Journal
ORGANIC LETTERS
Volume 16, Issue 21, Pages 5776-5779Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ol5028392
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Funding
- US National Institutes of Health [AI105106]
- US NIH Shared Instrumentation Grant [S10-RR027172]
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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 (6771% 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.
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