Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270103026933/na1627sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270103026933/na1627Isup2.hkl |
CCDC reference: 231081
Oxidation of commercially available dehydroepiandrosterone acetate according to the procedures described by Salvador & Clark (2001) afforded the compound androst-5-ene-7,17-dione-3β-yl-acetate, which in turn was reduced using zinc/acetic acid/ultrasound (Salvador et al., 1993), to give the mixture of the two isomers of (I). Crystals of (I) were obtained by fractional crystallization from n-hexane [m.p.: 416.0 (5) K]. Spectroscopic analysis: IR: 1726, 1739, 2867, 2948, 3004 cm−1; 1H NMR (CDCl3, 300 MHz, δ, p.p.m.): 0.83 (s, 18-H3), 0.91 (s, 18-H3), 2.04 (s, CH3CO), 4.73 (m, 3α-H); 13C NMR (CDCl3, 75.5 MHz, δ, p.p.m.): 126.87, 131.25 (C6, C7), 170.573 (CH3CO), 220.47 (C17), 73.37 (C—O).
All H atoms were refined as riding on their parent atoms using the SHELXL97 (Sheldrick, 1997) defaults [C—H = 0.93–0.98 Å and Uiso(H) = 1.2Ueq(C) Is this added text OK?]. The absolute configuration was not determined from the X-ray data but was known from the synthesis route. Due to the lack of any significant anomalous scattering at the Mo Kα wavelength, Friedel pairs were merged before refinement.
Data collection: CAD-4 Software (Enraf-Nonius, 1989); cell refinement: CAD-4 Software; data reduction: HELENA (Spek, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97.
Fig. 1. The molecular structure of (I), showing the atomic numbering scheme. Displacement ellipsoids are drawn at the ??% probability level and H atoms are shown as small spheres of arbitrary radii. |
C21H30O3 | Dx = 1.145 Mg m−3 |
Mr = 330.45 | Melting point: 416.0(5) K |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 25 reflections |
a = 12.6847 (17) Å | θ = 5.3–18.6° |
b = 9.2934 (17) Å | µ = 0.08 mm−1 |
c = 16.266 (3) Å | T = 293 K |
V = 1917.5 (6) Å3 | Block, colourless |
Z = 4 | 0.25 × 0.17 × 0.15 mm |
F(000) = 720 |
Enraf-Nonius CAD-4 diffractometer | 1252 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.047 |
Graphite monochromator | θmax = 27.5°, θmin = 2.5° |
profile data from ω/2θ scans | h = −16→16 |
Absorption correction: ψ scan North et al. (1968) | k = −12→0 |
Tmin = 0.941, Tmax = 0.988 | l = −21→0 |
4760 measured reflections | 3 standard reflections every 180 min |
2485 independent reflections | intensity decay: 1.9% |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.044 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.130 | H-atom parameters constrained |
