John Montgomery - US grants

DESCRIPTION (provided by applicant): Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. While advances in complex molecule synthesis have illustrated that a remarkable range of structures can be prepared, the underlying difficulties of potential synthetic approaches often prevent interesting chemical structures from being selected for study. The underlying objective of this proposal is to provide fundamentally new entries to (i) simple chemical substructures that serve as subunits or precursors of many bioactive natural products and other complex structures, and (ii) complex carbohydrate- containing structures of the type that are well known to modulate the bioactivity of chemical entities, but that are often exceptionally challenging to prepare efficiently by existing methods. The first specific aim focuses on developing a mechanistically-driven approach for discovery of highly regioselective and enantioselective reductive coupling procedures. The expected impact of solving challenges in the regio- and enantioselective reductive union of aldehydes and alkynes will be the creation of a process that becomes widely adopted by synthetic chemists. This outcome will be broadly significant since allylic alcohols are an integral feature in many bioactive compounds and serve as versatile building blocks for a wide range of complexity-building and diastereoselective or enantioselective transformations. Furthermore, developing a fundamental understanding of the origin of regiocontrol in the catalytic operation will facilitate related advances in many other reactions that require regioselectivity in a catalytic insertion process. The second specific aim focuses on development of a suite of orthogonal catalytic processes for chemoselective glycosylation of complex molecules. The expected impact of our efforts to develop chemical methods for site-selective glycosylation will be that the speed, efficiency, and selectivity with which complex glycosylated structures may be obtained will be significantly improved. This outcome will allow the rapid preparation of either a specific target molecule or small collections of unnatural or natural product-derived glycosylated structures to examine as medicinal chemistry leads or probe molecules for biochemical studies. The approach represents a merger of two distinct fields: catalytic reductive coupling technology and carbohydrate chemistry, which have not previously been examined synergistically. This unique perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.

The Synthetic Organic Program is awarding a grant to John Montgomery at the Department of Chemistry, Wayne State University. This grant will continue his research into asymmetric nickel-catalyzed cyclizations. Mechanistic studies and the development of new catalytic, enantioselective processes will be pursued. The preparation of a number of (poly)cycles to illustrate the utility of the methodology will be carried out.

Professor Montgomery's research provides an excellent training ground for students in organic and organometallic chemistry. These students then enter the pharmaceutical and chemical workforce, as well as academia. This research into nickel-catalyzed cyclizations to form new cyclic compounds is most likely to find applications in the preparation of pharmaceutical agents.

With support from the Chemistry Research Instrumentation and Facilities (CRIF) Program, the Department of Chemistry at Wayne State University will purchase a Mass Spectrometer. This equipment will enhance research in a number of areas including 1) the development of new nickel-catalyzed reactions and the total synthesis of complex natural products; 2) the development of new metathesis-based approaches to C-glycosides; 3) the total synthesis of pharmacologically active natural products; 4) synthesis of complex carbohydrates and natural products; 5) synthesis of natural products through biosynthetic pathway engineering; and 6) the design and synthesis of enzyme and receptor inhibitors.

Mass spectrometry (MS) is a technique used to probe intimate structural details and to obtain the molecular compositions of a vast array of organic, bioorganic, and organometallic molecules. It is one of the fastest growing and most widely used analytical instrumentation techniques. Because of this, it is important for undergraduate and graduate students to be exposed to the technique. Graduate students, undergraduate summer and postdocs will use this instrument for their research.

The focus of this research involves four goals: First, to develop catalytic processes that involve the alkylation of nickel enolates within a metallacycle framework. Second, to develop total synthesis applications of [3+2] alkylative cycloaddition of enals and alkynes. Third, to develop conjugate addition procedures that do not require preformed organometallic nucleophiles. Fourth, to study the role of organozincs and related species in accelerating the rate of nickel-catalyzed processes.

