Dynamic resolution processes

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris- 

Jacobs has used Adam s catalyst with a lipase enzyme to effect the DKR of a variety of amines in high yield and optical purity (Table 13.1 [16]). The nature of the Pd catalysts may prevent wide application, as they are nonspecific and can affect other groups in the substrate. 

Reactions in toluene at 70°C. 5.7mol% of 5% Pd on BaSO4, 250wt% Candida antarctic lipase, 0.1 bar Hl 

The practical difficulty with carrying out a crystalhzation DTR process is the need to operate under conditions that allow selective crystalhzation of the least soluble diastereomer while permitting the racemization to take place. Amine racemization catalysts, such as SCRAM , Shvo, Pd/C, and Adam s, are more active at higher temperatures, which runs counter to the conditions required for crystaUization. A solution to this problem is to separate the diastereomeric resolution and racemization steps but couple them with a flow engineering design. In this way each reaction can be operated under optimal conditions for example, temperature, concentration and solvent, via an intermediary solvent exchange unit Since the racemization catalyst itself may affect the crystalhzation (or indeed the crystalhzation may affect the catalyst), it is preferred to keep them separate. This can be achieved by having the catalyst or product either permanently or temporarily in a different phase by immobilization, extraction, precipitation, distil- 

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Scheme 7.19 The synthesis of homochiral L-(S)-tert-leucine via a lipase-catalyzed dynamic resolution process.

The dynamic cyanohydrin system was next challenged with lipase-catalyzed transesterification resolution using different operational conditions. Thus, different lipases, organic solvents, additives, and acyl donors were evaluated. Isopropenyl acetate 26 was chosen and used as acyl donor because its reaction produces acetone as by-product, which does not interfere in the reaction and the NMR spectra. Molecular sieve 4 A was also added in the dynamic resolution process to control the water activity. The lipase preparation PS-C I was chosen in the resolution process since it expressed the highest lipase activities for both the substrate structure and the enantiomeric selectivities. Different organic solvents were also... 

An alternative enzyme/transition metal combination employs transfer hydrogenation catalysts that are capable of racemizing secondary alcohols. The racemization procedure temporarily converts the alcohol into an achiral ketone, which is reduced back to the racemic alcohol. Coupling this racemization procedure to an enzyme-catalyzed acylation reaction affords a dynamic resolution process (Fig. 9-12). Several enzyme/transition metal combinations have been shown to be effective for these reactions, although ruthenium complexes 1-3 appear to be especially effective for the in situ racemization of the alcohol. The product esters are not prone to racemization under the reaction conditions. Early results employing transfer hydrogenation catalysts to effect the racemization of alcohols required the use of added ketone 21, 22. However, it was subsequently shown that added ketone was not required when appropriate transition metal complexes were used as catalysts. Furthermore, the use of 4-chlorophenyl acetate as the acyl donor afforded improved results. 

ATCC 8750. An isolated yield of 94% of the enantiomerically pure mandelic add was obtained, indicating that a dynamic resolution process is occurring. 

The recycling of the undesired enantiomer from the enzymatic resolution is of crucial importance particularly on an industrial scale [107]. The classical chemical method consists of the thermal racemization of an amino acid ester at about 150-170°C. Milder conditions can be employed for the racemization of the corresponding amides via intermediate formation of Schiff bases with aromatic aldehydes such as benzaldehyde or salicylaldehyde (Scheme 2.14). More recently, intense research has been devoted to the use of isomerase enzymes (such as amino acid racemases [108]) aiming at the development of dynamic resolution processes. 

Kinetic and Dynamic Resolution of rac-Nitriles. a-Hydroxy and a-amino acids can be obtained from the corresponding a-hydroxynitriles (cyanohydrins) and a-aminonitriles [684], which are easily synthesized in racemic form from the corresponding aldehyde precursors by addition of hydrogen cyanide or a Strecker synthesis, respectively (Schemes 2.107 and 2.108). In aqueous systems, cyanohydrins are stereochemically labile and undergo spontaneous racemization via HCN elimination, which furnishes a dynamic resolution process. From aliphatic rac-cyanohydrins, whole cells of Torulopsis Candida yielded the corresponding (S)-a-hydroxy acids [685], while (R)-mandelic add is produced from rac-mandelraiitrile... 

Dynamic Resolution. Lipase-catalyzed acyl transfer has become a well-established and popular method for the kinetic resolution of primary and secondary alcohols. In order to circumvent the limitations of kinetic resolution (i.e., a 50% theoretical yield of both enantiomers), several strategies have been developed, which achieve a more economic dynamic resolution process and allow the formation of a single stereoisomer as the sole product (for the theoretical background see Sect. 2.1.1). In contrast to compounds bearing a chiral center adjacent to an electron-withdrawing... 

On the other hand, various biocatalytic hydrolysis methods have been developed on the basis of DKR. The a-hydrogens of thioesters are more acidic than those of (non-activated) oxoesters, although the rates of base-catalysed hydrolysis of thioesters and oxoesters are very similar. Several thioesters have been subjected to enzymatic resolution by lipases, but their exceptional a-H-acidity has more rarely been exploited for a dynamic resolution process this concept having been verified with several thioesters of a-(phenylthio)pro-pionate (Scheme 3.36). 

Dynamic resolutions are kinetic resolutions modified with an additional feature, i.e., a racemization step (Scheme 9). This can afford 100% yield of the fastest reacting enantiomer if rac — and product racemization does not occur. Furthermore, in contrast to a classic resolution process, the enantiomeric excess of the product in a dynamic resolution process becomes independent of the conversion. 

Scheme 12 a Upase-catalyzed dynamic resolution process with in situ enzymatic racemization [111]. 

No racemization was observed in the presence of phenylethylamine of either the product amide or the substrate ester in the absence of enzyme. This represents a dynamic resolution process with in situ enzymatic racemization. The picture is still unclear as to whether the substrate ester is racemized or if the racemization takes place in the acyl enzyme. 

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