Selective Bi-directional amide bond cleavage of N-methylcysteinyl peptide

Article abstract of DOI:10.1002/ejoc.201402261

A selective bi-directional peptide bond cleavage mediated by N-methylcysteine (MeCys) in Xaa-MeCys-Yaa peptides (Xaa and Yaa, non-cysteine residues) leading to thioesters and thiolactones is described. Rate and product analyses showed that an N^α-amide bond cleavage occurred at the Xaa-MeCys bond by an N-S acyl shift to generate an Xaa-S-(MeCys-Yaa) thioester at pH 1-5, whereas under strongly acidic conditions of H₀ = -5, the MeCys-Yaa bond underwent a C^α-amide bond cleavage via an oxazolone intermediate, which was trapped by thiocresol (TC) as an Xaa-MeCys-TC thioester. This thioester was then transformed into an Xaa-MeCys-β- thiolactone at pH 4-5. Replacing MeCys by a Cys residue did not result in significant bi-directional peptide bond cleavage, which suggests that N-methylation in a MeCys residue is important for the N-S acyl shift reaction and formation of oxazolone. The isomerization of amides and thioesters was successfully used to prepare cyclic peptides. Copyright