Yu-Hui Wang1,2, Jun-Song Tian1, Peng-Wei Tan1, Qiang Cao1, Xue-Xin Zhang1, Zhong-Yan Cao3, Feng Zhou1, Xin Wang4, Jian Zhou1,5. 1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N. Zhongshan Road, Shanghai, 200062, China. 2. Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China. 3. College of chemical engineering, Zhejiang university of technology, Chaowang road, 18N, Hangzhou, 310014, P. R. China. 4. College of Chemistry, Sichuan University, Chengdu, Sichuan, 610064, P. R. China. 5. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, P. R. China.
Abstract
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.
Azacycles such as indoles and n class="Chemical">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.
Authors: Shengfei Jin; Hang T Dang; Graham C Haug; Viet D Nguyen; Hadi D Arman; Oleg V Larionov Journal: Chem Sci Date: 2020-07-01 Impact factor: 9.825