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

Recently, we designed 12-membered macrocyclic template caps to entrain pept ides into alpha-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 precur sors and it appeared that the generation of large molecular dipoles, caused by aligning the carbonyl groups, prevented reaction. While this work was i n progress, Kemp's group published the structure elf a 12-membered macrocyc lic triproline template designed to initiate an alpha-helix that was very s imilar in structure to one of our own targets. However, the compound failed to cyclise in a conformation required for alpha-helix initiation and one o r more carboxamide dipoles were not aligned. Here we provide a detailed con formational analysis of the system and test two methods for forcing the acy clic precursor into the macrocyclic conformation required for helix initiat ion. The first is the destabilisation of unwanted conformations in the tran sition state for cyclisation, and the second is the stabilisation of the fa voured transition state structure through the introduction of a hydrogen-bo nding interaction. Both strategies were unsuccessful and the reasons are di scussed. A successful strategy which does not require the carbonyl dipoles to align in the transition state is presented in the following paper.