3β,5α,6β-Trihy­droxy­androstan-17-one

Andrade, L.C.R.; Almeida, M.J.B.M. de; Paixão, J.A.; Carvalho, J.F.S.; Sá e Melo, M.L.

doi:10.1107/S1600536811011706

organic compounds

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ISSN: 2056-9890

Volume 67| Part 5| May 2011| Pages o1056-o1057

doi:10.1107/S1600536811011706

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3β,5α,6β-Trihydroxyandrostan-17-one

L.C.R. Andrade,^a M.J.B.M. de Almeida,^a J.A. Paixão,^a ^* J.F.S. Carvalho ^b and M.L. Sá e Melo ^b,^c

^aCEMDRX, Department of Physics, University of Coimbra, P-3004-516 Coimbra, Portugal, ^bCentre for Neuroscience and Cell Biology, University of Coimbra, P-3004-517 Coimbra, Portugal, and ^cFaculty of Pharmacy, University of Coimbra, P-3000-548 Coimbra, Portugal
^*Correspondence e-mail: jap@pollux.fis.uc.pt

(Received 24 March 2011; accepted 29 March 2011; online 7 April 2011)

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, P 2₁ 2₁ 2₁
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[F² > 2σ(F²)] = 0.037
wR(F²) = 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

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
Symmetry codes: (i) $[-x+{\script{3\over 2}}, -y+1, z-{\script{1\over 2}}]$ ; (ii) $[x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z]$ ; (iii) x-1, y, z.

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.

Supporting information

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

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

checkCIF report

Comment top

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.

Related literature top

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 top

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).

Computing details top

Data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 2006); data reduction: SAINT (Bruker, 2006); 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 (Sheldrick, 2008).

Figures top

Fig. 1. ORTEPII plot of the title compound. Displacement ellipsoids are drawn at the 50% level.

3β,5α,6β-Trihydroxyandrostan-17-one top

Crystal data top

C₁₉H₃₀O₄	D_x = 1.290 Mg m⁻³
M_r = 322.43	Melting point: 574 K
Orthorhombic, P2₁2₁2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 6253 reflections
a = 5.8132 (1) Å	θ = 3.1–30.3°
b = 13.3880 (3) Å	µ = 0.09 mm⁻¹
c = 21.3298 (5) Å	T = 293 K
V = 1660.04 (6) Å³	Prism, colourless
Z = 4	0.23 × 0.13 × 0.13 mm
F(000) = 704

Data collection top

Bruker APEXII CCD area-detector diffractometer	2276 independent reflections
Radiation source: fine-focus sealed tube	1874 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.031
ϕ and ω scans	θ_max = 27.9°, θ_min = 1.8°
Absorption correction: multi-scan (SADABS; Sheldrick, 2000)	h = −7→6
T_min = 0.937, T_max = 1.00	k = −17→17
40718 measured reflections	l = −27→25

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.098	H-atom parameters constrained
S = 1.04	w = 1/[σ²(F_o²) + (0.0563P)² + 0.2093P] where P = (F_o² + 2F_c²)/3
2276 reflections	(Δ/σ)_max < 0.001
213 parameters	Δρ_max = 0.20 e Å⁻³
0 restraints	Δρ_min = −0.20 e Å⁻³

Crystal data top

C₁₉H₃₀O₄	V = 1660.04 (6) Å³
M_r = 322.43	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 5.8132 (1) Å	µ = 0.09 mm⁻¹
b = 13.3880 (3) Å	T = 293 K
c = 21.3298 (5) Å	0.23 × 0.13 × 0.13 mm

Data collection top

Bruker APEXII CCD area-detector diffractometer	2276 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 2000)	1874 reflections with I > 2σ(I)
T_min = 0.937, T_max = 1.00	R_int = 0.031
40718 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.037	0 restraints
wR(F²) = 0.098	H-atom parameters constrained
S = 1.04	Δρ_max = 0.20 e Å⁻³
2276 reflections	Δρ_min = −0.20 e Å⁻³
213 parameters

