9α-Chloro-3β,11β-di­hydroxy-5α-androstan-17-one

In the title compound, C₁₉H₂₉ClO₃, the hydroxyl linkage in ring A is equatorial. The six-membered rings A, B and C have chair conformations. The five-membered ring D adopts a 14α envelope conformation. The A/B, B/C and C/D ring junctions are trans. The packing of the mol­ecules is assumed to be dictated mainly by two strong intermolecular hydrogen bonds of the type O—H...O.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.033
• wR factor = 0.099
• Data-to-parameter ratio = 8.9

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry

General Notes



ABSTM_02  When printed, the submitted absorption T values will be replaced
          by the scaled T values. Since the ratio of scaled T's is
          identical to the ratio of reported T values, the scaling does
          not imply a change to the absorption corrections used in the
          study.
          Ratio of Tmax expected/reported      1.589
          Tmax scaled      0.566 Tmin scaled      0.392

REFLT_03
         From the CIF: _diffrn_reflns_theta_max           69.15
         From the CIF: _reflns_number_total               1893
         Count of symmetry unique reflns         1742
         Completeness (_total/calc)            108.67%
         TEST3: Check Friedels for noncentro structure
         Estimate of Friedel pairs measured       151
         Fraction of Friedel pairs measured     0.087
         Are heavy atom types Z>Si present          yes
          WARNING: Large fraction of Friedel related reflns may
                   be needed to determine absolute structure

---

S1. Comment

Topical corticosteroids became available for medical use in the 1950's when hydrocortisone was introduced demonstrating substantial topical anti-inflamatory potency. Modification of the basic corticosteroid molecule, e.g. by halogenation or the optimization of the vehicle, enhances their effectiveness, the former by raising the potency and the latter by increasing the percutaneous absorption (Lutsky et al., 1979). The strategy and importance for the synthesis of these compounds have its antecedents in similar structures, with anabolic and/or androgenic activity, replacing positions 9α and 11β with fluorine and hydroxyl, respectively (Shapiro et al., 1987). An example of this is 9α-fluoro-11β,17α-dihydroxy-17α-methyl-4-androsten-3-one (halotestin), a commercial compound 20 times more androgenic and 10 times more anabolic than methyltestosterone. In connection with our studies on the synthesis and characterization of bioactive steroids, the structure of the title compound, (I), could allow the prediction of the possibility of a compound of presenting/displaying anabolic and/or androgenic properties. The absolute configuration turned out to be the same as that predicted beforehand from the synthesis route.

Fig. 1 shows the molecular structure of the title compound, with the corresponding numbering scheme. The C3—O3 bond of the hydroxy group is equatorially oriented and (-)antiperiplanar to the C4—C5 bond. The presence of OH bounded to C3 does not disturb the chair conformation in the ring A of the steroidal nucleus. Ring A has a chair conformation with all asymmetry parameters (Duax et al., 1976) below 9.2 (3)°. The average magnitude of the torsion angles is 54.27 (12)°. Ring B displays a chair conformation, as does ring C (Pfeiffer et al., 1985). The five-membered ring D adopts a 14α-envelope conformation (Altona et al., 1968). The A/B, B/C and C/D ring junctions are trans. Bond distances and valence angles are close to expected values (Honda et al., 1996). The packing of the molecules is assumed to be dictated mainly by two intermolecular hydrogen bonds, i.e. O3—H3a···O17 and O11—H11a—O3.

S2. Experimental

The synthesis of the title compound has been described by Ruíz (1997). M.p. 399 K. Crystals were grown by slow evaporation from ethanol.

S3. Refinement

H atoms were calculated geometrically and included in the refinement, but were restrained to ride on their parent atoms. The isotropic displacement parameters of the H atoms were fixed to 1.3U_eq of their parent atoms. The torsion angles about the C—OH and C—CH₃ bonds were allowed to refine. Number of Friedel pairs used: 232 [Flack (1983) parameter = 0.01 (2)]. Friedel pairs were treated as independent data.

Computing details

Data collection: XSCANS (Siemens1996); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: DIAMOND (Bergerhoff, 1996); software used to prepare material for publication: PLATON (Spek, 1990), PARST (Nardelli, 1983, 1995) and PARSTCIF (Nardelli, 1991).

