3β,5α,6β-Trihy­droxy­androstan-17-one

LCR Andrade; MJBM de Almeida; JA Paixão; JFS Carvalho; ML Sá e Melo

doi:10.1107/S1600536811011706

. 2011 Apr 7;67(Pt 5):o1056–o1057. doi: 10.1107/S1600536811011706

3β,5α,6β-Trihydroxyandrostan-17-one

LCR Andrade ^a, MJBM de Almeida ^a, JA Paixão ^a,^*, JFS Carvalho ^b, ML Sá e Melo ^b,^c

PMCID: PMC3089281 PMID: 21754383

Abstract

The title compound, C₁₉H₃₀O₄, is an androstan-17-one derivative synthesized from the dehydroepiandrosterone through a sequential addition of an oxidant, followed by a trans-diaxial opening of the epoxide generated, with Bi(OTf)₃ (OTf is trifluoromethanesulfonate). The six-membered rings have a slightly flattened chair conformation, while the five-membered ring adopts a 14-α envelope conformation. All rings are trans fused. In the crystal, the molecules are connected by O—H⋯O hydrogen bonds involving the hydroxyl and carbonyl groups, forming a three-dimensional network. A quantum mechanical ab initio Roothan Hartree–Fock calculation of the free molecule gives bond lengths, valency angles and ring torsion angles of the free molecule at equilibrium geometry (energy minimum) close to the experimental values.

Related literature

For the synthesis of the title compound, see: Carvalho et al. (2010b ▶). For 3β,5α,6β-hydroxylation pattern occurance in several natural products, see: Mizushina et al. (1999 ▶); Hata et al. (2002 ▶); Tanaka et al. (2002 ▶); Sun et al. (2006 ▶). For natural products as scaffolds for drug discovery, see: Li & Vederas (2009 ▶); Rosén et al. (2009 ▶). For angiotoxicity of 3β,5α,6β-trihydroxy steroids, see: Imai et al. (1980 ▶); Peng et al. (1985 ▶). For the in vivo genesis of osteoporosis and atherosclerosis, see: Hongmei et al. (2005 ▶); Imai et al. (1980 ▶); Peng et al. (1985 ▶). For the cytotoxicity of steroids with a 3β,5α,6β-hydroxylation motif against cancer cells, see: Aiello et al. (1995 ▶); Carvalho et al. (2010a ▶); El-Gamal et al. (2004 ▶). For the use of 3β,5α,6β-trihydroxy steroids in the synthesis of Δ⁴-3,6-dione steroids. see: Tischler et al. (1988 ▶); Aiello et al. (1991 ▶); Pardo et al. (2000 ▶). For their use as molecular probes for the study of aromatase inhibition, see: Numazawa & Tachibana (1994 ▶); Pérez-Ornelas et al. (2005 ▶); Nagaoka & Numazawa (2004 ▶). For the use of the title compound as an intermediate in the synthesis of the aromatase inhibitor androst-4-ene-3,6,17-trione, see: Ehrenstein (1939 ▶); Numazawa et al. (1987 ▶); Anthony et al. (1999 ▶). For related structures, see Anthony et al. (1999 ▶). For puckering parameters, see: Cremer & Pople (1975 ▶) and for asymmetry parameters, see: Duax & Norton (1975 ▶); Altona et al. (1968 ▶). For reference bond-length data, see: Allen et al. (1987 ▶). For the program GAMESS used to perform the quantum chemical calculations, see: Schmidt et al. (1993 ▶).

Experimental

Crystal data

C₁₉H₃₀O₄
M _r = 322.43
Orthorhombic,
a = 5.8132 (1) Å
b = 13.3880 (3) Å
c = 21.3298 (5) Å
V = 1660.04 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 293 K
0.23 × 0.13 × 0.13 mm

Data collection

Bruker APEXII CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2000 ▶) T _min = 0.937, T _max = 1.00
40718 measured reflections
2276 independent reflections
1874 reflections with I > 2σ(I)
R _int = 0.031

Refinement

R[F ² > 2σ(F ²)] = 0.037
wR(F ²) = 0.098
S = 1.04
2276 reflections
213 parameters
H-atom parameters constrained
Δρ_max = 0.20 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: SAINT (Bruker, 2006 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811011706/bt5502sup1.cif

e-67-o1056-sup1.cif^{(23.3KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811011706/bt5502Isup2.hkl

e-67-o1056-Isup2.hkl^{(111.9KB, 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
O3—H3⋯O17ⁱ	0.82	2.11	2.931 (2)	175
O5—H5⋯O3ⁱⁱ	0.82	1.99	2.8063 (19)	171
O6—H6A⋯O5ⁱⁱⁱ	0.82	2.39	3.120 (2)	148

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

Acknowledgments

This work was supported by the Fundação para a Ciência e Tecnologia. We gratefully acknowledge the LCA–UC for a grant of computer time in the Milipeia cluster and Mr Carlos Pereira for help with the analysis of the output of the GAMESS code.

