Divergent Total Synthesis of Triptolide, Triptonide, Tripdiolide, 16-Hydroxytriptolide, and Their Analogues

A divergent route was developed for the formal total synthesis of triptolide, triptonide, and tripdiolide, as well as a total synthesis of 16-hydroxytriptolide and their analogues in an enantioselective form. Common advanced intermediate 5 was concisely assembled by employing an indium­(III)-catalyzed cationic polycyclization reaction and a palladium-catalyzed carbonylation–lactone formation reaction as key steps. This advanced intermediate was readily converted to the above natural products by using palladium-catalyzed cross-coupling or the Claisen rearrangement reaction as key steps. Additionally, preliminary structure–cytotoxic activity relationship studies of C13 suggested that it might be a new modification site that could still retain the cytotoxicity.