Overview of Professor Zhang Xumu's work in recent years at Southern University of Science and Technology

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Introduction of Professor Zhang Xumu

Born in October 1961 in Ezhou, Hubei Province, Professor Zhang Xumu received his bachelor's degree from Wuhan University in 1982, his master's degree from the Fujian Institute of Material Structure of the Chinese Academy of Sciences in 1985 under the tutelage of Academician Lu Jiaxi, and his master's degree from the University of California, San Diego in 1987 under the tutelage of Professor Gerhard N. Schauzer He received his Ph.D. from Stanford University in 1992 under the tutelage of Professor James P. Collman, an academician of the National Academy of Sciences; postdoctoral research at Stanford University from 1992 to 1994; taught at Pennsylvania State University from 1994 to 2006 and received tenured professorships; from 2007 to 2015, he was a Distinguished Chair Professor at the College of Chemistry at the State University of New Jersey; and from 2015 to 2018, He is the chair professor and head of the Department of Chemistry of Southern University of Science and Technology, the vice dean of the School of Science of Southern University of Science and Technology from 2018 to the present, the dean of the Institute of Biomedicine of Southern University of Science and Technology from 2019 to the present, and the dean of the Pingshan Institute of Biomedicine of Southern University of Science and Technology from 2020 to the present.

Professor Xumu Zhang at Science, Nat. Chem., J. Am. Chem. Soc., Angew. Chem. and other academic journals published more than 400 academic papers, he cited more than 15>,000 papers, of which he cited 1700 times> in a single paper, H index 72, for many years in the world's well-known publisher Elsevier released by the highly cited scientists, into the United States Stanford University released the 2020 "world's top 2% of scientists" list. Professor Zhang xumu received the American Chemical Society's Cope Scholar Award in 2002, and was the first scientist born Chinese mainland to receive this award. Professor Zhang Xumu's Zhang enyne cycloisomerization reaction, developed by Professor Zhang Xumu, has become a personal name reaction named after his surname because of its importance, and only a few Chinese people in the world currently have this honor. Professor Zhang Xumu was awarded the title of the first "Deep Scholar of the Times" in Shenzhen in 2016 for the establishment of the Chinese mainland first research institution named after the Nobel Prize winner, the Shenzhen Grubbs Research Institute.

Professor Zhang Xumu has long been committed to the development of efficient and highly selective asymmetric catalytic reactions, using his original chiral ligand toolbox as a technology platform, with major drugs as a breakthrough in industrialization, and developing a new process of green synthesis of drugs with independent intellectual property rights, safety, environmental protection, low cost and high quality. Professor Zhang Xumu has established Chiral Quest (Suzhou) (technology products) and Catalis (technology platform). Founded in 2008, Kerrystar has put into production more than 20 new process routes with an annual output of more than 5 tons, producing hundreds of tons of pharmaceutical intermediates and APIs every year, affecting the drug demand of hundreds of millions of patients around the world. Founded in 2015, Catliss (Shenzhen) Technology Co., Ltd. officially launched the project research and development in 2018, and has made a major breakthrough in the new process route of more than 10 kinds of large varieties of drugs such as Yizhi Maibu, Menglust, Benforin, Shakubiqu and so on.

Professor Zhang Xumu's team

Professor Zhang Xumu has more than 20 years of research experience in the field of asymmetric hydrogenation and chiral phosphine ligand research, and has achieved fruitful research results. Professor Zhang Xumu is an authoritative expert in the field of phosphorus chemistry in the world, and has been invited to give lectures at the 16th and 17th International Phosphorus Chemistry Conferences for two consecutive times (Birmingham, UK; 2007, Xiamen, China). The chiral toolbox developed by Professor Zhang Xumu is widely used in asymmetric hydrogenation, asymmetric hydroformylation and other fields, and has a wide international influence in the field of asymmetric catalysis, among which DuanPhos, Binapine, TangPhos, TunePhos and other ligands are widely used internationally.

