Steroid 19,B-dinor-8,10-iso-analogues

The Birch reduction of 3-methoxy-B-nor-8-isoestra-1,3,5(10)-trienes followed by acid hydro­lysis produces steroid androgen 19,B-dinor-8,10-iso-analogues. By means of X-ray analysis and correlation NMR spectroscopy of 16,16-di­methyl-D-homo-19,B-dinor-8-isotestosterone, C₂₀H₃₀O₂, it is demonstrated that the main conformations in the crystal and in solution for two 19,B-dinor-8,10-iso-analogues are, in general, the same.

S1. Comment

Steroid estrogen B-nor-8-isoanalogues are known to have more favourable biological properties than the natural hormones (Name et al., 1970). Similar androgen steroids have remained practically uninvestigated. The Birch reduction of 17β-hydroxy-18-methyl-3-methoxy-B-nor-8-isoestra-1,3,5(10)-triene and subsequent acid hydrolysis were reported to give only 16,16-dimethyl-D-homo-19,B-dinor-8-isotestosterone, (II), whose structure has been reported previously by Rao et al. (1977) but which has not been strictly established. The object of the present investigation is the determination of the configuration at C10, since this is critical for revealing structure-activity relationships.

We decided to carry out the Birch reduction (see Scheme) of 17aβ-acetoxy-16,16-dimethyl-3-methoxy-D-homo-B-nor-8-isoestra-1,3,5(10)- triene, (I), because, according to our data, it does not have any uterotropic activity at doses up to 100 mg kg^-1 of body weight per day. The oestrogen- and androgen-receptor hormone-binding domains being similar (Ekena et al., 1998), we expect that the final androgen analogue, (II), will not have hormonal activity, and it will be possible to evaluate the convenience of such compounds for the realisation of nongenomic mechanisms of action. \sch

The synthesis of (II) has been described earlier by Egorov, Grinenko et al. (2001). Is this the correct reference? By means of the present X-ray analysis, the conformation of (II) in the solid state has now been determined (Fig. 1).

Ring B is a 9β-envelope, and the angle between the C5/C6/C8/C10 and C8/C9/C10 planes is 39.7°. Ring C is a half-chair, and the angle between the C2/C3/C4/C5/C10 and C1/C2/C10 planes is 48.4°. Atoms H1β and H2α are pseudo-axial. All chiral centres have the S-configuration. Rings B and C possess a cis-junction which causes the rings to be folded; this is usual for 8-isoanalogue molecules. The angle between the planes containing rings A and B (the angle between the C2/C3/C4/C5/C10 and C5/C6/C8/C10 planes is 0.8°), and C and D (the angle between planes C9/C11/C13/C14 and C13/C14/C16/C17 is 7.7°) is 91.1°.

In the crystal structure of (II), two molecules are joined by O2—HO2···O1 hydrogen bonds, with O1···O2 2.829 Å, HO2···O1 2.030 Å and O2—HO2···O1 164.58°. Positional parameters, bond lengths and angles, and torsion angles have been deposited in the Cambridge Crystallographic Database, No. 164256. Using correlation NMR spectroscopy, we also found that (II) in chloroform solution has the same structure as that reported by Egorov, Grinenko et al. (2001). Is this the correct reference?

As we have stated, H10 has an α orientation, contrary to the assumption of Rao et al. (1977), who synthesized a similar 19,B-dinoranalogue with a five-membered D ring and a methyl group at C18. We reproduced their synthesis and proved by correlation NMR spectroscopy that the orientation of H10 was α (Egorov, Starova & Shavva, 2001). Is this the correct reference? Our results are in agreement with data published by Banerjee et al. (1969), concerning an analogous synthesis and X-ray structure determination of a six-membered B-ring analogue of (II).

In the light of these results, we can conclude that the Birch reduction of 3-methoxy-B-nor-8-isoestra-1,3,5(10)-trienes followed by acid hydrolysis produces steroid androgen 19,B-dinor-8,10-isoanalogues, irrespective of the size and substitutions of ring D.

There are two different Egorov et al. (2001) references. Please make sure that each citation above is correct.

S2. Experimental

Compound (II) was synthesized according to the method described by Egorov, Grinenko et al. (2001). Is this the correct reference? Colourless crystals of (II) suitable for diffraction analysis were obtained from hexane-ethyl acetate solution by slow evaporation at room temperature.

S3. Refinement

H atoms were treated as riding, with O—H = 0.82 Å and C—H = 0.93–0.98 Å, and U_iso(H) = 1.5U_eq of the parent atom. Are these the correct restraints?

