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Using ‘pinpoint’ catalysts to innovate chemical synthesis

Kei Manabe, Initiative Research Scientist, has developed an innovative ‘pinpoint’ catalyst, which can drastically decrease the number of synthetic processes, thereby attempting to bring innovation to chemical synthesis.

Our life is supported by various chemical substances such as medicines, detergents, chemical fibers, and plastics. However, many useful chemical substances require many synthetic processes, and the larger the number of synthetic processes, the higher is the energy consumption and the more the waste materials. Furthermore, some useful chemical substances may remain unprocessed because much time and expense are required to complete the large number of processes.

Kei Manabe, Initiative Research Scientist, has developed an innovative ‘pinpoint’ catalyst, which can drastically decrease the number of synthetic processes, thereby attempting to bring innovation to chemical synthesis.

Aiming at an ‘engine of creation’

“When I was a college student, I did not think that chemical synthesis was an attractive subject,” says Manabe, looking back on his college days. “A synthetic process for a complex chemical substance requires as many as dozens of synthetic processes because it starts with a simple, easily available compound, which is gradually transformed through many synthetic processes into the target substance. I wondered why the process required so many processes, and what method would allow us to synthesize a complex compound more flexibly.”

It was when he was a graduate student that he happened to read Engines of Creation: The Coming Era of Nanotechnology, in which K. E. Drexler, the author, showed us the world of nanotechnology as early as in the 1980s. In this book Manabe was greatly impressed by an imaginary machine called an assembler that could connect a molecule to any specific site of another molecule. Experts in this field would have found what was written in this book difficult to understand, and the book itself only a kind of science fiction story. However, it made him think of carrying out the research needed to build engines of creation like that assembler.

Using ‘pinpoint’ catalysts to drastically shorten the time required for synthetic processes

Why do conventional methods require so many synthetic processes? For example, even if we try to attach an object molecule to a target molecule at a particular site on the target molecule, the object molecule tends to bind to the target molecule at the site where the target reacts readily with other molecules, its reactive site.

A typical method of connecting an object molecule to a target molecule at an specific site requires multiple synthetic processes. It starts with a process to attach an object molecule to the target’s reactive site, to prevent the target from binding to other molecules there. Then the target molecule is processed so that the intended attachment site on the target can react readily with other molecules. Finally, the site is activated by a catalyst to bind to the object molecule.

The more synthetic processes are used, the longer the synthesis takes, the more energy is consumed and the more waste materials are produced. Many approaches have therefore been taken to reduce the number of synthetic processes and waste materials. “Various chemical reactions and techniques have been developed. Combining these accumulated methods has allowed chemists to gradually decrease the number of synthetic processes. There are, however, too many synthetic processes.”

To decrease the number of synthetic processes, Manabe came up with the concept of a completely new catalyst. He called this a ‘pinpoint’ catalyst; it is able to activate the target molecule exactly at its intended site and force an object molecule to bind to the target at the site in much the same way as the assembler in Engines of Creation.

“Conventional catalysts can also activate molecules. However, they only activate the site that can react readily with other molecules because they cannot activate the intended site of a target molecule. The pinpoint catalyst requires two factors: a structure that allows the catalyst to discriminate a target molecule and to move towards the intended site of the target, and a strong catalysis that activates the intended site of the target molecule.”

With current techniques it is difficult to design the shape of the structure that can discriminate a target molecule. “The best method is to form structures of various shapes, and to select some special structures that can exactly discriminate the target molecule from them.”

For forming these kinds of structure, we can consider the enzymes in our bodies. Enzymes are proteins that serve as catalysts; they are sensitive enough to act on specific molecules from among the many molecules within an organism.

Proteins are a folded chain of amino acids linked together. There are 20 amino acids that constitute proteins, linked in various orders and in different lengths on the basis of genetic information, which results in many protein structures. Some of these proteins serve as catalysts with exquisite specificity for their target molecules.

Why, then should we not use our knowledge of genetic engineering to develop enzymes that can be used as pinpoint catalysts? “There are only a limited number of chemical reactions in which enzymes serve as catalysts,” explains Manabe.

“In addition, their catalytic power is not strong, and enzymes are inactivated at high temperatures because they are proteins. We have only a limited number of practical enzyme-based chemical reactions. I am therefore planning to create a catalyst that can be used for a number of chemical reactions.”

Structure formation with oligoarenes

Manabe came up with the idea of using a molecular unit called an ‘oligoarene’ as the structure. Just as a protein is a chain of amino acids, an oligoarene is a chain of benzene ring units (monomers). “We thought the oligoarene would be the best molecule from the following viewpoints: (1) it is stable and resistant to various chemical reactions, (2) it can be designed into various stable shapes, (3) its monomers are easily connected, and (4) various kinds of monomers are available.”

