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4885445 
Journal Article 
Total Synthesis of (-)-Tetrodotoxin and 11-norTTX-6(R)-ol 
Maehara, T; Motoyama, K; Toma, T; Yokoshima, S; Fukuyama, T 
2017 
Yes 
Angewandte Chemie (International Edition)
ISSN: 1433-7851
EISSN: 1521-3773 
56 
6 
1549-1552 
English 
28074621 
WOS:000394998300017 
The enantioselective total synthesis of (-)-tetrodotoxin [(-)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.