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

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‐(diphenylph...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2024-03, Vol.63 (13), p.e202314906-n/a
Main Authors: Gunasekera, Shanal, Pryyma, Alla, Jung, Jimin, Greenwood, Rebekah, Patrick, Brian O., Perrin, David M.
Format: Article
Language:English
Subjects:
Amines
Biocompatibility
Biomolecules
Catalysts
Congeners
Cytotoxicity
Fulvestrant
Functional groups
late-stage functionalization
Ligands
Metals
Natural products
Peptides
Rhodium
S-imination
Substrates
sulfilimines
Sulfoxides
sulfoximines
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Summary: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. Metal‐free, and high‐yielding sulfur‐imination using O‐(diphenylphosphinyl)hydroxyl amine to access sulfilimine salts and free‐NH sulfoximines has been reported. Its generality was evidenced using a broad substrate scope along with late‐stage functionalization of complex, biologically relevant substrates including a notorious amatoxin. DPPH was also shown to iminate sulfoxides with high yields under Rh catalysis to afford sulfoximines.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202314906