Computing details

Data collection: SMART (Bruker, 1997); cell refinement: SMART; data reduction: SHELXTL (Bruker, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: Please provide missing details.

Figures

Fig. 1. The asymmetric unit of (II) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

16,16-dimethyl-D-homo-19,B-dinor-8,10-isotestosterone

Crystal data

C20H30O2	F(000) = 664
Mr = 302.44	Dx = 1.203 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 6.957 (2) Å	Cell parameters from 612 reflections
b = 12.035 (3) Å	θ = 2.5–23.1°
c = 19.950 (6) Å	µ = 0.08 mm^−1
β = 90.100 (6)°	T = 293 K
V = 1670.4 (8) Å^3	Plate, colourless
Z = 4	0.4 × 0.3 × 0.1 mm

Data collection

Bruker SMART 1000 CCD area-detector diffractometer	1587 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.047
Graphite monochromator	θmax = 25.0°, θmin = 2.0°
ϕ and ω scans	h = −8→7
7713 measured reflections	k = −13→14
2925 independent reflections	l = −23→16

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.061	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.164	H-atom parameters constrained
S = 0.91	w = 1/[σ^2(Fo^2) + (0.0886P)^2] where P = (Fo^2 + 2Fc^2)/3
2925 reflections	(Δ/σ)max < 0.001
199 parameters	Δρmax = 0.34 e Å^−3
0 restraints	Δρmin = −0.21 e Å^−3

Special details

Experimental. Egorov, M. S., Starova, G. L. & Shavva, A. G. (2001). Collected Abstacts of the Third National Conference of X-ray Synchrotron Radiation of Neutrons and Electrons to the Investigation of Materials. Rne, Moscow, p.69. (In Russian).

