMes)Ni. [(DP*BPh)Ni]2(N2) and (DP*BMes)Ni(N2) correspondingly showed no activity for hydrogenation of polar substrates such as ketones, aldehydes, or CO2.
\r\n\r\nLastly, the synthesis of a new trisphosphinoborane ligand (ArP3B) with bulky aryl substituents on the phosphines and its metalation with Fe is described. The anionic-N2 adduct [(ArP3B)Fe(N2)][Na(12-C-4)2] was observed to react with H+ sources to generate the first observed parent iron-diazenido (ArP3B)Fe(NNH) and an iron-hydrazido(2-) [(ArP3B)Fe(NNH2)]+. [(ArP3B)Fe(NNH2)]+ was found to have similar spectroscopic properties to the previously reported [(TPB)Fe(NNH2)]+. A thorough characterization of [(ArP3B)Fe(N2)][Na(12-C-4)2], (ArP3B)Fe(NNH), and [(ArP3B)Fe(NNH2)]+ by a variety of continuous wave and pulsed ERP techniques is presented along with 57Fe M\u00f6ssbauer data. The new (ArP3B)Fe system was also canvassed for activity as a catalyst for conversion of N2 to NH3 and found to yield substoichiometric amounts of NH3 in the presence of KC8 and HBArF24\u20222Et2O while no NH3 was observed using CoCp*2 and [H2NPh2][OTf].
", "doi": "10.7907/Z9G15Z28", "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:10807", "collection": "thesis", "collection_id": "10807", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04162018-150106151", "primary_object_url": { "basename": "Buss_Thesis_2018.pdf", "content": "final", "filesize": 36966980, "license": "other", "mime_type": "application/pdf", "url": "/10807/1/Buss_Thesis_2018.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Molybdenum Para-Terphenyl Diphosphine Complexes", "author": [ { "family_name": "Buss", "given_name": "Joshua Alan", "orcid": "0000-0002-3347-8583", "clpid": "Buss-Joshua-Alan" } ], "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": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "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 dissertation describes studies exploring the coordination chemistry and reactivity of molybdenum complexes bearing a flexible and redox non-innocent para-terphenyl diphosphine ligand. Within this context, transformations relevant to energy storage and conversion, fundamental structure function studies, and unusual group transfer reactivity are presented.
\r\n \r\nChapter 2 accounts the ability of Mo para-terphenyl diphosphine complexes to catalyze extensive ammonia borane dehydrogenation, releasing greater than two equiv. of hydrogen (H2). Initially believed to be a frontrunner as a high energy density H2 storage medium, AB is a Lewis acid/base adduct that features both hydridic B\u2013H bond and protic N\u2013H bonds. As a highly reactive molecule, the controlled dehydrogenation of AB, accessing \u2265 2 of the 3 stored equiv. of H2, is uncommon. We disclose a catalytic system, utilizing an earth-abundant metal, that is capable of such reactivity. The mechanism by which the catalysis proceeds is dependent on the oxidation state of the precatalyst, with MoII proceeding through a II/IV cycle and Mo0 proceeding through a 0/II cycle. Several Mo hydride complexes were characterized in conjunction with this work. Importantly, the ability of the para-terphenyl diphosphine ancillary ligand to support a range of Mo oxidation states and coordination numbers was established, a feature that provides a foundation for the work presented in subsequent chapters.
\r\n \r\nIn Chapter 3, new features of the para-terphenyl diphosphine ligand were discovered, namely facilitation of electron loading that subsequently leads to small molecule functionalization and cleavage. From the Mo dicarbonyl complex described in Chapter 2, stepwise reduction affords Mo0, Mo-II, and Mo-III compounds, all of which were characterized both structurally and by a variety of spectroscopies. The latter two complexes were demonstrated to react with silyl electrophiles, instigating deoxygenative reductive coupling of the bound CO ligands to a metal-free C2O1 fragment. This remarkable four-electron process was studied in detail, characterizing twelve different reaction intermediates, including rare examples of bis(siloxy)carbyne, terminal carbide, and mixed dicarbyne motifs. The cleavage of a bound carbon monoxide (CO), subsequent coupling, and spontaneous product release was an unprecendented sequence of chemical transformations, the detailed mechanistic study of which provides valuable precedent for catalyses for the conversion of C1 oxygenates to multicarbon products.