Figure 1. A chiral toolbox developed by Zhang Xumu's team

1. Development and application of rigid, electronic-rich chiral biphosphine ligands

Professor Zhang Xumu has done a lot of pioneering work in the synthesis and application of chiral ligands, and has developed a series of rigid, electron-rich trialkyl bisphosphine ligands, such as TangPhos, DuanPhos, Binapine, etc. for asymmetric hydrogenation of rhodium metals. This class of electron-rich phosphine ligands can accelerate the oxidation addition of monovalent Rh to hydrogen and improve reactivity (Figure 1.2). At the same time, the strong anti-neutral effect can reduce product inhibition and increase the number of conversions. Due to the rigidity of the ligand, it can give good stereoselectivity. The above several properties make this class of ligands into ultra-practical ligands in rhodium metal asymmetric hydrogenation, which are widely used in the industrial production of Careysdale Biochemical (Suzhou) Co., Ltd., in which the metal complexes of multiple ligands have become commercially available high-efficiency metal catalysts, which can be purchased from the reagent company Strem or Aldrich (Fig. 1.3) (Acc. Chem. Res. 2020, 53, 1905–1921; Acc. Chem. Res. 2007, 40, 1278-1290; Chem. Rev. 2003, 103, 3029-3069; Chin. J. Chem. 2020, 38, 954-968)。

Figure 1.1 Structure and chiral induction model of TangPhos

Figure 1.2 Representative rigid, electron-rich biphosphine ligand developed by Zhang Xumu's team

Figure 1.3 Commercially available chiral catalyst developed by Zhang Xumu's team

2. Development and application of ultra-efficient chiral multi-tooth ligand based on ferrocene skeleton

In the 1990s, Professor Zhang Xumu was the first in the world to apply chiral trident ligands to simple ketone asymmetric (transfer) hydrogenation. In 1998, the first development of the three-tooth ligand ambox showed excellent enantioselective control in asymmetric transfer hydrogenation and asymmetric transfer hydrogenation. Since 2016, using inexpensive Ugiamine as chiral raw materials, a series of easy-to-synthesize, structure-adjustable chiral trident ligands such as f-amphox, f-amphol, f-ampha, f-amphamide, etc. have been developed, which have super high catalytic efficiency (TON: 1,000,000) and enantioselectivity (>99% ee) in the asymmetric hydrogenation of carbonyl compounds. The introduction of the phosphine majorosotric ferrocene skeleton not only improves the activity and selectivity of the ligand, but also makes the ligand more stable and easier to modify.

Figure 2.1 Design model of chiral three-tooth ligand ambox

Compared with Noyori's catalytic system, the three-tooth ligand developed by Zhang Xumu's team has the following characteristics: (1) the iridium catalyst formed is abnormally stable; (2) it has ultra-high reactivity; and (3) coordination saturation effectively prevents the inhibition of the product. In addition, the tridential ligand has better tolerance for alkalis, has higher catalytic efficiency, and has a wider range of substrate applications.

Fig. 2.2 Three-tooth ligand design concept and comparison of catalytic efficiency of ambox and f-amphox

Chiral trident ligands based on iron dibrene skeleton exhibited ultra-high catalytic efficiency and very wide substrate universality in the asymmetric hydrogenation of iridium-catalyzed ketones (Figure 2.3). At present, the chiral three-tooth ligand f-phamidol has achieved kilogram-scale production and has been successfully applied to the efficient synthesis of key intermediates of various major drugs such as ezezermebu, benfol, montelukast and so on.

