Crystal structure of an epoxysterol: 9α,11α-epoxy-5α-cholest-7-ene-3β,5,6α-triol 3,6-diacetate

The title compound is a polyoxygenated epoxy steroid that crystallizes in the P212121 space group.


Chemical context
Polyoxygenated steroids (Fig. 1) are metabolites both of terrestrial and marine origin possessing a number of remarkable biological activities (D'Auria et al., 1993). Our previous studies in this field focused on the isolation and synthesis of a number of such substances possessing new nuclear oxygenation patterns (Madaio et al., 1988;Migliuolo et al., 1992). In this context, new ruthenium tetroxide-catalysed oxidation methods (Bifulco et al., 2003a,b;Piccialli et al., 2007Piccialli et al., , 2010Piccialli, 2014) were developed to introduce suitable oxygenated functionalities in the B, C and D rings of the steroid nucleus. Among others, 9,11-epoxysterols have been isolated from various marine organisms (Gunasekera et al., 1983) and display diverse biological activities. In particular, the 3deacetyl analogue of the title compound ( Fig. 1) has shown to inhibit the binding of [I125] IL-8 to the human recombinant IL-8 receptor type A (de Almeida Leone et al., 2000). Selected biologically active polyoxygenated steroids of marine origin.
We are carrying out a broad research program aimed at discovering new biologically active substances. In recent years, we have synthesized and studied, among others, purine nucleoside analogues (D'Errico et al., 2011(D'Errico et al., , 2012aD'Atri et al., 2012;Oliviero et al., 2008Oliviero et al., , 2010a, cyclic ethers and polyethers (Piccialli et al., 2007(Piccialli et al., , 2009Piccialli, D'Errico et al., 2013;Piccialli, 2014) and nitrogen-rich fused-ring compounds . Within this program, and on the basis of the reduced amount of direct structural information available on epoxy steroids, we have synthesized the title compound (1), by diacetylation of 3, in turn obtained from cheap commercially available 7-dehydrocholesterol (2) (see Fig. 2), according to a previously reported procedure (Migliuolo et al., 1991). In particular, during the synthesis, two diastereomers, with opposite configuration at C6, were obtained, with predominance of the trans-isomer (5-OH/6-OH). The structural analysis was performed in order to unambiguously assign the configuration of the title compound.

Structural commentary
The crystallographically independent molecule is shown in Fig. 3. From the figure it is evident that the two acetyloxy groups have a different stereochemical orientation (3,6) and that the stereochemical orientation of the hydroxy group is the same as that of the acetyloxy group at C6 (5,6). In addition, the orientation of the epoxy oxygen atom is on the opposite side as compared with the methyl groups C18 and C19 (9,11-epoxy) and on the same side of the hydroxy group bonded to C5. The stereoselectivity in the formation of the epoxy ring is probably related to the steric hindrance due to the methyl groups.
We have reported the crystal structure of a steroid closely related to the title compound (Piccialli, Tuzi et al., 2013), in which the two acetyloxy groups, the C18 and C19 methyl groups and the alkyl tail have the same configuration as in the present one, and, moreover, an hydroxy group at C9 and a keto group at C11 are present. In Fig. 4 the two molecular structures are superimposed. The superposition is very good, apart for a small difference in the torsion angle for the acetyl group at C3.

Supramolecular features
The crystal packing of the title compound is shown in Fig. 5. Molecules in the crystal form chains by hydrogen bonding between the alcohol O1-H donor and the O4 carbonyl acceptor (Table 1). The chains run parallel to the b axis and are wrapped around a 2 1 crystallographic screw axes. Adjacent chains along the a axis are held by weak hydrogen bonding between C29-H donor and O6 carbonyl acceptor.
In order to detect additional packing features, we have examined the Hirshfeld surface (Spackman & McKinnon, 2002;Wolff et al., 2012). In Fig. 6   Synthesis of the title compound.

Figure 3
ORTEP view of the molecular structure of the title compound. Displacement ellipsoids are drawn at 30% probability level. Only the most populated orientation of the disordered chain is shown.

Figure 4
Overlay of the X-ray molecular structure of the title compound with the previously reported 3,6-diacetoxy-5,9-dihydroxy-5-cholest-7-en-11one (Piccialli, Tuzi et al., 2013). point of the Hirshfeld surface enveloping the molecule in the crystal, the distance d i to the nearest atom inside the surface and the distance d e to the nearest atom outside the surface are shown. The color of each point in the plot is related to the abundance of that interaction, from blue (low) to green (high) to red (very high).
A distinctive feature of the plot is represented by the two blue spikes at d i + d e = 2.0 Å , pointing to the lower left of the plot and symmetrically disposed with respect to the diagonal. They correspond to the strong hydrogen bonds present in the packing. Another feature is the central green strip along the diagonal, centered at d i + d e = 3.2 Å , indicating a large number of loose HÁ Á ÁH contacts. As expected, they are the predominant intermolecular contacts in the packing of the title compound. The central green strip ends up in the blue sting at at d i = d e = 1.0 Å , which reflects points on the Hirshfeld surface that involve nearly head-to-head close HÁ Á ÁH contacts.

Figure 5
Partial crystal packing of the title compound. Only the most populated orientation of the disordered chain is shown.

Figure 6
Hirshfeld fingerprint plot of the crystallographically independent molecule of the title compound.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Some atoms of the alkyl chain are disordered over two orientations. The two split positions were refined by applying DFIX and SAME restraints on bond lengths.