Special details top

Experimental. IR (film) 3442, 3348, 2942, 2861, 1723, 1471, 1373, 1077, 1047, 1030, 1001, 960, 874 cm^-1; ¹H NMR (300 MHz, DMSO-d6) δ p.p.m. 0.77 (3H, s, 18-CH₃), 1.04 (3H, s, 19-CH₃), 2.36 (1H, dd, J=19.0, 8.2 Hz), 3.35 (1H, m, 6α-H), 3.74 (1H, s, OH), 3.78 (1H, m, 3α-H), 4.22 (1H, d, J=5.8 Hz, OH), 4.51 (1H, d, J=4.3 Hz, OH); ¹³C NMR (75 MHz, DMSO-d6) δ p.p.m. 13.4, 16.2, 20.0, 21.4 (CH₂), 29.6, 31.0 (CH₂), 31.5 (CH₂), 32.0 (CH₂), 33.3 (CH₂), 35.3 (CH₂), 37.9 (C-10), 40.8 (CH₂), 44.8, 47.2 (C-13), 50.5, 65.6, 73.8, 74.3 (C-5), 220.0 (C-17); MS m/z (%): 321.3 (9) [M—H]⁺, 293.2 (20), 280.4 (23), 265.5 (100), 250.2 (13), 90.3 (54).

