Pradhan Sukumar, Maiti Sudip, Dutta Suparna, Adam Russell C, Tyagi Sameer, Maiti Debabrata
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India.
Syngenta Ltd, Jealott's Hill International Research Center, Bracknell, Berkshire, RG 42 6EY, United Kingdom.
Angew Chem Int Ed Engl. 2025 Jan 2;64(1):e202412979. doi: 10.1002/anie.202412979. Epub 2024 Nov 4.
The rapid construction of three-dimensional (3D) heterocyclic frameworks is a key challenge in contemporary medicinal chemistry. The molecules with three-dimensional complexity hold a greater probability to improve clinical outcomes, solubility, selectivity for target proteins, and metabolic stability. However, the prevalence of flat molecules persists among new drug candidates, primarily owing to the multitude of chemical methods available for their synthesis. In principle, the dearomative functionalization of N-heteroarene allows for the conversion of readily available planar molecules into partially or fully saturated nitrogen heterocycles, which are most significant structural motifs of pharmaceuticals and natural products. Unfortunately, these reactions are very rare because of the inherent challenge imposed by heteroarenes' poor reactivity, rendering the process thermodynamically unfavorable. Herein, we report a modular approach for accessing 3D chemical space in translating planar heteroarenes into valuable 3D heterocycles via the installation of a highly versatile cyano group as a new vector. This approach is enabled by the in situ generation of reactive, non-symmetric iodane by combining cyanide anion and bench-stable PhI(OAc). This reaction represents a rare example of 1,2-dicyanation of N-heteroarenes that meets the numerous requirements for broad implementation in drug and agrochemical discovery. The transformation is highly selective and amenable to a wide range of N-heteroarenes and late-stage partial saturation of drugs and agrochemicals.
三维（3D）杂环骨架的快速构建是当代药物化学中的一项关键挑战。具有三维复杂性的分子更有可能改善临床疗效、溶解度、对靶蛋白的选择性以及代谢稳定性。然而，在新药候选物中，平面分子仍然普遍存在，这主要是由于有多种可用于其合成的化学方法。原则上，N-杂芳烃的去芳构化官能团化能够将容易获得的平面分子转化为部分或完全饱和的氮杂环，而这些氮杂环是药物和天然产物中最重要的结构基序。不幸的是，由于杂芳烃反应性差所带来的固有挑战，这些反应非常罕见，使得该过程在热力学上不利。在此，我们报道了一种模块化方法，通过安装一个高度通用的氰基作为新载体，将平面杂芳烃转化为有价值的3D杂环，从而进入3D化学空间。这种方法是通过将氰根阴离子与市售稳定的PhI(OAc)2结合原位生成反应性非对称碘鎓盐来实现的。该反应代表了N-杂芳烃1,2-二氰化的一个罕见例子，满足了在药物和农用化学品发现中广泛应用的众多要求。该转化具有高度选择性，适用于多种N-杂芳烃以及药物和农用化学品的后期部分饱和。
