The objective of this research program is the discovery and development of new reaction methodology en route to the synthesis of complex bioactive molecules. Our proposed studies will focus on the advancement of enantioselective palladium- catalyzed oxidation reactions that do not involve oxygen atom transfer. These reactions include the oxidative kinetic resolution of secondary alcohols and new cyclizations that deliver enantiopure heterocycles and carbocycles. The processes that we develop will find utility in the synthesis of a variety of complex biologically active molecules for which there is currently no efficient synthetic roadmap. As a consequence of this approach, we will have a) access to novel, medicinally relevant structures, b) a general method for their synthesis, and c) new synthetic methods that will be beneficial for a host of general applications. Specifically, we plan to target two classes of highly biologically relevant complex alkaloids, the Dragmacidins (1-3) and the Cephalotaxines (e.g., 4). The former have been shown to selectively inhibit brain Nitric Oxide Synthase (bNOS), and may have therapeutic importance for the treatment of Alzheimer's and other neurodegenerative disorders. The latter are potent antitumor agents, and have been used to overcome the Multiple Drug Resistance problems associated with many chemotherapeutic agents. The ultimate impact of our research will resonate across numerous disciplines including synthetic and organometallic chemistry, chemical biology, and human medicine.
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