The mechanism of the spontaneous autoxidation of dihydroartemisinic acid

Dihydroartemisinic acid undergoes slow spontaneous autoxidation to artemisinin and other natural products, which have been reported from the medicinal plant Artemisia annua. The mechanism of this complex transformation is shown to involve four steps: (i) initial reaction of the Delta(4.5)-double bond of dihydroartemisinic acid with molecular oxygen, (ii) Hock cleavage of the resulting tertiary allylic hydroperoxide; (iii) oxygenation of the enol product from Hock cleavage; and (iv) cyclization of the resulting vicinal hydroperoxyl-aldehyde to the 1,2,4-trioxane system of artemisinin. (C) 2002 Elsevier Science Ltd. All rights reserved.