Regio- and Site-Selective Processes Using Main Group and Transition Metal Catalysis

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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.