Total syntheses of Tetrodotoxin and 9-epiTetrodotoxin

Peihao Chen, Jing Wang, Shuangfeng Zhang, Yan Wang, Yuze Sun, Songlin Bai, Qingcui Wu, Xinyu Cheng, Peng Cao and Xiangbing Qi ()
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Peihao Chen: Peking University
Jing Wang: National Institute of Biological Sciences
Shuangfeng Zhang: National Institute of Biological Sciences
Yan Wang: National Institute of Biological Sciences
Yuze Sun: National Institute of Biological Sciences
Songlin Bai: National Institute of Biological Sciences
Qingcui Wu: National Institute of Biological Sciences
Xinyu Cheng: National Institute of Biological Sciences
Peng Cao: National Institute of Biological Sciences
Xiangbing Qi: National Institute of Biological Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects. Here, we present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol. The optically pure cyclohexane skeleton is assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents are established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydroxylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation deliver the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enable the rapid assembly of Tetrodotoxin, anhydro-Tetrodotoxin, 9-epiTetrodotoxin, and 9-epi lactone-Tetrodotoxin.

Date: 2024
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DOI: 10.1038/s41467-024-45037-0

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