CHEMICAL BIOLOGY

Pharmaceutical Industry, Biocatalysts and Chemocatalysts

David J. Ager, DSM Pharmaceutical Products, Raleigh, North Carolina

Oliver May, DSM Pharmaceutical Products, Advanced Synthesis, Catalysis and Development, Geleen, The Netherlands

doi: 10.1002/9780470048672.wecb651

Catalytic reactions provide the opportunity to perform more environmentally friendly reactions. As the pharmaceutical industry produces a large amount of waste for a relatively small amount of drug product manufactured, the use of catalytic reactions is becoming more important. Catalysts can be biological or chemical in nature and can be used to effect a wide variety of transformations.

The pharmaceutical industry employs a wide variety of chemical transformations to prepare the active components of drugs. Cost and environmental pressures encourage the use of catalytic reactions for both bond-forming reactions and the creation of stereogenic centers. As the pharmaceutical industry generates a large amount of waste in the preparation of a relatively small amount of drug product, catalytic reactions will only increase in importance in this industrial sector (1). The E-factor, which is the amount of waste produced (Kg) to make a Kg of product, is high for the fine chemical and pharmaceutical industries. The use of catalytic methods, rather than stoichiometric ones, can help reduce waste (2). The development of a “green” process, however, has to be weighed against the speed of developing the process to the target molecule.

The purpose of this article is to provide an overview of the different types of chemical and biological catalysis currently available to the pharmaceutical industry in the process area. In other words, these transformations can be performed at scale. The types of catalysts that have been used are given together with systems that show potential for future application. The chemocatalytic area has addressed the synthesis of aromatic and heterocyclic compounds, which are common classes in pharmaceutically active compounds, whereas biocatalyst applications tend to be aimed toward the production of chiral molecules.

The uses of catalysts for asymmetric pharmaceutical synthesis have been reviewed by others (see the Further Reading section).

Types of Catalysts

Catalysts can be classified in many ways. A summary of the methods discussed in this article is given in Table 1. For enzyme catalysts, the recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB) have been followed (3). Enzymes are classified into six general groups, and the first digit of the enzyme commission number corresponds to the following general categories: 1) oxidoreductases, 2) transferases, 3) hydrolases, 4) lyases, 5) isomerases, and 6) ligases. The number of large-scale applications differs significantly among these enzyme types. Most commercial applications use hydrolases or oxidoreductases, which can be attributed to the broad range of enzymes available in these two classes (4).

Table 1. Catalysts useful for pharmaceutical applications

Biological Catalysts

In a few cases, biocatalysts have the advantage that no chemo-catalytic alternative exists. It usually occurs when the exquisite stereoselection of a biocatalyst is used to distinguish between two equally reactive groups within a molecule based on stereochemistry; the stereoselective oxidations of steroids and aromatic compounds are examples (5). Another instance in which biocatalysts are very powerful and no chemocatalyst equivalent is available is for glycosylation reactions and the stereocon-trolled synthesis of polysaccharides. In many areas, however, biological and chemical catalysts compete; examples of this competition include the reduction of ketones (vide infra) and the desymmetrization of cyclic anhydrides (6, 7). In these cases, the choice of which catalyst system to use will depend on accessibility and on process performance in such areas as selectivity, activity, and consumption, as well as cost. These parameters are highly product specific and often are difficult or impossible to predict. For the development of syntheses of new products, the fast screening of highly diverse libraries, be they biocatalytic or chemocatalytic, is, therefore, an important tool to determine the best choice of a catalytic system (8, 9). The use of molecular biological methodologies do allow for highly selective and efficient biocatalysts to be developed in a relatively short period of time (7). Without precedence, the development of a chemocatalyst is a long-term option.

Enzymes

Enzymes can be used in different formulations, immobilized or soluble, and with different degrees of purity, such as cell preparations and crude or enriched isolates. Isolation to a purified form takes time and effort and is usually avoided unless absolutely necessary. In many cases, molecular biology allows for an enzyme to be highly enriched (overproduced) in an organism, which reduces the need for purification (10). Such recombinant cells are, therefore, often used as cell preparations except if the cell needs to be treated to make the substrate accessible to the biocatalyst. More than 50 different enzyme subclasses are commercially available and can be used to prepare chiral molecules. A summary (11-14) of the most often used classes of enzymes that have been used in chemical synthesis is given in Table 2 (16-45). Reactions do not have to be performed in totally aqueous media as some enzymes can tolerate organic solvents (15).

