Enzymes as chiral catalysts

Enzymes as chiral catalysts play a role in all three methods. In nature enzymes catalyse all production of chiral compounds. In the laboratory enzymes can catalyse asymmetric synthesis, as well as resolve racemates. Which of the three methods is chosen in different cases depends on several factors, like price of starting materials, number of synthetic steps, available production technology and know-how etc. There is at present a constant ongoing development of synthetic methods and biotransformation is one field. Utilization of method i) requires knowledge of classical organic synthesis, enzymes have already played their role. Enzymes may play a part both in asymmetric synthesis and resolution. 

Although the use of enzymes as chiral catalysts will undoubtedly increase as they become more available, nonenzymic catalytic asymmetric synthesis is a very powerful tool in organic chemistry. 

Another approach, called kinetic resolution, depends on the different rates of reaction of two enantiomers with a chiral reagent. A very effective form of kinetic resolution uses enzymes as chiral catalysts to selectively bring about the reaction of one enantiomer in a racemic mixture (enzymatic resolution). Lipases, or esterases, enzymes that catalyze ester hydrolysis, are often used. In a typical procedure, one enantiomer of the acetate ester of a racemic alcohol undergoes hydrolysis and the other is left unchanged when hydrolyzed in the presence of an esterase from hog liver. 

Resolution is the separation of a racemic mixture into its enantiomers. Because two enantiomers have the same physical properties, separating them, in general, is difficult, but scientists have developed a number of ways to do it. In this section, we illustrate just two of the several laboratory methods for resolution the use of enzymes as chiral catalysts and the use of solid chiral materials to differentiate between enantiomers made to come in contact with these materials. 

Enantiomers have identical physical and chemical properties in achiral environments but different properties in chiral environments, such as in the presence of plane-polarized light. They also have different properties in the presence of chiral reagents and enzymes as chiral catalysts. 

In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [1, 3]. This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. 

Groger, H. Wilken, J. The Application of L-Proline as an Enzyme Mimic and Further New Asymmetric Syntheses using Small Organic Molecules as Chiral Catalysts, Angew. Chem. Ira. Ed. 2001,40, 529-532. 

The potential of enzymes as catalysts in asymmetric synthesis has been recognised for many years.2-i2 Rate acceleration and stereoseiectivity, together with techniques for the iow-cost production and the rational alteration of their properties, make enzymes attractive as chiral catalysts in organic synthesis. Enzyme-catalyzed reactions have been categorised into six main groups ll as shown in Table 1. Three of them, oxido-reductases, hydrolases, and lyases have been found useful in organic synthesis. 

A cell of a living microorganism can be considered as a small factory consisting of different reactors containing different catalysts (enzymes). In this way, the cell can perform multi-step conversions without the need for recovery or purification of intermediate products. Through this so-called metabolic pathway, i.e. the consecutive conversion of the starting material into the end product, one fermentation can replace a multi-step chemical and/or catalytic procedure. In addition, as the enzymes are chiral catalysts, only one of the two optical isomers is produced. 

L-Proline as an enzyme mimic and new asymmetric syntheses using small organic molecules as chiral catalysts 01AG(E)529. 

The purpose of this appendix is to survey chiral auxiliaries, solvents, reagents, and catalysts which are often used in stereoselective bond-forming reactions, thus avoiding repetition of details on the synthesis of these compounds in the other sections of Houben-Weyl Volume E21 which discuss specific reaction types. It will not contain every chiral compound ever used in asymmetric synthesis, but will focus on compounds mentioned in this Houben-Weyl volume. Reagents used exclusively for the resolution of racemates are not included, as these are treated in more detail in Section A.2. Enzymes, which can also be considered as chiral catalysts, are also not discussed they are beyond the scope of this section, which concentrates on chemical techniques. 

Goger, H. and Wilker, J. (2001) The application of L-proline as an enzyme mimic and further new asymmetric s3mtheses using small organic molecules as chiral catalysts. Angewandte Chemie - International Edition, 40, 529-532. 

We shall see that when reactions like this are carried out in the presence of a chiral influence, such as an enzyme or chiral catalyst, the result is usually not a racemic mixture. 

CBS (Corey, Bakshi, and Shtbata) Catalyst Itsuno [67] paved the way for the discovery of oxazaborolidines as chiral catalysts for the borane-mediated enantioselective reduction of a wide variety of achiral ketones, the so-called CBS reduction. Scheme 2.139 summarizes some of these results and the proposed transition state [68], These data show that the CBS reduction process results in exceUent enanti-oselectivities and leads to a product whose absolute configuration can be predicted from the relative effective steric bulk of the two carbonyl appendages. It is noteworthy that the oxazaborolidine catalyst behaves like an enzyme in the sense that it binds with both ketone and borane and brings... 

Lipases are an important class of industrial enzymes and are used as chiral catalysts in a variety of reaction types. In organic synthesis, lipases are one of the most widely utilized and versatile biocatalysts. Lipases maintain activity in a nonaqueous environment, a property resulting in several advantages over other classes of enzymes. The water-insoluble enzymes and products can be readily recovered and the enzymes recycled. The absence of water can decrease the likelihood of side reactions and decrease product or substrate inhibition [6]. 

On the other hand, various ( l-cyanohydrins have been prepared using (5)-hydroxy-nitrile lyases from plants (Fig. 34). The (5)-cyanohydrins can be further converted to a-hydroxy acids by acid hydrolysis without racemization [107]. A recent example is the hydroxynitrile lyase from Manihot esculenta, which was cloned in E. coli and used as chiral catalyst for the synthesis of a broad range of optically active a-hydroxynitriles including keto-(5)-cyanohydrins using diisopropyl ether as organic solvent and HCN as cyanide source [112]. Compared to the enzymes from leaves, the overexpressed enzyme in E. coli showed higher enantioselectivity. 

Several approaches to enantioselective synthesis have been taken, but the most efficient are those that use chiral catalysts to temporarily hold a substrate molecule in an unsymmetrical environment—exactly the same strategy that nature uses when catalyzing reactions with chiral enzymes. While in that unsymmetrical environment, the substrate may be more open to reaction on one side than on another, leading to an excess of one enantiomeric product over another. As an analog)7, think about picking up a coffee mug in your... 

These examples are part of a broader design scheme to combine catalytic metal complexes with a protein as chiral scaffold to obtain a hybrid catalyst combining the catalytic potential of the metal complex with the enantioselectivity and evolvability of the protein host [11]. One of the first examples of such systems combined a biotinylated rhodium complex with avidin to obtain an enantioselective hydrogenation catalyst [28]. Most significantly, it has been shovm that mutation-based improvements of enantioselectivity are possible in these hybrid catalysts as for enzymes (Figure 3.7) [29]. 

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