research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2056-9890

Crystal structure of a bioactive sesquiterpene isolated from Artemisia reticulata

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aBioorganic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 85, India, bClemens Schöpf-Institut für Organische, Chemie und Biochemie, Technische Universität Darmstadt, Petersenstrasse 22, D-64287 Darmstadt, Germany, and cAccident & Emergency Department, Franco, Vietnamese Hospital, 7-Nguyen, Luong Bang Street, HoChiMinh City, Vietnam
*Correspondence e-mail: nguyendonhuquynh@yahoo.com

Edited by A. J. Lough, University of Toronto, Canada (Received 13 January 2016; accepted 25 February 2016; online 4 March 2016)

The title compound, C15H24O2 {systematic name: 1-[6-hy­droxy-7-(propan-2-yl)-4-methyl­idene-2,3,3a,4,5,6,7,7a-octa­hydro-1H-inden-1-yl]ethanone} was iso­la­ted from A. reticulata by column chromatography over silica gel by gradient solvent elution. The mol­ecule comprises a bi­cyclo­[4.3.0]nonane ring bearing acet­oxy, hy­droxy and isopropyl substituents, and an exocyclic double bond on the cyclo­hexane ring. In the bicyclic skeleton, the cyclo­hexane ring adopts a chair conformation ring and the cyclo­pentane ring is in an envelope conformation. In the crystal, mol­ecules are linked by O—H⋯O hydrogen bonds, forming chains along [010]. These chains are cross-linked by C—H⋯O hydrogen bonds.

1. Chemical context

The title compound is a natural product, which has been isolated from the Indian herb A. reticulata by column chroma­tography over silica gel. A. reticulata (family: Asteraceae) is a traditional herb which has many applications in folklore medicine for conventional therapy against several diseases such as malaria (Klayman et al., 1984[Klayman, D. L., Lin, A., Acton, N., Scovill, J. P., Hoch, J. M., Milhous, W. K., Theoharides, A. D. & Dobek, A. S. (1984). J. Nat. Prod. 47, 715-717.]; Malagon et al., 1997[Malagon, F., Vazquez, J., Delgado, G. & Ruiz, A. (1997). Parassitolgia, 39, 3-7.]; Newton & White, 1999[Newton, P. & White, N. (1999). Annu. Rev. Med. 50, 179-192.]), cancer (Efferth et al., 2001[Efferth, T., Dunstan, H., Sauerbrey, A., Miyachi, H. & Chitambar, C. R. (2001). Int. J. Oncol. 18, 767-773.]; Lai et al., 1995[Lai, H. & Singh, N. P. (1995). Cancer Lett. 91, 41-46.]), cardiovascular (Guantai et al., 1999[Guantai, A. N. & Addae-Mensah, I. (1999). Pharm. Biol. 37, 351-356.]), vasodilatory (Walker, 1996[Walker, A. F. (1996). Biologist, 43, 177-180.]), hepatitis (Aniya et al., 2000[Aniya, Y., Shimabukuro, M., Shimoji, M., Kohatsu, M., Gyamfi, M. A., Miyagi, C., Kunii, D., Takayama, F. & Egashira, T. (2000). Biol. Pharm. Bull. 23, 309-312.]) and diabetes (Iriadam et al., 2006[Iriadam, M., Musa, D., Gumushan, H. & Baba, F. (2006). J. Cell. Mol. Biol. 5, 19-24.]). It is found as a constituent in many ayurvedic or herbal drug preparations such as forkolin and Afsanteen in Indian traditional medicinal systems (Nadkarni, 1954[Nadkarni, A. K. (1954). Indian Materia Medica, 3rd ed. Bombay: Popular Prakashan.]; Satyavati et al., 1987[Satyavati, G. V., Gupta, A. & Tandon, N. (1987). In Medicinal Plants of India. New Delhi: ICMR.]; Subramoniam et al., 1996[Subramoniam, A., Pushpangadan, P., Rajasekharan, S., Evans, D. A., Latha, P. G. & Valsaraj, R. (1996). J. Ethnopharmacol. 50, 13-17.]; Drury, 1978[Drury, C. H. (1978). The useful Plants of India: with notices of their chief value in commerce, medicine and the arts. London: William H. Allen & Co.]). The Artemisia species are a rich source of bioactive sesquiterpenenoids (Klayman et al., 1984[Klayman, D. L., Lin, A., Acton, N., Scovill, J. P., Hoch, J. M., Milhous, W. K., Theoharides, A. D. & Dobek, A. S. (1984). J. Nat. Prod. 47, 715-717.]) such as artemisinin, artemisin etc. Artimisinin and artemisin are secondary metabolites isolated from herbs of the species A. annua (Klayman, 1985[Klayman, D. L. (1985). Science, 228, 1049-1055.]) belonging to the sesquiterpene class. The title mol­ecule possesses anti­plasmodial activity and it is now under clinical trial for the treatment of malaria. Our group are currently searching for artemisin, artemisinin or their analogues from other varieties of Artemisia species and as part of these studies, the structure of the title compound is now reported.

