17β-Ethoxy-3-methoxy-8-isoestra-1,3,5(10)-triene

The conformation of the crystal of 17β-ethoxy-3-methoxy-8-iso­estra-1,3,5(10)-triene, C₂₁H₃₀O₂, (I), has been established and compared with the molecular structure of a typical steroid estrogen 8-iso-analogue, (II). Calculations of distances separating some of the H-atom pairs in (I) and (II) by molecular-mechanical and semi-empirical methods revealed the similarity of the values to the H...H distances obtained from X-ray analysis.

S1. Comment

Steroid estrogens are widely used for hormone replacement therapy (Krempler et al., 1995; Vickers et al., 1995; Sotelo et al., 1997) but many of these compounds increase the incidence of endometrium cancer (Sulak et al., 1997) and breast cancer (Vessay et al., 1997; Colditz et al., 1995) under long-term application. One of the possible mechanisms contributing to carcinogenesis is the metabolic activation of estrogens by hydroxylation, resulting in? 16α-hydroxyestron formation (Palomino et al., 1990; Kabat et al., 1997; Shon et al., 1997). Hence, any modifications of estrogen molecules that hinder such metabolic activation could reduce the incidence of carcinogenesis. At the same time, the tolerance of target physiological activities to these modifications is required.

We synthesized steroid estrogen 8-isoanalogues with a 17β-ethoxy group (Egorov et al., 2003) and investigated their biological properties. This substituent could prevent ketone formation at the C17 position and could also shield the C16 position from metabolic hydroxylation. We found that such steroids, given orally to ovariectomized rats for 35 d, normalized serum cholesterol level and prevented mineral bone-content loss, which highlights the importance of investigating the molecular structure of such compounds. Structure investigations were carried out for 17β-ethoxy-3-methoxy-8-isoestra- 1,3,5(10)-triene, (I), synthesized from 17β-acetoxy-3- methoxy-8-isoestra-1,3,5(10)-triene, (II), via the Brown reaction (reference?), and the crystal conformation was determined by X-ray analysis (Fig.1). Positional parameters, bond lengths, bond angles and torsion angles have been deposited in the Cambridge Structural Database (No. 164258; Allen, 2002) and presented at the III National Conference on X-ray SRNE in Moscow (Shavva et al., 2001).

Ring A is planar, and ring B has a distorted 8α-half-chair conformation. Atoms C6 and C9 lie practically in the plane of ring A, whereas atoms C7 and C8 deviate +0.33 and −0.44 Å, respectively, from the plane. The angle between the C5/C6/C9/C10 and C7/C8/C9 planes is 43.0°. Ring C has a regular 9α,13β-chair conformation, and the angles between the C8/C11/C12/C14 plane (`chair bottom') and planes C8/C9/C11 and C12/C13/C14 are 131.4 and 131.9°, respectively. Ring D has almost a regular 13β- envelope conformation, with an angle between planes C14/C15/C16/C17 (base of the envelope) and C13/C14/C17 of 46.7°. The molecule of the steroid in question is approximately `flat' compared with B-nor-8-isoanaog (Egorov et al., 2002); the plane of the aromatic ring makes an angle of 43.1° with the `chair bottom' of ring C and an angle of 32.3° with the base of the envelope of ring D. The O1—O2 distance, which is known to be important for binding to an estrogen receptor, is 10.916 (5) Å.

It is common knowledge that estrogen-receptor modulations of biological properties are determined mainly by the corresponding ligand-receptor complex structure (Anstead et al., 1997; Gao et al., 1999; Shiau et al., 2002), and for this reason, attention is increasingly being focused on the analysis of such complexes with the aim of discovering biological-activity prediction principles for the design of new ligands (Shiau et al., 1998). At the first stage of investigation, ligand conformations based on X-ray analysis data and confromations calculated using molecular-mechanical methods are compared (Sedee et al., 1985; Kayser et al., 1995).

