Zhou Jian
Shanghai Molecular Therapy and New Drug Creation Engineering Technology Research Center Director of Shanghai Molecular Therapy and New Drug Creation Engineering Technology Research Center, Professor
Yu Jinsheng
Beijing time On the afternoon of October 6, 2021, Royal Swedish Academy of Sciences announced the 2021 Nobel Prize in Chemistry to fall in the Max and Prudent Coal Research Institute in Germany Benjamin Listml3 (Benjamin Listml6) and David from Princeton University in the United States Professor McMillan (David MacMillan) in recognition of their outstanding contributions to "developing asymmetric organic catalysis".
So far, all three basic methods of asymmetric catalysis have been favored by the Nobel Prize in Chemistry: metal catalysis (2001), , enzyme catalysis (2018), and organic catalysis (2021) , demonstrating the great research value and vitality in the field of efficient catalytic synthesis of chiral compounds.
What is chirality
The so-called chirality refers to the fact that matter or object cannot overlap with its mirror, just like the relationship between the left hand and the right hand. Chirality is a basic property of nature, from nebula, planetary rotation, and typhoon vortex to small climbing plants, snail shells, and microscopic molecules such as amino acid and carbohydrate molecules, all of which are chiral.
However, it was recognized that a pair of enantiomers of chiral compounds may exhibit distinct properties in organisms, after the drug disaster "response stop" event - a drug called "thalidomide" designed to alleviate pregnancy responses in pregnant women, resulting in the birth of about 20,000 short-limb deformities children with harbor seals. The "thalidomide" drug with chiral carbon is taken in the form of racemates (a mixture of equal amounts of levo and dexteralisomers), but the dexteralisomers can sedate, while the levoisomers are strongly teratogenic.
This painful incident made people realize that although the molecular formula and atomic connection method are the same, the different spatial arrangement positions of atoms will lead to differences in pharmacological activity, toxicity and metabolic processes in organisms . This is because the basic substances such as nucleic acids, proteins, , and sugars that make up living organisms are chiral. They form a chiral environment in the living organisms, and chiral drug molecules must be chirally matched with the targeted molecules in the living organisms to cause effective pharmacological reactions.
After decades of research, people have found that 2/3 of the commonly used drugs in clinical practice are chiral, and chiral drugs and their enantiomers may have the same or similar pharmacological activities, or they may have low or inactive enantiomers, and even the pharmacological activities of the two are different, such as "reaction stop" molecules. Therefore, since , the US Food and Drug Administration, , required that all chiral new drugs marketed in the United States, conduct pharmacological and toxicity experiments on left- or dextro isomers respectively, and my country has also required this since 2006. In addition, chiral pesticides, fragrances or food additives also have chiral requirements. For example, the activity of the widely used herbicide isopropyl chloride is mainly contributed by the isomers of the S-configuration; the sweetener aspartame used in coffee and cold drinks has a sweetness of about 200 times that of sucrose, but its enantiomer is bitter.
The culprit of the "reaction stop" event, a pair of enantiomers of the thalidomide molecule,
, can improve efficacy and reduce side effects using a single chiral drug. Even if the enantiomer is harmless but has low activity, the use of single chiral drugs can achieve efficacy at lower doses, thereby reducing metabolic burden.
The use of chiral pesticides can also reduce the amount and number of applications and reduce the impact on the environment.For example, after the above-mentioned herbicide was applied with chiral drugs instead of racemates since 1997, the usage volume was reduced by 40%, which was equivalent to reducing the emission of more than 8,000 tons of chemical substances to the environment every year.
Asymmetric catalysis of chiral synthesis
As chiral substances become more and more widely used in medicine, pesticides, fragrances, materials and information, it is undoubtedly very important to synthesize single chiral molecules in cost-effectively and efficiently.
Initially, people tried to isolate chiral compounds from natural products, but the types of chiral compounds that can be directly obtained from nature are limited, and the content is often not high. Take the anti-cancer star molecule paclitaxel as an example. Only 1 gram of paclitaxel can be extracted from 1 ton of yew bark. Conventional synthesis methods can only obtain a pair of enantiomeric molecules at the same time, and effective isomers are required to obtain through chiral resolution. This will result in half of the product being wasted and consume a lot of energy, manpower and material resources during the separation process, and generate a lot of waste. Therefore, chiral synthesis methods must be developed to obtain chiral compounds.