Figure 2.3 A series of three-tooth ligands based on ferrocene developed by Zhang Xumu's research group and their applications

3. Development of a new chiral biphosphonic ligand based on the strategy of "non-covalent bond interaction"

The development of transition metal-catalyzed asymmetric reactions is highly dependent on the development of chiral ligands, in order to further improve the enantioselectivity and reactivity of asymmetric catalytic reactions, it is of great significance to develop more efficient and practical chiral phosphine ligands that are easy to synthesize and air stable. Non-covalent bond interactions play an important role in the design of catalysts, stabilizing the transition state of the reaction, reducing the degrees of freedom in the transition state, and reducing the activation energy of the reaction. Representative non-covalent bond interactions include spatial repulsion, hydrogen bond and ion pair interactions, of which hydrogen bond and ion pairs interact strongly. Based on the "non-covalent bond interaction" strategy, Zhang Xumu's research team introduced hydrogen bond and ion pair interaction into chiral biphosphine ligands to develop a new and efficient chiral biphosphine ligand. Chem. This part of the work is described in detail on Res. (Acc. Chem. Res. 2020, 53, 1905-1921)。

3.1 Based on the "hydrogen bond interaction" strategy, a bifunctional organic-metal-catalyzed chiral bisphosphine-(thio)urea ligand was developed

Metal catalysis and organic catalysis have been hugely successful over the past few decades, but there are still many reactions that are difficult to achieve using organic catalysis alone or metal catalysis. Combining organic catalysis and metal catalysis to solve the challenges of a single catalyst is one of the hot research areas. There are often incompatibilities between catalysts, substrates, intermediates, etc. between the organic and metal dual catalytic modes. Therefore, it is very necessary to develop a new asymmetric catalytic strategy, combine organic catalysis and metal catalysis into the same molecule, develop a new type of organic-metal catalyst with dual functions, on the one hand, use the organic catalytic unit to activate the substrate and chiral induction, on the other hand, multi-activate the substrate through the metal catalytic unit, and efficiently realize some reactions that are difficult to catalyze with only organic catalysis or metal catalysis, providing a powerful way to achieve challenging new reactions.

Based on this, Zhang Xumu's research team used the "hydrogen bond interaction" strategy to develop the new organic-metal bifunctional bisphos-thiourea ligand ZhaoPhos (Figure 3.1), which contains the chiral biphosphonic ligand skeleton in metal catalysis and the thiourea skeleton in organic catalysis, which has several advantages: the synthetic raw material is inexpensive, bifunctional activation, the structure is easy to modify, the air is stable, and can be synthesized on a large scale.

Figure 3.1 Development of bifunctional chiral bisphosphine-thiourea ZhaoPhos ligand based on organo-metal catalytic strategy

Based on the "hydrogen bond interaction" strategy, the bifunctional chiral biphosphine-thiourea ZhaoPhos ligand has excellent performance, and Zhang Xumu's research team uses the thiourea skeleton of the ligand as a hydrogen bond donor, and forms a hydrogen bond with the nitro, amide and other groups on the substrate as hydrogen bond receptors, which plays an activating substrate and good chiral induction, and efficiently realizes a series of rhodium-catalyzed asymmetric hydrogenation reactions (more than 20 categories). The team successfully developed the first asymmetric hydrogenation of maleimide based on transition metal-bisphosphonium ligand catalysis and hydrogen bond interaction of thiourea groups, under mild conditions, multiple 3-substituted maleimides can achieve asymmetric hydrogenation with high yield and high ee values, while the reactivity is also greatly improved under the activation of thiourea groups, and the TON can reach up to 2 000 (Figure 3.1). Nuclear magnetic titration experiments and control experiments verified the hydrogen bond interaction between ligands and substrate carbonyl groups. After the publication of the research results (ACS Catal., 2016, 6, 6214), the internationally renowned review journal Synfacts presented the highlights of the research work (Synfacts, 2016, 12, 1170).

In addition, Zhang Xumu's research team successfully applied the "hydrogen bond interaction" strategy to the asymmetric hydrogenation of β-nitroenamide, and the thiourea skeleton on ZhaoPhos formed a hydrogen bond with the nitro group on the substrate to activate the substrate, thereby improving the activity and stereoselectivity of the reaction, and the easily reduced nitro group was retained, and a series of highly optically active chiral β-nitroamine compounds (up to 96% ee, 96% yield) were constructed, and the research results (Org. Lett., 2016, 18, 40) published, the internationally renowned review magazine Synnfacts presented the research work (Synfacts, 2016, 12, 378).

