Total Synthesis of (−)-Tetrodotoxin and 11-norTTX-6(R)-ol

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• 作者：Tomoaki Maehara ; Dr. Keisuke Motoyama ; Dr. Tatsuya Toma ; Dr. Satoshi Yokoshima and Prof. Tohru Fukuyama
• 刊名：Angewandte Chemie
• 出版年：2017
• 出版时间：February 1, 2017
• 年：2017
• 卷：129
• 期：6
• 页码：1571-1574
• 全文大小：767K
• ISSN：1521-3757

文摘

The enantioselective total synthesis of (−)-tetrodotoxin [(−)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.