S = 1.01 | w = 1/[σ2(Fo2) + (0.0599P)2 + 0.1192P] where P = (Fo2 + 2Fc2)/3 |
2485 reflections | (Δ/σ)max < 0.001 |
220 parameters | Δρmax = 0.12 e Å−3 |
0 restraints | Δρmin = −0.13 e Å−3 |
C21H30O3 | V = 1917.5 (6) Å3 |
Mr = 330.45 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 12.6847 (17) Å | µ = 0.08 mm−1 |
b = 9.2934 (17) Å | T = 293 K |
c = 16.266 (3) Å | 0.25 × 0.17 × 0.15 mm |
Enraf-Nonius CAD-4 diffractometer | 1252 reflections with I > 2σ(I) |
Absorption correction: ψ scan North et al. (1968) | Rint = 0.047 |
Tmin = 0.941, Tmax = 0.988 | 3 standard reflections every 180 min |
4760 measured reflections | intensity decay: 1.9% |
2485 independent reflections |
R[F2 > 2σ(F2)] = 0.044 | 0 restraints |
wR(F2) = 0.130 | H-atom parameters constrained |
S = 1.01 | Δρmax = 0.12 e Å−3 |
2485 reflections | Δρmin = −0.13 e Å−3 |
220 parameters |
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | ||
O3B | 0.5116 (3) | 0.5584 (5) | 0.3697 (2) | 0.1317 (13) | |
O3A | 0.6295 (2) | 0.7269 (4) | 0.40259 (14) | 0.0957 (8) | |
O17 | 0.6861 (2) | 0.6341 (4) | 1.06694 (16) | 0.1094 (10) | |
C1 | 0.7394 (2) | 0.6913 (4) | 0.61514 (18) | 0.0633 (9) | |
H1A | 0.8075 | 0.7241 | 0.6349 | 0.076* | |
H1B | 0.7348 | 0.5887 | 0.6256 | 0.076* | |
C2 | 0.7334 (3) | 0.7167 (4) | 0.52285 (19) | 0.0728 (9) | |
H2A | 0.7502 | 0.8166 | 0.5114 | 0.087* | |
H2B | 0.7858 | 0.6574 | 0.4957 | 0.087* | |
C3 | 0.6271 (3) | 0.6829 (4) | 0.48820 (18) | 0.0700 (10) | |
H3 | 0.6163 | 0.5786 | 0.4906 | 0.084* | |
C3A | 0.5680 (4) | 0.6567 (7) | 0.3507 (3) | 0.1046 (16) | |
C3B | 0.5808 (5) | 0.7182 (10) | 0.2637 (2) | 0.175 (3) | |
H3B1 | 0.5440 | 0.6582 | 0.2252 | 0.263* | |
H3B2 | 0.6542 | 0.7213 | 0.2496 | 0.263* | |
H3B3 | 0.5521 | 0.8138 | 0.2619 | 0.263* | |
C4 | 0.5380 (3) | 0.7559 (5) | 0.53369 (18) | 0.0781 (11) | |
H4A | 0.4708 | 0.7228 | 0.5125 | 0.094* | |
H4B | 0.5421 | 0.8593 | 0.5260 | 0.094* | |
C5 | 0.5472 (2) | 0.7193 (4) | 0.62520 (16) | 0.0614 (8) | |
H5 | 0.5483 | 0.6140 | 0.6278 | 0.074* | |
C6 | 0.4541 (2) | 0.7635 (4) | 0.67485 (19) | 0.0682 (9) | |
H6 | 0.3893 | 0.7717 | 0.6486 | 0.082* | |
C7 | 0.4589 (2) | 0.7916 (3) | 0.75410 (19) | 0.0591 (7) | |
H7 | 0.3965 | 0.8109 | 0.7820 | 0.071* | |
C8 | 0.5599 (2) | 0.7939 (3) | 0.80119 (16) | 0.0494 (7) | |
H8 | 0.5808 | 0.8947 | 0.8076 | 0.059* | |
C9 | 0.64840 (18) | 0.7169 (3) | 0.75354 (17) | 0.0471 (6) | |
H9 | 0.6278 | 0.6153 | 0.7513 | 0.057* | |
C10 | 0.6523 (2) | 0.7681 (3) | 0.66387 (19) | 0.0527 (7) | |
