Redetermination of dihydro­artemisinin at 103 (2) K

Jerry P Jasinski; Ray J Butcher; H S Yathirajan; B Narayana; T V Sreevidya

doi:10.1107/S1600536807063180

. 2007 Dec 6;64(Pt 1):o89–o90. doi: 10.1107/S1600536807063180

Redetermination of dihydroartemisinin at 103 (2) K

Jerry P Jasinski ^a,^*, Ray J Butcher ^b, H S Yathirajan ^c, B Narayana ^d, T V Sreevidya ^d

PMCID: PMC2915045 PMID: 21200966

Abstract

Tthe structure of the title compound, C₁₅H₂₄O₅, has been redetermined at 103 (2) K, with much improved precision. The title compound was first reported by Luo, Yeh, Brossi, Flippen-Anderson & Gillardi [Helv. Chim. Acta (1984). 67, 1515–1522]. It is a derivative of the antimalaria compound artemisinin and consists primarily of three substituted ring systems fused together. A cyclohexane ring (with a distorted chair conformation), is fused to a tetrahydropyran group (also with a distorted chair conformation), and is adjacent to an oxacycloheptane unit containing an endoperoxide bridge. This gives the molecule a unique three-dimensional arrangement. The crystal packing is stabilized by intermolecular C–H⋯O and O–H⋯O interactions between an H atom from the cyclohexane ring and an O atom from the endoperoxide bridge, as well as between the hydroxyl H atom and an O atom from a tetrahydropyran ring.

Related literature

For crystal structures of similar compounds, see: Flippen-Anderson et al. (1989 ▶), Yue et al. (2006 ▶), Li et al. (2006 ▶); Karle & Lin (1995 ▶); Brossi et al. (1988 ▶). For the biological activity of artemisinin derivatives in vitro and in vivo, see: Li et al. (2001 ▶); Yang et al. (1997 ▶); Grace et al. (1998 ▶); Maggs et al. (2000 ▶). For endoperoxide sesquiterpene lactone derivatives, see: Venugopalan et al. (1995 ▶); Wu et al. (2001 ▶); Saxena et al. (2003 ▶). For the synthesis of artemisinin and its derivatives, see: Lui et al. (1979 ▶); Liu (1980 ▶); Robert et al. (2001 ▶). For related literature, see: Allen et al. (1987 ▶); Cremer & Pople (1975 ▶); Lisgarten et al. (1998 ▶); Qinghaosu Research Group (1980 ▶); Shen & Zhuang (1984 ▶); Wu & Li (1995 ▶); Luo et al. (1984 ▶).

Experimental

Crystal data

C₁₅H₂₄O₅
M _r = 284.34
Orthorhombic,
a = 5.5910 (6) Å
b = 14.1309 (14) Å
c = 18.8062 (19) Å
V = 1485.8 (3) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 103 (2) K
0.67 × 0.11 × 0.09 mm

Data collection

Bruker APEXII CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T _min = 0.940, T _max = 0.992
16573 measured reflections
2475 independent reflections
2130 reflections with I > 2σ(I)
R _int = 0.044

Refinement

R[F ² > 2σ(F ²)] = 0.038
wR(F ²) = 0.100
S = 1.06
2475 reflections
185 parameters
H-atom parameters constrained
Δρ_max = 0.37 e Å⁻³
Δρ_min = −0.22 e Å⁻³

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: APEX2; data reduction: SAINT (Bruker, 2006 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997 ▶); molecular graphics: SHELXTL (Bruker, 2000 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536807063180/fj2084sup1.cif

e-64-00o89-sup1.cif^{(19.9KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536807063180/fj2084Isup2.hkl

e-64-00o89-Isup2.hkl^{(121.6KB, 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
O5—H5⋯O2ⁱ	0.84	1.95	2.7799 (19)	168
C5—H5A⋯O4ⁱⁱ	1.00	2.38	3.381 (3)	175

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

Acknowledgments

RJB acknowledges the Laboratory for the Structure of Matter at the Naval Research Laboratory, Washington DC, USA, for access to their diffractometers. BN thanks Strides Arco Labs, Mangalore, India, for a gift sample of the title compound.

