Diphenylphosphinylhydroxylamine (DPPH) Affords Late‐Stage S‐imination to access free‐NH Sulfilimines and Sulfoximines

Abstract

AbstractSulfilimines, 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.