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Making and Breaking C‒F Bonds via Palladium-Catalysis
No full textMaking and Breaking C‒F Bonds via Palladium-CatalysisByRichard ThornburyDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProfessor F. Dean Toste, ChairChapter 1 – A ligand controlled, palladium-catalyzed, enantioselective 1,3-arylfluorination of [2H]-chromenes was developed. The products were obtained in high enantioselectivity and with a syn- relationship of the introduced substituents. The pyranyl fluoride products were further derivatized to demonstrate the utility of the products. A ligand dependent divergent formation of 1,3- and 2,1- alkene difunctionalization products was also observed. This bifurcation in reactivity was investigated with a combination of experimental, computational, and statistical analysis tools. Ultimately, the site selectivity was found to be dependent on the ligand denticity and metal electrophilicity, the electronics of the boronic acid, and the donor ability of the directing group in the substrate.Chapter 2 – A palladium-catalyzed defluorinative coupling of 1-aryl-2,2-difluoroalkenes with boronic acids was developed. Broad functional tolerance arises from a redox-neutral process in which a palladium(II) active species which is proposed to undergo a β-fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (≥50:1) in all cases. As a demonstration of this method’s unique combination of reactivity and functional group tolerance, a Gleevec analogue, using a monofluorostilbene as an amide isostere, was synthesized in 4 steps from commercially available materials
Multidimensional Correlations in Asymmetric Catalysis through Parameterization of Uncatalyzed Transition States
No full textThe study of the oxidative amination of tetrahydroisoquinolines under chiral-anion phase-transfer (CAPT) catalysis by multidimensional correlation analysis (MCA) is revisited. The parameterization of the transition states (TSs) for the uncatalyzed reaction, the introduction of conformational descriptors, and the use of computed interaction energies and distances as parameters allowed access to a considerably simplified mathematical correlation of substrate and catalyst structure to enantioselectivity. The equation obtained is suggestive of key interactions occurring at the TS. Specifically, the CAPT catalyst is proposed to coordinate the intermediate iminium cation by P=O⋅⋅⋅H-O hydrogen-bonding and N⋅⋅⋅H-C electrostatic interactions. The conformational freedom of the benzyl substituent of the substrate was also found to be important in providing an efficient mode of molecular recognition
Flexible NO2-Functionalized N-Heterocyclic Carbene Monolayers on Au(111) Surface
No full textInvited for the cover of this issue are Elad Gross, F. Dean Toste, and co-workers at The Hebrew University and UC Berkeley. The image depicts the flexible anchoring geometry of addressable carbene molecules on Au surface, which upon exposure to reducing conditions changed their orientation from a standing into a flat-lying position. Read the full text of the article at 10.1002/chem.201903434
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The Development of Synthetic Supramolecular Hosts as Mechanistic Probes and Selective Catalysts
No full textAbstractThe Development of Synthetic Supramolecular Hosts as Mechanistic Probes and Selective CatalystsByMariko Morimoto
Doctor of Philosophy in Chemistry
University of California, Berkeley
Professor F. Dean Toste, Co-Chair
Professor Kenneth N. Raymond, Co-ChairChapter 1. An overview of various supramolecular hosts and their application as synthetic catalysts is presented. Particular emphasis is placed on more recent advances in the field, ranging from organic and organometallic reactivity, through site-selective modifications, to challenging photochemical reactivity enabled by these hosts. By introduction of the various modes of catalytic reactivity, the unique advantages of non-covalent, macromolecular catalysis as a synthetic tool and its powerful potential for practical applications are discussed. Chapter 2. The effects of host structural features on supramolecular catalysis are experimentally determined by employing a series of [M4L6]n- hosts as mechanistic probes. The synthesis of a novel supramolecular [Si4L6]8- host is first described, which serves as an isostructural analogue to [Ga4L6]12- Raymond tetrahedron differing only in overall charge. Through a number of parallel kinetic experiments, the specific role of host charge on the efficacy of microenvironment catalysis is quantitatively determined. Next, the syntheses of catalytically active [In4L6]12- and [Ge4L6]8- hosts are presented, and the effect of altering the metal vertices on host reactivity is elucidated. This work represents the first example of a thorough investigation that connects discrete structural components of a synthetic supramolecular catalyst to specific mechanisms of reactivity.
