An Efficient Preparation of N-Methyl-alfa-amino Acids from N-Nosyl-alfa-amino Acid Phenacyl Esters

In this paper we describe a simple and efficient solution-phase synthesis of N-methyl-N-nosyl-alpha-amino acids and N-Fmoc-N-methyl-alpha-amino acids. This represents a very important application in peptide synthesis to obtain N-methylated peptides in both solution and solid phase. The developed methodology involves the use of N-nosyl-alpha-amino acids with the carboxyl function protected as a phenacyl ester and the methylating reagent diazomethane.An important aspect of this synthetic strategy is the possibility to selectively deprotect the carboxyl function or alternatively both amino and carboxylmoieties by using the same reagent with a different molar excess and under mild conditions. Furthermore, the adopted procedure keeps unchanged the acid-sensitive side chain protecting groups used in Fmoc-based synthetic strategies.