The chemical synthesis of potent antitumor agents is vital to the development of effective treatment strategies for cancer. Pleurotin, an antibacterial quinone fungal metabolite, was found recently to be one of the most potent known inhibitors of thioredoxin reductase, an enzyme associated with angiogenesis, proliferation, drug resistance, and suppression of apoptosis in tumors. However, insufficient supply has hampered medical research. A method for the synthesis of pleurotin via a diastereoselective benzyl halide- initiated carbopalladation / carbonylation cascade is proposed. Initial studies will involve the development of a catalytic system to effect carbonylative carbopalladation of benzyl halides. This process will involve oxidative addition of Pd(0) into a benzyl halide, subsequent carbopalladation of an alkene or alkyne, and then carbonylation of the resulting organopalladium species to produce the desired product. Extension of the method to a diastereoselective cascade process will allow the construction of complex carbocyclic frameworks. The utility of this novel cascade sequence will be demonstrated by a concise enantioselective total synthesis of pleurotin. Relevance to Public Health This proposal describes a synthetic route to the anticancer agent pleurotin. By developing a new chemical reaction, the molecule will be constructed rapidly, allowing the production of substantial quantities of pleurotin. Access to this molecule will allow further medical research and potentially lead to new drugs for the treatment of cancer.
