The Nobel Prize in Chemistry: The Achievement of Professor Ryoji Noyori

It was October 2001 when Professor Ryoji Noyori of Nagoya University in Japan (now the president of RIKEN) received the Nobel Prize in Chemistry. Professor Noyorifs achievement had already been so well-recognized within the field of organic chemistry that the prize could have been given much earlier to the world-leading chemist. However, just by watching the news or reading newspapers, it must have been unclear for non-experts to appreciate what he did so great to deserve it. To explain, first I want you to get familiar with the concept of gasymmetric carbon.h

What the Prize Was for
Picture the image of a carbon atom having four single-bonding arms (sp3 carbon). It becomes interesting when all of these four arms are attached to different atoms or different groups of atoms. As you can see in Figure 1, there are two possible arrangements or configurations in these cases.
Like the right and left hands, the two configurations represent the mirror images of each other and canft be spatially overlapped. This type of relationship is called enantioisomerism or enantiomorphism, and the central carbon atom is called an asymmetric carbon.


Fig. 1 asymmetric carbon

A molecule containing an asymmetric carbon is referred as gchiralh or to ghave chirality.h The word is based on a Greek chiro, which means ghandedness.h The two mirror images or enantiomers of a chiral molecule sometimes have different properties (for instance, one is a drug and the other is a poison, or one has pleasant smell while the other has foul odor), so it becomes very important to distinguish them during synthesis.
It turns out, however, preparing only one enantiomer of a chiral compound is extremely difficult. As explained in more detail later, ordinary reactions always produce a one-to-one mixture (called racemic mixture) of right- and left-hand structures. Is it possible to convert a compound having no chirality into a chiral one in enantiomerically pure form? Providing an answer to this question by realizing gasymmetric catalysis,h which hadnft been considered possible, was what made Professor Noyori famous.

Creating an Asymmetric Carbon by Hydrogenation

Letfs think about a reaction called hydrogenation, which converts a double bond into a single bond by adding a molecule of hydrogen (H2), as an example. Figure 2 illustrates how the addition of H2 to a double bond creates asymmetric carbon centers.


Fig 2 hydrogenation reaction

Carrying out this reaction without any special additives will produce a mixture of right- and left-hand structures at 50:50 ratio. This is because hydrogen molecules react with the originally flat molecule from its top and bottom sides in completely random fashion (Figure 3).


Fig 3

If you can somehow control which side of the molecule H2 reacts, it will be possible to make only the desired enantiomer. But since you are working with tiny invisible molecules, this canft be done one by one by hand. Handling of small molecules requires the work of equally small specialists or robots, called catalysts.
For hydrogenation reactions, metals such as nickel, palladium and rhodium are used as catalysts. The molecule containing a double bond and a hydrogen molecule grideh on the metal and leave after reacting with each other. The same reaction is then repeated on the metal for another pair of reactants. Simply put, the metal catalyst brings the two reactants together to promote a chemical reaction, basically playing a role of a matchmaker or perhaps an assembly line robot.
These grobotsh wonft have the ability to tell the difference between right- and left hands if they are symmetrical themselves. Only a racemic mixture will be produced.
Then, if they are designed to be either right- or left handed, shouldnft it solve the problem?

Designing Asymmetric Catalysts
Making a good catalyst often relies on the metal-coordinating property of phosphorus compounds. An appropriately designed phosphorus compound coordinates or binds to a metal to surround its environment and provide a chiral space. Ideally, this allows only one side of the double bond to attach on the metal, and as a result produces the product in which H2 has added from only one side. This kind of catalyst is known as gasymmetric catalyst.h It wasnft easy in the beginning, however, to develop a rational concept on how you could design an effective catalyst. The time of trial and error continued, as an enormous number of asymmetric ligands were synthesized around the world.
Noyorifs group succeeded in asymmetric catalysis of a reaction called cyclopropanation, which represent the pioneering work in the field (although the right/left ratio was still below 45 to 55). The first practical result was reported by Professor Henry Kagan in France, who in 1971 successfully prepared a right-handed amino acid in 86 to 14 ratio using the ligand DIOP (Figure 4) in hydrogenation. In the following year of 1972, the group at Monsanto led by Dr. William Knowles used the ligand DiPAMP (Figure 5) for hydrogenation to achieve as high as 93 to 7 ratio, which led to the industrial production of a drug for the Perkinsonfs disease, L-DOPA (Figure 6). As the recognition of this success, Dr. Knowles was awarded the Nobel Prize in 2001 along with Professors Noyori and K. Barry Sharpless.