With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. John Montgomery in the Department of Chemistry at Wayne State University. Professor Montgomery will focus his work on development of new processes that involve the generation and functionalization of nickel enolates. The research will advance the fields of nickel catalysis, conjugate addition chemistry and transition metal enolate chemistry in general. The project has potential for broader impact in the pharmaceutical industry and the project serves as an excellent training ground for undergraduates, graduate students and postdoctorals. The inclusion of underrepresented minorities to the project will be stressed.

The general goal of this proposal is to develop new cycloaddition technologies for preparing five-membered rings. The types of simple feedstocks such as alkenes, alkynes, and dienes that are so powerful in Diels Alder reactions and other widely used cycloaddition methods typically cannot directly combine to allow assembly of odd-numbered rings. This proposal aims to develop several solutions to this existing limitation of currently available transformations. The first goal involves developing a new strategy that allows two simple even-numbered pi-systems to combine in a catalytic cycloaddition to generate a five-membered ring product while the starting materials undergo a net two-electron reduction. Secondly, simple cyclopropyl ketones and imines will be used in ring-opening cycloadditions that install a three-carbon unit from the cyclopropane into a five-membered ring product. Finally, two new reactions will be developed that involve cycloaddition of two simple two-atom pi-systems with a one carbon unit or one-silicon unit to prepare carbocyclic or silacyclic five-membered rings. In addition to new cycloaddition approaches, the proposal will also develop a novel reductive coupling procedure of alkynes and electron deficient alkenes in order to address challenges and limitations of currently available conjugate addition procedures.

With this award, the Organic and Macromolecular Chemistry Program is renewing support for the work of Professor John Montgomery, of the Department of Chemistry at the University of Michigan. While powerful methods have been developed for the synthesis of molecules containing six-membered rings, general approaches for the synthesis of five-membered rings have lagged behind. Professor Montgomery and his students are discovering fundamentally new cycloaddition processes affording access to these smaller-sized rings, which are ubiquitous in compounds displaying biological or pharmacological activity, as well as in numerous compounds of interest in a variety of other disciplines, including materials science and molecular electronics. Professor Montgomery will also be involved in a study of the feasibility of a major multi-institution program designed to attract and mentor students from under-represented groups.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

With this award from the Chemistry Research Instrumentation and Facilities Multiuser Program (CRIF:MU), Professor Carol A. Fierke from the University of Michigan and colleagues Adam J. Matzger, John Montgomery, Vincent L. Pecoraro and Melanie S. Sanford will acquire a single crystal X-ray diffractometer with a strong copper source to obtain high-resolution structural information in diverse fields including synthetic organic chemistry, materials science and inorganic chemistry. This instrument will support education and research in complexes from metallacrowns producing soft materials; determination of absolute and relative stereochemistry of molecules important in catalytic reactions; in synthesis and characterization of biological properties of fluorinated proteins; in mechanistic studies of late metal complexes with high oxidation states; and in metal-organic frameworks.

An X-ray diffractometer allows accurate and precise measurements of the full three dimensional structure of a molecule, including bond distances and angles, and provides accurate information about the spatial arrangement of a molecule relative to neighboring molecules. The studies described here will impact a number of areas, including chemistry, materials chemistry and biochemistry. This instrument will be an integral part of teaching as well as research.

