A Template for Stabilization of a Peptide α-Helix: Synthesis and Evaluation of Conformational Effects by Circular Dichroism and NMR

The bicyclic diacid 1 was designed as a semi-rigid template for the hydrogen-bonding pattern of a peptide α-helix. The protected precursor 7 was synthesized in eight steps from tert-butyl 3,5-dimethoxybenzoate and linked to l-alanine and l-lactic acid to provide derivatives appropriate for coupling to a peptide. Both the amide 8-N and the ester 12-O were obtained in each of the four diastereomeric forms. The structure of R,R-8-N was determined by X-ray crystallography, which facilitated assignment of the diastereomers and confirmed the intended conformational effects of the quaternary methyl groups. The bicyclic amide and ester derivatives were appended to the peptide EALAKA-NH2, and their influence on the conformation was evaluated in aqueous solution using circular dichroism and NMR. The amide analogs have only a slight effect on the appended peptide, whereas the ester-linked template in S,S-9-O induces 32−50% helical character at 23 °C and 49−77% at 0 °C, depending on the method of determination; signi...