We decided to compare the molecular structure of (I) with the typical steroid estrogen 8-isoanalog (II), the X-ray data of which were reported by Starova et al. (2001). We found no diference in the general geometry of these molecules (Fig. 2). We also calculated interatomic distances (H1—H11α, H1—H11β, H1—H9α, H7α—H15α, H7α—H15β, H7β—H11β, H7β—H15α, H7β—H15β, H8α—H9α, H8α—H12α, H8α—H14α, H9α—H12α, H9α—H14α, H11α—H12α, H11α—H12β, H11β—H12α, H11β—H12β, H12α—H14, H12α—H17α, H14α—H17α, H15α—H16α, H15α—H16β, H15β—H16α, H15β—H16β, O1—O2) in (I) and (II) by a molecular-mechanical method, MM+, and a semi-empirical method, PM3 (Hypercube Inc., 2000; Sizova et al., 2000), and compared the results with the values obtained from X-ray data (Table 1). It is evident from Figs. 3 and 4 that the experimental and calculated H—H distances are very similar, and this fact is the basis for potential testing by the MM+ method in a preliminary study of the ligand-receptor complexes of 8-isoanalogs. We intend to report the results of such testing in the near future.

S2. Experimental

Colourless crystals of (I) suitable for diffraction analysis were obtained from a hexane/ethyl acetate solution by slow evaporation at room temperature.

S3. Refinement

H atoms were treated as riding, with C—H distances of 0.93–0.98 Å and U_iso(H) values equal to 1.5Ueq of the parent atom.

Computing details

Data collection: SMART (Bruker, 1997); cell refinement: SAINT (Bruker, 1997); data reduction: SHELXTL (Bruker, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997) and CSD (Acselrud et al., 1989); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997)..

Figures

	Fig. 1. A view of the all-S enantiomer of (I), showing the atom-numbering scheme and displacement ellipsoids at the 50% probability level.
	Fig. 2. A comparison of X-ray interatomic distances in (I) and (II).
	Fig. 3. The correlation of interatomic distances in (I) calculated by molecular-mechanical and semi-empirical methods compared with X-ray analysis data.
	Fig. 4. The correlation of interatomic distances in (II) calculated by molecular-mechanical and semi-empirical methods compared with X-ray analysis data.

17β-Ethoxy-3-methoxy-8-isoestra-1,3,5(10)-triene

Crystal data

C21H30O2	F(000) = 688
Mr = 314.45	Dx = 1.155 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 14.316 (2) Å	Cell parameters from 162 reflections
b = 7.7313 (11) Å	θ = 3–28°
c = 17.678 (3) Å	µ = 0.07 mm^−1
β = 112.43°	T = 293 K
V = 1808.7 (4) Å^3	Plate, colorless
Z = 4	0.32 × 0.28 × 0.08 mm

Data collection

Bruker CCD area detector diffractometer	1359 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.089
Graphite monochromator	θmax = 28.4°, θmin = 2.3°
ϕ and ω scans	h = −15→18
10591 measured reflections	k = −10→10
4239 independent reflections	l = −23→17

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.046	H-atom parameters constrained
wR(F^2) = 0.096	Calculated w = 1/[σ^2(Fo^2) + (0.0288P)^2] where P = (Fo^2 + 2Fc^2)/3 w = 1/[σ^2(Fo^2) + (0.0288P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.76	(Δ/σ)max = 0.002
4239 reflections	Δρmax = 0.14 e Å^−3
209 parameters	Δρmin = −0.14 e Å^−3
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0122 (12)

