Distinguished Guest Lectures

 

Ryoji NoyoriASYMMETRIC CATALYSIS:
ROLES IN BIOMEDICAL SCIENCE AND TECHNOLOGY


Ryoji Noyori

RIKEN (The Institute for Physical and Chemical Research), Wako, Saitama 351-0198, Japan, and Nagoya University, Department of Chemistry and Research Center for Materials Science, Chikusa, Nagoya 464-8602, Japan

 

In concert with the recent elucidation of human genome sequences, scientists started to intensively investigate the structures and functions of the corresponding proteins. One of the major aims of this study is to develop effective pharmaceutical drugs that prevent or cure painful diseases. Pharmaceutical drugs are precisely structured organic compounds that are compatible with proteins or other large biomolecules in human bodies. They mostly have a low molecular weight, <500, and are largely synthetic rather than natural in origin. The world pharmaceutical market has been growing steadily, and some important drugs mark a very high sales figure. For example, Simvastatin, C 25 H 37 O 5 , manufactured by Merck Company is an excellent drug for hypercholesterolemia, whose annual sales exceeds US$ 5 billion. Our concern is how to efficiently discover and how to economically synthesize such important compounds. The biochemical information of protein structures obviously helps the development of potent pharmaceutical drugs. I emphasize that chemistry plays crucial roles in the discovery, research, and production of such significant compounds. Without chemical synthesis, the pharmaceutical industry would not exist.

The major concern of chemists is on molecules and molecular assemblies. Any molecule, by definition, has a fixed elemental composition, a definite atom connectivity, a single configuration, and some conformations. On the basis of such structural characteristics, interesting and significant molecular functions emerge. Most importantly, in principle, any molecule can be designed and synthesized as desired. Thus, a diverse array of properties and functions can be generated by utilizing accumulated chemical knowledge. Chemistry is a science not only concerned with the observation and understanding of nature but is characterized by the capability of producing highly valuable compounds from almost nothing.

  I personally have been interested in the molecular chirality of organic compounds (Noyori, 2002). Molecular chirality normally emerges when a carbon atom possesses four different atoms or groups, resulting in two stereoisomers, called enantiomers ( R and S ), that are mirror images of one another and have identical free energy. The differences among enantiomers are slight but become important when these enantiomers are involved in biological or physiological phenomena (Figure 1). Enantiomers often taste and smell different. For example, ( S )-glutamic acid monosodium salt is tasty, while the R form is bitter. ( R )-Limonene has the fragrance of orange, while its S isomer has that of lemon. ( S )-Carvone has a fragrance of caraway seeds, while its R isomer has a component of spearmint and smells completely different. These phenomena are based on precise molecular interactions between such small chiral molecules and large protein receptors in our bodies, where the molecular chirality plays a key role.

 

Biological activities of enantiomers
(Figure 1) Biological activities of enantiomers

 

The structural differences between them may have deleterious effects in the case of synthetic drugs. An example of the incompatible relationship between molecular chirality and pharmacological activity was provided by the tragic administration of thalidomide to pregnant women in the 1960s. The commercial thalidomide is a 50:50 (racemic) mixture of right- and left-handed enantiomers (Figure 1). ( R )-Thalidomide has desirable analgesic properties, while its S enantiomer is a teratogenic and induces fetal malformations. Although there still exists a controversy in this interpretation, such problems arising from inappropriate molecular recognition in the human body must be avoided at all costs. Thus, the selective chemical synthesis of enantiomers, called asymmetric synthesis, is crucial in the pharmaceutical industry. However, until recently this remained extremely difficult. In 1990, approximately 1800 pharmaceutical drugs were on market. They come from various sources and have different chiralities, as shown in Figure 2. It should be noted that 88% of the synthetic chiral drugs were sold still in the racemic form, despite the thalidomide tragedy. Then, in 1992, FDA of the USA introduced the guidelines on "racemic switch", encouraging the commercialization of enantiomerically pure drugs produced by practical asymmetric synthesis. As a consequence, the proportion of enantiomerically pure drugs increased up to 40%, thanks largely to the efforts of synthetic organic chemists.

 

Chirality of pharmaceutical drugs
(Figure 2) Chirality of pharmaceutical drugs

 

To this end we require some general principle. Our method is to use a chiral molecular catalyst that consists of a metallic element and an attached chiral ligand, as schematically illustrated in Figure 3 (Noyori, 1994). The active metal center generates catalytic reactivity, accelerating a reaction repeatedly, while the attached chiral ligand controls stereoselectivity in the absolute sense. Our concerns are twofold. First, we must address the productivity and rate of a reaction; how many times does the catalyst turn over and how fast is the reaction? Second, we are concerned about the extent of enantioselectivity, which ranges from 50:50 (nonselective) to 100:0 (perfectly selective). Asymmetric catalysis is four-dimensional chemistry (Noyori, 1994). Thus a high efficiency can be achieved using a combination of both an ideal three-dimensional structure ( x, y, z ) and suitable kinetics ( t ) (Noyori et al., 2004). This is a general principle of asymmetric catalysis that is widely practiced in organic synthesis. Indeed, we were the first who discovered this principle in 1966 (Nozaki et al., 1966).