Chapter 3. Challenging oxidative addition reactions of iodoarenes across CuI and PdII organometallics facilitated by the [Ga4L6]12- Raymond tetrahedron under unusually mild, room temperature conditions are described. Atypical reactivity and selectivity are observed among regio-isomeric iodotoluene substrates, which demonstrate that the transformation is specific to strongly bound guests. Background reactivity in the absence of host is assessed by a series of control experiments with various solvents and additives, which result either in no observable reactivity or degradation of the starting material. This lack of observable background reactivity is indicative of a rare circumstance in which the host not only accelerates but alters the lowest energy reaction pathway of an organometallic reaction from that in bulk solution.
Chapter 4. A series of chemo- and site-selective reduction reactions mediated by the Raymond tetrahedron using a pyridine borane reductant are described. The host-catalyzed reaction demonstrates an unusually broad substrate scope for small molecule reduction, including ketones, enones, oximes, hydrazones, and imines. Furthermore, reactivity is maintained for partially encapsulated pendant carboxylate substrates, which enables high ε-selective reductive amination of lysine with a variety of halogenated benzaldehyde electrophiles. Inspired by the post-translational modification of complex biomolecules by enzymatic systems, this supramolecular reaction is then applied to the lysine-selective labeling of peptides and proteins
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Pursuing Selectivity: Data-Science Driven Reaction Development and Catalysis
No full textAbstractPursuing Selectivity:
Data-Science Driven Reaction Development and CatalysisByCaroline Rouget-Virbel Doctor of Philosophy in Chemistry
University of California, Berkeley
Professor F. Dean Toste, ChairThroughout my doctoral studies, I have endeavored to address the questions and challenges stemming from structure-activity relationships in catalysis. Mechanistic understanding is of central importance in the reaction development and the design of novel catalyst classes to ensure control over reactivity and selectivity. Physical organic chemistry methods and statistical analysis, in particular, guide the rational and strategic construction of specific interactions between substrates and catalysts to achieve the desired transformations. The work presented in the following chapters encompasses collaborative efforts with the University of Utah, and Genentech, Inc., towards the efficient design of catalytic and synthetic platforms. Chapter 1: The first chapter presented herein offers a brief overview of the historical development in organic synthesis and catalysis which have paved the way to the research work described thereafter. Some principles of selectivity in synthesis are explored, alongside with an introduction to physical organic tools such as linear-free energy relationships and statistical models. The principles delineated in this chapter are meant to provide a frame of reference for the discussion of rational catalyst design and reaction optimization outlined in the following chapters. Chapter 2: The design of efficient catalysts for organic reactions often relies on understanding the subtle relationship between structure and reactivity. Historically, this process has laid the foundation for the development of catalysts heavily biased towards more rigid and sterically-incumbered structures. Indeed, venturing outside of these steric repulsion models often complicates the generation of accurate predictions for a potential catalyst class to offer selectivity, due to the poorly understood nature of flexibility and its role in effecting attractive non-covalent interactions between catalysts and substrates. Herein, we disclose a novel class of flexible chiral phosphoric acid scaffold incorporating a single point of chirality. Data science techniques were first used to select a diverse training set of catalysts. Using a univariate classification algorithm and multivariate linear regression, key catalyst features necessary for high levels of selectivity were deconvoluted for the transfer hydrogenation of 8-aminoquinolines. The resulting model was found to accurately predict the selectivity of out-of-set catalysts. This workflow enabled extrapolation to a new catalyst providing higher selectivity than both peptide-type and BINOL-type catalysts (up to 95:5 er). These techniques were then successfully applied towards two additional transformations to illustrate the power of combining rational design with data science (ab initio) in the development of new catalysts. Chapter 3: Even though substituted pyrazoles have been shown to possess beneficial biological