**1. Introduction**

The 2021 Nobel Prize in Chemistry was awarded to Drs. Benjamin List and David MacMillan in recognition of their relevant contributions in the field of asymmetric organocatalysis. **Figure 1** shows photographs of Benjamin List and David MacMillan when they were the age at which they carried out the research work that eventually led to the award of the Nobel Prize, in the year 2000.

Benjamin List was born and raised in Frankfurt, Germany, and studied organic chemistry at the Free University of Berlin, in the group of Professor Johann Mulzer,

**Figure 1.**

*Benjamin List (left) (https://es.wikipedia.org/wiki/Benjamin\_List) and David W. C. MacMillam (right) (https://es.wikipedia.org/wiki/David\_MacMillan).*

with whom he worked for the conformation of his doctoral thesis on the synthesis of vitamin B12, a molecule with the minimum formula C72H100CoN18O17P. This ambitious project requires the construction – piece by piece—of the target molecule, which involves a large consumption of time, chemical reagents and solvents. List then realized that for the realization of the proposed goal it would be much more efficient to carry out the reactions involved with the help of catalysts similar to enzymes that very selectively catalyze the chemical processes that occur in nature.

In a fortunate coincidence, in the late 1980s the research group of Dr. Richard Lerner, a leading researcher at the Scripps Institute in California, United States, was already exploring the possibility of using antibodies produced by the immune system of humans and animals as stereoselective catalysts. Thus, with a grant from the Alexander von Humboldt Foundation, List had the opportunity to collaborate with Lerner, who later promoted his hiring as an independent researcher at the Scripps Institute. List immediately set about examining small organic molecules that could function as enantioselective catalysts.

For his part, David W. C. MacMillan is of Scottish origin, having been born in the town of Bellshill, near Glasgow, where he carried out his professional studies in the field of chemistry, to later carry out doctoral studies at the University of California— Irvine, under the tutelage of Larry Overman. During his doctoral studies MacMillan devoted himself to the asymmetric synthesis of natural products. His interest in asymmetric organic synthesis took him to Harvard in 1996, where he was a postdoctoral research associate in the group of Professor David A. Evans.

MacMillan began his career as an independent researcher at the Department of Chemistry at the University of California—Berkeley in 1998. Two years later, in 2000, he published the seminal work where he demonstrated the potential of chiral organic molecules to perform asymmetric catalysis. At that time, he was offered tenure at Berkeley, but MacMillan decided to accept another offer that was presented to him at the time and moved to the California Institute of Technology (Caltech). In 2004 he moved with his research group to Princeton University, where he has been director of the Institute of Catalysis ever since.

To understand the relevance of the projects addressed by List and MacMillan, it is convenient to review the concept of *chirality* of molecules that contain asymmetric tetravalent carbon. Thus, in the mid-nineteenth century, examples were known of molecules with the same *composition* (that is, the same type and number of constituent atoms) and the same *connectivity* (that is, the same way in which such atoms are linked together), and yet they are not the same. An illustrative example is -hydroxypropionic acid (lactic acid) isolated by Scheele from milk in

*The 2021 Nobel Prize in Chemistry: Relevance of Asymmetric Organocatalysis and Green… DOI: http://dx.doi.org/10.5772/intechopen.105162*


#### **Figure 2.**

*-Hydroxypropionic acids as an example of molecules that have the same composition and connectivity and are nevertheless different, as can be seen from their different physical and biological activity: lactic acid with negative optical rotation is salty while -hydroxypropionic acid isolated from muscle tissues such as the frog's leg is tasteless.*

1780, which has the same C3H6O3 composition and the same connectivity as the -hydroxypropionic acid isolated from a frog's leg in 1807 by Berzelius, and which are different as it is shown by the values of the optical rotation of these compounds, which is of the same magnitude but different sign (**Figure 2**).

It would take several decades, until the year 1874, for this dilemma to be solved. Independently, chemists Joseph Achille Le Bel and Jacobus Henricus van't Hoff realized that it is very important to visualize molecules in three dimensions. Most relevantly, when four different substituents on the tetravalent carbon atom are oriented towards the vertices of a tetrahedron instead of being located on one shared plane, then the molecule will be asymmetric, as in the case of α-hydroxypropionic acid (**Figure 3**).