People have successively developed methods such as natural product conversion and chiral synthesis involving chiral raw materials, but these methods can only obtain a chiral product from one chiral raw material, which is difficult to meet the growing demand for chiral compounds. Therefore, how to achieve chiral proliferation of , that is, obtaining tens or hundreds or even millions of chiral products with high optical purity from a chiral catalyst, has become one of the core research contents of synthetic chemistry. The study of is called asymmetric catalysis. It has flourished in the past half century and has successfully developed three strategies: metal catalysis, enzyme catalysis and organic small molecule catalysis.
Metal Catalysis refers to the use of chiral metal catalyst formed by ligands and metals to catalyze the reaction enantioselectively. Usually, the metal of the catalyst provides the reaction site, while chiral ligands create a chiral induction environment. This is the research idea pioneered by Dr. Knowles, a Monsanto company in the United States, in the 1960s, which subsequently flourished and has been widely used in industrial production. Some efficient methods such as asymmetric hydrogenation can achieve the use of a chiral metal catalyst to produce millions of chiral products. To this end, Knowles shared the 2001 Nobel Prize in Chemistry with Professor Noyori from Nagoya University in Japan, who made outstanding contributions in this field, and Professor Sharpless from from the Scripps Institute in the United States.
enzyme catalyzed has also been widely used due to its high efficiency and specificity, and has formed a multidisciplinary research field such as organic chemistry, biochemistry and microbiology . In particular, the engineering enzymes obtained through directional evolution will play a greater role in asymmetric catalysis due to their advantages such as higher activity, higher thermal stability and better stereoselectivity. Professor Arnold from California Institute of Technology also won the 2018 Nobel Prize in Chemistry for his pioneering contribution to "directed evolution of enzymes." The progress of asymmetric organic catalysis
organic small molecules catalyzing , that is, using organic small molecule compounds instead of metals to catalyze the reaction. It can be traced back to 1894 Knoevenagel used ethylenediamine to promote the condensation reaction of formaldehyde and malonic acid ester. The earliest attempt to verify asymmetric organic catalysis was to use natural products of alkaloids to catalyze the preparation of chiral carboxylic acids in 1904. Although
has been tried one after another, early exploration did not achieve ideal results. It was not until the early 1970s that the first successful asymmetric organic catalytic reaction was independently reported by several researchers from Roche and Schering. They found that simple proline can catalyze intramolecular asymmetric aldehyde reactions with important applications under mild conditions, achieving up to 93% enantiomer excess values (ee). Although the study demonstrates many advantages of organic catalysis, blind spots in thinking lead to the belief that the method is limited to intramolecular reactions and is therefore not given enough attention. In the following 20 years, only in 1984, the Merck research team developed the highlight of chiral phase transfer catalysis.
Since 1996, the research on asymmetric organic catalysis has ushered in a small climax and entered a stage where a new catalytic model and catalytic system is blooming. Some landmark achievements are introduced in chronological order as follows:
Hong Kong University Professor Yang Dan (currently working at West Lake University ) and Professor Shi Yian, who was at Colorado State University in the United States, developed chiral ketone catalysis, and Professor MIT Fu (Fu) developed chiral ketone catalysis The nucleophilic catalysis of pyridine derivatives has also been reported in , professor Zhang Xumu, , who is currently working at the University of Pennsylvania, in the United States, professor Zhang Xumu, who is currently working at the Southern University of Science and Technology, professor Zhang 3, professor Zhang 3 of Harvard University, has pioneered chiral hydrogen bond donor catalysis, and professor Deng Li, who is currently working at the University of West Lake, , who is currently working at the University of West Lake, has expanded the bifunctional catalysis of cinchonaline.
These original research is refreshing and demonstrates the potential of organic catalysis from different angles, such as the spark of stars igniting the dawn of hope for organic catalysis in the early 21st century.
entered the millennium, and two young professors, Liszt and McMillan, research on chiral amine catalysis, emerged.
