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Regiodivergent Intramolecular Nucleophilic Addition of Ketimines for the Diverse Synthesis of Azacycles
Author(s) -
Wang YuHui,
Tian JunSong,
Tan PengWei,
Cao Qiang,
Zhang XueXin,
Cao ZhongYan,
Zhou Feng,
Wang Xin,
Zhou Jian
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201910864
Subject(s) - enantioselective synthesis , intramolecular force , stereocenter , chemistry , regioselectivity , combinatorial chemistry , nucleophile , nucleophilic addition , catalysis , nucleophilic substitution , stereochemistry , organic chemistry
Azacycles such as indoles and tetrahydroquinolines are privileged structures in drug development. Reported here is an unprecedented regiodivergent intramolecular nucleophilic addition reaction of imines as a flexible approach to access N‐functionalized indoles and tetrahydroquinolines, by the control of reaction at the N‐terminus and C‐terminus, respectively. Using ketimines derived from 2‐(2‐nitroethyl)anilines with isatins or α‐ketoesters, the regioselective N‐attack reaction gives N‐functionalized indoles, while the catalytic enantioselective C‐attack reaction affords chiral tetrahydroquinolines featuring an α‐tetrasubstituted stereocenter. Mechanistic studies reveal that hydrogen‐bonding interactions may greatly facilitate such unusual N‐attack reactions of imines. The utility of this protocol is highlighted by the catalytic enantioselective formal synthesis of (−)‐psychotrimine, and the construction of various fused aza‐heterocycles.