Science: let cobalt have rhodium properties - Asymmetric Hydrogenation of enamide catalyzed by cobalt

Asymmetric catalytic synthesis of single enantiomers has been widely used in medicine, fine chemicals and other industries Because of the different biological properties of chiral isomers, FDA has strict requirements for chiral drugs The asymmetric hydrogenation of olefins catalyzed by transition metals can be used to prepare chiral pure pharmaceutical active ingredients (API), which is undoubtedly an exciting thing for the field of organic synthesis and medicine Rhodium and iridium, as common noble metal catalysts, play an important role in olefin hydrogenation However, the developed metal catalysts, such as iron, cobalt, nickel, which are rich in reserves, are still difficult to compare with precious metal catalysts in performance They are sensitive to air and humidity, and are not resistant to the functional groups in many drug molecules, so they are not suitable for industrial application Asymmetric hydrogenation usually depends on the stereochemical information transfer between chiral ligands and substrates, so it is very important to understand and control the coordination and dissociation equilibrium of ligands to maintain the stability of catalysts The performance of classical transition metal catalysts is greatly influenced by the dissociation equilibrium of phosphine and the coordination of halides, such as (pH 3P) 3RhCl and (pH 3P) 3rucl2 (Fig 1a and C) These problems can be solved by the generation of open ligands through the auxiliary hydrogenation of weakly coordinated anions, dienes or triene ligands, such as Schrock Osborn type catalysts and cationic ruthenium catalysts [(P-P) Ru (H) (triene)] [BF 4] (Fig 1b and D) (source: Science) in 2013, Professor Paul J chirik of Princeton University developed a co catalyst with C 2-Symmetric (BIS) phosphine ligands, which can be used for the efficient asymmetric hydrogenation of simple dehydrogenation - α - amino acid derivatives (Fig 1E) The mechanism shows that cobalt dihydrogen (II) is an active species promoting olefin insertion (Science, 2013, 342, 1076) The disadvantage of these catalysts is that they need to use the flammable lich2sime3 as the activator, and they are sensitive to air Recently, the research team and Dr Michael shevlin of Merck Research Laboratory in the United States developed a simple trick to make cobalt more like rhodium They combined with zinc methanol activation system to realize the asymmetric hydrogenation of olefins catalyzed by cobalt (Science, 2018, 360, 888) Firstly, the effects of solvent, cobalt source, activator, temperature and catalyst on the dehydrogenation of levetiracetam (1) were investigated by high throughput screening The experimental results show that the reaction has a significant solvent dependence: methanol, ethanol and trifluoroethanol can significantly improve the yield and EE value of the reaction The above experimental results show that the active species cobalt (II) dihydrogen can be formed in proton solvent On this basis, the author proposes a new activation strategy: adding reductant to the reaction system to reduce the high valence cobalt, and then providing the active species of cobalt dihydrogen through the oxidation addition of cobalt (0) by H 2 Therefore, some mild reducing agents, including zinc, manganese, magnesium and iron powder, were investigated The results show that the highest yield and EE value can be obtained by adding zinc powder into the reaction system It is confirmed that the reductive cobalt species which can activate H 2 is produced in the reaction system with methanol as the medium Subsequently, 216 chiral bidentate ligands were screened by using CoCl2 and zinc powder as activators and methanol as solvent The results show that the number of effective ligands in the activation system is significantly higher than that of the previously reported organic lithium activation methods (Fig 2a and b) Among these ligands, r-bpe and r-duphos can obtain excellent reaction results at very low catalyst loading (0.20 mol%) (Fig 2C) (source: Science) on the other hand, phosphine dissociation is a reversible reaction leading to deactivation of catalyst The author found that methanol can replace the phosphine ligands in cobalt (II) and lead to the dissociation of phosphine (Fig 3a), while the zinc methanol method can reduce cobalt (II) to low-cost cobalt, thus reducing the possibility of phosphine replacement by methanol and obtaining a more stable catalytic system In addition to cobalt (I), cobalt (0) complexes can also be prepared by two successive single electron reduction In order to prove the catalytic performance of cobalt (I) and cobalt (0), the catalytic hydrogenation of compound 1 was carried out by using 3A and 4A respectively without zinc (Fig 3b) Under the action of 50 ℃, 500 psi H 2 and 0.5 mol% 3a, 1 was transformed into levetiracetam in 99.9% yield and 98.2% ee value, while under the action of 4A and 55 psi H 2, 1 was transformed into levetiracetam in 99.1% yield and 97.5% ee value This further shows that substrate 1 can induce the disproportionation of cobalt (I) to produce cobalt (II) and cobalt (0), which can enter the catalytic cycle with H2 (source: Science) in order to verify the practicability of the zinc methanol method, the author carried out a hydrogenation reaction of up to 200g scale, and obtained levetiracetam (Fig 4) with 97% separation yield and 98.2% ee value This result shows that cobalt can also be used in the industrial synthesis of single enantiomers in environmentally friendly solvents These findings show the advantages of the first transition metal in catalytic hydrogenation (source: Science) conclusion: Professor Paul J chirik of Princeton University and Dr Michael shevlin of Merck Research Laboratory in the United States have jointly developed a new method for asymmetric hydrogenation of olefins using the rich metal cobalt combined with zinc methanol activation system In this strategy, the unstable cobalt (II) complex was reduced to more stable cobalt (I) by adding zinc powder into the reaction system in the presence of protonic solvent methanol This method can achieve high yield and high enantioselectivity of olefin catalytic hydrogenation under very low catalyst loading, and is compatible with a wide range of bidentate ligands Using this method, the author has achieved 200 g scale-up reaction under 0.08 mole% catalyst loading, which proves its practicability.