First- and second-generation total synthesis of ciguatoxin CTX3C
First- and second-generation total synthesis of ciguatoxin CTX3C
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DOI：
10.1073/pnas.0401684101
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发表时间：
2004-08-17
影响因子：
11.1
通讯作者：
Hirama, M
中科院分区：
文献类型：
--
作者：
Inoue, M;Miyazaki, K;Hirama, M
在亚热带和热带地区，每年有超过2万人遭受雪卡水海鲜中毒。鱼类中被称为雪卡毒素的致病性神经毒素含量极低，这阻碍了分离、详细的生物学研究和制备用于检测这些毒素的抗雪卡毒素抗体。此外，雪卡毒素的大（长度为3nm）和复杂的分子结构阻碍了化学家完成它们的全合成。在这篇文章中，提供了导致雪卡毒素CTX3C全合成的研究的全部细节。第一代方法的关键要素包括左右翼片段形成O，O-缩醛，O，O-缩醛转化为O， s -缩醛，G环环化的自由基反应，F环闭合的复分解反应，以及2-萘基甲基保护基团的最终去除。随后的研究提供了第二代全合成，它更简洁，产量更高。第二代合成由-氯硫化物和仲醇直接合成关键中间体O， s -缩醛完成，这些合成确保了雪卡毒素在生物应用中的实际供应。
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.