On the evening of October 5, Beijing time, the Royal Swedish Academy of Sciences announced that the 2022 Nobel Prize in Chemistry will be awarded to Carolyn R. Bertozzi of Stanford University in the United States, Morten Meldal of the University of Copenhagen in Denmark ) and K. Barry Sharpless (Carl Barry Sharpless) of the Scripps Research Institute in the United States, in recognition of their contributions to the "development of click chemistry and bioorthogonal chemistry".

Following Friedrich Sanger, Barry Sharpless became the second scientist to win two Nobel Prizes in Chemistry. Looking at all directions, only Marie Curie, John Bardeen and Friedrich Sanger have won two Nobel Prizes in Science of three people. In addition, Sharpless won two awards in this century, and only 21 years apart, which is a great honor.

In 2001, Barry Sharpless won the Nobel Prize in Chemistry together with William Knowles and Ryoji Noyori for his two asymmetric reaction methodologies——Sharpless asymmetric epoxidation and dihydroxylation reaction. half. In the above two reactions, the epoxy/diol product of the desired specific configuration can be efficiently obtained by changing the stereostructure of the catalyst, so it can be used in the synthesis of various natural products and drugs. The theme of the Nobel Prize that year - Chirality / chirality, is also a brilliant summary of the work of these three winners.

2001 Nobel Prize in Chemistry

2001 - Sharpless asymmetric epoxidation reaction

2001 - Sharpless asymmetric dihydroxylation reaction

For the vast majority of people, the Nobel Prize is closer to a lifelong achievement and summary. Except for a very few, the award-winning work has been recognized more than ten years ago, and there are even some scientists who have made great contributions I have not been able to obtain it in my whole life; not to mention, there are literally only a handful of scientists who have won two Nobel Prizes, even rarer than those who can leave their names on the periodic table of elements through the ages.

Sharpless can completely retire at the age of 60 after winning the award, but because of a unique work shortly after winning the award - the 1,3-dipolar cycloaddition reaction of azide and alkyne, he has a glimpse of infinite possibilities . Therefore, not only did he not bid farewell to the academic stage, but he forged ahead day by day, and Sharpless was actively involved in cooperative research groups all over the world.

Finally, after 21 years, he won the Nobel Prize again.

It is well known that ring formation is the chemistry of the element carbon—a unique and important field in organic chemistry.

Compared with other elements, the No. 6 element carbon has a suitable atomic radius and electronic structure, and its richness in chemical bonds makes the compounds containing carbon—organic substances occupy the vast majority of known human beings with only one place in the periodic table. most. At the same time, carbon, which is not a high element abundance on the earth, builds the vibrant biosphere and is also an important part of life.

In organic matter, a large class of representative compounds is cyclic compounds composed of carbon atoms and/or heteroatoms. In fact, the composition of protein - 21 kinds of amino acids, including 5 kinds of cyclic compounds; and in the carrier of genetic factors - DNA, deoxyribose and all ATGC bases contain one or more ring systems .

Now it has been revised to 21 kinds of amino acids, and an amino acid containing Se has been added

Base structure of DNA and RNA (ATGC/AUGC)

Among ring structures of various sizes, five-membered rings and six-membered rings are the most common and stable ring systems. During millions of years of chemical evolution, organisms have also accumulated a large number of ring-shaped bioactive molecules. ; At the same time, a large number of non-carbon atoms/heteroatoms in organisms are often involved in the formation of ring systems. Therefore, for the current biochemistry and medicine fields, it is very important and challenging to study the synthesis and reaction of heterocyclic compounds.

In this award-winning work, the 1,3-dipolar cycloaddition reaction/Huisgen reaction and its improvement based on azide compounds and alkynes are the basis and core of the field of click chemistry, and its product is a five-membered ring. Heterocyclic triazole compounds.

Original Huisgen reaction

In fact, Huisgen reported this reaction as early as 1961, but at first, the reaction did not receive much attention. There are many reasons for this, including the toxicity and explosiveness of azide compounds, the intense heating reaction conditions, the mixed products of the reaction...

Until 2002, Meldal and Sharpless independently discovered the Huisgen reaction catalyzed by Cu(I). At room temperature, the reactants were reacted in an aqueous solution, and high-purity products could be obtained efficiently, and they had extremely high regioselectivity. A single product of the desired specific structure.

The above papers are also an important basis for the selection and distribution of bonuses.

