Enzyme-Controlled Bidirectional Enantioselectivity in Asymmetric Decarboxylative Mannich Reaction for Synthesizing β-Sulfonamide Ketones

In this study, the asymmetric decarboxylative Mannich reaction (DMR) provides an attractive method for assembling C–N bonds to synthesize high-value-added nitrogenous scaffolds. Here, we report an enzyme-controlled method for the asymmetric DMR of cyclic sulfonamides with β-ketone esters. The method utilizes two types of enzymes, namely, copper artificial metalloenzyme (Cu-ArM) and commercial lipase (Novozym 435), to control the bidirectional enantioselectivity in DMR. The Cu-ArM is produced by anchoring a biotinylated Cu-complex (4-OHPIP-biotin*CuI) within wild-type streptavidin (WT-Sav). The resulting Cu-ArM catalyzes the asymmetric DMR to obtain a series of R-configurated β-sulfonamide ketones with good yield and enantioselectivity. By contrast, the S-configurated β-sulfonamide ketones are obtained with satisfying stereoselectivity and yield when Novozym 435 is used as the catalyst. Molecular dynamics (MD) simulations of both enzymes, along with preliminary stereochemical model analysis, elucidate the key site contact leading to good catalytic performance. Furthermore, MD simulations offer a plausible explanation for the superior reactivity of cyclic imines compared to noncyclic imines.