1,2-Bis[(3,6,9-trimethyl-3,12-epoxy-3,4,5,5a,6,7,8,8a,9,10,12,12a-dodecahydropyrano[4,3-j][1,2]benzodioxepin-4-yl)oxy]ethane

The title compound, C32H50O10, prepared from a mixture of α- and β-dihydroartemisinin, has two β-arteether moieties linked via an –OCH2CH2O– bridge, so that the molecule is symmetric about the bridge. Each asymmetric unit contains a β-arteether moiety and an –OCH2 group, which is only one-half of the molecule. The endo-peroxide bridges of the parent compounds have been retained in each half of the diol-bridged dimer. The rings exhibit chair and twist-boat conformations.

The title compound, C 32 H 50 O 10 , prepared from a mixture ofand -dihydroartemisinin, has two -arteether moieties linked via an -OCH 2 CH 2 O-bridge, so that the molecule is symmetric about the bridge. Each asymmetric unit contains a -arteether moiety and an -OCH 2 group, which is only one-half of the molecule. The endo-peroxide bridges of the parent compounds have been retained in each half of the diolbridged dimer. The rings exhibit chair and twist-boat conformations.  (2006). For the synthesis, see: Posner et al. (1997). For puckering parameters, see: Cremer & Pople (1975 Dihydroartemisinin is reported to be more therapeutically active than the parent compound. Some trioxane dimers have been found to possess high antimalarial activities (Venugopalan et al., 1995) and moderate antitumor activities. (Woerdenbag et al., 1993). The dihydroartemisinin triethylene glycol dimers, have strong in vitro growth-inhibitory activity. The dimer with β-stereochemistry at both of the lactol acetal positions is very active and highly antiproliferative (Posner et al., 1997). We conclude, therefore, that the stereochemistry of the diol linkage is an important determinant for cytotoxicity. We chose the simplified analogue, the title compound, whose structure and activity have not been reported, to find out the relationship between the activity and stereo-structure. Hence, knowledge of the structure of the title compound is of interest and is reported here.

Related literature
The X-ray structures of artemisinin and artemisinin derivatives have been reported, including dihydroartemisinin, artemether, artesunic acid (Luo et al., 1984), both cis-deoxyarteether (Brossi et al., 1988) and trans-deoxyarteether (Dominguez Gerpe et al., 1988), α-artesunate, β-artesunate (Haynes et al., 2002, the symmetric form of the ether dimer of deoxydihydroartemisinin (Flippen-Anderson et al.,1989), the asymmetric form of the ether dimer of dihydroartemisinin (Yue et al., 2006), and the phthalate dimer (Paik et al. 2006). Although the endoperoxide group is an important determinant for cytotoxicity, no crystal structure of a diol dimer of dihydroartemisinin with a peroxy unit has been reported previously. We report here the crystal structure of a diol dimer of dihydroartemisinin, the title compound, which is a diol dimer of dihydroartemisinin with a unique 1,2,4-trioxane peroxy bridge.
The title molecule is symmetrical. Each moiety of the dimer is totally the same, hence we describe only the asymmetric unit here.

Experimental
The title compound has been prepared according to a literature procedure (Posner et al., 1997). To a solution of dihydroartemisinin (297 mg, 1.05 mmol) in toluene (30 mL) at 293~298 K, glycol (0.029 mL, 0.53 mmol) was added followed by BF 3 Et 2 O (0.032 mL, 0.26 mmol). The reaction was stirred at the same temperature for 3 h. The mixture was then diluted with methylene chloride and was washed twice with water. The organic portions were collected, dried over (MgSO 4 ) and concentrated. The crude product was purified by column chromatography (flash, 7-20% ethyl acetate/petro ether) to produce the title compound (50.7 mg, 0.085 mmol, yield 17%). Crystals were obtained from ether, diffused with hexane at room temperature.

Refinement
The methyl H atoms were constrained to an ideal geometry (C-H = 0.96 Å) with U iso (H) = 1.5U eq (C), but were allowed to rotate freely about the C-C bonds. All other H atoms were placed in geometrically idealized positions and constrained to ride on their parent C atoms at distances of 0.97 or 0.98 Å for methylene or methine groups, respectively, and with U iso (H) = 1.2U eq (C). As there are no significant anomalous scatterers in the molecule, attempts to confirm the absolute structure by refinement of the Flack parameter (Flack & Bernardinelli, 2000) in the presence of 1614 sets of Friedel equivalents led to an inconclusive value for the parameter. Therefore, the Friedel pairs were merged before the final refinement and the absolute configuration was assigned to correspond to that determined for artemisinin (Qinghaosu Research Group, 1980).  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 > σ(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.