Rivera-Chao Eva, Corpas Javier, Lonardi Giovanni, Derdau Volker, Ruffoni Alessandro, Leonori Daniele
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, Aachen, 52056, Germany.
Integrated Drug Discovery, R&D, Sanofi, Germany, Industriepark Hoechst, Frankfurth am Main, 65926, Germany.
Angew Chem Int Ed Engl. 2025 Jun 17;64(25):e202500627. doi: 10.1002/anie.202500627. Epub 2025 May 8.
Isotope labeling, particularly with deuterium (H), plays a critical role in drug discovery due to its ease of incorporation and its potential to switch unwanted metabolic transformations. Deuterium incorporation can enhance drug stability, affect pharmacokinetics, and alter metabolism pathways. Current deuterium labeling methods focus on hydrogen isotope exchange (HIE), and typically rely on the use of transition metal catalysis. Herein, we present a metal-free approach for aromatic HIE, utilizing photoexcitation in deuterated hexafluoroisopropanol (HFIP-d). By exploiting the enhanced basicity of excited-state aromatics, this method achieves selective deuteration at positions often inaccessible by traditional methods. The approach is efficient and was demonstrated across a broad number of complex drug molecules. Transient absorption spectroscopy confirms the formation of deuterated arenium ions.
同位素标记，特别是用氘（H）标记，由于其易于引入以及改变不需要的代谢转化的潜力，在药物发现中起着关键作用。引入氘可以提高药物稳定性、影响药代动力学并改变代谢途径。目前的氘标记方法侧重于氢同位素交换（HIE），通常依赖于过渡金属催化的使用。在此，我们提出了一种用于芳香族HIE的无金属方法，利用氘代六氟异丙醇（HFIP-d）中的光激发。通过利用激发态芳烃增强的碱性，该方法在传统方法通常无法到达的位置实现了选择性氘代。该方法效率高，并在大量复杂药物分子中得到了验证。瞬态吸收光谱证实了氘代芳鎓离子的形成。
