Synthesis and antimalarial activity of heteroatom-containing bicyclic endoperoxides

Abstract

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 substituents. Distinguishing between endoperoxide and cyclobutane cyclization products was achieved reliably by 13C NMR spectroscopy. Antimalarial testing of endoperoxides 4- 6 in vitro showed them to have only weak activities (IC 50 = 500-1100nM). 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 intermediacy of any oxidatively damaging hich-valent iron-oxo intermediate appears unlikely.