Research group of Professor Zhang Wanbin of Shanghai Jiaotong University: palladium catalyzed asymmetric hydrogenation of large sterically hindered imines to prepare large sterically hindered chiral amines

The author: Chen Jianzhong, assistant researcher of asymmetric catalytic hydrogenation, has been widely concerned because of its high efficiency, green and industrial application prospect In recent years, palladium catalyzed asymmetric hydrogenation has gradually become a research hotspot, and some excellent stereocatalytic effects have been achieved However, compared with ruthenium, rhodium and iridium, there are still obvious deficiencies Especially in the aspect of catalytic efficiency, the mass ratio (s / C) of substrate to catalyst is mostly 25-100 It is well known that the asymmetric homogeneous hydrogenation reduction reaction has been applied in industry at present, but the catalytic systems of ruthenium, rhodium and iridium are generally used, while palladium catalyzed asymmetric hydrogenation is difficult to realize its industrial application, mainly because the S / C of the reaction is low and the amount of catalyst needed is large In view of the above problems, the research group of Professor Zhang Wanbin of Shanghai Jiaotong University focused on palladium catalytic asymmetric hydrogenation At the beginning, the research group developed a series of new palladium catalytic hydrogenation systems (Tetrahedron lett 2010, 51, 2044; tetrahedron 2013, 69, 6839), which improved the stereocatalytic effect of the catalytic reaction Then, the research team started to study the catalytic efficiency of palladium catalytic hydrogenation, and used electron rich diphosphonic ligands to catalyze asymmetric hydrogenation and hydrogenolysis of arylketones (angelw Chem Int ed 2013, 52, 11632; angelw Chem Int ed 2016, 55, 8444), which greatly increased s / C to 5000 and 6000, proved the possibility of palladium catalytic hydrogenation in industrial application (Fig 1) Recently, the research group has made a breakthrough in palladium catalyzed asymmetric hydrogenation of large position imides The related research results are published in NAT Commun (DOI: 10.1038 / s41467-018-07462-w) Figure 1 Palladium catalyzed asymmetric hydrogenation and hydrogenolysis of large sterically hindered chiral amines are important intermediates widely used in the synthesis of optically active substances, functional molecules, drugs and ligands (Figure 2a) However, at present, only a few reports on the synthesis of these chiral compounds can not achieve satisfactory results For example, in 2007, the Fu team developed the catalytic asymmetric addition reaction of HN 3 with ketene (angel W chem Int ed 2007, 46, 4367) Only one large block product, phenyl tert butyl amino ester, has a enantioselectivity of 76% ee In 2009, Zhang Xumu's team reported the asymmetric hydrogenation of imine hydrochloride substrate catalyzed by iridium (j.am.chem.soc 2009, 131, 9882) The enantioselectivity of two large steric hindrances, tert BUTYLPHENYL and tert butylmethyl, was 80% ee and 17% ee, respectively Fig 2 A) chiral ligands, drugs, etc with steric steric hindrance framework; b) previous studies on asymmetric hydrogenation of small hindrance imines; c) in this paper, studies on asymmetric hydrogenation of large hindrance imines (source: Nat Commun.) in the hydrogenation of imines, most of the current studies are The asymmetric hydrogenation of small site imides, including ruthenium, rhodium, iridium, palladium and other catalysts, can achieve excellent stereocatalytic effect However, with the increase of the adjacent hindrance of imine, the catalytic effect becomes worse For example, in 1996, Charette and Giroux introduced ruthenium catalyzed asymmetric hydrogenation of imines (Tetrahedron lett 1996, 37, 6669) When the adjacent substituents of imines were from methyl to ethyl, then to isopropyl, the yield and enantioselectivity of the corresponding products showed a significant downward trend In 2006 and 2007, Zhang Xumu and Zhou Yonggui respectively reported palladium catalyzed hydrogenation of imines When the adjacent substituents of imines were from methyl to ethyl, the enantioselectivity of the corresponding products also decreased, indicating that the potential resistance of the substrate had a significant adverse effect on the reaction (Fig 2b) On this basis, the author explored the palladium catalyzed asymmetric hydrogenation of large sterically hindered imines using electron rich diphosphonic ligands and palladium complexes (Fig 2C) Firstly, the ligand (R) - dtbm segphos and Pd (ococf 3) 2 were used as catalysts to obtain complete conversion and high enantioselectivity (92.2% ee) Surprisingly, the complexation of ligand (R, R) - quinoxp * with PD (OAC) 2 also achieved complete conversion and 99.9% ee value It can be seen from the literature that PD (OAC) 2 with low toxicity has never performed well in asymmetric catalytic hydrogenation before When the hydrogen pressure drops to 1 atmospheric pressure, the same results are obtained for the complexation catalysis of (R, R) - quinoxp * and Pd (OAC) 2 at room temperature In addition, the author found that trifluoroethanol was the best solvent Under optimized conditions, all substrates can react completely (Fig 3) Firstly, we investigated the substrates with different sulfonyl substituents and different steric hindrance groups Except for the product 2c, which obtained 96% ee