Part I. Design, synthesis, and evaluation of antimalarial 1,2,4-trioxanes. Part II. Ketone enolate-epoxide openings

The preparation and testing of new antimalarial 1,2,4-trioxanes containing sulfide, sulfone, and sulfonamide functionalities is described. These trioxanes were found to have antimalarial activity with an in vitro IC₅₀ range of 33–91 nM. A series of semisynthetic artemisinin-based dimers linked with N-substituted pyrazoles was also synthesized. These unsymmetrical dimers were found to have antimalarial activity with an in vitro IC₅₀ range of 2.3–20 nM.; The development of a ketone enolate epoxide opening methodology is described. The epoxides are activated towards nucleophilic attack by the ketone enolates by using BF₃·OEt₂ as the Lewis acid. The reaction is conducted at −78°C in THF and provides kinetic γ-hydroxy ketone products. The epoxide ring openings proceed with good yields and good diastereoselectivities for a series of cyclic ketone enolates with cyclopentene oxide and cyclohexene oxide. The methodology was used to synthesize three natural product curculigine-related aglycons.