\r\n \r\nChapter 4 discusses continuations of this work in an attempt to model Fischer-Tropsch catalysis with higher fidelity. To this end, the silyl electrophiles used in the fundamental studies in Chapter 3 needed to be replaced with protons. Addition of protons to the super-reduced Mo complexes resulted in formal arene hydrogenation; no evidence for C\u2013O functionalization was obtained. These diene-linked complexes; however, provided an opportunity to explore how the nature of the basal \u03c0-system effects CO catenation chemistry and ultimately led to the preparation of a Mo-bound C3O3 unit derived entirely from CO. Reactivity with protons was likewise explored for downstream intermediates. Carbide protonation yields a stable methylidyne carbonyl complex, that, upon treatment with hydride, forms a methylidene. Comparison to a silyl-bearing model system suggests that subsequent carbene carbonylation affords enthenone.
\r\n \r\nChapter 5 and 6 focus on the synthesis and reactivity of Mo(IV) terminal pnictogen complexes isoelectronic to the carbyne and carbide complexes prepared in Chapters 3 and 4. Chapter 5 describes successful N\u2013C bond formation through N\u2013 transfer to CO from a MoII anionic nitride precursor. In Chapter 6, the first example of a terminal transition metal phosphide with d-electrons was prepared via a 4 e\u2013 oxidative group transfer. This species can undergo a single-electron oxidation, providing, at low temperatures, an unstable Mo(V) phosphide cation that studied extensively by CW and pulse EPR techniques. Upon warming, P\u2013P bond formation is evidenced by chemical trapping and characterization of coupling byproducts. Related phosphinidene (Mo=PR), phosphide (Mo-PR2), and dinuclear \u03bc-phosphido compounds are also reported. In a collaboration with Mr. Yohei Ueda and Dr. Masa Hirahara these complexes were explored for proton reduction reactivity. Isotopic labeling suggests formation of a dinuclear \u03bc-phosphinidene upon treatment with acid, and a bimetallic hydride \u03bc-phosphide was accessed from reaction with hydride.
\r\n \r\nThe final chapters of this dissertation are focused on the reduction of carbon dioxide (CO2). Chapter 7 presents a fundamental study involving Lewis acid (LA) aditives, that demonstrates the importance of kinetic stabilization, and not just thermodynamic activation, in productive small molecule functionalization chemistry. Upon addition of LAs, well-defined adducts are formed with Mo-bound CO2. Protonation results in C\u2013O bond cleavage, utilizing two electrons from the metal center to reduce CO2 to CO and H2O. Though the degree of CO2 activation trends well as a function of Lewis acidity, the residence time of the bound CO2, reported via the rate of CO2 self-exchange, is shown to correlate to the degree of C\u2013O scission. Chapter 8 looks at CO2 reactivity with E\u2013H bonds, describing first stoichiometric reactivity with silanes. In this system, CO2 is reduced to CO and silanol; mechanistic studies suggest a pathway that involves oxygen atom transfer to silane from a transient Mo oxo. In a collaboration with Dr. Naoki Shida, CO2 hydrogenation was explored, with demonstration of bidirectional catalysis in addition to detailed studies investigating the elementary steps of both formate formation and formic acid dehydrogenation.