Table 2. Enzymes used in the preparation of pharmaceuticals

Enzymatic processes are now being applied to a wide range of pharmaceutical product syntheses (46). Examples are given for the preparation of cyanohydrins, which can then be used to prepare α-hydroxy acids and α-amino acids.

Cyanohydrins are a very useful class of compounds as they can be transformed into a wide variety of compounds while retaining the stereogenic center (32, 35). Hydroxy nitrilases are available from natural sources (13), which can give access to either enantiomer of the product cyanohydrin (Fig. 1) (47).

Figure 1. Cyanohydrin formation with hydroxy nitrilases.

An example of an acylase to perform a resolution is provided by the Degussa process to L-methionine (1). The racemic acetylmethionine (2) is prepared by a chemical synthesis. The acylase hydrolyses only the L-isomer (Fig. 2). The D-isomer is racemized by base and put back into the process stream (48).

The most powerful approaches, which can be used with several different enzyme systems, lead to a single enantiomer as the product in high yield and do not rely on a classic resolution approach in which the unwanted enantiomer is discarded. These approaches include dynamic kinetic resolutions, deracemizations, and asymmetric and desymmetrization reactions (49, 50). In some cases, a chemical catalyst may be available to “recycle” the unwanted isomer in the same reactor (vide infra). It is sometimes possible to racemize the unwanted isomer of the substrate and then to perform the reaction again (51).

Figure 2. Synthesis of L-methionine.

Whole cells

When chemical transformations were performed by whole cells, such as the reduction of carbonyl compounds by baker’s yeast, low asymmetric induction could result as two enzymes are present in the organism that provide the antipodes of the product (52). This result has now been circumvented by the use of genetically modified microorganisms so that the desired enzyme is overproduced (53, 54).

The use of a whole cell allows for a required enzyme cofactor to be regenerated. In other cases, it allows for several enzymes to work in parallel and to perform many complex transformations. An example is provided by the synthesis of D-amino acids from hydantoins (Fig. 3). The carbomylase drives the reaction to completion as carbon dioxide and ammonia are evolved. The same approach has been used with the L-versions of the enzymes to synthesize L-amino acids (14, 42, 55).

Several complex antibiotics are prepared by whole-cell fermentations. Examples are the pencillin antibiotics in which the side chain can be removed and replaced with a synthetic one to enhance activity or stability. Other examples include the macrolide antiobiotics, such as avermectin (56) and erythromycin (57), in which the organism uses an enzyme “cassette” to build up the seco-chain before cyclization.

Figure 3. Synthesis of D-amino acids from hydantoins.

In some instances, metabolic engineering of an organism can provide the desired compound. As an example, shikimic acid is used as the starting material in the synthesis of Tamiflu (Roche Laboratories, Inc., Nutley, NJ), which is an antiviral drug. Bacteria produce shikimic acid as an intermediate on the biosynthetic route to chorismic acid, itself an intermediate for several essential products such as phenylalanine, tyrosine, and ubiquinone that the cell needs to function (58). By knocking out or controlling the genes that develop the enzymes that use shikimic acid as the substrate, the organism can be persuaded to overproduce this valuable starting material (Fig. 4).

Chemists have also taken lessons from nature and often use biomimetic syntheses or approaches to complex molecules; here, reactions used in an organism are mimicked in the laboratory (59, 60). In addition, catalytic transformations can be coupled, and it could be two chemocatalysts (vide infra) (61, 62).

Figure 4. Biosynthetic access to chorismic and shikimic acids.

Chemical Catalysts

Transition metal

Transition metal-based catalysts perform a wide variety of reactions. Many useful reactions can be used to build the carbon-carbon framework of the target molecule or to introduce functional groups into complex molecules. Many achiral methods exist; they often are named after the person who discovered or popularized them (see Table 3) (64-170). In some instances, the achiral reaction has been adapted to provide an asymmetric method; the latter examples are included in Table 4 (93, 118, 120, 124, 142, 149-202). The use of metal catalysts that act as Lewis acids or bases have been omitted as numerous examples can be described (63).

Table 3. Transition metal catalyzed reactions

^aThese include couplings such as the Kumada, Sonogashira, Negishi, and Stille reactions.

