Theoretical Insights into Enantioselective [3 + 2] Cycloaddition between Cinnamaldehyde and Cyclic N -Sulfonyl Trifluoromethylated Ketimine Catalyzed by N -Heterocyclic Carbene.

The density functional theory (DFT) method was used to investigate the mechanism and the origin of stereoselectivity of N -heterocyclic carbene (NHC)-catalyzed [3 + 2] cycloaddition between enals and cyclic imine N -sulfonyl trifluoromethyl ketimines at the M06-2X/SMD/6-311+G(d,p)//M06-2X/SMD/6-31G (d,p) level. The results show that the favorable reaction path consists of five steps: nucleophilic attack, proton transfer, the formation of the C-C bond, the tautomerism of the enol intermediate, the formation of the five-membered ring, and the regeneration of the catalyst. For the process of proton transfer, the base-assisted reaction can reduce the activation free energy and make the reaction easier to occur compared with the direct proton transfer process. The formation of the C-C bond is the crucial step of stereoselectivity, in which two chiral centers and four configurations of intermediates (RR/RS/SR/SS) were generated. The free energy barriers obtained and the noncovalent interaction analysis confirm that the dominant configuration is SS, becoming the final trans-type product observed in experiment. Furthermore, through the analyses of the conceptual DFT and natural atomic charges, it is revealed that NHC acts as a double catalyst, which can not only increase the nucleophilicity of reactants by Lewis base but also activate the C-H bond and promote the proton transfer process. The understanding of the mechanism obtained in this study should be helpful to the other organic catalytic reactions with high stereoselectivity.