On the afternoon of October 6, Beijing time, the 2021 Nobel Prize in Chemistry was announced. Benjamin List and David W.C. MacMillan were awarded the 2021 Nobel Prize in Chemistry for "developments in asymmetric organic catalysis."
Benjamin List was born in 1968 in Frankfurt, Germany. He received his Ph.D. from the University of Frankfurt in 1997. He is currently a researcher at the Max Planck Coal Research Institute in Germany.
David S. W· David W.C. MacMillan was born in 1968 in Bearshill, England. He received his Ph.D. from the University of California, Irvine in 1996. He is currently a professor at Princeton University.
An ingenious tool for constructing molecules
Constructing molecules is a difficult art. Benjamin List and David MacMillan were awarded the 2021 Nobel Prize in Chemistry for developing a new tool for precise molecular construction—organic catalysis. This has had a huge impact on drug research and has made chemistry more environmentally friendly.
Many fields of research and industry rely on the ability of chemists to construct molecules that can form elastic and durable materials that store energy in batteries or inhibit the progression of disease. This work requires catalysts, which are substances that control and accelerate chemical reactions, rather than becoming part of the final product. For example, catalysts in cars convert toxic substances in exhaust gases into harmless molecules. Our bodies also contain catalysts in the form of thousands of enzymes that chisel out molecules necessary for life.
Thus, catalysts are the basic tools of chemists, but researchers have long believed that in principle there are only two catalysts: metals and enzymes. Benjamin Liszt and David Macmillan were awarded the 2021 Nobel Prize in Chemistry for each of them independently developing a third catalysis in 2000. It is called asymmetric organic catalysis and is built on small organic molecules.
Johan Åqvist, chairman of the Nobel Committee on Chemistry, said: "The concept of catalysis is both simple and ingenious, in fact, many people wonder why we did not think of it earlier."
Organic catalysts have a stable framework of carbon atoms on which more active chemical groups can attach. They usually contain common elements such as oxygen, nitrogen, sulfur or phosphorus. This means that these catalysts are both environmentally friendly and cheap.
The rapid expansion of the use of organic catalysts is mainly due to their ability to drive asymmetric catalysis. When molecules form, there are usually two different cases of molecular formation, just like our hands, mirroring each other. Chemists usually only need one of these, especially when it comes to producing pharmaceuticals
Since 2000, organic catalysis has evolved at an astonishing rate. Benjamin List and David MacMillan remain leaders in this field, and they have demonstrated that organic catalysts can be used to drive large numbers of chemical reactions. Using these reactions, researchers can now construct anything more efficiently, from new drugs to molecules that can capture light in solar cells. In this way, organic catalysts bring the greatest benefits to humans.
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Experimental study of the chiral origin of biomolecules : Asymmetric autocatalysis
Wang wei
introduction
I have a college classmate who does organic synthesis and is studying for a Ph.D. at the University of Science and Technology of China. Once, somehow, he talked to him about the origin of chirality, and he expressed great interest in it, but to the many hypotheses I mentioned about the chiral origin of biomolecules (that is, the ones I mentioned in my previous blog post), he said that he did not understand these physical factors very well, but as a student of organic chemistry, his first reaction was asymmetric catalysis, because only asymmetric catalysis could achieve high asymmetric excesses of enantiomers. He sent me several List and Macmillian articles about asymmetric catalysis that night. It was also at that time that I began to slowly understand this knowledge.
Asymmetric catalysis
As early as the 1930s, there were reports of metal loading on silk and then catalytic hydrogenation to synthesize products with certain optical activity, but no progress has been made for a considerable period of time since then. Until 1968, Monsanto's Knowles of the United States used chiral lin ligands and complexes formed by rhodium metal as catalysts, and invented the asymmetric catalytic hydrogenation reaction for the first time in the world. Although the results were not perfect at the time, and the results were only published in cc, it was this original work that pioneered the homogeneous asymmetric catalytic synthesis of chiral molecules. In the early 1970s, Knowles used asymmetric hydrogenation methods at Monsanto to realize the chiral drug L-Dopa for the treatment of Parkinson's disease. This not only became the world's first example of chiral synthesis industrialization, but more importantly, it became a banner for asymmetric catalytic synthesis of chiral molecules, which greatly promoted the development of this research field. Since then, Japan's Ryoji Noyori (when I was in graduate school, the main teacher of Bioorganic Chemistry spent 2 hours to introduce this person's work, it is said that this person is extremely diligent, known as the "immortal bird" in Japan) has made creative development of this work, invented the ligand molecule represented by chiral biphosphine BINAP, and formed a series of novel and efficient chiral catalysts by matching with suitable metals for asymmetric catalytic hydrogenation reactions, obtaining up to 100% The stereoselectivity, as well as the activity of the reactants to the catalyst is as high as hundreds of thousands, realize the high efficiency and practicality of asymmetric catalytic synthesis, and improve the asymmetric catalytic hydrogenation reaction to a very high degree.
