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Interview with Dr. Ryoji Noyori: Nobel Prize Memorial Interview -- Ryoji Noyori

The World of Chirality

Ryoji Noyori

Professor at Department of Chemistry, Graduate School of Science and Director, Research Center for Materials Science, Nagoya University. He shared the 2001 Nobel Prize in Chemistry with Dr. Williams S. Knowles (St. Louis, Missouri, USA) and Dr. K. Barry Sharples (The Stripps Research Institute, La Jolla, California, USA). He holds a model of BINAP in this photograph. The yellow part at the center is the Ru atom.

Many molecules exist in two forms that are mirror images to each other, like our right hand and left hand. These are called chiral molecules, after the Latin word "cheir" meaning the hand. Dr. Ryoji Noyori at Nagoya University developed a process of asymmetric synthesis, which selectively produces only one of these forms. For this achievement, Dr. Noyori was awarded the Nobel prize in chemistry. We asked him how he pursued this study with such a great deal of originality. We also discussed about the problems related to the study and education environment in Japan.

Why Chiral Reactions Are Important

-- First of all, please accept our hearty congratulations on your Nobel Prize. Your work is related to chiral molecules, which occur in the right-handed and left-handed forms. Artificial synthesis of a chiral substance usually produces both forms in a 50 to 50 ratio. But in nature, there are processes that easily result in the formation of only one form. What is the difference between these natural processes and the artificial asymmetric synthesis you developed?

Dr. Noyori: Biomolecules such as sugars, DNA and RNA, and amino acids in proteins are all of one hand -- they are not mixtures of right-handed and left-handed forms. Living organisms can synthesize molecules in the form they want, because they use enzymes that also have chirality. In modern days, many artificial substances are developed as pharmaceuticals and for other uses. If chirality is important in these applications, we need artificial catalysts that produce only one of the two possible mirror images.

Enzymes, the living catalysts, are huge molecules. I wonder whether such a large molecular mass is really needed for the purpose of controlling the synthesis of small molecules. Smaller molecules could be equally effective to achieve the same goal. Because the catalyst molecules we developed are much smaller than enzymes, I think our catalysts are on a par with enzymes, even if they are much poorer in reaction efficiency. I admit that enzymes work through elaborate mechanisms, but this fact in itself does not deserve admiration. You can't say natural things are always nice (laugh).

-- In 1851, the French chemist Pasteur said that asymmetric synthesis was impossible. When was this assertion overturned?

Dr. Noyori: Practically, his saying held true until 1980. If we want to achieve effective asymmetric synthesis, we need two things.

First, we must be able to separate the right-handed and left-handed molecules accurately from each other. This separation, in fact, is a continuous process. But practical utilization requires clear-cut separation -- ideally 100 to 0. Second, the reaction involved in asymmetric synthesis must be a catalytic reaction. The reagent must not be used up after a single run, but be able to work many times. This also is a very difficult requirement. Because of these reasons, it was long believed that practical asymmetric synthesis would not be realized.

As you remember, the thalidomide tragedy took place in the 1960's. But it was not until the 1980's that we understood the cause of the problem. It became clear that one enantiomer (mirror-image form) of thalidomide was teratogenic, while the other had medical efficacy. The importance of chirality in pharmaceuticals was recognized clearly around this time.

Since 1992, the US Food and Drug Administration (FDA) has been enforcing the policy of "racemic switch." If only one enantiomer has medical efficacy, either this enantiomer must be used singly, or the other enantiomer must be proved harmless before marketing. In this situation, the percentage of single-enantiomer drugs increased from 15% in 1990 to 40% at present. The sales of single-enantiomer drugs amount to 15 trillion yen in the world total.

Pursuing a Beauty

-- You discovered the first asymmetric catalyst in 1966. How was your discovery appreciated at that time?

Dr. Noyori: At that time, I unexpectedly found an asymmetric catalyst, which consisted of a chiral organic molecule coordinate-bonded to a copper atom. To say the truth, synthesis wasn't the purpose of this work. I was studying the reaction mechanism, and found this catalyst by chance. This discovery attracted little attention.

