Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.
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Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols.
Org Biomol Chem
May 2010
Department of Chemistry, University of Liverpool, P.O. Box 147, Liverpool, UK L69 3BX.
Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit.
View Article and Find Full Text PDFSynthesis of 1,2,4-trioxepanes via application of thiol-olefin co-oxygenation methodology.
Bioorg Med Chem Lett
December 2006
Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK.
Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates beta-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.
View Article and Find Full Text PDFDiels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore.
Bioorg Med Chem Lett
June 2006
Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK.
A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g.
View Article and Find Full Text PDFApplication of thiol-olefin co-oxygenation methodology to a new synthesis of the 1,2,4-trioxane pharmacophore.
Org Lett
September 2004
Department of Chemistry, University of Liverpool, P.O. Box 147, Liverpool L69 3BX, UK.
[reaction: see text] Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates alpha-hydroxyperoxides that can be condensed in situ with various ketones to afford a series of functionalized 1,2,4-trioxanes in good yields. Manipulation of the phenylsulfenyl group in 4a allows for convenient modification to the spiro-trioxane substituents, and we describe, for the first time, the preparation of a new class of antimalarial prodrug.
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