value, the others all obtained more than 99% ee value (2A - G) The product (2 h - W) with the EE value higher than 99% can be obtained from the aromatic ring substrate containing electron donor, electron acceptor, disubstituted, fused ring and even all alkyl skeleton Figure 3 Substrate expansion (source: Nat Commun.) in order to further expand the scope of the substrate, the author also conducted an in-depth study on the functionalized substrate (Figure 4) The functionalized substrates containing different ester groups, amides and oxygen heterogroups all obtained very good enantioselectivity (2x - AE) In particular, not only the EE value of 99.9% but also the de value of 99% were obtained for the symmetrical diimide substrate Figure 4 Further development of functionalized substrate (source: Nat Commun.), the author carried out amplification reaction When s / C reaches 5000 and 60 ATM H 2 / 60 o C / 48h, the product 2A can be obtained by 1A complete reaction, and the EE value is still above 99% 2A is further converted to compound 4 According to the method of literature, we have synthesized chiral ligand 5 and molecular motor 6 from compound 4 Some other useful chiral compounds, such as the chiral carbene ligands with large steric hindrance, leucine, CXCR2 / CXCR1 antagonists, can be synthesized from compound 4 In addition, the functionalized products 2x and 2Y can easily synthesize useful γ - or δ - lactams (8x and 8y, FIG 5) Fig 5 Application of the product (source: Nat Commun.) the author judges the absolute configuration of products 2a and 7x according to the single crystal diffraction pattern (Fig 6) 2a is s configuration and 2x is r configuration This shows that no matter whether the substrate is aryl or alkyl, palladium and hydrogen species attack from the same side Fig 6 Single crystal diffraction analysis (source: Nat Commun.) optimized (R, R) - quinoxp * - Pd (OAC) 2 catalytic system can almost all have good catalytic effect on the tested substrate, and the S / C can be as high as 5000 These results all promote the author's further Study on the reaction mechanism Based on the previous studies on palladium catalyzed asymmetric hydrogenation mechanism, the author speculated the reaction process by calculation (Fig 7) Figure 7 The energy curve of catalytic cycle (source: Nat Commun.) Figure 7 shows that the critical step (ETS (s) > ETS 2 (s)) and the enantioselective control step (ETS (s) < ETS (R)) of the reaction are both the first transition state (Figure 7) In particular, through figure 8, it can be seen that there is a significant difference in stability between the transition state TS (s) and TS (R), mainly due to the different way of complexation between catalyst and substrate When the catalyst is close to the Si surface, it can form a stable quaternion ring structure with imine When it is close to the re surface, it is difficult to form a quaternion ring with the Z-type substrate with stable spatial structure due to the hindrance of steric hindrance group, so it can only synthesize a six membered ring with sulfonyl oxygen complex The calculated values of pd-h distance (1.56 Å vs 1.69 Å) and the data of catalytic chelation dihedral angle (pd-h-c-n, 13.4o vs 74.6o) indicate that TS (s) is a more "early" transition state, which is more conducive to the migration of negative hydrogen In addition, the results show that the weak interaction between the catalyst and the substrate may be the reason for the high catalytic activity of the catalyst Figure 8 Calculation results of transition state TS (s) and TS (R) (source: Nat Commin.) to sum up, based on in-depth study and understanding of reaction mechanism, the author uses low toxic (R, R) - quinox p * - Pd (OAC) 2 catalyst system has realized the highly efficient asymmetric hydrogenation of large position imides (EE value up to 99.9%, S / C up to 5000) At the same time, a series of useful chiral materials can be prepared by simple derivatization of the products The above results also prove that palladium catalytic hydrogenation has potential in industrial application In addition, the mechanism of the reaction was discussed by calculation, and it was concluded that the coordination mode determined the chiral selection of the reaction, weak interaction promoted the activity of the catalyst, and it was predicted that the substrates with similar stable spatial conformation should have similar excellent enantioselectivity The research results were recently published in NAT Commun (DOI: 10.1038/s41467-018-07462-w) The first author of the paper is Chen Jianzhong, assistant researcher of School of chemistry and chemical engineering, Shanghai Jiaotong University, and the corresponding author is Professor Zhang Wanbin This work is supported by NSFC, Shanghai Science and Technology Commission and Shanghai Education Commission in scientific research funds Special thanks to Professor Yu Zhixiang of Peking University and Associate Professor Liu Yuanyuan of East China Normal University for their help in mechanism calculation A review of previous reports: Professor Zhang Wanbin, Shanghai Jiaotong University Research Group: synthesis of a new ferrocenylphosphine oxazoline ligand without NH group and its application in iridium catalyzed asymmetric hydrogenation of ketones Zhang Wanbin research group of Shanghai Jiaotong University: asymmetric hydrogenation of small ring β - lactam and cyclobutanone with iridium biphenylphosphine oxazoline catalyst