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.