(20S,2′′S)-20-[4′-(3′′-Hydroxy-2′′-methyl­prop­yl)-3′-methylisoxazol-5-yl]-5β-preg­nan-3β,16β-diol

María-Guadalupe Hernández Linares; Jesús Sandoval Ramírez; Socorro Meza Reyes; Sara Montiel Smith; Sylvain Bernès

doi:10.1107/S1600536809050478

. 2009 Nov 28;65(Pt 12):o3265–o3266. doi: 10.1107/S1600536809050478

(20S,2′′S)-20-[4′-(3′′-Hydroxy-2′′-methylpropyl)-3′-methylisoxazol-5-yl]-5β-pregnan-3β,16β-diol

María-Guadalupe Hernández Linares ^a, Jesús Sandoval Ramírez ^b, Socorro Meza Reyes ^b, Sara Montiel Smith ^b, Sylvain Bernès ^c,^*

PMCID: PMC2972099 PMID: 21578960

Abstract

The title steroidal compound, C₂₉H₄₇NO₄, was prepared in a one-pot reaction starting from a sarsasapogenin derivative of known configuration. The isoxazole heterocycle is oriented towards the α face of the steroid nucleus and, although fully functionalized on C atoms, does not provoke steric hindrance with the adjacent D ring. The absolute configuration observed for chiral centers is as expected, and shows that no epimerization occurred in the precursors. In the crystal, the three OH groups serve as donors for hydrogen bonding with O and N atoms. The isoxazole N atom is involved in O—H⋯N hydrogen bonds, forming chains along [100]. These chains are further connected via O—H⋯O and weak C—H⋯O contacts, giving rise to a three-dimensional supramolecular network.

Related literature

For a general introduction to steroids functionalized with heterocycles, see: Banday et al. (2008 ▶); Pathak & Jindal (1998 ▶); Litvinovskaya et al. (1998 ▶); Beam et al. (2000 ▶). For the biological activity of danazol, a steroid sharing structural features with the title compound, see: Gupta et al. (1999 ▶). For 23-acetylsarsasapogenin, used as starting material, see: Meza-Reyes et al. (2005 ▶). graphic file with name e-65-o3265-scheme1.jpg

Experimental

Crystal data

C₂₉H₄₇NO₄
M _r = 473.68
Monoclinic,
a = 6.5540 (8) Å
b = 30.131 (4) Å
c = 7.1971 (10) Å
β = 98.500 (13)°
V = 1405.6 (3) Å³
Z = 2
Mo Kα radiation
μ = 0.07 mm⁻¹
T = 296 K
0.6 × 0.2 × 0.2 mm

Data collection

Bruker P4 diffractometer
8425 measured reflections
2534 independent reflections
2003 reflections with I > 2σ(I)
R _int = 0.030

Refinement

R[F ² > 2σ(F ²)] = 0.035
wR(F ²) = 0.092
S = 1.07
2534 reflections
322 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.13 e Å⁻³
Δρ_min = −0.12 e Å⁻³

Data collection: XSCANS (Siemens, 1996 ▶); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶) and Mercury (Macrae et al., 2006 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809050478/jj2015sup1.cif

e-65-o3265-sup1.cif^{(28.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809050478/jj2015Isup2.hkl

e-65-o3265-Isup2.hkl^{(124.5KB, 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
O32—H32⋯O33ⁱ	0.82 (5)	1.93 (5)	2.746 (3)	170 (5)
O33—H33⋯N24ⁱⁱ	0.85 (4)	2.03 (4)	2.828 (3)	157 (4)
O34—H34⋯O32ⁱⁱⁱ	0.90 (6)	1.89 (6)	2.775 (4)	166 (5)
O33—H33⋯O23ⁱⁱ	0.85 (4)	2.69 (4)	3.536 (3)	171 (4)
C18—H18C⋯O23ⁱⁱ	0.96	2.46	3.362 (4)	157
C28—H28C⋯O34^iv	0.97	2.60	3.471 (4)	150

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

Acknowledgments

This work was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT, grant 83049).

supplementary crystallographic information

Comment

There is a continuous interest for new synthetic routes affording steroids functionalized with heteroatoms and heterocycles, since these groups modify the biological activity of related molecules (Banday et al., 2008; Pathak & Jindal, 1998). For example, the synthesis of suitable precursors for steroids analogs to brassinosteroids has been reported (Litvinovskaya et al., 1998). Functionalization with an isoxazol heterocycle has been limited to date to few examples, where the heterocycle is fused with the A ring of the steroid. An example of a molecule belonging to this family is danazol (Gupta et al., 1999), a derivative of ethisterone, which has numerous medicinal applications.

In relation with this general goal, we have developed several reagents for the direct one-step functionalization of steroids on remote positions. The title compound was synthesized readily starting from 23-acetylsarsasapogenin (Meza-Reyes et al., 2005) in a one-pot reaction carried out in dry media (see Experimental). This new route improves known procedures, which make necessary the isolation of an oxime intermediate, prior to the heterocyclization in acid conditions (Beam et al., 2000). Full details about the involved chemistry and mechanistic aspects of this unprecedented reaction will be reported elsewhere. It was however essential to X-ray characterize the product, in order to determine if any epimerization occurred during the cleavage of rings E and F.

The title molecule displays the expected cis-fused A/B ring system, characteristic of sarsasapogenin derivatives (Fig. 1). Rings A,B and C have the expected chair conformation, while the 5-membered ring D is twisted on C13—C14. The spiroketal E/F system was cleaved during the reaction, affording a C₂₁-pregnane nucleus substituted at C20 by an isoxazol heterocycle. Positions for O and N atoms in the heterocycle were unambiguously determined from X-ray data, and are consistent with the positions for double bonds, C22=C26 and C25=N24. The isoxazol ring is oriented towards the α face, and its plane approximately bisects the mean plane of the A···D steroidal nucleus. This conformation avoids any hindrance with the methyl group, C21, and OH group at C16. The observed absolute configuration indicates that the E/F rings cleavage occurred without epimerization, despite use of the strongly acidic medium used for the reaction. C20 is retained as S, and the chiral C atom C29 in the lateral chain has the S configuration.

In the crystal, molecules are associated via O—H···N hydrogen bonds involving the isoxalic N atom as an acceptor, forming chains running along the [100] direction (Fig. 2). The hydroxyl groups at O32 and O34, form O—H···O contacts between chains. The resulting three-dimensional supramolecular network also includes weak C—H···O hydrogen bond interactions involving the O23 and O24 atoms as acceptors.

Experimental

A mixture of 23-acetylsarsasapogenin (2 mmol), hydroxylamine hydrochloride (4 mmol) and a previously prepared P₂O₅/SiO₂ reagent (1 g) were grounded thoroughly in a mortar. An immediate color change was observed. The mortar was covered with a watch glass and put inside a microwave device (2450 MHz, 1200 W). The mixture was irradiated for 3 min, allowing the reaction to complete (TLC). The mixture was then cooled to room temperature, and 10 ml of 5% aqueous HCl was added. The resulting solution was extracted with CH₂Cl₂ (2×10 ml) and dried over CaCl₂. Evaporation of solvent under reduced pressure gave the pure title compound, in 81% yield. Anal. found (calc. for C₂₉H₄₇NO₄): C 73.52 (75.53), H 9.98 (9.99), N 2.95 (2.95%). Single crystals were obtained by slow evaporation of an acetone solution.