Pharmaceutical Industry, Biocatalysts and Chemocatalysts

David J. Ager, Oliver May,

DSM Pharmaceutical Products, Raleigh, North Carolina DSM Pharmaceutical Products, Advanced Synthesis, Catalysis and Development, Geleen, The Netherlands
doi: 10.1002/9780470048672.wecb651

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Article Contents
Types of Catalysts Biological Catalysts Chemical Catalysts Systems with Biocatalysis and Chemocatalysis Future Outlook

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 ne 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).

catalysts, the recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB) have been followed (3). Enzymes are classied into six general groups, and the rst 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 signicantly 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).

Biological Catalysts
In a few cases, biocatalysts have the advantage that no chemocatalytic 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 stereocontrolled 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 specic and often are difcult or impossible to predict. For the development of syntheses of new products, the fast screening of highly diverse libraries, be they biocatalytic 1

Types of Catalysts
Catalysts can be classied in many ways. A summary of the methods discussed in this article is given in Table 1. For enzyme

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Table 1 Catalysts useful for pharmaceutical applications Type Biological Class Living whole cell Enzyme Catalyst Many within the cell Oxidoreductases Transferases Hydrolases Lyases Isomerases Ligases Hydrogenations Asymmetric hydrogenations Aryl coupling reactions Coupling reactions Isomerizations Metathesis Carboncarbon bond formation Oxidations Example of transformation Preparation of secondary metabolite Oxidations and reductions Methylation, glycosylation and amino group transfers Ester hydrolysis CC and CN bond formations Racemization Coupling reactions Alkene reductions Generation of new stereogenic center Preparation of biaryl compounds Aniline preparation Chiral imines from allyl amines Ring formation Aldol reaction Epoxidations

Chemical

Transition metal

Organocatalysis

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 efcient 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 puried 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 purication (10). Such recombinant cells are, therefore, often used as cell preparations Table 2 Enzymes used in the preparation of pharmaceuticals Enzyme subclass Racemases Oxidases Dehydrogenases Lipases Aldolases Hydroxynitrile lyases Esterases Nitrilases N -Acetylamino acid hydrolase Amidases Hydantoinases Halohydrin dehalogenases Ammonia lyases Proteases 2 Substrate -Hydroxy acids -Amino acids Alcohols Carbonyl compounds Esters, amides Carbonyl compounds Carbonyl compounds Esters Nitriles N -Acetyl amino acids Amino acids 5-Monosubstituted hydantoins Halohydrins, epoxides Cinnamic acid derivatives Amino acids

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 (1114) of the most often used classes of enzymes that have been used in chemical synthesis is given in Table 2 (1645). Reactions do not have to be performed in totally aqueous media as some enzymes can tolerate organic solvents (15). 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 -hydroxy acids and -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).

Product -Hydroxy acids -Amino acids Carbonyl compounds Alcohols, hydroxy acids, amino acids Alcohols, carboxylic acids, alcohols, amines Hydroxy carbonyl compounds Cyanohydrins Alcohols, carboxylic acids Carboxylic acids Amino acids Amino acids Amino acids Diols, epoxides, -hydroxynitriles Phenylalanine derivatives Peptides

Reference(s) 16 16, 17 18, 19 20, 21 2226 2730 27, 31, 32 33, 34 35 36, 37 3840 41, 42 43 44 45

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Figure 1 Cyanohydrin formation with hydroxy nitrilases.

Figure 2 Synthesis of L-methionine.

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).

Whole cells
When chemical transformations were performed by whole cells, such as the reduction of carbonyl compounds by bakers 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 modied 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. WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.

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Figure 4 Biosynthetic access to chorismic and shikimic acids.

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 Tamiu (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).

Chemical Catalysts
Transition metal
Transition metal-based catalysts perform a wide variety of reactions. Many useful reactions can be used to build the Table 3 Transition metal catalyzed reactions Reaction type Aryl coupling reactionsa Heck reaction Suzuki reaction Buchwald-Hartwig reaction Cyclizations Metathesis Hydrogenations Hydroformylations Hydrovinylations Hydroaminations Protecting group removal Pauson-Khand reaction Oxidations Substrate

carboncarbon 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) (64170). 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, 149202). The use of metal catalysts that act as Lewis acids or bases have been omitted as numerous examples can be described (63). 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. Rening 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 efcient to achieve the required cost benets. The economics of the

Product

Reference(s) 6471 7183 71, 73, 8486 8789 9092 93116 117120 121123 124 125127 128 129133 134136 137 138, 139 140

Alkene Boronic acid or ester Amine Alkene Alkene or alkyne Alkenes Alkenes Alkene Alkene Various Alkenes Alcohols Alkene Alkene Alkene

