DFT-Driven Elucidation of Stereoselectivity in the NHC-Catalyzed Asymmetric Annulation of Cyclohexadienone-Tethered Enal.

The asymmetric catalytic potential of chiral N-heterocyclic carbenes (NHCs) has been increasingly demonstrated through stereoselective transformations. This study unravels the mechanism and origin of stereoselectivity in an NHC-catalyzed annulation of cyclohexadienone-tethered enal using density functional theory (DFT) calculations. The participation of in situ generated acetate acid has been found to be vital in both the generation of the Breslow intermediate and the esterification process. The stereoselectivity computed is found to be in very good agreement with the experimentally known enantioselectivity as well as chemoselectivity, validating the theoretical model. The origin of high stereoselectivity is traced to a series of more effective noncovalent interactions (such as π···π, C-H···O, and O-H···π) between the enolate and cyclohexadienone moieties in the lower-energy transition state. This investigation provides crucial mechanistic insights that advance both theoretical understanding of NHC-catalyzed desymmetrization strategies.