The Royal Swedish Academy of Sciences awarded the 2021 Nobel Prize in Chemistry to Benjamin List and David MacMillan for their contributions to asymmetric organic catalysis.
Source: Screenshot of the live broadcast of the Nobel Prize Committee website
Chiral and chiral chemistry
Chiral phenomena are widespread in nature, and chiral phenomena in life on Earth are an eternal topic.
The origin of life in animals and plants is itself closely related to chirality, and it is one of the basic elements that control the activity of biological macromolecules in living organisms, such as nucleic acids, proteins, carbohydrates and countless biological small molecules.
"Chirality" is a basic property of microscopic small molecules and macroscopic matter, just like people's left and right hands, which mirror isomers of each other, but the left hand and the right hand cannot overlap each other.
Mirror heterogeneous phenomenon of left and right hands (mirrors cannot overlap)
All chiral molecules and objects have chiral characteristics as long as they do not overlap their mirror images.
Most often, chiral molecules and objects have no symmetry centers and no symmetry surfaces. There are a few exceptions, such as no symmetric surface but a symmetry center, and therefore no chirality.
Asymmetric surfaces have symmetric centers/chirality (mirror images can overlap)
So far, the main chiral types that have been discovered are: central chirality, shaft chirality, spiral chirality, biplanar chirality, rigid polyctic chirality (such as spirene chirality) and flexible polyfaceted chirality (such as folding chirality). Among them, the central chirality, the no-face chirality and the spiral ring chirality exist more widely in nature.
Chiral synthesis, also known as asymmetric synthesis, is a core part of chiral control in chemical synthesis. It is also an indispensable tool for the synthesis of chiral materials, and can control the selection to produce a wide variety of chiral compounds and substances.
Chiral drugs account for more than 60% of existing clinical drugs, and the proportion of chiral compounds in pesticides is also increasing year by year.
Chiral materials, especially optoelectronic materials, have a wide range of applications, including high-definition 3D display, optical detection, optical data storage/encryption, optical identification sensors, etc.
At the same time, they have a wide range of applications in biomarkers, pathological detection, especially in the early clinical detection of diseases.
Asymmetric synthetic chemistry controls chirality through four main pathways: chiral auxiliary substrates, chiral reagents (equivalent use), chiral catalysts, and chiral catalysts and chiral environments (such as chiral solvents).
Among them, the asymmetric synthesis controlled by chiral catalysts is the most challenging. Due to its chiral amplification effect, it is also one of the most efficient ways to synthesize chiral compounds.
Chiral catalysis and catalysts
Like ordinary catalysts, most chiral catalysts accelerate the reaction by reducing the free energy (energy barrier) of the transition state of the chemical reaction.
The key difference is that the chiral catalyst can be carried out in the direction of mirror isomer generation that is conducive to matching the chirality of the catalyst, thereby achieving the purpose of controlling chirality.
Chiral catalysis/catalysts can be divided into two categories: biocatalysis (such as enzymes, DNA/RNA catalysis) and chemical catalysis (metal and non-metallic catalysis).
The theme of the 2021 Nobel Prize in Chemistry - Chiral organic catalysis belongs to the non-metallic catalysis in chemical catalysis.
Classification summary of asymmetric catalysis and catalysts (red labeled for Nobel Prize work in 2021)
Chiral organic catalysts are mainly divided into acidic organic catalysts (such as proton-Brønsted acid) and alkaline organic catalysts (such as azacyclic carbine, nitrogen-containing amines and phosphorus- and sulfur-containing compounds), which can also be called Lewis acid and Lewis base. Protons with positive ions can also be broadly summarized as Lewis acids because they can accept solitary pairs of electron-paired chemical species.
All of these catalysts have advantages and disadvantages, but they can complement each other. Biocatalysis is highly stereoselective, but the substrate range is narrow, and usually only 1 enantiomer can be produced, and sometimes the catalytic conditions of biological systems are demanding. The substrate range of chemical catalysis is wide, but sometimes stereoselective control is difficult, and stereoselectivity changes a lot with the change of substrate. In addition, metal-catalyzed products are doped with metal impurities, which are sometimes difficult to remove.
It is for a variety of reasons such as these that scientists are always on the lookout for a variety of better chiral catalysts.
Amine chiral organic catalysts are based on primary and secondary amines (such as proline) and tertiary amines (such as quinine), which are catalyzed by nucleophilic function at the beginning of the reaction.
Benjamin List and David MacMillan's early work (and their award-winning work) were based primarily on secondary amines, and reaction substrates required the presence of electron-deficient atoms, such as carbonyl carbon (C=O).
