CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence
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nihms-1014732.pdf
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Accepted version
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1.61 MB
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Author(s)
Ye, Yuxuan
Kim, Seoung-Tae
Jeong, Jinhoon
Baik, Mu-Hyun
Buchwald, Stephen Leffler
Date Issued
January 2019
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Ye, Yuxuan et al. "CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence." Journal of the American Chemical Society 141, 9 (January 2019): 3901–3909 © 2019 American Chemical Society
Version
Author's final manuscript
Abstract
Enantioenriched molecules bearing indole-substituted stereocenters form a class of privileged compounds in biological, medicinal, and organic chemistry. Thus, the development of methods for asymmetric indole alkylation is highly valuable in organic synthesis. Traditionally, achieving N-selectivity in indole alkylation reactions is a significant challenge, since there is an intrinsic preference for alkylation at C3, the most nucleophilic position. Furthermore, selective and predictable access to either N- or C3-alkylated chiral indoles using catalyst control has been a long-standing goal in indole functionalization. Herein, we report a ligand-controlled regiodivergent synthesis of N- and C3-alkylated chiral indoles that relies on a polarity reversal strategy. In contrast to conventional alkylation reactions in which indoles are employed as nucleophiles, this transformation employs electrophilic indole derivatives, N-(benzoyloxy)indoles, as coupling partners. N- or C3-alkylated indoles are prepared with high levels of regio- and enantioselectivity using a copper hydride catalyst. The regioselectivity is governed by the use of either DTBM-SEGPHOS or Ph-BPE as the supporting ligand. Density functional theory (DFT) calculations are conducted to elucidate the origin of the ligand-controlled regiodivergence.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/jacs.8b11838
