At 5:45 p.m. Beijing time on October 6, the 2021 Nobel Prize in Chemistry was awarded to German scientist Benjamin List and American scientist David W.C. MacMillan for their contributions to the "development of asymmetric organic catalysis."
Figure | Benjamin List and David W.C. MacMillan (Source: Nobel Prize)
<h1 class="pgc-h-arrow-right" Data-track="5" asymmetric organic catalysis >: an ingenious tool for constructing molecules</h1>
The capabilities of molecules have long been used in many fields, which either make up resilient and durable materials, store energy in batteries, or inhibit disease progression, but all with catalysts.
We learned in junior high school that catalysts can control and accelerate chemical reactions, but they won't be part of the final product, such as cars using catalysts to convert toxic substances in exhaust gases into harmless molecules, and the human body contains thousands of catalysts in the form of enzymes. It can be said that catalysts are the basic tools of chemists. Scientists have long believed that in principle there are only two types of catalysts: metals and enzymes.
(Source: Official website of the Nobel Prize Committee)
At the beginning of this century, Liszt and McMillan each independently developed a third form of catalysis: "asymmetric organic catalysis" built on small organic molecules. Johan Åqvist, chairman of the Nobel Committee on Chemistry, also said: "This catalytic concept is both simple and ingenious, and in fact many people feel why we didn't think about it earlier. ”
Talking about the "past and present lives" of organic catalysis, Zeng Jie, a professor at the University of Science and Technology of China, told DeepTech that carbon has built a huge organic chemical system for the organic compounds of the skeleton, and the existence of various types of isomers has made the family of organic compounds more huge.
For sp3 hybrid carbon atoms with tetrahedral configurations, when four different groups are connected, an intrinsic asymmetry is acquired—chirality—and the corresponding chiral isomers are like our left and right hands, which are spatially symmetrical but completely unable to coincide.
In many natural molecules, there are often multiple chiral carbon atoms. But in reality, researchers need isomers with specific functions, but there may be only one, and how to control the synthesis of chiral compounds has become a huge challenge.
For example, strychnine contains only 6 chiral carbon atoms, but in the first work to synthesize it, it underwent 29 steps and a yield of only 0.0009%.
Therefore, scientists are constantly developing new methods to optimize and improve the yield of chiral compounds. The related field, asymmetric hydrogenation/oxidation reactions, also won the Nobel Prize in 2001, which is also a milestone in the development of asymmetric synthesis.
For traditional catalysis, scientists generally believe that highly active catalysts are only present in metal-based and enzyme-based systems. Although scientists have successfully synthesized many products with metal-based catalysts in many reactions, the high selectivity and high efficiency of the enzyme catalytic system have also given scientists new guidance ideas, can the active part of the enzyme be reduced to small molecules?
Thus was born a new field, the asymmetric synthesis of small organic molecules. Scientists initially set their sights on small organic molecules at the center of metals, but in 2001, two important reports injected new life into the field of organic small molecule catalysis.
Lister et al. reported asymmetric Aldol reactions mediated by proline transenylamine intermediates; MacMillan reported asymmetric Diels-Aldol reactions mediated by secondary amines mediated by imino positive ion intermediates.
These two reports on metal-free small molecule catalysts became the first in the field, and researchers slowly realized that this catalytic system has advantages that traditional metal-organic catalysts do not have: insensitive to humid environments, easy to obtain originals, low cost, easy to preserve, and low toxicity.
Based on the work of enylamines and imine positive ions, scientists have also developed various synthesis methods and theories to synthesize new compounds. Behind these brilliant academic achievements, there is the founding role of Liszt and MacMillan with advanced research vision.
In fact, "transition metal-catalyzed organic synthesis reactions have been widely used in the development of drug molecules, and the problem of transition metal residues has always been a pain point in the pharmaceutical industry." Inspired by enzyme catalysis, in 2000, Liszt and McMillan independently developed two catalytic systems, Enamine Catalysis and Iminium Catalysis, using proline and chiral imidazole as catalysts, respectively, establishing the concept of 'organic catalysis' and enabling a variety of asymmetric conversion reactions. With the development of asymmetric organic catalysis, the efficiency of organic catalysts is also getting higher and higher, and in many ways it can be fully comparable to transition metal catalysts. Wang Hao, an assistant researcher at Nankai University's School of Chemistry, told DeepTech.
Benjamin List and Hao Wang (Source: Interviewee)
Lu Zhan, a professor in the Department of Chemistry at Zhejiang University, also said that the reason why the two winners won the Nobel Prize was because the catalyst did not have metals, but instead let the organic small molecules use as catalysts. The metal residue in the drug molecule is a large hidden danger, and the use of small organic molecules for catalytic reactions does not require the use of metals, so there is no problem of metal residues.
The exquisiteness mentioned in the award speech corresponds to the concept of continuous catalysis. Specifically, it can be used with a single molecule to continuously produce chirality. In nature, chiral phenomena are widespread, like the left and right hands of people, which are generally difficult to identify. At this time, a catalyst can be used to identify the left hand and right hand very well, and the recognition efficiency is very high.
Drug molecules on the precious metal residue control is more stringent, before people use precious metals as catalysis, and finally make drugs, to continue to test. If the precious metal content does not reach a certain range, then the drug will not be sold, so the subsequent purification process often has to pay a great price.
The advantage of small molecules is that the whole process does not use metal at all, so there is no problem of metal residue, which is the main reason for the award speech.
