Isopeptide method: development of S ‐acyl isopeptide method for the synthesis of difficult sequence‐containing peptides

A novel strategy for a more efficient synthesis of difficult sequence‐containing peptides, the S ‐acyl isopeptide method, was developed and successfully applied. A model pentapeptide Ac–Val–Val–Cys–Val–Val–NH 2 was synthesized via its water‐soluble S ‐acyl isopeptide using an S ‐acyl isodipeptide unit, Boc–Cys(Fmoc–Val)–OH. An S ‐acyl isopeptide possessing excellent water solubility could be readily and quantitatively converted to the native peptide via an S N intramolecular acyl migration reaction at pH 7.4. Thus, the S ‐acyl isopeptide method provides a useful tool in peptide chemistry. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.