Mechanisms and regio- and stereoselectivities in NHC-catalyzed [3+3] annulations for the synthesis of axially and centrally chiral dihydropyridinones

Organocatalytic annulation strategies serve as an ideal approach for constructing molecules integrating both axial and central chirality, yet theoretical studies on the origin of stereoselectivity remain insufficient. In this study, the NHC-catalyzed [3+3] annulation between cinnamaldehyde and 2-aminomaleate was systematically investigated through density functional theory (DFT) calculations. The catalytic cycle involves eight key steps: nucleophilic addition, 1,2-proton transfer, oxidation, Michael addition, protonation, deprotonation, ring closure, and catalyst dissociation. Deprotonation is identified as the rate-determining step, with an overall energy barrier of 19.7 kcal mol^-1. The Michael addition step is the stereoselectivity-controlling step that preferentially generates the <i>R</i>-configuration product, consistent with the experimental results. The calculated enantiomeric excess value of 89.3% aligns well with experimental observations (90% ee). Noncovalent interaction (NCI) analysis revealed that the stability of the key stereoselective transition state can be traced to LP⋯π, C-H⋯O and C-H⋯N interactions. The mechanistic insights should be helpful for understanding the origins of stereoselectivity in NHC-catalyzed atroposelective annulations.