Figures

Fig. 1. Plot showing the atomic numbering scheme for the title compound. Displacement ellipsoids are drawn at 50% probability level for non-H atoms.

9α-chloro-3β,11β-dihydroxy-5α-androstan-17-one

Crystal data

C19H29ClO3	F(000) = 368
Mr = 340.87	Dx = 1.297 Mg m^−3
Monoclinic, P21	Melting point: 127 K
Hall symbol: P 2yb	Cu Kα radiation, λ = 1.54180 Å
a = 8.3450 (3) Å	Cell parameters from 40 reflections
b = 8.5536 (3) Å	θ = 10.5–28.0°
c = 12.6875 (5) Å	µ = 2.04 mm^−1
β = 105.482 (3)°	T = 293 K
V = 872.77 (6) Å^3	Prism, colourless
Z = 2	0.64 × 0.46 × 0.28 mm

Data collection

Siemens P4 four-circle diffractometer	1862 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.051
Graphite monochromator	θmax = 69.2°, θmin = 3.6°
ω/2θ scans	h = −10→1
Absorption correction: ψ scan (North et al., 1968)	k = −1→10
Tmin = 0.247, Tmax = 0.356	l = −15→15
2286 measured reflections	3 standard reflections every 100 reflections
1893 independent reflections	intensity decay: 0.0%

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.033	w = 1/[σ^2(Fo^2) + (0.0628P)^2 + 0.1216P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.099	(Δ/σ)max = 0.009
S = 1.10	Δρmax = 0.21 e Å^−3
1893 reflections	Δρmin = −0.28 e Å^−3
213 parameters	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
1 restraint	Extinction coefficient: 0.032 (2)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983)
Secondary atom site location: difference Fourier map	Absolute structure parameter: 0.012 (17)

