Enantioselective Pd-Catalysed Nucleophilic C(sp3)-H (Radio)fluorination

Abstract

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(sp³)-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(sp³)-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.

Fig. 1.. Catalytic C(sp³)–H fluorination strategies.

(A) Approaches to catalytic C(sp³)–F bond formation. (B) Limitations of catalytic nucleophilic and stereoselective C(sp³)–H fluorination. (C) Amide-derived scaffolds in drug discovery. (D) Enantioselective nucleophilic C(sp³)–H (radio)fluorination.

Fig. 2.. Ligand optimization of the enantioselective C(sp³)–H nucleophilic fluorination.

Reaction conditions: 1b (0.05 mmol, 1.0 equiv.), [Pd(PhCN)₂]Cl₂ (5 mol%), Ligand (12 mol%), Selectfluor (1.2 equiv.), AgF (3 equiv.), 3Å molecular sieves (2.5% m/v), HFIP (0.5 mL), 45 °C, under air, 20 h. Gas Chromatography (GC) yields are reported with perfluorobiphenyl as the internal standard. Highlighted yields were verified by ¹H NMR using CH₂Br₂ as standard. ^aReaction conditions: [Pd(PhCN)₂]Cl₂ (10 mol%), Ligand (25 mol%), Selectfluor (1.2 equiv.), AgF (2 equiv.), anhydrous MgSO₄ (2 equiv.), HFIP (0.5 mL), 45 °C, under air, 12 h.

Fig. 3.. Scope of ligand-enabled desymmetrisation via nucleophilic C(sp³)–H fluorination.

Reaction conditions: substrate (0.05 mmol, 1.0 equiv.), Selectfluor (1.2 equiv.), Pd(PhCN)₂Cl₂ (5 mol%), L34 (12 mol%), AgF (3 equiv.), 3Å molecular sieves (2.5% m/v), HFIP (0.5 mL), 45 °C, under air, 16 h. Isolated yields are reported. The absolute configuration of 2b was determined by single crystal X-ray diffraction analysis, other compounds were assigned by analogy to 2b. Absolute stereochemistry for the lactams 2ak and 2u was not determined. ^aee was determined by conversion to 5.

Fig. 4.. Scope of kinetic resolution via ligand-enabled nucleophilic C(sp³)–H fluorination.

Reaction conditions: substrate (0.05 mmol, 1.0 equiv.), Selectfluor (1.2 equiv.), Pd(PhCN)₂Cl₂ (5 mol%), L34 (12 mol%), AgF (3 equiv.), 3Å molecular sieves (2.5% m/v), HFIP (0.5 mL), 45 °C, under air, 16 h. Isolated yields are reported. The absolute configuration of compounds was assigned by analogy to 2b. Absolute stereochemistry for the lactams 2at-2az was not determined. ^aCalculated conversion, C = ee_SM/(ee_SM+ee_PR). ^bSelectivity factor, s = ln[(1 – C)(1 – ee_SM)]/ln[(1 – C)(1 + ee_SM)]. ^cUsing L28 for 12h.

Fig. 5.. Applications of enantioselective fluorination and radiochemistry studies.

(A) Scale-up of enantioselective C(sp³)–H fluorination and derivatisation of chiral fluorinated product. (B) Enantioselective ¹⁸F-radiolabelling of flutamide and fentanyl analogue precursors. 10 mCi of [¹⁸F]KF was used. Enantioselectivities determined under the same conditions using cold KF as the fluoride source. (C) Isotopic dilution studies. RCC was measured via radioHPLC. Enantioselectivities determined using cold KF. See Supplementary Methods (Radiochemistry studies) for full description of reaction set-up and conditions.

Fig. 6.. Mechanistic and computational studies.

(A) Mechanistic studies. See Supplementary Methods (Mechanistic Experiments) for experimental details. (B) Proposed catalytic cycle. (C), (D) Computational studies. Reported ΔΔG^≠ values are conformation-weighed. TS stands for transition state. See Supplementary Methods (Computational Data and Analysis) for computational details.