C ‐terminal N ‐alkylated peptide amides resulting from the linker decomposition of the Rink amide resin. A new cleavage mixture prevents their formation

Decomposition of the resin linkers during TFA cleavage of the peptides in the Fmoc strategy leads to alkylation of sensitive amino acids. The C ‐terminal amide alkylation, reported for the first time, is shown to be a major problem in peptide amides synthesized on the Rink amide resin. This side reaction occurs as a result of the Rink amide linker decomposition under TFA treatment of the peptide resin. The use of 1,3‐dimethoxybenzene in a cleavage cocktail prevents almost quantitatively formation of C ‐terminal N ‐alkylated peptide amides. Oxidized by‐product in the tested Cys‐ and Met‐containing peptides were not observed, even if thiols were not used in the cleavage mixture. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.