Stereocontrolled cyclization of inherently chiral medium-sized rings

Inherently chiral medium-sized rings, albeit displaying attractive properties for drug development, often suffer from severe synthetic limitations due to challenging cyclization steps that form these unusually strained, atropisomeric rings from sterically crowded precursors. In fact, no enantioselective cyclization method is known for inherently chiral seven-membered rings. In this work, we present a substrate preorganization-based, enantioselective, organocatalytic strategy to construct seven- and eight-membered rings featuring inherent chirality 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 believe that the mechanistic and ring size generality of this method will stimulate deeper inquiries and development of general asymmetric catalysts and challenging cyclization reactions.