6-Methyl­ideneandrost-4-ene-3,17-dione

L C R Andrade; M J M de Almeida; F M Fernandes Roleira; C L Varela; E J Tavares da Silva

doi:10.1107/S1600536812013207

. 2012 Mar 31;68(Pt 4):o1263. doi: 10.1107/S1600536812013207

6-Methylideneandrost-4-ene-3,17-dione

L C R Andrade ^a, M J M de Almeida ^a,^*, F M Fernandes Roleira ^b, C L Varela ^b, E J Tavares da Silva ^b

PMCID: PMC3344189 PMID: 22606192

Abstract

In the title compound, C₂₀H₂₆O₂, which is the 6-methylene derivative of androstenedione and a synthetic percursor of exemestane, the steroid A ring approximates to a sofa (or envelope) conformation, with the methylene group adjacent to the link to the B ring lying out of the plane of the other atoms. The B and C rings have slightly flattened chair conformations and the D ring is an envelope, with the CH group forming the flap. In the crystal, molecules are linked by two distinct C—H⋯O hydrogen bonds, involving acidic H atoms close to C=C and C=O double bonds.

Related literature

For the synthesis of the title compound, see: Annen et al. (1982 ▶). For exemestane aromatase inhibitor potency, see: Furr (2006 ▶). For elucidation of structural requirements needed to achieve antitumor activity, see: Cepa et al. (2005 ▶). For puckering parameters, see: Cremer & Pople (1975 ▶) and for asymmetry parameters, see: Duax & Norton (1975 ▶); Altona et al. (1968 ▶). For reference bond-length data, see: Allen et al. (1987 ▶).

Experimental

Crystal data

C₂₀H₂₆O₂
M _r = 298.41
Monoclinic,
a = 9.2343 (4) Å
b = 8.7162 (4) Å
c = 11.0798 (5) Å
β = 108.197 (2)°
V = 847.19 (7) Å³
Z = 2
Mo Kα radiation
μ = 0.07 mm⁻¹
T = 293 K
0.24 × 0.17 × 0.05 mm

Data collection

Bruker APEX CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2000 ▶) T _min = 0.835, T _max = 0.996
18560 measured reflections
1979 independent reflections
1433 reflections with I > 2σ(I)
R _int = 0.036

Refinement

R[F ² > 2σ(F ²)] = 0.040
wR(F ²) = 0.100
S = 1.02
1979 reflections
201 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.14 e Å⁻³
Δρ_min = −0.13 e Å⁻³

Data collection: SMART (Bruker, 2003) ▶; cell refinement: SAINT (Bruker, 2003) ▶; data reduction: SAINT ▶; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812013207/hb6686sup1.cif

e-68-o1263-sup1.cif^{(21.7KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812013207/hb6686Isup2.hkl

e-68-o1263-Isup2.hkl^{(97.4KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2A⋯O17ⁱ	0.97	2.43	3.345 (3)	158
C66—H66A⋯O3ⁱⁱ	0.93	2.47	3.365 (3)	163

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

This work was supported by funds from FEDER via the COMPETE (Programa Operacional Factores de Competitividade) programme and by the FCT (Fundação para a Ciência e a Tecnologia, project PEst-C/FIS/UI0036/2011).

supplementary crystallographic information

Comment

The title compound is the 6-methylene derivative of androstenedione, the natural substrate of aromatase, and is a key synthetic precursor of exemestane, the most potent steroid aromatase inhibitor clinically used in the breast cancer treatment (Furr, 2006). Following our work on the determination of several androstane structures of potential aromatase inhibitors and intermediates of their syntheses, the X-ray analysis of compound (I) aims to contribute to the elucidation of structural requirements needed to achieve antitumor activity (Cepa et al., 2005). From the single-crystal diffraction measurements one can conclude that bond lengths are within normal values (Allen et al., 1987) with an average C_sp³–C_sp³ bond length of 1.534 (13) Å. Due to the C4═C5 double bond ring A addopts a 1α–sofa conformation, slightly distorted towards a 1α,2β–halfchair one [asymmetry parameters (Duax and Norton, 1975): ΔC_s(1)=7.8 (3), ΔC₂(1,2)=17.5 (3) and ΔC₂(2,3)=51.4 (4)°]. Rings B and C have slightly flattened chair conformations evidenced by average torsion angle values of 50 (3) and 55 (3)°, respectively. The five member D ring assumes a 14α–envelope conformation [puckering parameters (Cremer and Pople, 1975): q₂=0.414 (3) Å and φ₂=211.3 (4)°; pseudo-rotation (Altona et al., 1968) and asymmetry parameters: Δ=25.4 (4), φ_m=42.7 (2)°, ΔC_s(14)=4.8 (3) and ΔC₂(13,14)=14.9 (3)°]. The pseudo-torsion angle C19–C10···C13–C18 of 2.2 (2)° indicates that the molecule is only slightly twisted. The 6-methylene group is in a beta equatorial position with an angle of 63.8 (2)°. Due to the acidic character of hydrogen atoms close to C═C or C═O double bonds, cohesion of the crystal can be attributed to a net of two C–H···O pseudohydrogen bonds, namely C2–H2A···O17 and C66–H66A···O3, connecting molecules aligned almost along [101], respectively head to tail and head to head.

Experimental

6-Methylenandrost-4-ene-3,17-dione was prepared according to a described procedure (Annen et al., 1982) as follows. A suspension of anhydrous sodium acetate (1.0 g, 12.19 mmol) in dry chloroform (30.0 cm³) containing formaldehyde dimethyl acetal (30.0 cm³, 340.0 mmol) and phosphoryl choride (1.9 cm³, 20.0 mmol) was heated at reflux for 1 h. Androstenedione (773.5 mg, 2.70 mmol) was then added and the mixture was supplemented dropwise with phosphoryl choride (1.9 cm³, 20.0 mmol) over a period of 3 h 30 min. The reaction mixture was subsequently refluxed under nitrogen for 10 h, after which was allowed to cool to room temperature. A saturated aqueous solution of sodium carbonate was then added under vigorous stirring until the aqueous layer became alkaline. This mixture was extracted with chloroform (200 cm³) and then the organic phase was washed with water (4x100 cm³), dried over anhydrous MgSO₄, filtered and concentrated to dryness. The resulting residue was purified by a silica gel 60 column chromatography (hexane/diethyl ether) affording the pure 6-methylenandrost-4-ene-3,17-dione (134.8 mg, 17%). Suitable crystals for X-ray studies were grown from slow evaporation from acetone/n-hexane: Mp. 435–437 K [lit 440 K (Annen et al., 1982)]; IR ν_max (NaCl plates, CHCl₃) cm^-1: 3084 (=C–H), 1738 (C₁₇=O), 1671 (C₃=O), 1599 (C═C); ¹H NMR (600 MHz, CDCl₃): δ 0.78 (3H, s, 18–H₃), 1.00 (3H, s, 19–H₃), 4.87 (1H, t, ═CH₂), 4.97 (1H, t, ═CH₂), 5.79 (1H, s, 4–H); ¹³C NMR (150 MHz, CDCl₃): δ 11.5 (C18), 14.9 (C19), 18.2, 19.5, 29.0, 31.6, 32.9, 33.0, 33.6, 36.6, 36.9, 45.3, 48.9, 50.3, 112.4 (═CH₂), 119.6 (C4), 143.2 (C6), 166.3 (C5), 197.4 (C3), 217.8 (C17).