Redetermination of dihydroartemisinin at 103 (2) K

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.

Tthe structure of the title compound, C 15 H 24 O 5 , 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][1516][1517][1518][1519][1520][1521][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-HÁ Á ÁO and O-HÁ Á ÁO 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.
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.

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 andSaxena 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 1 H-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 CDCl 3 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) C 15 H 24 O 5 , as n antimalarial drug, this paper reports a redetermination of the crystal structure first reported by Luo et al. (1984).

Refinement
All H atoms were initially located in a difference Fourier map. The methyl H atoms were then constrained to an ideal geometry with C-H distances of 0.98 Å and U iso (H) = 1.5U eq (C), but each group was allowed to rotate freely about its C-C bond. All other H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms with C-H distances in the range 0.98-1.00 Å and U iso (H) = 1.17-1.22U eq (C). The hydroxyl H was idealized with an O-H distance of 0.84Å and U iso (H) = 1.21U eq (O). Because no strong anomalous scattering atoms are present, the Friedel pairs were merged in the refinement.    Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. 0.0165 (9) 0.0170 (7) 0.0156 (7) −0.0003 (7) −0.0006 (7) −0.0007 (6)  C11 0.0160 (9) 0.0230 (8) 0.0161 (7) −0.0023 (8) −0.0016 (7) 0.0020 (7)