Fig. 3: Development of CuNiP for sulfonyl sulfimidation of methionine.

a Plausible mechanism for the formation of sulfonyl sulfimide product with methionine via Cu-nitrene pathway. NaCl is the only byproduct of this reaction pathway. b Screening of varying metal salts for the formation of sulfonyl sulfimide conjugate with a peptide Fmoc-VKQMK-CONH₂ shows CuBr is the most effective metal salt with 88% product to 12% sulfoxide. The optimal condition with CuBr is highlighted in red. c Computational analysis of the interaction energy of HOMO of methionine and LUMO of MeCN-bound Cu-nitrene complex clearly shows the flow of electrons from methionine to nitrene. d Calculated HOMO-LUMO gap between HOMO of reactive amino acids and LUMO of MeCN-bound Cu-nitrene species clearly shows the high reactivity and selectivity towards methionine. e Chemoselectivity studies with peptides Fmoc-KQYWCREHS-CONH₂ and Fmoc-KQYWCRMEHS-CONH₂ using chloramine-T and CuBr via Cu-nitrene pathway showed high selectivity for Met. f Stability studies of sulfonyl sulfimide towards hydrolysis as analyzed by NMR, showed no detectable decomposition to sulfoxide after 7 days. g Computational studies showed high hydrolytic stability of sulfonyl sulfimide due to the predominant double-bond character resulting from the high electron-density on nitrogen of sulfonyl sulfimide thus making it less electrophilic towards hydrolysis. Figure 3, created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license” (Agreement number: SS26NYD4Q8).