An analogy is the right and left hands, which have the same composition (the same pinkie, index, thumb, etc.) and the same connectivity (that is, the way they are attached to the palm of the hand), but actually they are not superimposable mirror images (**Figure 3**). Indeed, a right hand "fits" into the right glove but not into the left glove. Likewise, the left hand only fits into the complementary left glove. The fact that hand in Greek is called "*quir*" gives rise to the concepts "chirality", "chiral molecule" and "center of chirality" [1].

Thus, molecules that are non-superimposable mirror images are isomers called *enantiomers*, which have the same physical (e.g., melting point) and chemical (i.e., reactivity) properties except when interacting with other chiral agents. In particular, the different taste of enantiomeric α-hydroxypropionic acids is a consequence of their different interaction with the receptor for the sense of taste, made up of chiral biomolecules containing α-amino acids, which are also chiral.

With the proposed three-dimensional model advanced by Le Bel and van't Hoff originates the area of *stereochemistry*, which refers to the study of *chemistry in three dimensions*. The contribution of Le Bel and van't Hoff may seem trivial now, but this is not so since the essential change in the way one should consider molecules, taking

**Figure 3.**

*Molecules that have a carbon atom with four different substituents, as is the case of -hydroxypropionic acid, are asymmetric so that their mirror image is not the same, that is, they are not superimposable. Thus, the molecule and its mirror image are isomeric, and are called enantiomeric.*

into account the spatial arrangement of their constituent atoms, required of inspiration and genius!

Another term that we must introduce here is "*stereogenic center*", that is, a carbon atom that due to its asymmetry gives rise to the stereochemistry present in chiral molecules. A more complete discussion of these concepts can be found in reference 1.

The fact that enantiomeric molecules present different reactivity to reagents or biological receptors that are also chiral can have dramatic consequences in our daily lives. **Figure 4** shows two examples of chiral molecules that give rise to a desirable pharmacological effect in one specific configuration but provoke an undesirable effect in the opposite configuration. Thus, the (*S*) configured 1-chloro-2,3-propanediol is a valuable therapeutic agent while its (*R*) enantiomer is in fact a poison (*distomer*, from '*dis*' = bad; that is, the toxic enantiomer).

In one illustrative case that gave rise to the strongest arguments supporting the relevance of the enantioselective synthesis of chiral drugs, that is of *asymmetric synthesis* in which the objective is to synthesize exclusively the enantiomer with the properties of interest (*eutomer*, from '*eus'* = good, that is, the beneficial enantiomer) Thalidomide was administered in racemic form (that is, as a 50:50 mixture of its two enantiomers) in the 1960s for its effectiveness as a tranquilizing agent, without suspecting that the (*S*) enantiomer is a teratogenic compound (**Figure 4**). Indeed, even today, 60 years after the tragedy, there live affected people who were born without arms or legs as a result of the teratogenic activity of the bad enantiomer, the distomer.

In summary, in chiral bioactive molecules, as consequence of their stereospecific interaction with chiral bioreceptors, the biological activity is determined by their configuration. Thus, the control of enantiomeric purity is essential in the pharmaceutical, agrochemical, food and perfume industries, among others.

In this context, **Table 1** brings together a series of chiral drugs that were initially marketed as racemic mixtures but which, in the face of observations such as those

*The 2021 Nobel Prize in Chemistry: Relevance of Asymmetric Organocatalysis and Green… DOI: http://dx.doi.org/10.5772/intechopen.105162*

#### **Figure 4.**

*Importance of asymmetric synthesis. Two illustrative examples of chiral molecules with very different pharmacological properties depending on their configuration.*

mentioned above, required the development of asymmetric syntheses to produce exclusively the desired enantiomer (the eutomer) at an industrial level. This kind of development in the pharmaceutical industry is known as a "chiral switch" and it has enormous commercial value. For example, for decades the Mexican company Syntex distributed the anti-inflammatory agent Naproxen with great commercial success, but when the patent that protected it expired, Syntex was not able to develop the most efficient process for its asymmetric synthesis, which other pharmaceutical companies did. As consequence, the company's market shares lost value and it eventually had to be sold to the Swiss company H. La Roche, which dismantled the existing research laboratories in Mexico. Unfortunately, most of the chemists who worked in these laboratories had to move to the United States, which was a significant loss of talent for Mexico.