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 (Å²) top

	x	y	z	U_iso*/U_eq
O3	0.4447 (4)	0.39692 (11)	−0.03066 (6)	0.0551 (5)
H3	0.4176	0.4562	−0.0371	0.083*
O5	0.8749 (2)	0.26939 (10)	0.10844 (6)	0.0344 (3)
H5	0.8788	0.2198	0.0860	0.052*
O6	0.3172 (3)	0.20863 (13)	0.18197 (7)	0.0490 (4)
H6A	0.2372	0.2182	0.1509	0.074*
O17	1.1224 (3)	0.38845 (11)	0.44942 (6)	0.0396 (4)
C1	0.7513 (4)	0.47124 (14)	0.11921 (8)	0.0304 (4)
H1A	0.7555	0.5345	0.1414	0.036*
H1B	0.9085	0.4527	0.1093	0.036*
C2	0.6166 (4)	0.48453 (14)	0.05810 (8)	0.0358 (5)
H2A	0.4642	0.5098	0.0676	0.043*
H2B	0.6940	0.5334	0.0320	0.043*
C3	0.5956 (4)	0.38742 (14)	0.02260 (8)	0.0334 (5)
H3A	0.7485	0.3683	0.0075	0.040*
C4	0.5032 (4)	0.30359 (13)	0.06337 (8)	0.0298 (4)
H4A	0.5094	0.2414	0.0400	0.036*
H4B	0.3433	0.3170	0.0733	0.036*
C5	0.6392 (3)	0.29152 (13)	0.12470 (8)	0.0245 (4)
C6	0.5535 (4)	0.20277 (14)	0.16369 (9)	0.0326 (5)
H6	0.5743	0.1419	0.1388	0.039*
C7	0.6922 (4)	0.19194 (13)	0.22384 (8)	0.0333 (5)
H7A	0.8478	0.1718	0.2133	0.040*
H7B	0.6247	0.1395	0.2492	0.040*
C8	0.7015 (3)	0.28834 (13)	0.26229 (8)	0.0248 (4)
H8	0.5454	0.3049	0.2762	0.030*
C9	0.7942 (3)	0.37543 (13)	0.22212 (7)	0.0226 (4)
H9	0.9469	0.3549	0.2076	0.027*
C10	0.6459 (3)	0.39125 (12)	0.16226 (7)	0.0219 (4)
C11	0.8298 (4)	0.47172 (13)	0.26035 (8)	0.0332 (5)
H11A	0.9074	0.5205	0.2342	0.040*
H11B	0.6805	0.4989	0.2714	0.040*
C12	0.9702 (4)	0.45672 (14)	0.32058 (8)	0.0329 (5)
H12A	1.1280	0.4402	0.3100	0.039*
H12B	0.9712	0.5181	0.3448	0.039*
C13	0.8657 (3)	0.37305 (14)	0.35939 (8)	0.0267 (4)
C14	0.8548 (3)	0.27739 (13)	0.31973 (8)	0.0267 (4)
H14	1.0109	0.2665	0.3038	0.032*
C15	0.8117 (4)	0.19464 (15)	0.36767 (9)	0.0418 (5)
H15A	0.8561	0.1299	0.3512	0.050*
H15B	0.6513	0.1925	0.3801	0.050*
C16	0.9667 (5)	0.22585 (15)	0.42264 (10)	0.0460 (6)
H16A	0.8930	0.2110	0.4623	0.055*
H16B	1.1126	0.1908	0.4209	0.055*
C17	1.0028 (4)	0.33729 (15)	0.41549 (8)	0.0307 (4)
C18	0.6314 (4)	0.40438 (18)	0.38719 (9)	0.0436 (5)
H18A	0.6503	0.4641	0.4115	0.065*
H18B	0.5739	0.3519	0.4135	0.065*
H18C	0.5244	0.4166	0.3538	0.065*
C19	0.4042 (3)	0.42658 (15)	0.18101 (9)	0.0331 (5)
H19A	0.4118	0.4944	0.1955	0.050*
H19B	0.3460	0.3847	0.2139	0.050*
H19C	0.3038	0.4227	0.1454	0.050*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O3	0.0995 (15)	0.0344 (8)	0.0314 (8)	−0.0083 (10)	−0.0306 (9)	−0.0014 (6)
O5	0.0335 (7)	0.0368 (8)	0.0328 (7)	0.0077 (6)	0.0005 (6)	−0.0113 (6)
O6	0.0397 (8)	0.0592 (10)	0.0482 (8)	−0.0219 (9)	−0.0106 (7)	0.0154 (8)
O17	0.0437 (8)	0.0463 (8)	0.0289 (7)	0.0028 (8)	−0.0082 (7)	−0.0058 (6)
C1	0.0425 (11)	0.0251 (9)	0.0235 (9)	−0.0085 (9)	−0.0074 (8)	0.0012 (7)
C2	0.0548 (13)	0.0278 (9)	0.0247 (9)	−0.0095 (10)	−0.0092 (10)	0.0023 (8)
C3	0.0461 (12)	0.0328 (10)	0.0213 (9)	−0.0015 (10)	−0.0054 (9)	−0.0025 (8)
C4	0.0398 (10)	0.0236 (9)	0.0260 (9)	−0.0050 (9)	−0.0069 (8)	−0.0041 (7)
C5	0.0256 (9)	0.0230 (9)	0.0250 (8)	−0.0013 (8)	−0.0021 (7)	−0.0039 (7)
C6	0.0417 (11)	0.0227 (9)	0.0335 (10)	−0.0083 (9)	−0.0086 (9)	−0.0010 (8)
C7	0.0468 (12)	0.0202 (9)	0.0330 (10)	−0.0055 (9)	−0.0082 (9)	0.0033 (7)
C8	0.0257 (9)	0.0237 (8)	0.0251 (8)	−0.0010 (8)	−0.0020 (7)	0.0016 (7)
C9	0.0249 (9)	0.0215 (8)	0.0213 (8)	−0.0010 (7)	−0.0017 (7)	−0.0010 (7)
C10	0.0249 (9)	0.0193 (8)	0.0216 (8)	−0.0004 (7)	−0.0009 (7)	−0.0018 (7)
C11	0.0504 (13)	0.0231 (9)	0.0262 (9)	−0.0037 (9)	−0.0092 (9)	−0.0002 (7)
C12	0.0458 (12)	0.0289 (9)	0.0240 (9)	−0.0060 (9)	−0.0066 (9)	−0.0018 (7)
C13	0.0293 (9)	0.0294 (9)	0.0215 (8)	0.0035 (8)	−0.0006 (8)	−0.0011 (7)
C14	0.0287 (10)	0.0256 (9)	0.0258 (8)	0.0003 (8)	−0.0008 (8)	0.0008 (7)
C15	0.0570 (14)	0.0325 (11)	0.0359 (10)	−0.0053 (11)	−0.0098 (10)	0.0095 (9)
C16	0.0661 (16)	0.0387 (11)	0.0332 (10)	0.0014 (12)	−0.0136 (11)	0.0086 (9)
C17	0.0310 (10)	0.0391 (11)	0.0220 (9)	0.0048 (9)	0.0027 (8)	−0.0005 (8)
C18	0.0364 (11)	0.0598 (14)	0.0346 (10)	0.0160 (11)	0.0025 (10)	−0.0060 (10)
C19	0.0303 (11)	0.0382 (11)	0.0306 (9)	0.0076 (9)	−0.0034 (9)	−0.0043 (8)