Professor Lister, who was also the leader of the Scripps Institute at the time, collaborated with Professor Lerner (Lerner) and Professor Barbas III to achieve proline-catalyzed intermolecular aldehyde reactions of highly enantioselective acetone and aldehydes. This highly selective "intermolecular" reaction that is difficult to achieve under mild conditions, subverts the previous misunderstanding that amino acid catalysis is limited to intramolecular reactions and lays the foundation for modern asymmetric enamine catalysis.
Almost at the same time, the McMillan research team of the University of California, Berkeley reported that the use of chiral secondary amines to activate conjugated endal and conjugated diene to undergo [4+2] cycloaddition reaction, and high stereoselective construction of six-membered ring compounds. This study set a precedent for the catalysis of modern asymmetric imine , and the key is to use chiral amines to in-site activation of conjugated enal (ketone) to form unsaturated imine positive ion with higher electrophilicity.
asymmetric catalysis three times won the Nobel Prize in Chemistry
asymmetric organic catalysis development event
published two award-winning work one after another. shows that chiral amines can be used as enamine catalysts and imine catalysts to develop new asymmetric catalytic reactions, and the reaction conditions are relatively mild and easy to operate. , coupled with the characteristics of chiral amines that are usually easy to prepare and preserve, immediately attracted many research groups around the world to join the track of chiral amine catalysis research - using chiral amine catalysts of various structures to develop new reactions to synthesize chiral aldehydes or ketones, because these chiral products have important application value in the synthesis of natural products, drugs and fine chemicals.
chiral amine catalysis has another unique charm, the two modes of enamine catalysis and imine catalysis can also be converted to each other under certain conditions, complementing each other to form . The same chiral amine catalyst can perform the art of "face change" according to the reaction design, and repeatedly perform enamine catalysis or imine catalysis, so that multiple reactions can be modularly combined to achieve the synthesis of complex multichiral molecules from the "one-pot method" starting from simple raw materials. Professor Lister once summarized and introduced this characteristic by "yin and yang catalyzed by asymmetric amines". The breakthrough progress of chiral amine catalysis in
has triggered the explosive development of organic catalysis research, promoting the continuous emergence of new catalytic systems and strategies. An important development in
is the chiral phosphonic acid catalysis developed simultaneously in 2004 by Professor Akiyama of Japan University of Learning and Professor Terada of Tohoku University , opening up a new field of chiral protonic acid catalysis.
In addition, two Nobel Prize winners further enriched chiral amine catalysis.
For example, Professor McMillan proposed the concept of organic relay catalysis, developed the single-electron-occupying orbital (SOMO) catalysis of chiral amines, and combined chiral amine catalysis and photocatalysis to achieve reactions that cannot be solved by single catalysis.Professor Lister combined chiral phosphoric acid catalysis to expand the scope of enamine and imine catalysis, and then developed a new synthesis strategy of asymmetric counter-anion catalysis, as well as designed and developed a chiral strong acid system with stronger acidity, which increased the efficiency of organic catalysis to a new level.
To this day, organic small molecule catalysis has established its position as a three-legged stamina with metal catalysis and enzyme catalysis, and has demonstrated some unique advantages:
has rich activation modes, and can choose different activation modes to design new reactions according to the characteristics of the substrate; catalyst can often be easily prepared from optically pure natural raw materials, and is insensitive to air and water, and is easy to store and use; the effect between
catalyst and substrate can be achieved through covalent bond , ions on or hydrogen bonding, and has strong chiral control ability;
has good compatibility, which helps to achieve synthesis problems that cannot be solved by single catalysis through synergistic catalysis;
does not need to worry about the contamination of heavy metal ions on products, etc. These advantages are very attractive for drug development.
Asymmetric Catalysis Future
Asymmetric Catalysis Research Again won the Nobel Prize seems to indicate that the research on chiral synthesis is relatively mature. In fact, this area is not the case. There are still many problems worth exploring in depth. According to the high standards pointed out by Professor Ryoji Noi, the 2001 Nobel Prize winner:
"The future synthetic chemistry must be economical, safe, environmentally friendly and resource-saving chemistry. Chemists need to work hard to achieve 'perfect reaction chemistry', that is, to generate only the required products with 100% selectivity and 100% yield without waste." Most of the existing asymmetric catalytic methods still have a lot of room for improvement in the efficiency of most of the existing asymmetric catalytic methods. Whether you seek the answer to the unsolved mystery of "the origin of chirality" or develop the "ideal" asymmetric catalytic synthesis method to provide various chiral substances to meet the needs of life and development, you still need to search up and down.
