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Top>Research>Organic Synthesis-Molecular Construction and Manipulation


Tamejiro Hiyama

Tamejiro Hiyama [Profile]

Education Course

Organic Synthesis-Molecular Construction and Manipulation

Tamejiro Hiyama
Professor of Organic Synthesis, Organic Chemistry and Organic Metallic Chemistry, Center for Research and Development Initiatives, Chuo University

When ordering the subject of scientific disciplines from metaphysical subjects to human beings, the list goes as follows: mathematics, physics, chemistry, biology, agriculture, pharmacy and medicine. Chemistry is located in almost the middle of this list and is referred to as a central science. This remains true even now that new science and technology focusing on information have been born. New disciplines are born one after another and the border between disciplines has become unclear. However, chemistry remains to support the foundation of other disciplines and expand its territory.

We live owing to the reactions of organic molecules

When breaking down matter, we arrive at more than 100 different types of atoms. Each atom has been given a name known as an element. Molecules are formed when various atoms combine in a specific array. Atoms join together to create the form and shape of molecules and to exert characteristics and function. Polymers are formed when these bonds are repeated hundred or more than thousand times. Polymers exert functions such as synthetic fibers and plastics which are essential to modern life. When molecules gather together through weak bonds, molecular assemblies and supramolecules are formed. It has become clear that these molecular assemblies and supramolecules are related to an important mechanism in all living things. Incidentally, are you aware that our bodies are dependent on chemical reactions? We were born because our parent's genes underwent a reaction to form new genes. These new genes underwent self-replication. We are the result of biosynthesis of functional proteins and numerous other biological molecules. Our bodies are made from organic molecules which are based on carbon. We live because these organic molecules undergo various chemical reactions under subtle balance.

Synthetic chemists are craftsmen who manipulate organic molecules

When looking at the periodic table of the elements, carbon (C) is located in the 14th group, 2nd period. Silicon (Si) is located directly below carbon (in the 3rd period). The chemical compound of carbon is called an organic compound or organic matter. In addition to bonds between carbon elements, carbon also bonds with a variety of elements, particularly a carbon-hydrogen bond. Conversely, silicon is a main element of inorganic compounds such as glass. Silicon oxide, known as silica, is crystals formed by orderly three-dimensional bonds of silicon. Inorganic compounds are formed through the involvement of various metallic elements. Recently, our lifestyle has been enriched by major developments in organometallic chemistry which deals with carbon-metal bonds. The organometallic chemistry is strongly advancing in last 50 years, leading organic synthesis by sometimes providing with polymer catalysts, asymmetric synthesis catalysts, and important reagents for highly selective transformations essential in manufacturing pharmaceuticals, agrochemicals, and materials. Stated simply, organic synthesis is science and technology for creating molecules which enrich our lifestyle. In that respect, chemists of organic synthesis are craftsman who manipulate organic molecules of the present and future.

My research theme is creating methods for efficiently constructing functional organic molecules. My greatest research interest is, in particular, the formation of carbon-carbon bonds which consists of the framework for important molecules. In the following section, I would like to describe two carbon-carbon bond forming reactions, to which was awarded the Humbolt Prize.

Grignard and Barbier

Phillipe A. Barbier (University of Lyon) was conducting research on the addition reaction of organic halides to carbonyl compounds using metallic magnesium. However, reproducibility was poor and he ordered his student Victor Grignard to conduct a detailed investigation. In 1900, Grignard discovered that organomagnesium reagents, now called Grignard reagents, were generated from organic halides and magnesium metal in anhydrous diethyl ether. Upon addition of carbonyl compounds to the Grignard reagents, he obtained the corresponding adducts in high yields with enough reproducibility, thus solving the initial problems. His discovery led to significant advances in organic chemistry and organometallic chemistry. In recognition of his discovery, Grignard was awarded the Nobel Prize in Chemistry in 1912. Although such honors were not bestowed on his mentor Barbier, there is a great merit in the Barbier method, which involves simple mixing of all the reactants. In fact, organomagnesium reagents are too reactive to hardly discriminate the reaction sites (functional groups). Accordingly the Grignard Method remained less applied in the late stage of total synthesis of complex structures.

Nozaki-Hiyama-Kishi Reaction

One solution to overcome the drawback of the Grignard Method is the reaction using chromium(II) that was disclosed by us in 1975. We had performed extensive research on this method when I was an assistant professor, but after I left Kyoto University, the research was continued independently in Kyoto University and Harvard University. The method is now known as the Nozaki-Hiyama-Kishi Reaction (abbreviated as the NHK reaction). Two chromium(II) reagents undergo a one-electron reduction of organic halides to make organochromium reagents, which can add to the coexisting aldehydes highly efficiently. The transformation is characterized by excellent chemoselectivity (functional group tolerance) and stereoselectivity, and also by the Barbier Method. Nickel catalyst is necessary in particular for alkenyl halides. This reaction exerts especially outstanding potential in coupling molecules susceptible to acids and bases and thus used many times in the manufacturing of the anticancer agent Halaven, which was approved in America (2010), Europe (2011) and Japan (2011).

