Unified Mechanistic Framework for the Fe(II)-Induced Cleavage of Qinghaosu and Derivatives/Analogues. The First Spin-Trapping Evidence for the Previously Postulated Secondary C-4 Radical

Qinghaosu and derivatives were easily reduced by ferrous sulfate in aqueous acetonitrile to give results different from those reported for other reducing systems. The unstable epoxide 7, a compound that was postulated earlier as a species responsible for the antimalarial activity, now has been isolated and characterized. The earlier speculative secondary C-4 radical has also been trapped with 2-methyl-2-nitrosopropane and thus provides the very first direct evidence for the involvement of radicals in the in vitro cleavage of QHS-type compounds. A unified mechanism featuring interchangeable radical anions and reversible intramolecular radical reactions is proposed for the ferrous ion induced cleavage of the 1,2,4-trioxanes (i.e., QHS and the like). On the basis of this framework, together with consideration of counterion and solvent effects, a large body of divergent experimental outcomes can be satisfactorily rationalized, not only the formation of the main products but also the product ratios as well as ...