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Four-step synthesis of the antimalarial cardamom peroxide via an oxygen stitching strategy.

Hu X, Maimone TJ - J. Am. Chem. Soc. (2014)

Bottom Line: A four-step synthesis of the antimalarial terpene cardamom peroxide, a 1,2-dioxepane-containing natural product, is reported from (-)-myrtenal and molecular oxygen.This highly concise route was guided by biosynthetic logic and enabled by an unusual manganese-catalyzed, tandem hydroperoxidation reaction.These studies reveal the generation of reactive intermediates distinct from previously studied endoperoxide natural products.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of California , Berkeley, California 94720, United States.

ABSTRACT
A four-step synthesis of the antimalarial terpene cardamom peroxide, a 1,2-dioxepane-containing natural product, is reported from (-)-myrtenal and molecular oxygen. This highly concise route was guided by biosynthetic logic and enabled by an unusual manganese-catalyzed, tandem hydroperoxidation reaction. The absolute configuration of the cardamom peroxide is reported, and its mode of fragmentation following Fe(II)-mediated endoperoxide reduction is established. These studies reveal the generation of reactive intermediates distinct from previously studied endoperoxide natural products.

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Reductive activation of the cardamom peroxide.
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fig2: Reductive activation of the cardamom peroxide.

Mentions: Fe(II)-mediated O–O bond reduction remains the hallmarkof peroxide-based antimalarials, and a strong consensus exists thatoxygen-centered radicals are initially formed.21 These fleeting intermediates are then believed to leadto a variety of toxic, downstream species, including carbon-centeredradicals, carbocations, and epoxides, which vary in structure andreactivity depending on the starting endoperoxides employed.2c,21 With sufficient quantities of cardamom peroxide in hand, we soughtto determine its mode of reductive cleavage (Figure 2). Subjecting 2 to stoichiometric FeCl2 in degassed MeCN/H2O at room temperature led to the formationof three isolable cleavage products identified as acids 11, 12, and 13 (the structures of 11 and 13 were verified by X-ray crystallography). Presumablythe cardamom peroxide generates an acyl radical intermediate (15) via C–C cleavage of oxygen-centered radical 14. Oxidation of 15 by Fe(III) produces an acyliumion (16) which in this case is quenched by water to form 12.22 The remaining hydroxyl groupsthen engage the 1,3- dicarbonyl motif in a cyclodehydration processaffording 11 and small amounts of 13.23


Four-step synthesis of the antimalarial cardamom peroxide via an oxygen stitching strategy.

Hu X, Maimone TJ - J. Am. Chem. Soc. (2014)

Reductive activation of the cardamom peroxide.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4353017&req=5

fig2: Reductive activation of the cardamom peroxide.
Mentions: Fe(II)-mediated O–O bond reduction remains the hallmarkof peroxide-based antimalarials, and a strong consensus exists thatoxygen-centered radicals are initially formed.21 These fleeting intermediates are then believed to leadto a variety of toxic, downstream species, including carbon-centeredradicals, carbocations, and epoxides, which vary in structure andreactivity depending on the starting endoperoxides employed.2c,21 With sufficient quantities of cardamom peroxide in hand, we soughtto determine its mode of reductive cleavage (Figure 2). Subjecting 2 to stoichiometric FeCl2 in degassed MeCN/H2O at room temperature led to the formationof three isolable cleavage products identified as acids 11, 12, and 13 (the structures of 11 and 13 were verified by X-ray crystallography). Presumablythe cardamom peroxide generates an acyl radical intermediate (15) via C–C cleavage of oxygen-centered radical 14. Oxidation of 15 by Fe(III) produces an acyliumion (16) which in this case is quenched by water to form 12.22 The remaining hydroxyl groupsthen engage the 1,3- dicarbonyl motif in a cyclodehydration processaffording 11 and small amounts of 13.23

Bottom Line: A four-step synthesis of the antimalarial terpene cardamom peroxide, a 1,2-dioxepane-containing natural product, is reported from (-)-myrtenal and molecular oxygen.This highly concise route was guided by biosynthetic logic and enabled by an unusual manganese-catalyzed, tandem hydroperoxidation reaction.These studies reveal the generation of reactive intermediates distinct from previously studied endoperoxide natural products.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of California , Berkeley, California 94720, United States.

ABSTRACT
A four-step synthesis of the antimalarial terpene cardamom peroxide, a 1,2-dioxepane-containing natural product, is reported from (-)-myrtenal and molecular oxygen. This highly concise route was guided by biosynthetic logic and enabled by an unusual manganese-catalyzed, tandem hydroperoxidation reaction. The absolute configuration of the cardamom peroxide is reported, and its mode of fragmentation following Fe(II)-mediated endoperoxide reduction is established. These studies reveal the generation of reactive intermediates distinct from previously studied endoperoxide natural products.

Show MeSH
Related in: MedlinePlus