Asymmetric synthesis emerged as a consolidated discipline at the end of the twentieth century. There are various strategies to carry out an asymmetric synthesis,


#### **Table 1.**

*Some chiral drugs that were initially marketed as racemic mixture but which later were produced as pure enantiomers via asymmetric synthesis.*

such as, for example, via the so-called "*chiral pool*" or using chiral auxiliaries, which are incorporated into "prochiral" molecules to induce the stereoselective formation of new chiral centers before removing (and if possible reusing) the chiral auxiliary [1].

On the other hand, at the end of the twentieth century the first examples of the application of chiral catalysts in asymmetric synthesis were reported. The great advantage of these catalytic processes is that a chiral molecule of the catalyst can generate thousands of new chiral molecules, that is, they afford a multiplying effect of chirality. Among the most successful chiral catalysts are those reported by William S. Knowles, Ryoji Noyori, and K. Barry Sharpless, who received the 2001 Nobel Prize in Chemistry for their contributions in catalytic asymmetric synthesis (**Figure 5**) [2].

A disadvantage of the catalysts developed by Knowles, Noyori and Sharpless is that they use transition metals such as rhodium, ruthenium and titanium, which pose a health risk. This is a risk that cannot be taken by pharmaceutical and food companies, in which the presence of potentially toxic metals cannot be tolerated. As we will see in later paragraphs, the 2021 Nobel Prize in Chemistry was awarded to Benjamin List and David MacMillan precisely for their fundamental contributions in the area of sustainable asymmetric organocatalysis, which proceeds in the absence of metals (**Figure 6**).

In this context, Nature has developed extremely selective and efficient catalysts; however, the complex and exquisite architecture exhibited by theses biomolecules involves the presence of thousands of components such as the constituent amino acids in the proteins of the corresponding enzymes (**Figure 7**).

In contrast to the metal catalysts developed by Knowles, Noyori, and Sharpless, List (while at the Scripps Institute in California), and MacMillan (at that time in the University of California at Berkeley) set about to design small organic molecules that could act as catalysts. In particular, knowing that aldolase enzymes (that is, the enzymes that catalyze enantioselective aldol reactions like the one shown in **Figure 7**) contain amino acid residues in the active site, List recalled that the enantioselective annealing reaction that Hajos, Parrish, Eder, Sauer and Wiechert had reported in the

#### **Figure 5.**

*The 2001 Nobel Prize in Chemistry was awarded (corresponding photographs arranged left to right) to William S. Knowles, Ryoji Noyori, and K. Barry Sharpless for developing asymmetric catalysis using metals coordinated to chiral organic ligands. (https://www.nobelprize.org/prizes/chemistry/2001/summary/).*

*The 2021 Nobel Prize in Chemistry: Relevance of Asymmetric Organocatalysis and Green… DOI: http://dx.doi.org/10.5772/intechopen.105162*

#### **Figure 6.**

*Asymmetric organocatalysis is based on the use of small organic molecules, in substoichiometric quantities, for the activation of prochiral substrates in the absence of metals.*

#### **Figure 7.**

*Enzymes such as aldolases are capable of catalyzing enantioselective reactions with great efficiency.*

1970s employed the amino acid (*S*)-proline as a catalyst. List then wondered whether (*S*)-proline can function as an enzyme and catalyze reactions by mechanisms similar to those used by aldolase enzymes.

And indeed, Benjamin List, Richard Lerner and Carlos Barbas demonstrated in the year 2000 that (*S*)-proline catalyzes the aldol condensation between acetone and benzaldehyde with 69% yield and an enantioselectivity of 76%, that is to say that the major enantiomer is obtained in 88% yield and the minor enantiomer in 12% yield (**Figure 8**) [3].

It should be noted that a phrase in the publication by List, Lerner and Barbas [3] "(*S*)-Proline acts as a micro-aldolase!" had a huge impact on the chemical community. Indeed, for the vast majority of chemists dedicated to organic synthesis, it is very attractive to be able to "compete" with Nature; specifically, the possibility of employing as enantioselective catalysts small chiral organic molecules that can exceed

#### **Figure 8.**

*Asymmetric aldol reaction catalyzed by (S)-Proline. (S)-Proline acts as a "micro-aldolase"!.*

the efficiency of natural biocatalysts (developed over millions of years of evolution) containing thousands of amino acids is very tempting.