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
C1	0.5934 (3)	0.2962 (3)	0.1122 (2)	0.0417 (6)
H1A	0.6068	0.2427	0.0476	0.052*
H1B	0.5531	0.2203	0.1559	0.052*
C2	0.4627 (3)	0.4240 (4)	0.0763 (2)	0.0482 (7)
H2A	0.4925	0.4900	0.0223	0.060*
H2B	0.3560	0.3763	0.0422	0.060*
C3	0.4476 (3)	0.5229 (4)	0.1714 (2)	0.0482 (7)
H3	0.4129	0.4553	0.2237	0.060*
O3	0.3203 (3)	0.6377 (3)	0.13196 (16)	0.0635 (6)
H3A	0.3035	0.6859	0.1839	0.079*
C4	0.6141 (3)	0.5952 (4)	0.2287 (2)	0.0487 (7)
H4A	0.6021	0.6593	0.2892	0.061*
H4B	0.6510	0.6619	0.1779	0.061*
C5	0.7430 (3)	0.4681 (4)	0.27123 (18)	0.0411 (6)
H5	0.6996	0.4039	0.3214	0.051*
C6	0.9112 (4)	0.5306 (4)	0.3378 (2)	0.0532 (7)
H6A	0.9604	0.5930	0.2908	0.067*
H6B	0.8946	0.5978	0.3955	0.067*
C7	1.0303 (3)	0.3990 (4)	0.3883 (2)	0.0498 (7)
H7A	0.9914	0.3500	0.4458	0.062*
H7B	1.1391	0.4434	0.4216	0.062*
C8	1.0478 (3)	0.2734 (3)	0.30564 (19)	0.0371 (5)
H8	1.1056	0.3215	0.2561	0.046*
C9	0.8768 (3)	0.2153 (3)	0.23467 (18)	0.0335 (5)
Cl9	0.77099 (7)	0.11880 (9)	0.33001 (5)	0.0480 (2)
C10	0.7654 (3)	0.3560 (3)	0.17903 (17)	0.0350 (5)
C11	0.8902 (3)	0.0766 (3)	0.1577 (2)	0.0387 (6)
H11	0.7794	0.0302	0.1307	0.048*
O11	0.9425 (2)	0.1288 (3)	0.06611 (12)	0.0492 (5)
H11A	0.8649	0.1218	0.0108	0.061*
C12	1.0107 (3)	−0.0532 (3)	0.2149 (2)	0.0438 (6)
H12A	0.9615	−0.1097	0.2648	0.055*
H12B	1.0271	−0.1266	0.1604	0.055*
C13	1.1781 (3)	0.0123 (4)	0.27799 (19)	0.0390 (6)
C14	1.1524 (3)	0.1348 (4)	0.36003 (18)	0.0390 (5)
H14	1.0890	0.0830	0.4049	0.049*
C15	1.3280 (3)	0.1620 (4)	0.4351 (2)	0.0497 (7)
H15A	1.3241	0.2091	0.5040	0.062*
H15B	1.3937	0.2275	0.4002	0.062*
C16	1.3967 (4)	−0.0060 (5)	0.4516 (2)	0.0544 (8)
H16A	1.5136	−0.0075	0.4535	0.068*
H16B	1.3840	−0.0492	0.5196	0.068*
C17	1.2957 (3)	−0.0996 (4)	0.3547 (2)	0.0466 (7)
O17	1.3094 (3)	−0.2381 (3)	0.34040 (19)	0.0647 (7)
C18	1.2827 (3)	0.0723 (5)	0.2022 (2)	0.0509 (8)
H18A	1.2925	−0.0089	0.1521	0.064*
H18B	1.3914	0.1015	0.2456	0.064*
H18C	1.2291	0.1616	0.1620	0.064*
C19	0.8461 (4)	0.4462 (4)	0.1014 (2)	0.0473 (7)
H19A	0.8332	0.3877	0.0351	0.059*
H19B	0.9622	0.4610	0.1360	0.059*
H19C	0.7930	0.5462	0.0846	0.059*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0410 (12)	0.0401 (14)	0.0394 (12)	0.0026 (12)	0.0027 (9)	−0.0014 (11)
C2	0.0506 (13)	0.0473 (16)	0.0395 (12)	0.0109 (13)	−0.0003 (10)	−0.0005 (13)
C3	0.0510 (14)	0.0510 (17)	0.0382 (12)	0.0180 (14)	0.0042 (10)	0.0023 (13)
O3	0.0666 (11)	0.0692 (15)	0.0459 (10)	0.0348 (13)	−0.0002 (9)	−0.0037 (12)
C4	0.0597 (14)	0.0435 (16)	0.0388 (11)	0.0150 (14)	0.0061 (11)	−0.0060 (12)
C5	0.0476 (13)	0.0416 (14)	0.0313 (10)	0.0073 (12)	0.0059 (9)	−0.0012 (11)
C6	0.0555 (16)	0.0461 (17)	0.0504 (15)	0.0058 (14)	0.0008 (12)	−0.0163 (14)
C7	0.0483 (13)	0.0516 (17)	0.0406 (13)	0.0041 (14)	−0.0038 (10)	−0.0130 (14)
C8	0.0370 (11)	0.0380 (13)	0.0345 (10)	−0.0021 (11)	0.0063 (9)	−0.0016 (11)
C9	0.0349 (10)	0.0352 (13)	0.0308 (10)	−0.0012 (10)	0.0097 (8)	0.0019 (11)
Cl9	0.0431 (3)	0.0537 (4)	0.0503 (3)	0.0056 (3)	0.0178 (2)	0.0192 (3)
C10	0.0393 (10)	0.0357 (13)	0.0289 (10)	0.0011 (10)	0.0072 (8)	0.0016 (10)
C11	0.0362 (10)	0.0371 (14)	0.0392 (11)	−0.0002 (10)	0.0037 (9)	−0.0040 (11)
O11	0.0509 (9)	0.0643 (13)	0.0299 (7)	0.0064 (12)	0.0066 (6)	−0.0039 (10)
C12	0.0421 (13)	0.0388 (15)	0.0475 (13)	0.0027 (12)	0.0064 (10)	−0.0039 (13)
C13	0.0357 (11)	0.0449 (15)	0.0353 (10)	0.0040 (11)	0.0077 (9)	0.0005 (12)
C14	0.0372 (10)	0.0451 (14)	0.0326 (10)	0.0006 (12)	0.0058 (8)	−0.0014 (12)
C15	0.0426 (12)	0.059 (2)	0.0401 (12)	0.0036 (13)	−0.0019 (10)	−0.0043 (13)
C16	0.0469 (14)	0.069 (2)	0.0418 (13)	0.0169 (15)	0.0027 (10)	0.0011 (15)
C17	0.0442 (12)	0.0541 (19)	0.0423 (12)	0.0115 (13)	0.0129 (10)	0.0036 (14)
O17	0.0710 (13)	0.0591 (16)	0.0580 (12)	0.0252 (13)	0.0068 (10)	−0.0024 (12)
C18	0.0439 (12)	0.072 (2)	0.0390 (12)	0.0008 (13)	0.0145 (10)	0.0038 (13)
C19	0.0575 (15)	0.0438 (16)	0.0424 (13)	−0.0007 (14)	0.0164 (11)	0.0109 (13)

