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 ) .

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The gas-phase stability of bridgehead carbocations has been determined by Fourier transform ion cyclotron resonance spectroscopy (FT ICR) based on dissociative proton attachment (DPA) of bridgehead bromides, chlorides, and alcohols. When appropriate leaving group corrections are applied, the relative ion stabilities obtained from these precursors are identical. The relative rate constants (log k) for solvolysis of bridgehead derivatives correlate with the stabilities of the cations over the entire reactivity range. Theoretical calculations of the stabilities of the ions relative to those of the respective hydrocarbons at the MP2/6-311G** level agree fully with the experimental data