activity in a variety of medicinal chemistry fields, the challenges facing their efficient synthesis have hindered their widespread application in hit-to-lead pharmaceutical pipelines. The practical and regioselective introduction of substitution into pyrazole motifs remains elusive, especially with regards to nitrogen substitution with electronically or sterically neutral moieties. The work presented herein describes the optimization process for the regioselective cyclization of N-methyl pyrazoles. Hoping to move away from substrate-driven selectivity, the small size of the hydrazine partner, lack of significant electronic induction from either starting materials, as well as the high variability of selectivity on multiple reaction parameters presented a challenge for traditional optimization methods. We describe the iterative use of Bayesian statistics to obtain catalyst-free yet selective reaction conditions for the synthesis of 3-(4-fluorophenyl)-1-methyl-1H-pyrazole, as well as the progress made towards the selective synthesis of isomer 5-(4-fluorophenyl)-1-methyl-1H-pyrazol
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Expanding the Structural Scope of Supramolecular Assemblies and their Applications as Mechanistic Probes
No full textAbstract Expanding the Structural Scope of Supramolecular Assemblies and their Applications as Mechanistic Probes by Cynthia Marilyn Hong Doctor of Philosophy in Chemistry University of California, Berkeley Professor F. Dean Toste, Co-Chair Professor Kenneth N. Raymond, Co-Chair Professor Robert G. Bergman Chapter 1. A brief background and perspective is provided for the field of supramolecular chemistry. Justification for the continued expansion of the field as well as the work described in this dissertation are presented. Chapter 2. A new synthetic strategy for the rapid diversification of M4L6 host structures is described. The outlined approach consists of two components: the first is the late-stage functionalization of a ligand precursor to access structural variation while preserving favorable self-assembly properties, and the second is the post-synthetic modification of these functional groups after host assembly. Through this approach, new amine-, azide-, and carboxylatefunctionalized hosts are described with preliminary work and outlook for future applications. Chapter 3. A novel supramolecular mechanistic probe is introduced, which serves as an experimental platform for isolating and evaluating the role of host charge in supramolecular catalysis. The probe consists of two isostructural metal–ligand catalysts of M4L6 stoichiometry with a significant variation in overall anionic charge: 12- versus 8-. Together, they enable a unique experimental investigation that allows supramolecular structural features to be connected to specific mechanisms of reactivity. Though the importance of charge and electrostatic effects have been highlighted in enzymes and other supramolecular catalysts, this is the first example in which these effects have been experimentally defined in a synthetic microenvironment. Chapter 4. An unusual enzyme-like mechanism of host–guest binding is described in a new metal–ligand host of Ga4L4 stoichiometry. The introduction of a sufficiently large and tightly bound guest enforces a configurational isomerization in the host from an S4-symmetric conformation to a T-symmetric conformation with a proposed larger internal volume. Detailed mechanistic investigations reveal that this configurationally adaptive binding phenomenon proceeds via a conformational selection mechanism, a unique enzymatic mechanism that has never been definitively recapitulated in a synthetic system prior to this work. This comprehensive study shows that a simple chemical system can stand as a model for analogous behavior in biological systems that are often too challenging to experimentally deconvolute and speaks to the symbiotic relationship between the fields of enzymology and supramolecular chemistry
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Development of Gold-Catalyzed Oxidative Alkene Heteroarylation and of Enantioselective Reactions Enabled by Phase Separation
