N-Methylation of N-alpha-acylated, fully C-alpha-methylated, linear, folded peptides: synthetic and conformational aspects

Peptides characterized by single or multiple N-methylated, C-alpha-trisubstituted (e.g., protein) amino acids are of great interest in medicinal chemistry. Several naturally occurring peptides, remarkably stable to enzymatic attacks, are based on N-methylated residues. The classical conditions (CH3I/Ag2O in DMF, 24 h, room temperature) for N-methylation of the peptide function are useful tools for distinguishing solvent exposed from intramolecularly H-bonded -CO-NH-groups in peptides. In this work we have extended this reaction to N-alpha-acylated, linear peptides based exclusively on helicogenic C-alpha-tetrasubstituted alpha-amino acids, e.g., Aib (alpha-aminoisobutyric acid) or (alpha Me)Nva (C-alpha-methyl norvaline) residues. Under the experimental conditions used, only amide monomethylation (on the N-terminal, acylated, residue) takes place. Methylation of internal peptide groups linking two C-alpha-tetrasubstituted residues was not observed. Our FT-IR absorption, NMR, and X-ray diffraction investigations support the view that the beta-turn and 3(10)-helical conformations preferred by the original peptides are not dramatically perturbed in the derivatives mono-methylated at position 1. In particular, the tertiary amide bonds are trans. Conversely, the packing modes it? the crystals are strongly influenced by the reduction of the number of H-bonding donors. The MeXxx-Xxx peptide bond is readily disrupted under mild acidic conditions.