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Optimized selective N‐methylation of peptides on solid support

Peptides containing Nα‐methylamino acids exhibit interesting therapeutic profiles and are increasingly recognized as potentially useful therapeutics. Unfortunately, their synthesis is hampered by the high price and nonavailability of many Nα‐methylamino acids. An efficient and practical three‐step procedure for selective N‐methylation of peptides on solid support is described. The procedure was based on the well known solid‐phase N‐methylation of Nα‐arylsulfonyl peptides, which was improved by using dimethylsulfate and the less expensive DBU as base. Every step of the procedure, amine activation by an o‐nitrobenzenesulfonyl group, selective N‐methylation and removal of the sulfonamide group, was optimized in respect of time and economy. The described optimized three‐step procedure is performed in 35 min without solvent changes, instead of 3 h. Tripeptides (Fmoc‐Phe‐MeXaa‐Leu‐OH) containing N‐methylated common amino acids were also prepared using the optimized procedure to demonstrate its compatibility with these amino acids. The described procedure allows an efficient synthesis of Nα‐methylamino acid containing peptides in a very short time using Fmoc solid‐phase peptide synthesis. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.