DFT study on the mechanism and origin of stereoselectivity of an NHC-catalyzed activation/transformation of an α-bromo enal†

In the present study, we theoretically investigated the mechanism and origin of stereoselectivity in an NHC-catalyzed enantioselective activation/transformation of an α-bromo enal, utilizing α,β-unsaturated acyl azolium as a key intermediate through density functional theory (DFT). Based on our calculations, the most energetically favorable pathway involves a sequential process comprising 1,4-addition, a stereoselective Mannich reaction, and a lactamization cascade to yield the fused-heterocyclic lactam product. The Michael addition acts as the stereoselectivity-determining step, resulting in a preferential generation of the SR-configurated isomer. Furthermore, we elucidated the origin of stereoselectivity through non-covalent interaction (NCI) analysis, which indicates that a greater number of weak interactions significantly contribute to achieving a high level of stereoselectivity.