Developing catalytic asymmetric synthesis recognised

THREE SCIENTISTS share this year's Nobel Prize in Chemistry: William S. Knowles, previously at Monsanto Company, St. Louis, Missouri, USA; Ryoji Noyori, Nagoya University, Chikusa, Nagoya, Japan and K. Barry Sharpless, The Scripps Research Institute, La Jolla, California, USA. They were awarded the Prize for their development of catalytic asymmetric synthesis. The achievements are of great importance for academic research, for the development of new drugs and materials, and are being used in many industrial syntheses of pharmaceutical products.

This year's Nobel Prize in Chemistry concerns the way in which certain chiral molecules can be used to speed up and control important chemical reactions. The word chiral comes from the Greek word cheir, which means hand. Our hands are chiral - our right hand is a mirror image of our left hand as are most of life's molecules. If, for example, we study the common amino acid alanine, we see that it can occur in two forms: (S)-alanine and (R)-alanine, which are mirror images.

However we twist or turn these forms, we cannot get them to overlap each other. Apparently, they do not have the same three- dimensional structure. The reason is that the carbon atom in the centre binds the four different groups H, CH{-3}, NH{-2} and COOH, which are located at the corners of a tetrahedron. The unbroken bonds to NH{-2} and COOH indicate that these bonds are in the plane of the paper, whereas the black wedge shaped bond and the broken wedge shaped bond show that they are directed upwards and downwards respectively in relation to the plane of the paper.

When alanine is produced in a lab a mixture is obtained, half of which is (S)-alanine and the other (R)-alanine. The synthesis is symmetrical (produces equal amounts of both enantiomers or forms). Asymmetric synthesis deals with the production of an excess of one of the forms.

Nature is chiral

When we study the molecules of the cells in close-up, it is evident that nature uses one of the two enantiomers. This applies to all living material amino acids, and therefore peptides, enzymes and other proteins.

Thus the enzymes in our cells are chiral, as are other receptors that play an important part in cell machinery. This means that they prefer to bind to one of the enantiomers. In other words, the receptors are selective; only one of the enantiomers fits the receptor's site. Since the two enantiomers of a chiral molecule often have totally different effects on cells, it is important to be able to produce each of the two forms pure.

Most drugs consist of chiral molecules. And since a drug must match the molecules it should bind to itself in the cells, it is often only one of the enantiomers that is of interest. In certain cases the other form may even be harmful.

Of late there has been intensive research into developing methods for producing - synthesising - one of the enantiomers rather than the other. In a synthesis starting molecules (substrate molecules) are used to build new molecules (products) by means of various chemical reactions. It is to researchers in this field that this year's Nobel Prize in Chemistry has been awarded. The Laureates have developed chiral catalysts for two important classes of reactions in organic chemistry: hydrogenations and oxidations.

Knowles' pioneer work

In the early sixties it was not known whether catalytic asymmetric hydrogenation was feasible. The breakthrough came in 1968 when William S. Knowles was working at the Monsanto Company, St Louis, USA. He discovered that it was possible to use a transition metal to produce a chiral catalyst that could transfer chirality to a non-chiral substrate and get a chiral product. The reaction was a hydrogenation in which the hydrogen atoms in H{-2} are added to the carbons in a double bond. A single catalyst molecule can produce millions of molecules of the desired enantiomer.

Knowles' experiments were based on two discoveries that had been made a few years previously. In 1966 Osborn and Wilkinson had published their pioneering synthesis of a soluble transition metal complex, that made it possible to catalyse a hydrogenation in solution. Their metal complex was not chiral. At the centre of the complex was the transition metal rhodium which bound four groups, ligands: three triphenylphosphine molecules and one chlorine.

The second discovery on which Knowles' pioneering work is based on, is Horner's and Mislow's syntheses of chiral phosphines, for example the enantiomer. B. Knowles' hypothesis was that it might be possible to produce a catalyst for asymmetric hydrogenation if the triphenylphosphine groups in Osborn and Wilkinson's metal complex (A) was replaced by one of the enantiomers of a chiral phosphine.

The phosphine first used by Knowles was not enantiomerally pure, yet it produced a mixture in which there was 15 per cent more of one enantiomer than the other. Although this excess was modest the result proved that it was in fact possible to achieve catalytic asymmetric hydrogenation. Other scientists (Horner, Kagan, Morrison and Bosnich) reached similar results shortly afterwards.

Knowles' aim was to develop an industrial synthesis of the amino acid L-DOPA, which had proved useful in the treatment of Parkinson's disease a discovery for which A. Carlsson was awarded last year's Nobel Prize in Physiology or Medicine. By testing enantiomers of phosphines with a varied structure Knowles and his colleagues quickly succeeded in producing usable catalysts that provided a high enantiomeric excess, that is, principally L-DOPA.

