Fig. 2: Development of non-nucleophilic chemical approach for the selective labeling of methionine.

a HOMO-LUMO gap of the methionine (5.7 eV) is lower than other reactive nucleophilic amino acids such as lysine (6.4 eV) and cysteine (6.3 eV), suggesting a high kinetic reactivity of methionine. b Use of N-tosyliminoiodinane with various copper salts for selective modification of methionine. Reaction with CuI in MeCN gave 95% (red) yield to the sulfonyl sulfimide product, with reduction in yield 75% (red) observed with the introduction of 20% water to the reaction c Cu(I)-nitrene mechanism for the formation of sulfonyl sulfimide product with methionine using N-tosyl iminoiodinane (Ph-I = N-Ts). d Chemoselectivity studies with N-tosyl iminoiodinane showed side-reactivity with Tyr (iodination), Cys (disulfide) and His (iodination). e Sulfonyl sulfimidation using water-soluble 1a on Fmoc-VKQMK-CONH₂ shows chlorination on lysine as a side product. f 1a carrying out the chlorination reaction via ionic pathway. g Chemoselectivity studies of 1a with FXV-CONH₂ (X = Y and K) showed chlorination of Tyr, Lys, and N-terminus. h Screening of halogen-trapping reagents for suppressing the chlorination reaction showed that pyrrole is the best halogen-scavenger. Figure 2, created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license” (Agreement number: OE26NYDGX5).