A concise synthesis of tetrodotoxin
A concise synthesis of tetrodotoxin
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DOI：
10.1126/science.abn0571
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发表时间：
2022-07-22
期刊：
影响因子：
56.9
通讯作者：
Trauner, Dirk
中科院分区：
文献类型：
--
作者：
Konrad, David B.;Ruehmann, Klaus-Peter;Trauner, Dirk
河豚毒素（Tetrodotoxin， TTX）是一种神经毒性天然产物，是神经科学中不可缺少的探针，是生物合成和生态领域的一个谜，也是合成化学的一个著名靶点。在这里，我们提出了一个立体选择性合成TTX，从葡萄糖衍生物进行22步。TTX的中心环己烷环和叔胺部分是通过分子内1,3-偶极环加成氧化腈建立的，然后在异恶唑啉上加成炔基。钌催化的羟基内酯化作用为二恶英-金刚烷核的形成奠定了基础。安装胍，氧化伯醇和后期的外聚化得到TTX和无水TTX的混合物。这种合成方法可以随时获得具有生物活性的衍生物。
Tetrodotoxin (TTX) is a neurotoxic natural product that is an indispensable probe in neuroscience, a biosynthetic and ecological enigma, and a celebrated target of synthetic chemistry. Here, we present a stereoselective synthesis of TTX that proceeds in 22 steps from a glucose derivative. The central cyclohexane ring of TTX and its alpha-tertiary amine moiety were established by the intramolecular 1,3-dipolar cycloaddition of a nitrile oxide, followed by alkynyl addition to the resultant isoxazoline. A ruthenium-catalyzed hydroxylactonization set the stage for the formation of the dioxa-adamantane core. Installation of the guanidine, oxidation of a primary alcohol, and a late-stage epimerization gave a mixture of TTX and anhydro-TTX. This synthetic approach could give ready access to biologically active derivatives.