It is worth mentioning that my country's organic chemists have been working hard since the 1980s and have been catching up in the field of asymmetric catalysis. At present, the gap with the international top level has been greatly narrowed. A number of dominant chiral ligands and catalysts that are well-known at home and abroad, represented by Zhou's chiral spirocyclic ligands and Feng's chiral binitrooxygen ligands have been designed and developed, and a series of new high-efficiency asymmetric catalytic methods represented by Roskamp-Feng reactions have been realized.
At present, my country has formed a gradient and reasonable vitality research team dominated by young and middle-aged backbones, and is committed to developing chiral technologies with independent intellectual property rights to serve the national strategic needs of new drug research and development, ecological security, high-tech materials, etc.
Chinese scientific researchers will definitely make due contributions to achieving the "precision" and "practical" of asymmetric catalysis and to solve the national strategic needs of "bottlenecks".
-This article is selected from the 1st issue of "Home • Frontiers of Science and Technology" column of " World Science " magazine, 2022 -
Press
Recommended
Read
Read
Quantum simulation, insight into the world︱Homehm html ︱ l4
Jiangfan : Pay attention to early childhood development and get rid of poverty from the root︱Home
Photonic chip Research progress and prospects︱Home
Silk hard disk: Synchronous storage of digital information and biological information︱Home
Human brain mystery: a new continent to be explored︱Home
Huilijian: liver regeneration and research paradigm conversion︱Home
END
For example, after the above-mentioned herbicide was applied with chiral drugs instead of racemates since 1997, the usage volume was reduced by 40%, which was equivalent to reducing the emission of more than 8,000 tons of chemical substances to the environment every year.Asymmetric catalysis of chiral synthesis
As chiral substances become more and more widely used in medicine, pesticides, fragrances, materials and information, it is undoubtedly very important to synthesize single chiral molecules in cost-effectively and efficiently.
Initially, people tried to isolate chiral compounds from natural products, but the types of chiral compounds that can be directly obtained from nature are limited, and the content is often not high. Take the anti-cancer star molecule paclitaxel as an example. Only 1 gram of paclitaxel can be extracted from 1 ton of yew bark. Conventional synthesis methods can only obtain a pair of enantiomeric molecules at the same time, and effective isomers are required to obtain through chiral resolution. This will result in half of the product being wasted and consume a lot of energy, manpower and material resources during the separation process, and generate a lot of waste. Therefore, chiral synthesis methods must be developed to obtain chiral compounds.
People have successively developed methods such as natural product conversion and chiral synthesis involving chiral raw materials, but these methods can only obtain a chiral product from one chiral raw material, which is difficult to meet the growing demand for chiral compounds. Therefore, how to achieve chiral proliferation of , that is, obtaining tens or hundreds or even millions of chiral products with high optical purity from a chiral catalyst, has become one of the core research contents of synthetic chemistry. The study of is called asymmetric catalysis. It has flourished in the past half century and has successfully developed three strategies: metal catalysis, enzyme catalysis and organic small molecule catalysis.
Metal Catalysis refers to the use of chiral metal catalyst formed by ligands and metals to catalyze the reaction enantioselectively. Usually, the metal of the catalyst provides the reaction site, while chiral ligands create a chiral induction environment. This is the research idea pioneered by Dr. Knowles, a Monsanto company in the United States, in the 1960s, which subsequently flourished and has been widely used in industrial production. Some efficient methods such as asymmetric hydrogenation can achieve the use of a chiral metal catalyst to produce millions of chiral products. To this end, Knowles shared the 2001 Nobel Prize in Chemistry with Professor Noyori from Nagoya University in Japan, who made outstanding contributions in this field, and Professor Sharpless from from the Scripps Institute in the United States.
