<p>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 ¹⁸F-radiolabelling. To date, methods for enantioselective nucleophilic fluorination of inert C(<i>sp</i>³)–H bonds remain unknown. Here we report our design and development of a palladium-based catalytic system bearing bifunctional monoprotected amino sulfonamide ligands which enabled highly regio- and enantioselective nucleophilic β-C(<i>sp</i>³)–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 ¹⁸F-radiolabelling of pharmaceutical derivatives using [¹⁸F]KF.</p><p></p>