Convergent Bidirectional Total Synthesis of Ciguatoxin CTX3C

The ciguatoxins and the other fused polycyclic ether natural products are produced by microscopic marine dinoflagellates and are found in a variety of organisms that feed on them as well as animals further up the food chain. The marine polyethers have exquisite molecular structures and are some of the largest and most complex compounds to have been isolated from natural sources. These natural products are amongst the most challenging targets currently confronting synthetic chemists because of the large number of interlocking rings and stereogenic centres they possess. For example, the marine polyether maitotoxin is the largest non-biopolymeric natural product known and only one of the 1.6 x 1029 possible stereoisomers of this compound corresponds to the natural product.

Marine polyether natural products such as CTX3C possess potent and unique biological activities. For example, members of the brevetoxin and ciguatoxin families of marine polyether are potent neurotoxins. The ciguatoxins in particular are responsible for thousands of cases of human food poisoning every year and there have been many fatalities following the consumption of contaminated fish and seafood. As a consequence of their potent neurotoxic properties, analogues of the ciguatoxins have potential to function as probe molecules for the exploration of nerve signalling processes in vertebrates. Closely related marine polyethers also have potential as lead compounds for the development of new drugs. For example, the polyether natural product brevenal has been identified as an important candidate for the development of new treatments for cystic fibrosis and the gambieric acids possess potent anti-fungal activity that exceeds the activity of some agents used in the clinic.

The goal of the research described in this proposal is the completion of a highly efficient and fully convergent total synthesis of the marine polyether ciguatoxin CTX3C. Construction of the target will be accomplished using a novel synthetic strategy that involves the deployment of novel iterative and bidirectional methods of ring construction for the rapid assembly of two polycyclic fragments that will coupled at a very late stage in the synthesis. It is expected that the synthesis of CTX3C will represent a step-change in terms of the synthesis of targets of high molecular complexity and will showcase novel and innovative tactics, strategies and methodology that will have relevance to other complex polycyclic natural products of structural and biological significance.

The successful completion of the synthesis of CTX3C will have a significant impact in the arena of natural product synthesis and in field of organic synthesis more generally. The previous syntheses of large fused polyether natural products have been achieved by a very small number of research groups based in the US or Japan, and completion of CTX3C would be a UK first in terms of the synthesis of a member of this family of natural products. Indeed, very few natural products of the size and complexity of CTX3C have been synthesised by UK research groups, and our total synthesis would help raise the international profile of UK target-directed synthesis after a prolonged period during which this has diminished.

Previous syntheses of marine polyethers such as the ciguatoxins and brevetoxins have been extremely lengthy and have delivered only miniscule amounts of the final natural products. We expect that our synthesis will deliver viable amounts of CTC3X along with late-stage intermediates / derivatives for full biological evaluation by Metrion Biosciences in Cambridge, a company that specialises in the discovery of drugs that act by modulating the activity of ion channels. The Hirama group has investigated the synthesis of CTX3C analogues as probes and for the generation of antibodies as part of a novel immunological test for CTX3C. A long-term goal of our project is to develop reliable strategies and a toolkit of reactions that will deliver CTX3C analogues that can be used for antibody generation.

The completion of the total synthesis of CTX3C will allow us to demonstrate the power of bidirectional synthesis, rapid iterative ring construction and our new fragment coupling strategy for the rapid and stereocontrolled construction of complex molecules containing multiple rings and stereogenic centres. It should encourage others, both in academia and industry, to address the synthesis of more complex targets by demonstrating what is possible with regard to the efficient construction of a highly complex target such as CTX3C.

The work described in the proposal will be of direct benefit to chemists working in both the academic and industrial sectors. Our results will also be of particular interest, relevance and benefit to scientists working in the pharmaceutical and agrochemical industries and specifically to those who are engaged in the construction of structurally complex bioactive targets as new lead compounds, especially those containing multiple rings and stereogenic centres.