In addition, Sharpless developed an asymmetric catalytic oxidation reaction from another side. As early as the early 1980s, the asymmetric epoxidation reaction of olefins was realized by using the complexes of diethyl tartrate (DET) and Ti (OPri)4, which were symmetrically chiral molecules of C2 symmetry, and in the nearly 10 years since then, this reaction has been improved and perfected from both experimental and theoretical aspects, making it another milestone in the field of asymmetric synthesis research. Since then, Sharpres has extended the asymmetric oxidation reaction to asymmetric dihydroxylation. At present, asymmetric epoxidation reactions and dihydroxylation reactions have become the most widely used chemical reactions in the world. In recent years, Sharpres has also discovered new concepts such as chiral amplification and nonlinear effects in asymmetric catalytic oxidation reactions, which are of great theoretical and practical significance.
The three shared the 2001 Nobel Prize in Chemistry for their outstanding contributions to asymmetric catalysis, which was also mentioned in the previous blog post (photo, http://blog.sciencenet.cn/m/user_content.aspx?id=202111). Since 1968, when Knowles achieved the first asymmetric catalytic reaction, this field of research has made great progress, thousands of chiral ligand molecules and chiral catalysts have been synthesized and reported, asymmetric catalytic synthesis has been applied to almost all types of organic reactions, and has begun to become an important method for the synthesis of chiral substances in industry, especially in the pharmaceutical industry. At present, asymmetric catalytic synthesis is being extended to the study of supramolecular chemistry and chemical biology, and artificial simulation of biocatalysis has become an important research direction of asymmetric catalysis.
Organic small molecules catalyze asymmetric synthesis
I don't know if you noticed that the catalysts used in the catalytic reaction mentioned above are mostly metal complexes of complex organic molecules, containing transition group elements such as Rh, Ti, and Ir, which seems to be unreasonable to explain the chiral origin of biomolecules. It would be a good explanation if there are small organic molecules that can catalyze asymmetric synthesis.
In fact, in the process of carrying out the "artificial simulation of biocatalysis" mentioned above, there is such a case. In organic chemistry, Aldol condensation is one of the most commonly used methods for forming C-C bonds. There is a class of enzymes called Aldolase in living organisms that can achieve this reaction. Most of these enzyme-catalyzed reactions involve metals, such as Class II Aldolase, which involves zinc. Over the years, chemists have developed many kinds of asymmetric Aldol condensations that mimic Class II Aldolase in artificially simulated biocatalysis processes, which are metal-catalyzed, ligand-controlled reactions. But there is also an Aldolase in living organisms, Class I Aldolase, that does not require metal involvement. The German chemist List (Figure 1) tried to use simple secondary amines to mimic complex enzymes, he first selected proline, and the results yielded unexpected results, achieving a yield of 68% and 76% ee (JACS, 122: 2395). Then List sifted through the catalysts and found that the cheapest proline was almost the best catalyst, which made people have to lament the magic of nature.
Figure 1: List
Since then, under the impetus of List (Ph.D. from Frankfurt University in Germany, after going to Barbas Laboratory in 1997, then doing AP, and returning to the German Max Planck Institute of Coal Chemistry in 2003), List's postdoctoral boss Carlos F. Barbas III (UCSD) and David W.C. MacMillan (UC Berkeley), etc., Organic asymmetric catalysis has made great strides (I mentioned them in my previous blog post when I predicted this year's Nobel Prize in Chemistry, http://blog.sciencenet.cn/m/user_content.aspx?id=201320). Later, small organic molecules with asymmetric catalytic effects such as proline derivatives or analogues, cinchona alkaloids, peptides and similar compounds were discovered, and the asymmetric yield of the products was also greatly mentioned (many of which can reach more than 98% of the ee value). The asymmetric catalytic function of these molecules, especially the proline that makes up bioproteins, undoubtedly supported the birth of biomolecules chirality. However, the reactions they catalyze are mainly The Aldol reaction, the Mannich reaction and the Michael addition and other limited types of reactions in the organic phase, and there are no similar research results on the chiral origin of biomolecules in the aqueous phase, so it is only a revelation.
Asymmetric autocatalysis – the Soai reaction
We all know that usually the chiral products of chemical reactions are racemates, that is, the two chiral properties are completely equal. But in 1995 Kenso Soai (Figure 2), a chemist at Tokyo University of Science in Japan, reported an incredible reaction on Nature (figure 3, Nature, 1995, 378: 767), in the process of generating 3 in the 1 and 2 reactions, if a small amount of low ee values of 3 is added, the two enantiomers of the resulting product 3 will appear significantly asymmetrical excess, even much higher than the ee value of the initial addition of 3. This reaction was later named the Soai reaction.
