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Organic Chemistry Highlights

Total Synthesis

Monday, May 7, 2018
Douglass F. Taber
University of Delaware

The Fukuyama Synthesis of Tetrodotoxin

The complex puffer fish poison tetrodotoxin (3) is at its heart a highly-substituted cyclohexane. Tohru Fukuyama of Nagoya University envisioned (Angew. Chem. Int. Ed. 2017, 56, 1549. DOI: 10.1002/anie.201611574) assembling the cyclohexene 1 by Diels-Alder cycloaddition, then installing the last two ring stereogenic centers by oxidation and cyclization to 2.

The combination of 4 with 5 gave a diketone, that was reduced under Luche conditions to the prochiral diol 6. The tricyclic skeleton of the Diels-Alder adduct directed both this reduction and the diastereoselectivity of subsequent transformations. Lipase resolution of 6 followed by protection and functional group interchange led to 8. The addition of the one-carbon synthon followed by dihydroxylation, protecting group interchange and oxidation then completed the assembly of 9.

The addition of 10 to 9, again directed by the bulk of the adjacent branched ring system, proceeded with high geometric control. Thermolysis expelled 5, leading, after reduction, to the diene 11. Following the protocol developed earlier by Professor Fukuyama, carbamoylation followed by dehydration led to rearrangement to the protected amine 13, the diastereoselectivity of the C-N bond formation being directed by the cis-fused acetonide.

Cleavage of the vinyl group generated an aldehyde. Addition of 14 proceeded with high diastereoselectivity to give, after partial hydrogenation, the Z-alkene 15. Elimination of the sulfonyl group followed by protection led to 1, that was cyclized and deprotected to give 2-isoxazoline 17.

The octalin 17 contains an extra carbon atom. Oxidative cleavage gave 18, that was benzylated and reduced to give 19. The extra carbon was excised by oxidation with lead tetraacetate, leading, after hydrolysis, protection and lactonization, to the protected amine 20. Guanidine formation with 21 gave 22, that was deprotected to tetrodotoxin (3).

It is instructive to compare this synthesis to the complementary approach described by Minoru Isobe (Synthesis of (-)-Tetrodotoxin 2005, May 2)

D. F. Taber, Org. Chem. Highlights 2018, May 7.