Wednesday, December 4, 2024
12/4/2024
Abstract. A central goal of our research program is to develop new platforms for the late-stage functionalization of small molecules and biomolecules such as proteins. In recent years, these efforts have focused on the application of photoredox catalysis as a uniquely enabling paradigm in synthetic chemistry. The distinct features of photocatalysts, in particular their ability to readily effect single-electron transfers and thereby generate reactive open-shell radical species, have created new opportunities for reaction development, providing highly enabling, novel bond disconnections in synthetic sequences. An area in which the application of photoredox catalysis has been notably successful is metallaphotoredox catalysis, the combination of photocatalysis with transition-metal catalysis. Metallaphotoredox platforms facilitate entry into reaction platforms that enable non-traditional partners to participate in cross-coupling chemistry. Accordingly, efforts by our group and others have addressed many long-standing synthetic challenges. This research proposal outlines new fields in which photoredox protocols have the potential to achieve significant impact. The objective of Research Program I is to develop new photoredox-mediated methodologies that will enable the selective bioconjugation of tyrosine and methionine residues in native proteins for application in drug delivery and bioimaging. In Research Program II, we propose to harness the ability of photoredox catalysis to reversibly cleave and form C–H bonds. This strategy will facilitate hydrogen isotope exchange and will enable dynamic control of C–H stereochemistry for application in uphill isomerizations and dynamic kinetic resolutions. Finally, Research Program III aims to explore novel directions in metallaphotoredox catalysis, such as harnessing photoredox activation modes to circumvent challenging elementary steps in copper and cobalt catalysis, as well as to expand the utility and scope of nickel/photoredox dual catalysis.
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