2. Structural commentary

The mol­ecular structure of the title compound is shown in Fig. 1[link]. The compound comprises fused cyclo­hexane and cyclo­pentane rings. It has been substanti­ated by a positive LB test (Liebermann Burchard Test), which indicates that it belongs to the sesquiterpene class. The compound is soluble in chloro­form but has poor solubility in methanol.

[Scheme 1]
[Figure 1]
Figure 1
The mol­ecular structure of the title compound, showing 50% probability displacement ellipsoids for non-H atoms.

The bicyclic skeleton contains one acetyl group at atom C1 of the cyclo­pentane ring, one isopropyl group and one hydroxyl group located at atoms C6 and C7 in the cyclo­hexane ring. An exocyclic olefinic double bond is located between atoms C9 and C15 and attached to the cyclo­hexane ring. The torsion angles C3—C4—C5—C6 and C9—C4—C5—C1 of −169.2 (3) and −170.9 (3)°, respectively, describe the geometry at the junction of the two rings. The C7—C6—C5 and C9—C4—C5 angles are 107.3 (2) and 109.2 (3)°, respectively.

3. Supra­molecular features

In the crystal, mol­ecules are linked by O—H⋯O hydrogen bonds, forming chains along [010] (Table 1[link] and Fig. 2[link]). These chains are cross-linked by weak C—H⋯O hydrogen bonds.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O1—H1O⋯O1i 0.82 2.11 2.927 (4) 175
C11—H11C⋯O2ii 0.96 2.53 3.430 (6) 157
Symmetry codes: (i) [-x+1, y+{\script{1\over 2}}, -z]; (ii) x, y+1, z.
[Figure 2]
Figure 2
Part of the crystal structure of the title compound, with hydrogen bonds shown as dashed lines.

4. Database survey

A search of Cambridge Structural Database (CSD, Version 5.36, last update May 2015; Groom & Allen, 2015[Groom, C. R. & Allen, F. H. (2014). Angew. Chem. Int. Ed. 53, 662-671.]) found only one mol­ecule, Pulioplopane A (15-hy­droxy-10 (14)-oplopen-4-one; Triana et al., 2005[Triana, J., López, M., Pérez, F. J., González-Platas, J., Quintana, J., Estévez, F., León, F. & Bermejo, J. (2005). J. Nat. Prod. 68, 523-531.]) that has a similar structural skeleton to the title sesquitertene although it is is unrelated in a biochemical sense.

5. Synthesis and crystallization

The title sesquiterpene was isolated as colourless solid from the methanol extract of A. reticulata by chromatography over silica gel with a mixture of ethyl acetate and hexane with a gradient elution followed by preparative thin layer chromatography. Crystals were obtained after recrystallization three times from ethyl acetate:hexane (1:4) at room temperature by the slow evaporation method. Bioassay of this mol­ecule has been conducted against human ovarian cancer cell line A 2780 and revealed that it possessed significant anti­proliferative activity (unpublished results).

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. H atoms were placed in calculated positions with C—H = 0.93–0.98 Å and O—H = 0.82 Å and refined in a riding-motion approximation with Uiso(U) = 1.2Ueq(C,O). No Friedel pairs were collected therefore the absolute configuration could not be determined from the X-ray data and the assignment is arbitrary.

