A strategy for the enantioselective synthesis of miyakolide, a potent anti-tumor marine natural product is proposed. Miyakolide was isolated from a marine sponge of the genus Polyfibrospongia, and shares a number of structural features similar to the potent anti-cancer bryostatins. Miyakolide is not only an intriguing target as a complex natural product, but its analysis may also provide insight in to what functional moieties are important in tumor inhibition by comparison to structurally similar, biologically active compounds. The proposed route toward miyakolide illustrates how transition metal-catalyzed coupling reactions can be used to construct complex natural products in an atom economical method. A tandem ruthenium-catalyzed alkene-alkyne coupling/palladium-catalyzed asymmetric allylic alkylation stereoselectively assembles a key intermediate. One of the more challenging hydropyran rings is constructed utilizing a unique palladium (ll)- catalyzed alkyne-alkyne coupling/cyclization cascade. A catalytic enantioselective anti-aldol reaction followed by macrolactonization completes the total synthesis of miyakolide. The convergent nature of the proposed route allows for the synthesis of structurally related analogs. The synthesis will also provide significant quantities of miyakolide for its development as a novel therapeutic agent, and for biological comparison studies to the anti-neoplastic bryostatins. ? ?