C11 | 0.7536 (2) | 0.7204 (4) | 0.79938 (19) | 0.0669 (9) | |
H11A | 0.7796 | 0.8186 | 0.8007 | 0.080* | |
H11B | 0.8046 | 0.6624 | 0.7698 | 0.080* | |
C12 | 0.7435 (2) | 0.6635 (4) | 0.88830 (18) | 0.0683 (9) | |
H12A | 0.7269 | 0.5616 | 0.8873 | 0.082* | |
H12B | 0.8101 | 0.6757 | 0.9168 | 0.082* | |
C13 | 0.6573 (2) | 0.7446 (3) | 0.93375 (18) | 0.0553 (8) | |
C14 | 0.5533 (2) | 0.7280 (3) | 0.88687 (16) | 0.0508 (7) | |
H14 | 0.5431 | 0.6245 | 0.8788 | 0.061* | |
C15 | 0.4699 (3) | 0.7753 (4) | 0.94812 (18) | 0.0707 (10) | |
H15A | 0.4013 | 0.7359 | 0.9342 | 0.085* | |
H15B | 0.4649 | 0.8793 | 0.9507 | 0.085* | |
C16 | 0.5112 (3) | 0.7125 (5) | 1.02957 (19) | 0.0808 (11) | |
H16A | 0.4994 | 0.7796 | 1.0743 | 0.097* | |
H16B | 0.4754 | 0.6229 | 1.0423 | 0.097* | |
C17 | 0.6271 (3) | 0.6867 (4) | 1.0178 (2) | 0.0717 (10) | |
C18 | 0.6886 (3) | 0.9031 (4) | 0.9494 (2) | 0.0836 (11) | |
H18A | 0.7535 | 0.9063 | 0.9796 | 0.125* | |
H18B | 0.6342 | 0.9499 | 0.9805 | 0.125* | |
H18C | 0.6975 | 0.9516 | 0.8977 | 0.125* | |
C19 | 0.6688 (3) | 0.9312 (3) | 0.6591 (2) | 0.0799 (10) | |
H19A | 0.7353 | 0.9557 | 0.6836 | 0.120* | |
H19B | 0.6130 | 0.9791 | 0.6882 | 0.120* | |
H19C | 0.6683 | 0.9611 | 0.6026 | 0.120* |
U11 | U22 | U33 | U12 | U13 | U23 | |
O3B | 0.146 (3) | 0.163 (4) | 0.086 (2) | −0.021 (3) | −0.023 (2) | −0.006 (2) |
O3A | 0.127 (2) | 0.113 (2) | 0.0471 (13) | −0.009 (2) | 0.0098 (15) | 0.0151 (15) |
O17 | 0.133 (2) | 0.127 (2) | 0.0687 (17) | 0.052 (2) | −0.0154 (17) | 0.0170 (17) |
C1 | 0.0612 (18) | 0.065 (2) | 0.064 (2) | 0.0005 (17) | 0.0100 (16) | 0.0012 (16) |
C2 | 0.085 (2) | 0.070 (2) | 0.064 (2) | −0.005 (2) | 0.0256 (19) | 0.0066 (18) |
C3 | 0.089 (2) | 0.075 (2) | 0.0457 (18) | −0.008 (2) | 0.0091 (17) | 0.0083 (17) |
C3A | 0.120 (4) | 0.141 (5) | 0.052 (2) | 0.021 (4) | 0.002 (3) | 0.009 (3) |
C3B | 0.205 (5) | 0.269 (9) | 0.052 (2) | 0.011 (6) | 0.006 (3) | 0.026 (4) |
C4 | 0.082 (2) | 0.099 (3) | 0.0532 (18) | 0.010 (2) | 0.0022 (17) | 0.004 (2) |
C5 | 0.0601 (18) | 0.075 (2) | 0.0492 (17) | 0.004 (2) | −0.0007 (15) | 0.0039 (17) |
C6 | 0.0526 (18) | 0.091 (2) | 0.061 (2) | 0.0066 (19) | −0.0059 (16) | 0.000 (2) |
C7 | 0.0526 (16) | 0.0711 (18) | 0.0535 (17) | 0.0123 (16) | 0.0042 (16) | 0.0024 (18) |
C8 | 0.0495 (16) | 0.0475 (15) | 0.0511 (16) | 0.0033 (14) | −0.0039 (13) | −0.0051 (14) |
C9 | 0.0469 (15) | 0.0412 (13) | 0.0532 (16) | 0.0007 (12) | −0.0023 (14) | −0.0013 (16) |
C10 | 0.0562 (17) | 0.0481 (16) | 0.0538 (18) | 0.0010 (14) | 0.0051 (14) | −0.0006 (14) |