", "doi": "10.7907/SJTG-3388", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:10549", "collection": "thesis", "collection_id": "10549", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10312017-153922571", "type": "thesis", "title": "Photoinduced, Copper-Catalyzed C-N and C-C Bond Formation and Photocatalytic Co-Mediated Nitrite Reduction to N\u2082O: Reactivity and Mechanism", "author": [ { "family_name": "Ratani", "given_name": "Tanvi Siraj", "clpid": "Ratani-Tanvi-Siraj" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "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": "Photocatalytic reactions with first-row transition metals are presented as a method for sustainable chemistry with great potential for new forms of reactivity and mechanistic pathways. Chapters 2 and 3 of this thesis discuss mechanism and reactivity of photoinduced, copper-catalyzed bond constructions. The Peters and Fu groups have reported that a variety of couplings of nitrogen, sulfur, oxygen, and carbon nucleophiles with organic halides can be achieved under mild conditions (\u221240 to 30 \u00b0C) through the use of light and a copper catalyst. Insight into the various mechanisms by which these reactions proceed may enhance our understanding of chemical reactivity and facilitate the development of new methods. We apply an array of tools (EPR, NMR, transient absorption, and UV\u2212vis spectroscopy; ESI\u2212MS; X-ray crystallography; DFT calculations; reactivity, stereochemical, and product studies) to investigate the photoinduced, copper-catalyzed coupling of carbazole with alkyl bromides. Our observations are consistent with pathways wherein both an excited state of the copper(I) carbazolide complex ([CuI(carb)2]\u2212) and an excited state of the nucleophile (Li(carb)) can serve as photoreductants of the alkyl bromide. The catalytically dominant pathway proceeds from the excited state of Li(carb), generating a carbazyl radical and an alkyl radical. The cross-coupling of these radicals is catalyzed by copper via an out-of-cage mechanism in which [CuI(carb)2]\u2212 and [CuII(carb)3]\u2212 (carb = carbazolide), both of which have been identified under coupling conditions, are key intermediates, and [CuII(carb)3]\u2212 serves as the persistent radical that is responsible for predominant cross-coupling. This study underscores the versatility of copper(II) complexes in engaging with radical intermediates that are generated by disparate pathways, en route to targeted bond constructions.
\r\n\r\nIn Chapter 3, we establish that photoinduced, copper-catalyzed alkylation can also be applied to C\u2212C bond formation, specifically, that the cyanation of unactivated secondary alkyl chlorides can be achieved at room temperature to afford nitriles, an important class of target molecules. In the presence of an inexpensive copper catalyst (CuI; no ligand coadditive) and a readily available light source (UVC compact fluorescent light bulb), a wide array of alkyl halides undergo cyanation in good yield. Our initial mechanistic studies are consistent with the hypothesis that an excited state of [Cu(CN)2]\u2212 may play a role, via single electron transfer, in this process. This investigation provides a rare example of a transition metal-catalyzed cyanation of an alkyl halide, as well as the first illustrations of photoinduced, copper-catalyzed alkylation with either a carbon nucleophile or a secondary alkyl chloride.
\r\n\r\nChapter 4 presents a mechanistic study of the photocatalytic reduction of nitrite to nitrous oxide with the use of an Ir photocatalyst ([Ir(ppy)2(phen)][PF6]) and a bimetallic CoMg co-catalyst with a diimine-dioxime ligand platform. Insights into the mechanism of this reaction may enhance our current understanding of N\u2013N coupling processes relative to other pathways of reactivity for nitrosyl ligands, such as nitroxyl (HNO) dimerization. We propose a mechanism in which a coordinated and an uncoordinated \u2022NO are coupled at a single Co center. One electron reduction of [(Cl)(NO)Co(Medoen)Mg(Me3TACN)(H2O)][BPh4] ({CoNO}8), a species we show to be catalytically relevant, forms a {CoNO}9 species that is characterized by UV-Vis, EPR, and FT-IR spectroscopy and whose electronic structure is supported by density functional theory (DFT). We formulate the {CoNO}9 as a 5-coordinate, S = 3/2 Co(II) antiferromagnetically coupled with an anionic S = 1 3NO\u2013 ligand. Experimental data suggest a mechanism in which this {CoNO}9 intermediate can release \u2022NO, thereby reducing the Co(II) center to Co(I). This free \u2022NO can react with another {CoNO}9 complex to generate a Co(NONO) intermediate which was observed by step-scan time-resolved IR spectroscopy and whose assignment was supported with DFT calculations. This Co(NONO) species, which can generate N2O and H2O, is formulated as a neutral hyponitrite intermediate with significant neutral radical character on both nitrosyl nitrogen atoms and a weak N\u2013N bond.
