Diphenylphosphinylhydroxylamine (DPPH) Affords Late‐Stage S‐imination to access free‐NH Sulfilimines and Sulfoximines
Shanal Gunasekera, Alla Pryyma, Jimin Jung, Rebekah Greenwood, Brian O. Patrick, David M. Perrin
Abstract
Sulfilimines, as potential aza-isosteres of sulfoxides, are valued as building blocks, auxiliaries, ligands, bioconjugation handles, and as precursors to versatile S(VI) scaffolds including sulfoximines and sulfondiimines. Here, we report a thioether imination methodology that exploits O-(diphenylphosphinyl)hydroxyl amine (DPPH). Under mild, metal-free, and biomolecule-compatible conditions, DPPH enables late-stage S-imination on peptides, natural products, and a clinically trialled drug, and shows both excellent chemoselectivity and broad functional group tolerance. This methodological report is extended to an efficient and high-yielding one-pot reaction for accessing free-NH sulfoximines with diverse substrates including ones of potential clinical importance. In the presence of a rhodium catalyst, sulfoxides are S-iminated in higher yields to afford free-NH sulfoximines. S-imination was validated on an oxidatively delicate amatoxin to give sulfilimine and sulfoximine congeners. Interestingly, these new sulfilimine and sulfoximine-amatoxins show cytotoxicity. This method is further extended to create sulfilimine and sulfoximine-Fulvestrant and buthionine analogues.