Molecular and crystal structure of gossypol tetramethyl ether with an unknown solvate

The title compound consists of two planar halves. There is one half-molecule in the asymmetric unit, the whole molecule being generated by twofold rotation symmetry. The crystal structure has wide channels of 5–6 Å in diameter extending along the c-axis direction. The molecules are associated into a three-dimensional network supported by some weak C—H⋯O hydrogen bonds and C—H⋯π interactions.


Chemical context
Gossypol [systematic name: 2,2 0 -bis(8-formyl-1,6,7-trihydroxyl-5-isopropyl-3-methylnaphthalene)] is an unique terpenoid found in Gossypium (cotton) and related species. Within plants, gossypol appears to act as a natural insecticide and fungicide (Adams et al., 1960). Because of its antinutritive effect, gossypol limits the feeding of cottonseed and cottonseed meal to ruminant animals. However, the compound also has a wide range of biological actions, including anti-HIV, anticancer, and antifertility effects (Liang et al., 1995;Dorsett et al., 1975;Coutinho, 2002;Royer et al., 1995). Gossypol is a surprisingly versatile host compound that forms inclusion complexes with a great variety of organic substances such as ketones, ethers, esters, organic and mineral acids, water, various benzyl compounds and chlorinated and brominated compounds. More than one hundred of these complexes with different guest molecules have been obtained and structurally characterized (Talipov et al., 2002;2003;2007;Ibragimov et al., 2004). A specific feature of gossypol is the existence of gossypol host-guest complexes in the form of polymorphic crystals. As a result of its comprehensive biological properties, there is current interest in the synthesis of new gossypol derivatives. Many derivatives have been reported, including ethers, acetates and Schiff bases with aldehydes Tilyabaev et al., 2009;Kenar, 2006). As first reported by Morris & Adams (1937), treatment with an alkali of a gossypol solution in a mixture of dimethyl sulfate and methanol, yields a white gossypol tetramethyl ether, the title compound.

Structural commentary
Gossypol can exist in one of the following tautomeric forms: aldehyde, quinoid and lactol (Adams et al., 1960). In most solvents it is found in the aldehyde form. However, there are some reports that gossypol also exists in a pure lactol form (Reyes et al., 1986) or as a dynamic equilibrium mixture of the aldehyde and lactol forms in some highly polar solvents (Kamaev et al., 1979). In the structure described here, the title compound exists in the lactol form.
The crystallographically imposed symmetry of the title molecule is C2; the twofold axis is perpendicular to the C2-C2A bond [symmetry code (A): Àx, y, 3 2 À z]. The symmetry of the molecule corresponds to symmetry of the crystal, the title compound molecule being situated on a twofold axis. An ORTEP diagram of the molecule showing the atomnumbering scheme is given in Fig. 1. The molecule consists of two fused ring systems, each containing a naphthalene ring system with a fused furan ring. The two napthyl bicycles of the molecule are nearly perpendicular and the dihedral angle between their least-squares planes is 83.8 (1) . The furan ring is not completely planar, with atom C12 deviating from the C1/ O1/C8/C9 plane by 0.225 (4) Å . The methoxy group at the C-7 position is almost coplanar with the plane of the naphthalene ring system; atomic deviations from this plane are 0.004 (3) for O3 and 0.163 (5) Å for C16. The methoxy group on the furan ring (C12-O2-C17H 3 ) and atom O1 are located on the same side of the host ring (C1-C4/C9/C10). The isopropyl groups are positioned with the ternary hydrogen atoms pointed outwards and away from the center of the molecule, the isopropyl groups bisect the extended naphthalene ring system plane.
There is an intramolecular O4-H4Á Á ÁO3 hydrogen bond (Table 1) which is similar to those observed previously in structures of gossypol and its Schiff bases. The values of the bond lengths and angles in the title molecule are within expected values. However, there are notable differences in the lengths of some of these bonds compared with typical values for gossypol structures. Compared with the relatively short C5-C6 aromatic ring bonds of gossypol molecules (1.36 Å ), the corresponding bond in the title molecule is longer at 1.380 (3) Å . In addition, the C7-C8 and C8-C9 bonds in the title compound are shorter than those in gossypol by 0.03 and 0.06 Å , respectively. The shortest bond within these rings is the C1-C2 bond with a length of 1.359 (3) Å . In the furan ring, there are some differences in the lengths of some bonds compared with the values found in dianhydrogossypol. In the title molecule, the C1-O1 bond [1.374 (3) Table 1 Hydrogen-bond geometry (Å , ).

Figure 1
The molecular structure of the title compound showing the atomic numbering and 50% probability displacement ellipsoids. Unlabeled atoms are related to labeled ones by the symmetry operation (A) Àx, y, 3 2 À z.

Figure 2
A portion of the crystal packing viewed approximately along the c axis.

Supramolecular features
The packing of the title molecules is shown in Fig. 2. Weak intermolecular C-HÁ Á ÁO and C-HÁ Á Á interactions (Table 1) consolidate the crystal packing, which exhibits channels with a diameter of approximately 6 Å extending along the c-axis direction. These channels are similar to the channels previously reported in a dianhydrogossypol crystal structure (Talipov et al., 2009). In the present structure, for each unit cell, the channels provide a void volume of 672 Å 3 corresponding to 19% of the unit-cell volume. Highly disordered solvent molecules, most probably water molecules, occupy these voids in the crystal; their contribution to the scattering was removed with the SQUEEZE routine of the PLATON program (Spek, 2009(Spek, , 2015.

Database survey
A search in the Cambridge Structural Database (Version 5.33, last update November 2013; Groom & Allen, 2014) indicated the presence of 191 entries for gossypol (137 entries) or gossypol derivatives. However, only four entries were found for fused-ring systems containing a naphthalene ring system with a fused furan ring. The dihedral angle between two fused ring systems in these structures is equal to 84.8 in TEYJEM (Ibragimov et al., 1995), 111.8 in TEYJEN (Ibragimov et al., 1995), 117.0 in YURMEE (Talipov et al., 1999) and 119.1 in FOVKEG (Talipov et al., 1999).

Synthesis and crystallization
Gossypol was obtained from the Experimental Plant of the Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan where it was produced from by-products of the cottonseed oil industry. The title compound was synthesized following the known procedure (Morris & Adams, 1937). In order to prepare single crystals suitable for X-ray experiments, powdered material was dissolved in acetone (20 mg/1 ml) and stored for few days at room temperature under slow evaporation of the solution.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The H atom of the hydroxyl substituent was located in an electron density map and its coordinates were freely refined with U iso = 1.5U eq (O). Cbound H atoms were positioned geometrically and refined using a riding model, with d(C-H) = 0.93 Å and U iso = 1.2U eq (C) for aromatic, d(C-H) = 0.98 Å and U iso = 1.2U eq (C) for methine, d(C-H) = 0.96 Å and U iso = 1.5U eq (C) for methyl H atoms.
Acta Cryst. (2015). E71, 184-187 research communications  (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).  (17) Special details Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.