John F. Hartwig - US grants

In three years at Yale Prof. Hartwig's group has developed a class of transition metal-catalyzed reactions that is fundamentally distinct from other metal-mediated processes. This proposal presents studies to extend the scope of this catalytic chemistry and to apply it to current synthetic problems. The reactions they have developed are palladium.catalyzed aminations of aryl halides. These reactions produce N-alkyl and N-aryl anilines by intermolecular amination or nitrogen-containing heterocycles from intramolecular amination in high yields and with high turnover numbers. Their published work has provided a thorough mechanistic understanding of palladium-catalyzed aminations. As a result of these studies, they have recently produced new reaction procedures, amide reagents, and palladium catalysts that significantly improve upon published methods. The research described in this proposal stems from these recent synthetic advances and includes the following specific aims. The general strategy for their proposed research is to develop the scope and essential mechanistic features of our recently developed systems for aryl halide amination including reactions with primary amines, heteroaromatics, aryl halides and aryl sulfonates. Concurrently, they will seek metal complexes that will catalyze the formation of aryl ethers from aryl halides and alkoxides. These methodological studies constitute the majority of this proposed work. Once the scope of these synthetic methods are developed to the stage of understanding the general strengths and limitations of the published and newly developed methods, however, they will use these reactions to construct isosteric analogs of isodityrosine-containing materials, to adapt these methods for their use in solid-phase reactions, and to evaluate their use in producing solid-supported libraries, including those of isodityrosine natural product analogs.

My group recently discovered a new class of C-C bond-forming reaction: the direct alpha-arylation of ketones catalyzed by palladium complexes. We have now extended this reaction to include the alpha-arylation of carboxylic acid derivatives such as amides and malonates, while finding remarkable catalysts that provide alpha-arylation of ketones at room temperature using aryl bromides and at only 70 C using aryl chlorides. Under NIH support my group would 1) study new alkylphosphine ligands for the catalytic process based on our hypothesis that sterically hindered, chelating alkyl phosphines accelerate reaction rates, 2) expand the scope of this new process to other types of carbonyl compounds, alkyl cyanides, and nitroalkanes and 3) develop a detailed, quantitative mechanistic understanding of the reactions comprising the catalytic cycle. More specifically, we will prepare alkylphosphine ligands containing large and small substituents at phosphorus and with backbones that provide large and small bite angles. These ligands will be used to further improve yields, rates, and substrate scope, while uncovering the features of our current ligands that provide such fast rates. These ligands will also be used in studies toward extending the scope of electrophiles to vinyl and heteroaromatic halides and sulfonates, and to nucleophilic partners such as the anions of alpha-diketones, alpha-siloxy ketones, alpha, beta-unsaturated ketones, beta-dicarbonyl compounds, esters, nitriles, nitroalkanes, and azlactones. A detailed mechanistic description of the catalytic chemistry based on firm quantitative data is an important goal of the proposed research. In general, we will conduct a careful study to determine how ligands steric and electronic properties affect each step of the catalytic cycle, including oxidative addition of aryl halide that is likely to be the rate determining step of the reaction, formation of an arylpalladium enolate complex from the resulting arylpalladium halide complex, and C-C bond-forming reductive elimination that is the crucial coupling step in the catalytic cycle. We have conducted the first direct observation of this type of reductive elimination. Beta-Hydrogen elimination from the palladium enolate complexes, which competes with reductive elimination, will be investigated to determine how this process can be prevented. Finally, we will begin a detailed mechanistic study of the initial asymmetric version of the ketone arylation process in conjunction with Buchwald's synthetic effort as a means for our two groups to create improved enantioselective catalysts.

