Enantioselective Hydrodifluoroalkylation of Alkenes with Conformationally Tuned Peptidyl Hydrogen Atom Transfer Catalysts

We report the enantioselective hydrodifluoroalkylation
of alkenes
proceeding via an asymmetric hydrogen atom transfer (HAT) event catalyzed
by thiol-containing tetrapeptides. Photocatalytic generation of a
difluoroacetyl radical followed by carbon–carbon bond formation
results in a prochiral carbon-centered radical that engages with the
chiral catalyst. A trialkylamine reductant is proposed to turn over
the catalyst in this net-reductive transformation. Notably, incorporating
an (S)-β-methyl-substituted cysteine as the N-terminal residue improved selectivity relative to that
of the native N-terminal cysteine (Cys) residue,
and X-ray crystallographic analysis supports the conformational underpinning
of this effect. A range of enantioenriched γ-substituted amides
were synthesized in up to a 96:4 enantiomeric ratio, demonstrating
the broad functional group tolerance of this method. Models accounting
for asymmetric induction are proposed with supporting DFT calculations.