Cinchona Alkaloid-Squaramide Catalyzed Sulfa-Michael Addition Reaction: Mode of Bifunctional Activation and Origin of Stereoinduction

The mechanism of the enantioselective sulfa Michael addition reaction catalyzed by a cinchona alkaloidsquaramide bifunctional organocatalyst was studied using density functional theory (DFT). Four possible modes of dual activation mechanism via hydrogen bonds were considered. Our study showed that Houk's bifunctional Bronsted acid hydrogen bonding model, which works for cinchonidine or cinchona alkaloid-urea catalyzed sulfa-Michael addition reactions, also applies to the catalytic system under investigation. In addition, we examined the origin of the stereoselectivity by identifying stereo controlling transition states. Distortion interaction analysis revealed that attractive interaction between the substrates and catalyst in the C-S bond forming transition state is the key reason for stereoinduction in this catalytic reaction. Noncovalent interaction (NCI) analysis showed that a series of more favorable cooperative noncovalent interactions, namely, hydrogen bond, pi-stacking, and C- H center dot center dot center dot pi interaction and C-H center dot center dot center dot F interactions, in the major R-inducing transition state. The predicted enantiornetric excess is in good accord with the observed value.