Table 4. Transition metal-based catalytic reactions that generate a new stereogenic center

When implementing a transition metal-catalyzed step at scale, many factors have to be considered, some of which also relate to biological and organocatalytic reactions. The one factor that does not overlap with these other types of systems is the price of the metal. Although cheaper metals such as iron, nickel, and copper can be used for some transformations, often the metal required is precious, such as palladium, platinum, rhodium, iridium, or ruthenium. The use of gold catalysis has recently become an area of intense research (141). These precious metals are expensive; usage needs to be minimal, and they must be recycled either for reuse in the reaction or through recovery. Refining has to be a topic of considerable economic concern. For some reactions, especially asymmetric transformations, the ligands needed to perform the reaction may be more expensive than the metal! Here, the catalyst has to be extremely efficient to achieve the required cost benefits. The economics of the transformation not only depend on the cost of the catalyst and how much is used (usually defined by turnover number, which is the number of times the catalyst goes round the catalytic cycle), but also the duration of the reaction. The turnover frequency is the number of times the catalyst completes a catalytic cycle per hour. Reactor time can be expensive, and time needs to be minimized but not at the cost of making the reaction so fast that it becomes unsafe or reagents, such as hydrogen, cannot be delivered at an appropriate rate.

An example of a metal-catalyzed reaction to form a biaryl product is the Suzuki reaction. The coupling can be performed without any phosphorus ligands for the metal and with only a small amount of the metal (0.05 mol %) (Fig. 5) (9). A reaction that has become popular is the preparation of aromatic amines by a palladium-catalyzed coupling reaction (Fig. 6). This methodology is general (89).

Figure 5. Biaryl compounds by Suzuki coupling.

Figure 6. Anilines by palladium catalysed coupling.

In addition to carbon-carbon bond formation, transition metal catalysts can also generate a stereogenic center. The first reaction of this type in which useful amounts of asymmetric induction were observed was an asymmetric hydrogenation to make phenylalanine and the method has been used for many years to synthesize the anti-Parkinsons drug, L-Dopa (3) (Fig. 7) (142, 143).

Figure 7. Asymmetric hydrogenation route to L-Dopa.

This transformation was important as it showed that a chemical catalyst could perform with similar asymmetric integrity to that of a biological system. Today, literally thousands of ligands and catalysts can be used to perform asymmetric hydrogenations as well as other reactions; see Table 4.

Many aspects must be considered in finding a catalyst to perform a step in the synthesis of a drug. The main aspect is the time required to find suitable catalyst systems. If a closely analogous reaction has been reported in the literature, then it may not be a large problem or concern. In most instances, however, this is not the case. In addition to enantioselectivity or diastereoselectivity, the factors necessary to find an efficient achiral catalyst must also be fulfilled.

Stereogenic centers can also be prepared by carbon-carbon bond-forming reactions or reductions of functional groups other than alkenes. Some reactions are also summarized in Table 4 (144); for a comprehensive work on asymmetric catalysts, see Reference 145. In some cases, two stereogenic centers can be created. This result can be achieved either in a single step as with the asymmetric reduction of a tetrasubstituted alkene, or by coupling two reactions together as with a conjugate addition followed by trapping the resultant enolate with an electrophile (146, 147). An illustration of this strategy is the synthesis of the bicyclic ketone 4 (Fig. 8) (147, 148). The allyl group is a good electrophile and is then converted to the analogous ketone by a Wacker oxidation.

Figure 8. Bicyclic enone synthesis by conjugate addition and aldol reaction.

An example of an asymmetric hydrogenation used in the preparation of a pharmaceutical intermediate is provided by a synthesis to carbapenems (5) (178). Reduction of the β-keto ester occurs under equilibrating conditions so that the erythro-product is formed in high yield and selectivity (203). Another catalytic step with ruthenium is used to introduce the acetoxy group (Fig. 9) (153).

Figure 9. Carbapenem synthesis by an asymmetric hydrogenation.

An asymmetric oxidation is used in the synthesis of esomeprazole (6), a proton pump inhibitor, which has therapeutic advantages over the racemic mixture omeprazole (Fig. 10) (204).

Figure 10. Esomeprazole synthesis by an asymmetric oxidation.

Chemocatalysts sometimes have an advantage over biological systems. Often the antipode of a ligand is accessible, although if a natural product is used as the source of the stereogenicity, then it may be less abundant and more expensive. As a last resort, and as ligands are relatively small molecules, an achiral synthesis and resolution might be used. This latter option is not available with a biological catalyst.

One of the main concerns of using a transition or heavy metal catalyst, especially toward the end of the synthetic sequence, is the removal of the metal. A wide variety of methods is known to accomplish this task. Metal-specific sequestering agents are now available. An alternative is to immobilize the catalyst, but it may not be a cost-effective solution for small volumes (205, 206). Of course, a heterogeneous catalyst can be used in the first place (207, 208).