No full textAbstractDevelopment of Gold-Catalyzed Oxidative Alkene Heteroarylation and of Enantioselective Reactions Enabled by Phase SeparationbyAaron Daniel LacknerDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProf. F. Dean Toste, ChairAs with many bodies of research compiled through the course of a graduate career, this thesis reflects an uneven progression of aim based on the accumulation of unexpected results. Three main topics will be discussed in this thesis' chapters that may appear somewhat disparate. In particular, a significant conceptual gap exists between the first topic, oxidative gold catalysis, and the second topic, chiral anion phase-transfer catalysis. However, these fields are united by the realization that the characteristics of a reagent integral to the former might also be uniquely suitable for implementation in the latter. Chapter 1 discusses the development of a redox-active Au(I)-Au(III) catalytic system for the functionalization of alkenes. Based on early precedent, we hoped to show that the strong dicationic oxidant Selectfluor could generate a catalytically active cationic Au(III) center that enables reactivity that cannot be achieved through Au(I) catalysis, terminating in an arylation rather than protonation to return the catalyst. Methods for the intra- and intermolecular heteroarylation of alkenes were developed and experiments were performed suggesting an unusual reaction mechanism. Attempts to expand the types of transformations that could be accomplished under this mode of reactivity unexpectedly led us to consider instead the properties of Selectfluor and how it could be effectively employed as a reagent in enantioselective transformations.Chapter 2 addresses this very topic. The dicationic nature of the electrophilic fluorination reagent Selectfluor imparts on it many favorable qualities, but solubility in organic solvents is not one of them. Using a concept developed earlier within our laboratories, we hoped to show that this insolubility could be used to suppress racemic background reaction in enantioselective fluorination reactions, a class of transformation that remains largely underdeveloped in the literature. Lipophilic chiral phosphate anions, which can undergo anion exchange with the reagent salt, serve to solubilize the cationic fluorinating agent, rendering it both chiral and available for reaction with a suitable substrate. This mode of reactivity, chiral anion phase-transfer catalysis, was used to develop the enantioselective fluorocyclization of alkenes. Studies in the use of another type of cationic electrophile for the enantioselective oxidation of alcohols will also be discussed.An extension of the concept of phase-separation for suppression of unwanted reactivity was applied to the deracemization of chiral amines, which is presented in Chapter 3. Single-operation deracemization, in which a racemic substrate is dynamically resolved to its enantioenriched form, generally employs an oxidant to destroy a stereocenter and a reductant to reform it, as well as a chiral element to impart enantioselectivity on at least one of these steps. The highly reactive nature of oxidants and reductants towards one another has thus far precluded the development of such a deracemization by purely chemical means. We hypothesized that by separating the oxidant, substrate, and reductant into different phases, we could use a single catalyst to promote both the oxidation and subsequent enantioselective reduction of chiral substrates. This concept was used in the development of a deracemization protocol for 3H indolines and other chiral amine substrates
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Phase-Transfer Deracemization, Development of Reagents for Electrophilic Trifluoromethylation, and Hydrogen-Mediated Deoxydehydration
No full textAbstractPhase-Transfer Deracemization, Development of Reagents for Electrophilic Trifluoromethylation, and Hydrogen-Mediated DeoxydehydrationbyAndrew Vivek SamantDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProfessor F. Dean Toste, Chair As is often the case in the chemical sciences, the research presented here represents a path that followed naturally from one step to the next in the laboratory while ending up in seemingly disparate areas of focus at the end of each project. Chapter 1 describes the development of a purely chemical deracemization system. Typical asymmetric reactions fall into two categories: those where the starting material must be transformed into a new compound, and those where enantioenriched starting materials can be recovered in a maximum of 50% yield. Deracemization is an alternate strategy which can generate enantioenriched starting material in 100% maximum yield. The major challenge to implementing a successful chemical deracemization is that, on its own, solution-phase deracemization is always thermodynamically unfavorable. In order to circumvent this, we developed a system where the deracemization process could be chemically pumped by coupling it to the quenching of a strong oxidant and a strong reductant. In particular, we used a phase-transfer strategy to promote selective reaction of the substrate with both a cationic, water-soluble oxidant and a highly insoluble reductant, rather than having the oxidant and reductant react directly with one another. An interest in cationic reagents similar to the oxidant used to accomplish