The oligoarene-type pinpoint catalysts currently under development consist of an oligoarene structure and two characteristic sites: a molecular recognition site that pinpoints a specific molecule and a catalytic active site that activates a specific site of a molecule.

In 2005 Manabe started a research unit at RIKEN. The Manabe Initiative Research Unit is one of the fixed-term five-year projects that provide young, excellent researchers with independent research opportunities. Manabe dared to take the fixed-term post, sacrificing his associate professorship at the University of Tokyo, a post under the mandatory retirement age system.

“It seemed reckless,” said Manabe with a laugh. “I thought this was the right time for me to take the post because I was already 40 years old and I knew that I did not have enough time to spend on studying.” At the interview with RIKEN, he relied only on the idea of the pinpoint catalyst because he had previously had no chance to conduct research on it. Some selection committee members wondered about the idea because he had no experimental data.

Developing catalysts that can cause new reactions

To begin with, Manabe tried to develop a method for connecting the monomers that constitute the basic unit of an oligoarene-type pinpoint catalyst. “Various kinds of catalyst can be created by combining different monomers with different shapes. However, there were no known methods that could effectively connect the monomers and easily produce various kinds of catalyst. So we focused on developing a new method, and successfully created several oligoarene-type pinpoint catalysts”.

Among them, he fortunately found a special catalyst that connected molecules at a specific site where conventional catalysts could not (Fig. 3). “The catalyst has a simple structure, but it caused a special chemical reaction that had not been possible with conventional catalysts. I believe that if we continue to advance our own research, we will be able to find more useful oligoarene-type pinpoint catalysts.”

Expectation for drug discovery

When asked, “Who are your rival researchers?” Manabe replied, “I don’t know of any.”

There is no other research in the world that is based on pinpoint catalysts. What innovation can this unique research bring to the world of chemical synthesis?

Manabe says he will be happy if his pinpoint catalyst is used to develop new drugs, because he graduated from a Faculty of Pharmaceutical Sciences. “Development of medicinal products starts with creating many candidate agents, from which only the effective ones are selected as drugs and medicines. In this process, however, chemical scientists focus on manufacturing chemical substances that can be easily manufactured, or that require fewer synthetic processes. They avoid manufacturing chemical substances that require many synthetic processes because they involve an immense amount of time and money. However, chemical substances requiring many synthetic processes may include effective drugs and medicines. If these can be easily manufactured with pinpoint catalysts, chemical scientists will surely be able to find unconventionally effective drugs and medicines among them.”

It goes without saying that the application of pinpoint catalysts is not limited to the development of drugs and medicines. They will bring about substantial innovation in the methods used for developing any chemical substance.

Study giving great encouragement

One of the important targets in developing oligoarene-type pinpoint catalysts is how to increase variations in its oligoarene structure. If Manabe succeeds in finding a method of connecting the monomers more effectively, he will be able to increase the variations further in about five years.

Another major target is to enhance the activation capability of oligoarene-type pinpoint catalysts. “Even though the structure of the catalysts recognizes a target molecule and pinpoints the specific site of the molecule that reacts with an object molecule, the target molecule sometimes fails to bind to the object molecule because of its weak activation capability.” He has used the same active site for a developed catalyst as for conventional existing catalysts. He intends to incorporate a new catalyst, recently developed by a research group, with a strong activation capability The structure of the oligoarene has the ability to incorporate various catalysts and make them function as required. “We also plan to develop new catalysts with a strong activation capability. However, it takes a lot of time to develop these sorts of active catalyst.”

The Manabe Initiative Research Unit held its interim appraisal and research achievement report meeting in July this year, halfway through its fixed-term five-year project.

“Our research received a high evaluation from the selection committee members. I was very happy when some young researchers at RIKEN said, ‘We are very encouraged by your research activities.’” Many young researchers are in an environment where they are asked to achieve good results in a short time. However, Manabe’s research into pinpoint catalysts received a high evaluation even though research of this kind should be evaluated from a medium-term to long-term viewpoint, not from a short-term viewpoint. This fact may have encouraged the young researchers. “I was also encouraged by young researchers who, in expressing their interest in our research activities, embrace their dreams for the future of chemical synthesis.”

The Manabe Initiative Research Unit will close in 2010, but Manabe is determined to continue the research and development into pinpoint catalysts as his life’s work.

About the researcher

Kei Manabe was born in Kanagawa, Japan. He completed his doctoral work in 1993 at the University of Tokyo. After working as a postdoctoral fellow at Columbia University, New York, US, he moved back to the University of Tokyo and worked as an Assistant Professor, Lecturer, and Associate Professor. In 2005, he joined RIKEN, where he is currently an Initiative Research Scientist. His research interests include the development of new catalysts for organic synthesis.

Kei Manabe
Initiative Research Scientist
Manabe Initiative Research Unit
Advanced Science Institute

Saeko Okada | Research asia research news
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