<h1 class="pgc-h-arrow-right" data-track="97" > the third catalyst after metals and enzymes</h1>
In fact, as early as the postdoctoral period, Liszt had studied catalytic antibodies and began to think seriously about how enzymes actually worked. Typically, enzymes are huge molecules made up of hundreds of amino acids, most of which contain metals that help drive chemical processes in addition to amino acids. However, some enzymes can catalyze chemical reactions without the need for metals.
Figure | Benjamin List
To this end, Liszt began to think, since metals are not necessary for catalytic processes, does the catalytic reaction really need a structurally intact enzyme? Is it possible that many kinds of amino acids are not needed, and one or several amino acids alone are enough to make up enzymes?
In fact, as early as the early 1970s, there were attempts to use an amino acid called proline as a catalyst. On this basis, Lister conducted research and tested whether proline could catalyze the hydroxyaldehyde reaction. He had thought that this simple experiment would not yield any results, but the results were unexpected. He also used this to prove that proline is an effective catalyst, and that proline can drive asymmetric catalysis.
He immediately realized that proline, although a small organic molecule, had great potential and that it had advantages that metals and enzymes could not match: simple structure, low cost, and environmental protection. It can be said that it is the tool that chemists dream of. "Continuing to design and search for catalysts of this type will be one of our goals for the future," he said.
At the same time, McMillan was thinking about how to solve the many inconveniences of catalysts in industrial applications, during which he discovered organic catalysis. At the time, he felt that the metal catalyst was too sensitive, so it was very inconvenient to use. Moreover, the production of most metal catalysts must be in anaerobic and anhydrous conditions, which is both cumbersome and uneconomical for large-scale industrial production.
Figure | David W.C. MacMillan
So McMillan began to wonder, is there a simpler catalyst? He also thought of organic molecules, which have the advantage of being simple in structure, less costly, and easy to design. The organic molecules that form ammonite ions first came to mind, and he selected several of them and tested their ability to catalyze Diels-Alder reactions. It was found that organic molecules not only have the ability to catalyze, but also some organic molecules have the ability to asymmetrically catalyze.
In fact, before that, there were other successful cases of using organic molecules to catalyze chemical reactions, but previous scholars did not study organic catalysis as a separate category of catalysts. McMillan realized this and named the new catalyst organocatalysis.
Wang Hao also said that the catalytic concept of the two winners is mainly based on ketone or aldehyde compounds, and amine compounds formed by dehydration and condensation of imines, and imine is not only an unstable compound, but also easy to obtain aldehydes or ketones through hydrolysis, which is the ingenuity of chemical reactions - the regulation of chemical balance.
Therefore, in order to achieve asymmetric catalytic conversion through imine intermediates, it is only necessary to replace one of the components with a substance containing chirality. Based on this idea, Liszt and McMillan used proline and chiral imidazole as catalysts in 2000 to achieve an asymmetrical Aldol reaction and an asymmetric Diels-Alder reaction, which is also known as "enylamine catalysis".
It is also worth mentioning that in 2018, Zhao Baoguo, a professor at the School of Chemistry and Materials Science of Shanghai Normal University, also proposed another concept of "carbonyl catalysis" for the first time.
Since 2000, organic catalysis has evolved at an astonishing rate. Liszt and McMillan remain leaders in the field to this day, demonstrating that organic catalysts can be used to drive multiple chemical reactions. With these reactions, researchers can build many things more efficiently, from novel drugs to molecules that capture light in solar cells. It can be said that organic catalysts are greatly benefiting mankind.
<h1 class="pgc-h-arrow-right" data-track="98" > Chemistry Nobel Prize return to pure chemistry, and the industry is very excited</h1>
Xu Jianhe, a professor of biochemistry at East China University of Science and Technology, told DeepTech that catalysts have three main directions: metal catalysis, biocatalysis and organic catalysis. Metal catalysis won the Nobel Prize in 2001, biocatalysis won the Nobel Prize in 2018, and asymmetric catalysis won the Nobel Prize in 2021. In his opinion, although organic catalysis is very popular, he did not expect to win the award so quickly.
Lu Zhan believes that it is not surprising that the award was given to the two winners, and the reaction of the organic small molecules made by these two winners belongs to pure chemistry. In recent years, the Nobel Prize in Chemistry has been awarded to scientists in the field of partial biology. This time it is equivalent to a pure return to organic chemistry, and he said that he is also more excited as an industry insider.
The total prize for the Nobel Prize for Chemistry is 10 million Swedish kronor (about 7.3 million yuan). Traditionally, the award ceremony will take place on December 10, 2021, the anniversary of the death of the award's founder, Alfred Nobel.
Lu Zhan said that the field of asymmetric organic catalysis has also accompanied the Nobel Prize for many years. The two of them proposed the concept of organic small molecule catalysis earlier, which is representative.
In 2001, the nobel laureate of chemistry at the time was awarded for metal catalytic asymmetry. Today, 20 years later, the winner's results do not use metal, which is also a very good complement to the awards of the year.
At the same time, the students trained by Nobel laureates are also taking root in various fields. Over the past three years, Dong Zhe has studied in The MacMillan research group. Today, he has returned to China and is working as an associate professor in the Department of Chemistry at Southern University of Science and Technology.
He told DeepTech: "Professor McMillan's deepest influence on me was the choice of topic. His choice of topic is basically the most novel topic and the most practical topic. Once he feels that this project is worth doing, no matter how difficult the subject is, he will always stick to it. My project was to change 7-8 different research groups before and tried it for three or four years. His high requirements and high standards for the subject made me gradually sink my heart in the group, and slowly polished and improved the subject. This process gave me a new understanding of the process of scientific research. I also benefited greatly from his high standards and high demands on scientific writing and expression during his writing. ”