Artemisinin—the next generation: Efficacies of artemisone against the malaria parasite are substantially greater than those of the current artemisinin “gold standard”, artesunate. Also, in contrast to most current artemisinins it displays low lipophilicity and negligible neuro‐ and cytotoxicity in in vitro and in vivo assays. Thus, the drug offers promise for use in artemisinin‐based combination therapy.

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Two pairs of enantiomerically pure cis-fused cyclopenteno-l,2,4-trioxanes (7, en!-7 and 8, ent-8) are prepared (Schemes 1-3). Their identities are established by dye-sensitized photo-oxygenation of ent-7 and 8 to the allylic hydroperoxides, reduction to the corresponding alcohols, and conversion to the (1s)-camphanoates (Scheme 4 ) , the structures of which are determined by X-ray analysis. The dynamic properties of em-7 are investigated by NMR spectroscopy and PM3 calculations. Evidence for an easily accessible twist-boat conformation is obtained. The in vitro and in vivo antimalarial activities of 7 , ent-7, 8, and ent-8 as well as those of the racemic mixtures are evaluated against Plasmodium faleiparum, P . berghei, and P . yoelii. No correlation is observed between configuration and activity. Racemates and pure enantiomers have commensurate activities. The mode of action on the intraerythrocytic parasite is rationalized in terms of close docking by the twist-boat conformer of the trioxane on the surface of a molecule of heme, single-electron transfer to the 0-0 u* orbital, and scission to the acetal radical which then irreversibly isomerizes to a C-centered radical, the ultimate lethal agent (Scheme 5 ) .