Exploiting pseudo-symmetry in the synthesis of the I–M fragment of ciguatoxin CTX3C

Marine polycyclic ethers are natural products isolated from marine plankton dinoflagellates such as Gambierdiscus toxicus and Karenia breve. They possess characteristic flat, semi-rigid, ladder-like structures and represent some of the largest, and most toxic, non-polymeric natural products discovered to date. Seafood contaminated with minute quantities of polycyclic ethers causes ciguatera, a debilitating illness that has been reported to last for more than 20 years. The first chapter of this thesis provides an introduction to marine polycyclic ethers, detailing their origins, biosynthesis and mechanism of action. Prior syntheses of members of the ciguatoxin family by Hirama, Isobe, Kadota and Fujiwara are reviewed, with focus on the cyclisation strategies employed by each group. The methodology and two-directional strategies developed by the Clark group are reviewed. Examples of the implementation of these strategies in the reported syntheses of the F–J fragment of the gambieric acids and the A–E fragment of CTX3C are provided. The second chapter of the thesis concerns the construction of the I–M fragment of CTX3C. The two-directional strategy is implemented over several steps, including alkylation, ringclosing metathesis and diastereoselective allylation. The synthetic route from tri-O-acetal-Dglucal to the I–L tetracycle is described and this section concludes with a future outlook