supplementary crystallographic information

Comment

Recently, the importance of natural products as scaffolds for drug discovery and design has been a subject of renewed interest (Li & Vederas, 2009; Rosén et al., 2009). The 3β,5α,6β-hydroxylation pattern is found in several natural products (Mizushina et al., 1999; Hata et al., 2002; Tanaka et al., 2002; Sun et al., 2006) and also in human tissues, mainly in an oxidation product of cholesterol. The same hydroxylation motif is present in several natural steroids with interesting biological properties, namely cytotoxicity against cancer cells (Aiello et al., 1995; El-Gamal et al., 2004). On the other hand, cholestane-3β,5α,6β-triol has been extensively studied, proving to display cytotoxicity (Carvalho et al., 2010a) and angiotoxicity (Imai et al., 1980; Peng et al., 1985) and has been suggested to participate in the in vivo genesis of pathological situations such as osteoporosis (Hongmei et al., 2005) and atherosclerosis (Imai et al., 1980; Peng et al., 1985). Such findings validate the 3β,5α,6β-hydroxylation pattern as biologically important, and in this context a recently new protocol for the straightforward synthesis of 5α,6β-dihydroxy-steroids from a broad diversity of 3β-hydroxy-Δ⁵-steroids was accomplished by our group (Carvalho et al., 2010b).

In addition, 3β,5α,6β-trihydroxy steroids are valuable intermediates for the synthesis of Δ⁴-3,6-dione-steroids, widely present in natural products (Tischler et al., 1988; Aiello et al., 1991; Pardo et al., 2000) and with proved utility as molecular probes for the study of aromatase inhibition (Numazawa & Tachibana, 1994; Pérez-Ornelas et al., 2005; Nagaoka & Numazawa, 2004). In fact, compound (I) is a synthetically valuable intermediate (Ehrenstein, 1939) of the biologically active androst-4-ene-3,6,17-trione compound, (Anthony et al., 1999) which is a well known aromatase inhibitor (Numazawa et al., 1987). Due to the interest of our group in the cytotoxic potential of steroids, a series of oxygenated steroids were further prepared and evaluated on HT-29 cancer cells (Carvalho et al., 2010a). Compound (I) showed no relevant cytotoxicity (IC₅₀ > 50µM), in contrast to cholestane-3β,5α,6β-triol and other cholestane derivatives. Such result points to the importance of a C-17 cholesteryl type side chain for cytotoxicity thus the importance of X-ray difraction structural studies on such compounds.

Bond lengths and valency angles are within the range of expected values for this type of compounds (Allen et al.,1987) with the exception of bonds C2–C3 and C3–C4 [1.510 (3); 1.518 (3) Å)] which are significantely smaller than the Csp₃–Csp₃ average value [1.535 Å].

Rings A to C have slightly flattened chair conformations, as shown by the Cremer & Pople (1975) parameters [ring A: Q = 0.570 (2) Å, θ = 5.6 (2)° and φ = 299 (2)°; B: Q = 0.5705 (19) Å, θ = 3.4 (2)° and φ = 255 (3)°; C: Q = 0.5727 (19) Å, θ = 7.04 (19)° and φ = 271.3 (16)°].

Ring D has a 14-α envelope conformation [Cremer & Pople (1975) parameters q₂ = 0.415 (2) Å and φ₂ = 213.5 (3)° and asymmetry parameters (Duax & Norton, 1975; Altona et al., 1968) ΔC_s(14) =2.4 (2)°; ΔC₂(13,14)=17.8 (2)°; φ_m=42.6 (1)°; Δ=30.6 (4)°]. All rings are fused trans.

In order to gain some insight on how the crystal packing of (I) might affect the molecular geometry we have performed quantum chemical calculations on the equilibrium geometry of the free molecule. The calculations were performed with the computer program GAMESS (Schmidt et al., 1993).

The ab-initio calculations reproduce well the observed experimental bond lengths and valency angles of the molecule. Also, the calculated conformation of the rings are very close to the experimental values.

The molecules are hydrogen-bonded via the hydroxyl and carbonyl groups forming a three-dimension hydrogen bond pattern. Each hydroxyl group acts as both donnor and acceptor, thus full potential for hydrogen bonding is achieved in the crystal struture. In addition to these bonds, three weak intramolecular interactions can be spotted involving atoms O5 and O6 and CH, CH₂ and CH₃ groups.

Experimental

Synthesis of (I) was performed using a new and recently reported (Carvalho et al., 2010b) fast and high yielding sequential chemical approach for the straightforward preparation of 5α,6β-dihydroxy-steroids using 3β-hydroxy-Δ⁵-steroids as raw materials. The protocol involves two steps: (i) formation of the epoxide from Δ⁵-steroids, using MMPP as oxidative agent; and (ii) trans-diaxial epoxide opening with Bi(OTf)₃ in commercial acetone. Crystallization from ethanol at room temperature afforded colorless crystals suitable for X-ray analysis. Analytical data of compound (I) is in accordance with the literature (Carvalho et al., 2010b).