. The development of new platforms for late stage functionalization of small molecules and biomolecules such as proteins is a central goal of our research program. Therefore, the application of photoredox catalysis to synthetic chemistry has been the main focus of recent research efforts in my laboratory. The distinct features of photocatalysts, namely their ability to readily participate as both strong oxidants and reductants, create unique opportunities for new reaction mechanism development. 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 can facilitate entry into reaction paradigms that enable non-traditional partners to participate in cross coupling chemistry. Accordingly, efforts by our group and others have addressed many previously elusive synthetic challenges. This research proposal outlines new fields in which multiply-catalytic photoredox protocols can be brought to bear. In particular, we have endeavored to focus our efforts on design of new multicatalytic platforms involving photocatalysis and the expansion of photocatalyst classes used in synthetic organic chemistry. The objective of Aim I is to develop the direct arylation of unactivated C?H bonds via the merger of decatungstate hydrogen atom transfer and nickel catalysis.
In Aim II, we propose a methodology for alcohol activation and cross-coupling utilizing a silyl radical mediated pathway.
Aim III envisions the use of silyl radical halogen atom abstraction to accomplish aryl halide difluoromethylation. In contrast to the metallaphotoredox approaches in Aims I-III, Aim IV proposes to harness a methodology for selective protein bioconjugation via an organic-based photoredox catalyst.
In Aim V, we plan to develop a dynamic kinetic resolution of traditionally non-racemizable substrates through the merger of photoredox and enzyme catalysis. Finally, Aim VI proposes to again leverage decatungstate hydrogen atom transfer catalysis to develop a general platform for hydrogen isotope exchange of unactivated C?H bonds.

Public Health Relevance

. Selective late stage functionalization of proteins and small molecules is an important goal in synthetic organic chemistry and one that is highly enabling in medicinally relevant contexts. By continuing to push the boundaries of photoredox dual catalysis, we aim to develop new methodologies for the selective activation and derivatization of a diverse array of small molecules and proteins.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Yang, Jiong
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Princeton University
Schools of Arts and Sciences
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Welin, Eric R; Le, Chip; Arias-Rotondo, Daniela M et al. (2017) Photosensitized, energy transfer-mediated organometallic catalysis through electronically excited nickel(II). Science 355:380-385
Capacci, Andrew G; Malinowski, Justin T; McAlpine, Neil J et al. (2017) Direct, enantioselective ?-alkylation of aldehydes using simple olefins. Nat Chem 9:1073-1077
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