Several efficient, transition metal-catalyzed routes to amines and ethers are presented in this proposal. Many amines and ethers are biologically active, and most of the best-selling drugs contain this type of functionality. During the past funding period, we uncovered several transition metal-catalyzed routes to amines and ethers. We developed palladium-catalyzed C-N and C-O coupling of aryl halides and we recently uncovered new metal-catalyzed hydroaminations. The amination of aryl halides and accompanying mechanistic information has already affected dramatically how drug discovery and process groups prepare arylamines. Our hydroaminations should influence the way they prepare alkylamines. In the next funding period, we will gain an understanding of how our new, most active catalysts work and we will determine the extent to which these catalysts improve the scope of C-N bond formation. In addition, we will seek an understanding of the mechanism of related C-O bond forming cross-couplings that use recently discovered catalysts. We will also outline rules that govern the scope and rates for palladium- catalyzed aromatic aminations with medicinally important heterocyclic substrates. In addition to aromatic C-N and C-O bond-forming processes, we will investigate our new hydroaminations of dienes and vinylarenes. Diene hydroaminations produce allylic amines, which are common synthetic intermediates. Vinylarene hydroaminations produce phenethylamines, which are part of drugs such as Sertraline. We will define the scope of these new processes, will investigate enantioselective hydroaminations and will obtain a detailed understanding of how the reactions occur. This information should enable us to design efficient hydroamination catalysts with broad substrate scope and to use mild reaction conditions for highly enantioselective hydroaminations.

DESCRIPTION (provided by applicant): Enolates are among the most common carbon nucleophiles, but reactions of these nucleophiles with aryl or vinyl electrophiles do not occur in the absence of catalyst. During the past grant period, we discovered and developed palladium complexes containing sterically hindered alkylphosphines that catalyze the coupling of several types of enolates with aryl halides in high yields with high turnover numbers. We propose to use as a launching pad for future studies recent preliminary data on new classes of enolate couplings and new classes of isolated palladium complexes. These studies will combine the development of synthetic methods with quantitative mechanistic experiments to create a conceptual framework that allows one to choose appropriate catalysts and predict reaction scope. Although arylations of ketones, esters, malonates and cyanoesters now occur efficiently with several types of aryl halides, the reactions of other common carbonyl compounds and nitriles are not yet efficient enough for widespread use in syntheses. Proposed studies will address these current limitations. We will develop methods to form quaternary amino acids directly from natural amino acids, use mechanistic data to improve amide and nitrile alpha-arylations, synthesize optically active, electron-rich phosphines for enantioselective couplings, and develop conditions for alpha-arylation of enolates in neutral media. Neutral media will tolerate a wider range of functional groups, increase selectivity for monoarylation, and create the potential to control enantioselectivity at enolizable stereocenters. Mechanistic studies will delineate the chemistry of reaction intermediates and the kinetic behavior of the overall catalytic cycle. We will study the formation and reactions of the first three-coordinate arylpalladium halide complexes, which are true intermediates in the coupling of enolates as well as other nucleophiles. We will study the reaction chemistry of arylpalladium complexes of functionalized alkyl groups to uncover, for the first time, the effect of alkyl group electronics on reductive elimination and will determine how the recently developed, highly active catalysts react with aryl chlorides and tosylates. Recent data suggests that the high activity of the catalyst is created, in part, by coordination of stoichiometric base, halide byproduct, or nucleophile to palladium(0) prior to reaction with aryl chloride or tosylate. Experiments on catalytic reactions and single turnovers are presented that will test this proposal in efficient catalytic systems.