Table 2
Experimental details

Crystal data
Chemical formula C15H24O2
Mr 236.34
Crystal system, space group Monoclinic, P21
Temperature (K) 299
a, b, c (Å) 8.849 (4), 5.336 (1), 14.994 (5)
β (°) 99.21 (2)
V3) 698.9 (4)
Z 2
Radiation type Cu Kα
μ (mm−1) 0.56
Crystal size (mm) 0.50 × 0.18 × 0.15
 
Data collection
Diffractometer Enraf–Nonius CAD-4
No. of measured, independent and observed [I > 2σ(I)] reflections 1916, 1392, 1260
Rint 0.052
(sin θ/λ)max−1) 0.597
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.060, 0.164, 1.10
No. of reflections 1392
No. of parameters 154
No. of restraints 1
H-atom treatment H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.46, −0.22
Computer programs: CAD-4-PC (Enraf–Nonius, 1993[Nonius (1993). CAD-4-PC Software. Enraf-Nonius, Delft, The Netherlands.]), REDU4 (Stoe & Cie, 1987[Stoe & Cie (1987). REDU4. Stoe & Cie GmbH, Darmstadt, Germany.]), SHELXS97 and SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]).

Supporting information


Computing details top

Data collection: CAD-4-PC (Enraf–Nonius, 1993); cell refinement: CAD-4-PC (Enraf–Nonius, 1993); data reduction: REDU4 (Stoe & Cie, 1987); 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).