enzyme catalyzed has also been widely used due to its high efficiency and specificity, and has formed a multidisciplinary research field such as organic chemistry, biochemistry and microbiology . In particular, the engineering enzymes obtained through directional evolution will play a greater role in asymmetric catalysis due to their advantages such as higher activity, higher thermal stability and better stereoselectivity. Professor Arnold from California Institute of Technology also won the 2018 Nobel Prize in Chemistry for his pioneering contribution to "directed evolution of enzymes." The progress of asymmetric organic catalysis
organic small molecules catalyzing , that is, using organic small molecule compounds instead of metals to catalyze the reaction. It can be traced back to 1894 Knoevenagel used ethylenediamine to promote the condensation reaction of formaldehyde and malonic acid ester. The earliest attempt to verify asymmetric organic catalysis was to use natural products of alkaloids to catalyze the preparation of chiral carboxylic acids in 1904. Although
has been tried one after another, early exploration did not achieve ideal results. It was not until the early 1970s that the first successful asymmetric organic catalytic reaction was independently reported by several researchers from Roche and Schering. They found that simple proline can catalyze intramolecular asymmetric aldehyde reactions with important applications under mild conditions, achieving up to 93% enantiomer excess values (ee). Although the study demonstrates many advantages of organic catalysis, blind spots in thinking lead to the belief that the method is limited to intramolecular reactions and is therefore not given enough attention. In the following 20 years, only in 1984, the Merck research team developed the highlight of chiral phase transfer catalysis.
Since 1996, the research on asymmetric organic catalysis has ushered in a small climax and entered a stage where a new catalytic model and catalytic system is blooming. Some landmark achievements are introduced in chronological order as follows:
Hong Kong University Professor Yang Dan (currently working at West Lake University ) and Professor Shi Yian, who was at Colorado State University in the United States, developed chiral ketone catalysis, and Professor MIT Fu (Fu) developed chiral ketone catalysis The nucleophilic catalysis of pyridine derivatives has also been reported in , professor Zhang Xumu, , who is currently working at the University of Pennsylvania, in the United States, professor Zhang Xumu, who is currently working at the Southern University of Science and Technology, professor Zhang 3, professor Zhang 3 of Harvard University, has pioneered chiral hydrogen bond donor catalysis, and professor Deng Li, who is currently working at the University of West Lake, , who is currently working at the University of West Lake, has expanded the bifunctional catalysis of cinchonaline.
These original research is refreshing and demonstrates the potential of organic catalysis from different angles, such as the spark of stars igniting the dawn of hope for organic catalysis in the early 21st century.
entered the millennium, and two young professors, Liszt and McMillan, research on chiral amine catalysis, emerged.
Professor Lister, who was also the leader of the Scripps Institute at the time, collaborated with Professor Lerner (Lerner) and Professor Barbas III to achieve proline-catalyzed intermolecular aldehyde reactions of highly enantioselective acetone and aldehydes. This highly selective "intermolecular" reaction that is difficult to achieve under mild conditions, subverts the previous misunderstanding that amino acid catalysis is limited to intramolecular reactions and lays the foundation for modern asymmetric enamine catalysis.
Almost at the same time, the McMillan research team of the University of California, Berkeley reported that the use of chiral secondary amines to activate conjugated endal and conjugated diene to undergo [4+2] cycloaddition reaction, and high stereoselective construction of six-membered ring compounds. This study set a precedent for the catalysis of modern asymmetric imine , and the key is to use chiral amines to in-site activation of conjugated enal (ketone) to form unsaturated imine positive ion with higher electrophilicity.
asymmetric catalysis three times won the Nobel Prize in Chemistry
asymmetric organic catalysis development event
published two award-winning work one after another. shows that chiral amines can be used as enamine catalysts and imine catalysts to develop new asymmetric catalytic reactions, and the reaction conditions are relatively mild and easy to operate. , coupled with the characteristics of chiral amines that are usually easy to prepare and preserve, immediately attracted many research groups around the world to join the track of chiral amine catalysis research - using chiral amine catalysts of various structures to develop new reactions to synthesize chiral aldehydes or ketones, because these chiral products have important application value in the synthesis of natural products, drugs and fine chemicals.
chiral amine catalysis has another unique charm, the two modes of enamine catalysis and imine catalysis can also be converted to each other under certain conditions, complementing each other to form . The same chiral amine catalyst can perform the art of "face change" according to the reaction design, and repeatedly perform enamine catalysis or imine catalysis, so that multiple reactions can be modularly combined to achieve the synthesis of complex multichiral molecules from the "one-pot method" starting from simple raw materials. Professor Lister once summarized and introduced this characteristic by "yin and yang catalyzed by asymmetric amines". The breakthrough progress of chiral amine catalysis in
has triggered the explosive development of organic catalysis research, promoting the continuous emergence of new catalytic systems and strategies. An important development in
is the chiral phosphonic acid catalysis developed simultaneously in 2004 by Professor Akiyama of Japan University of Learning and Professor Terada of Tohoku University , opening up a new field of chiral protonic acid catalysis.
