Anhydrodihydroartemisinin and Its 10-Trifluoromethyl Analogue: Access to Novel D-Ring-Contracted Artemisinin Trifluoromethyl Ketones

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Abstract
The preparation of the 10-trifluoromethyl hydroartemisinin, followed by dehydration, afforded the trifluoromethyl analogue 2 of anhydrodihydroartemisinin 1. The reactivity of these two glycals of artemisinin were compared in epoxidation and halogenation reactions. Iodination of glycal 1 in water and the further rearrangement of the produced iodo hemiacetal provided the new D-ring-contracted aldehyde 8α, where the methyl at C-9 is β. Epoxidation of 10-trifluoromethyl anhydrodihydroartemisinin 2 stereoselectively provided the β-epoxy ether 11 in high yield. When treated with hexafluoro-2-propanol or trifluoroethanol, 11 readily underwent a rearrangement yielding to the D-ring-contracted trifluoromethyl ketone 9α with retention of configuration at C-9.