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)s

A large number of macrocycles containing alternating repeats of cystine diO Me(-NH-CH-(CO2Me)-CH2-S-)(2) and either a conformationally rigid aromatic/a licyclic moiety or a flexible polymethylene unit (X) in the cyclic backbone with ring size varying from 13- to 78-membered have been examined by spect ral (H-1 NMR, FT-IR, CD) and X-ray crystallography studies for unusual conf ormational preferences. While H-1 NMR measurements indicated a turnlike con formation for all macrocycles, stabilized by intramolecular NH ... CO hydro gen bonding, as also supported by FT-IR spectra in chloroform, convincing p roof for beta-turn structures was provided by circular dichroism studies. S ingle-crystal X-ray studies on 39-membered cycle (Adm-L-Cyst)3 revealed a d ouble-helical fold (figure-eight motif) for the macrocycle. Only a right-ha nded double helix was seen in the macrocycle constructed from L-cystine. Th e mirror-image macrocycle made up of D-cystine units exhibited a double hel ix with exactly the opposite screw sense, as expected. The enantiomeric fig ure-eights were stabilized by two intramolecular NH ... CO hydrogen bonds a nd exhibited identical H-1 NMR and FT-IR spectra. The CD spectra of both is omers had a mirror-image relationship. The present results have clearly bro ught out the importance of cystine residues in inducing turn conformation t hat may be an important deciding factor for the adoption of topologically i mportant structures by macrocycles containing multiple S-S linkages.