Total Syntheses of Tetrodotoxin and 9-epiTetrodotoxin

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jan 23

PMID 38263179

Authors

Peihao Chen

Jing Wang

Shuangfeng Zhang

Yan Wang

Yuze Sun

Songlin Bai

Qingcui Wu

Xinyu Cheng

Peng Cao

Xiangbing Qi

Affiliations

Soon will be listed here.

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 SmI-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.

Citing Articles

Tetrodotoxin: The State-of-the-Art Progress in Characterization, Detection, Biosynthesis, and Transport Enrichment.

Zhang X, Qiao K, Cui R, Xu M, Cai S, Huang Q Mar Drugs. 2024; 22(12).

PMID: 39728106 PMC: 11676112. DOI: 10.3390/md22120531.

References

Cho Y, Carcache D, Tian Y, Li Y, Danishefsky S . Total synthesis of (+/-)-jiadifenin, a non-peptidyl neurotrophic modulator. J Am Chem Soc. 2004; 126(44):14358-9. DOI: 10.1021/ja045939p. View

Tomanik M, Xu Z, Herzon S . Enantioselective Synthesis of Euonyminol. J Am Chem Soc. 2021; 143(2):699-704. DOI: 10.1021/jacs.0c12998. View

Keana J, Kim C . Synthetic intermediates potentially useful for the synthesis of tetrodotoxin and derivatives. II. Reaction of diazomethane with some shikimic acid derivatives. J Org Chem. 1970; 35(4):1093-6. DOI: 10.1021/jo00829a050. View

Miyasaka T, Adachi M, Nishikawa T . Synthesis of the 8-Deoxy Analogue of 4,9-Anhydro-10-hemiketal-5-deoxy-tetrodotoxin, a Proposed Biosynthetic Precursor of Tetrodotoxin. Org Lett. 2021; 23(23):9232-9236. DOI: 10.1021/acs.orglett.1c03565. View

Chau J, Xu S, Ciufolini M . Assembly of a key dienic intermediate for tetrodotoxin via a Machetti-DeSarlo reaction. J Org Chem. 2013; 78(23):11901-10. DOI: 10.1021/jo401960p. View

Konrad D, Ruhmann K, Ando H, Hetzler B, Strassner N, Houk K . A concise synthesis of tetrodotoxin. Science. 2022; 377(6604):411-415. DOI: 10.1126/science.abn0571. View

Yuan C, Jin Y, Wilde N, Baran P . Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes. Angew Chem Int Ed Engl. 2016; 55(29):8280-4. PMC: 4972021. DOI: 10.1002/anie.201602235. View

Shen H, Liu D, Wu K, Lei J, Yan N . Structures of human Na1.7 channel in complex with auxiliary subunits and animal toxins. Science. 2019; 363(6433):1303-1308. DOI: 10.1126/science.aaw2493. View

Xu J, Trzoss L, Chang W, Theodorakis E . Enantioselective total synthesis of (-)-jiadifenolide. Angew Chem Int Ed Engl. 2011; 50(16):3672-6. PMC: 3159889. DOI: 10.1002/anie.201100313. View

10.

Kishi Y, Aratani M, Fukuyama T, Nakatsubo F, Goto T . Synthetic studies on tetrodotoxin and related compounds. 3. A stereospecific synthesis of an equivalent of acetylated tetrodamine. J Am Chem Soc. 1972; 94(26):9217-9. DOI: 10.1021/ja00781a038. View

11.

Song H, Ding W, Zhou Q, Liu J, Lu L, Xiao W . Photocatalytic Decarboxylative Hydroxylation of Carboxylic Acids Driven by Visible Light and Using Molecular Oxygen. J Org Chem. 2016; 81(16):7250-5. DOI: 10.1021/acs.joc.6b01360. View

12.

Chen Y, McDaid P, Deng L . Asymmetric alcoholysis of cyclic anhydrides. Chem Rev. 2003; 103(8):2965-84. DOI: 10.1021/cr020037x. View

13.

Zheng C, Wang Y, Xu Y, Chen Z, Chen G, Liang S . Ru-Photoredox-Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids through N-(acyloxy)phthalimide. Org Lett. 2018; 20(16):4824-4827. DOI: 10.1021/acs.orglett.8b01885. View

14.

Goto T, Kishi Y, Takahashi S, Hirata Y . Tetrodotoxin. Tetrahedron. 1965; 21(8):2059-88. DOI: 10.1016/s0040-4020(01)98344-9. View

15.

Good S, Sharpe R, Johnson J . Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin. J Am Chem Soc. 2017; 139(36):12422-12425. PMC: 5597490. DOI: 10.1021/jacs.7b07745. View

16.

Nishiumi M, Miyasaka T, Adachi M, Nishikawa T . Total Syntheses of the Proposed Biosynthetic Intermediates of Tetrodotoxin Tb-210B, Tb-226, Tb-242C, and Tb-258. J Org Chem. 2022; 87(14):9023-9033. DOI: 10.1021/acs.joc.2c00704. View

17.

Kishi Y, Fukuyama T, Aratani M, Nakatsubo F, Goto T . Synthetic studies on tetrodotoxin and related compounds. IV. Stereospecific total syntheses of DL-tetrodotoxin. J Am Chem Soc. 1972; 94(26):9219-21. DOI: 10.1021/ja00781a039. View

18.

Narahashi T, Moore J, Scott W . TETRODOTOXIN BLOCKAGE OF SODIUM CONDUCTANCE INCREASE IN LOBSTER GIANT AXONS. J Gen Physiol. 1964; 47:965-74. PMC: 2195365. DOI: 10.1085/jgp.47.5.965. View

19.

Noya B, Paredes M, Ozores L, Alonso R . 5-exo Radical cyclization onto 3-alkoxyketimino-1, 6-anhydromannopyranoses. Efficient preparation of synthetic intermediates for (-)-tetrodotoxin. J Org Chem. 2000; 65(19):5960-8. DOI: 10.1021/jo000325y. View

20.

Taber D, Storck P . Synthesis of (-)-tetrodotoxin: preparation of an advanced cyclohexenone intermediate. J Org Chem. 2003; 68(20):7768-71. DOI: 10.1021/jo0301189. View