The desoxazoline asidiacyclamide analogue cyclo(Gly–Thr–D-Val–Thz–Ile–Thr–D-Val–Thz) acetonitrile monosolvate

The title peptide [systematic name: 4-(butan-2-yl)-7,20-bis(1-hydroxyethyl)-10,23-bis(propan-2-yl)-12,25-dithia-3,6,9,16,19,22,27,28-octaazatricyclo[22.2.1.111,14]octacosa-1(26),11(28),13,24(27)-tetraene-2,5,8,15,18,21-hexone acetonitrile monosolvate], C32H48N8O8S2·CH3CN, an analogue of ascidiacyclamide (ASC) [cyclo(–Ile–Oxz–D-Val–Thz–)2], lies about a twofold rotation axis, so that the glycine (Gly) and isoleucine (Ile) residues are each disordered over two sites with equal occupancies. The acetonitrile molecule is also located on a twofold axis passing through the C and N atoms. In the peptide, the thiazole rings are faced to each other with a dihedral angle of 9.63 (15)° and intramolecular N—H⋯O and O—H⋯O hydrogen bonds are observed. A bifurcated N—H⋯(O,O) hydrogen bond links the peptide molecules into a layer parallel to the ab plane.


The desoxazoline asidiacyclamide analogue cyclo(Gly-Thr-D-Val-Thz-Ile-Thr-D-Val-Thz) acetonitrile monosolvate
A. Asano and M. Doi Comment Ascidiacyclamide (ASC) is an unique cyclic peptide accommodating the unusual amino acids of oxazoline (Oxz) and thiazole (Thz) units ( Fig. 1) (Hamamoto et al., 1983;Shioiri et al., 1987). These five-membered rings limit the rotations of N-Cα bonds (the φ angel) causing the conformational restrictions to the molecule. The title peptide has only the Thz units and the conformation is more flexible than ASC. The first residue, Ile, is replaced with Gly which has less steric hindrances. This analogue is designed for the fundamental studies to control the peptide structure and to develop new class analogues of ASC.
The structure is shown in Fig. 2. The peptide and MeCN molecules are located on the two-fold axis and the figure is drawn to show the whole molecular structure with the crystallographically independent atoms and duplicated atoms related by the symmetry of (3/2 -x, y -1/2, -z). The Gly and Ile residues are coexisted with the disordering state, but they are independently drawn in the figure for clarity. The peptide molecule is folded at the Thr residue and the Thz rings are faced to each other. The atomic radius of sulfur atom (S42), which is larger than that of carbon, causes a slight tilt between the Thz ring with a dihedral angle of 9.63 (15)°. The distance between the S42 atoms of Thz is 4.303 (1) Å. These structural characteristics indicate the similarity with the folded forms of ASC analogues (Schmitz et al., 1989;Asano, Doi et al., 2001).
The hydroxyl group of Thr (O22) is hydrogen-bonding to the preceding carbonyl group (O16) of Gly or Ile forming 7-membered ring. This interaction seems to be caused by 3R-configuration of Cβ atom (C22). In the previous studies for desoxazoline ASC analogues (Asano, Doi et al., 2001), the hydroxyl group of allo-Thr (3S-configuration) is interacted with its carbonyl group (O24 in this structure) forming 6-membered ring. In this structure, the O22···O24 hydrogen bond causing the rotation of Cα-Cβ bond would result the steric hindrances at the methyl group (C23). Therefore, the O22···O16 hydrogen bond is formed at the Thr residue. The configuration of Cβ atom interestingly contributes the direction of hydroxyl group of allo-Thr and Thr.

Experimental
The title peptide was synthesized by the previously described method (Asano et al., 2005). The peptide was purified by using preparative thin-layer chromatography. Single crystals were grown from an aqueous MeCN solution.

Refinement
The side chain atoms of Gly and Ile residues were observed as disordered state, and refined with the site of occupancy 0.5.