Solid-Phase Synthesis of Peptide Alcohols

Significance

A novel strategy for the synthesis of peptide alcohols through an O-N acyl-transfer ­reaction was developed. Polymer-supported β-amino alcohols 3a-c were prepared from Fmoc β-amino alcohols 2a-c by using a 2-chlorotrityl chloride resin. Acylation of 3a and 3b was performed with an N-protected amino acid in the presence of DIC and DMAP to give 4a and 4b, respectively. Treatment of 3c with Fmoc-Cys(Trt)-OH under the Mitsunobu conditions gave 4c without epimerization. Further elongation of 4a-c with amino acid derivatives gave the resin-anchored isopeptides 5a-c. Cleavage from the resin afforded the free isopeptides 6a-c. The intramolecular O-N acyl migration of 6a-c led to the corresponding desired peptide alcohols 1a-c.