Antimalarial artemisinin analogs. Synthesis via chemoselective CC bond formation and preliminary biological evaluation

The peroxide bond in artemisinin trioxane lactone (1) withstood exposure to lithiothiazole and to lithiobenzothiazole; nucleophilic addition of these powerful organometallic reagents to only the lactone carbonyl group was observed. Likewise, trioxane aldehyde 5 reacted with organolithium, Grignard, and phosphorus ylide nucleophiles exclusively via carbonyl addition. Also, trioxane ketone 7b reacted with phenyllithium via only carbonyl addition. These chemoselective lactone, aldehyde, and ketone carbonyl addition reactions produced a series of new, enantiomerically pure, C-10 non-acetal derivatives of natural trioxane artemisinin having high in vitro antimalarial potencies.