First- and second-generation total synthesis of ciguatoxin CTX3C.
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 alpha-chlorosulfide and a secondary alcohol. These syntheses ensure a practical supply of ciguatoxin for biological applications.
Inoue
Masayuki
M
Department of Chemistry, Graduate School of Science, Tohoku University and Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Sendai 980-8578, Japan.
Miyazaki
Keisuke
K
Uehara
Hisatoshi
H
Maruyama
Megumi
M
Hirama
Masahiro
M
D000818:Animals; D002625:Chemistry, Organic / Q000379:methods; D002922:Ciguatoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004141:Dinoflagellida / Q000737:chemistry / Q000472:pathogenicity; D005399:Fishes / Q000469:parasitology; D005517:Foodborne Diseases / Q000209:etiology; D006801:Humans; D015394:Molecular Structure
C466858:ciguatoxin 3C; D002922:Ciguatoxins