Convenient Synthesis ofN-Methylamino Acids Compatible with Fmoc Solid-Phase Peptide Synthesis

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Abstract
Nα-Methylamino acid containing peptides exhibit interesting therapeutic profiles and are increasingly recognized as potentially useful therapeutics. Unfortunately, their synthesis is hampered by the high price and unavaibility of many Nα-methylamino acids. An efficient and practical preparation of Nα-methyl-Nα-(o-nitrobenzenesulfonyl)-α-amino acids without extensive purification is described. The procedure is based on the well-known N-alkylation of Nα-arylsulfonylamino esters which was improved by using dimethyl sulfate and DBU as base. Ester cleavage is efficiently achieved by using an SN2-type saponification with lithium iodide, avoiding racemization observed with lithium hydroxide hydrolysis. Compatibility of the synthesized Nα-methylamino acids with Fmoc solid-phase peptide synthesis is demonstrated by using normal coupling conditions to efficiently prepare N-methyl dipeptides. The described procedure allows the preparation of Nα-methylamino acids in a very short period of time and a rapid synthesis of N-methyl peptides using Fmoc solid-phase peptide synthesis.