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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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(a) Variousterpene-derived endoperoxides with potent antimalarialactivity. (b) Desired hypothetical transformation and oxygen stitchingblueprint. (c) Previous attempts to forge the 1,2-dioxepane motifin 2 via peroxy radical cyclization have failed.
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fig1: (a) Variousterpene-derived endoperoxides with potent antimalarialactivity. (b) Desired hypothetical transformation and oxygen stitchingblueprint. (c) Previous attempts to forge the 1,2-dioxepane motifin 2 via peroxy radical cyclization have failed.

Mentions: Organic peroxides are pertinentto numerous facets of human health ranging from intermediates in lipidoxidation to potential treatments for cancer.1 Notwithstanding debate over their mechanism(s) of action,2 terpene-derived endoperoxides and derivativesthereof have proven exceptionally useful to combat malaria, a diseasewhich affects several hundred million people annually (Figure 1a).3 Artemisinin combinationtherapy (ACT), which includes derivatives of the sesquiterpene lactoneartemisinin (1), has remained a frontline treatment forchloroquine-resistant malaria for many years, yet reports of delayedparasite clearance in patients receiving ACTs are beginning to surface.4 Undoubtedly, the search for promising new antimalarialswill continue, and organic peroxides, which can generate numerousand diverse cytotoxic intermediates,2c continueto receive much attention. However, the number of readily availableperoxide-containing natural products, from which comprehensive medicinalchemistry efforts can be leveraged, remains quite limited and theeconomic constraints associated with small-molecule treatments forthis disease requires the design and execution of exceedingly simplesolutions if synthetic chemistry is to be employed.5,6 Thecardamom peroxide (2), isolated by Clardy and co-workers7 from Amomum krervanh Pierre(Siam cardamom), displays potent activity against P. falciparum (EC50 = 170 nM) and possesses a 1,2-dioxepane motif distinctfrom the trioxane found in 1. While many peroxide-containingnatural products have been isolated to date, only a very small subsetcontains these 7-membered peroxidic architectures.8,9 Theseattributes, combined with a complete lack of further biological investigation,unknown absolute configuration, and mysterious biosynthetic origins,make this terpene endoperoxide an attractive synthetic target anda valuable lead compound. We were drawn to hypothetical eq 1 (bluebox, Figure 1b), wherein inexpensive pinene(∼US$0.02/gram) and multiple units of molecular oxygen serveas the sole building blocks of 2, as a blueprint fora simple synthesis of 2. Herein we report a four-step,enantiospecific synthesis of the cardamom peroxide adhering to thisidea, determination of its absolute configuration, and elucidationof its mode of fragmentation following Fe(II)-mediated reductive activation.


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

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

(a) Variousterpene-derived endoperoxides with potent antimalarialactivity. (b) Desired hypothetical transformation and oxygen stitchingblueprint. (c) Previous attempts to forge the 1,2-dioxepane motifin 2 via peroxy radical cyclization have failed.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: (a) Variousterpene-derived endoperoxides with potent antimalarialactivity. (b) Desired hypothetical transformation and oxygen stitchingblueprint. (c) Previous attempts to forge the 1,2-dioxepane motifin 2 via peroxy radical cyclization have failed.
Mentions: Organic peroxides are pertinentto numerous facets of human health ranging from intermediates in lipidoxidation to potential treatments for cancer.1 Notwithstanding debate over their mechanism(s) of action,2 terpene-derived endoperoxides and derivativesthereof have proven exceptionally useful to combat malaria, a diseasewhich affects several hundred million people annually (Figure 1a).3 Artemisinin combinationtherapy (ACT), which includes derivatives of the sesquiterpene lactoneartemisinin (1), has remained a frontline treatment forchloroquine-resistant malaria for many years, yet reports of delayedparasite clearance in patients receiving ACTs are beginning to surface.4 Undoubtedly, the search for promising new antimalarialswill continue, and organic peroxides, which can generate numerousand diverse cytotoxic intermediates,2c continueto receive much attention. However, the number of readily availableperoxide-containing natural products, from which comprehensive medicinalchemistry efforts can be leveraged, remains quite limited and theeconomic constraints associated with small-molecule treatments forthis disease requires the design and execution of exceedingly simplesolutions if synthetic chemistry is to be employed.5,6 Thecardamom peroxide (2), isolated by Clardy and co-workers7 from Amomum krervanh Pierre(Siam cardamom), displays potent activity against P. falciparum (EC50 = 170 nM) and possesses a 1,2-dioxepane motif distinctfrom the trioxane found in 1. While many peroxide-containingnatural products have been isolated to date, only a very small subsetcontains these 7-membered peroxidic architectures.8,9 Theseattributes, combined with a complete lack of further biological investigation,unknown absolute configuration, and mysterious biosynthetic origins,make this terpene endoperoxide an attractive synthetic target anda valuable lead compound. We were drawn to hypothetical eq 1 (bluebox, Figure 1b), wherein inexpensive pinene(∼US$0.02/gram) and multiple units of molecular oxygen serveas the sole building blocks of 2, as a blueprint fora simple synthesis of 2. Herein we report a four-step,enantiospecific synthesis of the cardamom peroxide adhering to thisidea, determination of its absolute configuration, and elucidationof its mode of fragmentation following Fe(II)-mediated reductive activation.

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