Synthesis and antimalarial activity of heteroatom-containing bicyclic endoperoxides

Mechanism-based design and short syntheses involving novel Tebbe methylenations of a-heteroatom-substituted ketones led to preparation of heteroatom-containing bicyclic endoperoxides 4-6. The crucial final photo-oxygenative cyclization step succeeded only when the intermediate 1,6-dienes carried anisyl but not phenyl substitutents. Distinguishing between endoperoxide and cyclobutane cyclization products was achieved reliably by ¹³C NMR spectrscopy. Antimalarial testing of endoperoxides 4-6 in vitro showed them to have only weak activities (IC₅₀ = 500-1100 nM). Ferrous bromide-induced reductions of sulfonamide endoperoxides 4, although forming the expected hydroxylated ether and ring-contracted products 7 and 8, caused virtually no rearrangement of hexamethyl Dewar benzene; therefore, the intermedicacy of any oxidatively damaging high-valent iron-oxo intermediate appears unlikely.