Depth | Benjamin Liszt and David Macmillan: starting from different paths and meeting at the top of the Nobel Prize

21st Century Business Herald reporter Tao Li and contributing author Yuefan Wang report

Just this past week, the 2021 Nobel Prize in Chemistry was announced in Sweden. German scientist Benjamin Liszt and American scientist David Macmillan were awarded the 2021 Nobel Prize in Chemistry for "developments in asymmetric organic catalysis.".

Two winners, Benjamin List, born in 1968 in Frankfurt, Germany, have been deeply involved in the field for many years. He received his Ph.D. from the University of Frankfurt in 1997 and is currently a researcher at the Max Planck Coal Institute in Germany.

David W.C. MacMillan was born in 1968 in Bellshill, England. He received his Ph.D. from the University of California, Irvine in 1996 and is currently a professor at Princeton University.

Benjamin Liszt and David Macmillan set out from two paths, but eventually met in the middle of small molecule organic catalysis. Benjamin Liszt's idea is that the extreme efficiency and stereoselectivity of enzyme catalytic systems in nature is amazing, but many enzymes are driven by one or more amino acids in the catalytic behavior of enzymes. So do these catalytic amino acids have to be part of an enzyme to work, or can a single amino acid or some similar simple molecule do the same job?

In fact, most of the amino acid fragments in the enzyme structure are only to maintain the specific three-dimensional structure of the catalytic central environment, in addition, the fragments around the catalytic center will form a certain spatial thromposm, and then improve the selectivity by screening the structure of the substrate, which is indeed not directly involved in the catalytic process.

In a way, the extra fragments can be said to be nature's trial and error cost, which is the choice of many "trade-offs" in nature's multi-faceted evolutionary process, but if you look at the catalytic process alone, this may not be the optimal solution, and benjamin's doubts turn out to be correct.

David Macmillan started from the direction of metal catalysis, in response to some of the problems existing in metal catalysis, MacMillan tried to solve the problem is that the principle of metal catalysis is to temporarily provide or accommodate electrons, so can organic molecules do the same principle? The answer is yes.

David Macmillan and Benjamin Lister eventually reached the end of small molecule catalysis together, they were not the first scientists to do small molecule catalysis, but people did not think outside the box, thinking that small molecule catalysis is just a special case, and they were the first to realize the great power of small molecule catalysis, Macmillan named this method "organic catalysis".

The fact is that the development of any discipline is an evolution on the basis of its own academic history, supplemented by the knowledge or technical penetration of other disciplines, as well as its own inspiration and "divine strokes".

Asymmetric organic catalysis is one of the gods who brought organic synthetic chemistry into a new era, and the Nobel Prize in Chemistry also chose to show it to the public this year, and organic synthetic chemistry will directly affect the disciplines of everyone's life.

Taking the beginning of organic synthetic chemistry as an example, in 1828, human beings synthesized urea for the first time, breaking the misconception that life-related substances can only be synthesized by living organisms. In 1894, the synthetic synthesis of glucose brought the synthetic chemistry of the initial period to the peak, and glucose synthesis won the 1902 Nobel Prize in Chemistry.

Since then, organic synthetic chemistry has demystified the power of natural synthesis, and people have begun to realize that the wonderful existence of life is also driven by a series of chemical reactions.

Synthetic chemistry technology pioneered

With the emergence of the first series of synthetic methods, represented by robinson's synthesis of tropinone in 1917 and Fischer's synthesis of heme in 1929, organic synthetic chemistry entered a period of development in the early 20th century, and both were also awarded the 1947 and 1930 Nobel Prizes in Chemistry for their related work.

This stage is a period of uncompromising pioneering. Subsequently, Grignard reagent won the 1912 Nobel Prize in Chemistry, and people subsequently developed various types of metal-organic reagents and non-metallic organic reagents such as sulfur reagents, phosphorus reagents and boron reagents to construct organic molecules. Among them, the discovery and application of phosphorus reagents and boron reagents won the Nobel Prize in Chemistry in 1979.

The development of such a series of reagents was a hot spot in organic chemistry around the world before the 1970s. Numerous synthetic chemists brought it to a climax in the 1990s.

Quinine, commonly known as cinchona cream, is a medicine used to treat malaria. During World War II, due to a shortage of medicinal sources caused by the war, Woodward (Robert Burns Woodward) began experimenting with synthetic quinine. At that time, organic chemistry was still an experimental discipline in general, and it was generally believed that such complex molecules were difficult to synthesize.

In 1944, Woodward and his students successfully synthesized quinine—showing off the fact that organic synthesis can be understood and synthesized using knowledge of reactions and structures. It's not complicated or top-notch compared to Woodward's others, but it's the first of all the extremely complex and subtle synthesis woodward's life—it opens an era.

Rishempine is another masterpiece of Woodward's "artistic career" of full synthesis, a complex molecule with a total of five rings and multiple chiral centers, and how to synthesize so many rings while ensuring chirality is a huge problem.

The so-called chirality, that is, the composition of the molecule is the same, the chemical formula is the same, but there are differences in its spatial structure, just like the left hand and the right hand, which can be mirrored and coincided, but cannot be spatially coincident. Subtle differences lead to huge qualitative differences, such as the famous "reaction stop incident", which thus brings people extremely painful lessons. Reaction stop was originally a drug used by pregnant mothers to treat vomiting in the early stages of pregnancy, but because its main component, thalidomide, has two forms, one can be antiemetic and the other can cause teratogenicity, this negligence eventually led to thousands of newborn malformations and even stillbirth.

Multiple chiral centers mean that there are 2n spatial configurations of molecules, and it is a complex polycyclic structure, woodward with a breathtaking and pioneering synthesis idea to solve a series of problems, which has become a standard research method for later generations, Woodward and related work won the 1965 Nobel Prize in Chemistry.