Geometric parameters (Å, º)

C1—C2	1.526 (4)	C9—C10	1.568 (3)
C1—C10	1.546 (3)	C9—Cl9	1.869 (2)
C2—C3	1.506 (4)	C10—C19	1.540 (3)
C3—O3	1.436 (3)	C11—O11	1.418 (3)
C3—C4	1.517 (4)	C11—C12	1.543 (4)
C4—C5	1.523 (4)	C12—C13	1.520 (3)
C5—C6	1.528 (4)	C13—C17	1.521 (4)
C5—C10	1.562 (3)	C13—C14	1.532 (4)
C6—C7	1.525 (4)	C13—C18	1.549 (3)
C7—C8	1.535 (4)	C14—C15	1.538 (3)
C8—C14	1.524 (4)	C15—C16	1.541 (5)
C8—C9	1.551 (3)	C16—C17	1.520 (4)
C9—C11	1.560 (3)	C17—O17	1.209 (5)
C2—C1—C10	114.3 (2)	C1—C10—C5	109.6 (2)
C3—C2—C1	111.7 (2)	C19—C10—C9	111.38 (19)
O3—C3—C2	108.5 (2)	C1—C10—C9	110.2 (2)
O3—C3—C4	112.7 (3)	C5—C10—C9	107.99 (17)
C2—C3—C4	110.6 (2)	O11—C11—C12	107.9 (2)
C3—C4—C5	110.4 (2)	O11—C11—C9	111.3 (2)
C4—C5—C6	113.8 (3)	C12—C11—C9	113.6 (2)
C4—C5—C10	112.76 (19)	C13—C12—C11	112.0 (2)
C6—C5—C10	110.7 (2)	C12—C13—C17	116.8 (3)
C7—C6—C5	111.9 (3)	C12—C13—C14	109.53 (19)
C6—C7—C8	113.6 (2)	C17—C13—C14	100.3 (2)
C14—C8—C7	112.5 (2)	C12—C13—C18	112.7 (2)
C14—C8—C9	109.9 (2)	C17—C13—C18	103.4 (2)
C7—C8—C9	112.4 (2)	C14—C13—C18	113.5 (3)
C8—C9—C11	113.47 (19)	C8—C14—C13	113.06 (19)
C8—C9—C10	111.0 (2)	C8—C14—C15	119.9 (3)
C11—C9—C10	115.79 (18)	C13—C14—C15	104.0 (2)
C8—C9—Cl9	106.60 (15)	C14—C15—C16	101.6 (2)
C11—C9—Cl9	101.18 (16)	C17—C16—C15	106.0 (2)
C10—C9—Cl9	107.74 (15)	O17—C17—C16	125.7 (3)
C19—C10—C1	108.4 (2)	O17—C17—C13	126.2 (3)
C19—C10—C5	109.4 (2)	C16—C17—C13	108.1 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3A···O17^i	0.82	2.08	2.874 (3)	164
O11—H11A···O3^ii	0.82	2.05	2.862 (3)	171

Symmetry codes: (i) x−1, y+1, z; (ii) −x+1, y−1/2, −z.