Fig. 3.2 Application of zhaophos, a functional organic-metal-catalyzed chiral bisphos-(thi)urea ligand

3.2 Develop a novel chiral biphosphonic ligand based on the strategy of "non-covalent bonded ion pair interaction"

By increasing the secondary action group in the chiral ligand, the interaction between the ligand and the substrate is enhanced, and a non-enantiomeric transition state in the reaction transition state is selectively stabilized, and the chiral control ability and reaction activity of the catalyst are improved. Based on the activation strategy of non-covalent bond ions on secondary effects, Zhang Xumu's research team designed and synthesized a new type of ferrocene chiral biphosphine ligand containing secondary groups (Figure 3.3), using inexpensive and readily available chiral Ugi's amine as the starting material to introduce chiral phosphine groups on the iron diocene skeleton, and the amino-NMe2 on the ligand can form a non-covalent bond ion pair secondary interaction with the substrate, which plays a role in activating the substrate and improving the stereoselectivity of the reaction. This type of ligand has a front-handed and central chirality, a large steric hindrance group on the non-chiral phosphine and a ferrocene skeleton occupy three quadrants, and a small steric hindrance substituent on the chiral phosphine makes the fourth quadrant open, providing a good chiral induction environment.

Fig. 3.3 Novel bisphosphino ligands containing secondary groups and their quadrant structures

Zhang Xumu's team used a secondary group-containing ferrocene chiral biphosphonic biphosphonic ligand to achieve an asymmetric hydrogenation reaction of Rh-catalyzed 2-substitute acrylic acid, and the secondary group of the ligand- NMe2 interacted with the carboxyl group on the substrate to form a non-covalent bond ion pair, the reaction conditions were mild, no additional alkali was required, and up to 99% ee and > were obtained 99% conversion rate, TON up to 20,000 (Figure 3.4). Based on the single crystal structure of the product and the ligand, a transition state model of the 3D reaction was established, and it was found that the phenyl group on the substrate occupied the fourth quadrant of the open state, and there was a small repulsion effect with the catalyst, and it was conducive to the formation of non-covalent bond ion pair secondary interaction, thereby obtaining the carboxylic acid product of the (S) configuration. This model further illustrates that the non-covalent bond ion pair secondary interaction between the catalyst and the substrate and the three quadrants of the ligand are occupied to facilitate the provision of good chiral induction effects. The job (Chem. Sci., 2016, 7, 6669) has received widespread attention from international peers and has been positively evaluated by the international journal Synfacts (Synfacts, 2016, 12, 931).

Fig. 3.4 2-Asymmetric hydrogenation of substituted acrylic compounds

4. Asymmetric reduction amination catalyzed by transition metals

Chiral amine structures are widely present in natural products and drug molecules. In particular, chiral amines have been increasingly used in new drugs developed in the past 20 years (Figure 4.1). Not only that, in the design, synthesis and development of new chiral drugs, pesticides and daily chemicals, chiral amine skeleton is also one of the most examined and used types. In addition, chiral amines are also widely used in organic synthesis, especially in chiral amine ligand synthesis, and as an organic small molecule catalyst. Because of its importance, the development of efficient, highly selective and economical strategies to construct chiral amines has attracted great attention from chemists.

Figure 4.1 Representative drug molecule containing chiral amine structure

In 2018, Zhang Xumu's research group used inorganic ammonia salts as amine sources, c3*-TunePhos complexes of ruthenium as catalysts, and hydrogen as reducing agents to achieve asymmetric reduction amination of simple aryl ketones, through which chiral primary amine products can be efficiently synthesized (Figure 4.2). This reaction has very important application value and has been successfully applied to the asymmetric synthesis of key intermediates of the major drug Sinacasse (J. Am. Chem. Soc. 2018, 140, 2024-2027), the research work was selected as a highlight for review by the journal Synfacts (Synfacts 2018, 14, 0504).

