N-Heterocyclic Carbene-Catalyzed Asymmetric C−O Bond Construction between Benzoic Acid and o-Phthalaldehyde: Mechanism and Origin of Stereoselectivity

A computational study was contributed to explore the origin of stereoselectivity of NHC-mediated cyclization reaction between benzoic acid and o-phthalaldehyde for asymmetric construction of phthalidyl ester. The most energetically favorable pathway mainly includes the following steps: (1) nucleophilic attack on carbonyl carbon of o-phthalaldehyde by catalyst NHC, (2) formation of Breslow intermediate, (3) oxidation by DQ, (4) asymmetric formation of dual C-O bonds, and (5) dissociation of catalyst with the product. The C-O bond formation was testified as the stereoselectivity-determining step, the R-configurational pathway is more energetically favorable than the S-configurational one. The non-covalent interaction (NCI) and atom-in-molecule (AIM) analyses were performed to reveal that the O-H ⋅⋅⋅ O and C-H ⋅⋅⋅ O hydrogen-bond interactions are the key factors for controlling the stereoselectivity. The detailed mechanism and origin of stereoselectivity give useful insights for understanding organocatalytic reactions for asymmetric construction of C-O bond.