Cobalt-catalyzed highly enantioselective hydrogenation of α,β-unsaturated carboxylic acids

Asymmetric hydrogenation of α,β-unsaturated acids catalyzed by noble metals has been well established, whereas, the asymmetric hydrogenation with earth-abundant-metal was rarely reported. Here, we describe a cobalt-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acids. By using chiral cobalt catalyst bearing electron-donating diphosphine ligand, high activity (up to 1860 TON) and excellent enantioselectivity (up to >99% ee) are observed. Furthermore, the cobalt-catalyzed asymmetric hydrogenation is successfully applied to a broad spectrum of α,β-unsaturated carboxylic acids, such as various α-aryl and α-alkyl cinnamic acid derivatives, α-oxy-functionalized α,β-unsaturated acids, α-substituted acrylic acids and heterocyclic α,β-unsaturated acids (30 examples). The synthetic utility of the protocol is highlighted by the synthesis of key intermediates for chiral drugs (6 cases). Preliminary mechanistic studies reveal that the carboxy group may be involved in the control of the reactivity and enantioselectivity through an interaction with the metal centre.


Asymmetric hydrogenation of α-substituted acrylic acids Method C (for 3a-i).
In an argon-filled glovebox, CoCl2 (0.025 M in THF, 0.2 mL, 0.005 mmol) and (S,S)-Ph-BPE (2.53 mg, 0.005 mmol) in HFIP (0.2 mL) were stirred in a vial at room temperature for 10 min. Then zinc dust (0.65 mg, 0.01 mmol) and HFIP (0.2 mL) were added and the mixture was stirred for 15 min. After that, substrate (0.1 mmol) was added to the reaction mixture. The vial was subsequently transferred into an autoclave and purged by three cycles of pressurization/venting with H2. The reaction was then stirred under H2 (60 atm) at 50 o C for 48 h. The hydrogen gas was released slowly and carefully. The resulting solution was concentrated in vacuum and the residue was purified by chromatography on silica gel. The ee values were determined by HPLC with a chiral column.

Details of applications
Procedure for asymmetric hydrogenation of 1v.

Supplementary Note 1 Control experiments
To provide insight into the possible catalyst activation mode and the mechanism of the asymmetric hydrogenation of α,β-unsaturated carboxylic acids, several control and catalytic experiments were conducted. Only starting material was observed suggesting that no reaction occurred for the corresponding ethyl ester 1b' under standard conditions. Moreover, no hydrogenation product was observed when 1 mol% of CH3COOH or 1b was added to the reaction mixture as external carboxylic acid.  (1) In an argon-filled glovebox, Co(acac)2 (1.3 mg, 0.005 mmol), (S,S)-Ph-BPE (2.53 mg, 0.005 mmol) and THF (1 mL) were stirred in a vial at room temperature for 10 min.

Supplementary
The reaction mixture (0.2 mL) and THF (0.2 mL) were added to a quartz tube. The quartz tube was then glassed in liquid helium and subjected to X-band EPR analysis (Supplementary Figure 9).
(2) In an argon-filled glovebox, Co(acac)2 (1.3 mg, 0.005 mmol), (S,S)-Ph-BPE (2.53 mg, 0.005 mmol) and toluene (1 mL) were stirred in a vial at room temperature for 10 min. After that, 1b (1.6 mg, 0.01 mmol) was added to the reaction mixture and stirred for 10 min. The reaction mixture (0.2 mL) and toluene (0.2 mL) were added to a quartz tube. The quartz tube was then glassed in liquid nitrogen and subjected to X-band EPR analysis (Supplementary Figure 10). were added and the mixture was stirred for 15 min. After that, 1b (0.1 mmol) was added to the reaction mixture. The vial was subsequently transferred into an autoclave and purged by three cycles of pressurization/venting with H2. The reaction was then stirred under H2 (40 atm) at room temperature for 30 min. The gas was released slowly and carefully. The solvent was removed under vacuum and the autoclave was then transformed to glovebox. The residue was dissolved in toluene (1 mL) and filtrated through celite to remove the Zn. After that the filtrate (0.2 mL) and toluene (0.2 mL) were added to a quartz tube. The quartz tube was then glassed in liquid nitrogen and subjected to X-band EPR analysis (Supplementary Figure 11). (4) In an argon-filled glovebox, Co(acac)2 (0.050 M in iPrOH, 0.10 mL, 0.005 mmol) and (S,S)-Ph-BPE (0.050 M in THF, 0.10 mL, 0.005 mmol) were stirred in a vial at room temperature for 10 min. After that, 1b (0.1 mmol) was added to the reaction mixture. The vial was subsequently transferred into an autoclave and purged by three cycles of pressurization/venting with H2. The reaction was then stirred under H2 (60 atm) at 50 o C for 30 min. The gas was released slowly and carefully. The solvent was removed under vacuum and the autoclave was then transformed to glovebox. The residue was dissolved in toluene (1 mL). The solution (0.2 mL) and toluene (0.2 mL) were added to a quartz tube. The quartz tube was then glassed in liquid nitrogen and subjected to X-band EPR analysis (Supplementary Figure 12). were stirred in a vial at room temperature for 10 min. The reaction mixture (0.2 mL) and THF (0.2 mL) were added to a quartz tube. The quartz tube was then glassed in liquid helium and subjected to X-band EPR analysis (Supplementary Figure 13).
The EPR spectrum of Co(acac)2, Co(acac)2+BPE and Co(acac)2+BPE+substrate were recorded, and the EPR signal changed greatly after the addition of BPE and the substrate. The spectrum of Co(acac)2+BPE+substrate [Co(BPE)(O2CR)2] was very similar to that of BPE+Cobalt(II)(2-ethylhexanoate)2, indicating that coordination of BPE to Co(acac)2 and substitution of acac by the substrate probably happened. The reaction mixture in the presence of H2 after 30 min was also monitored with EPR, and the EPR spectra were very similar to that of [Co(BPE)(O2CR)2], indicating that the formation of Co(BPE)(O2CR)2 species during hydrogenation reaction and which was probably an off-cycle resting state in the current reaction.