Lewis acid catalysed methylation of N-(9H-fluoren-9-yl)methanesulfonyl (Fms) protected lipophilic α-amino acid methyl esters

This work reports an efficient Lewis acid catalysed N-methylation procedure of lipophilic α-amino acid methyl esters in solutionphase. The developed methodology involves the use of the reagent system AlCl3/diazomethane as methylating agent andα-amino acid methyl esters protected on the amino function with the (9H-fluoren-9-yl)methanesulfonyl (Fms) group. The removalof Fms protecting group is achieved under the same conditions to those used for Fmoc removal. Thus the Fms group can beinterchangeable with the Fmoc group in the synthesis of N-methylated peptides using standard Fmoc-based strategies. Finally,the absence of racemization during the methylation reaction and the removal of Fms group were demonstrated by synthesisinga pair of diastereomeric dipeptides.