Background

Each year that passes sees increasing interest in the application of enzymes and micro-organisms as catalysts in organic chemistry. Well-received national reports on the potential growth of biotechnology, not to speak of numerous reviews of the topic of biotransformation itself, have described the advantages which biological catalysis can bring to complex organic syntheses. At this time it is indeed an exciting prospect for anyone who has a role to play in the development of this new technology. But occasionally a prospective participant, as well as a reviewer, ought to stand back and ask, Why has this explosion of interest happened now?

An answer to such a question often lies in the historical context from which technologies and their underlying science develop. This is a topic worthy of greater attention than it usually receives from practising scientists. A resort to scientific papers more than one or two decades old is frequently viewed as perverse, while to consult the scientific literature of the past century in search of a pertinent contemporary lesson is simply eccentric. Yet this old literature can be worth reading for the light it can shed on current research, quite apart from which, it is, more often than not, a pleasure to read.

The biochemistry of the late nineteenth century has an interesting connection with the manufacture of vitamin C. The basis of this process relied on the development of the concepts of fermentation and catalysis, but it emerged directly from a microbial oxidation described in a short paper written by Adrian Brown (1886a).

Twenty years ago, only a handful of laboratories, some in industry and some in academia, were interested in using enzyme-catalysed reactions (biotransformations) in organic synthesis. At best those researchers were considered to be at the margin of mainstream synthetic organic chemistry; at worst they were considered to be downright odd.

In the 1980s there was an exponential increase in interest in the area of biotransformations. That worldwide increase in attention to this field of research can be assigned to several factors, including the perception and perseverance of the original researchers in the field, the increased availability of a wide variety of enzymes, and the realization that many families of enzymes will transform a wide range of unnatural compounds, as well as their natural substrates.

The utilization of enzymes in organic synthesis can be advantageous for several reasons:

1. Enzymes catalyse reactions under mild conditions with regard to temperature (ca. 37 °C), pressure (1 atm), and pH (ca. 7.0). The transformations are often remarkably energy-efficient when compared with the corresponding chemical processes.

2. Enzymes often promote highly chemoselective, regioselective, and stereoselective reactions, and being chiral catalysts, they are often able to generate optically active compounds. The increased awareness regarding the need to have optically pure compounds for such uses as Pharmaceuticals and agrichemicals (so as to avoid unnecessary toxicity and/or ecological damage) has been a significant driving force in the development and exploitation of non-natural enzyme-catalysed reactions.

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Introduction

As discussed in Chapter 1, there has been much interest, over many years, in oxidation and reduction reactions catalysed by micro-organisms. Processes for alcohol production and for the manufacture of vinegar and vitamin C have intrigued investigators for ages. Today there is great interest in discovering new whole-cell and isolated-enzyme-catalysed reactions of this type. As described in Chapter 3, the focus of the presentday work in this area is the production of compounds (often in optically active form) that might be useful as intermediates or end-products for the pharmaceutical, fragrance, flavour and agrichemical industries.

For many oxidation and reduction reactions it is often necessary to make a choice between using a whole-cell system or an isolated enzyme (with the requisite co-factors) for the biotransformation. In this area, factors that influence the choice often are much more complicated than those for hydrolysis reactions. The pros and cons of employing whole cells or partially purified oxidoreductase enzymes have been discussed in Chapter 2, and the salient features are summarized in Table 2.3. While the advantages and disadvantages will not be discussed in detail again, many of the points made earlier will recur in this discussion.

Reduction of ketones using whole cells

For example, consider one of the simplest reduction processes, namely the reduction of a ketone to a secondary alcohol. Of course, this can be accomplished chemically using sodium borohydride.

Introduction

Biological catalysis has such a pervasive influence on the industries which are closely associated with our daily lives that it is difficult to contain a short review within sensible bounds. The traditional large-scale crafts associated with agriculture, the manufacture of foods and drinks, and the preparation and cleaning of fabrics all use biological catalysis. At the other extreme, biological catalysis has an important role to play in analytical chemistry. Enzymes are used to monitor the levels of metabolites as an important feature in the diagnosis and therapy of disease. These techniques have been extended to the use of enzymes to amplify the responses in antibodybased assays, as well as to mediate the detection of an environmental pollutant at an electrode. The same catalysts also play a role in the degradation of pollutants, which is, perhaps, simply an extension of the role of biochemistry applied to the traditional craft of cleaning.

However, it is the use of enzymes in the large-scale manufacture of synthetic organic chemicals which is the main topic of this chapter. The recent interest amongst organic chemists arises from the high degrees of specificity and selectivity that characterize enzyme catalysis. That this is a valuable resource in manufacture cannot be doubted, as judged by the value of the products which it produces. Nevertheless, the methodology should not be oversold. Biocatalysis has a part to play in the modern chemical industry, but it also has limits which it is necessary to understand.