Cyclic peptides from unprotected precursors through ring-chain tautomerism

Abstract

In 1993, our laboratory introduced a novel approach of blockwise ligation through amide bonds for peptide synthesis using unprotected peptide segments under aqueous conditions [I]. This approach uses a pair of mutually reactive groups to achieve selective amide bond formation between a specific α-amine on one peptide and an α-acyl moiety on another peptide with both peptides containing free αand e-amines. Because of its exclusive chemoselectivity, we have referred to this approach as the orthogonal coupling strategy [ 151. By exploiting different pairs of reactive groups, several methods based on this strategy have been developed and applied successfully to the synthesis of proteins [5, 6]. In addition, we have found that the orthogonal coupling strategy is well suited for preparing cyclic peptides [7,8] when two reactive ends are present on a single chain, largely due to unprotected peptide segments undergoing the entropy-favored ring-chain tautomerization. Ring-chain tautomerization is a novel concept and has the attendant advantage of eliminating the requirement for high dilution in the macrocyclization of unprotected peptides. In this paper, we describe the concept of ring-chain tautomerization in combination with the orthogonal ligation strategy for intramolecular cyclization of unprotected peptides to form end-to-end cyclic peptides using two different orthogonal coupling methods.