Design, construction and properties of peptide N-terminal cap templates devised to initiate α-helices. Part 2.† Caps derived from N-[(2S)-2-chloropropionyl]-(2S)-Pro-(2S)-Pro-(2S,4S)-4-thioPro-OMe

Abstract

Recently, we designed 12-membered macrocyclic template caps to entrain peptides into α-helical structures, based on the covalent connection of the first and fourth residues of proline containing tetrapeptides. It was not possible to complete the synthesis of the templates from the acyclic precursors and it appeared that the generation of large molecular dipoles, caused by aligning the carbonyl groups, prevented reaction. While this work was in progress, Kemp’s group published the structure of a 12-membered macrocyclic triproline template designed to initiate an α-helix that was very similar in structure to one of our own targets. However, the compound failed to cyclise in a conformation required for α-helix initiation and one or more carboxamide dipoles were not aligned. Here we provide a detailed conformational analysis of the system and test two methods for forcing the acyclic precursor into the macrocyclic conformation required for helix initiation. The first is the destabilisation of unwanted conformations in the transition state for cyclisation, and the second is the stabilisation of the favoured transition state structure through the introduction of a hydrogen-bonding interaction. Both strategies were unsuccessful and the reasons are discussed. A successful strategy which does not require the carbonyl dipoles to align in the transition state is presented in the following paper.