 

Chiral organometallic molecular catalysts
(Figure 3) Chiral organometallic molecular catalysts

 

In 1980 after a six-year effort, we reported for the first time the synthesis of the BINAP/Rh complex (Miyashita et al., 1980). This beautifully shaped chiral molecular catalyst became very famous, when we applied it to the industrial synthesis of menthol, a popular fragrance (Figure 4). Thus, when geranyldiethylamine is exposed to a small amount of the ( S )-BINAP/Rh complex, ( R )-cintonellal diethylenamine is obtainable in >98% ee (ee = enantiomeric excess, ( R - S )/( R + S )) (Tani et al., 1982). This reaction is highly productive and applicable to a 9-metric-ton scale. This is the result of a fruitful academic/industrial collaboration between the universities of Shizuoka , Osaka , and Nagoya , the Okazaki Institute for Molecular Science, and Takasago International Corporation. Takasago produces various optically active terpenes, including 1000 metric tons (-)-menthol per year, corresponding to one-third of the world's demand (Akutagawa, 1992).

 

Takasago menthol plant
(Figure 4) Takasago menthol plant

 

This asymmetric allylamine-enamine double bond-shift reaction is a very important process but is rather unconventional. Then we decided to pursue a more common asymmetric catalysis, namely, asymmetric hydrogenation. H 2 is the simplest molecule and a clean and abundant resource. H 2 has unlimited applicability to basic and applied science, technology, and even industry. Although the hydrogenation of unsaturated compounds is the most fundamental chemical reaction, efficient methods remain limited. For more than two decades since 1980, we have developed a series of chiral BINAP/transition metal complex catalysts for asymmetric hydrogenation (Figure 5) (Noyori, 1989, 1990, 1992, 1992, 1996, 2002; Noyori and Ohkuma, 2001; Noyori and Takaya, 1990). A major breakthrough occurred in 1986 when we developed the BINAP/Ru dicarboxylate complexes (Noyori et al., 1986). Ru behaves differently from conventional Rh, allowing the selective synthesis of many enantiomeric compounds. The enantioselection is very distinct, often >99:1 and even 100:0.

 

BINAP/transition metal catalysts for asymmetric hydrogenation
(Figure 5) BINAP/transition metal catalysts for asymmetric hydrogenation

The utility of the Ru complexes is extensive. Previously we noted that the BINAP/Rh complex catalyzes the asymmetric hydrogenation of a dehydro amino acid derivative to yield the phenylalanine derivative in nearly 100% ee (Miyashita et al., 1980). However, the reaction was slow, and the scope of the olefinic substrates was narrow. Fortunately when Rh was replaced by Ru, the scope could be extended significantly, allowing the asymmetric hydrogenation of many types of olefinic substrate. For example, reaction with N-acylated benzylidene-tetrahydroisoquinolines yielded the benzyl-tetrahydroisoquinolines in near 100% ee, providing a general method of the asymmetric synthesis of isoquinoline alkaloids (Kitamura et al., 1994). Hydrogenation of the acrylic acid with an aromatic ring gave the anti-inflammatory ( S )-naproxen in 97% ee (Ohta et al., 1987). When geraniol was used as a substrate, hydrogenation occurred only at the allylic alcohol part, giving citronellol in more than 95% ee (Takaya et al., 1987). It is now possible to hydrogenate many other olefinic substrates using the new BINAP/Ru complexes. Most importantly, the list of potential substrates can even be extended to include various ketones (Kitamura et al., 1988). The catalyst is BINAP/Ru dichloride or dibromide, and the presence of halogen atoms is also crucial for the catalytic activity. ß-Keto esters are the best substrates for the BINAP/Ru-catalyzed asymmetric hydrogenation (Noyori et al., 1987). This method is superior to any other chemical or biological synthetic procedures, and it allows the synthesis of various chiral ß-hydroxy esters. This process can be performed at a very large scale (Noyori, 1992). For example, carbapenem antibiotics are now best synthesized by this asymmetric hydrogenation. In the presence of the ( R )-BINAP/Ru complex, racemic methyl a-(benzamidomethyl)acetoacetate (a chiral ß-keto ester) is hydrogenated to give the R,S -configured ß-hydroxy ester under dynamic kinetic resolution (Noyori et al., 1989, 1995). The erythro:threo diastereoselectivity is 94:6 and the 2 S ,3 R :2 R :3 S enantioselectivity is 99.5:0.5 (99% ee). This compound is now produced in large quantities at Takasago International Corporation. In addition, the simple asymmetric hydrogenation of acetol to ( R )-propanediol is employed for the synthesis of levofloxacin, a very important antibacterial agent developed at Daiichi Pharmaceutical Company in Japan .