Special details

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.79069 (10)	−0.0049 (2)	0.59144 (9)	0.0772 (5)
O2	1.04891 (10)	0.66533 (18)	0.16320 (8)	0.0657 (4)
C1	0.80640 (14)	0.3510 (3)	0.45792 (13)	0.0581 (6)
H1	0.7929	0.4713	0.4495	0.070*
C2	0.78810 (14)	0.2691 (3)	0.52059 (13)	0.0607 (6)
H2	0.7630	0.3323	0.5549	0.073*
C3	0.80713 (14)	0.0932 (3)	0.53230 (13)	0.0554 (6)
C3A	0.75918 (17)	0.0810 (3)	0.64811 (14)	0.0942 (8)
H3	0.8132	0.1577	0.6824	0.113*
H4	0.7439	−0.0045	0.6827	0.113*
H5	0.6985	0.1494	0.6185	0.113*
C4	0.84419 (13)	0.0049 (3)	0.48235 (13)	0.0530 (6)
H6	0.8574	−0.1154	0.4909	0.064*
C5	0.86288 (13)	0.0866 (3)	0.41974 (12)	0.0448 (5)
C6	0.90126 (14)	−0.0190 (2)	0.36583 (12)	0.0505 (5)
H7	0.8453	−0.0909	0.3288	0.061*
H8	0.9548	−0.0981	0.4006	0.061*
C7	0.94344 (13)	0.0902 (2)	0.31472 (11)	0.0506 (5)
H9	0.9533	0.0172	0.2724	0.061*
H10	1.0099	0.1381	0.3501	0.061*
C8	0.87094 (13)	0.2379 (2)	0.27381 (11)	0.0451 (5)
H12	0.8029	0.1841	0.2454	0.054*
C9	0.86101 (13)	0.3611 (2)	0.33898 (11)	0.0463 (5)
H11	0.7994	0.4332	0.3110	0.056*
C10	0.84386 (13)	0.2630 (3)	0.40685 (12)	0.0451 (5)
C11	0.95081 (14)	0.4862 (2)	0.37190 (11)	0.0545 (6)
H13	0.9395	0.5671	0.4109	0.065*
H14	1.0129	0.4193	0.4021	0.065*
C12	0.96677 (14)	0.5905 (2)	0.30406 (11)	0.0537 (6)
H15	0.9075	0.6660	0.2770	0.064*
H16	1.0270	0.6653	0.3284	0.064*
C13	0.98114 (13)	0.4723 (2)	0.24086 (11)	0.0436 (5)
C14	0.89156 (13)	0.3463 (2)	0.20971 (11)	0.0466 (5)
H17	0.8310	0.4230	0.1867	0.056*
C15	0.90091 (15)	0.2628 (3)	0.13428 (12)	0.0641 (6)
H18	0.8341	0.2245	0.0948	0.077*
H19	0.9472	0.1623	0.1499	0.077*
C16	0.94432 (15)	0.4092 (3)	0.09776 (12)	0.0652 (6)
H20	1.0074	0.3713	0.0921	0.078*
H21	0.8950	0.4438	0.0432	0.078*
C17	0.96527 (14)	0.5600 (3)	0.15874 (12)	0.0545 (6)
H22	0.9035	0.6343	0.1425	0.065*
C18	1.08614 (12)	0.3885 (2)	0.27522 (11)	0.0588 (6)
H23	1.1380	0.4790	0.2912	0.071*
H24	1.0947	0.3148	0.2333	0.071*
H25	1.0928	0.3183	0.3231	0.071*
C20	1.02588 (17)	0.7827 (3)	0.09849 (14)	0.0836 (8)
