Isothiourea-catalyzed acylation of paracyclophanols for the construction of planar chirality: the mechanism and origin of stereoselectivity

Abstract

Planar chiral macrocyclic paracyclophanols exhibit configurational lability due to the increased flexibility of their ansa-chains, and isothiourea catalysis has recently provided an effective experimental pathway for the highly enantioselective acylation of this class of compounds with planar chirality. However, systematic studies on the origin of planar chirality of this kind of reaction lag behind. Herein, density functional theory (DFT) was employed to investigate the possible mechanism and origin of planar chirality of the isothiourea (R)-benzotetramisole ((R)-BTM)-catalyzed acylation of paracyclophanols. The favorable pathway includes three steps: S_N2-type acyl transfer, acylation coupled with deprotonation of the hydroxyl group, and dissociation of the catalyst. Moreover, distortion–interaction analysis, non-covalent interaction (NCI) analysis, atoms-in-molecules (AIM) analysis, and Fukui function vector calculations were used to further explore the role of the catalyst and key factors governing stereocontrol in the stereoselectivity-determining step.