title: 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.
authors.affiliation: Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Fontaine
authors.forename: Antonio G
authors.initials: AG
authors.lastname: DiPasquale
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D005296:Ferrous Compounds / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007501:Iron / Q000737:chemistry; D015394:Molecular Structure; D009579:Nitrobenzoates / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D037621:Artemisinins; D005296:Ferrous Compounds; D006571:Heterocyclic Compounds; D009579:Nitrobenzoates; D007501:Iron