Hui-Zhen Du, Jingwei Li*, Stella Christodoulou, Si-Yuan Li, Yun-Shu Cui, Junliang Wu, Sumei Ren, Laurent Maron*, Zhang-Jie Shi and Bing-Tao Guan*,
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引用次数: 0
摘要
氘和氚标记化合物在药物开发过程中发挥着重要作用。使用过渡金属催化剂进行正交定向氢同位素交换(HIE)是标记各种芳香族化合物最成熟的方法之一,但在芳香族醚类和氟化物方面的成功率有限。在此,我们提出了一种在重碱金属酰胺催化下,用 D2/T2 气体对芳香族醚和氟化物进行定向 HIE 的实用方法。使用市售的酰胺钾 KN(SiMe3)2 作为 HIE 催化剂,我们成功地实现了具有高比活度的复杂药物化合物的三反应。这种简单实用的方法为过渡金属催化 HIE 提供了宝贵的补充,扩大了底物范围,拓宽了高效同位素标记的 HIE 工具箱。对照实验和密度泛函理论(DFT)计算揭示了芳香族 C-H 键与碱酰胺之间有趣的动力学去质子平衡,并很好地解释了碱酰胺催化剂 MN(SiMe3)2(M = Cs、K 和 Na)明显不同的行为。
Directed Aromatic Deuteration and Tritiation of Pharmaceuticals by Heavy Alkali Metal Amide Catalysts
Deuterium- and tritium-labeled compounds play a significant role in the pharmaceutical development process. Ortho-directed hydrogen isotope exchange (HIE) with transition metal catalysts is one of the most well-developed methods for the labeling of various aromatic compounds, but met with limited success with aromatic ethers and fluorides. Herein, we present a practical method for the directed HIE of aromatic ethers and fluorides with D2/T2 gas catalyzed by heavy alkali metal amides. Using commercially available potassium amide KN(SiMe3)2 as an HIE catalyst, we successfully achieved tritiations of complex pharmaceutical compounds with high specific activities. This straightforward and practical method provides a valuable complement to transition metal-catalyzed HIE, enabling expanded substrate scope and broadening the HIE toolbox for efficient isotope labeling. Control experiments and density functional theory (DFT) calculations reveal an intriguing kinetic deprotonative equilibrium between aromatic C–H bonds and alkali amides and well explain the obviously different behaviors of the alkali amide catalysts MN(SiMe3)2 (M = Cs, K, and Na).
期刊介绍:
ACS Catalysis is an esteemed journal that publishes original research in the fields of heterogeneous catalysis, molecular catalysis, and biocatalysis. It offers broad coverage across diverse areas such as life sciences, organometallics and synthesis, photochemistry and electrochemistry, drug discovery and synthesis, materials science, environmental protection, polymer discovery and synthesis, and energy and fuels.
The scope of the journal is to showcase innovative work in various aspects of catalysis. This includes new reactions and novel synthetic approaches utilizing known catalysts, the discovery or modification of new catalysts, elucidation of catalytic mechanisms through cutting-edge investigations, practical enhancements of existing processes, as well as conceptual advances in the field. Contributions to ACS Catalysis can encompass both experimental and theoretical research focused on catalytic molecules, macromolecules, and materials that exhibit catalytic turnover.