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.