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Knowledge Co-Creation - Profiles of researchers

Leading the World in the Total Synthesis of Biologically Active Natural Products

Professor Kuniaki Tatsuta
Waseda University Faculty of Science and Engineering

Study chemistry if you want to be involved in DNA

When I was in the 1st grade of junior high school, I heard in a lesson that the double-helix structure of DNA had been clarified by Watson and Crick. I was thrilled at this discovery and thought to myself that the age of DNA had come. This was a major impetus in my decision to become a researcher. I enjoyed catching dragonflies and fish near where I lived, and I had a vague notion that I wanted to do something involved with biology or nature.

Actually, my father had suddenly passed away the previous year. Even as a child, I worried about what the future would hold. Two sayings used almost every day by my father continued to remain in my heart like a kind of memento. The first saying was "All of the good universities in UK and USA are private. The future is the age of the private university." I eventually entered Keio University and I now work at Waseda University. I feel that I was guided by the words of my father.

My father, who tended to be away from home a great deal of time, would always place a map of the world and an encyclopedia on the table. He would then utter the second saying which I remember well: "Take a look at these". The custom of the world map and encyclopedia remained even after my father passed away. Keizo Yamada won the Boston Marathon in the same year that the double-helix was discovered, and I examined the map trying to find the location of Boston. However, exactly 20 years later, I would spend time as a researcher at Harvard University, which is also located in Boston. Again, I feel a mysterious relationship between these events.

I decided to enter the School of Medicine at Keio University because of the presence of Professor Itaru Watanabe (deceased), who was a groundbreaker in molecular biology in Japan. However, Professor Watanabe told me that "Japan still has no money, no record of research and no facilities. Therefore, it will be impossible to study this field in Japan for the next 20 or 30 years". Professor Watanabe also told me that if I really wanted to be involved in molecular biology in the future, then I should study chemistry now. He then introduced me to Professor Sumio Umezawa (deceased), an authority in antibiotics who taught in the School of Engineering. I transferred from the School of Medicine to the School of Engineering only 2 months after entering university.

The "art" of synthesis with refined originality

Under the guidance of Professor Umezawa, from my time in graduate school, I focused entirely on researching the synthesis of antibiotics. I wrote by master's thesis on the theme of "elucidating the absolute structure of kanamycin". I achieved the total synthesis of kanamycin and received my doctoral degree. "Absolute structure" refers to perfect determination of the right- and left-hand forms. Regardless of completely similar structures, there is a substance within objects that has totally different properties in an enantiomer reflected in a mirror. In the case of substances such as glucose, a clear distinction can be made between the right- and left-hand forms. This possesses vital meaning as a material for when elucidating the absolute structure.

This thesis received a great amount of attention and I ended up going to Harvard University. I was called to Harvard by Professor Robert Burns Woodward (deceased), who was called the "god of organic synthesis". At the time, Professor Woodward was attempting the synthesis of vitamin B12, and he believed that he needed my technology for the synthesis process of introducing the final sugar moiety. No one else possessed the necessary technology at the time. I replied that I would consider the necessary technology, but stated that I did not want to become involved in that kind of research and asked that I be allowed to pursue new areas. I then spent 3 years performing research at Harvard.

Professor Woodward had a policy of leaving people to their own devices, and it is funny to think that he taught me practically nothing! However, something that I learned from observing the Professor was to be "thoroughly original". The opinions of others are irrelevant; one's own idea is the true source for fundamental research. In 1965, Professor Woodward won the Nobel Prize in Chemistry for the theme "Art in the Organic Synthesis of Natural Products". In other words, Professor Woodward created a synthesis process using an original methodology which could not be imitated by any other person, and the reason that he won the Noble Prize was that his achievements rivaled art itself.

Even when synthesizing the same natural products, a different route will be taken by Researcher A and Researcher B. Individuality is manifested in how a researcher follows a complicated synthesis process with more than 50 steps in order to achieve the goal. Similarly, styles are found which are similar to works of art, just as Professor Woodward created a synthesis of his own. I was deeply influenced by these events, and until today I have sought a synthesis which is referred to as "the work of Professor Tatsuta". My fixation on the use of carbohydrates is in the same sensation as an artist who seeks to clearly create a style within a certain genre, and is a measure to express my own individuality.

In 1981, I saw Picasso's Guernica at the Modern Museum of Art in New York. A number of photographs of the process of creation were displayed next to the painting. These photographs introduced the figure of Picasso as he worked diligently to develop his work. Even Picasso, who is regarded as a genius, repeated the process of trial and error beginning from his initial sketch and refined the structure of his work many times until he was satisfied. Upon seeing this process, I was left with the strong impression that works of art are sublimated only through fundamental skill and effort that could even be called stubborn.

Everything begins from total synthesis

Since long ago, I have always advocated that "everything begins from total synthesis". Total synthesis refers to beginning from the simplest compounds which can be obtained and then synthesizing natural products which possess a complicated structure. Research in total synthesis was almost like a game. In this game, it seemed that researchers competed with each other to synthesize a natural product, and that the game ended when total synthesis had been achieved. However, I want to state that total synthesis is certainly not the goal of research. Rather, it is the beginning of everything.