Organocatalysts

This class of catalysts covers chemocatalysts that do not contain a transition metal. The class has been known for many years, but it is relatively recently that the term “organocatalyst” has been used (209). A wide variety of transformations can be performed, which is currently an area of intense research (209-218). Table 5 (220-252) summarizes some key transformations in which organocatalysis can be useful. Reactions range from the asymmetric epoxidation of alkenes, which need not be conjugated to another functional group, to aldol reactions and other carbon-carbon forming transformations. Some progress has also been made to couple two reactions together (219).

L-Proline catalyzes the aldol reaction. This approach has been applied to the synthesis of carbohydrate derivatives as illustrated by the glucose derivative 7 (Fig. 11) (237). The three-component Mannich reaction can be used to prepare β-amino and β-amino α-hydroxy carbonyl compounds in a single step (Fig. 12) (233). As with other types of catalysts, organocatalysts can be immobilized to aid recovery (253).

Table 5. Examples of transformations catalyzed by organocatalysts

Figure 11. Carbohydrate synthesis by an organocatalytic aldol reaction.

Figure 12. A three-component Mannich reaction.

Systems with Biocatalysis and Chemocatalysis

As enzymes usually only accept one enantiomer or isomer as substrate, many enzymatic reactions are resolutions; the unaffected isomer is waste. One way to circumvent this problem, which can have significant economical consequences, is to include a racemization or isomerization step with a second catalyst so that the substrate for the desired transformation can be accepted as the correct isomer (254, 255). This method allows dynamic kinetic resolutions to be performed with the desired product isomer being produced in high yield rather than with the 50% maximum available from a classic resolution approach (256).

A chemical catalyst can be used to racemize an alcohol, whereas an enzyme is used to prepare an ester of one of the enantiomers of that alcohol. In this example, reduced pressure was used to remove the isopropanol by-product and drive the reaction to completion whereas the Shvo catalyst was used to racemize the alcohol (Fig. 13) (257).

Figure 13. Dynamic kinetic resolution method to the ester of a chiral alcohol.

Future Outlook

Both biological and chemical-based catalysts are useful for a wide variety of reactions that range from carbon-carbon bond formation to the generation of a new stereogenic center. With the increasing awareness of green chemistry and the need to reduce waste in the pharmaceutical industry where this problem has been particularly bad, the use of catalytic reactions will surely continue to increase.

Biocatalysts are being applied widely in the industry, including the preparation of carbon-carbon bonds. Stereoselective oxidation with biocatalysts is an area where chemistry will find it hard to compete. A need still exists for new catalysts to replace stoichiometric reagents, as in the reduction of an amide to an amine, amide formation, and substitution of an alcohol (Mitsunobu reaction) (258). In both arenas of catalysis, the overall goal for green chemistry and stereoselectivity must be carbon-hydrogen bond activation.

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Further Reading

Ager DJ, ed. Handbook of Chiral Chemicals. 2nd edition. 2006. CRC Press, Boca Raton, FL.

Blaser H-U, Schmidt E, eds. Asymmetric Catalysis on Industrial Scale. 2004. Wiley-VCH, Weinheim, Germany.

Collins AN, Sheldrake GN, Crosby J, eds. Chirality in Industry: The Commercial Manufacture and Applications of Optically Active Compounds. 1992. John Wiley & Sons, Chichester, UK.II: Developments in the Commercial manufacture and Applications of Optically Active Compounds. 1997. John Wiley & Sons, Chichester, UK.

Collins AN, Sheldrake GN, Crosby J, eds. Chirality in Industry

de Meijere A, Diederich F, eds. Metal-Catalyzed Cross-Coupling Reactions, 2nd edition. 2004. Wiley-VCH: Weinheim, Germany.

de Vries JG, Elsevier CJ, eds. The Handbook of Homogeneous Hydrogenation. 2007. Wiley VCH, Weinheim, Germany.

Drauz K, Waldman H, eds. Enzyme Catalysis in Organic Synthesis: A Comprehensive Handbook. 1995. VCH, New York.

Jacobsen EN, Pfalz A, Yamamoto H. Comprehensive Asymmetric Catalysis. 2004. Springer, New York.

Patel RN, ed. Biocatalysts in the Pharmaceutical and Biotechnology Industries. 2007. CRC Press, Boca Raton, FL.

Sheldon RA. ChiroTechnology: Industrial Synthesis of Optically Active Compounds. 1993. Marcel Dekker Inc., New York.

Wong CH, Whitesides GM. Enzymes in Organic Synthesis. 1994. Pergamon Press, Oxford, UK.

See Also

Enzyme Catalysis, Chemical Strategies for