Diastereo- and Enantioselective Synthesis of Polycyclic Amines by Cascade Cyclization of Aromatic Aldimines with Tethered Alkenes via Scandium-Catalyzed C–H Activation
Aniket Mishra, Xiaobin Lin, Kakoli Maji, Masayoshi Nishiura, Xuefeng Cong, Zhaomin Hou
Abstract
The development of stereoselective and atom-efficient methods for constructing densely functionalized polycyclic amines bearing multiple stereocenters is of great interest and importance, but remains a significant challenge. Herein, we report an unprecedented regioselective and stereoselective cascade cyclization of aromatic aldimines with tethered alkenes via C–H activation by half-sandwich scandium catalysts. The reaction proceeds through ortho -C–H activation of an alkene-tethered aromatic aldimine by a scandium alkyl (or amido) species in the catalyst followed by intramolecular alkene insertion ( exo -selective cyclization) into the resulting scandium–aryl bond and the subsequent intramolecular nucleophilic addition (cyclization) to the imine unit. The use of a chiral half-sandwich scandium catalyst enabled the asymmetric cascade cyclization with a high level of enantioselectivity (up to 98:2 e.r.) and diastereoselectivity (>19:1 d.r.). This protocol offers a straightforward route for the efficient and selective synthesis of a unique family of multisubstituted benzo-fused polycyclic amines, featuring 100% atom-efficiency, broad substrate scope, and excellent diastereo- and enantioselectivity.