The ligand later used in Monsanto's industrial synthesis of L- DOPA was the diphosphine ligand DiPAMP. A rhodium complex with this ligand gave a mixture of the enantiomers of DOPA in 100% yield. The product contained of 97.5 per cent L-DOPA. Thus Knowles had in a short time succeeded in applying his own basic research and that of others to create an industrial synthesis of a drug. This was the first catalytic asymmetric synthesis.

How does a chiral catalyst molecule work?

What part does the catalyst molecule itself actually play in asymmetric hydrogenation? Studies by the inorganic chemist J. Halpern and others have clarified the reaction mechanism. The transition metal, rhodium for example which binds the chiral diphosphine, has the ability to simultaneously bind both H{-2} and the substrate. The complex obtained then reacts and H{-2} is added to the double bond in the substrate. This is the vital hydrogenation stage, when a new chiral complex is formed from which the chiral product is released. Thus from a substrate that is not chiral, chirality has been transferred from the chiral catalyst to the product. This product contains more of one enantiomer than of the other, that is, the synthesis is asymmetric.

The reason for the enantiomeric excess is to be found in the hydrogenation stage, as the hydrogen can be added in two ways that give the different enantiomers at different rates. These two pathways utilise different transition complexes, which are not mirror images and therefore have different energy. Hydrogenation takes place more rapidly via the complex with the lowest energy, thus producing an excess of one of the enantiomers.

In the development of better asymmetric hydrogenation catalysts it is important to increase the energy difference between the transition complexes in order to obtain, as a consequence, larger enantiomeric excess. This is of vital interest in industrial applications in which the aim is to achieve economy in the process and environmentally acceptable methods, that is, as few waste products as possible. This development has been led by another of this year's Laureates in chemistry, Ryoji Noyori.

The Japanese scientist Ryoji Noyori has carried out extensive research and developed better general catalysts for hydrogenation. In 1980 Noyori and co-workers published an article on the synthesis of both enantiomers of the diphosphine ligand BINAP. These catalyse, in complexes with rhodium, the synthesis of certain amino acids with an enantiomeric excess of up to 100 per cent.

But Noyori also saw the need for more general catalysts with broader applications. Exchanging rhodium, Rh(I), for another transition metal, ruthenium, Ru(II), proved, for example, to be successful. The ruthenium(II)-BINAP complex hydrogenates many types of molecules with other functional groups. These reactions give a high enantiomeric excess and high yields and can be scaled up for industrial use. Noyori's Ru-BINAP is used as a catalyst in the production of (R)-1,2-propandiol for the industrial synthesis of an antibiotic, levofloxacin.

Similar reactions are used for the synthesis of other antibiotics. Figure shown below gives an example of a stereoselective ketone reduction. Noyori's catalysts have found wide application in the synthesis of fine chemicals, pharmaceutical products and new, advanced materials.

Alongside the advances in chirally catalysed hydrogenation reactions, Barry Sharpless has developed corresponding chiral catalysts for other important reactions, oxidations. While hydrogenation removes a functional group because the double bond is saturated, oxidation leads to increased functionality. This creates new possibilities for building new complex molecules.

Sharpless realised that there was a great need for catalysts for asymmetric oxidations. He also had ideas as to how these could be achieved. He has made several important discoveries which here are exemplified by his chiral epoxidation. In 1980 he carried out successful experiments that led to a practical method for the catalytic asymmetric oxidation of allylic alcohols to chiral epoxides. This reaction utilised the transition metal titanium (Ti) and chiral ligands and gave high enantiomeric excess. Epoxides are useful intermediary products for various types of synthesis.

This method opened up the way for great structural diversity and has had very wide applications in both academic and industrial research.

Glycidol is used in the pharmaceutical industry to produce beta- blockers, which are used as heart medicines. Many scientists have identified Sharpless' epoxidation as the most important discovery in the field of synthesis during the past few decades.

Chirality in the amino acid alanine is illustrated with models of its two forms, which are mirror images of each other. They are designated (S) and (R).

(R)-limonene smells of oranges while its enantiomer (S)-limonene smells of lemons

Knowles exchanged the non-chiral phosphine triphenylphosphine in A to the chiral phosphine B and obtained a catalyst for asymmetric hydrogenation.

In this industrial synthesis of L-DOPA developed by Knowles and co-workers the compound C was used as the starting material. In the chiral hydrogenation one of the enantiomers of DiPAMP was used. The enantiomer D was 97.5% of the product and after acid hydrolysis of D, L-DOPA was obtained

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