Crystal structure of (20S)-21-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-4-yl]-20-(4-methylpentyl)-5-pregnen-3β-ol with an unknown solvate

In the title analogue of cholesterol, a new chain including an intermediate triazole and a tertiary hydroxyl group in the terminal position has been added at position 20, inducing a change in its stereochemistry.


Chemical context
The nuclear receptors (NRs) are a large family of ligandregulated transcriptional factors and include the receptors for steroid hormones, thyroid hormones, lipophilic vitamins and cholesterol metabolites (Mangelsdorf & Evans, 1995;Burris et al., 2013). Approximately half of NRs are classified as orphan NRs because they do not have well-characterized ligands (Hummasti & Tontonoz, 2008). Orphan NRs are an active area of research partly due to their potential for clinical agent development for various diseases (Mohan & Heyman, 2003). Recent studies have demonstrated that retinoic acid receptorrelated orphan receptors (RORs) have been implicated in several physiological and pathological processes. ISSN 2056-9890 Using the methodology developed in our research group for the synthesis of gemini-type vitamin D analogues (Fall et al., 2011;Pazos et al., 2016;Santalla et al., 2017) (modified with a double side chain), we can access new cholesterol analogues that can be of great interest in interactions with RORs. In this study, we present the structure of a new analogue of cholesterol (2), with eight stereocentres and a double side chain based on the aliphatic chain of cholesterol on the one hand and on the incorporation of a triazole ring on the other, since many azasteroids have proven to be biologically active. For example, some of them act as 5-reductase inhibitors, antifungal agents and -aminobutyric acid (GABA) receptor modulators (Tian et al., 1995;Burbiel & Bracher, 2003;Covey et al., 2000).

Structural commentary
In the title cholesterol gemini-type analogue 2, illustrated in Fig. 1, the four aliphatic rings are structurally identical to those in the cholesterol hormone, i-cholesteryl methyl ether (Bernal et al., 1940;Wang et al., 2014). In the title compound, atom C20 has a different stereochemistry than in the cholesterol molecule, as a result of stereospecific reactions of the synthetic pathway. Furthermore, a new chain, including an intermediate triazole and a tertiary hydroxyl group in the terminal position, has been added at atom C21. Although some steroid analogues with a triazole ring have been synthesized (Seck et al., 2015), there are no references to any crystallographic analyses of gemini cholesterols with a triazole group at position C21 (Cambridge Structural Database, version 5.39, last update February 2018;Groom et al., 2016). The terminal OH group (C2 0 /C3 0 /O3 0 ) is inclined to the triazole ring (N1 0 -N3 0 /C1 0 /C2 0 ) mean plane by 7.2 (2) .

Supramolecular features
The molecular association in the title compound 2, is based on hydrogen bonding involving the hydroxyl and triazole groups (Table 1). These intermolecular links are present in the form of two chains. The first, a C(18) chain (Fig. 2), is formed by the O3-H3Á Á ÁO3 'i hydrogen bond with O3-H3 acting as the donor and atom O3 0 acting as the acceptor. The second is a C(5) chain, in which the triazole group participates, and is formed by hydrogen bond O3 0 -H3 0 Á Á ÁN3 'ii (Fig. 3); the alcohol group O3 0 -H3 0 acts as the donor towards the acceptor atom N3 0 . The combination of these interactions Symmetry codes: (i) x þ 1 2 ; y þ 1 2 ; z þ 1; (ii) Àx À 1 2 ; y À 1 2 ; Àz.

Figure 1
The molecular structure of compound 2, with the atom labelling. Displacement ellipsoids are drawn at the 30% probability level. In this and other figures the minor disorder component atoms (C24B-C27B) of the aliphatic chain at C20 have been omitted for clarity.
results in the formation of layers lying parallel to the (201) plane, as shown in Fig. 4, and encloses R 4 4 (36) ring motifs, details of which are illustrated in Fig. 5.

Synthesis and crystallization
Compound 2: details of the synthesis are illustrated in Fig. 6. To a solution of triazole 1 (12 mg, 0.022 mmol;) in t BuOH (2 ml) and water (1 ml) was added p-TsOH (5 mg) and the mixture was heated to 353 K for 3 h. The reaction mixture was diluted with water and then extracted with CH 2 Cl 2 (3 Â 5 ml). The combined organic layers were dried with Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography (50% EtOAc/hexane) to afford the title diol (11 mg, 99%). Compound 2 was recrystallized as colourless prisms by slow evaporation of a solvent mixture of dichloro- A view approximately normal to the (201) plane of the crystal packing of compound 2. Hydrogen bonds (see Table 1) are shown as dashed lines, and only H atoms H3 and H3 0 have been included.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The O-H and C-bound hydrogen atoms were positioned geometrically (O-H = 0.84 Å , C-H = 0.95-1.00 Å ) and refined using a riding model with U iso (H) = 1.5U eq (O-hydroxyl, C-methyl) and 1.2U eq (C) for other H atoms. The isopropyl group is disordered about two positions with a refined occupancy ratio of 0.763 (5):0.237 (5) for atoms C24-C27/C24B-C27B.

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (