Mechanism and Origin of Stereoselectivity for the NHC-Catalyzed Desymmetrization Reaction for the Synthesis of Axially Chiral Biaryl Aldehydes

Organocatalytic desymmetrization reaction is a powerful tool for constructing axial chirality, but the theoretical study on the origin of stereoselectivity still lags behind even now. In this work, the N-heterocyclic carbene (NHC)-catalyzed desymmetrization reaction of biaryl frameworks for the synthesis of axially chiral aldehydes has been selected and theoretically investigated by using density functional theory (DFT). The fundamental pathway involves several steps, i.e., desymmetrization, formation of Breslow oxidation, esterification, and NHC regeneration. The desymmetrization and formation of Breslow processes have been identified as stereoselectivity-determining and rate-determining steps. Further weak interaction analyses proved that the C–H···O hydrogen bond and C–H···π interactions are responsible for the stability of the key stereoselective desymmetrization transition states. This research contributes to understanding the nature of NHC-catalyzed desymmetrization reactions for the synthesis of axially chiral compounds.