A Highly Enantioselective Oxa−Michael Addition Reaction Catalyzed by Chiral Bifunctional N-Heterocyclic Carbenes

Abstract

The development of highly enantioselective oxa‑Michael addition (OMA) reactions has long been a compelling yet unresolved challenge in asymmetric catalysis. Here, we report a highly stereoselective OMA that operates across a structurally diverse set of oximes and enones, enabled by a chiral bifunctional N‑heterocyclic carbene hydrogen‑bond‑donor (NHC−HBD) catalyst. This catalytic platform accommodates a wide range of aryl and alkyl enones as well as diverse aldoximes and ketoximes, delivering the corresponding β‑oxime ketones with consistently high enantioselectivity. The same noncovalent activation framework also enables asymmetric cycloetherification of δ‑ and ε‑hydroxyenones via intramolecular OMA, further expanding the synthetic utility of this noncovalent activation strategy to intramolecular architectures. Complementary computational studies elucidate key intermediates and stereodetermining transition states, providing a clear rationale for the observed selectivity trends. Together, these findings establish a versatile strategy for activating oxygen nucleophiles and represent a significant advance in NHC‑mediated organocatalysis, offering potential opportunities for the development of efficient asymmetric methodologies.