DESCRIPTION (provided by applicant): Purchase of a 700MHz NMR Spectrometer for Liquid Applications Project Summary Solution nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful spectroscopic tools available to the synthetic chemist for the elucidation of the structure of a molecule. Advances in computing power, high-field magnet technology, and improved electronics have dramatically increased both sensitivity and chemical shift dispersion such that detection of low natural abundance nuclei is now routine. Presently in the Chemistry department at the University of Michigan (UM, Ann Arbor) there is a rapidly growing gap between the existing capabilities offered by our aging/obsolete NMR spectrometers and the demands of our NIH-funded investigators. This demand stems from the fact that not only have the molecular systems under investigation grown in size and complexity, the questions being addressed by NMR are also more ambitious and include atomic characterization of molecular configuration, conformation, dynamics, interactions and mechanisms. The availability of a high field, multi-channel NMR spectrometer dedicated to liquid applications will have a significant impact on the investigation of complex natural products bearing multiple stereocenters, determination of relative stereochemistry of 5-membered carbocyclic ring systems such as cyclopentanes, tetrahydrofurans, and pyrrolidines possessing up to 4 stereocenters, characterization of unstable organoboron and organosilicon intermediates, and time-resolved kinetic studies of reactive organometallic intermediates formed in low concentrations. High-resolution structural information will be highly valuable in designing small molecule isoxazolidine transcriptional activators, as well as probing how enzymes use free radicals to catalyze chemically difficult transformations. Progress in these research projects and the training of chemistry students in cutting-edge NMR techniques are hampered due to the lack of an accessible modern high field NMR spectrometer. Therefore, to close this gap, we propose the purchase of a multi-channel 700 MHz NMR spectrometer outfitted with the latest in cryogenically cooled, triple resonance probe technology. Additionally, access to such a state-of-the-art instrument will be made available to NIH-funded chemistry projects at nearby institutions such as the University of Toledo, where significant benefit would be realized in the area of complex carbohydrate synthesis. PUBLIC HEALTH RELEVANCE The NIH-funded projects described herein will contribute to a greater understanding of areas that impact human health. Advances enabled by the requested instrumentation include the discovery of potential drug leads, the understanding of biological processes involved in disease progression or prevention, and the development of new strategies in synthesis that enable creative solutions to research projects of this type.

The general goal of this project is to develop new strategies for the discovery and implementation of transition metal-catalyzed couplings and cycloadditions. The focus will be the development of new approaches for transition metal catalyzed processes that proceed by either net two-electron reduction, or by redox-mediated pathways. While many classes of reductive coupling processes have been developed in recent years, this project aims to develop processes that complement existing methods while improving practicality, cost, and green considerations.

With this award, the Chemical Synthesis Program is supporting the research of Professor John Montgomery of the Department of Chemistry at the University of Michigan. Professor Montgomery's research efforts revolve around the discovery of new transition metal-catalyzed chemical transformations, the study of their mechanisms, and their application in the synthesis of complex molecules. The research being studied in this program seeks to provide efficient and environmentally friendly synthetic procedures that allow the rapid synthesis of complex structures from simple precursors. Successes in these areas stand to benefit a variety of important research areas, especially in the pharmaceutical, biotechnology, and agricultural industries.

DESCRIPTION (provided by applicant): The University of Michigan proposes to continue a predoctoral Chemistry-Biology Interface (CBI) Training Program for a selected group of Ph.D. students. The number of students requested for this new training program is 10 for a five-year period of support. The participating units are the Department of Chemistry and the Department of Biophysics from the College of Literature, Science, and the Arts; the Department of Biological Chemistry, the Department of Pharmacology, and the Department of Pathology from the Medical School; the Department of Medicinal Chemistry from the College of Pharmacy; the Program in Chemical Biology, and the Life Sciences Institute. The faculty of the CBI Training Program includes synthetic organic and inorganic chemists, bioorganic chemists, bioanalytical chemists, protein chemists, mechanistic enzymologists, spectroscopists, and crystallographers. The Ph.D. degrees will be awarded in Chemistry, Biophysics, Biological Chemistry, Chemical Biology, Pharmacology, Medicinal Chemistry, and Pathology. Students will be appointed to the training program for two years beginning in the second year of their Ph.D. program. The curriculum of the training program includes a novel student sabbatical to be completed before graduation and, preferably, while the trainee is supported by the training grant. This sabbatical program remains as one of the most significant and unique opportunities available to the University of Michigan CBI trainees. In an effort to enhance interaction between students and provide more opportunity for trainees to present their research, we have instituted a monthly luncheon that is attended by present and past CBI trainees. Career development activities will be available to students at the local and national level. Two core courses in Chemical Biology and regularly scheduled opportunities for the trainees to present their research results to the training program faculty and fellow trainees, are also integral to the program. Research opportunities for the trainees are varied and involve faculty with a wide range of expertise in research at the interface of chemistry and biology. The trainees have access to the most sophisticated techniques and instrumentation in modern research at this interface. The Michigan CBI training program supports students both from research groups that have historically focused on purely chemical or purely biological problems as well as research groups with a strong core emphasis in chemical biology. This varied perspective provides strengths and opportunities integral to the training program. The faculty of the training program has a long history of collaborative research, and this interactive approach to research is a central theme in the training of a new generation of scientists.

