. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM078201-13
Application #
9658912
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2006-07-07
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
13
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08543
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
Le, Chip; Liang, Yufan; Evans, Ryan W et al. (2017) Selective sp3 C-H alkylation via polarity-match-based cross-coupling. Nature 547:79-83
McCarver, Stefan J; Qiao, Jennifer X; Carpenter, Joseph et al. (2017) Decarboxylative Peptide Macrocyclization through Photoredox Catalysis. Angew Chem Int Ed Engl 56:728-732
Corcoran, Emily B; Pirnot, Michael T; Lin, Shishi et al. (2016) Aryl amination using ligand-free Ni(II) salts and photoredox catalysis. Science 353:279-83
Liu, Chun; Oblak, E Zachary; Vander Wal, Mark N et al. (2016) Oxy-Allyl Cation Catalysis: An Enantioselective Electrophilic Activation Mode. J Am Chem Soc 138:2134-7
Shaw, Megan H; Twilton, Jack; MacMillan, David W C (2016) Photoredox Catalysis in Organic Chemistry. J Org Chem 81:6898-926
Zhang, Patricia; Le, Chi Chip; MacMillan, David W C (2016) Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling. J Am Chem Soc 138:8084-7
Shaw, Megan H; Shurtleff, Valerie W; Terrett, Jack A et al. (2016) Native functionality in triple catalytic cross-coupling: spĀ³ C-H bonds as latent nucleophiles. Science 352:1304-8
Jeffrey, Jenna L; Petronijevi?, Filip R; MacMillan, David W C (2015) Selective Radical-Radical Cross-Couplings: Design of a Formal ?-Mannich Reaction. J Am Chem Soc 137:8404-7

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