ORGANIC
LETTERS
2009
Vol. 11, No. 3
507-510
Preparation of Bicyclic 1,2,4-Trioxanes
from γ,δ-Unsaturated Ketones
Armando P. Ramirez, Andrew M. Thomas, and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
Received October 1, 2008
ABSTRACT
Treatment of γ,δ-unsaturated ketones with hydrogen peroxide and acid provides a rapid entry into the medicinally important 1,2,4-trioxane
structure. Alkene substitution that stabilizes carbocationic intermediates proved to be important for the success of this transformation.
The 1,2,4-trioxane moiety of the sesquiterpene artemisinin
(1, Figure 1) is considered to be an important component of
Development of new syntheses of organic peroxides could
address many challenges associated with malaria treatment,
such as drug resistance and availability.4 In addition to
antimalarial properties, organic peroxides, such as artemisi-
nin, have notable activity against tumor cells5 and viruses
like HIV6 and hepatitus B.7
In this Letter, we describe the efficient synthesis of 1,2,4-
trioxanes 3 from simple γ,δ-enones 2 in one synthetic
operation, without the isolation of intermediates (Figure 2).
This procedure complements the multistep methods reported
by Wu8 and Griesbeck9 because it enables access to 1,2,4-
trioxanes with different substitution patterns.
Figure 1. 1,2,4-Trioxanes.
The synthesis of 1,2,4-trioxanes 3 was discovered when
we attempted to form geminal-dihydroperoxides from un-
saturated ketones 2 (Figure 2). Treatment of γ,δ-unsaturated
the potent antimalarial activity of this natural product.1
Artemisinin and its semisynthetic derivatives are some of
the most successful drugs for the treatment of malaria.2
Despite the effectiveness of artemisinin, malaria is still a
worldwide epidemic responsible for millions of deaths
annually, and strains of the Plasmodium falciparum parasite
are growing increasingly resistant to older drug therapies.3
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10.1021/ol8022853 CCC: $40.75
Published on Web 01/08/2009
2009 American Chemical Society