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

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.