H26	0.9698	0.8585	0.0977	0.100*
H27	1.0033	0.7187	0.0461	0.100*
C21	1.11534 (18)	0.8909 (3)	0.10660 (14)	0.0998 (9)
H28	1.1300	0.9702	0.1529	0.120*
H29	1.1010	0.9577	0.0563	0.120*
H30	1.1739	0.8160	0.1159	0.120*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0836 (11)	0.0884 (12)	0.0685 (10)	0.0002 (9)	0.0392 (9)	0.0105 (10)
O2	0.0602 (10)	0.0745 (11)	0.0639 (10)	−0.0028 (8)	0.0253 (8)	0.0176 (9)
C1	0.0626 (15)	0.0520 (15)	0.0644 (15)	0.0058 (11)	0.0293 (12)	0.0007 (13)
C2	0.0562 (14)	0.0684 (17)	0.0638 (16)	0.0042 (12)	0.0301 (12)	−0.0083 (14)
C3	0.0425 (13)	0.0721 (17)	0.0486 (14)	−0.0081 (12)	0.0141 (11)	0.0062 (14)
C3A	0.104 (2)	0.116 (2)	0.0816 (19)	−0.0161 (16)	0.0566 (16)	0.0009 (17)
C4	0.0477 (13)	0.0497 (14)	0.0589 (14)	0.0005 (10)	0.0174 (11)	0.0002 (13)
C5	0.0374 (12)	0.0458 (13)	0.0477 (13)	−0.0036 (10)	0.0125 (10)	−0.0057 (11)
C6	0.0462 (13)	0.0432 (12)	0.0603 (13)	0.0031 (10)	0.0183 (10)	−0.0010 (12)
C7	0.0536 (13)	0.0419 (12)	0.0577 (13)	0.0034 (11)	0.0229 (11)	−0.0073 (11)
C8	0.0371 (11)	0.0415 (12)	0.0524 (13)	−0.0018 (10)	0.0123 (10)	−0.0066 (11)
C9	0.0445 (12)	0.0439 (13)	0.0499 (13)	0.0073 (10)	0.0173 (10)	0.0017 (11)
C10	0.0409 (12)	0.0423 (13)	0.0522 (14)	0.0014 (10)	0.0178 (10)	−0.0049 (12)
C11	0.0709 (15)	0.0420 (12)	0.0533 (13)	−0.0066 (11)	0.0267 (11)	−0.0116 (11)
C12	0.0624 (14)	0.0445 (12)	0.0562 (13)	−0.0046 (10)	0.0248 (11)	−0.0048 (12)
C13	0.0412 (12)	0.0439 (12)	0.0450 (13)	0.0015 (10)	0.0156 (9)	0.0011 (11)
C14	0.0424 (12)	0.0455 (13)	0.0492 (13)	0.0029 (10)	0.0146 (10)	−0.0054 (11)
C15	0.0676 (15)	0.0712 (16)	0.0502 (14)	−0.0077 (12)	0.0188 (12)	−0.0154 (13)
C16	0.0587 (14)	0.0810 (16)	0.0565 (15)	−0.0006 (13)	0.0226 (12)	−0.0019 (14)
C17	0.0455 (13)	0.0606 (15)	0.0586 (15)	−0.0011 (11)	0.0212 (10)	−0.0005 (12)
C18	0.0438 (13)	0.0677 (14)	0.0640 (15)	−0.0009 (11)	0.0196 (11)	0.0033 (12)
C20	0.0902 (19)	0.0872 (19)	0.0737 (17)	−0.0040 (15)	0.0314 (15)	0.0130 (16)
C21	0.102 (2)	0.100 (2)	0.097 (2)	−0.0279 (17)	0.0363 (16)	0.0271 (17)