Most amine-catalyzed reactions in which chiral intermediates (neutral imines, alkenes, and positively charged imines) are produced as keys to the success of asymmetric catalytic reactions.
Organic small molecule catalysis
"Green chemistry" has become one of the main directions pursued by chemistry in the new century, and its core idea is to eliminate the source of pollution. In line with this development trend, the Nobel Prize in Chemistry favors the field of green organic catalysis.
Acids and alkalis are widely present in nature and have extremely important significance for people's production and life. For example, the catalytic group of the enzyme catalytic activity center in a living organism participates in the catalysis as a proton donor or acceptor, and almost all the acid-base catalysis mechanisms exist in the enzyme catalysis.
Although similar concepts and work on organic catalysis and organic small molecule catalysis have been proposed and carried out in the 20th century, the breakthroughs of Benjamin List and David MacMillan in organic small molecule catalysis, the clear formulation of the concept of organic catalysis, and the sorting out of field research have greatly promoted the development of this discipline.
To their credit, the work of the two laureates brought the Nobel Prize in Chemistry back into the field of synthetic methodology 10 years later. Of course, the 2016 Nobel Prize in Chemistry, Molecular Machines, also belongs to the field of synthetic chemistry.
An early study by Benjamin List's group at the Scripps Institute in the United States aimed to mimic natural enzyme catalytic strategies to develop chiral acid-base green catalysts with high stereoselectivity, plateau sub-economy, and high yield. Part of this work was carried out in collaboration with the late chemist Carlos Barbas III.
These catalysts avoid the use of inert shielding gases, protective groups, harmful solvents or high temperatures and pressures in chemical reactions.
Benjamin List group published an article in the Journal of the American Chemical Society in 2000 "Proline-catalyzed Direct Asymmetric Hydroxyl Aldehyde Reaction", this study used proline as a natural chiral catalyst to achieve a direct asymmetric aldehyde alcohol reaction between acetone and various aldehydes, which simulated the reaction mechanism of alder acetal antibody catalysis and natural class I aldolase catalysis, and achieved the above goals through small molecule proline catalysis.
Organic small molecule catalysis that mimics natural enzymes
In 2012 and 2016, Benjamin List designed a series of organic small molecule chiral catalysts with biaxial chiral skeletons such as iminobiphosphate (IDP), imino-iminobiphosphate (iIDP) and iminobiphosphimide (IDPi).
This type of chiral catalyst has the characteristics of strong acidity and high activity, of which the pKa value of imide diphosphorimide in acetonitrile reaches 4.5.
In addition, the biaxial chiral skeleton constructs a restricted space (chiral pocket) similar to the biological enzyme structure for the catalyst, and the active center of the chiral catalyst is wrapped in it, providing a special chiral microenvironment for the asymmetric reaction, which can further improve the catalyst's three-dimensional control ability of the reaction.
In recent years, this strongly acidic chiral organic small molecule catalyst has made a breakthrough in the asymmetric functionalization of inactivated olefins, and the more representative is the use of imine diphosphorimide catalysts, which can first protonize the carbon-carbon double bonds of inert olefin molecules, and then promote the intramolecular hydrane oxidation reaction of the olefin substrate, and obtain a series of cyclic compounds containing seasonal carbon centers with high enantioselectivity.
Imine bisphosphate organic catalyst of biaxial chiral skeleton
David MacMillan pioneered a new field of imine organic catalysis based on the chiral imidazodinone small molecule catalysts designed by his research group. These catalysts are easy to synthesize and have been industrially produced.
The catalytic mode of imine is different from that of enylamine. The catalysis of the latter is based on the reaction conversion of aldera in nature using the amino catalyzed aldehydes and ketones of lysine to generate enylamines, while the ion catalysis of imine ions is inspired by the catalytic activation of Michael receptors by Lewis acid.
In 2000, David MacMillan published the first work on imine asymmetric catalysis (Diels-Alder reaction) during his time at the University of California, Berkeley, in which he explicitly proposed the concept of organic catalysis. The reaction is carried out at room temperature and with the participation of an aqueous solution.
For the Diss-Alder reaction of cyclodene substrates, the chiral imidadone catalyst not only effectively controls the enantioselectivity, but also properly controls the endo/exo diasteric selectivity. The single crystal structure of the catalyst molecules helps explain the stereochemical control process of the reaction.