1-[6-Hydroxy-7-(propan-2-yl)-4-methylidene-2,3,3a,4,5,6,7,7a-octahydro-1H-inden-1-yl]ethanone top
Crystal data top
C15H24O2F(000) = 260
Mr = 236.34Dx = 1.123 Mg m3
Monoclinic, P21Cu Kα radiation, λ = 1.54180 Å
Hall symbol: P 2ybCell parameters from 25 reflections
a = 8.849 (4) Åθ = 5.5–27.1°
b = 5.336 (1) ŵ = 0.56 mm1
c = 14.994 (5) ÅT = 299 K
β = 99.21 (2)°Rod, colourless
V = 698.9 (4) Å30.50 × 0.18 × 0.15 mm
Z = 2
Data collection top
Enraf–Nonius CAD-4
diffractometer
Rint = 0.052
Radiation source: fine-focus sealed tubeθmax = 67.0°, θmin = 3.0°
Graphite monochromatorh = 103
ω/2θ scansk = 06
1916 measured reflectionsl = 1717
1392 independent reflections3 standard reflections every 120 min
1260 reflections with I > 2σ(I) intensity decay: 1.0%
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.060Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.164H-atom parameters constrained
S = 1.10 w = 1/[σ2(Fo2) + (0.1147P)2 + 0.0812P]
where P = (Fo2 + 2Fc2)/3
1392 reflections(Δ/σ)max < 0.001
154 parametersΔρmax = 0.46 e Å3
1 restraintΔρmin = 0.22 e Å3
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 &gt; 2sigma(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
xyzUiso*/Ueq
O10.5467 (3)0.0974 (5)0.03391 (14)0.0580 (7)
H1O0.52590.23800.01350.070*
O20.9664 (3)0.1293 (5)0.3910 (2)0.0680 (8)
C10.8020 (3)0.4666 (6)0.33401 (19)0.0401 (7)
H10.81840.61680.29920.048*
C20.7177 (4)0.5402 (8)0.4141 (2)0.0539 (9)
H2A0.78210.50690.47150.065*
H2B0.69120.71670.41120.065*
C30.5742 (4)0.3792 (9)0.4035 (2)0.0568 (9)
H3A0.59430.21880.43350.068*
H3B0.49230.46330.42770.068*
C40.5350 (3)0.3473 (7)0.3022 (2)0.0446 (7)
H40.50200.51090.27650.053*
C50.6918 (3)0.2887 (5)0.27514 (17)0.0355 (6)
H50.71910.11740.29520.043*
C60.6880 (3)0.2967 (5)0.17229 (17)0.0370 (7)
H60.65010.46290.15180.044*
C70.5672 (4)0.1059 (6)0.13003 (18)0.0439 (7)
H70.60390.06000.15170.053*
C80.4103 (4)0.1446 (9)0.1602 (2)0.0590 (10)
H8A0.36540.29910.13410.071*
H8B0.34290.00810.13710.071*
C90.4206 (4)0.1563 (8)0.2604 (2)0.0508 (8)
C100.9549 (4)0.3515 (7)0.3722 (2)0.0431 (7)
C111.0900 (4)0.5203 (9)0.3893 (3)0.0671 (11)
H11A1.16640.46370.35520.081*
H11B1.13130.51850.45260.081*
H11C1.05940.68780.37130.081*
C120.8473 (4)0.2670 (6)0.1447 (2)0.0447 (8)
H120.91600.37740.18470.054*
C130.8571 (5)0.3509 (9)0.0487 (2)0.0604 (10)
H13A0.82940.52460.04180.072*
H13B0.78820.25240.00670.072*
H13C0.95980.32860.03710.072*
C140.9125 (5)0.0040 (8)0.1601 (3)0.0613 (10)
H14A0.84540.11350.12510.074*
H14B0.92170.03770.22300.074*
H14C1.01160.00270.14190.074*
C150.3418 (5)0.0067 (11)0.3076 (3)0.0708 (12)
H15A0.27590.11340.27800.085*
H15B0.35280.02250.37010.085*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0792 (15)0.0505 (15)0.0419 (11)0.0110 (14)0.0024 (10)0.0077 (11)
O20.0730 (17)0.0337 (14)0.0893 (19)0.0019 (14)0.0110 (13)0.0124 (14)
C10.0543 (16)0.0251 (14)0.0392 (13)0.0004 (13)0.0022 (12)0.0020 (12)
C20.067 (2)0.045 (2)0.0479 (16)0.0059 (17)0.0046 (14)0.0101 (16)
C30.0614 (19)0.063 (2)0.0489 (17)0.0040 (18)0.0176 (14)0.0047 (18)
C40.0501 (16)0.0376 (17)0.0472 (16)0.0042 (15)0.0112 (12)0.0022 (14)
C50.0451 (14)0.0226 (14)0.0386 (14)0.0002 (12)0.0059 (11)0.0015 (12)
C60.0513 (16)0.0226 (14)0.0369 (13)0.0002 (13)0.0064 (11)0.0013 (12)
C70.0570 (17)0.0330 (17)0.0410 (14)0.0066 (15)0.0052 (13)0.0001 (14)
C80.0527 (18)0.062 (3)0.0603 (19)0.010 (2)0.0022 (14)0.004 (2)
C90.0423 (15)0.049 (2)0.0626 (18)0.0012 (16)0.0135 (13)0.0002 (17)
C100.0516 (17)0.0324 (16)0.0438 (15)0.0007 (14)0.0026 (12)0.0008 (14)
C110.0541 (19)0.047 (2)0.095 (3)0.0055 (18)0.0023 (18)0.002 (2)
C120.0551 (17)0.0307 (16)0.0492 (17)0.0035 (15)0.0108 (13)0.0007 (14)