", "doi": "10.7907/Z9ZP44BF", "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:10443", "collection": "thesis", "collection_id": "10443", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09202017-130540216", "primary_object_url": { "basename": "Buscagan_Trixia_2018_Thesis.pdf", "content": "final", "filesize": 8885097, "license": "other", "mime_type": "application/pdf", "url": "/10443/1/Buscagan_Trixia_2018_Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Transition Metals as Catalysts for Cross-Coupling and Dinitrogen Fixation", "author": [ { "family_name": "Buscagan", "given_name": "Trixia Marie", "orcid": "0000-0001-8242-9203", "clpid": "Buscagan-Trixia-Marie" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "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": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Rees", "given_name": "Douglas C.", "clpid": "Rees-D-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Transition metals are used as catalysts in the laboratory and by nature to facilitate difficult chemical transformations. Herein, three different metal containing catalysts are discussed: Pd and Ni catalysts towards the formation of carbon-carbon (C-C) bonds and Fe catalysts towards the reduction of N2 to NH3.
\r\n\r\nIn Chapter 2, mechanistic studies of Pd- and Ni-catalyzed cross-coupling reactions are discussed. The mechanism of transmetalation of a Pd-catalyzed Suzuki cross-coupling reaction is studied using a stereochemical probe, revealing that transmetalation occurs with retention of configuration, consistent with transmetalation occurring through a frontside-attack mechanism. Next, to explore the viability of a transmetalation first pathway in an asymmetric Negishi cross-coupling reaction, S = 1/2 NiIBr and NiI\u2013alkyl complexes were synthesized, crystallographically characterized, and their reactivities explored. Based on these reactivity studies, evidence against a transmetalation first pathway is provided using a variety of spectroscopic methods.
\r\n\r\nIn Chapter 3, new Fe(N2)(H)x complexes are synthesized. These complexes catalyze the reduction of N2 to NH3 and the yields for NH3 are improved if the reactions are performed in the presence of Hg lamp photolysis. Preliminary mechanistic studies exploring the role of light are discussed. In the final chapter, new ligand scaffolds are developed that can bind a Lewis acidic and Lewis basic metal center. These ligand frameworks support one- and two-atom bridges between the two metal sites. Finally, we discovered that some of the new complexes are catalysts for N2 to NH3 reduction and olefin hydrogenation.
", "doi": "10.7907/Z98P5XPM", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:10965", "collection": "thesis", "collection_id": "10965", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05292018-165300346", "type": "thesis", "title": "A Synthetic Nitrogenase: Insights into the Mechanism of Nitrogen Fixation by a Single-Site Fe Catalyst", "author": [ { "family_name": "Thompson", "given_name": "Niklas Bjarne", "orcid": "0000-0003-2745-4945", "clpid": "Thompson-Niklas-Bjarne" } ], "thesis_advisor": [ { "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": "Chan", "given_name": "Garnet K.", "clpid": "Chan-G-K" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "Resnick Sustainability Institute" }, { "literal": "div_chem" } ], "abstract": "Nitrogen fixation, specifically the conversion of molecular nitrogen into ammonia, is a fundamental reaction necessary to support life. Our group has recently discovered the first family of well-defined iron complexes that catalyze the conversion of dinitrogen to ammonia. This thesis details mechanistic study of the nitrogen fixation chemistry these complexes. Chapter 1 presents an abbreviated overview of catalytic nitrogen fixation, which places our work in a larger context. Chapter 2 details the synthesis and nitrogen fixation activity of a series of cobalt complexes that are homologous to the known iron-based catalysts. The central goal of this work was to provide a structure-function study of the isostructural cobalt and iron complexes, in which the nature of the transition metal ion was changed in a fashion that predictably modulated the electronics of the system. Chapter 3 details in situ mechanistic studies of nitrogen fixation catalyzed by the iron complexes under the originally-reported reaction conditions. In this study, we were able to achieve a nearly order-of-magnitude improvement of catalyst turnover. Study of the reaction dynamics evidence a single-site mechanism for dinitrogen reduction, which is corroborated by in situ monitoring of catalytic reaction mixtures using freeze-quench M\u00f6ssbauer spectroscopy. In Chapter 4, we study the key N-N bond cleavage step in the catalytic cycle for nitrogen fixation. In this chapter, we demonstrate that sequential reduction and low-temperature protonation of an iron catalyst results in the formation of ammonia and a terminal Fe(IV) nitrido complex. This result provides a compelling proposal for the mechanism of the catalytic nitrogen fixation reaction. Finally, in Chapter 5 we present spectroscopic and computational studies detailing the electronic structures of a redox series of Fe(NNR2) complexes that model key catalytic intermediates occurring prior to the N-N bond cleavage step. We evidence one-electron redox non-innocence of the \u201cNNR2\u201d ligand, which resembles that of the classically non-innocent ligand, NO, and may have mechanistic implications for the divergent nitrogen fixation activity of the some of the iron complexes studied by our group.
