Department of Chemistry, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, 558-8585, Japan.
Chem Asian J. 2021 Jul 19;16(14):1882-1886. doi: 10.1002/asia.202100383. Epub 2021 May 26.
Histrionicotoxin (HTX) alkaloids isolated from the poison arrow frogs possess a unique structure characterized by a 1-azaspiro[5.5]undecane skeleton common to the HTX family. The unique molecular architecture of HTXs and the interest as potential target drugs have prompted synthetic chemists to promote the total synthesis so far. However, all of the synthetic strategies to access the 1-azaspiro[5.5]undecane framework of HTXs take a multistep approach from linear starting materials due to stepwise construction of either six-membered carbo- or azacycle. Herein, we report the direct one-step construction of the 1-azaspiro[5.5]undecane skeleton from linear amino ynone substrates bearing an N-methoxycarbonyl group utilizing our mercuric triflate (Hg(OTf) )-catalyzed cycloisomerization reaction. The utility of this novel methodology was demonstrated by the total and formal syntheses of HTX-235A and HTX-283A, respectively, from the azaspirocycle.
从毒箭蛙中分离出的拟态毒素 (HTX) 生物碱具有独特的结构，其特征是 HTX 家族共有的 1-氮杂螺[5.5]十一烷骨架。HTX 的独特分子结构以及作为潜在靶标药物的兴趣促使合成化学家迄今为止推动了全合成。然而，由于六元碳环或氮杂环的逐步构建，所有用于构建 HTX 1-氮杂螺[5.5]十一烷骨架的合成策略都从线性起始原料出发采用多步方法。在此，我们报告了利用我们的三氟甲磺酸汞 (Hg(OTf) )-催化的环异构化反应，从带有 N-甲氧基羰基的线性氨基炔酮底物直接一步构建 1-氮杂螺[5.5]十一烷骨架。该新方法的实用性通过从氮杂螺环分别进行 HTX-235A 和 HTX-283A 的全合成和形式合成得到了证明。
