Crystal structure of (1R,3aR,7aR)-1-{(S)-1-[(2R,5S)-5-(3-hydroxypentan-3-yl)tetrahydrofuran-2-yl]ethyl}-7a-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-inden-4-one

The title compound contains an oxolane ring, and six defined stereocentres and may serve as a useful synthon for the synthesis of calcitriol analogues. The configurations of the chiral C atoms of the side chain were unambiguously established in the refinement.


Chemical context
The discovery of vitamin D3 (calcitriol) and its biological activity had a very important impact in the search for analogues of Vitamin D. In the structure of vitamin D, it is recognized that the side chain is the main site of metabolic degradation. Synthetic chemists have devoted considerable efforts to varying this chain in order to prepare analogues of vitamin D (Dai & Posner, 1994;Zhu et al., 1995;Posner & Kahraman, 2003) and study the degradation metabolisms of these new molecules. Our ongoing interest in the chemistry of heterocyclic compounds, and particularly in the synthesis of vitamin D analogues, has led us to develop several methods for the synthesis of these compounds (Ferná ndez et al., 2016;Gá ndara et al., 2009). We have also looked at their biological activities which are reported in the literature (Maehr et al., 2004). Recently, we reported the synthesis of a new vitamin D2 analogue and the evaluation of its biological activity on colon cancer (Gá ndara et al., 2012). In a continuation of our work on the analogues of vitamin D, we synthesized two new molecules of cacitriol from an oxolane ring and its side chains (Martínez et al., 2013). In this study we present the structure of a new analog of calcitriol with six stereo centres.

Structural commentary
The molecular structure of the title compound is shown in Fig. 1: the compound crystallizes in the non-centrosymmetric space group P2 1 and the absolute structure was unambiguously established. The molecule contains a cyclopentane ring trans-fused to a cyclohexanone ring. The lateral chain contains an oxolane ring. The cyclohexanone ring adopts a chair conformation, the cyclopentane ring is an envelope (flap atom = C5) and the heterocyclic ring is twisted about C13-O2. The configurations of the stereogenic centres are C5(R), C6(R), C9(R), C11(S), C13(R) and C16(S). All bond distances and angles are within their expected ranges. The Csp 3 -Csp 2 bonds involving C1 [1.499 (3) and 1.500 (3) Å ) are naturally slightly shorter than the Csp 3 -Csp 3 bonds [1.514 (3)-1.549 (5)

Supramolecular features
In the crystal, C2-H2BÁ Á ÁO1 C hydrogen bonds (Table 1, Fig. 2) link the molecules into C(4) chains, which propagate parallel to [101]. The chains are linked through very weak C(2) O3-H3OÁ Á ÁO3 hydrogen bonds, giving rise to a threedimensional supramolecular architecture. The O-HÁ Á ÁO hydrogen bond is very long, presumably due to steric hindrance of the -OH group.

Synthesis and crystallization
To a solution of diol 2 (0.18 mmol) in CH 2 Cl 2 (5 ml), pyridinium dichromate (PDC) (0.37 mmol) was added, and the mixture stirred at room temperature for 12 h, then the solvent was evaporated and the residue was chromatographed on sílica gel using (10% EtOAc/hexane) to afford ketone 1. The title compound was recrystallized as colourless blocks using a solvent mixture of hexane/ethyl ether (1:1).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The hydroxy H atom was located from a difference Fourier map and relocated to an idealized (O-H = 0.82Å ) location. The other H atoms (CH, CH 2 and CH 3 groups) were placed geometrically and refined as riding atoms with U iso (H) = 1.2U eq (C) (1.5 for CH 3 groups).    (7) 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.