DESCRIPTION (provided by applicant): We seek renewal of a highly productive multiple-PI research program involving the analysis and engineering of a broad class of monooxygenases from diverse natural product pathways. Cytochrome P450s are one of the most widely distributed groups of enzymes in nature, catalyzing the oxidation of natural product and xenobiotic small molecules. Although hundreds of P450s have been examined in the oxidative metabolism of xenobiotics and steroids, only a small number have been studied in bacterial secondary metabolism, especially in macrolide antibiotic biosynthetic pathways. In most of these systems, hydroxylation and/or epoxidation reactions occur in the late stages of biosynthesis after macrolide formation by the polyketide synthase (PKS). In addition to significant increases in biological potency, hydroxylation provides potential sites for chemical modification and further enhancement of bioactivities. Thus, the creation of novel macrolide analogs through in vivo metabolic engineering and in vitro chemoenzymatic synthesis warrants a concomitant effort towards the development of monooxygenases with defined substrate specificities. The aim of the proposed work is to expand our understanding of the substrate flexibility and functionality of a range of P450 monooxygenases from macrolide and select other natural product systems. Our progress over the first period of support has provided fascinating new insights into the molecular mechanisms of these biocatalysts, and their ability to generate novel products by hydroxylation, and epoxidation of natural and unnatural substrates. This information will direct protein engineering/substrate engineering efforts to better understand the function and positional specificity of the enzyme, as well as its ability to catalyze a range of oxidative reactions. Our program brings complementary approaches of synthetic chemistry to create diverse substrates, biochemistry to investigate and develop engineered monoxygenases with versatile substrate selectivity, and X-ray and NMR- based methods to obtain high resolution structural information for mechanistic understanding of these remarkable proteins. Specific Aim 1. Assess the impact of steric, electronic and directing group factors on catalytic promiscuity in the P450 PikC using a series of synthetic analogs of the natural macrolide substrate YC-17. Employ X-ray and solution NMR based structural biology approaches to gain detailed insights into binding parameters, protein-substrate dynamics, and the mechanistic basis for regio- and stereochemical specificity of natural and unnatural substrates. Specific Aim 2. Expand access to diverse synthetic substrates for a range of new P450 enzymes to investigate regio- and stereochemical details of monooxygenase-catalyzed hydroxylation and epoxidation reactions. Specific Aim 3. Pursue biochemical and structural studies of mixed-function iterative P450 enzymes to analyze substrate specificity and kinetics, as well as to investigate binding and catalytic mechanisms. PUBLIC HEALTH RELEVANCE: The studies proposed will broaden our knowledge of an important class of enzymes whose catalytic capabilities lead to important new medicinal agents in the form of natural product antibiotics and anticancer drugs. This new information will be used to generate novel biologically active compounds for the discovery and development of new pharmaceutical agents to fight human diseases.

In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor John Montgomery of the Department of Chemistry at the University of Michigan will explore the development of methods for transition metal-catalyzed couplings and cycloadditions. Strategies will be developed that enable carbonyl-activated substrates to be utilized in couplings, with deoxygenation occurring during the coupling process. New strategies for the cycloaddition assembly of five-membered rings will also be pursued, with a focus on multicomponent coupling processes. By the proposed strategies, the combination of three simple and widely available components will provide access to a range of structurally complex carbocycles. While some aspects of the specific aims will allow a comparative analysis of nickel and palladium catalysts, the majority of efforts will involve the utilization of inexpensive and readily available nickel catalysts.