C130.078 (2)0.052 (2)0.0559 (19)0.004 (2)0.0248 (17)0.0006 (18)
C140.070 (2)0.042 (2)0.077 (2)0.0144 (19)0.0264 (18)0.0068 (19)
C150.060 (2)0.076 (3)0.080 (2)0.014 (2)0.0229 (18)0.004 (2)
Geometric parameters (Å, º) top
O1—C71.424 (3)C7—C81.542 (5)
O1—H1O0.8200C7—H70.9800
O2—C101.219 (5)C8—C91.493 (5)
C1—C101.513 (4)C8—H8A0.9700
C1—C51.535 (4)C8—H8B0.9700
C1—C21.562 (5)C9—C151.335 (6)
C1—H10.9800C10—C111.486 (5)
C2—C31.521 (6)C11—H11A0.9600
C2—H2A0.9700C11—H11B0.9600
C2—H2B0.9700C11—H11C0.9600
C3—C41.513 (4)C12—C141.521 (5)
C3—H3A0.9700C12—C131.523 (5)
C3—H3B0.9700C12—H120.9800
C4—C91.501 (5)C13—H13A0.9600
C4—C51.539 (4)C13—H13B0.9600
C4—H40.9800C13—H13C0.9600
C5—C61.538 (3)C14—H14A0.9600
C5—H50.9800C14—H14B0.9600
C6—C71.537 (4)C14—H14C0.9600
C6—C121.540 (4)C15—H15A0.9300
C6—H60.9800C15—H15B0.9300
C7—O1—H1O109.5C6—C7—H7106.8
C10—C1—C5114.5 (3)C8—C7—H7106.8
C10—C1—C2108.6 (2)C9—C8—C7112.9 (3)
C5—C1—C2105.1 (2)C9—C8—H8A109.0
C10—C1—H1109.5C7—C8—H8A109.0
C5—C1—H1109.5C9—C8—H8B109.0
C2—C1—H1109.5C7—C8—H8B109.0
C3—C2—C1105.8 (3)H8A—C8—H8B107.8
C3—C2—H2A110.6C15—C9—C8123.8 (4)
C1—C2—H2A110.6C15—C9—C4124.0 (4)
C3—C2—H2B110.6C8—C9—C4112.2 (3)
C1—C2—H2B110.6O2—C10—C11121.0 (3)
H2A—C2—H2B108.7O2—C10—C1121.3 (3)
C4—C3—C2102.8 (3)C11—C10—C1117.7 (3)
C4—C3—H3A111.2C10—C11—H11A109.5
C2—C3—H3A111.2C10—C11—H11B109.5
C4—C3—H3B111.2H11A—C11—H11B109.5
C2—C3—H3B111.2C10—C11—H11C109.5
H3A—C3—H3B109.1H11A—C11—H11C109.5
C9—C4—C3121.8 (3)H11B—C11—H11C109.5
C9—C4—C5109.2 (3)C14—C12—C13109.7 (3)
C3—C4—C5102.5 (2)C14—C12—C6113.3 (3)
C9—C4—H4107.5C13—C12—C6114.6 (3)
C3—C4—H4107.5C14—C12—H12106.2
C5—C4—H4107.5C13—C12—H12106.2
C1—C5—C6118.0 (2)C6—C12—H12106.2
C1—C5—C4103.8 (2)C12—C13—H13A109.5
C6—C5—C4112.5 (2)C12—C13—H13B109.5
C1—C5—H5107.3H13A—C13—H13B109.5
C6—C5—H5107.3C12—C13—H13C109.5
C4—C5—H5107.3H13A—C13—H13C109.5
C7—C6—C5107.3 (2)H13B—C13—H13C109.5
C7—C6—C12115.3 (3)C12—C14—H14A109.5
C5—C6—C12113.1 (2)C12—C14—H14B109.5
C7—C6—H6106.9H14A—C14—H14B109.5
C5—C6—H6106.9C12—C14—H14C109.5
C12—C6—H6106.9H14A—C14—H14C109.5
O1—C7—C6113.9 (2)H14B—C14—H14C109.5
O1—C7—C8109.0 (2)C9—C15—H15A120.0
C6—C7—C8112.9 (3)C9—C15—H15B120.0
O1—C7—H7106.8H15A—C15—H15B120.0
C10—C1—C2—C3116.4 (3)C5—C6—C7—C852.9 (3)
C5—C1—C2—C36.5 (4)C12—C6—C7—C8179.9 (3)
C1—C2—C3—C431.5 (4)O1—C7—C8—C9179.9 (3)
C2—C3—C4—C9166.7 (3)C6—C7—C8—C952.2 (4)
C2—C3—C4—C544.5 (4)C7—C8—C9—C15124.2 (4)
C10—C1—C5—C695.1 (3)C7—C8—C9—C453.1 (4)
C2—C1—C5—C6145.9 (3)C3—C4—C9—C152.1 (6)
C10—C1—C5—C4139.6 (3)C5—C4—C9—C15121.1 (4)
C2—C1—C5—C420.5 (3)C3—C4—C9—C8175.3 (3)
C9—C4—C5—C1170.9 (3)C5—C4—C9—C856.3 (4)
C3—C4—C5—C140.5 (3)C5—C1—C10—O231.7 (5)
C9—C4—C5—C660.4 (3)C2—C1—C10—O285.3 (4)
C3—C4—C5—C6169.2 (3)C5—C1—C10—C11150.5 (3)
C1—C5—C6—C7179.0 (3)C2—C1—C10—C1192.5 (4)
C4—C5—C6—C758.0 (3)C7—C6—C12—C1453.3 (4)
C1—C5—C6—C1252.8 (3)C5—C6—C12—C1470.7 (4)
C4—C5—C6—C12173.7 (3)C7—C6—C12—C1373.6 (4)
C5—C6—C7—O1178.0 (2)C5—C6—C12—C13162.4 (3)
C12—C6—C7—O155.0 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1O···O1i0.822.112.927 (4)175
C11—H11C···O2ii0.962.533.430 (6)157
Symmetry codes: (i) x+1, y+1/2, z; (ii) x, y+1, z.
 

Acknowledgements

The authors thank Professor Dr Hartmut, FG Strukturforschung, Material-und Geowissenschaften, Technische Universität Darmstadt, Petersenstress 23, 64287 Darmstadt, and Professor Kingston, Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA, for their kind co-operation to measure diffraction data for the title compound and to carry out an anti­proliferative bioassay against cancer cell lines.

References

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