Enantiocontrolled Cyclization to Form Chiral 7- and 8-Membered Rings Unified by the Same Catalyst Operating with Different Mechanisms

Abstract

Chiral medium-sized rings, albeit displaying attractive properties for drug development, suffer from numerous synthetic challenges due to difficult cyclization steps that must take place to form these unusually strained, atropisomeric rings from sterically crowded precursors. In fact, catalytic enantioselective cyclization methods for the formation of chiral seven-membered rings are unknown, and the corresponding eight-membered variants are also sparse. In this work, we present a substrate preorganization-based, enantioselective, organocatalytic strategy to construct seven- and eight-membered rings featuring chirality that is intrinsic to the ring in the absence of singular stereogenic atoms or single bond axes of chirality. The reactions proceed under mild conditions and with high levels of stereocontrol. Notably, the same bifunctional iminophosphorane chiral catalyst orchestrates the cyclization of substrates of two different ring sizes, under two different mechanistic paradigms. We envision that the mechanistic and ring size versatility of this method could guide further applications of asymmetric catalysis to other challenging cyclization reactions.