  Furthermore, we recently devised new catalysts that allow rapid, productive and selective hydrogenation of simple ketones, which is otherwise difficult to achieve (Noyori and Ohkuma, 2001). For example, 600 g of acetophenone can be hydrogenated with only 2 mg of the well-designed chiral BINAP/1,2-diphenylethylenediamine Ru catalyst (Doucet et al., 1998). A single molecular catalyst has an overall turnover number of more than two million times and a turnover frequency of 60 times per second. The high efficiency is due to the operation of a nonclassical metal-ligand bifunctional mechanism. Molecular hydrogen is symmetrical. However, upon interaction with our Ru catalyst, the H-H bond is cleaved and asymmetrically activated, and the resulting species reduces ketones with high enantioface distinction. This process is repeated more than two million times.

Figure 6 shows some applications of our method to the asymmetric synthesis of bioactive compounds. This method is already at a very advanced technical level and some compounds are now produced in industries. This asymmetric hydrogenation provides a very powerful tool for producing important chiral compounds.

 

Asymmetric synthesis of biologically active compounds
(Figure 6) Asymmetric synthesis of biologically active compounds

 

How to discover such important compounds? As mentioned above, pharmaceutical drugs are relatively small, precisely structured man-made organic compounds. The discovery of effective drugs requires a global approach involving the fields of chemistry, biochemistry, pharmacology, clinical medicine, and computer science, and the use of various efficient analytical and diagnostic instruments. The development of drugs often requires a ten-year research period, up to 400 researchers in various fields, and an enormous cost as high as US$ 0.5-1 billion per drug. In addition, a range of the latest scientific information and the most advanced technologies are necessary. The current most serious problem is the high cost of pharmaceutical drugs. This is a problem in many countries. The market of pharmaceutical drugs in Japan is currently about US$ 60 billion, which considerably contributes to the total expenses for the national medical care system of up to US$ 300 billion. Therefore, a significant issue is how to decrease such a high cost incurred in developing new pharmaceutical drugs. Without a significant decrease, modern pharmaceutical drugs can be used only in rich, advanced countries but, unfortunately, not in developing countries. One of the major reasons for the high cost is that, currently, about 90% of candidate drugs are excluded during the clinical trials, due to their toxicity and/or unfavorable pharmacokinetics. Although various efforts should be made to decrease such a serious financial risk, we propose a possible scientific/technical way directed toward this goal.

We became interested in applying our asymmetric prostaglandin synthesis (Noyori and Suzuki, 1984, 1990) to the science of the human brain. In this context, we have established a fruitful interdisciplinary and international collaboration with Professor Suzuki, a long-term collaborator now at Gifu University , Professor Watanabe, a biomedical researcher at Osaka City University , and Professor Långström at Uppsala University (Figure 7) (Takechi et al., 1996; Suzuki et al., 2000b). We found that the prostacyclin-type carboxylic acid (R = H), called (15 R )-TIC, shows a strong, selective binding to certain receptors in the central nervous system. The unnatural R configuration is important and accessible using our asymmetric chemical method. This was discovered during an in vitro study using tritium-labeled (15 R )-TIC and frozen sections of a rat brain. However, this compound is not appropriate for investigations in the human brain, since b - -particles from tritium cannot penetrate human tissues. For this reason, we wanted to incorporate 11 C into the aromatic group allowing noninvasive PET studies. The very short half-life of 11 C , 20 minutes, is beneficial but leads to a new chemical problem. Thus, although the 11 CH 3 group must be incorporated in the final step of the synthesis of (15 R )-TIC methyl ester, the total time for the synthesis, workup, purification, and sterilization should be less than 40 minutes.

 

Application of the prostaglandin synthesis to brain science
(Figure 7) Application of the prostaglandin synthesis to brain science

One of my students made a tremendous effort to solve this problem and found a method of incorporating a methyl group in the aromatic ring within 5 minutes (Suzuki et al., 1997, 2000a). This technology was then transferred to the PET center at Uppsala University , where Professor Suzuki volunteered as a subject for testing this new compound (Figure 8). The 11 C-labeled (15 R )-TIC methyl ester, which was intravenously administered to his right arm, was carried by the blood stream, passed through the blood-brain barrier, reached his brain, and was hydrolyzed to the free carboxylic acid, which was finally bound to IP 2 receptors in his central nervous system. Figure 8 shows the PET scan of his brain. The clinical significance of this behavior is yet unclarified. However, an in vitro study indicated that this compound suppresses the death of neurons under a high oxygen concentration.

