. A fundamental goal of our research program is the development of novel synthetic strategies that will allow for the efficient construction of medicinally useful compounds from simple, readily available starting materials. Along these lines, our group has dedicated significant effort to the application of photoredox catalysis to organic synthesis. This field of catalysis employs transition metal complexes or organic dyes which are capable of absorbing visible light. Absorption of a photon promotes a photocatalyst to a long-lived excited state, which may then act as an oxidant or a reductant via single-electron transfer. As such, photoredox catalysts harness visible light as a source of chemical energy, which can be used to overcome significant reaction barriers. Recently, our group and others have demonstrated that photoredox catalysis can be successfully merged with other catalytic platforms in order to capitalize on the strengths of each individual mode of catalysis. We have become particularly interested in exploring reactivity at the interface of photoredox catalysis and transition metal cross-coupling catalysis. In this research proposal, we outline new directions for our photoredox multicatalysis-based research program. The successful completion of the proposed aims will provide access to currently unknown or inaccessible reaction pathways and will allow common and usually ?benign? organic compounds to be activated as participants in cross-coupling reactions.
In Aim I, we propose to develop an asymmetric decarboxylative cross-coupling via the merger of photoredox and nickel catalysis.
In Aim II, we aim to harness the ability of nickel catalysts to activate alkyl halides to accomplish a direct sp3?sp3 cross-coupling.
Aim III envisions the development of a nickel- and photoredox- catalyzed method for the conversion of esters into high-value scaffolds via CO2-extrusion- recombination.
While Aims I ?III focus on the cross-coupling of carboxylic acids, Aim IV proposes the introduction of a new class of readily available coupling partners by employing simple alcohol derivatives in nickel-photoredox cross-coupling.
In Aim V, it is our objective to employ three discrete catalysts in order to accomplish C?H arylation of amines, ethers, and alcohols via hydrogen atom transfer and cross-coupling.
Aim V I envisions the application of a related triple-catalytic strategy to develop a method for cross-electrophile coupling.
In Aim V II, it is our goal to harness photocatalytic control of transition metal oxidation states in order to accomplish a nickel-mediated C?N coupling reaction. Finally, as part of a Diversity Supplement, Aim VIII proposes the construction of the polypyrroloindoline alkaloid isopsychotridine using iterative applications of a copper-catalyzed method developed in our laboratory.
. The development of improved methods for the construction of pharmaceutically relevant compounds is a central goal of synthetic organic chemistry. Through the application of multicatalytic strategies harnessing both photoredox and nickel catalysis, we aim to develop a diverse array of new chemical transformations enabled by visible light. These reactions will provide efficient and rapid access to high-value molecular scaffolds that are not readily prepared via conventional methods.
| Kautzky, Jacob A; Wang, Tao; Evans, Ryan W et al. (2018) Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids. J Am Chem Soc 140:6522-6526 |
| Kim, Taehoon; McCarver, Stefan J; Lee, Chulbom et al. (2018) Sulfonamidation of Aryl and Heteroaryl Halides through Photosensitized Nickel Catalysis. Angew Chem Int Ed Engl 57:3488-3492 |
| Nacsa, Eric D; MacMillan, David W C (2018) Spin-Center Shift-Enabled Direct Enantioselective ?-Benzylation of Aldehydes with Alcohols. J Am Chem Soc 140:3322-3330 |
| Perry, Ian B; Brewer, Thomas F; Sarver, Patrick J et al. (2018) Direct arylation of strong aliphatic C-H bonds. Nature 560:70-75 |
| Liang, Yufan; Zhang, Xiaheng; MacMillan, David W C (2018) Decarboxylative sp3 C-N coupling via dual copper and photoredox catalysis. Nature 559:83-88 |
| Le, Chip; Chen, Tiffany Q; Liang, Tao et al. (2018) A radical approach to the copper oxidative addition problem: Trifluoromethylation of bromoarenes. Science 360:1010-1014 |
| Till, Nicholas A; Smith, Russell T; MacMillan, David W C (2018) Decarboxylative Hydroalkylation of Alkynes. J Am Chem Soc 140:5701-5705 |
| Zhang, Xiaheng; MacMillan, David W C (2017) Direct Aldehyde C-H Arylation and Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis. J Am Chem Soc 139:11353-11356 |
| Le, Chi Chip; Wismer, Michael K; Shi, Zhi-Cai et al. (2017) A General Small-Scale Reactor To Enable Standardization and Acceleration of Photocatalytic Reactions. ACS Cent Sci 3:647-653 |
| Loh, Yong Yao; Nagao, Kazunori; Hoover, Andrew J et al. (2017) Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. Science 358:1182-1187 |
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