Hiyama Coupling

Many people still remember the 2010 Nobel Prize in Chemistry being awarded to researchera involved in the cross-coupling reaction. Originally, the fact that a carbon-carbon bond could be easily formed by using a nickel catalyst in the reaction between the Grignard reagent and organic halide was discovered in 1972 by a research group led by Makoto Kumada and Kohei Tamao of Kyoto University. However, it became much easier to use when zinc (Eiichi Negishi) or boron (Akira Suzuki) was introduced in addition to the Grignard reagent and when a palladium catalyst is used in lieu of nickel. Therefore, a major reason for awarding the Nobel Prize was the wide applicability, as the corss-coupling reactions with boron and zinc are now used at laboratories and industries throughout the world. It is most preferable to use silicon compounds which are an abundant resource and possess low toxicity. Unfortunately, silicon reagents remained inactive until 1988, when we disclosed that silicon reagents could be used in cross-coupling reactions by introducing fluoride or hydroxyl ion to organosilicon compounds and creating pentacoordinated silicates. This is known as Hiyama Coupling. Organosilicon reagents, now commercially available and called HOMSi reagents, are environmentally-friendly, and thus I expect silicon will replace all other reagents in the near future.

Activation of Inactive Bonds

The research topic deserving the Nobel Prize after the cross-coupling reaction is possibly activation of inactive bonds for carbon-carbon bond formation. For example, C-C bonds and C-H bonds stable under normal conditions are activated by any method to convert into a C-C bond or C-X (hetero atom) in the target molecule. Unlike the cross-coupling method, it is not necessary to introduce metal or halogen in advance. This results in a favorable, environmentally-friendly manufacturing method with few or no byproduct formation. Researchers led by Shinji Murai of Osaka University were the first to activate the C-H bond by using a ruthenium catalyst. We showed that it is possible to selectively cleave C-CN bonds and C-H bonds by nickel(0) catalysts and Lewis acid cocatalysts. We also showed that it is possible to insert unsaturated substrates such as alkynes or alkenes. The respective reaction types are referred to the carboncyanation, hydro(hetero)arylation, and hydrocarbamoylation reactions. Currently, tough fierce competition is taking place in this field throughout the world and our laboratory at Chuo University is also pursuing unique reactions.

Creativity is essential for organic synthesis

My research style is invention of direct and useful synthetic reactions. If it is possible to invent a novel reaction, then novel structures (form/shape) are generated. Novel structures also result in novel functions (properties/characteristics/biological activity). In this way, the ultimate goal of organic synthesis is to invent (discover) pharmaceuticals, agrochemicals and functional materials that possess novel functions. All such results will enrich our lives. Similar to art, exercising creativity is an essential part of organic synthesis research, as a result, providing one with the opportunity of self-expression, and I truly find my work to be extremely engaging.

Tamejiro Hiyama
Professor of Organic Synthesis, Organic Chemistry and Organic Metallic Chemistry, Center for Research and Development Initiatives, Chuo University
Born in 1946 in Osaka. In 1969, graduated from the School of Industrial Chemistry at the Faculty of Engineering, Kyoto University.
1971: Completed the Master's Program in industrial chemistry at the Graduate School of Engineering, Faculty of Engineering, Kyoto University
1972: Quitted from the Doctor's Program in Industrial Chemistry at the Graduate School of Engineering, Faculty of Engineering, Kyoto University
1972: Became an Assistant Professor at the Department of Industrial Chemistry, Faculty of Engineering, Kyoto University
1981: Joined Sagami Chemical Research Institute, holding the positions of Research Fellow & Group Leader, Senior Research Fellow & Group Leader, and Executive Research Fellow & Group Leader
1992: Appointed to be a Professor of Research Laboratory of Resources Utilization, Tokyo Institute of Technology
1997: Became a Professor at the Graduate School of Engineering, Faculty of Engineering, Kyoto University
2010: Assumed current position
Areas of Expertise: Organic synthesis, organic chemistry and organometallic chemistry
Major written works include Synthetic Organic Chemistry (Tokyo Kagaku Dojin, 2012), Advanced Organic Synthesis (translated; Kagaku Dojin, 2009), Catalytic Reactions 103 for Organic Synthesis (Tokyo Kagaku Dojin, 2004), and Organofluorine Compounds: Chemistry and Applications (Springer, 2000).