Preparation of Dehydropeptides and Their Application in the Convergent Synthesis of Peptide Conjugates

Abstract

Beyond its utility in the preparation of lantibiotics, this method is also well suited for the preparation of peptide conjugates. The functionalities encountered in natural amino acids include nucleophilic, acidic, and basic groups, but no electrophilic moieties. Thus, introduction of an electrophilic group into peptides will provide a handle for the chemoselective incorporation of nucleophiles. Based on this analysis, a convergent route involving site-specific modification of the unprotected dehydropeptide (the electrophilic handle) by Michael additions of suitable nucleophiles was developed. The C-terminal sequence of N-Ras, a number of other lipid peptides and S-linked glycopeptides were prepared through the Michael addition of corresponding thiolates to dehydropeptides. Furthermore, the preparation of dehydropeptides and the Michael addition were also illustrated to be compatible with solid phase.