DESCRIPTION (provided by applicant): This research program encompasses palladium-catalyzed amination and etherification of aryl halides and palladium-catalyzed hydroamination of olefins. Studies during the previous grant period led to some of the most active catalysts for the palladium-catalyzed amination and etherification, including three different catalysts sold or used commercially. In unpublished work, we have isolated the true amido and alkoxo intermediates in reactions with the most active catalysts and have gained initial results that suggest a solution to the amination and etherification of heteroaromatic substrates, which typically poison or retard the activity of the most active palladium catalysts for aryl amination. We have also found palladium catalysts for the hydroamination of dienes and vinylarenes with both aromatic and aliphatic amines and have found conditions for highly enantioselective hydroamination of dienes. We have uncovered the mechanism for palladium-catalyzed hydroamination and have isolated the intermediate that reacts with amine to form the hydroamination product. Most recently, we discovered the first hydroamination of olefins catalyzed by ruthenium complexes, and the scope of the proposed research will expand to include these new catalysts for hydroamination. This application requests renewed support for studies of recently developed catalysts for each of these reactions. We will investigate the mechanisms of catalytic amination and etherification of aryl chlorides and tosylates. These investigations will include studies to reveal the chemistry of new three-coordinate amido and alkoxo complexes and studies to unravel the complex kinetic behavior that results from a dependence of the reaction rate on the concentration of base and halogen. In addition, we will investigate reactions with ligands based on a chelating structure with hindered dialkylphosphino substituents that will increase the scope of the couplings and should increase the lifetimes of the catalysts. The structure of this ligand generates palladium complexes that undergo fast oxidative addition but resist displacement by amines or basic heterocycles. In addition, we will investigate the scope and mechanism of the hydroamination reactions we have discovered. We will investigate the effects of varying ligand structure on the rates and selectivities of the palladium-catalyzed hydroamination of vinylarenes and will delineate the basic steps of the ruthenium-catalyzed reactions. With recently identified palladium catalysts that display higher activities than those of the original systems, we will investigate the functional group tolerance of the reactions catalyzed by these complexes. In addition, we will strive to develop conditions to add other nitrogen substrates to vinylarenes and to add amines to more substituted vinylarenes and simple alkenes.

[unreadable] DESCRIPTION (provided by applicant): My group discovered the direct a-arylation of ketones concurrently with two other groups and has contributed significantly in recent years to the development the a-arylation of many types of carbonyl compounds and nitriles into practical synthetic methods. The relevance of this chemistry to human health has been demonstrated by its use multiple times by process chemists in the past few years to produce clinical candidates on a multi-kilo scale and by its use countless times by medicinal chemists to produce compounds for SAR studies. Further, this chemistry has been used by the academic community to prepare biologically active natural products, and our papers on this topic have been cited hundreds of times. During the past grant period we developed general, coupling reactions of weakly basic zinc and silicon enolates and, sparked by a mechanistic insight, we recently developed highly enantioselective couplings of ketone enolates. These are rare, but important, examples of enantioselective processes that form quaternary stereocenters. We also extended our studies on metal-catalyzed substitutions of enolate nucleophiles during the past grant period to an iridium-catalyzed, enantioselective allylation of silyl enol ethers. The iridium- catalyzed reaction is unusual because it creates a new stereocenter at the allyl electrophile and does so with high enantioselectivity. Our mechanistic studies led us to develop the first reductive eliminations of arylpalladium enolate compounds and to use these compounds to reveal the origins of electronic effects on C-C bond forming reductive eliminations. We also showed that aryl chlorides, bromides and iodides can undergo oxidative addition to the same metal by three different mechanisms. We propose during the next grant period to develop new classes of enolate couplings, including the coupling of aldehydes, aldehyde and ketone surrogates, a,(3-unsaturated carbonyl compounds, and new classes of esters. Based on our recent highly enantioselective couplings of aryl triflates, we propose to develop enantioselective couplings of enolates to form quaternary stereogenic centers and to use weakly basic Zn and Si enolates to conduct enantioselective couplings to form tertiary stereocenters. The rate- limiting step of the catalytic processes is transmetalation of the enolate or oxidative addition of the haloarene to Pd(0). Because little is known about the mechanism of transmetalation and the mechanism of oxidative addition in the presence of halides remains ambiguous, we propose to study the mechanism of a series of transmetalations and to test a new mechanism proposed for oxidative addition in the presence of halides. Finally, we propose to expand the scope of the iridium-catalyzed allylations by conducting reactions with main group enolates and activators we developed for the palladium coupling. We also plan to study the allylation processes using new classes of ligands that are isoelectronic with those in the active catalyst. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This research program aims to develop catalytic synthetic methods that form amines, ethers and sulfides and to obtain precise mechanistic information for the design of new catalysts and for deducing relationships between emerging catalytic processes that form C-N, C-O and C-S bonds and related catalytic processes that form C-C or C-H bonds. The proposed research focuses on several synthetic methods that have become widely utilized and that have inspired other groups to develop related chemistry. Each of the specific aims of this proposal focuses on developing a firm mechanistic platform from which we will build new catalysts and reaction processes. One portion of the proposed research will focus on the development of a new generation of palladium catalysts for the coupling of amines with aryl halides using data on the factors that control catalyst initiation, the rates of individual steps of the catalytic cycle, and equilibria that control selectivity. A second portion of the proposal will establish a mechanistic understanding of copper-catalyzed couplings of aryl halides with nitrogen and oxygen nucleophiles and the use of this information as inspiration to develop catalysts for the formation of aryl carbon-heteroatom bonds using other metals. A third portion of the proposed research will focus on a recently discovered type of rhodium catalyst that promises to significantly increase the scope of alkene hydroaminations. These studies will use recent structural data to understand the mechanism of this process and to design new catalysts. A fourth portion of the research will focus on enantioselective methods to prepare allylic amines and ethers. Again, recent structural data will be used to understand the mechanism of the reaction and to design catalysts that react with classes of reagents that have not been encompassed by this process previously. Thus, the proposed research will significantly advance reactions with organometallic catalysts to form the carbon-heteroatom bonds in pharmaceutically important materials, while demonstrating approaches to use mechanistic data in the design and development of new organometallic catalysts that increase the efficiency, diversity and capability of organic synthesis. PUBLIC HEALTH RELEVANCE: Some of the catalysts that have resulted from this project dramatically improve methods to prepare pharmaceutical intermediates and new catalysts that will result from the proposed research promise to be equally important for the synthesis of these and other biologically active materials. Thus, successful development of the proposed research will significantly increase the accessibility of compounds that improve human health.

