Asymmetric Hydrogenation of Racemic 2‑Substituted Indoles via Dynamic Kinetic Resolution: An Easy Access to Chiral Indolines Bearing Vicinal Stereogenic Centers

• Published in: Journal of the American Chemical Society 2024-02, Vol.146 (8), p.5081-5087
• Main Authors: Rong, Nianxin, Zhou, Ao, Liang, Mingrong, Wang, Shou-Guo, Yin, Qin
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.4c00298

The asymmetric hydrogenation (AH) of N-unprotected indoles is a straightforward, yet challenging method to access biologically interesting NH chiral indolines. This method has for years been limited to 2/3-monosubstituted or 2,3-disubstituted indoles, which produce chiral indolines bearing endocyclic chiral centers. Herein, we have reported an innovative Pd-catalyzed AH of racemic α-alkyl or aryl-substituted indole-2-acetates using an acid-assisted dynamic kinetic resolution (DKR) process, affording a range of structurally fascinating chiral indolines that contain exocyclic stereocenters with excellent yields, diastereoselectivities, and enantioselectivities. Mechanistic studies support that the DKR process relies on a rapid interconversion of each enantiomer of racemic substrates, leveraged by an acid-promoted isomerization between the aromatic indole and nonaromatic exocyclic enamine intermediate. The reaction can be performed on a gram scale, and the products can be derivatized into non-natural β-amino acids via facile debenzylation and amino alcohol upon reduction.