Small molecule catalysis of organic chiral imidazolinone
As the founder and pioneer of organic catalysis, David MacMillan further proposed the SOMO Catalysis strategy based on single-electron transfer, which for the first time realized the asymmetric reaction of organic amines involved in free radicals, which laid the foundation for his future creation of asymmetric photoredox, and played an important leading role in the vigorous development of visible photocatalysis today.
Catalyst recovery and reuse
In such asymmetric reactions controlled by organic chiral acid-base catalysts, the amount of catalyst is large. This brings great inconvenience to asymmetric synthesis, especially the mass production stage of asymmetric synthesis, and also increases the cost of synthesis and production. Therefore, the development of recyclable and reusable organic catalysts is particularly important.
At present, there are three main methods, namely the use of polymers, organic salts and small molecule GAP chemical recovery catalysts.
The use of polymer-loaded chiral catalysts or the catalysts loaded onto organic salts plays a good role in promoting asymmetric catalysis. Although there are sometimes certain limitations, such as the large molecular weight of polymers, positive or negative ions of organic salt catalysts may have adverse effects on the reaction.
Li Guigen's small molecule GAP chemical method is to connect strong polar functional groups to chiral catalysts to control homogeneous asymmetric catalytic reactions.
In the case of solvent-free, due to the loading of strong polar functional groups, the GAP catalyst exists in solid form, and is a special solid like salt and non-salt, and the recovery catalyst only needs to be washed with organic solvents, and the operation is simple.
This recyclable and reusable GAP catalyst has been contrasted with David MacMillan's original catalyst in asymmetric reaction behavior and has yielded good results.
Recoverable and reusable GAP small molecule catalysts
Development and status of organic catalysis in China
In the past 20 years, Chinese chemists have made important contributions in the field of chiral amine catalysis, chiral phosphoric acid catalysis, chiral azerocyclic carbine catalysis, and nucleophilic Louise alkali catalysis.
Chiral amine catalysis aspect
Cheng Jinpei and Luo Sanzhong designed a new chiral Uncle Diamine catalyst, which successfully realized the asymmetric Aldol reaction and the construction of the chiral seasonal carbon center.
Feng Xiaoming realized the asymmetric cyanogenation reaction and several other asymmetric conversions catalyzed by chiral nitrogen oxygen and chiral amino acid salts.
The chiral prolylamide catalysts such as Gong Liuzhu and Xiao Wenjing's chiral prolylamide effectively catalyzed a variety of asymmetric Aldol reactions.
Zhong Guofu successfully used chiral proline for the asymmetric amine oxidation reaction of aldehydes to produce high enantio-pure 1,2-diol, which is simple and fast, and easy to apply.
Zhao Gang's chiral amino acid catalyst controlled the formation of carbon-carbon (oxygen, fluorine) bonds and the formation of multiple chiral centers in one step by one by the multi-component tandem reaction.
Rui Wang's cinchona alkali salt chiral catalyst and Ma Jun'an's sugar-derived chiral primary amine-thiourea catalyst were successfully applied to the asymmetric Michael addition reaction.
Jiang Zhiyong's asymmetric cyclization reaction catalyzed by chiral alkali provides a new strategy for the construction of chiral heterocyclic skeleton.
Wang Chunjiang developed an amide-derived chiral thiourea tertiary amine catalyst, which showed good catalytic effects in a variety of asymmetric transformations.
Xu Pengfei has developed a variety of chiral amine-catalyzed asymmetric multi-component reactions and tandem reactions, which provides a new strategy for the synthesis of chiral cyclic compounds.
Zhou Jian applied a class of cinchona alkali-derived phosphamide catalysts to asymmetric cyanogenation reactions.
Liu Xiaohua reported a new class of chiral guanidine catalysts, which exhibit excellent catalytic activity in a variety of asymmetric reactions.
Chen Yingchun developed a variety of catalytic asymmetric reactions with the primary amine derived from cinchonaine as a catalyst, and made a series of innovative works in the catalysis of dielene and trienylamine catalysis.
In terms of chiral phosphoric acid catalysis
Tu Yongqiang's design of the chiral phosphoric acid-catalyzed half-sheet nasol rearrangement reaction provides an efficient strategy for the synthesis of chiral spironyl ether compounds.
Zhou Qilin and Zhu Shoufei applied chiral phosphoric acid with a spiral ring skeleton to the asymmetric N-H insertion reaction.
Zhong Guofu developed the asymmetric Hydroxylation reaction catalyzed by chiral phosphoric acid.
The asymmetric reaction catalyzed by chiral phosphoric acid proposed by You Shuli has good regional and stereoselectivity.
