Peptide-Catalyzed Asymmetric Amination of Sulfenamides Enabled by DFT-Guided Catalyst Optimization

The enantioselective synthesis of chiral S(IV) and S(VI) compounds has received heightened interest from the medicinal and synthetic chemistry communities due to the improved potency and selectivity of S-chiral small molecules and agrochemicals relative to classical achiral analogs. Yet, the advancement of stereocontrolled methods to access many of these compounds is still in its infancy, particularly for highly nitrogenated species. In this work, we present a catalytic enantioselective amination of sulfenamides mediated by a peptide-based guanidine catalyst, affording desymmetrized sulfinamidines in good to excellent enantioselectivities. Highlights of the methods are the commercial availability and bench stability of the aminating reagent; the low catalyst loading; and the convenient, open-to-air room temperature setup. Catalyst optimization from a mildly selective hit was guided by DFT-based atomistic modeling, which unveiled the insufficiencies of initial and intermediate catalyst designs. The results of this work highlight an example of computationally guided catalyst optimization in generating novel asymmetric solutions to unsolved problems in asymmetric synthesis, particularly in optimizing highly tunable catalyst designs.