The overall objective of the research proposed in this application is to develop new chemical methods for the stereocontrolled synthesis of complex polycyclic molecules. The evolution of new efficient chemical synthesis methods will allow future promising pharmaceutical leads to be developed rapidly with potential therapeutic implications. During the proposed project period we will attempt to develop metal- catalyzed cyclizations of polyenes into a broadly applicable strategy for organic synthesis. This endeavor is founded on exciting new palladium- catalyzed cyclizations of dienyl aryl halides which were developed during the current GM-06-07 project years. We believe that metal-catalyzed polyene cyclinzations can evolve into a major synthesis method for preparing heterocycles and carbocycles and will compliment (not duplicate) existing methods based on cationic or radical intermediates. Our proposed studies are unusually broad in scope and encompass mechanistic, exploratory, and total synthesis endeavors. The total synthesis targets are structurally diverse and include the recently isolated scopadulcic acids A and B, which display cytotoxic and antiviral activity, and aphidicolin, a specific reversible inhibitor of type alpha eucaryotic DNA polymerases. A new approach for the synthesis of important analgesics of the morphinan and benzomorphan families will also be developed. This synthesis should be useful for preparing unusual analgesic analogs with electron-deficient aromatic rings. Other total synthesis targets include 6a-epipretazettine, the oxepene marine natural product isolaurepinnacin, and the unusual alkaloid nauclefiline. Where appropriate, analogs will be prepared to define structure activity relationships. Intermediates and target molecules prepared will be broadly screened for biological activity at NCI and Dow.
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