Deracemization Methods

Recently Turner and coworkers have sought to extend the deracemization method beyond a-amino acids to encompass chiral amines. Chiral amines are increasingly important building blocks for pharmaceutical compounds that are either in clinical development or currently licensed for use as drugs (Figure 5.7). At the outset of this work, it was known that type II monoamine oxidases were able to catalyze the oxidation of simple amines to imines in an analogous fashion to amino acid oxidases. However, monoamine oxidases generally possess narrow substrate specificity and moreover have been only documented to catalyze the oxidation of simple, nonchiral... 

For other biological resolution methods see Section 2.5.2.3 and Chapter 19. Another deracemization method uses radical chemistry. This topic is discussed in detail in Chapter 27. 

Deracemization by DKR is in principle a kinetic resolution process in which the non-transformed enantiomer is racemized in situ. The conditions are that a chiral catalyst promotes the transformation of one enantiomer (Rj) into the product (Rp) while the other enantiomer is racemized at a comparable rate and the racemic mixture (R -i- S ) is restored. The product (Rp) is not racemized under the same conditions. While a simple kinetic resolution yields a maximum of 50% of the product, with this technique a 100% conversion can be reached. Although the majority of chiral molecules of industrial interest are stiU prepared by kinetic resolution, the continuous development of industrial enzymes and racemizing processes fosters new chemo- or biocatalytic systems for DKR to appear. A great impulse for deracemization methods based on the one-pot/two-steps resolution racemization process was brought about by BackvaU et al. over a 10-year period... 

In this chapter deracemization methods for the preparation of multifunctional compounds (a- and P-hydroxy acids, a-hydroxynitriles, and a-amino acids) are discussed (Scheme 13.1). 

Many a- and P-hydroxy acids are found as natural products or incorporated into bioactive compounds and are required in both absolute configurations [5]. The biocatalytic asymmetric synthesis of these compounds has been reported in detail [6]. Since the racemic forms are easily available through conventional synthetic methods, the apphcation of deracemization methods appears a convenient approach for obtaining single enantiomers. 

For several reasons a-amino acids are ideal substrates for deracemization methods. They racemize easily by base catalysis under a number of conditions and they are racemized in Nature by the intervention of specific amino acid racemases. They are also recognized as substrates by oxidative enzymes to give the corresponding oxo-acids, in turn substrates for amino transferases and amino acid dehydrogenases. Several industrial preparations of L- and D-amino acids are based on processes of deracemization [26] or of separate two-steps resolution-racemization [27]. 

In order to be able to apply this deracemization method to a wide range of chiral amines, it was essential to identify monoamine oxidase enzymes possessing both... 

Servi, S., Tessaro, D., and Pedrocchi-Fantoni, G. (2008) Chemo-enzymatic deracemization methods for the preparation of enantiopure nonnatural a-amino acids. Coord. Chem. 

However, -stereoselective AOx applicable to the deracemization method have not yet been identified. 

Flafner et al first reported an oxidase-catalyzed deracemization method using amino acids as the substrate and pkDAAOx or LAAOx from Crotalus adamanteus together with sodium borohydride as the chemical reductant in 1971 [42]. A procedure for the successful deracemization of amino acids was previously reported by Soda et al. [43]. They focused on proline and pipecolic acid as substrates for the production of L-enantiomer by deracemization because these substrates formed stable imines rather than unfavorable keto acids in water by DAAOx. However, the enzyme was denatured by the chemical reaction with sodium borohydride. Turner et al developed an effective production method for (R)- or (S)-amino acids and (S)-amines by a deracemization method using milder chemical reducing reagents such as sodium cyanoborohydride and artificial transfer hydrogenase [44,45]. 

Tessaro D, Molla G, Pollegioni L, Servi S. Chemo-enzy-matic deracemization methods. In Fessner W-D, Anthon-sen T, editors. Modern biocatalysis stereoselective and environmentally friendly reactions. Weinheim Wiley-VCH 2009. p 195-228. 

Classic kinetic resolution starts from a racemate and ftimishes (in the ideal case) the optically pure diol and the epoxide in each 50% yield. This so-called classic kinetic resolution pattern is often regarded as a major drawback since the theoretical chemical yield of one stereoisomer can never exceed 50% based on the racemic starting material. Subsequently, the product has to be separated from the residual starting material and often the wrong enantiomer is of lesser or no importance. As a consequence, methods that offer a solution to this intrinsic problem of kinetic resolution are highly desirable. On the other hand, so-called deracemization methods that allow the transformation of a racemic starting... 

---