Efficient Synthesis of N-Methylamino Acids Compatible with Fmoc Solid-Phase Peptide Synthesis

摘要

Incorporation of N-methylamino acids into biologically active peptides has been shown to improve useful pharmacological parameters such as lipophilicity, proteolytic stability and conformational rigidity. It may also result in enhanced potency, new receptor subtype selectivity, and conversion of an agonist to an antagonist. Therefore, N~a-methylamino acid containing peptides are increasingly recognized as potentially useful therapeutics. Unfortunately, their synthesis is hampered by the high price and unavailability of many N~a-methylamino acids. Various methods have been developed for the synthesis of optically active N~a-methylamino acids but most of these methods are limited to aliphatic amino acids or are characterized by harsh reaction conditions and are incompatible with Fmoc-SPPS protecting groups. To date, there has been no method describing the synthesis of N-methyl derivatives of the common 20 amino acids in high yields by a common general procedure. Therefore we were interested in developing an easy and highly efficient procedure to prepare side chain protected N-methylamino acids with the possibility to use them directly in Fmoc-SPPS.