Discovery and mechanistic analysis of new catalytic reactions

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Controlling selectivity in reactions of complex molecules is a critical challenge for the chemistry field. The efficient and rapid preparation of drug candidates, new materials and tools for studying biochemical processes often hinges on the development of selective chemical transformations. Selectivity in organic synthesis is a multifaceted problem, encompassing stereoselectivity (control of the orientation of atoms in space), regioselectivity (control of the direction of bond formation), site-selectivity (positional selectivity in a molecule with several copies of the same reactive group) and chemoselectivity (reactivity of one group of atoms over another). In nature, these types of selectivity are under the control of enzyme catalysts, which accelerate one pathway so that it can outcompete other possibilities. Catalyst control of selectivity is one of the primary ways that nature constructs structurally and functionally diverse molecules from a set of simple precursors. The goal of the proposed research is to develop synthetic (laboratory) catalysts to address important problems related to the control of regioselectivity, stereoselectivity and site-selectivity in the preparation of organic compounds. Efficient methods for the synthesis or functionalization of carbohydrate (sugar) and nucleoside derivatives or analogs are a specific area of focus; these types of molecules are the building blocks for oligosaccharides and polynucleotides, two important classes of biological compounds. Their derivatives and analogs are used extensively in basic research and as prospective medicinal agents, particularly as antivirals or antibiotics. These structural classes pose particularly challenging selectivity issues; methods for their efficient laboratory synthesis are urgently needed to advance understanding of human health and disease and to enable the development of new drug candidates. Supported by our previous Discovery Grant, my group pioneered new catalytic reactions that have been widely adopted by end users in the carbohydrate chemistry and glycobiology communities to facilitate their research efforts, and have inspired further innovations by other catalysis researchers. Over the next five years, my team of diverse graduate and undergraduate students will conduct laboratory experiments to develop new catalytic processes of strategic value for the synthesis of carbohydrates, nucleosides and other complex chemical targets. By studying details of how these reactions work, they will build understanding of how to optimize and generalize them. The results will define new ways to prepare and study compounds that are urgently needed in the biochemistry, biotechnology and medicinal chemistry fields. While conducting this research, trainees will develop into well-rounded, creative and resourceful scientists while building valuable skills in modern synthetic and spectroscopic techniques, experimental design, data analysis and interpretation.