Total Synthesis of Marine Polyether Natural Products

Fused polycyclic ether natural products are produced by marine dinoflagellates but are also found in organisms that feed on them and in animals higher up the food chain. Although many of these natural products (e.g. the brevetoxins and ciguatoxins) are potent neurotoxins, some are potential lead compounds for the development of new drugs. Fused polyethers are some of the most structurally complex natural products to have been isolated and characterised. Their size, the number of stereogenic centres they possess and the presence of multiple medium-sized rings means that they constitute the ultimate challenge in the field of total synthesis. Over the past two decades, a small number of research groups has been successful in synthesizing some of the larger marine polyethers, but the small number of total syntheses that have been completed usually have longest linear sequences of 50-100 steps with overall step counts of several hundred. Clearly, there is a need to develop much shorter synthetic routes that will deliver these natural products more efficiently and allow them and their analogues to be subjected to full biological evaluation.
The objective of the research project is the invention of a novel, general and highly efficient method for the rapid synthesis of marine polyethers that exploits both the apparent and latent symmetry embedded in the structures of the polyether natural products. The new approach to polyether synthesis will involve the enantioselective desymmetrisation of centrosymmetric trans-fused bicyclic ethers. Centrosymmetric systems have been used very rarely in target-directed synthesis and their asymmetric desymmetrisation has not been explored extensively. In previous polyether syntheses, construction of fully functionalized building blocks that contain a single cyclic ether has usually required more than 15 steps. The proposed method will enable fused polyethers to be synthesised more efficiently because achiral bicyclic ether building blocks will be prepared from simple starting materials in just six or seven steps.