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

An efficient synthesis of rac -6-desmethyl-5β-hydroxy-d-secoartemisinin 2 , a tricyclic analog of R -(+)-artemisinin 1 , was accomplished and the racemate was resolved into the (+)- 2b and (-)- 2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R -(-)- 2a . Several new compounds 9 - 16 , 19a , 19b , 22 and 29 were synthesized from rac - 2 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 2 , 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 Plasmodium falciparum . Several of the analogs had moderate activity in comparison to the natural product 1 . Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22 , while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.