Geometric parameters (Å, º)

O1—C3	1.383 (2)	C9—H11	1.0000
O1—C3A	1.412 (2)	C11—C12	1.533 (2)
O2—C20	1.398 (2)	C11—H13	0.9900
O2—C17	1.425 (2)	C11—H14	0.9900
C1—C2	1.385 (3)	C12—C13	1.517 (2)
C1—C10	1.391 (2)	C12—H15	0.9900
C1—H1	0.9500	C12—H16	0.9900
C2—C3	1.387 (2)	C13—C18	1.534 (2)
C2—H2	0.9500	C13—C14	1.536 (2)
C3—C4	1.373 (3)	C13—C17	1.538 (2)
C3A—H3	0.9800	C14—C15	1.532 (2)
C3A—H4	0.9800	C14—H17	1.0000
C3A—H5	0.9800	C15—C16	1.546 (2)
C4—C5	1.386 (2)	C15—H18	0.9900
C4—H6	0.9500	C15—H19	0.9900
C5—C10	1.393 (2)	C16—C17	1.538 (2)
C5—C6	1.509 (2)	C16—H20	0.9900
C6—C7	1.520 (2)	C16—H21	0.9900
C6—H7	0.9900	C17—H22	1.0000
C6—H8	0.9900	C18—H23	0.9800
C7—C8	1.527 (2)	C18—H24	0.9800
C7—H9	0.9900	C18—H25	0.9800
C7—H10	0.9900	C20—C21	1.490 (3)
C8—C14	1.526 (2)	C20—H26	0.9900
C8—C9	1.543 (2)	C20—H27	0.9900
C8—H12	1.0000	C21—H28	0.9800
C9—C10	1.516 (2)	C21—H29	0.9800
C9—C11	1.534 (2)	C21—H30	0.9800
C3—O1—C3A	118.12 (19)	H13—C11—H14	107.8
C20—O2—C17	113.26 (16)	C13—C12—C11	111.22 (16)
C2—C1—C10	122.2 (2)	C13—C12—H15	109.4
C2—C1—H1	118.9	C11—C12—H15	109.4
C10—C1—H1	118.9	C13—C12—H16	109.4
C1—C2—C3	118.8 (2)	C11—C12—H16	109.4
C1—C2—H2	120.6	H15—C12—H16	108.0
C3—C2—H2	120.6	C12—C13—C18	110.53 (15)
C4—C3—O1	115.6 (2)	C12—C13—C14	108.48 (15)
C4—C3—C2	119.6 (2)	C18—C13—C14	115.60 (16)
O1—C3—C2	124.8 (2)	C12—C13—C17	114.65 (16)
O1—C3A—H3	109.5	C18—C13—C17	109.23 (15)
O1—C3A—H4	109.5	C14—C13—C17	97.97 (15)
H3—C3A—H4	109.5	C8—C14—C15	121.39 (17)
O1—C3A—H5	109.5	C8—C14—C13	116.98 (15)
H3—C3A—H5	109.5	C15—C14—C13	103.94 (15)
H4—C3A—H5	109.5	C8—C14—H17	104.2
C3—C4—C5	121.8 (2)	C15—C14—H17	104.2
C3—C4—H6	119.1	C13—C14—H17	104.2
C5—C4—H6	119.1	C14—C15—C16	103.76 (15)
C4—C5—C10	119.5 (2)	C14—C15—H18	111.0
C4—C5—C6	119.05 (19)	C16—C15—H18	111.0
C10—C5—C6	121.5 (2)	C14—C15—H19	111.0
C5—C6—C7	113.43 (16)	C16—C15—H19	111.0
C5—C6—H7	108.9	H18—C15—H19	109.0
C7—C6—H7	108.9	C17—C16—C15	105.32 (15)
C5—C6—H8	108.9	C17—C16—H20	110.7
C7—C6—H8	108.9	C15—C16—H20	110.7
H7—C6—H8	107.7	C17—C16—H21	110.7
C6—C7—C8	110.16 (15)	C15—C16—H21	110.7
C6—C7—H9	109.6	H20—C16—H21	108.8
C8—C7—H9	109.6	O2—C17—C16	114.02 (16)
C6—C7—H10	109.6	O2—C17—C13	112.40 (15)
C8—C7—H10	109.6	C16—C17—C13	104.27 (16)
H9—C7—H10	108.1	O2—C17—H22	108.7
