Professor Zhang Wanbin, Shanghai Jiaotong University Research Group: highly efficient asymmetric hydrogenation synthesis of chiral aryl α - glycine esters and their derivatives

Lead chiral α - glycine esters and their derivatives are widely used in the synthesis of chiral drugs, biomolecules, non protein amino acids and other active molecules (Fig 1) Therefore, how to synthesize optically pure α - glycine esters and their derivatives with high efficiency has been widely concerned by chemists Since 1980s, there have been many methods to synthesize these compounds In the past three decades, asymmetric catalytic synthesis methods have made great progress, such as asymmetric Strecker reaction, asymmetric amination and asymmetric Friedel Crafts reaction Especially asymmetric reduction is a more direct and efficient method, which has developed most rapidly, including hydrogen transfer, silanization, enantioselective l-selectride reduction, chiral substrate controlled Enantioselective hydrogenation and asymmetric hydrogenation Among them, asymmetric hydrogenation, which is the cleanest, most atom economical and most easily industrialized transition metal catalysis, is the most interesting method for the preparation of chiral α - glycine esters and their derivatives Only a few cases of asymmetric hydrogenation have been reported, which have some problems such as low reaction efficiency, expensive reagents and poor environmental friendliness, so they can not meet the requirements of industrial production Recently, Professor Zhang Wanbin's research group of Shanghai Jiaotong University has developed a highly efficient asymmetric hydrogenation of α - arylimine ester catalyzed by palladium acetate with low toxicity (org Lett 2019, 21, 9060) Figure 1 Some active molecules (source: org Lett.) containing the framework of chiral α - glycine ester and its derivatives At the same time, the research group has also worked closely with the industry to study the asymmetric catalytic synthesis and industrial application of chiral drugs, chiral perfumes and their intermediates Leading scientific research achievements: high efficiency asymmetric hydrogenation of chiral aryl α - glycine esters and their derivatives due to the special biological activities and simple and extensive derivatives of molecules containing chiral α - glycine esters and their derivatives, organic chemists have been interested in the synthesis of these compounds However, the efficiency of the methods reported in the literature is not high A series of new works of Professor Zhang Wanbin's research group in the field of asymmetric catalytic hydrogenation (chem Rev 2016, 116, 14769; chin J chem 2018, 36, 443; angelw Chem Int ed 2019, 58, 15767; angelw Chem Int ed 2019, 58, 11505; angelw Chem Int ed 2019, 58, 7329; nature commin 2018, 9, 5000; On the basis of angelw Chem Int ed 201 6, 55, 8444; angelw Chem Int ed 2015, 54, 2260; angelw Chem Int ed 2014, 53, 1901; angelw Chem Int ed 2013, 52, 11632; angelw Chem Int ed 2013, 52, 2203), using palladium acetate as catalyst, this important chiral compound was synthesized efficiently After screening a series of biphosphonic ligands and palladium salts, the researchers found that when the electron rich alkylphosphine ligand (R, R) - quinoxp * was used as the chiral catalyst, under the mild reaction conditions of 1 bar hydrogen pressure and room temperature, the product could obtain good yield (99%) and excellent enantioselectivity (97% ee) A good yield can be obtained by selecting different ester groups and imine protecting groups (Fig 2) The enantioselectivity (92-94% ee) of the product was not affected by the protecting group on ester group, while that on imine (73-94% ee) was slightly affected Fig 2 Protection group selection (source: org Lett.) the substrate used in this method is simple and easy to obtain, the substrate is widely applicable, the catalytic efficiency is good, and the synthesis efficiency of chiral α - glycine ester compounds is greatly improved (Fig 3) Excellent enantioselectivity (2 m - V, AA - ah, 83-97% ee) can be obtained by M - and p-arylimine substrates When the steric hindrance of imine and ester protecting group is reduced, the better enantioselectivity (2W - Z, 88% ee) can be obtained The catalytic effect of alkyl substrate is not good The enantioselectivity of amides was medium to good Figure 3 Substrate development (source: org Lett.) then, the research team studied the S / C of the reaction and the derivative of the product Under the condition of low catalyst dosage (s / C = 2000), hydrogen pressure of 60 OC and 60 at m, the substrate 1A can achieve complete conversion The aldose reductase inhibitor (s) - 3A can be obtained by simple hydrolysis of product (s) - 2A The enantioselectivity of the chiral amide (s) - 2ak can only be 54% if it is hydrogenated directly Similarly, histone deacetylase inhibitor precursor (s) - 4 can also be obtained by (s) - 2G hydrolysis and acylation (Fig 4) Figure 4 Derivation of chiral α - glycine esters (source: org Lett.) in a word, Zhang Wanbin group of Shanghai Jiaotong University realized high catalytic activity and enantioselective hydrogenation of α - arylimine esters under very mild conditions (1 bar hydrogen pressure and room temperature), using Pd (OAC) 2 - (R, R) - quinox p * The amount of catalyst is as low as 1 / 2000, and the product can be easily converted into active molecules This achievement was recently published in org Lett (org Lett 2019, 21, 9060) The authors of this paper are Jianzhong Chen, Feilong Li, Fang Wang, Yawen Hu, Zhenfeng Zhang, min Zhao, * and Wanbin Zhang * The above research work was supported by NSFC and Shanghai Science and Technology Commission Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.