Fig 4 Kagan's DIOP Fig 5 Knowles' DIPAMP

Fig 6 L-DOPA

After the asymmetric synthesis of a few certain compounds became feasible, there still remained the issue of gsubstrate specificity.h There was basically a compatibility problem where a catalyst worked excellent to make a compound A, but not for a compound B which had only slightly different structure.

Enter BINAP

Then came the arrival of Noyorifs BINAP catalyst. As shown in Figure 7, BINAP has a beautiful structure (itfs just my personal opinion, but the molecules with useful property seem to have beautiful structures or functional beauty as well). The BINAP catalyst was shown to catalyze hydrogenation with high enantioselectivity for a wide range of double bond-containing substrates, overcoming the conventional limitation.


Fig 7 BINAP (front view, side view)

Looking at the BINAPfs structure, you can see that the twisted binaphthyl backbone (light blue) could move flexibly like a pair of scissors, and that the four protruding phenyl rings (light green) surround the metal (blue) to limit the space for approaching substrate. The right-handed BINAP produces a right-handed product, and the left-handed catalyst produces a left-handed product.
Whatfs so great about these asymmetric catalysts is that one molecule of the catalyst is capable of producing many molecules of products. Just like no existence is created from nothing, an enantiomerically pure chiral compound can never be obtained from a reaction without a source of chirality. Itfs relatively easy to make one molecule of chiral product by using one molecule of chiral reagent, but this would be wasteful if the often-expensive and hard-to-make reagent is consumed after just one reaction. A molecule of asymmetric catalyst can make dozens to more than several thousands of chiral product molecules, so it allows the large scale synthesis of compounds which had been difficult to make and directly leads to significant cost downs.
The BINAP is an excellent ligand used in hydrogenation and other types of reaction. Its commercial application includes the industrical production of aroma chemical menthol (Figure 8) and antibiotic carbapenems (Figure 9). Numerous other useful compounds have been synthesized using BINAP-based catalysts, so the impact it had on the entire field of organic synthesis was immeasurable. More recently, a new process of asymmetric hydrogenation of carbon-oxygen double bonds has been reported, showing the expanding scope of its application.


Fig 8 menthol Fig 9 carbapenem

Professor Noyorifs intense work ethic toward his research is well-known, and I think that the source of his energy is his love for chemistry. Ifve heard that he decided to become a chemist after being fascinated by the beauty of hexagons in structural formula when he was young. And the BINAP indeed happens to be a molecule made up of hexagons. The optical resolution of BINAP is said to have taken seven years of time. The driving force for his determination to overcome it was probably based on his attachment and passion for the beautiful structure of BINAP. Itfs my personal opinion, but I think that these gfeelingsh are a really big part of the energy that pushes a research forward.

Lastly, I am adding that even though Professor Noyorifs achievement was outstanding, it doesnft mean that he was absolutely the greatest in the Japnanese chemistry community. As he stated when winning the Nobel Prize that he greceived it to represent the Japanese chemistry community,h there are many other professors who lead brilliant and creative research projects. I think that especially in the world of chemistry, a huge genius doesnft just appear suddenly, but the depth of talent is what eventually generates major results like the one leading to the Nobel Prize. It was exciting for the country of Japan to receive the Nobel Prize in Chemistry in three consecutive years since 2000, and I have no doubt that Japanfs chemistry still has a lot of potential to produce equally successful results in the future.

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