Recent Advances in the Synthesis of Chiral Tetrahydroisoquinolines via Asymmetric Reduction

Abstract

Enantiopure tetrahydroisoquinolines (THIQs), recognized as privileged skeletal structures in natural alkaloids, have attracted considerable attention from chemists due to their biological and pharmacological activities. Synthetic strategies for optically active THIQs have been rapidly and extensively developed in the past decades. In view of simplicity and atom economy, asymmetric reduction of N-heteroaromatics, imines, enamines, and iminium salts containing an isoquinoline (IQ) moiety should be the preferred approaches to obtain chiral THIQs. This review focuses on recent advances in the catalytic asymmetric synthesis of enantiopure THIQs via asymmetric reduction, including asymmetric hydrogenation, transfer hydrogenation, reductive amination, and deracemization. Highly enantioselective synthesis of THIQs was achieved via transition-metal-catalyzed asymmetric reduction and organocatalytic asymmetric reduction utilizing either catalyst activation or substrate activation strategy. Despite much progress in the enantioselective synthesis of THIQs, there still remain considerable opportunities and challenges for progress and developments in this field of research, particularly in the development of asymmetric catalytic systems for the direct reduction of IQs.