The 1st meaning of total synthesis is that it enables verification of the correctness of conventional chemistry and, speaking more broadly, conventional science. The 2nd meaning is that it enables the creation of new reactions and methodologies. The 3rd meaning of total synthesis is that it enables the elucidation of absolute structure in terms of both right and left, as discussed previously. The 4th meaning is that it enables scientific verification for the definite existence of bioactivity in natural products which has already been reported. Finally, the 5th meaning is that, in the case of successful research, it is possible to pinpoint the location of the central area which manifests that bioactivity. Total synthesis is a starting point for delving further into these various meanings.

Figure 1: Everything begins from total synthesis

There are cases in which the products which show bioactivity exist only on the level of micrograms. In order to perform correct synthesis of natural products (biologically active natural products), it is necessary to purely isolate this extremely small products. In other words, total synthesis is like a supreme court that delivers an absolute judgment on the existence or non-existence of discoveries in chemistry. By confirming bioactivity through total synthesis, prospects are established regarding the definite existence of the medicine and regarding the possibility of using the product in new medicine.

Nothing useful will come from the act of simply synthesizing natural products. I have long advocated the idea of "learning from nature and then surpassing nature". In other words, it is important that the knowledge gained from the synthesis of natural products is utilized for the benefit of mankind. If a pharmaceutical company actually decides to manufacture a medicine, synthesis consisting of 50 processes is totally unrealistic. In such a case, the question is what areas of the structure should be discarded and how should synthesis be simplified in order to realize a streamlined manufacturing process of approximately 10 processes? Even while completely executing fundamental research as a scientist, I believe that it is important to make practical contributions that consider synthesis methods for use in industry. Based on this way of thinking, I have had the good fortune of being able to contribute to the creation of medicines such as antibiotics and drugs for the treatment of diabetes.

Aiming for the "big four antibiotics"

Receiving the Japan Academy Prize in the presence of the Emperor and Empress

In 2000, I achieved total synthesis for the last remaining of the big four antibiotics and was the first person in the world to successfully perform total synthesis for all of the big four antibiotics. Much like a mountain climber appeals to the world by aiming to conquer Mt. Everest, the highest peak in the world, I thought that it was best for me to target the big four antibiotics which are known to everyone throughout the world. Even so, I first decided that I might be able to achieve this feat around 1990, which was when I had already completed synthesis for the second of the big four antibiotics!

Figure 2: Using carbohydrate in the total synthesis of the big four antibiotics

Antibiotics were the ultimate discovery of the 20th century. Therefore, I was enthusiastic to complete the total synthesis of antibiotics before the end of the 20th century. The final total synthesis of tetracycline required 12 years and ended exactly in the year 2000. This was also the 50 year milestone since tetracycline was discovered. Each of the big four antibiotics possesses a completely different structure, and my achievement of total synthesis for all of the big four antibiotics was highly evaluated. I was very happy at the coverage given by newspapers such as the Asahi Shimbun, which wrote that "the achievement rivals that of scaling the all of highest peaks on the five continents".

In recent research, Professor Tatsuta has discovered natural products which are effective in the regeneration of nerve cells. He has also completed total synthesis for these products. The photograph on the left shows nerve cells before administration of the natural products. The photograph on the right shows evidence of neurite elongation after administration.

Until now, I have accomplished the total synthesis of 97 natural products. This number is, without question, the highest of any person in the world. Right now, I think I will be able to reach 100, but I am not so sure about 101. Forming ideas for the synthesis method inevitably becomes all-night work. Through a process of trial and error, a consecutive series of 50 to 80 processes must be considered all at once. If I take a break and try to rethink the series the next day, I find that my degree of focus has changed and that I cannot complete the series smoothly. Therefore, I attempt to refine my focus as much as possible, and once I am visited by an idea, I absolutely do not sleep until I have taken the idea to completion. Once I have read everything until the final process, I will never forget that series. I can write the series on paper anytime that I want, so it is OK for me to finally sleep!

I have received recognition for the research results that I produced over many years. Beginning with the Fujihara Award in 2008 and continuing with the Japan Academy Prize in 2009, I received a string of the highest awards given to a scientist in Japan. The synthetic organic chemistry of Japan ranks at the top level throughout the world, so begin recognized within Japan is equal to being recognized internationally. I am very proud of what I have accomplished.

Professor Kuniaki Tatsuta
Waseda University Faculty of Science and Engineering

Born in 1940. Completed the Doctoral Program of Keio University Graduate School in 1968 (doctorate in engineering). After employment at Takeda Pharmaceutical Co., Ltd., became a Research Associate at Keio University in 1969. In 1973, assumed the position of Visiting Researcher of Harvard University. In 1977, became Assistant Professor at Keio University and became Professor at the same university in 1986. Assumed the position of Visiting Professor (full-time) at Waseda University in 1993. Assumed his current position in 1997. Has served as the leader of the Center for Practical Nano-Chemistry, Waseda University's 21st Century COE program. Has also served as the Director of the Graduate School of Science and Engineering and as a Visiting Professor at Cambridge University and Oxford University in England. In addition, since 2006, he has held the position of Director of the Waseda University Institute for Advanced Study. Has won numerous awards including the Fujihara Award in 2008, the Japan Academy Prize in 2009, the Chemical Society of Japan Prize, and the National Medal with Purple ribbon of Japan.

WASEDAWASEDA UNVERSITY Research Promotion  http://www.waseda.jp/rps/