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Synthesis of (±)-Tetrodotoxin
Synthetic Studies on Tetrodotoxin and Related Compounds. IV. Stereospecific Total Syntheses of dl-Tetrodotoxin.
J. Am. Chem. Soc. 1972;
18 February 2020 (online)
Key words(±)-tetrodotoxin - Diels–Alder cycloaddition - Beckmann rearrangement - Baeyer–Villiger oxidation
In 1972, Kishi and co-workers disclosed the first total synthesis of (±)-tetrodotoxin, a potent neurotoxin commonly associated with sea food poisoning. Tetrodotoxin has found application in medicinal chemistry as analgesic treatment option in cancer therapy. Kishi describes the complete total synthesis in a series of four publications; the one presented here and J. Am. Chem. Soc. 1972, 94, 9217, Tetrahedron Lett. 1970, 11, 5129, and Tetrahedron Lett. 1970, 11, 5127.
D was accessed by Diels–Alder reaction of B with butadiene (C). Subsequent Beckmann rearrangement of D allowed access to acetamide E, which underwent epoxidation and in situ ether-bridge formation. Conversion of K into L was enabled by Bayer–Villiger oxidation followed by lactone cleavage and in situ epoxide opening.