Synthesis and antimalarial activity of heteroatom-containing bicyclic endoperoxides

Gary H. Posner, Lluïsa González, Jared N. Cumming, Donna Klinedinst, Theresa A. Shapiro

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)37-50
Number of pages14
JournalTetrahedron
Volume53
Issue number1
DOIs
StatePublished - Jan 6 1997

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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