Nickel-Catalyzed Enantio- and Diastereoselective Synthesis of Fluorine-Containing Vicinal Stereogenic Centers

Abstract

The construction of fluorinated architectures has been a topic of interest to medicinal chemists due to their unique ability to improve the pharmacokinetic properties of bioactive compounds. However, the stereoselective synthesis of fluoro-organic compounds with vicinal stereogenic centers is a challenge. Herein, we present a directing-groupfree nickel-hydride catalyzed hydroalkylation of fluoroalkenes to afford fluorinated motifs with two adjacent chiral centers in excellent yields and stereoselectivities. Our method provides expedient access to biologically relevant, highly enantioenriched organofluorine compounds. Furthermore, the strategy can be used for the diastereo- and enantioselective synthesis of vicinal difluorides, which have recently gained attention in the fields of organocatalysis and peptide mimics.

Figure 1

Context of enantio- and diastereoselective synthesis of fluorine-containing vicinal stereogenic centers. (a) Representative examples of biologically relevant molecules. h5-HT_2A, serotonin 2A receptor, AMACR, α-methylacyl CoA racemase. (b) Limitations and challenges. Left panel: Necessity of a directing group or proximal p/π orbital to control reaction regioselectivity. Right panel: unproductive C–F cleavage. (c) This work: Enantio- and diastereoselective coupling of fluoroalkenes with secondary alkyl halides to access compounds with fluorine-containing vicinal stereogenic centers and vicinal difluorides. DG, directing group.

Figure 2

Optimization of ligands. Conditions: NiCl₂·DME (10 mol %), ligand (15 mol %), 1a (0.20 mmol), 2a (0.10 mmol), (EtO)₂MeSiH (0.25 mmol), KF (0.25 mmol), and DMA (1.0 mL) at RT for 20 h; yields and dr were measured by ¹⁹F NMR of the crude reaction mixture. The ee was determined using chiral HPLC analysis of the product after purification. ^a1a (0.13 mmol), DMA/t-BuOH (0.5:0.5 mL) as solvent, 0 °C, 40 h. Mes, 2,4,6-trimethylphenyl; DME, dimethoxyethane; DMA, N,N-dimethylacetamide; RT, room temperature.

Figure 3

Scope of nickel-catalyzed enantio- and diastereoselective hydroalkylation, part I. Conditions: NiCl₂·DME (10 mol %), L8 (15 mol %), 1a (0.13 mmol), 2a (0.10 mmol), (EtO)₂MeSiH (0.25 mmol), KF (0.25 mmol), and DMA/t-BuOH (0.5:0.5 mL) at 0 °C for 40 h; dr was measured by ¹⁹F NMR of the crude reaction mixture. The ee was determined using chiral HPLC analysis of the product after purification. ^a1a (0.15 mmol). PMP, 4-methoxyphenyl. Yields refer to isolated yields of the major diastereomer (>99:1) except for 3ea (isolated dr 91:9), 3ac (92:8), 3ad (98:2), 3ae (96:4), 3af (95:5), and 3ai (82:18).

Figure 4

Scope of nickel-catalyzed enantio- and diastereoselective hydroalkylation, part II. Conditions: NiCl₂·DME (10 mol %), L8 (15 mol %), 1 (0.20 mmol), 4 (0.10 mmol), (EtO)₂MeSiH (0.25 mmol), KF (0.25 mmol), and DMA/t-BuOH (0.5:0.5 mL) at 0 °C for 60 h; dr was measured by ¹⁹F NMR of the crude reaction mixture. The ee was determined using chiral HPLC analysis of the product after purification. Yields refer to isolated yields of the major diastereomer (>98:2). ^aNiCl₂·DME (15 mol %), L8 (22.5 mol %). ^bAlkyl bromide with 1 equiv of KI was used.

Figure 5

Synthesis of vicinal difluorides. Conditions: NiCl₂·DME (10 mol %), L8 (15 mol %), 1a (0.20 mmol), 2a (0.10 mmol), (EtO)₂MeSiH (0.25 mmol), KF (0.25 mmol), KI (0.10 mmol) and DMA/t-BuOH (0.5:0.5 mL) at 0 °C for 60 h. Yields refer to isolated yields of the major diastereomer (>99:1). The dr was measured by ¹⁹F NMR of the crude reaction mixture. The ee was determined using chiral HPLC analysis of the product after purification.

Figure 6

Synthetic application. (a) Functionalization of drug and natural product derivatives. (b) Synthetic elaboration of hydroalkylation products to enantioenriched organofluorine compounds of value to asymmetric synthesis. (c) Synthesis of a key intermediate in the preparation of an α-methylacyl-CoA racemase (AMACR) inhibitor. See Supporting Information for full details. ^aThe ee was determined after performing a subsequent transformation. THF, tetrahydrofuran; DMAP, 4-dimethylaminopyridine.

Figure 7

Mechanistic study. (a) An experiment using a radical scavenger TEMPO performed under the standard reaction conditions. (b) A radical clock experiment. (c) ¹⁹F NMR spectra for Z/E isomerization tracking experiments using PhCF₃ as internal standard. Amounts of the product and alkene isomers are given as equivalents per starting lactam (0.4 mmol, 1 equiv). (d) Experiment with pure (E)-1a. (e) A deuterium labeling experiment performed under the standard reaction conditions. (f) Nonlinear effect study. (g) Outline of a plausible mechanism. See Supporting Information for full details of a–f. HRMS, high-resolution mass spectrometry.