C11 | 0.0523 (17) | 0.082 (2) | 0.067 (2) | 0.0059 (19) | −0.0049 (16) | −0.0049 (19) |
C12 | 0.0571 (17) | 0.084 (2) | 0.063 (2) | 0.0121 (18) | −0.0155 (17) | 0.0003 (18) |
C13 | 0.0611 (18) | 0.0531 (18) | 0.0516 (17) | 0.0024 (15) | −0.0102 (15) | −0.0042 (15) |
C14 | 0.0544 (16) | 0.0489 (16) | 0.0491 (16) | 0.0044 (16) | −0.0010 (14) | −0.0067 (14) |
C15 | 0.075 (2) | 0.082 (2) | 0.0552 (19) | 0.011 (2) | 0.0016 (17) | −0.0053 (18) |
C16 | 0.099 (3) | 0.093 (3) | 0.0507 (18) | 0.011 (2) | 0.0033 (19) | 0.002 (2) |
C17 | 0.093 (3) | 0.065 (2) | 0.057 (2) | 0.022 (2) | −0.0101 (19) | −0.0074 (18) |
C18 | 0.093 (3) | 0.071 (2) | 0.087 (3) | −0.011 (2) | −0.019 (2) | −0.020 (2) |
C19 | 0.108 (3) | 0.0561 (19) | 0.075 (2) | −0.003 (2) | 0.010 (2) | 0.0056 (18) |
O3B—C3A | 1.200 (6) | C8—H8 | 0.9800 |
O3A—C3A | 1.322 (6) | C9—C11 | 1.528 (4) |
O3A—C3 | 1.452 (4) | C9—C10 | 1.535 (4) |
O17—C17 | 1.200 (4) | C9—H9 | 0.9800 |
C1—C2 | 1.522 (4) | C10—C19 | 1.532 (4) |
C1—C10 | 1.536 (4) | C11—C12 | 1.545 (4) |
C1—H1A | 0.9700 | C11—H11A | 0.9700 |
C1—H1B | 0.9700 | C11—H11B | 0.9700 |
C2—C3 | 1.495 (5) | C12—C13 | 1.520 (4) |
C2—H2A | 0.9700 | C12—H12A | 0.9700 |
C2—H2B | 0.9700 | C12—H12B | 0.9700 |
C3—C4 | 1.511 (5) | C13—C17 | 1.518 (5) |
C3—H3 | 0.9800 | C13—C14 | 1.531 (4) |
C3A—C3B | 1.535 (6) | C13—C18 | 1.547 (5) |
C3B—H3B1 | 0.9600 | C14—C15 | 1.519 (4) |
C3B—H3B2 | 0.9600 | C14—H14 | 0.9800 |
C3B—H3B3 | 0.9600 | C15—C16 | 1.540 (4) |
C4—C5 | 1.531 (4) | C15—H15A | 0.9700 |
C4—H4A | 0.9700 | C15—H15B | 0.9700 |
C4—H4B | 0.9700 | C16—C17 | 1.502 (5) |
C5—C6 | 1.488 (4) | C16—H16A | 0.9700 |
C5—C10 | 1.543 (4) | C16—H16B | 0.9700 |
C5—H5 | 0.9800 | C18—H18A | 0.9600 |
C6—C7 | 1.317 (4) | C18—H18B | 0.9600 |
C6—H6 | 0.9300 | C18—H18C | 0.9600 |
C7—C8 | 1.493 (4) | C19—H19A | 0.9600 |
C7—H7 | 0.9300 | C19—H19B | 0.9600 |
C8—C14 | 1.524 (4) | C19—H19C | 0.9600 |
C8—C9 | 1.540 (4) | ||
C3A—O3A—C3 | 117.5 (3) | C19—C10—C9 | 111.0 (3) |
C2—C1—C10 | 113.6 (3) | C19—C10—C1 | 109.6 (3) |
C2—C1—H1A | 108.8 | C9—C10—C1 | 111.7 (2) |
C10—C1—H1A | 108.8 | C19—C10—C5 | 112.8 (3) |
C2—C1—H1B | 108.8 | C9—C10—C5 | 105.6 (2) |
C10—C1—H1B | 108.8 | C1—C10—C5 | 106.0 (2) |
H1A—C1—H1B | 107.7 | C9—C11—C12 | 112.2 (2) |
C3—C2—C1 | 112.6 (3) | C9—C11—H11A | 109.2 |
C3—C2—H2A | 109.1 | C12—C11—H11A | 109.2 |
C1—C2—H2A | 109.1 | C9—C11—H11B | 109.2 |
C3—C2—H2B | 109.1 | C12—C11—H11B | 109.2 |
C1—C2—H2B | 109.1 | H11A—C11—H11B | 107.9 |
H2A—C2—H2B | 107.8 | C13—C12—C11 | 110.2 (3) |