Arylalkene Biaryl Aniline Various Alkene or alkyne Alkanes Aldehydes Alkene Amine Various Ketones Carbonyl compounds Epoxide Diol Carbonyl compounds

a These

include couplings such as the Kumada, Sonogashira, Negishi, and Stille reactions.
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Table 4 Transition metal-based catalytic reactions that generate a new stereogenic center Reaction type Hydrogenation Enamides ,-Unsaturated carboxylic acid derivatives Enamines Imines Ketones Alkenes Ketones Alkene Alkene Carbonyl compounds Carbonyl compounds Carbonyl compounds Carbonyl compounds Carbonyl compounds Allyl esters or similar Carbonyl compounds ,-Unsaturated compounds Carbonyl compounds Alkene Epoxides Alkenes Alkenes Allyl alcohols Suldes Alkenes Alkenes Various Alkene Alkenes -Amino acid derivatives -Substituted carboxylic acid derivatives Amines Amines Alcohols Alkanes Alcohols Amine Alkene Alcohols -Substituted carbonyl compounds Alcohols -Amino nitriles -Hydroxy nitriles Alkene -Hydroxy carbonyl compounds -Substituted compounds -Halocarbonyl compounds Alkene Diols Epoxides Aziridines Epoxy alcohols Sulfoxides Diols Amino alcohols Various Arylalkene Alkenes Substrate Product Reference(s) 118, 120, 149153 118, 142,152154 118, 152, 153 118, 118, 118, 118, 158 159 124 160 161 152, 153 152, 153 152, 153, 155, 156 157

Reductions Hydroamination Hydrovinylation Hydrosilylations Alkylations

Strecker reaction Cyanohydrin formation Allylic alkylations Aldol and related reactions Conjugate additions Halogenations Isomerizations Hydrolysis Oxidations

162164 165 166168 169172 173 174176 177 178, 153 179, 180 181 182188 189 190192 193 192, 194, 195 196198 199, 200 71, 201, 202 93

CH activation Heck reaction Metathesis

transformation not only depend on the cost of the catalyst and how much is used (usually dened 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

Figure 5 Biaryl compounds by Suzuki coupling. WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.

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Figure 6 Anilines by palladium catalysed coupling.

amines by a palladium-catalyzed coupling reaction (Fig. 6). This methodology is general (89). In addition to carboncarbon bond formation, transition metal catalysts can also generate a stereogenic center. The rst 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). 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 nding a catalyst to perform a step in the synthesis of a drug. The main aspect is the time required to nd 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 nd an efcient achiral catalyst must also be fullled. Stereogenic centers can also be prepared by carboncarbon 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

Figure 7 Asymmetric hydrogenation route to L-Dopa.

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

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. 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 -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).

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). 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

Figure 9 Carbapenem synthesis by an asymmetric hydrogenation. WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.

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Figure 10 Esomeprazole synthesis by an asymmetric oxidation.

Table 5 Examples of transformations catalyzed by organocatalysts Reaction type Epoxidation Alkylations Aldol reaction Mannich reaction Conjugate additions Baylis-Hillman reaction Acylations Hydroxylations Reductions Stetter and benzoin reactions Substrate Alkene Carbonyl compounds Carbonyl compounds Amino acid derivatives Carbonyl compounds Carbonyl compounds Unsaturated carbonyl compounds ,-Unsaturated carbonyl compounds Alcohol Carbonyl compounds Carbonyl compounds Aldehydes Catalyst type Carbohydrate derivatives Ylides Alkaloids, amines Alkaloids Amino acid derivatives Amino acid derivatives Various Nucleophilic Ester Amino acid derivatives Dihydropyridines Carbenes Reference(s) 220, 221 222, 223 224, 225 225230 231240 233, 240, 241 242 243245 246249 250 251 249, 252

to accomplish this task. Metal-specic 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 rst 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 (209218). Table 5 (220252) 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 carboncarbon 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 -amino and -amino -hydroxy carbonyl compounds in a single step (Fig. 12) (233). As with other types of catalysts, organocatalysts can be immobilized to aid recovery (253).

Systems with Biocatalysis and Chemocatalysis

As enzymes usually only accept one enantiomer or isomer as substrate, many enzymatic reactions are resolutions; the

Figure 11 Carbohydrate synthesis by an organocatalytic aldol reaction.

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Figure 12 A three-component Mannich reaction.

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

unaffected isomer is waste. One way to circumvent this problem, which can have signicant 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).

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Future Outlook
Both biological and chemical-based catalysts are useful for a wide variety of reactions that range from carboncarbon 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 carboncarbon bonds. Stereoselective oxidation with biocatalysts is an area where chemistry will nd 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 carbonhydrogen 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

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