", "doi": "10.7907/T4WQ-TM68", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "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: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: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: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: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:9581", "collection": "thesis", "collection_id": "9581", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02242016-013157998", "primary_object_url": { "basename": "creutz_thesis.pdf", "content": "final", "filesize": 14691473, "license": "other", "mime_type": "application/pdf", "url": "/9581/1/creutz_thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Design, Synthesis, and Study of Novel Platforms for Iron-N2 Chemistry and Photoinduced, Copper-mediated C-N Bond Formation", "author": [ { "family_name": "Creutz", "given_name": "Sidney E.", "clpid": "Creutz-Sidney-E" } ], "thesis_advisor": [ { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Several new ligand platforms designed to support iron dinitrogen chemistry have been developed. First, we report Fe complexes of a tris(phosphino)alkyl (CPiPr3) ligand featuring an axial carbon donor intended to conceptually model the interstitial carbide atom of the nitrogenase iron-molybdenum cofactor (FeMoco). It is established that in this scaffold, the iron center binds dinitrogen trans to the Calkyl anchor in three structurally characterized oxidation states. Fe-Calkyl lengthening is observed upon reduction, reflective of significant ionic character in the Fe-Calkyl interaction. The anionic (CPiPr3)FeN2- species can be functionalized by a silyl electrophile to generate (CPiPr3)Fe-N2SiR3. This species also functions as a modest catalyst for the reduction of N2 to NH3. Next, we introduce a new binucleating ligand scaffold that supports an Fe(\u03bc-SAr)Fe diiron subunit that coordinates dinitrogen (N2-Fe(\u03bc-SAr)Fe-N2) across at least three oxidation states (FeIIFeII, FeIIFeI, and FeIFeI). Despite the sulfur-rich coordination environment of iron in FeMoco, synthetic examples of transition metal model complexes that bind N2 and also feature sulfur donor ligands remain scarce; these complexes thus represent an unusual series of low-valent diiron complexes featuring thiolate and dinitrogen ligands. The (N2-Fe(\u03bc-SAr)Fe-N2) system undergoes reduction of the bound N2 to produce NH3 (~50% yield) and can efficiently catalyze the disproportionation of N2H4 to NH3 and N2. The present scaffold also supports dinitrogen binding concomitant with hydride as a co-ligand. Next, inspired by the importance of secondary-sphere interactions in many metalloenzymes, we present complexes of iron in two new ligand scaffolds ([SiPNMe3] and [SiPiPr2PNMe]) that incorporate hydrogen-bond acceptors (tertiary amines) which engage in interactions with nitrogenous substrates bound to the iron center (NH3 and N2H4). Cation binding is also facilitated in anionic Fe(0)-N2 complexes. While Fe-N2 complexes of a related ligand ([SiPiPr3]) lacking hydrogen-bond acceptors produce a substantial amount of ammonia when treated with acid and reductant, the presence of the pendant amines instead facilitates the formation of metal hydride species.
\r\n\r\nAdditionally, we present the development and mechanistic study of copper-mediated and copper-catalyzed photoinduced C-N bond forming reactions. Irradiation of a copper-amido complex, ((m-tol)3P)2Cu(carbazolide), in the presence of aryl halides furnishes N-phenylcarbazole under mild conditions. The mechanism likely proceeds via single-electron transfer from an excited state of the copper complex to the aryl halide, generating an aryl radical. An array of experimental data are consistent with a radical intermediate, including a cyclization/stereochemical investigation and a reactivity study, providing the first substantial experimental support for the viability of a radical pathway for Ullmann C-N bond formation. The copper complex can also be used as a precatalyst for Ullmann C-N couplings. We also disclose further study of catalytic Calkyl-N couplings using a CuI precatalyst, and discuss the likely role of [Cu(carbazolide)2]- and [Cu(carbazolide)3]- species as intermediates in these reactions.
