Brusatol

Shu-Zhi Hu; Lu Jin; Tong Yu; Hai-Yan Tian; Ren-Wang Jiang

doi:10.1107/S1600536812018582

. 2012 May 2;68(Pt 6):o1592–o1593. doi: 10.1107/S1600536812018582

Brusatol

Shu-Zhi Hu ^a, Lu Jin ^a, Tong Yu ^a, Hai-Yan Tian ^a, Ren-Wang Jiang ^a,^*

PMCID: PMC3379203 PMID: 22719401

Abstract

The title compound, C₂₆H₃₂O₁₁, is composed of an α,β-unsaturated cyclohexanone ring (A), two cyclohexane rings (B and C), a six-membered lactone ring (D) and tetrahydrofuran ring (E). Ring A exists in a half-chair conformation with a C atom displaced by 0.679 (2) Å from the mean plane through the remaining five atoms. Ring B exists in a normal chair conformation. Both rings C and D exist in a twisted-chair conformation due to the O-atom bridge and the carbonyl group in rings C and D, respectively. Ring E shows an envelope conformation with a C atom displaced by 0.761 (1) Å from the mean plane through the remaining five atoms. The ring junctions are A/B trans, B/C trans, C/D cis and D/E cis. An intramolecular O—H⋯O hydrogen bond occurs. In the crystal, O—H⋯O hydrogen bonds involving the hydroxy, lactone and ester groups and C—H⋯O interactions are observed.

Related literature

For the isolation of brusatol, see: Sim et al. (1968 ▶); Kim et al. (2004 ▶). For its anticancer activity, see: Zhao et al. (2011 ▶) and for its antiviral activity, see: Yan et al. (2010 ▶). For the enhancement of the efficacy for chemotherapy, see: Ren et al. (2011 ▶). For the crystal structure of bruceine A, see: Feng et al. 2010 ▶. For the absolute configuration of simalikalactone D, see: Moher et al. (1992 ▶). graphic file with name e-68-o1592-scheme1.jpg

Experimental

Crystal data

C₂₆H₃₂O₁₁
M _r = 520.52
Orthorhombic,
a = 6.7162 (1) Å
b = 13.6796 (2) Å
c = 25.9859 (5) Å
V = 2387.45 (7) Å³
Z = 4
Cu Kα radiation
μ = 0.96 mm⁻¹
T = 288 K
0.44 × 0.15 × 0.11 mm

Data collection

Oxford Gemini S Ultra Sapphire CCD diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.748, T _max = 1.000
4961 measured reflections
3380 independent reflections
3182 reflections with I > 2σ(I)
R _int = 0.020

Refinement

R[F ² > 2σ(F ²)] = 0.032
wR(F ²) = 0.085
S = 1.03
3380 reflections
338 parameters
H-atom parameters constrained
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.18 e Å⁻³
Absolute structure: Flack (1983 ▶), 1167 Friedel pairs
Flack parameter: −0.07 (19)

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: XP in SHELXTL; software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812018582/vm2168sup1.cif

e-68-o1592-sup1.cif^{(28.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812018582/vm2168Isup2.hkl

e-68-o1592-Isup2.hkl^{(165.8KB, 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
O2—H2A⋯O1	0.82	2.17	2.629 (3)	116
O3—H3A⋯O11ⁱ	0.82	2.09	2.911 (2)	173
O4—H4A⋯O9ⁱⁱ	0.82	2.41	3.180 (2)	157
O4—H4A⋯O8ⁱⁱ	0.82	2.33	3.066 (2)	149
C11—H11A⋯O9ⁱⁱ	0.98	2.54	3.368 (4)	142
C5′—H5′B⋯O1ⁱⁱⁱ	0.96	2.76	3.650 (3)	155

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

Acknowledgments

This work was supported by grants from the New Century Excellent Talents Scheme of the Ministry of Education (NCET-08–0612), the National Science Foundation of China (21072078), the Guangdong High Level Talent Scheme and the Fundamental Research Funds for the Central Universities (21609202).

supplementary crystallographic information

Comment

The title compound brusatol is a natural product originally isolated from the seeds of Brucea sumatrana (Sim et al., 1968). It was also isolated from the chinese herbal medicine Brucea javanica (Kim et al., 2004). Brusatol was found to show potent anticancer activity (Zhao et al., 2011) and antiviral activity against the tobaccomosaic virus (Yan et al., 2010). Furthermore, it was reported that brusatol could effectively enhance the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism (Ren et al., 2011). The crystal strcuture of bruceine A, an analogue of brusatol, was reported recently (Feng et al., 2010); however, no detailed structural information was provided. We report herein the three-dimensional structure of the title compound.

Brusatol consists of an α,β-unsaturated cyclohexanone ring (A), two cyclohexane rings (B and C), a six-membered lactone ring (D) and tetrahydrofuran ring (E). Ring A exists in a half chair conformation with C10 displaced by 0.679 (2) Å from the least squares plane through the remaining five atoms (C1, C2, C3, C4 and C5). Ring B exists in a normal chair conformation. Both rings C and D exist in a twisted chair conformation due to the oxygen bridge and carbonyl group in rings C and D, respectively. Ring E shows an envelop conformation with C14 displaced by 0.761 (1) Å from the least squares plane through the remaining four atoms (C8, C13, C20 and O7). The planes through rings A and E are roughly perpendicular to each other with a dihedral angle of 86.15 (9)°. There are two side chains at C13 and C15. The planes through the two ester groups in the side chains make a dihedral angle of 62.36 (10). The ring junctures are A/B trans, B/C trans, C/D cis and D/E cis. The absolute configuration determined for simalikalactone D (Moher et al., 1992), a similar quassinoid, was invoked, giving the assignments of the chiral centres in the molecule as shown in Fig. 1.

Intermolecular O–H···O hydrogen bonds (Table 1) between the hydroxyl groups at C11 and the ester group at C1' [O3···O11ⁱ = 2.911 (2) Å, symmetry code: (i) -x, 0.5 + y, 0.5 - z], between the hydroxyl group at C12 and the lactone group at C16 [O4···O8ⁱⁱ = 3.066 (2) Å and O4···O9ⁱⁱ = 3.180 (2) Å, symmetry code: (ii) 1 - x, 0.5 + y, 0.5 - z], and short C–H···O contacts between the methine group at C11 and the lactone group at C16 [C11···O9ⁱⁱ = 3.368 (4) Å] link adjacent molecules into chains along the b-axis. Adjacent chains are further linked by weak C–H···O interactions between the terminal methyl group and the ketone group at C2 [C5'···O1ⁱⁱⁱ = 3.650 (3) Å, symmetry code: (iii) 0.5 - x, 1 - y, 0.5 + z] into a three-dimensional network (Fig. 2).

Experimental

Dried seeds of brucea javanica (10 kg) were milled and extracted with 95% ethanol at room temperature and the extracted solution were concentrated to afford a syrup. The crude syrup was suspended in distilled water and partitioned with petroleum ether, ethyl acetate and n-butanol, successively. The ethyl acetate extract (82 g) was dissolved in warm methanol. After cooling, the raw brusatol precipitated as white powder. Then the powder (100 mg) was subjected to reverse phase HPLC to afford pure brusatol (83 mg). Colorless needles of the title compound were crystallized directly from the HPLC eluate acetonitrile: water 45:55.