N-Methylation of Peptides on Selected Positions during the Elongation of the Peptide Chain in Solution Phase

An efficient and general solution-phase method for the site-specific N-methylation of peptides hasbeen developed. This novel procedure involves synthesis of N-nosyl protected peptides and theirsubsequent N-methylation with diazomethane. Its efficiency was proved by the successful synthesisof various hindered oligopeptides containing N-methyl amino acid residues with excellent yieldand purity. The method is particularly attractive in that the adopted conditions do not cause anydetectable racemization of the peptide stereocenters and the process does not require chromatographicpurification of the methylated products. A further advantage is the compatibility of thismethodology with Fmoc solution-phase peptide synthesis.