Enantioselective [2+2+2] Cycloaddition of Internal Alkynes to Access Axially Chiral Biaryl Hexasubstituted Benzene

Abstract

Multisubstituted benzene is a fundamental building block commonly found in natural products, organic semiconductors, and chiral ligands. The asymmetric synthesis of multisubstituted benzene with sterically hindered axial surfaces remains a significant challenge in organic synthesis. Herein, we present a neighboring group-directed, Rh-catalyzed asymmetric [2+2+2] cycloaddition of unactivated ortho-formamido aryl alkynes for the de novo construction of axially chiral biaryl hexasubstituted benzene derivatives. A crucial molecular size effect of the directing group was observed, with the formyl group, which has the minimum steric hindrance, providing the best results. Furthermore, to activate the free ortho-hydroxyl aryl alkynes, we developed an unprecedented Rh/thiourea cooperative catalyzed [2+2+2] cycloaddition, facilitating the rapid assembly of axially chiral biaryl naphthols. The success of this reaction is attributed to the organocatalyst, which activates the ortho-hydroxyl naphthyl alkyne, forming a vinylidene ortho-quinone methide (VQM) intermediate that participates in the cycloaddition.