Late-Stage Peptide Modifications through S-imination enable Chemoselective Installation of free-NH Sulfilimines and Sulfoximines

Sulfilimines, the mono aza-analogues of sulfoxides have sparked acute interest in the fields of chemistry and biology with the discovery of a S=N crosslink in collagen IV. They serve as potential bioconjugation handles, bioisosteric pharmacophores, and are precursors to medicinally relevant S(VI) scaffolds. S-imination strategies to access sulfilimines have been employed for methionine (Met) functionalization in peptides and proteins for conjugation and also for chemoproteomic profiling of Met. Herein, we report the use of diphenylphosphinylhydroxylamine (DPPH) for S-imination to access sulfiliminium salts and sulfoximines under safe, mild, metal-free, and bio-molecule-compatible conditions with excellent chemoselectivity, broad functional group tolerance, and applicability in late-stage derivatization. These S-imination methods afforded successful chemoselective installation of sulfiliminium and sulfoximine scaffolds on clinically relevant methionine, buthionine, and also on complex peptides such as cholecystokinin and bombesin. α-amanitin is a sulfoxide bearing bicyclic octapeptide which is a potent inhibitor of RNA polymerase II, explored as a payload in targeted cancer therapy. DPPH mediated S-imination renders late-stage synthetic access to sulfilimine, sulfoximine, and sulfondiimine amatoxins; and cytotoxicity assays were employed to address their potential bioisosterism. Collectively, these results attest to the robustness of this S-imination strategy for chemoselective installation of versatile sulfilimine and sulfoximine scaffolds on peptides.