Chiral α-substituted propionic acids serve as crucial scaffolds in the pharmaceutical and chemical industries. They act as key intermediates in the synthesis of various biologically active compounds, including anti-inflammatory drugs like (S)-Ibuprofen and (S)-Naproxen, as well as the antimalarial drug Artemisinin (Fig. 1a). Historically, the asymmetric hydrogenation of α-substituted acrylic acids to prepare chiral α-substituted propionic acids has been dominated by catalysts based on rare and expensive metals such as rhodium, ruthenium, and iridium (Fig. 1b). Despite their effectiveness, these approaches are unsustainable due to the high cost and scarcity of these metals. Nevertheless, research on using earth-abundant metal catalysts remains inadequate in the academic and industrial contexts (Fig. 1b).^1-3

Fig.1 | Chiral α-substituted propionic acid scaffolds and their synthetic methods

  Due to the lower steric hindrance of disubstituted olefins, which complicates the control of stereoselectivity in the reaction, the majority of studies have concentrated on tri- and tetrasubstituted olefins. In recent years, it have been discovered that the multiple attractive dispersion interactions (MADI) between the catalyst and substrate significantly influence the activity and selectivity of asymmetric catalytic reactions.^4-9 Thus, we considered applying this discovery to the asymmetric hydrogenation of disubstituted substrates. Herein, we report an efficient enantioselective nickel-catalyzed hydrogenation of α-substituted acrylic acids, yielding the corresponding chiral α-substituted propionic acid products with excellent results, exemplifying green chemistry application (Fig 1b).

  We began our investigation using 2-phenylacrylic acid as the model substrate. Initial experiments utilized 1.0 mol% Ni(OAc)₂·4H₂O with the chiral ligand (R,R)-QuinoxP* under 30 bar H₂ at 50°C in 2,2,2-trifluoroethanol (TFE) for 24 hours. This setup yielded moderate conversion and enantioselectivity (70% conversion, 76% ee). Further optimization revealed that using (R,R)-BenzP*, another P-chiral ligand, significantly improved both conversion (>99%) and enantioselectivity (96%), even at a lower catalyst loading (0.2 mol%). With the optimized conditions in hand, we next evaluated the α-aryl acrylic acids (19 examples) as well as α-alkyl acrylic acids (6 examples) and found that most of the tested substrates were converted to their corresponding chiral products with good yields and excellent enantioselectivities (Fig. 2).

Fig. 2 | Selected chiral products.

  To further evaluate the activity of the catalyst and applicability of this catalytic system, the catalyst loading was first tested. To our delight, the model substrate 1a, in the presence of a much lower catalyst loading (1/10000), was reacted completely on a gram scale to give 2a in 98% yield and 96% ee (Fig. 3a). To the best of our knowledge, this result represents the highest TON (turnover number) for the Ni- catalyzed asymmetric hydrogenation of olefins reported to date. Dihydroartemisinic acid (R)-2z is the key intermediate for preparing Artemisinin, which is one of the most effective drugs for the treatment of malaria. Thus, the asymmetric hydrogenation of artemisinic acid (1z) was conducted using this catalytic system. Fortunately, 1z was reduced completely to give dihydroartemisinic acid (R)-2z with 98% yield and 99.8:0.2 dr, even at a 0.020mol% catalyst loading (S/C= 5000), indicating the potential of this methodology for industrial application (Fig. 3b).

Fig. 3 | The study of catalyst efficiency and practical applications.

  In order to explore a possible mechanism, we conducted several deuterium-labelling experiments. These experiments revealed that α- and β-H in the products mainly originate from both H₂ and the protic solvent, respectively. Next, DFT calculations showed that the hydrogenation involves the formation of a Ni-H complex, which coordinates with the substrate's C=C bond, followed by a reversible migratory insertion and a rate-determining protonolysis step from the carboxylic acid group (Fig. 4). Kinetic studies confirmed the reaction mechanism, highlighting the essential role of the carboxylic acid proton. Control experiments with acids, bases, and esterified substrates further verified this, demonstrating the necessity of the carboxylic acid group for the reaction's success. Additionally, IGMH analysis indicated that weak interactions stabilize the transition states, enhancing enantioselectivity.

Fig. 4 | Study on the catalytic mechanism.

  For more details, especially on product derivatization and further discussions of the mechanistic studies, please see our article: https://rdcu.be/dMIO2 

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