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	0.0185 (3)	0.20907 (15)	1.07510 (9)	0.0388 (5)
O2	0.1301 (3)	0.22146 (14)	0.57850 (9)	0.0388 (5)
HO2	0.2469	0.2298	0.5806	0.058*
C1	0.3486 (4)	0.1225 (2)	0.94397 (12)	0.0329 (7)
H1A	0.3620	0.1981	0.9277	0.049*
H1B	0.4738	0.0871	0.9421	0.049*
C2	0.2766 (4)	0.1240 (2)	1.01619 (13)	0.0326 (7)
H2A	0.2806	0.0491	1.0341	0.049*
H2B	0.3620	0.1697	1.0431	0.049*
C3	0.0762 (4)	0.1681 (2)	1.02202 (14)	0.0310 (7)
C4	−0.0510 (4)	0.1559 (2)	0.96449 (13)	0.0322 (7)
H4	−0.1747	0.1849	0.9665	0.048*
C5	0.0069 (4)	0.1035 (2)	0.90854 (13)	0.0309 (6)
C6	−0.1073 (4)	0.0827 (2)	0.84564 (13)	0.0355 (7)
H6A	−0.1497	0.1520	0.8258	0.053*
H6B	−0.2188	0.0368	0.8549	0.053*
C8	0.0353 (4)	0.0214 (2)	0.79882 (13)	0.0310 (7)
H8	0.0245	−0.0579	0.8092	0.046*
C9	0.2347 (4)	0.0588 (2)	0.82350 (12)	0.0305 (6)
H9	0.3311	0.0031	0.8112	0.046*
C10	0.2081 (4)	0.0596 (2)	0.90007 (13)	0.0310 (7)
H10	0.2080	−0.0179	0.9151	0.047*
C11	0.2908 (4)	0.1718 (2)	0.79422 (12)	0.0333 (7)
H11A	0.2084	0.2289	0.8130	0.050*
H11B	0.4223	0.1888	0.8068	0.050*
C12	0.2729 (4)	0.1729 (2)	0.71805 (13)	0.0333 (7)
H12A	0.3631	0.1197	0.6996	0.050*
H12B	0.3089	0.2459	0.7017	0.050*
C13	0.0705 (4)	0.1451 (2)	0.69203 (13)	0.0296 (6)
C14	0.0092 (4)	0.0327 (2)	0.72298 (13)	0.0303 (6)
H14	0.0984	−0.0217	0.7038	0.045*
C15	−0.1887 (4)	−0.0039 (2)	0.69833 (13)	0.0321 (7)
H15A	−0.2833	0.0505	0.7122	0.048*
H15B	−0.2215	−0.0741	0.7193	0.048*
C16	−0.1988 (4)	−0.0175 (2)	0.62205 (13)	0.0322 (7)
C16A	−0.0871 (4)	−0.1202 (2)	0.59997 (13)	0.0377 (7)
H161	0.0452	−0.1125	0.6130	0.056*
H162	−0.0954	−0.1277	0.5521	0.056*
H163	−0.1407	−0.1849	0.6209	0.056*
C16B	−0.4065 (4)	−0.0335 (2)	0.59954 (14)	0.0380 (7)
H164	−0.4099	−0.0474	0.5522	0.057*
H165	−0.4790	0.0324	0.6094	0.057*
H166	−0.4615	−0.0956	0.6229	0.057*
C17	−0.1173 (4)	0.0879 (2)	0.58883 (13)	0.0322 (7)
H17A	−0.1052	0.0745	0.5411	0.048*
H17B	−0.2087	0.1480	0.5948	0.048*
C17A	0.0763 (4)	0.1249 (2)	0.61589 (13)	0.0308 (6)
H171	0.1702	0.0661	0.6068	0.046*
C18	−0.0627 (4)	0.2438 (2)	0.70704 (14)	0.0365 (7)
H181	−0.1937	0.2225	0.6990	0.055*
H182	−0.0297	0.3051	0.6784	0.055*
H183	−0.0478	0.2656	0.7531	0.055*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0342 (12)	0.0441 (12)	0.0380 (12)	−0.0042 (9)	0.0043 (9)	−0.0072 (9)
O2	0.0315 (11)	0.0428 (12)	0.0420 (12)	−0.0037 (9)	0.0012 (9)	0.0122 (9)
C1	0.0276 (16)	0.0337 (15)	0.0375 (17)	−0.0005 (12)	0.0005 (12)	0.0022 (12)
C2	0.0315 (17)	0.0316 (15)	0.0348 (16)	−0.0017 (12)	0.0009 (13)	−0.0003 (12)
C3	0.0320 (17)	0.0257 (14)	0.0352 (16)	−0.0073 (12)	0.0019 (13)	−0.0018 (12)
C4	0.0267 (16)	0.0311 (15)	0.0389 (17)	−0.0015 (12)	0.0003 (12)	0.0006 (12)
C5	0.0303 (16)	0.0295 (15)	0.0328 (16)	−0.0063 (12)	−0.0005 (12)	0.0027 (12)
C6	0.0279 (16)	0.0445 (17)	0.0342 (16)	−0.0048 (13)	0.0012 (12)	0.0002 (13)
C8	0.0311 (16)	0.0281 (15)	0.0338 (16)	−0.0037 (11)	0.0029 (12)	−0.0003 (11)
C9	0.0270 (15)	0.0316 (15)	0.0329 (16)	0.0028 (12)	0.0036 (12)	−0.0036 (11)
C10	0.0293 (16)	0.0296 (14)	0.0342 (16)	−0.0015 (12)	0.0037 (12)	0.0028 (11)
C11	0.0246 (16)	0.0379 (16)	0.0375 (17)	−0.0006 (12)	0.0028 (12)	−0.0013 (12)
C12	0.0305 (16)	0.0355 (15)	0.0338 (16)	−0.0041 (12)	0.0022 (12)	0.0032 (12)
C13	0.0240 (15)	0.0313 (15)	0.0336 (16)	0.0008 (11)	0.0006 (12)	−0.0001 (11)
C14	0.0285 (15)	0.0285 (14)	0.0338 (16)	0.0004 (11)	0.0006 (12)	−0.0009 (11)
C15	0.0291 (16)	0.0303 (15)	0.0369 (17)	−0.0042 (12)	0.0052 (13)	0.0012 (11)
C16	0.0269 (16)	0.0370 (16)	0.0328 (16)	0.0005 (12)	0.0018 (12)	−0.0004 (12)
C16A	0.0390 (18)	0.0367 (16)	0.0373 (17)	0.0007 (13)	−0.0009 (13)	−0.0024 (12)
C16B	0.0331 (17)	0.0441 (17)	0.0368 (17)	−0.0005 (13)	0.0024 (13)	−0.0036 (13)
C17	0.0277 (16)	0.0349 (16)	0.0341 (16)	0.0041 (12)	0.0013 (12)	−0.0011 (12)
C17A	0.0285 (16)	0.0293 (15)	0.0347 (16)	0.0007 (12)	0.0046 (12)	0.0054 (12)
C18	0.0379 (18)	0.0317 (15)	0.0400 (17)	0.0030 (13)	−0.0016 (13)	−0.0024 (12)

Geometric parameters (Å, º)