supplementary crystallographic information

Comment

Artemisinin and its derivatives, dihydroartemisinin, artemether, arteether and artesunate are antimalarial drugs which possess bioactivity with less toxicity (Wu & Li, 1995). Artemisinin is isolated from the leaves of plant Artemisia annua (Qinghao). It is a sesquiterpene lactone with an endoperoxide linkage. Artemisinin derivatives are more potent than artemisinin and are active by virtue of the endoperoxide. Their activity against strains of the parasite that had become resistant to conventional chloroquine therapy and the ability due to its lipophilic structure, to cross the blood brain barrier, it was particularly effective for the deadly cerebral malaria (Shen & Zhuang, 1984). Because of their shorter life time and decreasing activity, they are used in combination with other antimalarial drugs. The notable activity of artemisinin derivatives in vitro and in vivo has been reported in literature (Li et al. 2001 & Yang et al. 1997). However, some derivatives of artimisinine showed moderate cytotoxicity in vitro. The electronegativity and bulk of the substituents that attached to the aryl group plays an insignificant role in cytotoxicity. The antimalarial activity and cytotoxicity of some sesquiterpenoids has been reported in the literature (Venugopalan et al. 1995; Wu et al. 2001 and Saxena et al. 2003). The endoperoxide moiety present in these compounds plays an important role in antimalarial activity. Its 1,2,4 trioxane ring is unique in nature. After being opened in the plasmodium it liberates singlet oxygen and forms free radical which inturn produces oxidative damage to the parasites membrane. Artemisinin is hydrophobic in nature and are partitioned into the membrane of the plasmodium. The structures of the antimalarials dihydroqinghaosu, artemether and artesunic acid derived from qinghaosu were elaborated by ¹H-NMR spectroscopy, and supported with X-ray data have been reported (Luo et al. 1984). The crystal structure of an ether dimer of deoxydihydroqinghaosu, a potential metabolite of the antimalarial arteether is reported (Flippen-Anderson et al. 1989). The correlation of the crystal structures of diastereomeric artemisinin derivatives with their proton NMR spectra in CDCl₃ is reported (Karle & Lin, 1995). The crystal structure of artemisinin is reported (Lisgarten et al. 1998). The crystal structure of a dimer of α- and β-dihydroartemisinin (Yue et al. 2006) and that of 9,10-dehydrodeoxyartemisin is recently reported (Li et al. 2006). The synthesis of artemisinin and its derivatives are described (Lui et al. 1979; Lui, 1980; Robert et al. 2001). The synthesis and antimalarial properties of arteether have been reported (Brossi et al. 1988). β-Arteether (AE) is an endoperoxide sesquiterpene lactone derivative currently being developed for the treatment of severe, complicated malaria caused by multidrug-resistant Plasmodium falciparum (Grace et al. 1998). β-Artemether (AM), the O-methyl ether prodrug of dihydroartemisinin (DHA), is an endoperoxide antimalarial (Maggs et al. 2000). In view of the importance of the title compound, (I) C₁₅H₂₄O₅, as n antimalarial drug, this paper reports a redetermination of the crystal structure first reported by Luo et al. (1984).

The six-membered cyclohexane ring (A, C1—C6) is a slightly distorted chair, with Cremer & Pople (1975) puckering parameters Q, θ and φ of 0.553 (2) Å, 4.8 (2)° and 170 (3)°, respectively. The tetrahydropyran group (D, C1—C2—C12—C11—O2—C10) is also a slightly distorted chair configuration with puckering parameters Q, θ and φ of 0.539 (2) Å, 2.7 (2)° and 227 (4)°, respectively. For an ideal chair θ has a value of 0 or 180°. Similar conformations for rings A and D were found in 9,10-dehydrodeoxyartemisinin (Shu-Hui Li et al. 2006). The seven-membered ring B (C1/C6—C9/O1—C10) contains the important peroxy linkage [O3—O4 = 1.471 (2) Å]. The six-membered ring C (O1—C9—O3—O4—C1—C10) which contains both an oxygen bridge and a peroxy bridge is best described by a twist-boat conformation with puckering parameters Q, θ and φ of 0.750 (2) Å, 85.26 (15)° and 96.58 (11)°, respectively. For an ideal twist-boat conformation, θ and φ are 90° and (60n + 30)°, respectively. This conformation is consistent with both 9,10-dehydrodeoxyartemisinin (Li et al. (2006) and dihydroartemisinin (Qinghaosu Research Group, 1980).

Experimental

The title compound (C₁₅H₂₄O₅)was obtained in the pure form from Strides Arco Labs, Mangalore, India. X-ray diffraction quality crystals were grown from acetone-methylacetoacetate (1:1). (m.p.: 413 K).