(2S*,3S*,3aS*,6S*,7aR*)-3-Hy­droxy-2-[(2R*,3S*)-3-isopropyl­oxiran-2-yl]-3,6-dimethyl-3,3a,5,6,7,7a-hexa­hydro-1-benzofuran-4(2H)-one

Mingruo Ding; Qiaoyin Zhang; Lei Chen; Nianyu Huang; Junzhi Wang

doi:10.1107/S1600536812038470

. 2012 Sep 19;68(Pt 10):o2949. doi: 10.1107/S1600536812038470

(2S,3S,3aS,6S,7aR)-3-Hydroxy-2-[(2R,3S*)-3-isopropyloxiran-2-yl]-3,6-dimethyl-3,3a,5,6,7,7a-hexahydro-1-benzofuran-4(2H)-one

Mingruo Ding ^a, Qiaoyin Zhang ^a, Lei Chen ^a, Nianyu Huang ^a, Junzhi Wang ^a,^*

PMCID: PMC3470321 PMID: 23125734

Abstract

In the title compound, C₁₅H₂₄O₄, the six-membered ring shows a distorted chair conformation and the five-membered ring adopts an envelope conformation with the C atom bearing the methyl and OH groups as the flap. In the crystal, O—H⋯O hydrogen bonds link the molecules into chains running along the a-axis direction.

Related literature

The title compound was synthesized as a potential gastric cytoprotective agent. For background to gastric diseases, see: Palmer et al. (2010 ▶). For pharmacological uses of bisabolangelone, a sesquiterpene isolated from the roots of Angelica polymorpha Maxim, see: Fang & Liao (2006 ▶); Muckensturm et al. (1981 ▶). Huang et al. (2012 ▶); Wang et al. (2009 ▶). For the crystal structure of bisabolangelone, see: Wang et al. (2007 ▶).

Experimental

Crystal data

C₁₅H₂₄O₄
M _r = 268.34
Orthorhombic,
a = 6.616 (7) Å
b = 9.261 (9) Å
c = 25.12 (3) Å
V = 1539 (3) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 296 K
0.35 × 0.28 × 0.26 mm

Data collection

Rigaku Mercury 375R CCD area-detector diffractometer
Absorption correction: multi-scan (CrystalClear; Rigaku, 2011 ▶) T _min = 0.972, T _max = 0.980
16467 measured reflections
2058 independent reflections
1568 reflections with I > 2σ(I)
R _int = 0.176

Refinement

R[F ² > 2σ(F ²)] = 0.067
wR(F ²) = 0.185
S = 1.03
2058 reflections
177 parameters
H-atom parameters constrained
Δρ_max = 0.20 e Å⁻³
Δρ_min = −0.19 e Å⁻³

Data collection: CrystalClear (Rigaku, 2011 ▶); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812038470/bt6831sup1.cif

e-68-o2949-sup1.cif^{(20.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812038470/bt6831Isup2.hkl

e-68-o2949-Isup2.hkl^{(101.3KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812038470/bt6831Isup3.cml

Supplementary material file. DOI: 10.1107/S1600536812038470/bt6831Isup4.cdx

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—H3A⋯O4ⁱ	0.82	2.02	2.827 (4)	166

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Symmetry code: (i) Inline graphic .

Acknowledgments

We gratefully acknowledge financial support by the National Natural Science Foundation of China (Nos. 30970296 and 21102084), the Scientific and Technological Research Project of Hubei Provincial Department of Education (No. Q20111210), the Doctoral Startup Foundation of China Three Gorges University (No. KJ2009B046) and the Pre-research Foundation of the College of Chemistry and Life Sciences (No. HY0905).

supplementary crystallographic information

Comment

Acid-related diseases are highly prevalent in the developed world, and the inhibition of the gastric proton pump enzyme (H⁺/K⁺-ATPase) represents a major approach in the development of drugs against these medical conditions (Palmer et al., 2010). Bisabolangelone, a sesquiterpene isolated from the roots of Angelica polymorpha Maxim with the traditional Tujia medicine name of Zijinsha (Fang et al., 2006), displayed attractive bioactivity such as anti-feeding and insecticidal effect (Muckensturm et al., 1981). Recently, we found bisabolangelone and its derivatives also exhibited remarkably preventive and therapeutic action on gastric ulcer, and its anti-ulcer mechanism might be related to inhibition of the H⁺/K⁺-ATPase and reduction of the secretion of H⁺ (Wang et al., 2009). With the aim of studying the relationship between its structure and H⁺/K⁺-ATPase inhibition activity, the catalytic hydrogenated reduction (Huang et al., 2012) and epoxidation of bisabolangelone were undertaken, and the structure determination of the target compound was conducted by X-ray single-crystal analysis for the first time.

Compared with the crystal structure of bisabolangelone (Wang et al., 2007), most bond lengths in the title compound are in the normal range of single or double bonds. The 6-membered ring C(1)—C(2)—C(3)—C(4)—C(5)—C(6) shows a distorted chair conformation [Φ = 319.3 (9)°, Θ = 146.4 (5)°, puckering amplitude (Q) = 0.485 (4)°]. The 5-membered ring O(2)—C(5)—C(6)—C(8)—C(10) adopts an envelope conformation with C(8) at the flap. Intermolecular O—H···O interactions link the molecules into infinite zigzag chains along the a axis, which contribute to the stability of the structure.

Experimental

3-Hydroxy-3,6-dimethyl-2-(3-methylbut- 2-enylidene)-3,3a,7,7a-tetrahydrobenzofuran- 4(2H)-one (bisabolangelone, I, 1.00 g, 4.0 mmol) and Pd/C (0.10 g, 10% w/w) was dissolved in MeOH (30 ml) at 10\%C under dry nitrogen atmosphere, then hydrogen gas (99%) was bubbled into the vigorous stirred solution (50 ml/minute) for 2.0 h until the bisabolangelone was consumed. The hydrogen gas was diluted by large amounts of nitrogen and released into air through special pipeline, and the reaction mixture was filtered to recover the catalyst. Removing the solvents at reduced pressure to give white solids, which was purified by column chromatography on silica with ethyl acetate/petroleum ether (1:10, v/v) as eluent to give the pure intermediates 3-hydroxy-3,6-dimethyl-2-((E)-3-methylbut-1-enyl)hexahydrobenzofuran-4(2H)-one (II) as colorless needles (0.85 g). The m-CPBA (0.52 g, 1.5 mmol) and solid NaHCO₃ (0.19 g, 2.5 mmol) were added to a solution of the intermediates II (0.25 g, 1.0 mmol) in dry CH₂Cl₂ (20 ml) at 0 °C. The solution was stirred for 10 h until complete consumption of the starting material. The reaction was quenched with saturated aqueous sodium thiosulfate solution and extracted with CH₂Cl₂ (3 × 15 ml). The combined organic extracts were washed with saturated aqueous NaHCO₃ solution (25 ml) and dried over Na₂SO₄. The solventwas removed in vacuo and the residue purified by flash column chromatography on silica gel to give the pure (2S,3S,3aS,6S,7aR)-3-hydroxy-2-((2R,3S)-3-isopropyloxiran-2-yl)-3,6-dimethylhexahydrobenzofuran-4(2H)-one III (Eluant: ethyl acetate/petroleum ether = 1: 20, v/v). Single crystals suitable for X-ray diffraction were prepared by slow evaporation of a dilute solution of the title compound III in n-hexane:ethyl acetate, 10: 1 at room temperature.