\r\n \r\nFinally, we report a series of four-coordinate, pseudotetrahedral P3FeII-X complexes supported by tris(phosphine)borate ([PhBP3FeR]-) and phosphiniminato X-type ligands (-N=PR'3) that in combination tune the spin-crossover behavior of the system. Low-coordinate transition metal complexes such as these that undergo reversible spin-crossover remain rare, and the spin equilibria of these systems have been studied in detail by a suite of spectroscopic techniques.
\r\n", "doi": "10.7907/Z92V2D1M ", "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: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:8505", "collection": "thesis", "collection_id": "8505", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06082014-155448927", "primary_object_url": { "basename": "kelley_paul_2014_full_thesis_compiled.pdf", "content": "final", "filesize": 8722525, "license": "other", "mime_type": "application/pdf", "url": "/8505/119/kelley_paul_2014_full_thesis_compiled.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Fundamental Studies of Carbon Oxygen Bond Activation in Nickel Diphosphine Ether Complexes. And, Metallomacrocycles as Ligands: Synthesis and Characterization of Aluminum-Bridged Bisglyoximato Complexes of Iron and Cobalt", "author": [ { "family_name": "Kelley", "given_name": "Paul", "clpid": "Kelley-Paul" } ], "thesis_advisor": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-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": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "In order to develop better catalysts for the cleavage of aryl-X bonds fundamental studies of the mechanism and individual steps of the mechanism have been investigated in detail. As the described studies are difficult at best in catalytic systems, model systems are frequently used. To study aryl-oxygen bond activation, a terphenyl diphosphine scaffold containing an ether moiety in the central arene was designed. The first three chapters of this dissertation focus on the studies of the nickel complexes supported by this diphosphine backbone and the research efforts in regards to aryl-oxygen bond activation.
\r\n\r\nChapter 2 outlines the synthesis of a variety of diphosphine terphenyl ether ligand scaffolds. The metallation of these scaffolds with nickel is described. The reactivity of these nickel(0) systems is also outlined. The systems were found to typically undergo a reductive cleavage of the aryl oxygen bond. The mechanism was found to be a subsequent oxidative addition, \u03b2-H elimination, reductive elimination and (or) decarbonylation.
\r\n\r\nChapter 3 presents kinetic studies of the aryl oxygen bond in the systems outlined in Chapter 2. Using a series of nickel(0) diphosphine terphenyl ether complexes the kinetics of aryl oxygen bond activation was studied. The activation parameters of oxidative addition for the model systems were determined. Little variation was observed in the rate and activation parameters of oxidative addition with varying electronics in the model system. The cause of the lack of variation is due to the ground state and oxidative addition transition state being affected similarly. Attempts were made to extend this study to catalytic systems.
\r\n\r\nChapter 4 investigates aryl oxygen bond activation in the presence of additives. It was found that the addition of certain metal alkyls to the nickel(0) model system lead to an increase in the rate of aryl oxygen bond activation. The addition of excess Grignard reagent led to an order of magnitude increase in the rate of aryl oxygen bond activation. Similarly the addition of AlMe3 led to a three order of magnitude rate increase. Addition of AlMe3 at -80 \u00b0C led to the formation of an intermediate which was identified by NOESY correlations as a system in which the AlMe3 is coordinated to the ether moiety of the backbone. The rates and activation parameters of aryl oxygen bond activation in the presence of AlMe3 were investigated.
\r\n\r\nThe last two chapters involve the study of metalla-macrocycles as ligands. Chapter 5 details the synthesis of a variety of glyoxime backbones and diphenol precursors and their metallation with aluminum. The coordination chemistry of iron on the aluminum scaffolds was investigated. Varying the electronics of the aluminum macrocycle was found to affect the observed electrochemistry of the iron center.
\r\n\r\nChapter 6 extends the studies of chapter 5 to cobalt complexes. The synthesis of cobalt dialuminum glyoxime metal complexes is described. The electrochemistry of the cobalt complexes was investigated. The electrochemistry was compared to the observed electrochemistry of a zinc analog to identify the redox activity of the ligand. In the presence of acid the cobalt complexes were found to electrochemically reduce protons to dihydrogen. The electronics of the ancillary aluminum ligands were found to affect the potential of proton reduction in the cobalt complexes. These potentials were compared to other diglyoximate complexes.
\r\n", "doi": "10.7907/ZKZ0-TP24", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "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: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" } ]