There were two reasons for that. First, the reaction I studied was an unusual one, and the reaction mechanism could not be generalized. Second, the efficiency of chiral recognition was as poor as 55 to 45. There was a small deflection from 50 to 50, but it was not practical. I found the principle, but the material it produced was rubbish.

I thought how these problems could be overcome. I wanted to invent a catalyst that would work in a common reaction with much higher chiral recognition efficiency. After all, I set out to work on hydrogenation. Hydrogen has a small atomic mass; it is clean, inexpensive, and very common. If chiral hydrogenation could be realized, it would be of great theoretical interest, and would find many applications in society and industries. A great number of chemists in the world thought in this way. I was a late-starter among them.

A catalyst for asymmetric synthesis is designed so that coordinate bonds are formed between a metal atom and an organic compound. One of the organic compounds used in asymmetric catalysts is BINAP (see bottom figure on the next page). Made of several hexagons, this molecule is very simple and beautiful. In Germany, it is said, "function is beautiful." I believe in the close relationship between beauty and functionality. Many chemists, predominantly men, yearned for this beauty, and more than a dozen groups tried to succeed in synthesis. It was like all men proposed to a beautiful woman, but she was beyond their reach.

Nobody succeeded, because they used similar approaches. Scientists in the same era tend to be much the same in what they do, like all men wooing women would write letters and give flowers in our days, or send email for young people nowadays. I took a different approach, and finally succeeded in producing BINAP in 1978. This work was published in an American journal in 1980. It took six years after I started in 1974, and some people were amazed by the sheer length of time.

-- Formerly, chiral chemistry was a matter of producing a mixture of two enantiomers and separating one from the other. You changed the face of research in this field. Bu the way, while you first used rhodium (Rh) as the metal to be bound to BINAP in your first paper in 1980, you switched to ruthenium (Ru) later. What was the reason for this change?

Dr. Noyori: We can, in principle, design any molecule and synthesize it at will. While we can look for useful enzymes in various living organisms, we can also create them using our knowledge. The compound of Rh and BINAP was known to have a limitation. It was only useful for the synthesis of amino acids.

With certain expectation, I switched from Rh to Ru in 1986. This led to a great breakthrough. The catalyst containing Ru was able to handle double bonds between carbon atoms. More importantly, it was effective for carbon-oxygen double bonds, and thus was useful in producing chiral alcohols. By this fact, this catalyst made great contribution to the development of pharmaceuticals. This catalyst was also excellent in performance. After several years of improvement, we made catalyst molecules that could work for more than 2,400,000 cycles, at a rate of 70 cycles per second (see "catalytic cycle" in bottom figure on the previous page). This reaction rate is faster than that of ordinary enzymes. Anyway, we can use if we have suitable enzymes, and we can use artificial catalysts when we need them.

Against the established system

-- Next, we'd like to ask about the government policies and problems related to science and education. As mentioned often, we have no organizations in Japan that are truly capable of evaluating scientific study. To make a good evaluation, it is important to define what is needed on the side of society.

Dr. Noyori: That's right. Young people like to base their judgment on the number of citations to a paper, because they think it's clear and objective. But the number of citations bears little meaning. What is more important is the needs of society. For example, if the public expects that the University of Tokyo should be the number-one, then the mission of the University of Tokyo is to be equal to Harvard University. The mission of a university school of medicine may be to save more people. It is important to evaluate whether each academic establishment is doing good job for the mission given to it.

-- Then, what is the mission of the graduate school?

Dr. Noyori: The graduate school must be an international top player. Taking an example of the Graduate School of the University of Tokyo, I have to say that the level of chemistry being done at the School of Science and the School of Engineering is far from comparable to Harvard and Stanford. If they are top-ranking sumo wrestlers, we are first-grade wrestlers. In this respect, we are not fulfilling the mandate of society. There are several factors underlying this situation, such as a defective system of education, and the lack of motivation, ability, and interest on the side of students. However, a student who has worked in our laboratory (Noyori Lab, Nagoya University) should have essentially the same ability as I in the expertise acquired there. Bringing out the ability of students is the mission of the graduate school.