Fig. 4.2 Ruthenium-catalyzed asymmetric transfer of alkyl aryl ketones to hydrogenation to synthesize primary amines

In the same year, Zhang Xumu's research group also realized the dynamic kinetics of cyclic β-ketoamide by splitting asymmetric reduction amination, which can synthesize chiral primary amine products with up to 98% yield and 99% ee values, which can be synthesized into key intermediates of many drugs after simple transformation (Figure 4.3), which has very good practical value (Angew. Chem. Int. Ed., 2018, 57, 14193-14197)。

Fig. 4.3 Dynamic kinetics of ruthenium-catalyzed β-ketoamide by splitting asymmetric reduction amination

5. Design, synthesis and application of chiral oxygen heterospiper ring ligands

Due to its structural rigidity and stability, spiral ring ligands have received more and more attention from organic synthetic chemists. In particular, the research work of Zhou Qilin's research group of Nankai University has pushed the development of spiral ring ligands to a climax, so that chiral spiral ring ligands have developed into a widely used advantageous structural ligand in just a few decades. The most representative chiral ligand in Zhou Qilin's research group is SpiraPAP, and the iridium complex of this ligand can obtain up to 99.9% enantioselectivity and 4,550,000 TONS in the asymmetric hydrogenation of simple ketons, creating the highest record for TON in the field of asymmetric hydrogenation (Angew. Chem. Int. Ed., 2011, 50, 7329-7332)。

However, the spiral ring ligand also has shortcomings such as a single skeleton structure. In order to overcome the above problems, in 2018, Zhang Xumu's research group efficiently synthesized a new oxygen heterospirondiol skeleton O-SPINOL with the dual aromatic nucleophilic substitution within the molecule as the key step, and synthesized O-SpiroPAP ligand with O-SPINOL as the starting material, which showed excellent reactivity and enantioselectivity in the dynamic kinetic separation asymmetric reduction of Bringmann lactone (Fig. 5.1) (J. Am. Chem. Soc. 2018, 140, 8064-8068), the research work was selected as a highlight by the journal Synfacts for review (Synfacts 2018, 14, 1050).

Fig. 5.1 Synthesis of oxalocylene ligands and their application in The Reduction of Bringmann Lactone.

In addition, the O-spinol-based bisphosphonic ligand O-SDP exhibits excellent reactivity and selectivity in asymmetric hydrogenation of α, β-unsaturated carboxylic acid. In addition, the ruthenium complex of this ligand can be used in the asymmetric synthesis of the major drug shakupid, which has very important application value (Fig. 5.2) (CCS Chem., 2020, 2, 468-477).

Fig. 5.2 Application of the oxygen heterospironiocyclic ligand O-SDP in asymmetric hydrogenation of unsaturated carboxylic acids

6. Rhodium-catalyzed asymmetric oleyne ring isomerization (tensionene ring isomerization reaction)

As early as 2000, Zhang Xumu's research group found that 1,6-enene substrates can obtain pentasyneous heterocyclic rings or carbocyclic compounds with very high regional selectivity under the action of rhodium-bisphosphine ligand catalysts, which is the first case of rhodium-catalyzed 1,6-enocyne ring isomerization reaction (Angew. Chem. Int. Ed. 2000, 39, 4104-4106)。 Subsequent studies have found that the use of BINAP as a chiral ligand can obtain a very high enantioselectivity, and the reaction has a very wide range of substrate applications, in 2016, Zhang Xumu's team successfully extended the substrate application range of the reaction from cis double bond substrate to the more common trans double bond substrate.

Fig. 6.1 The first rhodium-catalyzed asymmetric ring isomerization reaction of 1,6-enone

In March 2014, Professor Zhang Xumu's research result "Cyclic Isomerization Of Ene", was named "Zhang enyne cycloisomerization". The results have been included in the international authoritative work of chemistry, Name Reactions, becoming one of the few human name reactions named after Chinese (Figure 6.2).

