Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 6, Pages 1549-1552Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201611574
Keywords
alkaloids; natural products; stereocontrol; tetrodotoxin; total synthesis
Categories
Funding
- JSPS [25221301, 16H01141]
- Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan
- JSPS
- Yoshida Scholarship Foundation
- Grants-in-Aid for Scientific Research [14J11303] Funding Source: KAKEN
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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.
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