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

41 Citations (Scopus)

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

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Dioxolanes
Acetals
Peroxides
Antimalarials
Alkenes
Carbon
Iron
Electrons
Ions
Bearings (structural)
Atoms
Oxygen
artemisinine

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Spiro- and dispiro-1,2-dioxolanes : Contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides. / Wang, Xiaofang; Dong, Yuxiang; Wittlin, Sergio; Creek, Darren; Chollet, Jacques; Charman, Susan A.; Tomas, Josefina Santo; Scheurer, Christian; Snyder, Christopher; Vennerstrom, Jonathan L.

In: Journal of Medicinal Chemistry, Vol. 50, No. 23, 15.11.2007, p. 5840-5847.

Research output: Contribution to journalArticle

Wang, Xiaofang ; Dong, Yuxiang ; Wittlin, Sergio ; Creek, Darren ; Chollet, Jacques ; Charman, Susan A. ; Tomas, Josefina Santo ; Scheurer, Christian ; Snyder, Christopher ; Vennerstrom, Jonathan L. / Spiro- and dispiro-1,2-dioxolanes : Contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 23. pp. 5840-5847.
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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.",
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