-- Your work is a typical case of industry-academia collaboration. There are voices from industry arguing that the mission of universities is to train researchers like you. But I understand that you yourself emphasize the importance of basic study.

Dr. Noyori: I don't agree with the industry-academia collaboration as promoted today. Why the industrial power of Japan is so weak? It's because industry is not producing generic technologies. It's because there are no original ideas. Consequently, industry expects help from universities, and the government encourages such cooperation by allocating budgets to universities supporting industry. This situation is grossly unreasonable.

The fault of universities lies in the fact that they are not giving education properly. To make things right, universities should train very able people and send them out to society and industry. Nobody seems to understand this simple fact.

Universities are places for basic study. According to my motto, study must be "fresh, simple, and clear." So, I do scientific study using my sensitivity. The fundamental driving force of science is the motivation toward the goal of enhancing one's own spirit. So, freshness is essential to any study. Generally speaking, science creates one from zero, while industrial technology builds on seven and makes eight. I want to do study which not only creates one from zero, but also has a potential to develop into eight, nine, and ten in the future.

-- As a result of the government policy for so-called "pressure-free education," many students are now graduated from high schools without receiving much science education. Students taking college entrance examinations are often required to choose only one scientific subject, even if they are sitting for entrance to scientific departments. Many incoming freshmen have learned only one or two scientific subjects. What do you say about this situation?

Dr. Noyori: The problem is that all examinations are based on relative evaluation of students. They're not designed for proper assessment of qualification. What is the primary meaning of a selective examination? It is to select the best students if and only when there are many qualified candidates. Some people argue that such a system will decimate the number of candidates, but what's wrong with that?

The largest problem is that professors and associate professors also often lack qualification. A person is appointed to the post of associate professor not because he's excellent but because he's relatively better. In this way, we're caught in a negative spiral. Professors blame students, but what a shame that professors can't write good English, or even good Japanese. This isn't a recent phenomenon. The quality of Japanese professors has been on a low level from decades ago. Before discussing solutions, they must first face reality. The largest problem is that the people who are currently in teaching positions do not grasp or understand this situation. They should correct their wrongs, but they should not be too much ashamed of themselves, because in the end, they have to work with pride and self-esteem.

-- Your Nobel Prize encouraged many young people. Could you give a message to young people who are our future?

Dr. Noyori: If Japan is going to play its part among the G7 countries in the 21st century, it is important that we develop both international competitiveness and cooperativeness. My advice to young people is to have a high purpose and act on their own responsibility. I want to continue my work as long as possible, always keeping my purpose in mind.

[October 15, 2001, at Nagoya University]

Words from an interviewer

In these days of gloomy headlines, the news of Dr. Noyori's Nobel Prize enlivened Japanese people. Although he was very busy with media interviews, he welcomed us and talked in a crisp way of speaking and adding some humor. The citizens of Nagoya welcomed the news enthusiastically, and Chunichi Shimbun, an influential newspaper, published a feature article on his achievements. We talked with a taxi driver, who was deeply impressed by the personality of Dr. Noyori.

"Do not mention 'Nature' too much" was the words Dr. Noyori said to us after the interview. Publication in Nature, the scientific journal in the U.K., is regarded as a proof of excellent study. But Dr. Noyori warned that a paper is published in Nature because it is excellent and evaluated highly; a work is not excellent because it appeared in Nature. The fields of science nowadays have been extremely segmented and specialized. Even researchers in the same general field, such as chemistry or physics, cannot always understand the importance of work in unfamiliar subdivisions. In this situation, on what should we base our judgment of the originality and importance of scientific study, if we do not rely on Nature and other prestigious journals? Many citizens, as well as scientists, might have learned about mirror-image isomers before hearing about this news, but I wonder how many people had been familiar with the term "asymmetric synthesis".

As we want to be proud of the science practiced in this country, it seems necessary to foster competent journalism as an evaluation organ.

[Hiromi Yokoyama, Science Writer]

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