Geometric parameters (Å, º) top

O3—C3	1.441 (2)	C8—H8	0.9800
O3—H3	0.8200	C9—C11	1.539 (2)
O5—C5	1.444 (2)	C9—C10	1.555 (2)
O5—H5	0.8200	C9—H9	0.9800
O6—C6	1.430 (3)	C10—C19	1.535 (3)
O6—H6A	0.8200	C11—C12	1.535 (2)
O17—C17	1.215 (2)	C11—H11A	0.9700
C1—C2	1.531 (2)	C11—H11B	0.9700
C1—C10	1.538 (2)	C12—C13	1.520 (3)
C1—H1A	0.9700	C12—H12A	0.9700
C1—H1B	0.9700	C12—H12B	0.9700
C2—C3	1.510 (3)	C13—C17	1.515 (3)
C2—H2A	0.9700	C13—C14	1.536 (2)
C2—H2B	0.9700	C13—C18	1.543 (3)
C3—C4	1.518 (3)	C14—C15	1.528 (2)
C3—H3A	0.9800	C14—H14	0.9800
C4—C5	1.537 (2)	C15—C16	1.537 (3)
C4—H4A	0.9700	C15—H15A	0.9700
C4—H4B	0.9700	C15—H15B	0.9700
C5—C6	1.533 (3)	C16—C17	1.514 (3)
C5—C10	1.558 (2)	C16—H16A	0.9700
C6—C7	1.522 (3)	C16—H16B	0.9700
C6—H6	0.9800	C18—H18A	0.9600
C7—C8	1.530 (2)	C18—H18B	0.9600
C7—H7A	0.9700	C18—H18C	0.9600
C7—H7B	0.9700	C19—H19A	0.9600
C8—C14	1.522 (2)	C19—H19B	0.9600
C8—C9	1.544 (2)	C19—H19C	0.9600

