Total Synthesis of (−)‐Tetrodotoxin and 11‐norTTX‐6(<i>R</i>)‐ol

Maehara, Tomoaki; Motoyama, Keisuke; Toma, Tatsuya; Yokoshima, Satoshi; Fukuyama, Tohru

doi:10.1002/anie.201611574

Cited by 43 publications

(19 citation statements)

References 43 publications

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“…11–19 “Tetrodamine” ( 2 , Scheme 1a) is a common conceptual target in tetrodotoxin syntheses. 11–18 The C6–C7–C8–C8a stereotetrad comprises a challenging functional group constellation. The C7/C8 syn diol is suggestive of a cis alkene difunctionalization; direct dihydroxylation of a suitably substituted benzene has been suggested as a potential entry point for tetrodotoxin 20 and OsO 4 -catalyzed alkene functionalization was realized en route to 1 .…”

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confidence: 99%

Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin

2017

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Benzenoids in principle represent attractive and abundant starting materials for the preparation of substituted cyclohexanes; however, the synthetic tools available for overcoming the considerable aromatic energies inherent to these building blocks limit the available product types. In this paper, we demonstrate access to heretofore unknown heterotricyclic structures by leveraging oxidative dearomatization of 2-hydroxymethyl phenols with concurrent N-hydroxycarbamate dehydrogenation using a common oxidant. The pairwise-generated, mutually reactive species then participate in a second stage acylnitroso Diels–Alder cycloaddition. The reaction chemistry of the derived [2.2.2]-oxazabicycles, bearing four orthogonal functional groups and three stereogenic centers, is shown to yield considerable diversity in downstream products. The methodology allows for the expeditious synthesis of a functionalized intermediate bearing structural and stereochemical features in common with the complex alkaloid tetrodotoxin.

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confidence: 99%

Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin

2017

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“…Alkaloid 19 was also a major product in another synthesis of TTX by Isobe group in 2004–2006, as well as a minor product in the TTX synthesis by the Fukuyama group in 2017, see Sections 5.3.1 and 5.4.4, respectively. Both racemic and optically active alkaloid 19 was also obtainedas an advanced intermediate during yet another total synthesis of TTX by Sato in 2005 and 2008, cf.…”

Section: Synthesis Of Ttx Analoguesmentioning

confidence: 99%

“…A recent total synthesis of (−)‐TTX was completed by Fukuyama in 2017 and represented, at that time, the shortest total synthesis of the natural product …”

Section: Synthesis Of Ttxmentioning

confidence: 99%

Tetrodotoxin: History, Biology, and Synthesis

et al. 2019

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This review provides a comprehensive coverage of the history, biology and chemistry of tetrodotoxin (TTX). It traces the origin of this remarkable molecule all the way back to the ancient Chinese medicine records. The discovery of biological activity, isolation, and a brief overview of structure elucidation are summarized. Next, the biology of TTX is discussed, primarily in the context of its activity in the sodium channels, its anesthetic properties, and its potential use in cancer treatment or drug addiction. Biosynthesis of TTX is covered before the discussion of the total syntheses. All total, formal or partial syntheses are covered but those total syntheses that have been discussed in previous reviews are only briefly summarized. Finally, the synthesis of natural and unnatural derivatives is surveyed, and a conclusion and outlook are provided for this very extensive field of endeavor. To the best of our knowledge the literature coverage is complete up to December 2018.

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“…Although several total syntheses and many synthetic studies of tetrodotoxin have been reported to date, it deserves further synthetic efforts even today since biological and chemical behaviors of the densely functionalized molecules have not been fully controlled. Since our total synthesis of tetrodotoxin was reported in 2017, we have been pursuing investigations toward this attractive molecule with quite different synthetic strategies. Herein we disclose our novel total synthesis of tetrodotoxin.…”

Section: Figurementioning

confidence: 99%