Chekshin Nikita, Liu Luo-Yan, Phan D Quang, Donnelly David J, Ouyang Yuxin, Yeung Kap-Sun, Qiao Jennifer X, Yu Jin-Quan
Department of Chemistry, The Scripps Research Institute; 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Small Molecule Drug Discovery, Bristol-Myers Squibb Research and Development; P.O. Box 4000, Princeton, New Jersey 08543, USA.
Nat Catal. 2025 Jul;8(7):678-687. doi: 10.1038/s41929-025-01366-x. Epub 2025 Jul 14.
Despite increasing demand for chiral fluorinated organic molecules, enantioselective C-H fluorination remains among the most challenging and sought-after transformations in organic synthesis. Furthermore, utilizing nucleophilic sources of fluorine is especially desirable for F-radiolabelling. To date, methods for enantioselective nucleophilic fluorination of inert C(sp)-H bonds remain unknown. Herein, we report our design and development of a Pd-based catalytic system bearing bifunctional MPASA ligands which enabled highly regio- and enantioselective nucleophilic β-C(sp)-H fluorination of synthetically important amides and lactams, commonly present in medicinal targets. The enantioenriched fluorinated products can be rapidly converted to corresponding chiral amines and ketones which are building blocks for a wide range of bioactive scaffolds. Mechanistic studies suggest that the C-F bond formation proceeds via outer-sphere reductive elimination with direct incorporation of fluoride, which was applied to late-stage F-radiolabelling of pharmaceutical derivatives using [F]KF.
尽管对手性氟化有机分子的需求不断增加，但对映选择性C-H氟化仍然是有机合成中最具挑战性且备受追捧的转化反应之一。此外，利用亲核氟源进行F-放射性标记尤其理想。迄今为止，惰性C(sp)-H键的对映选择性亲核氟化方法仍然未知。在此，我们报告了一种基于钯的催化体系的设计与开发，该体系带有双功能MPASA配体，能够实现对合成中重要的酰胺和内酰胺（常见于药物靶点中）进行高度区域和对映选择性的亲核β-C(sp)-H氟化。对映体富集的氟化产物可快速转化为相应的手性胺和酮，它们是多种生物活性支架的构建单元。机理研究表明，C-F键的形成通过外层球还原消除直接引入氟化物来进行，该方法已应用于使用[F]KF对药物衍生物进行后期F-放射性标记。
