Spiro- and dispiro-1,2-dioxolanes: Contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides

Xiaofang Wang, Yuxiang Dong, Sergio Wittlin, Darren Creek, Jacques Chollet, Susan A. Charman, Josefina Santo Tomas, Christian Scheurer, Christopher Snyder, Jonathan L. Vennerstrom

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Fourteen spiro- and dispiro-1,2-dioxolanes were synthesized by peroxycarbenium ion annulations with alkenes in yields ranging from 30% to 94%. Peroxycarbenium ion precursors included triethylsilyldiperoxyketals and -acetals derived from geminal dihydroperoxides and from a new method employing triethylsilylperoxyketals and -acetals derived from ozonolysis of alkenes. The 1,2-dioxolanes were either inactive or orders of magnitude less potent than the corresponding 1,2,4-trioxolanes or artemisinin against P. falciparum in vitro and P. berghei in vivo. In reactions with iron(II), the predominant reaction course for 1,2-dioxolane 3a was two-electron reduction. In contrast, the corresponding 1,2,4-trioxolane 1 and the 1,2,4-trioxane artemisinin undergo primarily one-electron iron(II)-mediated reductions. The key structural element in the latter peroxides appears to be an oxygen atom attached to one or both of the peroxide-bearing carbon atoms that permits rapid β-scission reactions (or H shifts) to form primary or secondary carbon-centered radicals rather than further reduction of the initially formed Fe(III) complexed oxy radicals.

Original languageEnglish (US)
Pages (from-to)5840-5847
Number of pages8
JournalJournal of Medicinal Chemistry
Volume50
Issue number23
DOIs
StatePublished - Nov 15 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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