Design, construction and properties of peptide N-terminal cap templates devised to initiate α-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

Abstract

The structural features required of N-terminal helix caps which might display high α-helix-forming propensities (Zimm–Bragg σ-values close to unity) were considered and two systems were identified as initial candidates for 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 generate a better nucleophile, and then ring-close by displacing the 4-halogen atom as halide. The precursor was prepared in moderate overall yield and displayed conformational isomerism in chloroform solution. Some of the conformers 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 generate an alkoxide anion and then ring-close by displacing halide ion from the 2-chloropropionyl moiety. The precursor was prepared in moderate overall yield 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 for the cyclisation, originating from the requirement for the alignment of the carboxamide carbonyl groups. Useful modifications to the systems described here that were designed to overcome or minimise the effect of the dipole in destabilising the required conformation for helix cap generation are presented in the following two articles.