This research award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports work by Professor John F. Hartwig at the University of Illinois at Urbana-Champaign to develop reactions at typically unreactive C-H bonds. This work will create new methods to prepare organic molecules by selective chemical transformations at positions that are inert to most reagents. Complexes containing bonds between transition metals and boron catalyze these reactions, and this grant will reveal the properties of the transition metal that lead to this unusual reactivity. The reactions catalyzed by these complexes have been and will continue to be applied to the synthesis of polymers containing new properties, organic molecules with enhanced abilities to emit light, components of catalysts for other reactions, and organic probes for understanding biological systems. Work emanating from the proposed research is part of new curricula for the classroom, short-courses, many external lectures, and a major textbook project that will be completed in the next grant period by the PI.

This research will lead to new methods to conduct chemical synthesis in fewer steps, with less waste, and with less reliance on the installation and protection of functional groups. In addition, this research creates the underlying principles on which future design of catalysts and processes for more efficient synthesis are based. Studies to define how the electronic properties of the metal and how electrophilic or nucleophilic properties of the reactive ligand affect C-H bond cleavage and functionalization will create these principles.

DESCRIPTION (provided by applicant): Cross-couplings to form carbon-carbon bonds are some of the most utilized reactions for the synthesis of molecules that improve human health. They constitute nearly a quarter of all carbon-carbon bond-forming reactions practiced by process chemists in the pharmaceutical industry. Our long-term objective for this NIH program is to create new transition metal-catalyzed coupling reactions that form the types of carbon-carbon bonds in molecules with medicinal activity. We seek to do so while gaining a quantitative and precise understanding of the mechanisms of these reactions to create a platform for further reaction discovery and to create a framework within which to rationally apply these classes of reactions to synthetic problems. To meet these objectives, we will seek to uncover new transformations with catalysts we discovered previously, to reveal new catalysts that turn notoriously capricious reactions into reliable methods, and to gain precise information about the individual steps of these catalytic processes to build a connection between the structure and properties of the catalytic intermediates and the rates and selectivities of the overall reaction. Our goals for the next grant period are based on published and unpublished findings on 1) new classes of coupling reactions of enolates we discovered that are becoming commonly practiced, 2) new classes of complexes we discovered that mediate the coupling of aryl, vinyl, and allyl electrophiles with enolates, cyanide, trifluoromethyl anions, and main group organometallic reagents with control of absolute stereochemistry in many cases, and 3) new mechanistic information we recently discovered that mandates a reassessment the identity and reactivity of previously proposed intermediates in these and additional commonly practiced coupling and C-H bond functionalization reactions. To achieve these short-term goals we will develop 1) palladium-catalyzed reactions of aryl halides with enolates that currently do not undergo coupling in high yields with broad scope, 2) copper-catalyzed reactions of aryl halides with enolates and sources of trifluoromethyl anions that complement palladium-catalyzed chemistry (and that reduce catalyst cost), 3) palladium-catalyzed coupling reactions, such as the cyanation of aryl halides and carbonylative couplings, that are important for the synthesis of medicinally active compounds but are currently poorly developed or unreliable, 4) coupling of aryl halides with arenes catalyzed by ligandless palladium systems derived from our mechanistic studies, and 5) enantioselective or stereoretentive palladium- and iridium-catalyzed reactions of enolates or hard nucleophiles that form products containing stereogenic quaternary carbons. All of these reactions occur with common nucleophiles and ubiquitous aryl or vinyl halide electrophiles. It is the ability to use these reactions of common reagents for the direct synthesis of key intermediates and pharmacophores from a single, readily available synthetic or commercial intermediate that causes drug candidates to contain the types of carbon-carbon bonds formed by the chemistry of this proposal.

