The aim of this proposal is the development of new tandem bismuth-catalyzed inter- and intramolecular etherification reactions for the construction of non-adjacent and fused polycyclic ethers. The bismuth-catalyzed etherification reactions exhibit remarkable catalytic activity and unusual chemoselectivity, in which the direct addition to the carbonyl does not compete with the formation of the oxocarbenium ion. The bismuth catalysts are commercially availabile, inexpensive and non-toxic, making them ideal for many synthetic applications. The development of metal-catalyzed multi-component reactions for the rapid construction of complex polycyclic skeletons provides new and exciting opportunities for the synthesis of pharmacologically active agents. The specific areas of interest are summarized as follows: Tandem Stereoselective Intra- and Intermolecular Etherifications: The first section of the proposal will involve the development of tandem diastereoselective bismuth-catalyzed etherification reactions, through the sequencing of oxocarbenium ions, for the construction of non-adjacent tetrahydropyran rings. This methodology will then be applied to a convergent total synthesis of the potent antitumor agent leucascandrolide A. Annulation and Reductive Etherifications for Fused Polycyclic Ethers: The second aspect of the proposal details the development of new bismuth-catalyzed one-step annulation reactions in combination with ring-closing metathesis for the construction of polycyclic ethers. We will also examine the merit of temporary silicon-tethered ring-closing metathesis followed by the stereoselective bismuth-catalyzed reductive etherification, and its subsequent application to the DEFGH portion of the gambieric acids A-D. Finally, we will examine a series bismuth-catalyzed bis-reductive etherification reactions for the construction of linear fused polycyclic ethers.