In addition, two Nobel Prize winners further enriched chiral amine catalysis.
For example, Professor McMillan proposed the concept of organic relay catalysis, developed the single-electron-occupying orbital (SOMO) catalysis of chiral amines, and combined chiral amine catalysis and photocatalysis to achieve reactions that cannot be solved by single catalysis.Professor Lister combined chiral phosphoric acid catalysis to expand the scope of enamine and imine catalysis, and then developed a new synthesis strategy of asymmetric counter-anion catalysis, as well as designed and developed a chiral strong acid system with stronger acidity, which increased the efficiency of organic catalysis to a new level.
To this day, organic small molecule catalysis has established its position as a three-legged stamina with metal catalysis and enzyme catalysis, and has demonstrated some unique advantages:
has rich activation modes, and can choose different activation modes to design new reactions according to the characteristics of the substrate; catalyst can often be easily prepared from optically pure natural raw materials, and is insensitive to air and water, and is easy to store and use; the effect between
catalyst and substrate can be achieved through covalent bond , ions on or hydrogen bonding, and has strong chiral control ability;
has good compatibility, which helps to achieve synthesis problems that cannot be solved by single catalysis through synergistic catalysis;
does not need to worry about the contamination of heavy metal ions on products, etc. These advantages are very attractive for drug development.
Asymmetric Catalysis Future
Asymmetric Catalysis Research Again won the Nobel Prize seems to indicate that the research on chiral synthesis is relatively mature. In fact, this area is not the case. There are still many problems worth exploring in depth. According to the high standards pointed out by Professor Ryoji Noi, the 2001 Nobel Prize winner:
"The future synthetic chemistry must be economical, safe, environmentally friendly and resource-saving chemistry. Chemists need to work hard to achieve 'perfect reaction chemistry', that is, to generate only the required products with 100% selectivity and 100% yield without waste." Most of the existing asymmetric catalytic methods still have a lot of room for improvement in the efficiency of most of the existing asymmetric catalytic methods. Whether you seek the answer to the unsolved mystery of "the origin of chirality" or develop the "ideal" asymmetric catalytic synthesis method to provide various chiral substances to meet the needs of life and development, you still need to search up and down.
It is worth mentioning that my country's organic chemists have been working hard since the 1980s and have been catching up in the field of asymmetric catalysis. At present, the gap with the international top level has been greatly narrowed. A number of dominant chiral ligands and catalysts that are well-known at home and abroad, represented by Zhou's chiral spirocyclic ligands and Feng's chiral binitrooxygen ligands have been designed and developed, and a series of new high-efficiency asymmetric catalytic methods represented by Roskamp-Feng reactions have been realized.
At present, my country has formed a gradient and reasonable vitality research team dominated by young and middle-aged backbones, and is committed to developing chiral technologies with independent intellectual property rights to serve the national strategic needs of new drug research and development, ecological security, high-tech materials, etc.
Chinese scientific researchers will definitely make due contributions to achieving the "precision" and "practical" of asymmetric catalysis and to solve the national strategic needs of "bottlenecks".
-This article is selected from the 1st issue of "Home • Frontiers of Science and Technology" column of " World Science " magazine, 2022 -
Press
Recommended
Read
Read
Quantum simulation, insight into the world︱Homehm html ︱ l4
Jiangfan : Pay attention to early childhood development and get rid of poverty from the root︱Home
Photonic chip Research progress and prospects︱Home
Silk hard disk: Synchronous storage of digital information and biological information︱Home
Human brain mystery: a new continent to be explored︱Home
Huilijian: liver regeneration and research paradigm conversion︱Home
END
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-