? DESCRIPTION (provided by applicant): Methods for the catalytic functionalization of C-H bonds are widely considered to possess the potential to revolutionize the synthesis of complex molecules, but the realization of this potential requires the selective functionalization of a singe C-H bond in compounds containing many other C-H bonds and functional groups that are typically more reactive than the C-H bond. The PI is developing an unusual strategy for the functionalization of C-H bonds involving the reactions of boranes and, more recently, of silanes with aryl, heteroaryl, and alkyl C-H bonds. The products from these reactions are valuable synthetic intermediates that can be converted to diverse final products containing new C-C, C-N, C-O, and C-S bonds. The fundamental innovation underlying the C-H bond functionalization in this proposal is the higher reactivity of complexes containing covalent transition metal-main group bonds toward C-H bond functionalization than those containing typical organometallic ligands. During the past several years, the PI's group has discovered a new class of catalyst for the silylation of aryl C-H bonds; silylmetal complexes that are catalytically competent and react with arenes to form arylsilanes; iridium-catalyzed borylations of aliphatic C-H bonds of cyclopropanes, amines and cyclic ethers; borylations of secondary alkyl and benzyl C-H bonds directed by alcohols and amines; a catalyst for broadly applicable borylations of heteroarenes; and one-pot combinations of borylation and subsequent functionalization to create sterically controlled functionalizations of arenes, alkylations of arenes, and mild access to unstable arylboronate intermediates. The proposed research will build upon these studies and additional preliminary data. The PI's group will prepare new ligand structures that enable metal-catalyzed borylations of primary C-H bonds with limiting substrate, increase the reactivity of the catalysts toward basic heteroarenes, and create practical methods for the silylation of functionalized arenes. In addition, they will use these catalysts to achieve directed borylations and silylations of alkyl C-H bonds and methods for the generation and characterization of intermediates in the iridium-catalyzed borylations and silylations. To achieve these goals, seven major aims are proposed: 1) to design new ligands for the borylation and silylation of aryl and alkyl C-H bonds by iridium and rhodium catalysts; 2) To discover new borylations of aliphatic C-H bonds enabled by the ligands of Aim 1; 3) To gain a mechanistic understanding of the relationships between iridium catalyst structure and activity for C-H borylation; 4) To broaden the scope of directed silylations of aliphatic C-H Bonds; 5) To create intermolecular silylations of aromatic C-H bonds that occur with remote steric effects and high functional group compatibility; 6) To reveal the mechanism of these intermolecular silylations of arenes, and 7) To develop new functionalizations of the main group products of the C-H bond functionalizations.

The Chemical Catalysis Program of the Chemistry Division supports the project by Professor John F. Hartwig in the Department of Chemistry at the University of California, Berkeley. In this program, Professor Hartwig is developing a mechanistic understanding of catalytic reactions that use transition metal complexes bonded to fluorine-containing alkyl groups. These studies answer a series of questions about the impact of fluorine atoms on the metal-bound carbon atom. The studies also assess several approaches to control the reactivity of these fluoroalkyl complexes of transition metals. By developing methods to control the reactivity of fluoroalkyl complexes, this research enables the development of new catalytic reactions that add fluoroalkyl groups into organic molecules. Organic molecules containing fluorine are vital to materials, agricultural, and medicinal sciences. For example, over 20% of new pharmaceuticals and 25% of licensed herbicides contain fluorine. The project is well suited for providing a broad education to Ph.D. scientists and undergraduates, including those of underrepresented groups. A series of outreach activities for K-12 students, the general public, and the general scientific community are part of Professor Hartwig's efforts resulting from the research program.

