Biotransformations dynamic kinetic resolution

Biotransformations in Small-molecule Pharmaceutical Development 1.3.4.2 Dynamic Kinetic Resolution... 

Optically active a-hydroxy carboxylic acids are useful intermediates in medicinal chemistry and asymmetric synthesis (Coppola and Schuster 1997). Enantioselective biotransformations of a-hydroxy nitriles (cyanohydrins) are important because they can lead to a dynamic kinetic resolution from readily available starting material. 

The use of microorganisms or commercially available enzymes to perfonn biotransformations is well established. Numerous routes have been developed to prepare chiral fine chemicals with enzymes from all classes, often in combination with chemical methods, and it is clear that many of the major phannaceutical companies are investing heavily in this type of research and development. With approaches such as dynamic kinetic resolution, pathway engineering, and screening for biocatalysts showing such promise, many new biotransformations will undoubtedly be discovered to develop novel, "green bioprocesses in the future. 

The product class of enantiomerically pure amines is of considerable importance in both pharmaceutical and agrochemical applications. For instance, enantiopure aryl-alkyl amines are utilized for the synthesis of intermediates for pharmaceutically active compounds such as amphetamines and antihistamines. Several chemical as well as biotransformation methods for the asymmetric synthesis/dynamic kinetic resolution [29] or separation of enantiomers of chiral amines have been described. These are illustrated in Scheme 4.5 for (S)-a-methylbenzylamine [30]. 

Enzymes - and thus hydrolases - can realize all kinds of selectivities such as chemo-, regio-, diastereomer and diastereotopic selectivity, as well as enantiomer and enantiotopic selectivity [83]. Accordingly, lipases were apphed in all possible kinds of stereoselective biotransformations [29, 30, 79, 81, 83] such as KR [79, 84], deracemization, and dynamic kinetic resolution (DKR) [85]. In this review, we wish to concentrate on methods enabling the continuous-mode hydrolase-mediated production of compounds in high enantiomeric purity. 

Enantioselective transformations catalyzed by nitrilases often suffer from poor chiral recognition. Exceptions from this trend are benzaldehyde and phenylac-etaldehyde cyanohydrins. As an additional advantage, these substrates racemize readily at near-neutral pH via reversible loss of hydrogen cyanide representing good starting materials for dynamic kinetic resolution processes. This was demonstrated using 22 substituted phenyl and heteroaryl derivates 25 with two recombinant nitrilases a preparative biotransformation yielded (S)-phenyllactic add 26 in 84% yield and 96% ee on 1 g scale (Scheme 9.7) [31]. 

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