Large-scale Biocatalysis

Many of today s large-scale applications use immobilized enzymes. In particular, the Japanese industry has for a long time pioneered this sector of biotechnology. In the multi-author publication edited by Tanaka, Tosa and Kobayashi [90] and in a more recent review [89], a number of well-established continuous production processes with immobilized biocatalysts are described in detail (for a selection, see below). Complementary information on some of these Japanese bioprocesses as well as additional case studies for other bioprocesses has been compiled by Cheetham [170], 

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The following examples illustrate Lonza s activities in large-scale biocatalysis for asymmetric synthesis. There are more examples of resolutions than true asymmetric syntheses, and this reflects the general current situation in the field of large-scale biotransformations. However, considerable research work is underway, both in universities and industry, to broaden the types of biocatalytic reactions that can be applied on a commercial scale. 

Hinge, R.D. (1990) Large-scale manufacture of oxattmiquine. nReal products from Industrial Biocatalysis, Royal Society of Chemistiy. 

The production of natural esters is the first example of a large-scale application of solid/gas biocatalysis, and many other systems are being studied today with a view to short or medium term development. 

Applications of biocatalysis in large-scale processes in industry advance only slowly against established chemical processes, even with stoichiometry-based chemistry. Introduction of biocatalysis into existing processes often requires process modifications that are not economical in view of the short life span of the product and/or the low fixed costs of the existing process owing to written-off plant. It should be emphasized that the desire to reduce chemical wastes, imposed by either company policy or governmental measures, needs to be matched by favorable process economics. Therefore, the introduction of biocatalytic options at the very beginning of product and process development is of the utmost importance. 

Although numerous chemicals have been produced at a pilot scale using biocatalysis, there are only a modest number of materials produced at the ton scale or greater. Some materials such as fructose syrup, acrylamide, and aspartame are produced on a large scale (>1000 tons per year), whereas others, including most pharmaceutical intermediates, are manufactured at considerably smaller... 

Supercritical fluids (SCFs) and in particular supercritical carbon dioxide (scC02) have also been shown to provide a unique medium in which to perform biocatalytic transformations. The ability to perform biocatalysis in a supercritical fluid was first demonstrated in 1985 by several groups. There are several advantages to the use of SCFs, as well as some drawbacks that need to be addressed if large-scale processes are to be developed. 

Large-scale applications of biocatalysis in the asymmetric synthesis of laboratory chemicals... 

Lonza is a major custom manufacturer of intermediates for the life science industries, and uses biocatalysis in many of its processes. Some of the products for which a biotransformation is used are achiral, however, an important characteristic of enzymes is their chirality, and this characteristic is used by Lonza to produce a number of chiral synthons. Biotransformations for the synthesis of asymmetric compounds can be divided into two types of reactions those where an achiral precursor is converted into a chiral product (true asymmetric synthesis) and those involving the resolution of a racemic mixture. Both types of reaction are used at Lonza, and several examples of each type of reaction are described for large-scale syntheses of chiral molecules that use a biotransformation in one or more of the steps. 

Large-Scale Applications of Biocatalysis in the Asymmetric Synthesis of Laboratory Chemicals... 

The large-scale resolution of racemic 2-alkanols to enantiomerically pure (R-)-and (S-t-)-alkanols by lipase shows environmental, health and safety advantages of biocatalysis compared with nonenzymatic syntheses. The biocatalytic Baeyer-Villi-ger oxidation of racemic bicyclo[3.2.0]-hept-2-en-6-one to enantiomerically pure 2-oxabicyclo[3.3.0]-oct-6-en-3-one and 3-oxabicyclo[3.3.0]-oct-6-en-2-one by CHMO represents an asymmetric Baeyer-Villiger oxidation. 

If you have reached this point in the chapter with the feeling that enzymes are all very well for the experts but that you are unlikely ever to use one, then this section is for you. Immobilized enzymes are now freely available from several companies and pharmaceutical companies use them on a large scale almost as a matter of routine. There are still problems of course and most asymmetric synthesis is not done with enzymes. In this section we set out to convince you that enzymes are practical reagents in organic solvents as well as in water and that practical minded chemists use them. An excellent review may convince you more.49 Recently a whole issue of the journal Organic Process Research and Development (2002, 6, issue 4, 420 ff.) was devoted to biocatalysis and the introductory article50 makes the point too. 

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