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Organic Chemistry Highlights

Total Synthesis

Monday, June 5, 2023
Douglass F. Taber
University of Delaware

The Trauner Synthesis of Tetrodotoxin

Tetrodotoxin (4), the lethal principle of pufferfish (and some salamanders!) is a highly-substituted cyclohexane. Dirk Trauner of the University of Pennsylvania assembled the intermediate cyclohexane 3 via an intramolecular dipolar cyclization initiated by the conjugate addition of the alkoxide 2 to the nitroalkene 1 (Science 2022, 377, 411 DOI: 10.1126/science.abn0571).

The synthesis began with the glucose derivative 5. Benzylation followed by oxidation and methylenation led to the alkene 6. Selective reduction followed by catalytic osmylation gave the diol 7. Formation of the acetonide followed by an Appel reaction delivered the iodide 8, that was reduced with tBuLi. Nitromethane was added to the resulting aldehyde to give, after dehydration, the nitroalkene 1.

Conjugate addition of the alkoxide 2 to 1 proceeded with high diastereoselectivity, leading to the intermediate nitronate, that on exposure to Boc2O was converted into the nitrile oxide 9. The subsequent dipolar cycloaddition proceeded with high diastereoselectivity, but to give 3, having the wrong relative configuration at 4a (tetrodotoxin numbering) for the natural product. In fact, this was advantageous.

The importance of the axial substituent at 4a became apparent in the next step. Selective deprotection of 3 led to the free alcohol. The addition of the alkynyl anion 10 then proceeded with high diastereoselectivity, to give, after deprotection, the α-quaternary amine 11. Protection with 12 led to the acetonide 13, that was reduced and selectively protected, then cyclized and oxidized to the α-hydroxy lactone 14. Deprotection delivered the amino diol 15, that was protected, condensed with the reagent 16 to form the guanidine, then oxidized with Collins reagent to give an intermediate aldehyde that epimerized at 4a to the more stable equatorial configuration in the course of the cyclization to tetrodotoxin (4).

It is instructive to compare this synthesis to the complementary approaches described by Minoru Isobe (Highlights May 2, 2005) and Tohru Fukuyama (Highlights May 7, 2018).

D. F. Taber, Org. Chem. Highlights 2023, June 5.