Design, synthesis and in vitro antimalarial activity of spiroperoxides

Several spiroperoxy antimalarial compounds were designed and synthesized using the hydrogen peroxide in UHP (urea-H₂O₂ complex) as the source of the peroxy bond. Incorporation of the H₂O₂ into the organic molecule framework through ketal exchange reaction in the present cases was greatly facilitated by the potential to form a five- or six-membered cyclic hemiketal due to the presence of a hydroxyl group γ or δ to the ketone carbonyl group. When the electron-withdrawing group in the Michael acceptor was a nitro group, the closure of the peroxy ring occurred readily under the hydroxidation conditions. Presence of a benzene ring fused to the peroxy ring effectively reduced the degrees of freedom in the transition state for the ring-closure step and made the otherwise very difficult seven-membered 1,2-dioxepane rather easy to form through the intramolecular Michael addition.