Diosgenin-3,6-dione: second polymorph in space group P212121

A polymorphic modification of the title steroidal compound, derived from diosgenin, results from a conformational alteration for the A/B ring system.

The title steroid, [(25R)-spirost-4-en-3,6-dione, C 27 H 38 O 4 ], is obtained by oxidation of diosgenin, using the Jones reagent (CrO 3 /H 2 SO 4 ). The crystal structure was previously reported in space group P2 1 2 1 2 1 , but nonetheless with the wrong absolute configuration and omitting positions for H atoms [Rajnikant et al. (2000). Mol. Cryst. Liq. Cryst. Sci. Technol. Sect. C,12,[101][102][103][104][105][106][107][108][109][110]. The diffraction data set reported herein is for a second polymorph in the same space group, as evidenced by simulated powder patterns. Both forms are characterized by a similar orthorhombic unit cell, and a similar arrangement of the molecules in the crystal structure. However, the conformation of the A/B rings in the steroid nucleus is slightly modified, leading to the observed polymorphism.

Structure description
Diosgenin [(3,25R)-spirost-5-en-3-ol, C 27 H 42 O 3 ] is a natural product that has played a pivotal role in the early stages of the industry of steroidal compounds, including the largescale synthesis of cortisone, and the manufacturing of the first combined oral contraceptive pills, at Syntex S.A., in Mexico (Djerassi, 1992). Diosgenin treated with the Jones reagent gives the expected oxidation product, with carbonyl groups at C3 and C6. This compound was characterized by X-ray crystallography, and its structure reported twenty years ago (Rajnikant et al., 2000). The reported refinement is rather technically unsound, since all H atoms were omitted in the model and the wrong absolute configuration was assigned to the molecule (see refcode QUPKUH in the CSD; Groom et al., 2016). Since data reports the Jones oxidation does not affect the E/F rings of diosgenin, chiral centre C25 is expected to retains its original R configuration, while the structure currently deposited in the CSD has a 25S configuration. A suitable model can be restored after inversion of the structure and addition of H atoms in calculated positions.
While working with this molecule, we obtained high-quality, well-shaped prismatic crystals (Fig. 1), and collected diffraction data with the purpose of improving the previously reported structure. However, it soon became clear that a new form had been crystallized instead; although the crystal symmetry was unchanged, differences in cell parameters as large as 2 Å were observed. After structure refinement (Table 1), a simulated powder diffraction pattern was compared with that obtained with the model of Rajnikant et al. (2000). Patterns are clearly different, as expected for two polymorphic forms (Fig. 2). The polymorphism seems to be a consequence of a slight modification of the conformation for rings A and B (Fig. 2, inset). In the structure reported herein, ring A displays a distorted envelope conformation, with a puckering amplitude q = 0.458 (3) Å , and ring B is a distorted half-chair, with q = 0.476 (3) Å . For the previously characterized polymorph, ring A is nearest to an half-chair, and B to a chair conformation. The conformational flexibility of the A ring of steroids bearing a conjugated 4-ene-3,6-dione fragment had already been pointed out (Anthony et al., 1998), and related to the modulation of the steroid-receptor interactions, which control hormonal responses for these molecules (Duax et al., 1994).
Since the space group is unchanged, there is a degree of similarity between the crystal structures for the polymorphic forms: the molecules, placed in general positions, lie approximately parallel to [010]. However, if a common orientation is chosen for the asymmetric units in both forms, the position of the molecule in the unit cell is shifted. With the selection made in Fig. 3, the centroid of the molecule constituting the asymmetric unit for the form reported herein is found at (0.313, 0.661, 0.380), while for the previously reported form, the centroid lies at (0.951, 1/5, 0.628). The action of the screw axis of space group P2 1 2 1 2 1 then generates different crystal structures. This kind of polymorphism, resulting from the rearrangement of the asymmetric unit within a common space group, is certainly favoured by the lack of supramolecular interactions. The title molecule does not include donor groups for hydrogen bonds, and only very weak C-HÁ Á ÁO contacts are present in the crystals. A closely related type of polymorphism in space group P2 1 was reported for diosgenone [(25R)-spirost-4-en-3-one, C 27 H 40 O 3 ; Herná ndez Linares et al., 2012], which crystallizes with Z 0 = 2. In that case, one of the independent molecules in the asymmetric unit changes its orientation, and unit-cell parameters vary considerably between polymorphs, even though crystal symmetry is retained.

Synthesis and crystallization
To a solution of diosgenin (2.0 g, 4.8 mmol) in 20 mL of CH 2 Cl 2 and 40 mL of acetone was slowly added a solution of Jones reagent (10 mL: 1.8 g, 18.4 mmol of CrO 3 in H 2 O/H 2 SO 4 8:2) over 10 min in an ice bath. The reaction was kept under stirring at room temperature and monitored by TLC until a Simulated powder patterns (Macrae et al., 2020) for the two P2 1 2 1 2 1 polymorphs of the title compound, with = 1.54 Å . Some reflections are indexed, in order to illustrate reflection shifts and intensity variations between both polymorphs. The inset shows an overlay between molecular structures, obtained by fitting C and O atoms in rings C/D/E/F. In the case of QUPKUH (Rajnikant et al., 2000), coordinates deposited in the CSD were inverted, and H atoms were placed in idealized positions.

Figure 3
Comparison of the crystal structure for the new polymorph (left) with that previously reported (right). One molecule is chosen arbitrarily as the asymmetric unit and displayed in ball-and-stick style, in order to have roughly the same orientation with respect to cell axis in both forms. Projections are viewed down crystallographic a axis.

Figure 1
Molecular structure of the title steroid, with displacement ellipsoids for non-H atoms at the 30% probability level. The inset is the crystal used for data collection. The largest dimension is 0.5 mm. change in colour (orange to green) was observed. Subsequently, 2-propanol was added to quench unreacted Jones reagent, and the reaction mixture was poured into a separating funnel and extracted with ethyl acetate. The solution was washed with distilled H 2 O, neutralized with NaHCO 3 , separated, dried over Na 2 SO 4 and evaporated to dryness under reduced pressure. The purification was carried out on a chromatographic column with silica gel (hexane:EtOAc, 9:1), affording 1.63 g (80% yield) of the title compound, while remaining solid was identified as starting material (20%). Single crystals for the compound of interest were obtained by slow evaporation of the corresponding chromatographic fraction.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1.

Funding information
Funding for this research was provided by: Consejo Nacional de Ciencia y Tecnología (grant No. 268178;grant No. 294412).

Special details
Refinement. All H atoms were placed in calculated positions and refined as riding to their carrier C-atoms (Sheldrick, 2015b).