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CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence.


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.

SUBMITTER: Ye Y 

PROVIDER: S-EPMC6402987 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence.

Ye Yuxuan Y   Kim Seoung-Tae ST   Jeong Jinhoon J   Baik Mu-Hyun MH   Buchwald Stephen L SL  

Journal of the American Chemical Society 20190220 9


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  ...[more]

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