Antimalarial artemisinin analogs. Synthesis via chemoselective C-C 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 obs erved. 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. T hese chemoselective lactone, aldehyde, and ketone carbonyl addition reactio ns produced a series of new, enantiomerically pure, C-10 non-acetal derivat ives of natural trioxane artemisinin having high in vitro antimalarial pote ncies. (C) 1999 Elsevier Science Ltd. All rights reserved.