A concise synthesis of tetrodotoxin

David B. Konrad, Klaus Peter Rühmann, Hiroyasu Ando, Belinda E. Hetzler, Nina Strassner, Kendall N. Houk, Bryan S. Matsuura, Dirk Trauner

Research output: Contribution to journalArticlepeer-review


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 α-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.

Original languageEnglish (US)
Pages (from-to)411-415
Number of pages5
Issue number6604
StatePublished - Jul 22 2022


  • Catalysis
  • Cycloaddition Reaction
  • Guanidine/chemistry
  • Ruthenium/chemistry
  • Stereoisomerism
  • Tetrodotoxin/chemical synthesis
  • Voltage-Gated Sodium Channel Blockers/chemical synthesis


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