This proposal outlines in detail a planned enantioselective synthesis of the potent anticancer agent Amphidinolide A, a unique macrolide natural product isolated from Okinawan marine organisms. The proposed synthesis utilizes a series of chelation-controlled additions to alpha- alkoxy aldehyde substrates to install the 1,2-diol functionalities and exo-methylene groups present in the macrolide framework. Chelation- controlled additions to carbonyl compounds are well-precedented and are expected to provide excellent acyclic stereocontrol. Efficient construction of the dienoate portion of the macrolide is based on a highly stereoselective palladium-catalyzed coupling of an intermediate alkenyl zirconocene and vinyl iodide. Finally, a novel ruthenium- catalyzed macrocyclization to provide the natural product is proposed. If the macrocyclization is successful, the methodology would represent a powerful tool for the synthesis of other bioactive macrolides. Furthermore, the proposed synthesis would confirm the absolute stereochemistry of Amphidinolide A and also represent the first total synthesis of any member of the Amphidinolide family of natural products. Successful completion of the proposed synthesis will provide additional quantities of Amphidinolide A, and other structural derivatives, to allow for additional evaluation of these unique macrolides as potential anticancer drugs. Subsequent investigation of the structure-activity relationship of various structural derivatives may also provide insight into the mechanism of action of Amphidinolide A.
