Synthesis of Cα methylated carboxylic acids: isosteres of arginine and lysine for use as N-terminal capping residues in polypeptides

Replacement of the N-terminal α-amine with the isosteric methyl functionality in bioactive peptides can influence various pharmacokinetic parameters, including hydrophobicity and stability. Cα methylated amino acid analogues are thus of great interest to expand the repertoire of nonnatural synthons available as N-terminal ‘capping’ residues for peptide-based drug design. Several novel arginine and lysine analogues stereoselectively modified in the Cα position with a methyl group in place of the α-amine were prepared.