Journal
SCIENCE
Volume 377, Issue 6604, Pages 411-415Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abn0571
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Funding
- NSF [CHE-1900154]
- Friedrich-Ebert-Stiftung
- NYU MacCracken Fellowship
- JSPS Overseas Challenge Program for Young Researchers
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A stereoselective synthesis of TTX from a glucose derivative is presented, proceeding via 22 steps. This method provides ready access to biologically active derivatives.
Tetrodotoxin (TTX) is a neurotoxic natural product that is an indispensable probe in neuroscience, a biosynthetic and ecological enigma, and a celebrated target of synthetic chemistry. Here, we present a stereoselective synthesis of TTX that proceeds in 22 steps from a glucose derivative. The central cyclohexane ring of TTX and its alpha-tertiary amine moiety were established by the intramolecular 1,3-dipolar cycloaddition of a nitrile oxide, followed by alkynyl addition to the resultant isoxazoline. A ruthenium-catalyzed hydroxylactonization set the stage for the formation of the dioxa-adamantane core. Installation of the guanidine, oxidation of a primary alcohol, and a late-stage epimerization gave a mixture of TTX and anhydro-TTX. This synthetic approach could give ready access to biologically active derivatives.
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