5α,6α-Epoxy-7-norcholestan-3β-yl acetate

The title cholestan, C28H46O3, was prepared by epoxidation of 7-norcholest-5-en-3β-yl acetate and crystallized by slow evaporation from an ethanolic solution. All rings are trans fused. The 3β-acetate and the 17β-cholestane side chain are in equatorial positions. The molecule is highly twisted due to its B-nor characteristic. A quantum chemical ab-initio Roothaan Hartree–Fock calculation of the equilibrium geometry of the isolated molecule gives values for bond lengths and valency angles in close agreement with the experimental ones.

The title cholestan, C 28 H 46 O 3 , was prepared by epoxidation of 7-norcholest-5-en-3-yl acetate and crystallized by slow evaporation from an ethanolic solution. All rings are trans fused. The 3-acetate and the 17-cholestane side chain are in equatorial positions. The molecule is highly twisted due to its B-nor characteristic. A quantum chemical ab-initio Roothaan Hartree-Fock calculation of the equilibrium geometry of the isolated molecule gives values for bond lengths and valency angles in close agreement with the experimental ones.

Related literature
For the chemistry of the title compound, see: Carvalho et al. (2009aCarvalho et al. ( , 2010a. For studies of biological activity of steroids, see: Carvalho et al. (2009bCarvalho et al. ( , 2010b. For the influence of structural characteristics of B-nor steroids on the outcome of many reactions, see: Uyanik & Hanson (2009). For asymmetry parameters, see: Duax & Norton (1975); Altona et al. (1968). For reference bond-length data, see: Allen et al. (1987). For puckering parameters, see: Cremer & Pople (1975). For the melting point of the title compound, see: Joska et al. (1963). For the software used in ab-initio calculations, see Schmidt et al. (1993).

Experimental
Crystal data  (Carvalho et al., 2009a, Carvalho et al., 2010a and biological activity (Carvalho et al., 2009b, Carvalho et al., 2010b of steroids, we have been exploring the cytotoxic potential of oxysterols and their synthetic analogues against a panel of cancer and normal cell lines. We found that several chemical features are important for cytotoxicity such as the cholestane side-chain, a free or an in vivo easily generated 3β-hydroxyl group and the presence of an additional hydroxyl group at either 6β-or 7β-position. B-Norsteroids comprise a particular class of steroids, which bear a five-membered ring B, instead of the usual six-membered ring. As discussed recently (Uyanik & Hanson, 2009) this structural characteristic affects the outcome of many reactions, and quite often unexpected products are obtained. On the other hand, very few studies address the consequences of a shorter ring B in biological outcome comparatively to the normal sixmembered analogs. We have recently found that an α-epoxide in position C5 and C6 of a cholestane affords different cytotoxic results, when ring B bears only five carbons, instead of the usual six-membered ring B of cholesterol. Specifically, the B-nor-α-epoxycholestane displays a higher cytotoxicity (IC 50 = 40.9 µM) than the six-membered ring B analogue (IC 50 > 65 µM) (Carvalho et al., 2009b). We hypothesized that such biological result must be correlated with the α-orientation of the two epoxycholestane derivates. In this way, the evaluation of the three-dimensional structure of compound (I) by X-ray crystallography will contribute to correlate the importance of the geometry of ring B and the orientation of the epoxy moiety with the biological effect observed. Single crystal diffraction measurements allowed us to conclude that ring bond lengths have normal values (Allen et al.,1987) with average C(sp 3 )-C(sp 3 ) of 1.530 (3) Å, excluding the shorter C5-C6 bond of 1.458 (3) Å.
These ab-initio calculations reproduce well the observed bond lengths and valency angles of the molecule with the exception of a few C-C bonds in the cholestane ligand that are somewhat larger than the measured values, probably as a result of the larger displacement ellipsoids of these atoms. The calculation also reproduces the observed molecular conformation, with puckering parameters that agree well with those determined from the crystallographic study. The high value of the supplementary materials sup-2 pseudo-torsion angle is well reproduced by the calculations (obs: 12.68 (18), calc: 13.5°). The calculated configuration of the 3β-acetate and the 17β-cholestane side-chain are also close to those observed in the crystal.
Since there is no strong hydrogen bond donor in the molecule, cohesion of the crystal structure can only be attributed to van der Waals interactions.

Refinement
All hydrogen atoms were refined as riding on their parent atoms using SHELXL97 defaults.