Copper-Photocatalyzed Enantioselective S‑Alkylation of Sulfenamides Enabled by Amino-Acid-Derived N,N,N‑Tridentate Ligand

Chiral sulfilimines are valuable sulfur-stereogenic motifs
in medicinal
chemistry and serve as versatile precursors to sulfoximines and sulfondiimines.
Despite their importance, enantioselective S-alkylation
of sulfenamides accessing to sulfilimines from abundant alkyl feedstocks
remains largely unexplored, particularly via radical pathways. Herein,
we report the enantioselective copper-photoredox-catalyzed S-alkylation of sulfenamides enabled by a family of amino-acid-derived N,N,N-tridentate ligands.
This strategy allows the use of alkyl carboxylic acids via decarboxylative
radical sulfilimination to afford enantioenriched sulfilimines in
high yields and enantioselectivities. Importantly, the platform is
further extended to alkyl iodides through an XAT-induced radical pathway,
demonstrating the generality of this enantioselective S-alkylation manifold. A broad range of primary, secondary, and tertiary
alkyl radicals, diverse sulfenamides, and complex bioactive substrates
are well tolerated. Mechanistic studies support a radical process
involving a stereoinvertive SH2-type substitution at a
copper-sulfenamide intermediate. Gram-scale synthesis and downstream
oxidation to pharmaceutically relevant sulfoximines underscore the
synthetic utility of this method.