**Figure 8** also includes the accepted mechanism for the organocatalyzed enantioselective aldol reaction catalyzed by (*S*)-proline. First, the condensation of acetone with (*S*)-proline generates an iminium ion that rearranges itself to give a chiral enamine, which is the key intermediate in the process, since it can differentiate the prochiral faces of the aldehyde. Indeed, the addition of the enamine occurs predominantly on one of the carbonyl faces to give, after the hydrolysis of a new iminium ion, the major enantiomeric aldol product as well as the (*S*)-proline that can restart another catalytic cycle.

In the case of the work carried out by David MacMillan et al, a small chiral organic molecule was also used, a heterocyclic molecule called imidazolidinone. This chiral organic molecule readily condenses with unsaturated prochiral aldehydes to afford reactive chiral dienophiles that can then differentiate the prochiral faces of cyclopentadiene to give chiral bicyclic products in an enantioselective manner (**Figure 9**) [4].

Another topic of great relevance in the XXI century is the so-called "Green Chemistry", which refers to the design of chemical products and processes that minimize or eliminate the production and handling of substances that are dangerous for the environment or for human health [5]. Indeed, it has been asserted that the survival of humanity depends on the ability of chemistry professionals to correctly apply the principles and goals of Green Chemistry [6].

In this context, my research group has been dedicated for the last 12 years to the development of methodologies that increase the sustainability of asymmetric organocatalysis [7, 8]. In particular, we have synthesized chiral dipeptides derived from (*S*)-proline that catalyze enantioselective aldol reactions in the absence of solvent by means of mechanochemical activation.

**Figure 10** shows various types of mills used for grinding solid substances in the absence of solvent, from the mortar and pestle used since ancient times to the vibrational or planetary type mills used in chemistry laboratories.

*The 2021 Nobel Prize in Chemistry: Relevance of Asymmetric Organocatalysis and Green… DOI: http://dx.doi.org/10.5772/intechopen.105162*

#### **Figure 9.**

*David MacMillan et al. demonstrated that a chiral imidazolidinone can catalyze the enantioselective Diels-Alder reaction between α, β-unsaturated aldehydes and dienes [4].*

#### **Figure 10.**

*(a–c): Some milling equipment used for the mechanochemical activation of laboratory-scale reactions. (d): Example of container used for grinding in the vibratory mill. (Photographs taken from reference [8]. (a) Mortar and pestle, (b) vibratory mill, (c) planetary mill, (d) stainless steel ball and container.*

**Figure 11** shows the aldol reaction between cyclohexanone and *p*-nitrobenzaldehyde catalyzed by the chiral dipeptide containing a (*S*)-proline residue and a phenylalanine residue. This reaction was carried out with mechanochemical activation (ball milling) in the absence of solvent. The reactions proceed with excellent yield and good diastereo- and enantioselectivity (95% enantiomeric excess, that is, the 1*S*,1′*R* enantiomeric product predominates over the 1*R*,1′*S* enantiomer in a ratio of 97.5 to 2.5) [9, 10].

#### **Figure 11.**

*Asymmetric aldol reaction catalyzed by chiral dipeptides (S)-Proline-(S)-Phe in the absence of solvent [9, 10]. The symbol with three pellets below the arrow indicates that the reaction is activated by ball milling.*

#### **Figure 12.**

*Improving the catalytic performance of (S)-Proline as an organocatalyst in asymmetric aldol reactions in the presence of Solvate Ionic Liquids: participation of a supramolecular aggregate [11].*

*The 2021 Nobel Prize in Chemistry: Relevance of Asymmetric Organocatalysis and Green… DOI: http://dx.doi.org/10.5772/intechopen.105162*

More recently we found that the efficacy of (*S*)-proline as a chiral organocatalyst in asymmetric syntheses is markedly increased in the presence of so-called solvate ionic liquids, which are complexes of glymes with lithium salts (**Figure 12**) [11].

The evidence collected through theoretical calculations indicates the formation of an aggregate between (*S*)-proline and the solvate ionic liquid, that apparently leads to a sufficiently robust transition state that explains the observed high stereoselectivity (**Figure 13**).
