Diastereo- and Enantioselective Synthesis of Polycyclic Amines by Cascade Cyclization of Aromatic Aldimines with Tethered Alkenes via Scandium-Catalyzed C-H Activation.

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.