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Efficient and stereocontrolled synthesis of 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery.

ABSTRACT: Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3? substitution pattern that enables ferrous iron-dependent drug delivery is reported. The key synthetic step involves a diastereoselective Griesbaum co-ozonolysis reaction to afford primarily products with a trans relationship between the 3? substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3?-substituted 4-nitrobenzoate analogue.

SUBMITTER: Fontaine SD

PROVIDER: S-EPMC4227544 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

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Efficient and stereocontrolled synthesis of 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery.

Fontaine Shaun D SD DiPasquale Antonio G AG Renslo Adam R AR

Organic letters 20141021 21

Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ substitutio ...[more]

PMID: 25331549

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