The overall objective of the proposed research is to utilize sequential palladium catalyzed reactions as a general strategy for the construction of several compounds possessing antitumor properties. A palladium catalyzed version of the Alder ene reaction to generate a dialkylidenecyclopentane from a l,6-enyne followed by condensation with a trimethylenemethane palladium intermediate provides facile entry into the five-seven bicyclic core of the pseudolaric acids A and B. The pseudolaric acids have demonstrated potent cytotoxicity against various tumor cells with each compound exhibiting tumor specificity in the disease-oriented human tumor cell line panels. The advantage of this palladium methodology is that a functionalized five-seven ring system can be assembled rapidly allowing for the production of many structural analogs of the pseudolaric acids. These analogs can be used in structure- activity relationship studies to probe the precise nature of their mechanism of action in cells. Furthermore, the immense utility of the palladium cyclization strategy is demonstrated by its ability to provide facile entry into the ABC tricyclic skeleton of the promising chemotherapeutic agent taxol.
