Synthesis of small cyclic peptides: An auxiliary approach to address the “difficult cyclization” problem

Abstract

Cyclic peptides in general, and head-to-tail cyclic peptides in particular, comprise a large and important class of biologically active molecules. Whereas the synthesis of linear peptides generally proceeds well, head-to-tail cyclization is often troublesome, especially for small peptides of less than seven residues in length [1]. We are interested in developing chemical strategies that facilitate the assembly of libraries of small cyclic peptides [2]. In order to address the sequence-related inefficiency of small peptide cyclization we have aimed at utilizing auxiliary strategies that preorganize the Nand C-termini for head-to-tail cyclization. Here we describe a novel peptide cyclization auxiliary, 6-nitro-2hydroxybenzyl, which has enabled the formation of small cyclic peptides from ‘difficult’ linear precursors.