Useful Designs in the Synthesis of Trans-Fused Polyether Toxins

Alvarez, Eleuterio.; Candenas, Luz; Pérez, Ricardo; Ravelo, José L.; Martı́n, Julio D.

doi:10.1021/cr00038a008

Cited by 202 publications

(61 citation statements)

References 36 publications

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“…The well known characteristics of mediumsized rings in terms of strain, unfavorable transannular interactions, [25] and difficulties associated with their construction, together with the complex stereochemistry and sheer size make the total synthesis of brevetoxin A (1) a special challenge. [26] As was the case with brevetoxin B (2), a number of new synthetic methods had to be developed and various strategies were attempted in order to face the challenge of brevetoxin A (1) before final success. [19] Results and Discussion…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Brevetoxin A: Part 1: First Generation Strategy and Construction of BCD Ring System

et al. 1999

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Discussed herein is our first generation strategy for the total synthesis of brevetoxin A. This approach relies upon dissection of the molecule at the nine-membered ring site (ring E). A Wittig coupling of requisite polycyclic fragments 3 and 4 followed by hydroxy dithioketal cyclization was expected to furnish the polycyclic framework of brevetoxin A (1). Intermediate 8 was anticipated to be a valid synthetic precursor to phosphonium salt 3, and its synthesis was accomplished by a bis(lactonization)/ thionolactone formation/ functionalization sequence. In order to test our synthetic strategy, the synthesis of an advanced model system (36) was attempted. Aldehyde 38 and phosphonium salt 37 were successfully synthesized and coupled through a Wittig reaction. Unfortunately, the planned hydroxy dithioketal cyclization to form the crucial nonacene (ring E) did not proceed as anticipated and this synthetic approach was discontinued.

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Section: Introductionmentioning

confidence: 99%

Total Synthesis of Brevetoxin A: Part 1: First Generation Strategy and Construction of BCD Ring System

et al. 1999

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“…The synthetic challenge posed by 1 reflects its highly complex molecular structure; 13 oxygen atoms and 52 carbon atoms are coiled in a polycyclic macromolecule that includes 13 rings and 30 stereogenic centers. Apparently, an efficient convergent strategy is crucial for practical construction of this large molecule (26)(27)(28)(29)(30)(31).…”

Section: Resultsmentioning

confidence: 99%

First- and second-generation total synthesis of ciguatoxin CTX3C

Inoue

Miyazaki

Uehara

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

115

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More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. Furthermore, the large (3 nm in length) and complex molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. In this article, the full details of studies leading to the total synthesis of ciguatoxin CTX3C are provided. The key elements of the first-generation approach include O,O-acetal formation from the right and left wing fragments, conversion from O,O-acetal to O,S-acetal, a radical reaction to cyclize the G ring, a ring-closing metathesis reaction to close the F ring, and final removal of the 2-naphtylmethyl protective groups. Subsequent studies provided a second-generation total synthesis, which is more concise and results in a higher yield. Second-generation synthesis was accomplished by using a direct method of constructing the key intermediate O,S-acetal from ␣-chlorosulfide and a secondary alcohol. These syntheses ensure a practical supply of ciguatoxin for biological applications.ciguatera ͉ polyether ͉ convergent strategy C iguatera is a human intoxication caused by the ingestion of certain reef fish (1). More than 20,000 people suffer annually from ciguatera, making it one of the most common forms of nonbacterial food poisoning. Ingestion of affected fish leads to neurological, gastrointestinal, and cardiovascular disorders, which may last up to a month or more. The most prominent symptom is a disorder of temperature sensation. Specifically, touching cold water can induce pain similar to that of an electric shock. Other symptoms include diarrhea, vomiting, muscle pain and itching, whereas paralysis, coma, and even death may occur in severe cases.Yasumoto et al. (2) identified an epiphytic dinoflagellate, Gambierdiscus toxicus, as the causative organism and demonstrated that dinoflagellate-derived toxins are transferred by the food chain to various fish. About 100 species of fish cause ciguatera, and ciguateric fish look, taste, and smell like normal uncontaminated fish. In addition, the occurrence of poisoning is completely unpredictable. Current difficulties in predicting, detecting, and treating ciguatera have had an adverse socioeconomic impact, in particular, in developing countries.Ciguatoxins are regarded as the principal causative toxins of ciguatera seafood poisoning (Fig. 1) (3, 4). In 1989, the Yasumoto group successfully elucidated the structures of ciguatoxin (CTX) (4) and CTX4B (3) (5, 6), which were found to be large polycyclic ethers having molecular lengths Ͼ3 nm. They subsequently isolated other congeners including CTX3C (1) (7) and 51-hydroxyCTX3C (2) (8). To date, the structures of Ͼ20 congeners of ciguatoxins have been determined (9, 10).The lethal potencies of ciguatoxins (LD 50 ϭ 0.25-4 g͞kg) by i.p. injection into mic...

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“…[19][20][21][22][23][24] The 12 ether rings, ranging from six-to nine-membered, are fused in a trans/ syn manner, and the five-membered ring is spirally attached at the end. Owing to the size and complexity of the molecule, efficient assembly of the structural fragments is crucial for its successful construction.…”

Section: Plan Of Convergent Strategymentioning

confidence: 99%

Evolution of a Practical Total Synthesis of Ciguatoxin CTX3C

Inoue

Hirama

2004

Acc. Chem. Res.

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More than 20 000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered their isolation, detailed biological study, and preparation of anti-ciguatoxin antibodies for detecting these toxins. Ciguatoxins consist of 12 trans-fused polycyclic ethers, ranging from six- to nine-membered, and include a spirally attached five-membered cyclic ether at one end. The large (3 nm in length) and complicated molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. In 2001, we achieved the first total synthesis of ciguatoxin CTX3C by assembly of four structural fragments. Since then, protocols to combine the fragments have significantly improved in terms of overall stereoselectivity, efficiency, and practicality. In this Account, we describe recently evolved methodologies for the total synthesis of CTX3C.

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Useful Designs in the Synthesis of Trans-Fused Polyether Toxins

Cited by 202 publications

References 36 publications

Total Synthesis of Brevetoxin A: Part 1: First Generation Strategy and Construction of BCD Ring System

Total Synthesis of Brevetoxin A: Part 1: First Generation Strategy and Construction of BCD Ring System

First- and second-generation total synthesis of ciguatoxin CTX3C

Evolution of a Practical Total Synthesis of Ciguatoxin CTX3C

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