Fig. 6.2 Heteromerization reaction of the zhangenyne ring and its mechanism

"Tension alkyne ring isomerization reaction" has a wide range of applicability and practicality, the use of this reaction can be convenient to achieve asymmetric cyclization of olefins and alkyne molecules, efficient construction of a series of five-membered heterocyclic compounds, in the synthesis of bioactive molecules and drug molecules have important applications. For example, the world-renowned organic chemist Professor Nicolaou used the personal name reaction developed by Professor Zhang Xumu to achieve the total synthesis of the complex active molecule plated mycin (J. Am. Chem. Soc. 2009, 131, 16905-16918)。 Zhang Xumu's team also used this synthesis method to achieve efficient asymmetric synthesis of Kainic acid (Chem. Commun. 2018, 54, 727-730)。

Fig. 6.3 Efficient synthesis of prostaglandin compounds

In 2021, Zhang Xumu's team once again made important progress in the field of enocyne ring isomerization, with the asymmetric hydrogenation of enones catalyzed by the three-tooth ligand iridium complex and the "isomerization of the alkenyl ring" developed by the research group as the key steps to achieve a series of prostaglandins and related drugs of concise and efficient asymmetric total synthesis, shortening the synthesis step to 6 steps, greatly improving the synthesis efficiency, and achieving 20 grams of synthetic fluprostol (fluprostenol), the relevant research results published in Nat. Chem.on (Nat. Chem. 2021, 13, 692-697)。 Prostaglandins are a class of hormones with extensive biological activity, with very good druggability, at present, there are more than 20 prostaglandins listed drugs worldwide. The research results have greatly improved the synthesis efficiency of prostaglandin compounds, which is of great significance for the study of prostaglandin-related drugs (Figure 6.3).

7. Rhodium-catalyzed asymmetric hydroformylation

Hydroformylation is an important reaction to the efficient synthesis of aldehyde compounds from olefins and syngas. Because aldehyde compounds have extremely important applications in industrial synthesis, hydroformylation reactions have been widely studied by academia and industry, and have developed into one of the largest homogeneous catalytic reactions in industry today. According to statistics, the global production capacity of aldehydes and alcohols through hydroformylation has reached a scale of tens of millions of tons. In contrast, the development of asymmetric hydroformylation reactions using chiral catalysts to synthesize chiral aldehydes is relatively slow, and there are no industrial applications reported. Chiral ligands have a significant impact on the activity, chemical selectivity and enantioselectivity of asymmetric hydroformylation reactions, and the types of chiral ligands that can be applied to asymmetric hydroformylation reactions are very limited, and the development of new chiral ligands is the most challenging problem in this field, and nearly half of the chiral ligands in this field are developed by Zhang Xumu's research team (Figure 7.1).

Figure 7.1 Chiral ligand applied to asymmetric hydroformylation reactions

YanPhos developed by Prof. Zhang Xumu is one of the most widely used chiral ligands in asymmetric hydroformylation reactions, showing excellent reactivity and enantioselectivity in asymmetric hydroformylation reactions of multiple substrate types: (1) YanPhos exhibits excellent reactivity and enantioselectivity in the desymmetric asymmetric hydroformylation reactions of 4-substitute cyclopentene substrates (up to 96% yield, up to > 99:1 dr, up to 97% ee; Angew. Chem. Int. Ed., 2016, 55, 6511-6514)。 (2) YanPhos exhibited excellent regional selectivity and enantioselectivity in asymmetric hydroformylation reactions of 1,2-disubstituted silicon olefins (up to 98% yield, up to >99:1 dr and up to 97% ee; Nat. Commun. 2018, 9, 2045)。 (3) YanPhos exhibited excellent regional selectivity and enantioselectivity in asymmetric hydroformylation reactions of challenging substrates 1,1-dihydropedic olefins (J. Am. Chem. Soc, 2018, 140, 4977-4981)。

Figure 7.2 Application of YanPhos in asymmetric hydroformylation of cyclopentene and silicon olefins

Fig. 7.3 Rh/(S,S)-DTB-YanPhos catalyzed non-functional grouping of 1,1-disubstituted olefin asymmetric hydroformylation