This work will provide insights into the use of first row metals for the catalytic assembly of complex structures from simple and readily available substrates. New strategies for the development of environmentally benign catalytic processes will be elucidated by these studies. The advances from these studies could be applied to research questions in the pharmaceutical, biotechnology, agricultural, polymer, and petroleum industries. The students engaged in these studies will obtain skills that will enable them to be productive members of these industries or in academic positions at large universities or undergraduate institutions. Student coworkers with an interest in small college academic positions will be given the opportunity to develop collaborative projects with faculty at neighboring institutions.

? DESCRIPTION (provided by applicant): Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. The underlying objective of this proposal is to provide fundamentally new strategies for highly selective bond formations that will enable more rapid and efficient access to biologically active compounds of potential therapeutic value. A common theme throughout the proposal is the development of methods that accomplish highly selective bond formations when two or more similarly reactive parts of a structure are present. Using small molecule transition metal catalysts, the regioselective derivatization of simple structural subunits such as alkenes and alkynes will be addressed. Through careful mechanistic analysis, new insights will be provided to guide general strategies toward this objective in a broad range of contexts. Using engineered biological catalysts, strategies will be developed to enable regioselective oxidations of C-H bonds in complex substrates, using a novel substrate engineering approach that directs cytochrome P450-mediated oxidations towards a desired C-H bond embedded within a complex molecular framework. The development of new methods for the installation of carbohydrates will also be addressed. A new class of carbohydrate-derived silane reagents will enable considerable generality and control of stereochemistry during the installation of glycosidic bonds. The goals of this research program, including the precise generation of molecular frameworks, the selective oxidation of C-H bonds, and the installation of stereodefined carbohydrates, are all highly effective strategies for impacting and enhancing the biological properties of complex structures. Put together, the strategies present a toolbox of methods for enabling novel approaches for the synthesis of bioactive compounds. In collaborative work, these studies will be combined with the unique capabilities of biosynthetic enzymes to provide a synergistic combination of synthesis and biocatalysis to address key hurdles in the preparation of biologically active structures. The approach represents a merger of rarely combined fields of chemistry and biology: transition metal catalysis, C-H oxidation methodology, carbohydrate chemistry, and biocatalysis. This unique multidisciplinary perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.

The Chemical Synthesis Program of the Chemistry Division supports the research by Professor John Montgomery. Professor Montgomery is a faculty member in the Department of Chemistry at the University of Michigan. The goal of this project is to develop new processes for synthetic organic chemistry that are catalyzed by the earth-abundant metals nickel and copper. The new processes offer improved stability and reactivity, lower cost, and ease of access compared with existing alternatives. The new catalysts are being used to discover new organic transformations of readily available substrates. These efforts create versatile and efficient new catalysts and synthetic procedures that enable the creation of high-value products. The products are prepared from simple and widely available feedstocks in an environmentally sustainable manner. Students engaged in the work are trained in the discovery of new reactions, synthetic methods development, organometallic chemistry, and mechanistic chemistry. A substantial emphasis is placed on the career development of graduate students. Graduate students interested in employment at undergraduate institutions have they opportunity to work in that environment. Through a collaboration with a highly successful laboratory at an undergraduate institution, the graduate student gains experience conducting research and mentoring undergraduates. Other students have the opportunity to conduct collaborative research in international research labs.Professor Montgomery and his research team also are involved in outreach activities that provide engaging exposure to science for young students from the Detroit metropolitan area. These activities impact the academic experiences of many young students including underrepresented minorities while sharing with them the excitement of chemistry fields.

