Cystinophanes, a Novel Family of Aromatic-Bridged Cystine Cyclic Peptides: Synthesis, Crystal Structure, Molecular Recognition, and Conformational Studies

A novel family of aromatic-bridged cystine cyclic peptides (cystinophanes) has been synthesized by a single-step procedure involving condensation of 1,3 aromatic (Ph or Pyr unit) dicarbonyl dichloride with either the simple l -cystine dimethyl ester to provide cystinophanes of 26-, 39-, and 52-membered rings through 2+2, 3+3, and 4+4 cyclization, respectively, or with cystine bis-peptides (H 2 N-Xaa-Cyst-Xaa-NH 2 ) leading to a variety of 1+1 cystine-based peptidocyclophanes. 1 H NMR and CD studies have shown these cystinophanes to adopt a β-turn-like structure in solution. X-ray crystal structure of a representative member ( 3a ) containing two aromatic rings has shown a collapsed ring conformation with a near parallel face-to-face orientation of aromatic rings a feature also suggested by NMR studies. The propensity of cystinocyclophanes to adopt β-turn-type conformation is attributed to the presence of S−S linkage and the need to maintain a near orthogonal value of its torsion angle. The potential of cystinophanes to serve as artificial receptors in molecular recognition and host−guest complexation studies has been demonstrated with 26-membered, pyridine-bridged macrocycle 3b, which binds ( 1 H NMR) to a number of 1,ω-alkane dicarboxylic acids [(CH 2 ) n (COOH) 2, n = 1, ..., 4] and shows maximum affinity ( K assoc = 3.69 × 10 2 M - 1 ) and selectivity for glutaric acid ( n = 3) dicarboxylate. Crystal parameters for 3a are as follows: C 32 H 36 N 4 O 12 S 4 ·H 2 O·2C 4 H 8 O 2, space group P 2 1 2 1 2 1 with a = 11.748(1) Å, b = 17.317(1) Å, and c = 24.306(2) Å.