N-Methylation of N-alpha-acetylated, fully C-alpha-ethylated, linear peptides

"Mono-N-methyl scan" is a rational approach for the optimization of the peptide biological properties. N-Methylation of the -CONH- functionality is also a useful tool for discriminating solvent exposed from intramolecularly H-bonded secondary amide groups in peptides. We are currently extending this reaction to linear peptides based on C alpha-tetrasubstituted alpha-amino acids. Following our study on the synthesis and conformation of the mono-N-methylated peptides from C alpha-methylated residues, in this work we investigated the N-methylation reaction on homo-peptides to the pentamer level from the C alpha-ethylated residue C alpha,alpha-diethylglycine. Under the classical experimental conditions used, exclusively mono-N-methylation (on the N-terminal, acetylated residue) takes place, as unambiguously shown by mass spectrometry, 2D-NMR, and X-ray diffraction techniques. This backbone modification does not seem to involve any significant change in the peptide conformation in the crystalline state.