Uptake of (15 R )-[ 11C]-TIC in the human brain
(Figure 8) Uptake of (15 R )-[ 11C]-TIC in the human brain

 

The principle of PET is simple. A 11 C nucleus undergoes ß + decay forming 11 B and a positron with a half-life of 20 minutes. The positrons collide with neighboring electrons and disappear, resulting in the emission of intense gamma rays of 511 keV. The measurement and computer analysis of these gamma rays result in a molecular imaging of the drug in the human body. Notably, 11 C has a very high specific radioactivity and a very short half-life of approximately 20 minutes. Most importantly, this method is noninvasive and negligibly harmful. This analysis is performed by microdosing of a drug and also outside the living human body. The extensive use of PET for research must be beneficial for developing new pharmaceutical drugs. In Japan , the PET technology is extensively used for diagnosis but, unfortunately, not at all in research for drug discovery. This noninvasive approach is crucial for developing evidence-based medicines. In addition, I am certain that the application of this method at an early stage of a clinical trial contributes to a decrease in the total cost of drug development.

In summary, the roles of asymmetric catalysis in biomedical science and technology are significant (Noyori, 2002). Well-designed chiral molecular catalysts permit the chemical synthesis of various bioactive compounds and functional materials. Asymmetric syntheses can be performed on a very large scale, as in the case of menthol synthesis, whereas brain research can be carried out on a very small, subfemtomole scale. In all cases, further studies of molecular chirality promise to yield great clinical and scientific benefits in the years to come.

References

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  • Doucet, H., Ohkuma, T., Murata, K., Yokozawa, T., Kozawa, M., Katayama, E., England , A. F., Ikariya, T. and Noyori, R. (1998) trans -[RuCl2 (phosphane) 2 (1,2-diamine)] and Chiral trans -[RuCl2 (diphosphane)(1,2-diamine): Shelf-Stable Precatalysts for the Rapid, Productive, and Stereoselective Hydrogenation of Ketones. Angew. Chem., Int. Ed. Engl. , 37, 1703.
  • Kitamura, M., Ohkuma, T., Inoue, S., Sayo, N., Kumobayashi, H., Akutagawa, S., Ohta, T., Takaya, H. and Noyori, R. (1988) Homogeneous Asymmetric Hydrogenation of Functionalized Ketones. J. Am. Chem. Soc ., 110, 629.
  • Kitamura, M., Hsiao, Yi., Ohta, M., Tsukamoto, M., Ohta, T., Takaya, H. and Noyori, R. (1994) General Asymmetric Synthesis of Isoquinoline Alkaloids. Enantioselective Hydrogenation of Enamides Catalyzed by BINAP-Ruthenium (II) Complexes. J. Org. Chem ., 59, 297.
  • Miyashita, A., Yasuda, A., Takaya, H., Toriumi, K., Ito, T., Souchi, T. and Noyori, R. (1980) Synthesis of 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), an Atropisomeric Chiral Bis(triaryl)phosphine, and Its Use in the Rhodium(I)-Catalyzed Asymmetric Hydrogenation of a -(Acylamino)acrylic Acids. J. Am. Chem. Soc ., 102, 7932.
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  • Noyori, R., Ohkuma, T., Kitamura, M., Takaya, H., Sayo, N., Kumobayashi, H. and Akutagawa, S. (1987) Asymmetric Hydrogenation of b -Keto Carboxylic Esters. A Practical, Purely Chemical Access to b -Hydroxy Esters in High Enantiomeric Purity. J. Am. Chem. Soc. , 109, 5856.
  • Noyori, R., Ikeda, T., Ohkuma, T., Widhalm, M., Kitamura, M., Takaya, H., Akutagawa, S., Sayo, N., Saito, S., Taketomi, T. and Kumobayashi, H. (1989) Stereoselective Hydrogenation via Dynamic Kinetic Resolution. J. Am. Chem. Soc ., 111, 9134.
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  • Takechi, H., Matsumura, K., Watanabe, Yu., Kato, K., Noyori, R., Suzuki, M. and Watanabe, Y. (1996) A Novel Subtype of the Prostacyclin Receptor Expressed in the Central Nervous System. J. Biol. Chem. , 271, 5901.
  • Tani, K., Yamagata, T., Otsuka, S., Akutagawa, S., Kumobayashi, H., Taketomi, T., Takaya, H., Miyashita, A., and Noyori, R. (1982) Cationic Rhodium(I) Complex-Catalysed Asymmetric Isomerisation of Allylamines to Optically Active Enamines. J. Chem. Soc ., Chem. Commun ., 600.