Compared with precious metal counterparts, nickel and copper catalysts offer unique reactivity and orthogonal capabilities. A primary focus of the research is to capitalize on the characteristic reactivity of nickel and copper to discover and develop synthetic processes that are unknown with other metals and that provide rapid access to high-value products. In particular, silyloxyarenes, which are an underutilized but widely available and inexpensive class of organic substrates, are employed in a wide array of carbon-hydrogen, carbon-silicon, and carbon-carbon bond-forming processes. In efforts involving copper catalysis, novel cascade processes that derivatize substrates possessing two or more unsaturated structural units are devised through processes that simultaneously incorporate multiple boron and cyano functional groups. The education plans involve innovative practices to provide career development training and international research opportunities to graduate students at the University of Michigan.

Project Summary / Abstract (Montgomery, Sherman, Nagorny) Carbohydrates are essential structural motifs that play a key role in many biological processes. They provide the primary structural features that govern many molecular recognition events that are central in biology. Essential molecular properties such as protein folding, biological target recognition, stability, and distribution are governed by glycosidic positioning and structure. Furthermore, alteration of glycosidic functionality has been demonstrated to enhance the potency and specificity of pharmaceutically important compounds. Despite the key role that carbohydrates play in biology and their promise in strategies for the improvement of human health, significant hurdles exist in the efficient access to rare and high-value monosaccharides and their chemical manipulation. Many sugars that are essential in governing the bioactivity of natural products and that hold promise for the discovery of new structures that could impact human health are currently not available to the scientific community. Furthermore, those that are available typically require complex synthetic manipulations that are beyond the expertise of scientists who are not specialists in organic synthesis. The major objective of this research proposal is to develop synergies between methods in biosynthesis and small molecule catalysis to overcome these barriers that are limiting progress in glycoscience. Through innovative biosynthetic strategies, efficient access to rare, high-value monosaccharides will be obtained. The approach brings together state-of-the-art advances in genome mining, synthetic biology, and biotransformation technologies. These advances will partner with novel approaches using transition metal catalysts and organocatalysts to convert biosynthetically derived monosaccharides into versatile and widely available reagents for the stereoselective construction of glycosidic bonds. Additionally, methods will be devised to convert common, widely available monosaccharides into rare sugars through redox manipulations. Innovative techniques in synthesis involving newly devised chiral phosphoric acid catalysts and carbohydrate-derived silane reagents will be developed in the course of the proposed studies. An innovative approach for solid- phase monosaccharide capture and synthetic elaboration will be developed. The unique multidisciplinary perspective of this effort will allow the development of strategies that cannot be addressed by conventional approaches. The outcome will be greatly improved access to valuable reagents and innovative methods for the assembly of glycosylated structural motifs that will enable progress in glycoscience that is currently hindered by limitations and difficulties of current approaches.

Project Summary / Abstract Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. The underlying objective of the parent award is to provide fundamentally new strategies for highly selective bond formations that will enable more rapid and efficient access to biologically active compounds of potential therapeutic value. Using small molecule transition metal catalysts, the regioselective derivatization of simple structural subunits such as alkenes and alkynes will be addressed. Through careful mechanistic analysis, new insights will be provided to guide general strategies toward this objective in a broad range of contexts. Using engineered biological catalysts, strategies will be developed to enable regioselective oxidations of C-H bonds in complex substrates, using a novel substrate engineering approach that directs cytochrome P450-mediated oxidations towards a desired C-H bond embedded within a complex molecular framework. The goals of this research program will provide highly effective strategies for impacting and enhancing the biological properties of complex structures. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied. This supplement application requests funds for purchase of a Gas Chromatography ? Mass Spectrometry (GCMS) instrument. This instrument will greatly increase both the accuracy and the speed of analyses conducted on the projects described above. These improvements will enable new discoveries and will increase productivity and efficiency of our group personnel funded on the parent award.