O1—C3	1.236 (3)	C12—C13	1.536 (4)
O2—C17A	1.432 (3)	C12—H12A	0.9700
O2—HO2	0.8200	C12—H12B	0.9700
C1—C10	1.515 (4)	C13—C18	1.537 (3)
C1—C2	1.526 (4)	C13—C17A	1.539 (4)
C1—H1A	0.9700	C13—C14	1.547 (3)
C1—H1B	0.9700	C14—C15	1.526 (3)
C2—C3	1.496 (4)	C14—H14	0.9800
C2—H2A	0.9700	C15—C16	1.532 (3)
C2—H2B	0.9700	C15—H15A	0.9700
C3—C4	1.455 (4)	C15—H15B	0.9700
C4—C5	1.344 (4)	C16—C16B	1.525 (4)
C4—H4	0.9300	C16—C16A	1.525 (4)
C5—C6	1.505 (4)	C16—C17	1.539 (4)
C5—C10	1.506 (4)	C16A—H161	0.9600
C6—C8	1.550 (4)	C16A—H162	0.9600
C6—H6A	0.9700	C16A—H163	0.9600
C6—H6B	0.9700	C16B—H164	0.9600
C8—C14	1.530 (4)	C16B—H165	0.9600
C8—C9	1.538 (4)	C16B—H166	0.9600
C8—H8	0.9800	C17—C17A	1.517 (4)
C9—C11	1.530 (3)	C17—H17A	0.9700
C9—C10	1.539 (3)	C17—H17B	0.9700
C9—H9	0.9800	C17A—H171	0.9800
C10—H10	0.9800	C18—H181	0.9600
C11—C12	1.525 (3)	C18—H182	0.9600
C11—H11A	0.9700	C18—H183	0.9600
C11—H11B	0.9700
C17A—O2—HO2	109.5	C13—C12—H12B	108.7
C10—C1—C2	109.8 (2)	H12A—C12—H12B	107.6
C10—C1—H1A	109.7	C12—C13—C18	108.6 (2)
C2—C1—H1A	109.7	C12—C13—C17A	110.0 (2)
C10—C1—H1B	109.7	C18—C13—C17A	109.3 (2)
C2—C1—H1B	109.7	C12—C13—C14	108.0 (2)
H1A—C1—H1B	108.2	C18—C13—C14	115.6 (2)
C3—C2—C1	112.6 (2)	C17A—C13—C14	105.3 (2)
C3—C2—H2A	109.1	C15—C14—C8	113.5 (2)
C1—C2—H2A	109.1	C15—C14—C13	111.9 (2)
C3—C2—H2B	109.1	C8—C14—C13	116.1 (2)
C1—C2—H2B	109.1	C15—C14—H14	104.6
H2A—C2—H2B	107.8	C8—C14—H14	104.6
O1—C3—C4	121.2 (3)	C13—C14—H14	104.6
O1—C3—C2	120.8 (2)	C14—C15—C16	113.0 (2)
C4—C3—C2	117.9 (2)	C14—C15—H15A	109.0
C5—C4—C3	121.3 (3)	C16—C15—H15A	109.0
C5—C4—H4	119.3	C14—C15—H15B	109.0
C3—C4—H4	119.3	C16—C15—H15B	109.0
C4—C5—C6	127.7 (3)	H15A—C15—H15B	107.8
C4—C5—C10	122.5 (2)	C16B—C16—C16A	107.2 (2)
C6—C5—C10	109.7 (2)	C16B—C16—C15	110.4 (2)
C5—C6—C8	104.1 (2)	C16A—C16—C15	110.5 (2)
C5—C6—H6A	110.9	C16B—C16—C17	109.1 (2)
C8—C6—H6A	110.9	C16A—C16—C17	110.8 (2)
C5—C6—H6B	110.9	C15—C16—C17	108.9 (2)
C8—C6—H6B	110.9	C16—C16A—H161	109.5
H6A—C6—H6B	108.9	C16—C16A—H162	109.5
C14—C8—C9	113.3 (2)	H161—C16A—H162	109.5
C14—C8—C6	118.6 (2)	C16—C16A—H163	109.5
C9—C8—C6	104.2 (2)	H161—C16A—H163	109.5
C14—C8—H8	106.6	H162—C16A—H163	109.5
C9—C8—H8	106.6	C16—C16B—H164	109.5
C6—C8—H8	106.6	C16—C16B—H165	109.5
C11—C9—C8	111.6 (2)	H164—C16B—H165	109.5