Although a large fraction of pharmaceuticals and agrochemicals contain fluorine, fluorinated structures are largely limited to those derived from simple fluoroarenes, trifluoromethylarenes or trifluoroacetates. Many of the potential methods to synthesize more diverse structures containing fluoroalkyl groups require new approaches to induce and control the reactivity of fluoroalkyl transition-metal complexes in catalytic reactions. This research creates these capabilities by demonstrating, by a combination of kinetic analysis of catalytic reactions and synthesis of catalytic intermediates, how to induce productive reactivity in fluoroalkyl complexes of palladium. This project also creates new catalytic reactions that couple partially fluorinated alkyl groups to aromatic and heteroaromatic molecules to form products that are difficult to access by current synthetic methods. With this information, fluoroalkylation reactions that are currently stoichiometric are being made catalytic. Additionally, new reactions of aryl halides that form fluoroalkylarenes with novel structures that are difficult to prepare by alternative methods are being created. This research enables the preparation of new classes of fluorinated molecules for materials science, medicinal chemistry, and agroscience. As part of the educational plan, Professor Hartwig teaches short-courses for those lacking formal training in organometallic catalysis, co-authors a sophomore organic text that includes content on catalysis in medicinal and green organic chemistry, and delivers lectures to general audiences, predominantly in forums in which he reaches potential scientists from underrepresented groups.

ABSTRACT The College of Chemistry at the University of California, Berkeley requests funds to acquire a CryoProbeTM Prodigy and related accessories for the 600 MHz Bruker Nuclear Magnetic Resonance (NMR) spectrometer located in the Department of Chemistry. The requested instrument will be integrated into the College of Chemistry NMR Core facility (CoC-NMR) to serve the current and future analytical needs of a large number of NIH-funded researchers. The goal of this proposal is to expand access to more advanced NMR instrumentation for experimental scientists at UC Berkeley and transform their ability to study chemistries and related biological activities. The requested instrument has superior sensitivity for NMR experiments, specifically for NMR of broad-band nuclei, compared to the best existing equipment available at the CoC-NMR. Many of our researchers work on health related problems that involve analytical determination of molecular identity, structure and reaction dynamics for the development of small molecule therapeutics, and design of chemical methods that facilitate new means to produce therapeutics effectively, or to synthesize them from existing natural compounds more cost effectively. For this purpose, experimental scientists utilize a wide range of NMR methods and they have an immediate and critical need, specifically for directly-observed X-nuclei, to perform routine NMR experimentation of low sensitivity broad-band nuclei for sample- and time-limited studies. Thus, superior sensitivity of the requested cryo-probe will allow researchers to utilize 13C NMR spectroscopy to routinely monitor their reactions to guide their experimental design, including multi-step reactions where samples for intermediate products are available only in small quantities of approximately 1-5 mg. Furthermore, the new instrument will allow the study of complex organometallic systems by their naturally occurring NMR- active nuclei, such as 31P, 15N, 29Si or 13C at meaningful concentration levels. This will be crucial for identification of active catalysts and catalyst decomposition products, and monitoring complexes in the catalyst reservoir, all of which are inherently at low concentrations. Moreover, researchers will be capable of monitoring reaction kinetics or equilibria, especially for slowly relaxing signals of broad-band nuclei, such as 31P or 29Si, at elevated temperatures, which is critical for determination of reaction activation barriers. The requested instrument will address the immediate and future needs of a broad community of NIH-supported research groups who are engaged in health driven molecular science. CryoProbeTM Prodigy will be operated, maintained and supported by the CoC-NMR and will fulfill important roles in the long-term biomedical research goals of the College of Chemistry, the facility users, and UC Berkeley.