And, this might be one of JOC's brightest moments.

Meldal Paper Cover Image - JOC

Sharpless paper cover image - Angew. Chem. Int. Ed.

After avoiding the fate of being rejected by Angewandte Chemie, Sharpless was keenly aware of the universality of this methodology, and began to expand various substrates and explore reaction conditions. After fully exploring and summarizing, Sharpless called it CuAAC reaction, that is, copper (Cu) catalyzed azide (A)-alkyne (A) 1,3-dipolar cycloaddition reaction (C).

The efficiency of the reaction is high and the accuracy is strong, and it can achieve the effect of pointing and hitting. So, under the prompt of Mrs. Sharpless, the concept of click chemistry/click chemistry was born. Just like the "Kodak" of the shutter, click chemistry is like the buckle of a seat belt, and the two parts can be firmly combined with a "Click", which is the source of its name.

Time has entered the 21st century, which is the century of life sciences.

With the great progress in high-throughput reaction systems, computational chemistry, structural biology and other fields, the progress of chemical biology and biochemistry has been advancing by leaps and bounds. Human beings are no longer satisfied with the static observation of living organisms, but have begun to explore the tracking methods of dynamic life processes.

In 2000, Carolyn Bertozzi discovered that by modifying the existing Staudinger reaction, the sugar groups on the surface of the cell membrane can also be modified with the help of azide compounds, so as to realize the labeling and tracking of the glycoproteins on the surface of the cell membrane. However, the efficiency of this reaction is too low, and it may be oxidized and metabolized by organisms, so further improvement is urgently needed.

Improved Staudinger reaction

At this time, Bertozzi also saw Sharpless' CuAAC methodology and tried to transfer this reaction to living cells. She realized that the copper catalyst, the key to the reaction, is highly toxic and using it directly would lead to cell death. The experiment hit a bottleneck.

Under the enlightenment of organic chemistry, by replacing the substrate with a high-tension cyclooctyne derivative (subsequently using trans-cyclooctene, etc.), the linear triple bond becomes a double bond with a smaller bond angle after the reaction. (or the trans double bond in the ring becomes a freer single bond), which releases the ring tension of the substrate, so the reaction activity can be greatly improved, so that the reaction can be carried out efficiently without the need for an external copper catalyst, and it can be directly activated At the same time, the reaction removes toxic catalysts and has almost no impact on the physiological processes of cells or even living organisms. At the same time, the reaction in the organism has no hindrance to the artificial reaction system to be introduced, and can even realize the biological process. In vivo fluorescent labeling.

Cycloaddition Reaction of Two Highly Stressed Rings

Bertozzi summarized it as a tension-driven azide-alkyne 1,3-dipolar cycloaddition reaction (Strain-promoted Azide-Alkyne Cycloaddition, SpAAC), and then she also gave this type of efficient and safe in vivo reaction an important A famous name - bio-orthogonal reaction, which means that just like the mutually perpendicular/orthogonal geometric relationship, the artificially introduced reaction system does not interfere with the biochemical reaction in the organism.

Labeling reactions in living cells

Bioorthogonal reaction to fluorescent labeling of live zebrafish

Today, Morten Meldal, Barry Sharpless and Carolyn Bertozzi share the 2022 Nobel Prize because of their creative use of the azide-alkyne cycloaddition reaction in their respective fields and the creation of two new fields of click chemistry and bioorthogonal reactions. Bell Prize in Chemistry.

In fact, there are still subtle differences in the research directions of the three awardees. Meldal is engaged in the research of traditional organic chemical reactions; Sharpless mainly explores the fields of chemical biology and pharmacy from the perspective of organic reaction methodology; while Bertozzi is a biochemist who studies the dynamic processes in living bodies. Probably because of this, and taking into account their independent contributions, the award committee finally decided that the three should share the award of the year equally.

The product of click chemical reaction——triazole derivatives are important precursors of many drug molecules, and their structures can be quickly obtained through appropriate modification to a variety of active structures. Potential for high-throughput reactions. Therefore, this reaction has great potential in the field of organic chemistry and pharmaceutical manufacturing.

The bioorthogonal reaction can efficiently label specific molecules in organisms. Compared with the achievement of the 2008 Nobel Prize in Chemistry - Green Fluorescent Protein (GFP), small molecule labeling is more flexible and convenient, and can affect the physiological processes of organisms. The likelihood is lower, and the impact may be more far-reaching.