O3A—C3—C2 | 106.5 (3) | C13—C12—H12A | 109.6 |
O3A—C3—C4 | 111.0 (3) | C11—C12—H12A | 109.6 |
C2—C3—C4 | 113.3 (3) | C13—C12—H12B | 109.6 |
O3A—C3—H3 | 108.6 | C11—C12—H12B | 109.6 |
C2—C3—H3 | 108.6 | H12A—C12—H12B | 108.1 |
C4—C3—H3 | 108.6 | C17—C13—C12 | 116.4 (3) |
O3B—C3A—O3A | 124.2 (4) | C17—C13—C14 | 101.3 (2) |
O3B—C3A—C3B | 125.7 (6) | C12—C13—C14 | 109.1 (2) |
O3A—C3A—C3B | 110.0 (5) | C17—C13—C18 | 104.7 (3) |
C3A—C3B—H3B1 | 109.5 | C12—C13—C18 | 111.6 (3) |
C3A—C3B—H3B2 | 109.5 | C14—C13—C18 | 113.5 (3) |
H3B1—C3B—H3B2 | 109.5 | C15—C14—C8 | 121.4 (2) |
C3A—C3B—H3B3 | 109.5 | C15—C14—C13 | 104.2 (2) |
H3B1—C3B—H3B3 | 109.5 | C8—C14—C13 | 111.6 (2) |
H3B2—C3B—H3B3 | 109.5 | C15—C14—H14 | 106.2 |
C3—C4—C5 | 108.6 (3) | C8—C14—H14 | 106.2 |
C3—C4—H4A | 110.0 | C13—C14—H14 | 106.2 |
C5—C4—H4A | 110.0 | C14—C15—C16 | 102.6 (3) |
C3—C4—H4B | 110.0 | C14—C15—H15A | 111.3 |
C5—C4—H4B | 110.0 | C16—C15—H15A | 111.3 |
H4A—C4—H4B | 108.3 | C14—C15—H15B | 111.3 |
C6—C5—C4 | 114.0 (3) | C16—C15—H15B | 111.3 |
C6—C5—C10 | 112.5 (2) | H15A—C15—H15B | 109.2 |
C4—C5—C10 | 113.4 (3) | C17—C16—C15 | 106.5 (3) |
C6—C5—H5 | 105.3 | C17—C16—H16A | 110.4 |
C4—C5—H5 | 105.3 | C15—C16—H16A | 110.4 |
C10—C5—H5 | 105.3 | C17—C16—H16B | 110.4 |
C7—C6—C5 | 123.3 (3) | C15—C16—H16B | 110.4 |
C7—C6—H6 | 118.3 | H16A—C16—H16B | 108.6 |
C5—C6—H6 | 118.3 | O17—C17—C16 | 126.2 (4) |
C6—C7—C8 | 123.0 (3) | O17—C17—C13 | 125.9 (3) |
C6—C7—H7 | 118.5 | C16—C17—C13 | 107.8 (3) |
C8—C7—H7 | 118.5 | C13—C18—H18A | 109.5 |
C7—C8—C14 | 114.6 (2) | C13—C18—H18B | 109.5 |
C7—C8—C9 | 111.1 (2) | H18A—C18—H18B | 109.5 |
C14—C8—C9 | 108.3 (2) | C13—C18—H18C | 109.5 |
C7—C8—H8 | 107.5 | H18A—C18—H18C | 109.5 |
C14—C8—H8 | 107.5 | H18B—C18—H18C | 109.5 |
C9—C8—H8 | 107.5 | C10—C19—H19A | 109.5 |
C11—C9—C10 | 115.4 (2) | C10—C19—H19B | 109.5 |
C11—C9—C8 | 112.4 (2) | H19A—C19—H19B | 109.5 |
C10—C9—C8 | 110.9 (2) | C10—C19—H19C | 109.5 |
C11—C9—H9 | 105.8 | H19A—C19—H19C | 109.5 |
C10—C9—H9 | 105.8 | H19B—C19—H19C | 109.5 |
C8—C9—H9 | 105.8 | ||
C3A—O3A—C3—C2 | 151.2 (4) | C19—C10—C13—C18 | −6.9 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
C1—H1B···O17i | 0.97 | 2.49 | 3.263 (4) | 137 |
C3—H3···O3B | 0.98 | 2.38 | 2.683 (5) | 97 |
Symmetry code: (i) −x+3/2, −y+1, z−1/2. |
Experimental details
Crystal data | |
Chemical formula | C21H30O3 |
Mr | 330.45 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 293 |
a, b, c (Å) | 12.6847 (17), 9.2934 (17), 16.266 (3) |
V (Å3) | 1917.5 (6) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.08 |