Project Summary: Discovery and Development of Organic Reactions Catalyzed by Transition-Metal Complexes Valuable for Medicinal Chemistry The proposed research focuses on the discovery, development, and mechanistic evaluation of a series of chemical reactions catalyzed by transition-metal complexes that provide new approaches to the synthesis of organic molecules that are important for human health. Research on these reactions addresses several of the major unmet needs in chemical synthesis: 1) the need for reactions that occur at C-H bonds with high selectivities and high tolerance for auxiliary functional groups; 2) the need for reactions that occur with catalyst-controlled site selectivity for one of many similar functional groups; 3) the need to functionalize complex molecules directly to modulate the structures and properties of biologically active compounds; 4) the need to assemble aliphatic sub-structures with control of the absolute and relative configurations of stereogenic centers to create more complex three-dimensional architectures; and 5) the need for greater mechanistic understanding of catalytic methods to help select or invent catalysts and reagents that achieve these synthetic goals. The types of reactions proposed for study include some of the most widely used catalytic reactions during the drug-discovery process. For example, these reactions include selective functionalizations of C-H bonds to form main group compounds that have become common synthetic intermediates. The proposed research further includes C-H bond functionalizations that form organic azides and halides that can serve as intermediates or biogically important final products. The proposed research also encompasses reactions occuring in aliphatic structures by addition and substitution reactions, including the addition of N-H bonds across unactivated alkenes with unprecedented efficiency, coupling processes forming carbon-heteroatom bonds with organic electrophiles that have rarely coupled with heteroatom nucleophiles, and coupling processes forming carbon-heteroatom and carbon-carbon bonds with unique control over the combination of regioselectivity, enantioselectivity, and diastereoselectivity. New small-molecule catalysts also will be studied that reverse the typical site selectivity observed for oxidation of alcohols, allowing modification of complex natural products, such as polyols. Finally, the proposed research includes reactions catalyzed by a new class of hybrid system generated by formally exchanging the metal of natural metalloenzymes with a platinum-group metal. These artificial metalloenzymes can form products with site-selectivity and stereoselectivity that are difficult or impossible to achieve with natural enzymes or small-molecule catalysts. In all cases, the proposed research includes detailed mechanistic analysis by kinetic stuides and independent synthesis of catalytic intermediates, as well as the use of these mechanistic data to select or design next-generation systems.

Microbes can make organic molecules with complex structures. Many of these molecules or their analogs are central ingredients in a variety of products, but the diversity of these molecules is limited by the range of the reactions catalyzed by natural enzymes. Engineering cells to produce artificial metalloenzymes (AMEs) will expand the range of possible reactions. Novel biosynthetic pathways will be created by complementing natural enzymes with AMEs. Graduate students and postdoctoral associates will be trained in this convergent field of synthetic chemistry and synthetic biology. Outreach activities to encompass topics related to artificial biosynthesis will be offered to underserved high school students and teachers, as well as to K-8 students.


This project will build upon the general concept of creating artificial biosynthetic pathways containing artificial metalloenzymes and preliminary results showing the feasibility of creating these pathways in bacteria. We will increase the numbers and types of microorganisms that can host the chemistry catalyzed by artificial metalloenzymes to expand the range of natural products that react with AMEs; expand the types of metallo-cofactors that are incorporated intracellularly into AMEs to increase the scope of unnatural reactions in these pathways; and combine the abiotic chemistry with natural biosynthesis in varying sequences. Specifically, we will 1) introduce AMEs into Streptomyces strains and test activity on heterologously produced terpenes and polyketides; 2) incorporate new cofactors into AMEs expressed in E. coli and Streptomyces; 3) broaden the scope of transformations catalyzed by AMEs in the artificial biosynthetic pathways to encompass abiotic C-H bond functionalizations; 4) create pathways in which the unnatural chemistry occurs in the middle of the artificial biosynthesis; and 5) elucidate the pathways for diazo-containing small molecules. By doing so, we will generate the fundamental knowledge and demonstrate guiding principles to create artificial biosynthetic pathways that convert simple carbon sources to valuable unnatural products in whole microorganisms.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.