Another problem at this time is that Woodward's synthesis method, although beautiful, is difficult to reproduce by others —some of his ideas seem to come from intuition, and it seems difficult for ordinary people to come up with such a beautiful synthesis path. And as the variety of natural organic matter grows in an avalanche, organic chemists desperately need a standardized way of thinking.

The reverse synthesis analysis method came into being - its essence is the separation of the target molecule, through the analysis of the structure of the target molecule, gradually disassemble it into simpler and easier to synthesize precursors and raw materials, so as to complete the design of the route.

Corey was the first organic chemist to systematically propose this idea, for which he won the 1990 Nobel Prize in Chemistry. At this point, Corey transformed total synthesis from an art to a science— a job that any highly trained organic synthetic chemist can do ever since.

Another wave of metal-catalyzed orgasms

In another direction, while trying to synthesize more kinds of elemental organic compounds, more compounds with novelties in structure and properties represented by ferrocene were discovered, and the related pioneering work won the Nobel Prize in Chemistry in 1973. At the same time, the huge potential of metals as catalysts to participate in compound construction has also been explored.

But in fact, as early as the end of the 19th century, Sabatier (Paul Sabattier) discovered that the metal Ni can catalyze hydrogenation, and won the 1912 Nobel Prize in Chemistry. Early applications of metal-catalyzed organic reactions appeared in the preparation of polymers such as polyethylene in industry, and the synthesis of organic polymers was achieved by the Ziegler-Natta catalyst, so Ziegler (Carl Ziegler) and Natta (Guglio Nata) won the 1963 Nobel Prize in Chemistry.

With the discovery, rise and wide application of metal catalysts, on the one hand, the status of traditional elemental organic reagents in total synthesis has been weakened, on the other hand, it has greatly enriched the methods and scope of people's synthesis of natural products, from the synthesis of many complex natural products by Woodward and Corey in the early peak period, to the end of the 20th century, almost all natural products can be synthesized. Because of the great achievements of metal catalysts, the 2005 and 2010 Nobel Prizes in Chemistry awarded olefin re-decomposition reactions and palladium-catalyzed cross-coupling reactions.

The development of metal catalysts has developed the peak of full synthesis to the extreme, but it has not been able to lead to the arrival of a new era of synthetic chemistry. The main reason is that the reserves of precious metals (Pd/Pt/Au) required for catalysts are limited and the cost is high, and although inexpensive metal catalysts such as Ni/Fe have been developed, the performance has also been reduced; secondly, as a homogeneous catalytic reaction, it is more difficult to fully separate the residual catalysts in the product, which is especially important in the pharmaceutical field; finally, low-cost metals have more stringent requirements for reaction conditions such as anhydrous and anaerobic, which also limits possible application scenarios.

In addition, the traditional synthesis method is too inefficient, the traditional synthesis method "step by step", each reaction must be separated and purified after completion, in order to carry out the next reaction, can not carry out multiple reactions at the same time to make the synthesis more efficient.

Taking Woodward's first synthesis of strychnine as an example, a total of 29 reactions were experienced, and only 7 mg of product was finally obtained from kilogram-level raw materials, with a total yield as low as 0.0009%. There are only 6 chiral centers in the structure of strychnine, corresponding to 26 = 64 stereoisomers, while there are 64 chiral centers of sand anemone toxin (Palytoxin), and there are 264 = 18446744073709551616 kinds of stereoisomers alone, and the difficulty of taking the traditional synthesis idea is unimaginable.

Organic catalysis debuts

As a result, biological enzymes and organic catalysts have also begun to receive attention. Compared to metals and enzymes, organic catalysis is simple, inexpensive and environmentally friendly, making it a coveted tool for chemists. More centrally, organic catalysis inherits the advantages of enzymes: drive asymmetric catalysis – in two possible mirror structures, one of which generates much more than the other, and unlike the traditional chemical synthesis process of "one step at a time", the production process of organic catalysis, several steps can often be carried out continuously and uninterruptedly, the so-called "cascade reaction", which can greatly reduce waste in chemical production.

The birth of benjamin and Macmillan's two works also means that organic catalysis has gradually formed a systematic discipline from a few examples of independent discovery, and synthetic chemistry has officially entered the fourth period , the future period.

In today's vigorous development of basic science, human beings' control of the microscopic world is becoming more and more sophisticated. From moving individual atoms and molecules to synthesizing molecules with complex structures, research and technology in related fields are changing rapidly. As a science for observing and manipulating organic molecules, the Nobel Prize in Chemistry over the past 120 years has also shown this in the field of organic chemistry.

Starting from Fischer's synthesis of sugars, purines and other biomolecules in 1902, the award-winning projects in organic chemistry range from natural products to artificial dyes and polymers, from single organic reactions to the total synthesis of complex molecules, from the study of life processes to the creation of supramoleculars and molecular machines... Despite such grand achievements, this may be just the beginning for the rich molecular world of carbon.

In the future, human beings may be able to optimize the specific reaction conditions required by high-throughput screening and machine learning methods infinitely and finely, so that they can reach or even exceed the efficiency of natural enzymes; perhaps, with the improvement of the level of manipulating molecules and the growth of computing power, human beings can design molecules in advance through the structure-activity relationship, and arbitrarily connect atoms and atomic clumps like building blocks to obtain the complex structure of the specific functions required; even, human beings can be like the creator, creating a reaction system that has never appeared in nature. Even man-made molecular systems that can replicate and transform themselves— life.

The future cannot be easily predicted, but the unknown also means that there are endless possibilities. (Intern Li Qiang also contributed to this article)

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