C14—C8—C7	118.24 (16)	C16—C17—H22	108.7
C14—C8—C9	108.32 (15)	C13—C17—H22	108.7
C7—C8—C9	110.36 (15)	C13—C18—H23	109.5
C14—C8—H12	106.4	C13—C18—H24	109.5
C7—C8—H12	106.4	H23—C18—H24	109.5
C9—C8—H12	106.4	C13—C18—H25	109.5
C10—C9—C11	112.34 (15)	H23—C18—H25	109.5
C10—C9—C8	111.76 (17)	H24—C18—H25	109.5
C11—C9—C8	111.69 (15)	O2—C20—C21	111.10 (19)
C10—C9—H11	106.9	O2—C20—H26	109.4
C11—C9—H11	106.9	C21—C20—H26	109.4
C8—C9—H11	106.9	O2—C20—H27	109.4
C1—C10—C5	118.2 (2)	C21—C20—H27	109.4
C1—C10—C9	119.21 (19)	H26—C20—H27	108.0
C5—C10—C9	122.60 (19)	C20—C21—H28	109.5
C12—C11—C9	112.84 (15)	C20—C21—H29	109.5
C12—C11—H13	109.0	H28—C21—H29	109.5
C9—C11—H13	109.0	C20—C21—H30	109.5
C12—C11—H14	109.0	H28—C21—H30	109.5
C9—C11—H14	109.0	H29—C21—H30	109.5
C10—C1—C2—C3	−0.5 (3)	C8—C9—C11—C12	55.4 (2)
C3A—O1—C3—C4	175.76 (17)	C9—C11—C12—C13	−56.9 (2)
C3A—O1—C3—C2	−4.8 (3)	C11—C12—C13—C18	−73.84 (19)
C1—C2—C3—C4	0.5 (3)	C11—C12—C13—C14	53.86 (19)
C1—C2—C3—O1	−178.86 (17)	C11—C12—C13—C17	162.18 (15)
O1—C3—C4—C5	179.10 (15)	C7—C8—C14—C15	56.2 (2)
C2—C3—C4—C5	−0.3 (3)	C9—C8—C14—C15	−177.38 (15)
C3—C4—C5—C10	0.1 (3)	C7—C8—C14—C13	−72.7 (2)
C3—C4—C5—C6	−178.55 (16)	C9—C8—C14—C13	53.8 (2)
C4—C5—C6—C7	−165.38 (15)	C12—C13—C14—C8	−55.5 (2)
C10—C5—C6—C7	16.0 (2)	C18—C13—C14—C8	69.3 (2)
C5—C6—C7—C8	−46.9 (2)	C17—C13—C14—C8	−174.86 (16)
C6—C7—C8—C14	−170.94 (16)	C12—C13—C14—C15	167.76 (15)
C6—C7—C8—C9	63.61 (19)	C18—C13—C14—C15	−67.5 (2)
C14—C8—C9—C10	−178.08 (14)	C17—C13—C14—C15	48.37 (17)
C7—C8—C9—C10	−47.2 (2)	C8—C14—C15—C16	−167.90 (16)
C14—C8—C9—C11	−51.27 (19)	C13—C14—C15—C16	−33.53 (19)
C7—C8—C9—C11	79.6 (2)	C14—C15—C16—C17	4.78 (19)
C2—C1—C10—C5	0.2 (3)	C20—O2—C17—C16	78.7 (2)
C2—C1—C10—C9	179.40 (17)	C20—O2—C17—C13	−162.87 (17)
C4—C5—C10—C1	0.0 (3)	C15—C16—C17—O2	148.46 (16)
C6—C5—C10—C1	178.57 (16)	C15—C16—C17—C13	25.51 (19)
C4—C5—C10—C9	−179.16 (16)	C12—C13—C17—O2	76.5 (2)
C6—C5—C10—C9	−0.6 (3)	C18—C13—C17—O2	−48.2 (2)
C11—C9—C10—C1	70.9 (2)	C14—C13—C17—O2	−168.92 (15)
C8—C9—C10—C1	−162.69 (16)	C12—C13—C17—C16	−159.53 (15)
C11—C9—C10—C5	−110.02 (19)	C18—C13—C17—C16	75.81 (17)
C8—C9—C10—C5	16.4 (2)	C14—C13—C17—C16	−44.92 (17)
C10—C9—C11—C12	−178.11 (16)	C17—O2—C20—C21	179.31 (17)