Project Summary / Abstract The University of Michigan proposes a predoctoral Chemistry-Biology Interface (CBI) Training Program for a select group of Ph.D. students. The number of training slots requested for this program is ten per year for a five-year period of support. Students will be appointed to the training program for two years beginning in the second year of their Ph.D. program. A diverse cohort of talented and promising trainees will be selected, and faculty mentors will adopt best practices in the retention of trainees throughout their graduate studies. The participating units are the Department of Chemistry, the Biophysics Program, and the Department of Molecular Cellular and Developmental Biology from the College of Literature, Science, and the Arts; the Department of Biological Chemistry, the Department of Pharmacology, and the Department of Pathology from the Medical School; the Department of Medicinal Chemistry from the College of Pharmacy; the Program in Chemical Biology, and the Life Sciences Institute. The faculty of the CBI Training Program includes chemical biologists, synthetic organic and inorganic chemists, bioorganic chemists, bioanalytical chemists, mechanistic enzymologists, spectroscopists, and crystallographers. The curriculum of the training program includes a novel student sabbatical to be completed before graduation and, preferably, while the trainee is supported by the training grant. This sabbatical program is one of the most significant and unique opportunities available to the University of Michigan CBI trainees. Innovative career development training, including panels and hands-on training through the sabbatical program, will provide students with exposure to a wide range of possible career paths. Two core courses in Chemical Biology and a CBI seminar course are integral to the program. Research and classroom training will also emphasize responsible conduct in research and strategies for conducting reproducible research with the highest standards of scientific rigor. Research opportunities for the trainees are varied and involve faculty with a wide range of expertise in research at the interface of chemistry and biology. The trainees have access to the most sophisticated techniques and instrumentation in modern research at this interface. The Michigan CBI training program supports students both from research groups that have historically focused on purely chemical or purely biological problems as well as research groups with a strong core emphasis in chemical biology. This varied perspective provides strengths and opportunities integral to the training program. The faculty of the training program has a long history of collaborative research, and this interactive approach to research is a central theme in the training of a new generation of scientists.

Project Summary / Abstract Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. The underlying objective of this proposal is to provide fundamentally new strategies for highly selective bond formations that will enable more rapid and efficient access to biologically active compounds of potential therapeutic value. A suite of new reactions will be developed that rely on the boron-catalyzed coupling of organofluorine and organosilane substrates. Glycosylation reactions that rely on this reactivity paradigm will be developed in concert with catalyst design, mechanistic study, and computational evaluation. Robust methods that enable efficient assembly of glycosidic bonds with high degrees of stereocontrol and broad functional group tolerance will allow access to any desired stereochemical outcome while allowing a platform for iterative assembly of complex oligosaccharides. New late transition metal-catalyzed processes will be developed utilizing the framework of connecting organofluorine with organosilane substrates using boron co-catalysis. Methods where remote complexation of fluorine allows leaving groups to be activated on demand will developed as a general strategy for applications in carbohydrate chemistry and in carbon-carbon bond-forming methodology. Following the above focus on the development of new catalytic methods, approaches to the efficient assembly of glycosylated structures will be pursued to provide new methods for accessing novel chemical probes and potential therapeutic agents. This component will include developing new strategies for accessing rare carbohydrates and for the stereoselective glycodiversification of peptides, natural products, and complex synthetic intermediates. Methods for tailoring complex naturally occurring and synthetic structures will include derivatization of existing hydroxyl functionality or biocatalytic functionalization of unactivated C-H bonds. These capabilities will serve as a foundation for a broad array of collaborative studies including the discovery of new antimicrobial and anticancer therapeutic agents and new chemical probes to provide insight into diverse biological questions such as mechanisms of transcriptional activation and enzymatic degradation of host and dietary oligosaccharides. The synthetic approaches developed represent a merger of rarely combined fields of chemistry and biology: main group element catalysis, transition metal catalysis, carbohydrate chemistry, and biocatalysis. The unique multidisciplinary perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.