C11—C9—C10	113.9 (2)	C16—C16B—H166	109.5
C8—C9—C10	102.1 (2)	H164—C16B—H166	109.5
C11—C9—H9	109.7	H165—C16B—H166	109.5
C8—C9—H9	109.7	C17A—C17—C16	114.6 (2)
C10—C9—H9	109.7	C17A—C17—H17A	108.6
C5—C10—C1	111.0 (2)	C16—C17—H17A	108.6
C5—C10—C9	103.1 (2)	C17A—C17—H17B	108.6
C1—C10—C9	119.9 (2)	C16—C17—H17B	108.6
C5—C10—H10	107.4	H17A—C17—H17B	107.6
C1—C10—H10	107.4	O2—C17A—C17	106.6 (2)
C9—C10—H10	107.4	O2—C17A—C13	113.2 (2)
C12—C11—C9	111.6 (2)	C17—C17A—C13	111.9 (2)
C12—C11—H11A	109.3	O2—C17A—H171	108.3
C9—C11—H11A	109.3	C17—C17A—H171	108.3
C12—C11—H11B	109.3	C13—C17A—H171	108.3
C9—C11—H11B	109.3	C13—C18—H181	109.5
H11A—C11—H11B	108.0	C13—C18—H182	109.5
C11—C12—C13	114.1 (2)	H181—C18—H182	109.5
C11—C12—H12A	108.7	C13—C18—H183	109.5
C13—C12—H12A	108.7	H181—C18—H183	109.5
C11—C12—H12B	108.7	H182—C18—H183	109.5
C10—C1—C2—C3	−54.1 (3)	C11—C12—C13—C17A	−168.5 (2)
C1—C2—C3—O1	−156.0 (2)	C11—C12—C13—C14	−54.1 (3)
C1—C2—C3—C4	27.1 (3)	C9—C8—C14—C15	−179.8 (2)
O1—C3—C4—C5	−174.7 (2)	C6—C8—C14—C15	−57.1 (3)
C2—C3—C4—C5	2.2 (4)	C9—C8—C14—C13	−48.0 (3)
C3—C4—C5—C6	179.0 (2)	C6—C8—C14—C13	74.7 (3)
C3—C4—C5—C10	−3.3 (4)	C12—C13—C14—C15	−178.3 (2)
C4—C5—C6—C8	179.0 (2)	C18—C13—C14—C15	60.0 (3)
C10—C5—C6—C8	1.0 (3)	C17A—C13—C14—C15	−60.8 (3)
C5—C6—C8—C14	−152.4 (2)	C12—C13—C14—C8	49.2 (3)
C5—C6—C8—C9	−25.3 (3)	C18—C13—C14—C8	−72.5 (3)
C14—C8—C9—C11	47.9 (3)	C17A—C13—C14—C8	166.8 (2)
C6—C8—C9—C11	−82.4 (2)	C8—C14—C15—C16	−167.0 (2)
C14—C8—C9—C10	170.0 (2)	C13—C14—C15—C16	59.2 (3)
C6—C8—C9—C10	39.6 (2)	C14—C15—C16—C16B	−169.8 (2)
C4—C5—C10—C1	−25.0 (3)	C14—C15—C16—C16A	71.8 (3)
C6—C5—C10—C1	153.1 (2)	C14—C15—C16—C17	−50.1 (3)
C4—C5—C10—C9	−154.6 (2)	C16B—C16—C17—C17A	170.0 (2)
C6—C5—C10—C9	23.5 (3)	C16A—C16—C17—C17A	−72.2 (3)
C2—C1—C10—C5	52.2 (3)	C15—C16—C17—C17A	49.5 (3)
C2—C1—C10—C9	172.2 (2)	C16—C17—C17A—O2	178.8 (2)
C11—C9—C10—C5	82.1 (3)	C16—C17—C17A—C13	−56.9 (3)
C8—C9—C10—C5	−38.4 (2)	C12—C13—C17A—O2	−64.2 (3)
C11—C9—C10—C1	−41.9 (3)	C18—C13—C17A—O2	54.9 (3)
C8—C9—C10—C1	−162.3 (2)	C14—C13—C17A—O2	179.7 (2)
C8—C9—C11—C12	−52.7 (3)	C12—C13—C17A—C17	175.3 (2)
C10—C9—C11—C12	−167.6 (2)	C18—C13—C17A—C17	−65.5 (3)
C9—C11—C12—C13	58.1 (3)	C14—C13—C17A—C17	59.2 (3)
C11—C12—C13—C18	71.9 (3)