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Organic Chemistry Highlights

Total Synthesis

Monday, May 2, 2005
Douglass Taber
University of Delaware

Synthesis of (-)-Tetrodotoxin

Tetrodotoxin 3, the toxic principle of pufferfish poison, is a formidable challenge for synthesis, with each carbon of the cyclohexane functionalized. Minoru Isobe of Nagoya University recently reported (Angew. Chem. Int. Ed. 2004, 43, 4782. DOI: 10.1002/anie.200460293) a second-generation synthesis of enantiomerically-pure tetrodotoxin. This synthesis features the rapid construction of the cyclohexene by Diels-Alder cycloaddition using an enantiomerically-pure dienopile, the early introduction of the aminated quaternary center, and the use of that center to direct the relative configuration of further functionalization around the ring.

The synthesis started with levoglucosenone 4, available by the pyrolysis of cellulose, e.g. old newspapers. Bromination-dehydrobromination gave the enantiomerically-pure Diels-Alder dienophile 5, which was combined with isoprene to give predominantly the crystalline adduct 1. Hydrolysis and acetylation led to 6, which was carried on to the geometrically-defined allylic alcohol 7 via reduction with Zn-Cu couple. Overman rearrangement of 7 proceeded with high facial control, to give 8.

The next stage of the synthesis was ring oxygenation, to convert 8 into 13. The key to this transformation was the observation that the amide oxygen of 8 participated in the solvolysis of the allylic bromide, setting, after hydrolysis, the new secondary stereocenter of 9. Hydroxyl-directed epoxidation gave 10, which was rearranged with Ti(O-i-Pr)4 to 11. After some experimentation, it was found that the derived dione 12 could be reduced to the desired cis diol 13 with LiBr and LiAlH(O-t-Bu)3 followed by NaBH4/CeCl3.

Silylation followed by selenium dioxide oxidation converted 13 into 14. Epoxidation of the derived TES ether proceeded by addition of oxygen to the more open face of the alkene, leading to 15. Ozonolysis followed by diastereoselective one-carbon homologation provided 17. This set the stage for intramolecular epoxide opening by the carboxylate, to give 2, in which all of the stereogenic centers of tetrodotoxin have been established.

Justin Du Bois of Stanford University has put forward (J. Am. Chem. Soc. 2003, 125, 11510. DOI: 10.1021/ja0368305) a quite different total synthesis of tetrodotoxin, including an elegant late-stage introduction of the nitrogen.

D. F. Taber, Org. Chem. Highlights 2005, May 2.