Totally Synthetic by Paul H. Docherty, 10 July 2006

Total Synthesis of Ciguatoxin

Inoue, Hirama

M. Inoue, K. Miyazaki, Y. Ishihara, A. Tatami, Y. Ohnuma, Y. Kawada, K. Komano, S. Yamashita, N. Lee, M. Hirama, J. Am. Chem. Soc. 2006, 9352-9354.

DOI: 10.1021/ja063041p

This total synthesis is a tasty number to start with. Or rather not that tasty at all, considering the toxicity of this molecule! Originally isolated from four metric tonnes of Moray Eels, at least the eels can breath a sigh of relief that Hirama et al. have finished their total synthesis of Ciguatoxin and its 51-HydroxyCTX3C analogue. Most of the ground work for this synthesis has been published already, including the synthesis of the main fragments, constituting their synthesis of CTX3C.

Starting with the pair of fragments shown above, they formed the S,O-acetal directly, and then used that to create the G-ring using an interesting radical cyclisation, which, by using the the correct protecting group they were able to derive the correct stereochemistry.

This then set them up for a final RCM to make the 9-member ring-F, and completion of the molecule. Interestingly, they have used the NAP protecting group throughout this project, which seems to be easily removed with DDQ.

So, a massive effort, and a slightly difficult to read paper (that main scheme is busy)…

Btw: Derek Lowe has a great piece on his blog about the isolation of ciguatoxin.