C3—O3—H3	109.5	C19—C10—C1	107.80 (16)
C5—O5—H5	109.5	C19—C10—C9	109.59 (14)
C6—O6—H6A	109.5	C1—C10—C9	111.35 (14)
C2—C1—C10	112.67 (15)	C19—C10—C5	112.05 (14)
C2—C1—H1A	109.1	C1—C10—C5	107.44 (13)
C10—C1—H1A	109.1	C9—C10—C5	108.61 (13)
C2—C1—H1B	109.1	C12—C11—C9	113.91 (15)
C10—C1—H1B	109.1	C12—C11—H11A	108.8
H1A—C1—H1B	107.8	C9—C11—H11A	108.8
C3—C2—C1	111.62 (15)	C12—C11—H11B	108.8
C3—C2—H2A	109.3	C9—C11—H11B	108.8
C1—C2—H2A	109.3	H11A—C11—H11B	107.7
C3—C2—H2B	109.3	C13—C12—C11	109.85 (16)
C1—C2—H2B	109.3	C13—C12—H12A	109.7
H2A—C2—H2B	108.0	C11—C12—H12A	109.7
O3—C3—C2	111.65 (16)	C13—C12—H12B	109.7
O3—C3—C4	107.56 (16)	C11—C12—H12B	109.7
C2—C3—C4	112.23 (14)	H12A—C12—H12B	108.2
O3—C3—H3A	108.4	C17—C13—C12	116.91 (17)
C2—C3—H3A	108.4	C17—C13—C14	101.13 (14)
C4—C3—H3A	108.4	C12—C13—C14	109.33 (14)
C3—C4—C5	112.54 (15)	C17—C13—C18	104.28 (15)
C3—C4—H4A	109.1	C12—C13—C18	111.22 (17)
C5—C4—H4A	109.1	C14—C13—C18	113.69 (16)
C3—C4—H4B	109.1	C8—C14—C15	120.83 (16)
C5—C4—H4B	109.1	C8—C14—C13	112.78 (14)
H4A—C4—H4B	107.8	C15—C14—C13	104.05 (14)
O5—C5—C6	106.23 (15)	C8—C14—H14	106.1
O5—C5—C4	107.77 (14)	C15—C14—H14	106.1
C6—C5—C4	112.08 (14)	C13—C14—H14	106.1
O5—C5—C10	106.01 (13)	C14—C15—C16	102.55 (16)
C6—C5—C10	113.17 (13)	C14—C15—H15A	111.3
C4—C5—C10	111.12 (14)	C16—C15—H15A	111.3
O6—C6—C7	106.51 (16)	C14—C15—H15B	111.3
O6—C6—C5	114.67 (17)	C16—C15—H15B	111.3
C7—C6—C5	111.02 (15)	H15A—C15—H15B	109.2
O6—C6—H6	108.1	C17—C16—C15	105.81 (17)
C7—C6—H6	108.1	C17—C16—H16A	110.6
C5—C6—H6	108.1	C15—C16—H16A	110.6
C6—C7—C8	112.96 (15)	C17—C16—H16B	110.6
C6—C7—H7A	109.0	C15—C16—H16B	110.6
C8—C7—H7A	109.0	H16A—C16—H16B	108.7
C6—C7—H7B	109.0	O17—C17—C16	125.09 (19)
C8—C7—H7B	109.0	O17—C17—C13	126.38 (17)
H7A—C7—H7B	107.8	C16—C17—C13	108.53 (17)
C14—C8—C7	111.77 (14)	C13—C18—H18A	109.5
C14—C8—C9	108.37 (14)	C13—C18—H18B	109.5
C7—C8—C9	110.60 (14)	H18A—C18—H18B	109.5
C14—C8—H8	108.7	C13—C18—H18C	109.5
C7—C8—H8	108.7	H18A—C18—H18C	109.5
C9—C8—H8	108.7	H18B—C18—H18C	109.5
C11—C9—C8	112.67 (13)	C10—C19—H19A	109.5
C11—C9—C10	113.30 (14)	C10—C19—H19B	109.5
C8—C9—C10	111.41 (14)	H19A—C19—H19B	109.5
C11—C9—H9	106.3	C10—C19—H19C	109.5
C8—C9—H9	106.3	H19A—C19—H19C	109.5
C10—C9—H9	106.3	H19B—C19—H19C	109.5

