Wei Wan-Xu, Kuang Yangjin, Tomanik Martin
Department of Chemistry, New York University, New York, New York 10003, United States.
J Am Chem Soc. 2025 Jan 8;147(1):1034-1041. doi: 10.1021/jacs.4c14418. Epub 2024 Dec 20.
Complexity-generating reactions that access three-dimensional products from simple starting materials offer substantial value for drug discovery. While oxygen-containing heterocycles frequently feature unique, nonaromatic architectures such as spirocyclic rings, exploration of these chemical spaces is limited by conventional synthetic approaches. Herein, we report a copper-catalyzed annulation and alkene transposition cascade reaction that enables a modular preparation of complex, spirocyclic ethers from readily available alkenol substrates via a copper-catalyzed annulation and transannular 1,5-hydrogen atom transfer-mediated C-H functionalization. Our transformation displays a broad substrate scope, shows excellent heteroatom compatibility, and readily constructs spirocycles of varying ring sizes. The wider synthetic utility of this method is highlighted by numerous product diversifications and a short synthesis of the all-carbon framework of spirotenuipesine A. We anticipate that this transformation can significantly streamline access to a privileged class of three-dimensional oxygen-containing heterocycles and will find broad application in natural product synthesis.
从简单起始原料生成具有三维结构产物的复杂性生成反应，对药物发现具有重大价值。虽然含氧杂环常常具有独特的非芳香族结构，如螺环，但对这些化学空间的探索受到传统合成方法的限制。在此，我们报道了一种铜催化的环化和烯烃转位串联反应，该反应能够通过铜催化的环化和跨环1,5-氢原子转移介导的C-H官能化，从容易获得的链烯醇底物模块化制备复杂的螺环醚。我们的转化反应具有广泛的底物范围，显示出优异的杂原子兼容性，并且能够轻松构建不同环大小的螺环。该方法更广泛的合成效用通过众多产物多样化以及短步骤合成螺环菌素A的全碳骨架得以凸显。我们预计，这种转化反应能够显著简化获取一类重要的三维含氧杂环的途径，并将在天然产物合成中得到广泛应用。