Figure 2 Kenso Soai
Figure 3 Soai reaction
Further in-depth research later revealed even more startling results: 1) Soai found that even if the ee value of the initial 3 was extremely low, as low as 10-5%, the final product ee value could reach 99.5% (Angew, 42: 315); 2) Singleton found that if the chiral 3 was not added at the beginning, but the product of the reaction was added to another reaction as a "primer", after a multi-step reaction, it could get a product with an ee value of 3-86% (Figure 4, JACS, 124:10010); for this reaction, Singleton later wrote on OL that since the two configurations of naturally occurring enantiomers are not exactly equal, there should be a statistical deviation of n1/2/2 (this has been mentioned in the previous blog post "2.1.2, statistical origin theory" http://blog.sciencenet.cn/m/user_content.aspx?id=203082), It was this weak deviation that led to asymmetric amplification in the Soai reaction, which was shown to require only a small excess (10-16mol, 60,000 molecules) to lead to the formation of a single chiral product (OL, 5:4337); 3) Soai also found that many chiral compounds other than 3 could also induce asymmetric Soai reactions, such as ee value of 2% leucine, 1% valine (JACS, 120:12157). Epoxides (Tetrahed.Asym. 15:3699), DPNE (OL, 6:1613), etc., and all have an optical yield of up to 98%.
Figure 4
The Soai reaction was studied for 12 years from the discovery of the Soai reaction in 1995, when it was studied as the only asymmetric autocatalytic reaction until 1997, when Mauksch discovered that a class of Mannich reactions also had this feature (Angew, 46:393). But the mechanism of asymmetric autocatalysis is still not to blame.
A study of the origin of the Soai reaction to biological chirality
Given the remarkable character of the products of the Soai reaction as near-monochiral, it is natural to think that this asymmetric autocatalytic mechanism is most appropriate to explain the chiral origin of biomolecules. In fact, as early as 55 years ago, the British physicist Frank proposed such a statement (Biochim.Biophys. Acta, 1953,11:459）。 Blackmond of Imperial College London, who has studied the dynamics of the Soai reaction, revisited this topic in PNAS in 2004 (PNAS, 2004, 101: 5732), arguing that if asymmetric autocatalytic mechanisms (self-amplification) exist in more reactions, it undoubtedly provides an excellent model for explaining the chiral origin of biomolecules.
Soai combined the results of the asymmetric studies we mentioned earlier and did a great deal of work on the amplification of weak asymmetries: 1) instead of introducing chiral products or other molecules in the reaction, he used chiral crystals or minerals, such as the chiral NaClO4 mentioned in the article (Angew, 39: 1510; J. Mol. Catal. A 216:209), spiral silica (Tetrahed.Lett., 44:721), quartz (JACS, 121:11235), etc., found that 80-98% of the products could also be obtained; 2) combined with the circular polarized light hypothesis, he added the slightly asymmetrical 3 (JACS, 127:3274) or Olefin (Angew, 43:4490) obtained by circular polarized photolysis as chiral sources to the Soai reaction. It was found that products with a value of up to 99.5% ee3 were obtained. In fact, the addition of 2% leucine and 1% valine (JACS, 120: 12157) mentioned earlier has the same meaning as this.
It is undeniable that some chiral small molecules can better achieve asymmetric catalysis, and the Soai reaction is able to use its own asymmetric amplification and the slight asymmetry of the "chiral source" caused by statistical asymmetry or external factors to achieve the single chirality of the product, and ultimately produce a single chiral molecular world. However, since there are very few types of organic small molecule catalytic and asymmetric autocatalytic reactions found so far, and they all occur in organic phase reactions, their significance for the chiral origin of biomolecules is only hypothetical. Hopefully, in the future, such mechanisms can be extended to the synthesis of biomolecules in the aqueous phase.
Polymerization reaction selectivity
This formulation suggests that racemic amino acids tend to prefer L-amino acids in the process of polymerizing peptide chain nucleoproteins, and related experiments have achieved some good results. Wrote a morning, tomorrow to Beijing for a meeting, but also to prepare PPT, but also in order to end this topic as soon as possible, this will not be said in detail, interested in referring to the literature.
Science,2002,295:1266
Helvetica Chimica Acta,2003,86:1423
Chem Latvia 2001:324
Nature,1984,310:602
Chem. Eur. J. 2003, 9:1782
Chem. Common., 2000, 2497
Inorganic Chemistry Acta 357 (2004) 649–656
FASEB 1998,12:503
These are just a few hypotheses about the origin of biomolecule asymmetry, and it is not yet known whether the homogeneous world of biomolecules was formed before or after the emergence of life; if it is the former, what factors lead to the separation of chiral enantiomers remains a mystery.
The article "Experimental Research on the Origin of ChiralIty of Biomolecules: Asymmetric Autocatalysis" is reproduced from the Wang Wei blog of Science Network
Source: Science Network