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5.5.1.1 O-glycosides (126 and 127) The ethers and esters of dihydroartemisinin noted above may be considered as its O-glycosides (126) (Structure 5-10). Because of the high content (0.6 1.1%) of qinghaosu in A. annua L. planted in some regions and an ef cient process of extraction, a large quantity of qinghaosu is available in China. Based on the early work, it was known that little changes of C-12 substituents always lead to a great difference in the antimalarial activity; hence, more dihydroartemisinin derivatives were synthesized. A series of ethers and esters in which C-12 substituents contained halogen (especially, F), nitrogen, sulfur atoms, and others were prepared.163 Afterward, several mono- and poly uorinated artemisinin derivatives were reported by Pu et al.164 Recently, tri uoromethyl analoges of dihydroartemisinin, artemether, artesunate, and other analogs (Structure 5-11) were synthesized by French groups.165 167 The presence of the CF3 group at C-12 of artemisinin clearly increased the chemical stability under simulated stomach acid conditions. Venugopalan et al. also prepared some ethers and thioethers of dihydroartemisinin.168 Haynes et al. synthesized many new C-12 esters and ethers of dihydro- artemisinin.169 Compared with similar work performed 20 years ago, they successfully prepared some b-aromatic esters of dihydroartemisinin by means of Schmit and Mitsunobu procedures. Another type of O-glycosides (127), 12-b aryl ethers of dihydroartemisinin, was synthesized by a reaction of acetyl dihydroartemisinin or tri uoroacetyl dihydroartemisinin with various substituted phenols in the presence of tri uoroacetic acid. Most of these compounds were proved to have better antimalarial activity against P. berghei in mice than qinghaosu, but less activity than artemether. Unexpectedly,



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