Westphalen’s diol diacetate: 19(10→5)-abeo-5β-cholest-9-ene-3β,6β-diyl diacetate

The structure of the title steroid [alternative name: 3β,6β-diacetoxy-5β-methyl-19-norcholest-9(10)-ene], C31H50O4, confirms the generally accepted mechanism for the rearrangement of a cholestan-5α-ol derivative reported a century ago by Westphalen. The methyl group at position 10 of the starting material migrates to position 5 in the steroidal nucleus, while a Δ9 bond is formed, as indicated by the C=C bond length of 1.347 (4) Å. The methyl transposition leaves the 5R configuration unchanged, with the methyl oriented towards the β face. During the rearrangement, the steroidal B ring experiences a conformational distortion from chair to envelope with the C atom at position 6 as the flap. In the title structure, the isopropyl group of the side chain is disordered over two positions, with occupancies of 0.733 (10) and 0.267 (10). The carbonyl O atom in the acetyl group at C3 is also disordered with an occupancy ratio of 0.62 (4):0.38 (4).

The structure of the title steroid [alternative name: 3,6diacetoxy-5-methyl-19-norcholest-9(10)-ene], C 31 H 50 O 4 , confirms the generally accepted mechanism for the rearrangement of a cholestan-5-ol derivative reported a century ago by Westphalen. The methyl group at position 10 of the starting material migrates to position 5 in the steroidal nucleus, while a Á 9 bond is formed, as indicated by the C C bond length of 1.347 (4) Å . The methyl transposition leaves the 5R configuration unchanged, with the methyl oriented towards the face. During the rearrangement, the steroidal B ring experiences a conformational distortion from chair to envelope with the C atom at position 6 as the flap. In the title structure, the isopropyl group of the side chain is disordered over two positions, with occupancies of 0.733 (10) and 0.267 (10). The carbonyl O atom in the acetyl group at C3 is also disordered with an occupancy ratio of 0.62 (4):0.38 (4).

Related literature
For the initial report on the Westphalen rearrangement, see: Westphalen (1915). For applications in steroid synthesis, see: Rodig et al. (1961); Knights & Hanson (2004); Pinto et al. (2008Pinto et al. ( , 2009. For mechanistic aspects of this rearrangement, see: Kočovský & Č erný (1977); Kočovský et al. (1979); Kamernitskii et al. (1987). prepared under the Westphalen conditions in the cholestane series. Treatment with acetic anhydride and sulfuric acid promotes dehydration of the cholestan-5α-ol substrate, and the resulting carbocation is rearranged through the methyl 1,2-shift, before formation of the olefinic bond Δ 9 . The empty p orbital of the carbocation is electronically stabilized by the electron density of the O atom of the acetate at C6. With such a mechanism, a single epimer is expected as product, with the methyl at C5 oriented towards the β face. This stereochemistry has been confirmed in all the studied cases, but, surprisingly, the product of the very first report by Westphalen (1915) was never X-ray characterized.

Experimental
During a study on the optimization of reaction conditions for the Westphalen rearrangement carried out on 5-hydroxy-5α-cholestane-3β,6β-diyl diacetate, which was the substrate used by Westphalen, we obtained in 80% yield the rearrangement product (see Experimental). The molecular structure ( Fig. 1) and the absolute configuration for chiral centers are as expected. The saturated A and C rings have a chair conformation, while the B ring, which includes the C9═C10 double bond, is distorted to a half-chair conformation, close to an envelope with C6 as flap. Finally, the D ring adopts a half-chair conformation twisted on C13-C14. The observed conformation is indeed very similar to that described by Pinto et al. (2008) for the closely related derivative 3β-acetoxy-6β-hydroxy-5β-methyl-19-norcholest-9(10)ene. An overlay between the steroidal nucleus of this structure and that of the title molecule gives a r.m.s. deviation limited to 0.156 Å, the largest deviation arising from the side chain. This group presents a degree of flexibility, as reflected by the disorder detected in the title compound for the isopropyl group. The same conformation for the A-D ring system was also observed for a Westphalen product in the pregnane series (Pinto et al., 2009).
Experimental 5-Hydroxy-5α-cholestane-3β,6β-diyl diacetate (6.1 g, 12.09 mmol) was treated with acetic anhydride (150 ml) for 20 min at 363 K. Then, NaHSO 4 was added (1.74 g, 12.78 mmol) and stirred until complete consumption of the starting material (ca. 30 min). The mixture was poured in a 500 ml Erlenmeyer with pyridine and ice and vigorously stirred. The product, which deposited on the glass vessel, was dissolved in ethyl acetate, and then washed with saline solution, 5% HCl, distilled water, and finally 10% NaHCO 3 . This phase was dried over Na 2 SO 4 , and the solvent evaporated under reduced pressure. The crude (80% yield) was chromatographed over silicagel with petroleum ether and ethyl acetate (95:5) and crystallized from ethyl acetate. When KHSO 4 was used, the Westphalen compound was obtained in 35% yield.

Refinement
The isopropyl group in the lateral chain was found to be disordered over two positions, C251/C261/C271 and C252/C262/C272, and occupancies converged to 0.733 (10) and 0.267 (10), respectively. Both parts were restrained to have similar displacement parameters and geometry (SIMU and SAME restraints; Sheldrick, 2008). On the other side of the molecule, the carbonyl O atom in the acetyl group at C3 is also disordered over two sites, O301 and O302, with occupancies 0.62 (4) and 0.38 (4). All H atoms were placed in calculated positions and refined as riding to their carrier C atoms. C-H bond lengths were set to 0.96 (methyl) 0.97 (methylene) or 0.98 Å (methine), and isotropic parameters for H atoms were calculated as U iso (H) = xU eq (carrier C) with x = 1.5 (methyl) or x = 1.2 (methylene and methine groups).
Friedel pairs (714) were merged, and absolute configuration assigned by fixing the configuration of known chiral centers.

Figure 1
ORTEP view of the title molecule, with displacement ellipsoids for non-H atoms at the 30% probability level. For disordered parts, sites with occupancy less than 0.5 have been omitted.