A Preparation of N-Fmoc-N-methyl-alfa-amino acids and N-nosyl-N-methyl-alfa-amino acids

A convenient route for the synthesis of lipophilicN-Fmoc-N-methyl-alpha-amino acids and N-nosyl-N-methyl-alpha-amino acids, interesting building blocks to be used for the preparation of N-methylated peptides, is presented.Both nosyl- and Fmoc-protected monomers areaccessible, so these compounds can be used in solution as well as in solid phase peptide synthesis. The methodology is based on the use of benzhydryl group to protect temporarily the carboxyl function of N-nosyl-alpha-amino acids and on the subsequent methylation of the N-nosyl-alpha-aminoacid benzhydryl esters with diazomethane. The benzhydrylesters offer several beneficial features such as simple preparation, stability to methylation and selective deprotection under mild conditions. The overall procedure is highly efficient in that the adopted conditions keep thechiral integrity of amino acid precursors and the process does not require chromatographic purification of the methylated products.