. A central goal of our research program is the development of new catalytic platforms that provide access to highly enabling technologies for the construction of complex, medicinally relevant molecular scaffolds. In this regard, research efforts in my laboratory have recently been focused on exploring the application of photoredox catalysis to the field of organic chemistry. A key feature of photoredox catalysis is the ability to convert visible light into chemical energy through excitation of light-harvesting catalysts. The photoexcited catalysts can act as both a strong oxidant and reductant simultaneously, creating a unique reaction environment that my group has exploited in the development of previously elusive synthetic transformations. In particular, our group and others have shown that this distinct feature provide opportunities for the design of multicatalytic platforms combining photoredox with alterative catalytic manifolds. The merger of photoredox and transition metal catalysis has recently been established as a powerful platform, providing entry to mechanistic pathways that are inaccessible under `standard' transition metal catalysis conditions which are singly oxidative, reductive or neutral. Indeed, my group has demonstrated that this reaction paradigm can facilitate novel Ni-catalyzed technologies through modulation of the oxidation state of the transition metal catalyst and photoredox-mediated generation of versatile C- centered radical coupling partners. In this research proposal, we outline new directions for metallaphotoredox catalysis that exploit the distinct reactivity of different transition metal catalysts and use photoredox activation modes to facilitate the functionalization of `non-traditional' abundant cross-coupling partners.
In Aim I, we propose the direct, selective functionalization of aldehydic C?H bonds through the merger of hydrogen atom transfer, photoredox and nickel catalysis. The objective of Aim II is develop a decarboxylative Ni-catalyzed hydrofunctionalization of alkynes to enable rapid access to complex olefins from simple starting materials.
While Aims I -II focus on the merger of photoredox and nickel catalysis, Aim III envisions the development of a dual photoredox copper catalysis strategy for C(sp3)- trifluoromethylation. Here, we anticipate that photoredox catalysis will enable the use of both carboxylic acids and alcohols as radical precursors in this multicatalytic platform, resulting in methods for decarboxylative and deoxy- trifluoromethylation, respectively.
In Aim I V, we propose to harness the ability of silyl radicals for halogen abstraction to develop a general protocol for the trifluoromethylation of aryl bromides.
Aim V envisions the use of visible light-promoted cobalt catalysis to accomplish our goal of developing a protocol for the amidation of sterically encumbered aryl boronic acids via aryl radical generation. Finally, Aim VI proposes the development of general platform for decarboxylative C(sp3)?N and C(sp3)?O bond formation through the combination of copper and photoredox catalysis.

Public Health Relevance

A key goal for synthetic organic chemistry is the development of improved methods for the construction of high value, medicinally relevant molecules. By harnessing the merger of visible light photoredox catalysis and transition metal catalysis, we aim to develop new bond-forming technologies that were previously inaccessible via either individual catalytic manifold. These methods will enable rapid entry to structurally complex molecular scaffolds by revealing novel synthetic disconnections and providing access to streamlined chemical sequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM093213-10
Application #
9699496
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2010-04-01
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
10
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
Zuo, Zhiwei; Cong, Huan; Li, Wei et al. (2016) Enantioselective Decarboxylative Arylation of ?-Amino Acids via the Merger of Photoredox and Nickel Catalysis. J Am Chem Soc 138:1832-5
Zhang, Xiaheng; MacMillan, David W C (2016) Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp3-sp2 Cross-Coupling of Oxalates with Aryl Halides. J Am Chem Soc :
Johnston, Craig P; Smith, Russell T; Allmendinger, Simon et al. (2016) Metallaphotoredox-catalysed sp(3)-sp(3) cross-coupling of carboxylic acids with alkyl halides. Nature 536:322-5
Terrett, Jack A; Cuthbertson, James D; Shurtleff, Valerie W et al. (2015) Switching on elusive organometallic mechanisms with photoredox catalysis. Nature 524:330-4
Ventre, Sandrine; Petronijevic, Filip R; MacMillan, David W C (2015) Decarboxylative Fluorination of Aliphatic Carboxylic Acids via Photoredox Catalysis. J Am Chem Soc 137:5654-7
Welin, Eric R; Warkentin, Alexander A; Conrad, Jay C et al. (2015) Enantioselective ?-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from ?-Cyanoaldehydes. Angew Chem Int Ed Engl 54:9668-72
Chu, Lingling; Lipshultz, Jeffrey M; MacMillan, David W C (2015) Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of ?-Oxo Acids. Angew Chem Int Ed Engl 54:7929-33
Zuo, Zhiwei; MacMillan, David W C (2014) Decarboxylative arylation of ?-amino acids via photoredox catalysis: a one-step conversion of biomass to drug pharmacophore. J Am Chem Soc 136:5257-60
Prier, Christopher K; MacMillan, David W C (2014) Amine ?-heteroarylation via photoredox catalysis: a homolytic aromatic substitution pathway. Chem Sci 5:4173-4178
Terrett, Jack A; Clift, Michael D; MacMillan, David W C (2014) Direct ?-alkylation of aldehydes via photoredox organocatalysis. J Am Chem Soc 136:6858-61

Showing the most recent 10 out of 24 publications