Enantioselective synthesis of chiral α,α-dialkyl indoles and related azoles by cobalt-catalyzed hydroalkylation and regioselectivity switch

Jiangtao Ren, Zheng Sun, Shuang Zhao, Jinyuan Huang, Yukun Wang, Cheng Zhang, Jinhai Huang, Chenhao Zhang, Ruipu Zhang, Zhihan Zhang (), Xu Ji () and Zhihui Shao ()
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Jiangtao Ren: Yunnan University
Zheng Sun: Yunnan University
Shuang Zhao: Yunnan University
Jinyuan Huang: Yunnan University
Yukun Wang: Yunnan University
Cheng Zhang: Yunnan University
Jinhai Huang: Yunnan University
Chenhao Zhang: Yunnan University
Ruipu Zhang: Yunnan University
Zhihan Zhang: Central China Normal University
Xu Ji: Yunnan University
Zhihui Shao: Yunnan University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp3)−C(sp3) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles. The utility of this methodology has been demonstrated by late-stage functionalization of drug molecules, asymmetric synthesis of bioactive molecules, natural products and functional materials, and identification of a class of molecules exhibiting anti-apoptosis activities in UVB-irradiated HaCaT cells. Ligands play a vital role in controlling the reaction regioselectivity. Changing the ligand from bi-dentate L6 to tridentate L12 enables CoH-catalyzed Markovnikov hydroalkylation. Mechanistic studies disclose that the anti-Markovnikov hydroalkylation involves a migratory insertion process while the Markovnikov hydroalkylation involves a MHAT process.

Date: 2024
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DOI: 10.1038/s41467-024-48175-7

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