deracemization led (albeit quite indirectly) to the development of the reagents described in Chapter 2. Widely used iodine(III)-based electrophilic trifluoromethyling agents (e.g. Togni reagents) are typically neutral species, which require activation by a Lewis acid in order to trifluoromethylate nucleophiles such as alcohols and imidazoles. In contrast, we have developed a new class of trifluoromethyliodonium chlorides, which possess a high degree of cationic character and are capable of accomplishing these trifluoromethylations in the absence of an activator. Furthermore, we have demonstrated that these iodonium chlorides serve as good surrogates for reactive intermediates produced during acid-mediated trifluoromethylation. This equivalence has allowed us to gain a better understanding of these systems and has led to observations that could aid in the development of even more effective classes of reagent in the future. Chapter 3 describes a new and promising method for the conversion of biomass into commodity chemicals. Most modern commercial biomass conversion relates to the transformation of lipids (e.g. triglycerides) into chemically simple biofuels. Carbohydrate-based feedstocks, which include abundant natural resources such as glucose and cellulose, have the potential to be converted into more complex monomers and fine chemicals. In the course of our research, we developed a system capable of reducing sugar-derived compounds, such as glucaric acid and its derivates, directly to commercially relevant starting materials such as adipate esters using hydrogen gas as the reductant. This dual-catalytic system uses palladium on carbon to activate hydrogen gas and high-valent soluble rhenium catalysts to deoxygenate polyols. Additionally, we have investigated the unusual alpha,beta-selectivity that this deoxydhydration system provides, and used to selectively convert ribonolactone and gluconolactone into compounds which retain a high degree of chemical complexity but are less highly oxygenated than the starting materials
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Enantioselective Transformations of Carbon-Carbon Multiple Bonds Using Electrophilic Catalysts and Reagents
No full textThe activation of relatively unreactive carbon-carbon (C-C) multiple bonds is an important tool for the introduction of functional groups and stereochemical information in organic molecules. In recent years, the use of electrophilic cationic gold(I) complexes for the functionalization of alkynes and allenes has seen rapid development. An especially general application of gold catalysis is the nucleophilic trapping of gold-activated ð bond to give a heterocyclic compound. In the case of allenes, chiral ligands have been used to generate product with excellent enantiocontrol. In the first part of this Thesis we report studies on the development of an enantioselective cyclization using the gold-catalyzed transformation of propargyl esters to generate allenes in situ. A subsequent gold-catalyzed dynamic kinetic asymmetric cyclization of a phenol onto the allene resulted in the generation of enantioenriched cyclized chromanone derivatives from racemic starting material. The optimal catalyst for this transformation was a (biscarbene)digold(I) complex, which delivered better enantioselectivities than previously known phosphine-gold and phosphoramidite-gold complexes.Electrophilic sources of the halogens (fluorine, chlorine, bromine, and iodine) activate C-C multiple bonds in much the same way as gold(I) complexes, but the electrophilic atom of the reagent is incorporated into the final product. Because halogen atoms are amenable to further functional group manipulation and are also present in complex natural products, the enantioselective synthesis of halofunctionalized products from alkenes is an important synthetic goal. Typically, enantioselectivity is achieved using a chiral catalyst to activate the electrophilic reagent. However, high enantioselectivities may be hampered by uncatalyzed background reactivity. The Toste research group has introduced a new approach for electrophilic functionalization (chiral anion phase transfer catalysis) by inducing ion pairing between a phosphate anion chiral source and a cationic electrophilic reagent by phase transfer. This concept was initially demonstrated for fluorination, using the cationic reagent F-TEDA-BF4 (Selectfluor®). In the second part of the Thesis, we report studies on the extension of this strategy to the heavier halogens. With the successful development of bromination and iodination reagents suitable for chiral anion phase transfer, we applied these reagents to the synthesis of halogenated benzoxazines with high levels of enantioselectivity
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