Synthesis of 1,2,4-trioxepanes via application of thiol-olefin Co-oxygenation methodology

Richard Amewu, Andrew V. Stachulski, Neil G. Berry, Stephen A. Ward, Jill Davies, Gael Labat, Jean Francois Rossignol, Paul M. O'Neill

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates β-hydroxy peroxides that can be condensed in situ with various ketones, to afford a series of functionalised 1,2,4-trioxepanes in good yields. Manipulation of the phenylsulfenyl group in 8a-8c allows for convenient modification to the spiro-trioxepane substituents. Surprisingly, and in contrast to the 1,2,4-trioxanes examined, 1,2,4-trioxepanes are inactive as antimalarials up to 1000 nM and we rationalize this observation based on the inherent stability of these systems to ferrous mediated degradation. FMO calculations clearly show that the σ* orbital of the peroxide moiety of 1,2,4-trioxane derivatives 4a and 14b are lower in energy and more accessible to attack by Fe(II) compared to their trioxepane analogues 8b and 9b.

Original languageEnglish
Pages (from-to)6124-6130
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume16
Issue number23
DOIs
Publication statusPublished - 1 Dec 2006
Externally publishedYes

Keywords

  • 1,2,4-trioxane
  • Artemisinin
  • Endoperoxide
  • Malaria
  • Mechanismof action

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