Synthesis of O-Acyl Isopeptides: Stepwise and Convergent Solid-Phase Synthesis.

Abstract

The O-acyl isopeptide method was developed for the preparation of difficult sequence-containing peptides, whose hydrophobic nature hampers both peptide chain construction on resin and purification with HPLC after deprotection. In the O-acyl isopeptide method, the target peptide is synthesized in an O-acyl isopeptide form, which contains an O-acyl isopeptide bond instead of the native N-acyl peptide bond at a hydroxy group-containing amino acid residue, such as Ser or Thr. The hydrophilic O-acyl isopeptide can be isolated, e.g., as a lyophilized TFA salt. The target peptide can be quantitatively obtained by a final O-to-N intramolecular acyl migration reaction with exposure to neutral conditions. Additionally, the O-acyl isopeptide is important as a hydrophilic precursor peptide for biological peptide assays that are difficult to handle. This chapter describes the synthesis of such O-acyl isopeptides by stepwise and convergent Fmoc solid-phase peptide synthesis.