Structure-Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of -5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action.

An efficient synthesis of -6-desmethyl-5β-hydroxy-d-secoartemisinin , a tricyclic analog of -(+)-artemisinin , was accomplished and the racemate was resolved into the (+)- and (-)- enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer -(-)-. Several new compounds -, , , and were synthesized from - but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of , a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of . Several of the analogs had moderate activity in comparison to the natural product . Iron (II) bromide-promoted rearrangement of gave, in 50% yield, the ring-contracted tetrahydrofuran , while the 5-ketone provided a monocyclic methyl ketone (50%). Neither nor possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.