This research proposal seeks to invent and develop broad new asymmetric catalytic strategies, which will provide enantioselective access to a range of privileged functional motifs not readily available through current approaches. Each of the methods to be pursued in this grant addresses a prominent and long-standing challenge in synthetic organic chemistry. A main focus of this proposal is the invention of new asymmetric methods based on the powerful multicatalytic strategy of synergistic catalysis. This concept envisions the productive merger of two simultaneous catalytic cycles, which operate in concert to separately activate each reactant, culminating in a single bond- forming event. Because of its enormous potential to enable the development of previously inconceivable chemical transformations, and to dramatically improve the selectivity of existing reactions, we anticipate that asymmetric synergistic catalysis will emerge as a transformative synthetic paradigm. The research to be pursued in Aim I of this grant is directed toward the development of new synergistic methods based on the merger of organocatalysis and copper catalysis.
Aims II and III of this proposal outline the development and application of a novel asymmetric catalytic activation mode, recently identified in our laboratory, that utilizes ligated copper catalysis with iodonium salts, to effect the asymmetric functionalization of nucleophilic substrates. Specifically Aim I envisions the development, through the synergistic merger of organocatalysis and copper catalysis, of a collection of powerful new asymmetric methods, namely: -arylation of aldehydes; -vinylation of aldehydes using either vinyl iodonium salts or vinyl borane coupling partners; -methylation of aldehydes; and -arylation of aldehydes.
Aim II outlines the development, through application of a novel ligated copper catalysis platform, of a series of new asymmetric transformations by which to achieve: -arylation of carbonyls; -vinylation of carbonyls; and dearomatizing arylation of tryptamine and tryptophol substrates, to deliver pyrroloindoline and furanoindoline motifs. Finally, in Aim III of this proposal, we will demonstrate the ability of our newly developed asymmetric dearomatizing arylation protocol to facilitate the construction of complex target systems, through a convergent asymmetric synthesis of the 3- arrylpyrroloindoline natural product, naseseazine A.
The objective of this research is to establish a new catalytic strategy for chemical synthesis whereby natural products, bioactive compounds and medicinal agents can be generated in a highly accelerated fashion from cheap, inexpensive and readily available starting materials.
| 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 |
| 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 |
| 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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