Crystal size (mm) | 0.25 × 0.17 × 0.15 |
Data collection | |
Diffractometer | Enraf-Nonius CAD-4 diffractometer |
Absorption correction | ψ scan North et al. (1968) |
Tmin, Tmax | 0.941, 0.988 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 4760, 2485, 1252 |
Rint | 0.047 |
(sin θ/λ)max (Å−1) | 0.649 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.044, 0.130, 1.01 |
No. of reflections | 2485 |
No. of parameters | 220 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.12, −0.13 |
Computer programs: CAD-4 Software (Enraf-Nonius, 1989), CAD-4 Software, HELENA (Spek, 1997), SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), ORTEPII (Johnson, 1976), SHELXL97.
C6—C7 | 1.317 (4) | ||
C3A—O3A—C3—C2 | 151.2 (4) | C19—C10—C13—C18 | −6.9 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
C1—H1B···O17i | 0.97 | 2.49 | 3.263 (4) | 137 |
C3—H3···O3B | 0.98 | 2.38 | 2.683 (5) | 97 |
Symmetry code: (i) −x+3/2, −y+1, z−1/2. |
Aromatase (oestrogen synthetase) is a cytochrome P-450 enzyme complex which catalyzes the conversion of androgens, androstenedione and testosterone into oestrogens, oestrone and oestradiol (Thomson & Siiteri, 1974; Miller & Santem, 2001). Aromatization of androgens is thought to proceed with three sequential oxygenations at the C19 position. In the third step, the angular methyl group at C19 and the 1β,2β H atoms are eliminated, resulting in the aromatization of the A ring of the androgen to form the oestrogen.
Steroid analogues of androstenedione with substitutions at C4, C6, C7, C14 and C19 are known to be potent inhibitors of aromatase (Brodie & Njar, 2000; Brodie & Long, 2001), and for this reason they may be of value in the treatment of oestrogen-dependent diseases. Indeed, some of these compounds, namely formestane (Lentaron) and examestane (Aromasin), have already been approved for breast cancer therapy (Brueggemeier, 2002; Buzdar, 2003).
The biological activity of these steroids and their ability to bind to the enzyme depends on whether the configuration at C5 is α or β, due to the shape of the two epimers (Laurence et al., 1986). The 5α steroids are flat, whereas the 5β epimers are bent at the A/B ring junctions. Structure-activity relationships and recent aromatase modelling studies have revealed the existence of a hydrophobic binding pocket with a limited accessible volume in the region corresponding to the β-side, rather than the α-side, of the C4, C6 and C7 positions of the androstenedione substrate (Numazawa et al., 2002).