Shi Feng developed the asymmetric transformation reaction of chiral phosphoric acid-catalyzed indole platform molecules, which provided a new strategy for the efficient construction of chiral indole skeleton.
Tan Bin realized the catalytic asymmetric construction of a variety of axial chiral skeletons catalyzed by chiral phosphoric acid and the reaction of the four-component Ugi, helping asymmetric axial chiral chemistry to be selected as one of the top ten hot topics of chemistry and materials science in 2020.
Xinyuan Liu used the combined catalytic system of chiral phosphoric acid and metal to realize the asymmetric bifunctional grouping of olefins and the dynamic kinetic asymmetric hydrogenation of racemic biolenes or diolefins.
Sun Jianwei realized the chiral phosphoric acid-catalyzed oxetane ring-opening reaction, which provided a new strategy for the synthesis of active alkaloids.
Du Daming reported on a class of phosphoric acids of the bipennaphthalene backbone and applied it to the asymmetric hydrogen transfer reaction of quinoline.
Liuzhu Gong and Wenhao Hu reported the combined catalytic strategy of chiral phosphoric acid and metal, which achieved high enantioselective capture of hydroxylid by electrophiles.
Zhou Yonggui used the bionic relay catalytic strategy of chiral phosphoric acid and metal to achieve asymmetric hydrogenation of various heteroary rings.
Through the hydrogen bond-oriented compact ion pair strategy, Ye Longwu realized a series of catalytic asymmetric aromatization reactions (CADA) based on chiral phosphoric acid direct activation of carbon-carbon triple bonds based on hydrogen bonding, starting from the alkyneamide substrate substituted with hydrogen bond donor aryl group and using various types of chiral phosphoric acid as catalysts.
Yang Xiaoyu synthesized enantiomerically pure 4H-3,1-benzoxazine by using chiral phosphoric acid to catalyze the efficient kinetic folding of 2-aminobenzyl alcohol.
Lin Xufeng's design of chiral spiroic acid (SPAs), second-generation chiral spirophosphate (SPAs 2.0) and planar chiral phosphoric acid (PPAs) and other new chiral phosphoric acid catalysts have been applied to a series of asymmetric catalytic synthesis and commercialized.
Ding Kuiling developed an asymmetric Bayyer-Villiger oxidation reaction catalyzed by chiral phosphoric acid, which uses inexpensive hydrogen peroxide as an oxidant and high enantioselectivity to obtain γ-lactone derivatives.
Chiral azerocyclic carbine catalysis
You Shuli designed a camphor-derived chiral azetidine carbine catalyst to achieve the aldehyde-ketone asymmetric cross-Benzoin reaction.
Ye Song developed a chiral azerocarbine catalyst derived from proline silicone, which enabled the asymmetric cyclization of enones.
Sun Jianwei achieved the asymmetric electrophilic fluorination reaction catalyzed by chiral azerocyclic carbine for the first time. In this work, the conjugate enol anion with dual nucleophilic sites achieves the construction of carbon-fluorine bonds at the carbonyl α with high regional selectivity and enantioselectivity.
Huang Yong used the proton migration strategy to effectively solve the bottleneck of non-enantioselectivity and catalyst cycling, reported the first case of asymmetric carbon-carbon synthesis based on nitrogen heterocyclic carbine non-covalent catalysis, and extended it to chiral synthesis of carbon-nitrogen, carbon-sulfur, and carbon-phosphorus bonds, becoming a universal asymmetric catalytic model.
Chi Yonggui realized the asymmetric reaction of various azetidyclic carbine catalyzed by saturated ester β-bit activation, which provided a good material for chiral azerocyclic carbine catalysis.
Wang's azerocyclic carbine catalyst successfully induced enantioselective [3+3] cyclization reactions and asymmetric fluoridation reactions that are important for medicinal chemistry.
Nucleophilic Lewis base catalysis
Wanbin Zhang developed the bicyclimidazole nucleophilic Lewis base catalyst and applied it to the Steglich reaction.
Zhong Guofu and Luo Ping used the phosphine catalyst derived from chiral amino acids to achieve the synthesis of chiral aza-Rauhut-Currier reaction.
Zhang Junliang and Huang Youyou respectively developed chiral sulfinamide-derived phosphine catalysts and polyfunctional group skeleton chiralphosphine catalysts containing phenolic hydroxyl groups and amide groups, and applied them effectively to the asymmetric Rauhut-Currier reaction.
Shi Min developed chiral bifunctional phosphine catalysts to solve the problem of difficult stereoselectivity in the Morita-Baylis-Hillman reaction.
