UC Berkeley

Podophyllotoxin-based glycosidic derivatives have seen numerous uses in cancer chemotherapy. However, these analogs are primarily derived from semisynthetic modifications of the natural product, and the inherent restriction of semisynthesis has prevented further development of new analogs. In the first chapter of this dissertation, a concise and modular total synthesis of the prototypical aryltetralin lignan, podophyllotoxin, is disclosed. Central to the overall strategy is a palladium-catalyzed C-H arylation reaction as the point of diversification. From an advanced intermediate, a two-step sequence furnished not only the natural product but also fully synthetic podophyllotoxin analogs. Moreover, this work uncovered subtle previously overlooked conformational effects governing reductive elimination from high-valent palladium centers.

In the second chapter, a general strategy for the synthesis of complex meroterpene natural products is reported. First, a modular 10-step synthesis of the flagship PPAP, hyperforin, is disclosed. The synthetic approach includes two key transformations 1.) a novel annulation reaction between lithium enolates and diketene, and 2.) an oxidative ring expansion reaction mediated by hypervalent iodine. Second, the substrate scope of the diketene annulation reaction is reported. Finally, a synthesis of berkeleyone A, a complex meroterpene derived from 3,5-dimethylorsellinic acid, is reported in thirteen steps.