The title compound, (I), is a key intermediate for the synthesis of new steroid inhibitors, possibly including inactivators of aromatase, and is particularly interesting due to the presence of a strategic double bond in the B ring which is easily functionalized. Furthermore, compound (I) itself is a potential aromatase inhibitor, as it combines the due steric requirements with the presence of the C17 carbonyl group, which is crucial to the inhibition of the enzyme. The preliminary biological evaluation of (I) is currently in progress. \sch
A view of the molecule of (I), with the corresponding atomic numbering scheme, is shown in Fig.1. Bond lengths and angles are within the expected ranges (Allen et al., 1987), with average distances Csp3—Csp3 1.53 (1), Csp2═Csp2 1.317 (4), Csp3—Csp2 1.503 (8), O-Csp3 1.452 (4), O-Csp2 1.322 (6) and O═Csp2 1.200 (6) Å. All ring junctions are trans. Rings A and C have average torsion angles of 55.2 (13) and 57.5 (15)°, respectively, and slightly flattened chair conformations, as shown by the Cremer & Pople (1975) puckering parameters [ring A (C1—C5,C10): Q = 0.567 (4) Å, θ = 6.9 (4) and ϕ = 254 (3)°; ring C (C8,C9,C11—C14): Q = 0.590 (3) Å, θ = 5.7 (3) and ϕ = 279 (3)°]. The conformation of ring B, which contains a double bond between atoms C6 and C7, is close to half-chair, with a weighted average torsion angle of 43 (9)° and a pseudo-binary axis running through the middle of the C6—C7 and C9—C10 bonds [asymmetry parameter (Reference?) ΔC2(C6—C7) = 5.0 (4)°; puckering parameters(C5—C10) Q = 0.529 (3) Å, θ = 46.4 (3)° and ϕ = 276.0 (5)°].
The five-membered D ring has a 14-envelope conformation with an average torsion angle of 30 (6)°. The puckering parameters calculated using the atom sequence C13—C17 are q2 = 0.411 (4) Å and ϕ2 = 210.2 (5)° [pseudo-rotation (Altona et al., 1968) and asymmetry parameters: Δ = 23.7 (6), ϕm = 42.4 (2), ΔCs(14) = 5.4 (3)°].
The C3 substituent is equatorial to ring A. The acetyl group is planar, with an average deviation of the non-H atoms from the least-squares plane of 0.001 (5) Å. The angle between this plane and the least-squares plane of ring A is 58.34 (15)°. The distance between the terminal atoms, O17···C3B, is 13.156 (5) Å and the C19—C10···C13—C18 torsion angle is −6.9 (3)°, showing that the molecule is twisted. For trans-fused rings, this torsion angle rarely exceeds 4%, except when bulky sustituents, e.g. attached to ring D at C17, induce larger deviations due to steric effects (Andrade et al., 2001). In the crystal structure of the closely related compound androst-5,15-diene-3β-ol-17-one acetate (Khazheeva et al., 1989), an even larger twist angle of 10° was observed.
In order to investigate whether this unusual twist would be present in the isolated molecule of (I), we have performed an ab initio molecular orbital Roothaan Hartree-Fock (MO-RHF) calculation of the equilibrium molecular geometry using the computer program GAMESS (Schmidt et al., 1993). An extended 6–31 G(d,p) basis set was used and tight conditions were applied for the self-consistent field convergence (SCF) cycles and location of the equilibrium geometry, the final electron-density variation at the SCF cycles and maximum energy gradient at the end of the geometry optimization being less than 10−5 atomic units. The code was run in parallel on a cluster of 12 Compac XP1000 workstations (Alpha EV67 processors, 667 MHz) running Linux.
The conformation of the steroid nucleus as determined from the X-ray data is well reproduced by the MO-RHF calculations, the mean deviation of bond lengths and angles being 0.012 Å and 0.52°. The largest deviation between the two geometries is the torsion angle of the acetyl susbtituent, which has some rotational freedom around O3A—C3. The calculated value of the C3A—O3A—C3—C2 torsion angle for the isolated molecule is 154.2°, compared with the value measured in the crystal of 151.1 (4)°.
Interestingly, the equilibrium geometry of the isolated molecule also features a sizeable C19—C10···C13—C18 twist angle of −8.2°, to be compared with the experimental value of −6.9 (3)°. It can be concluded that the observed twist is not due to packing effects but probably arises from the unusal conformation of ring B, due to the C6═C7 double bond.
There are no strong hydrogen bonds in the structure of (I), due to the absence of standard donor groups, and thus cohesion of the crystal structure is maintained through weak intermolecular interactions. A short contact is present between one of the H atoms attached to atom C1 and atom O17, and this can be classified as one of these weak interactions. Another short contact exists between the H atom bound to atom C3 and atom O3B, which may exert some influence in the orientation of the acetyl group.