Tong Xiaofeng used cinchonaine as a chiral nucleophilic Lewis base catalyst to achieve the participation of dienes in asymmetric tandem cyclization.
Guo Hongchao reported the asymmetric cyclization reaction catalyzed by chiral phosphine, which provided a new strategy for the catalytic asymmetry construction of chiral heterocyclic skeletons.
Other aspects of organic small molecule catalysis
Ding Kuiling developed a chiral glycol hydrogen bonding catalyst and applied it to the asymmetric Diels-Alder reaction.
Gang Zhao designed a bifunctional azazidine catalyst and successfully applied it to the asymmetric [3+2] ring addition reaction of diolemates and biactivated olefins.
Ma Junan developed a flexible duplex naphthalene skeleton phase transfer catalyst that exhibited good catalytic activity in asymmetric conjugate addition reactions.
Guo Qixiang developed a chiral catalyst for the skeleton of the conaphthal, and realized the asymmetric direct α-alkylation reaction of chiral aldehyde-catalyzed amino acid esters.
Zhao Baoguo used a shaft chiral N-methylpyridoxal catalyst to achieve a bionic asymmetric Manigixi reaction using a strategy applied to carbonyl catalysis.
Through hydrogen bond catalysis, Yan Hailong successfully realized the difficult construction of the Azepine skeleton containing a variety of chiral primitives.
Outstanding contributions made by overseas Chinese chemists in the field of organic catalysis
In 1996, Shi Yian and Yang Dan developed sugar-derived chiral ketones and chiral ketones of the binaphthal skeleton, respectively, which were successfully used for asymmetric epoxide of olefins.
Deng Li developed a citrine-catalyzed desormalization of succinic anhydride derivatives.
Wei Wang developed a chiral tetrahydropyrrolidine sulfonamide catalyst to achieve an efficient asymmetric Michael addition reaction, and he also used the oxide amine strategy to achieve the β-functional grouping reaction of aldehydes.
Xumu Zhang used a rigid chiral phosphine catalyst to control stereoselectivity in the cyclization reaction involving the acrylate.
Chen Junfeng developed chiral biguanide catalysts and used them for asymmetric cyclization reactions, followed by further development of chiral guanidine salt phase transfer catalysts and ion pair catalysts, realizing the asymmetric nucleophilic substitution reaction of tertiary haloalkanes that is difficult to achieve by conventional means.
Lu Yixin et al. developed dipeptide chiral phosphine catalysts and developed the application of such catalysts in tandem cyclization reactions.
Li Guigen applied the small molecule chiral GAP catalyst to the Diels-Alder and Friedel-Crafts reactions, and successfully controlled the enantioselectivity, endo/exo non-enantioselective selectivity and regional selectivity.
conclusion
Organic asymmetric catalysis belongs to the research of green environmental chemistry and will play an important role not only in chemical science, but also in the field of chiral drugs and chiral materials, especially in the field of optoelectronic materials.
The work of the two Nobel laureates in chiral amine catalysis must involve a carbonyl functional group. Chiral acid catalysis is also mostly based on carbonyl substrates.
The development of chiral organic catalysts and catalytic systems with a more efficient and wide range of substrate applications needs to be further strengthened.
The study of push-Pull multi-bit collaborative catalytic mode and effective catalytic cycle mechanism will help improve the chemical reaction speed and stereoselectivity.
The cross-fusion of synthetic chemistry, computational chemistry and artificial intelligence (AI), combined with the establishment of the catalyst-substrate consortium library and screening, will accelerate the conditional optimization process of various asymmetric reactions.
Organic asymmetric catalysis under photoelectric conditions and site-specific selective control of substrates will also be hot spots for researchers.
Biomimetic catalysis and simulated catalysis of biological enzymes, the development of new catalyst systems and efficient control modes, and the development of new efficient asymmetric reactions are an important development trend of organic asymmetric catalysis in the future.
In the future, more, more efficient, more widely used, recyclable and reusable chiral organic catalysts will also be needed.
About author:Guigen Li, Professor, Institute of Chemistry and Biomedical Sciences, Nanjing University, Department of Chemistry and Biochemistry, Texas Tech University, USA, research direction is chirality, chiral chemistry, new reactions, new reagents, new concepts.
The full text of the paper will be published in the "Science and Technology Herald" No. 22, 2021, originally titled "Chiral Control: Asymmetric Organic Catalysis - A Brief Analysis of the 2021 Nobel Prize in Chemistry Achievements", this article has been deleted, welcome to subscribe to view.