Double-helical cyclic peptides: design, synthesis, and crystal structure of figure-eight mirror-image conformers of adamantane-constrained cystine-containing cyclic peptide cyclo (Adm-Cyst)₃

Abstract

A large number of macrocycles containing alternating repeats of cystine diOMe(-NH-CH(CO₂Me)-CH₂-S-)₂ and either a conformationally rigid aromatic/alicyclic moiety or a flexible polymethylene unit (X) in the cyclic backbone with ring size varying from 13- to 78-membered have been examined by spectral (¹H NMR, FT-IR, CD) and X-ray crystallography studies for unusual conformational preferences. While ¹H NMR measurements indicated a turnlike conformation for all macrocycles, stabilized by intramolecular NH···CO hydrogen bonding, as also supported by FT-IR spectra in chloroform, convincing proof for β-turn structures was provided by circular dichroism studies. Single-crystal X-ray studies on 39-membered cyclo (Adm-l-Cyst)₃ revealed a double-helical fold (figure-eight motif) for the macrocycle. Only a right-handed double helix was seen in the macrocycle constructed from l-cystine. The mirror-image macrocycle made up of d-cystine units exhibited a double helix with exactly the opposite screw sense, as expected. The enantiomeric figure-eights were stabilized by two intramolecular NH···CO hydrogen bonds and exhibited identical ¹ H NMR and FT-IR spectra. The CD spectra of both isomers had a mirror-image relationship. The present results have clearly brought out the importance of cystine residues in inducing turn conformation that may be an important deciding factor for the adoption of topologically important structures by macrocycles containing multiple S-S linkages.