C10—C1—C2—C3	−56.4 (2)	O5—C5—C10—C1	59.79 (17)
C1—C2—C3—O3	172.65 (17)	C6—C5—C10—C1	175.84 (15)
C1—C2—C3—C4	51.8 (2)	C4—C5—C10—C1	−57.03 (19)
O3—C3—C4—C5	−175.47 (15)	O5—C5—C10—C9	−60.77 (17)
C2—C3—C4—C5	−52.3 (2)	C6—C5—C10—C9	55.28 (19)
C3—C4—C5—O5	−60.09 (19)	C4—C5—C10—C9	−177.60 (14)
C3—C4—C5—C6	−176.63 (16)	C8—C9—C11—C12	50.7 (2)
C3—C4—C5—C10	55.7 (2)	C10—C9—C11—C12	178.37 (16)
O5—C5—C6—O6	−177.18 (15)	C9—C11—C12—C13	−52.8 (2)
C4—C5—C6—O6	−59.7 (2)	C11—C12—C13—C17	170.85 (16)
C10—C5—C6—O6	66.9 (2)	C11—C12—C13—C14	56.8 (2)
O5—C5—C6—C7	62.06 (18)	C11—C12—C13—C18	−69.57 (19)
C4—C5—C6—C7	179.52 (15)	C7—C8—C14—C15	−55.8 (2)
C10—C5—C6—C7	−53.9 (2)	C9—C8—C14—C15	−177.90 (16)
O6—C6—C7—C8	−72.2 (2)	C7—C8—C14—C13	−179.62 (16)
C5—C6—C7—C8	53.2 (2)	C9—C8—C14—C13	58.24 (19)
C6—C7—C8—C14	−176.03 (16)	C17—C13—C14—C8	173.72 (15)
C6—C7—C8—C9	−55.2 (2)	C12—C13—C14—C8	−62.4 (2)
C14—C8—C9—C11	−51.4 (2)	C18—C13—C14—C8	62.6 (2)
C7—C8—C9—C11	−174.26 (16)	C17—C13—C14—C15	41.03 (18)
C14—C8—C9—C10	179.96 (14)	C12—C13—C14—C15	164.95 (17)
C7—C8—C9—C10	57.1 (2)	C18—C13—C14—C15	−70.1 (2)
C2—C1—C10—C19	−62.94 (19)	C8—C14—C15—C16	−168.04 (17)
C2—C1—C10—C9	176.82 (15)	C13—C14—C15—C16	−40.2 (2)
C2—C1—C10—C5	58.0 (2)	C14—C15—C16—C17	23.2 (2)
C11—C9—C10—C19	−62.1 (2)	C15—C16—C17—O17	−177.7 (2)
C8—C9—C10—C19	66.23 (18)	C15—C16—C17—C13	2.2 (2)
C11—C9—C10—C1	57.1 (2)	C12—C13—C17—O17	34.9 (3)
C8—C9—C10—C1	−174.59 (14)	C14—C13—C17—O17	153.5 (2)
C11—C9—C10—C5	175.23 (15)	C18—C13—C17—O17	−88.3 (2)
C8—C9—C10—C5	−56.48 (18)	C12—C13—C17—C16	−145.00 (19)
O5—C5—C10—C19	178.02 (15)	C14—C13—C17—C16	−26.4 (2)
C6—C5—C10—C19	−65.9 (2)	C18—C13—C17—C16	91.8 (2)
C4—C5—C10—C19	61.19 (19)	C19—C10—C13—C18	1.68 (16)

Hydrogen-bond geometry (Å, º) top

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

Symmetry codes: (i) −x+3/2, −y+1, z−1/2; (ii) x+1/2, −y+1/2, −z; (iii) x−1, y, z.

Experimental details

Crystal data
Chemical formula	C₁₉H₃₀O₄
M_r	322.43
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	293
a, b, c (Å)	5.8132 (1), 13.3880 (3), 21.3298 (5)
V (Å³)	1660.04 (6)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.09
Crystal size (mm)	0.23 × 0.13 × 0.13

Data collection
Diffractometer	Bruker APEXII CCD area-detector diffractometer
Absorption correction	Multi-scan (SADABS; Sheldrick, 2000)
T_min, T_max	0.937, 1.00
No. of measured, independent and observed [I > 2σ(I)] reflections	40718, 2276, 1874
R_int	0.031
(sin θ/λ)_max (Å⁻¹)	0.659

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.037, 0.098, 1.04
No. of reflections	2276
No. of parameters	213
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.20, −0.20

Computer programs: APEX2 (Bruker, 2006), SAINT (Bruker, 2006), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O17ⁱ	0.82	2.11	2.931 (2)	174.9
O5—H5···O3ⁱⁱ	0.82	1.99	2.8063 (19)	170.5
O6—H6A···O5ⁱⁱⁱ	0.82	2.39	3.120 (2)	148.2

Symmetry codes: (i) −x+3/2, −y+1, z−1/2; (ii) x+1/2, −y+1/2, −z; (iii) x−1, y, z.

Acknowledgements

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.

References

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