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 goal of this research effort is to develop versatile new methods for the preparation of compounds of biomedical significance. Through a multidisciplinary approach, improvements in the speed, efficiency, selectivity, and cost of introducing structural subunits that impact the biological properties and function of complex structures will be developed.
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