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Catalysts all the way

Print edition : Oct 27, 2001 T+T-

Developers of chiral catalysts for asymmetric synthesis in hydrogenation and oxidation win the Nobel Prize for Chemistry.

MANY naturally occurring molecules, particularly biological molecules, are found in two forms that are mirror images of each other, just as human hands mirror each other. Such molecules are chiral or handed, derived from the Greek word cheir, meaning hand. The two forms are called enantiomers. The amino acid alanine, for example, occurs as S-alanine and R-alanine. When the molecule is produced in the laboratory under normal conditions, a mixture containing equal amounts of the two enantiomers is obtained. That is, the synthesis is symmetrical. Asymmetric synthesis concerns the production of one of the enantiomers in excess over the other. In many applications, particularly pharmaceuticals, asymmetric synthesis is very important because, while one form may be beneficial to health, the other may even be harmful, as in the case of thalidomide. One form of this drug was known to prevent nausea in pregnant women while the other was found to cause foetal damage.

For many biological molecules, nature seems to prefer one form over the other. In plant and animal systems amino acids, peptides, enzymes and other proteins, nucleic acids such as DNA and RNA and carbohydrates occur as only one kind of enantiomer. Receptors in human cells too are chiral and so they, like the glove to a hand, prefer to bind only to one form. In fact, the two enantiomers can have different effects on the cells. Limonene, for example, is chiral and occurs as S-limonene and R-limonene which produce quite different sensations in our olfactory cells. The former smells of lemons and the latter of oranges. Therefore, it becomes important to be able to produce the two enantiomers in pure and unmixed form. This is particularly important in the case of drugs, the active ingredients in many of which are chiral molecules.

The Nobel Prize in Chemistry has been awarded to developers of catalysts (substances which speed up chemical reactions without themselves being consumed), which themselves are chiral, for asymmetric synthesis in two important classes of reactions in organic chemistry: hydrogenation and oxidation. One half of the award has been made jointly to William S. Knowles (84), formerly of Monsanto, St. Louis, U.S., and Ryoji Noyori (63), director of the Research Centre for Materials Science, Nagoya University, Nagoya, Japan, "for their work on chirally catalysed hydrogenation reactions", and the other half to K. Barry Sharpless (60) of Scripps Research Institute, La Jolla, California, "for his work on chirally catalysed oxidation reactions".

Winners of the Nobel Prize for Chemistry William S. Knowles, Ryoji Noyori and K. Barry Sharpless for key research that has been used to create numerous products, including antibiotics and heart drugs.

In any chemical synthesis, starting molecules (substrate) are used to build new molecules (products) by means of various chemical reactions. In the early 1960s it was not known whether catalytic asymmetric hydrogenation reaction, which will produce one enantiomer in excess, was possible. Knowles achieved the breakthrough in 1968 when he discovered that a transition metal based chiral catalyst could transfer chirality or handedness to a non-chiral substrate and get a chiral product. The reaction was a hydrogenation in which the hydrogen atoms H2 are added to carbon atoms in a double bond. A single catalyst molecule can produce millions of molecules of the desired product.

Knowles' experiments, based on two earlier discoveries, was to develop an industrial synthesis of the amino acid L-DOPA which was known to be useful in treating Parkinson's disease. By testing enantiomers of phosphine with varied structure, Knowles and colleagues succeeded in identifying a usable catalyst that would principally synthesise L-DOPA. The catalytic reaction that Monsanto used for the industrial synthesis of L-DOPA gave a 97.5 per cent yield of the enantiomer. This instance is one of the few where in a very short time the scientist has been able to apply his own basic research to create an industrial synthesis of a drug. Monsanto process was the first commercialised catalystic asymmetric synthesis employing a chiral transition metal complex and it has been in use since 1974. The spectacular success of Knowles'technique has contributed significantly to the explosive growth of the field and many other asymmetric catalytic processes have since followed.

How does the mechanism work? The inorganic chemist J. Halpern has provided an insight into this. The transition metal (metal rhodium in this case) that binds the chiral molecule (phosphine in this case) has the ability to catalyse both H2 and the substrate simultaneously. The complex thus obtained reacts and H2 is added to the double bond in the substrate. This is the hydrogenation stage when a new chiral complex is formed from which the final chiral product is released. Thus from a substrate that is not chiral, chirality has been transferred from the chiral catalyst to the product. The reason for the enantiometric excess (EE) lies in the fact that during hydrogenation, H2 can be added in two ways corresponding to the two enantiomers but the two pathways use different transition complexes which are not mirror images of each other and, therefore, have different energy. Hydrogenation via the process that has the lowest energy dominates results in EE.

Ryoji Noyori in Nogoya realised that to achieve higher EE the key was to maximise the energy difference between the two complexes. This would result in process economy as well as an environmentally acceptable process without the wastage of the undesirable enantiomer. He and his colleagues developed better and more general hydrogenation catalysts in the 1980s. Instead of Rh as the transition metal, Noyori used ruthenium (Ru) and found that Ru complex hydrogenated many other types of molecules. Noyori's Ru-based catalyst is being used in the production of R-1,2-propandiol for the industrial synthesis of the antibiotic levofloxacin. Similar reactions are being used for other antibiotics. Noyori's generalised catalysts have found applications in the synthesis of fine chemicals, pharmaceutical products and new advanced materials.

SHARPLESS developed chiral catalysts for oxidation reactions. As against hydrogenation, which reduces the functionality of the compound because H2 saturates the double bond, oxidation results in increased functionality. This opens up the possibility for creating complex new molecules. In 1980, Sharpless made several discoveries in the field, the most important being his "chiral epoxidation". He found a practical method for the catalytic asymmetric oxidation of allyl alcohols to chiral epoxides. This reaction utilised the transition metal titanium (Ti), which gave high EE. Epoxides are useful intermediaries for various types of syntheses. This method has wide applications in research and industry. For example, the synthesis of R-glycidol, which is used in the pharmaceutical industry to produce beta-blockers used in cardiac medicines, uses Sharpless' Ti-based chiral catalyst. The Nobel citation says that Sharpless' epoxidation has been the most important discovery in the field of synthesis during the past few decades.

The discoveries have also applications in the production of flavouring and sweetening agents. The discoveries have also provided academic research with many important tools not only in chemistry but the molecular world in general and have enabled investigations in materials science, biology and medicine.