Design, construction and properties of peptide N-terminal cap templates devised to initiate alpha-helices. Part 1. Caps derived from N-(4-chlorobutyryl)-(2S)-Pro-(2S)-Pro-(2S)-Ala-OMe and N-[(2S)-2-chloropropionyl]-(2S)-Pro-(2S)-Pro-(2S,4S)-4-hydroxyPro-OMe

The structural features required of N-terminal helix caps which might displ ay high a-helix-forming propensities (Zimm-Bragg sigma-values close to unit y) were considered and two systems were identified as initial candidates fo r synthesis and evaluation. The first system was an eleven-membered cyclic all-trans triamide derived from N-(4-chlorobutyryl)-(2S)-Pro-(2S)-Pro-(2S)- Ala-OMe in which it was intended to remove the only amide NH proton to gene rate a better nucleophile, and then ring-close by displacing the 4-halogen atom as halide: The precursor was prepared in moderate overall yield and di splayed conformational isomerism in chloroform solution. Some of the confor mers appeared to contain one or more cis amide bonds,No suitable conditions could be found to effect macrocyclisation. The second system was a twelve- membered cyclic all-trans triamide derived from N-[(2S)-2-chloropionyl]-(2S )-Pro-(2S)-Pro-(2S,4S)-4-hydroxyPro-OMe in which it was intended to generat e an alkoxide anion and then ring-close by displacing halide ion from the 2 -chloropropionyl moiety. The precursor was prepared in moderate overall yie ld and populated one all-trans rotameric form in chloroform solution. This system also failed to macrocyclise under a variety of conditions, The major reason for the lack of reactivity in each system was analysed and appeared to be the generation of large molecular dipoles in the transition state fo r the cyclisation, originating from the requirement for the alignment of th e carboxamide carbonyl groups. Useful modifications to the systems describe d here that were designed to overcome or minimise the effect of the dipole in destabilising the required conformation for helix cap generation are pre sented in the following two articles.