Origin of stereoselectivity in NHC-catalyzed desymmetrization of pseudo-para-substituted [2.2]paracyclophane dialdehydes toward planar chirality

Abstract

Organocatalytic construction of bridged bicyclic compounds bearing planar chirality has become a hot topic in the asymmetric synthesis field; however, systematic theoretical studies have not kept pace with experimental advances in understanding the origin of stereoselectivity. Herein, density functional theory (DFT) was employed to investigate the detailed mechanism of N-heterocyclic carbene (NHC)-catalyzed desymmetrization of dimethyl-formylated [2.2]paracyclophane (PCP). The calculation results clearly verify that the catalytic cycle consists of five steps: desymmetrization, construction of the Breslow intermediate, oxidation, esterification, and catalyst regeneration. The stability of the key stereoselective desymmetrization transition state was further confirmed by weak interaction analyses to be jointly maintained by the C–H⋯O hydrogen bond and C−H⋯π interactions. This work provides in-depth mechanistic insights into the NHC-catalyzed desymmetrization for the construction of bridged bicyclic compounds bearing planar chirality and discloses the determining factors for regulating stereoselectivity in this kind of reaction.