Other Deracemization Processes

Deracemization via the biocatalytic stereoinversion is usually achieved by employing whole cells. In the case of secondary alcohols, it is believed that microbial stereoinversion occurs by an oxidation-reduction sequence 

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Other racemization systems that may be amenable to conversion to deracemization processes in future have recently been reported by Faber and coworkers [33]. Resting cells of L. paracasei have been used for biocatalytic racemization of open-chain and cyclic dialkyl-, alkyl-aryl-, and diaryl-substituted acyloins (29/30) (Figure 5.20). Both... 

It should be mentioned that the great majority of dynamic kinetic resolutions reported so far are carried out in organic solvents, whereas all cyclic deracemizations are conducted in aqueous media. Therefore, formally, this latter methodology would not fit the scope of this book, which is focused on the synthetic uses of enzymes in non-aqueous media. However, to fully present and discuss the applications and potentials of chemoenzymatic deracemization processes for the synthesis of enantiopure compounds, chemoenzymatic cyclic de-racemizations will also be briefly treated in this chapter, as well as a small number of other examples of enzymatic DKR performed in water. 

Deracemization. In this type of process, one enantiomer is converted to the other, so that a racemic mixture is converted to a pure enantiomer, or to a mixture enriched in one enantiomer. This is not quite the same as the methods of resolution previously mentioned, although an outside optically active substance is required. To effect the deracemization two conditions are necessary (7) the enantiomers must complex differently with the optically active substance (2) they must interconvert under the conditions of the experiment. When racemic thioesters were placed in solution with a specific optically active amide for 28 days, the solution contained 89% of one enantiomer and 11 % of the other. In this case, the presence of a base (Et3N) was necessary for the interconversion to take place. Biocatalytic deracemization processes induce deracemization of chiral secondary alcohols. In a specific example, Sphingomonas paucimobilis NCIMB 8195 catalyzes the efficient deracemization of many secondary alcohols in up to 90% yield of the (R)-alcohol. ... 

The kinetic resolution of amines was exploited first with co-TAs since the reaction is thermodynamically favored using pyruvate as acceptor [21]. Unfortunately, the inherent maximum 50% yield limits the practical applications of this approach and, therefore, will nof be considered in fhis confribufion. Thus, the other methodologies (stereoselective synthesis and deracemization) are preferred since a theoretical yield of 100% is possible. The asymmefric amination allows fhe preparation of enantiomer-ically pure amines at the expense of an amine donor, usually an amine or an AA (Scheme 2.2b). On the other hand, the combination of two stereocomplementary co-TAs enables to establish a deracemization process (Scheme 2.2c). Deracemization strategies are recommended when amines are readily available or the corresponding carbonyl compounds lack stability. 

AAOs have also been coupled with other enzymes, like amino transferases, in order to achieve an alternate deracemization process. For example, a racemic a-AA with a bulky heterobiaryl residue was converted to the (S)-enantiomer by combination of an oxidative kinetic resolution performed by the d-AAO from Trigonopsis variabilis and an (o-TA from Burkholderia sp. (Scheme 2.31). A conversion of 85% after 22 h led to 72% isolated product yield widi an excellent stereoselectivity (>99.5% ee). 

Deracemization. In this type of process, one enantiomer is converted to the other, so that a racemic mixture is converted to a pure enantiomer, or to a mixture enriched in one enantiomer. This is not quite the same as the methods of resolution previously mentioned, though an outside optically active substance is required. 

Relatively little attention has been paid to the conversion of racemic compounds into their enantiomerically pure versions in a single process, in other words a deracemization. For certain classes of chiral compounds such as secondary alcohols, this approach should provide many benefits, particularly to the pharmaceutical industry. Existing routes to high value intermediates in their racemic form may be modified to provide the equivalent homochiral product, thus reducing the extent of development chemistry required. In addition, the... 

Oxidoreductases are, after lipases, the second most-used kinds of biocatalysts in organic synthesis. Two main processes have been reported using this type of enzymes-bioreduction of carbonyl groups [39] and biohydroxylation of non-activated substrates [40]. However, in recent few years other processes such as deracemization of amines or alcohols [41] and enzymatic Baeyer-Villiger reactions of ketones and aldehydes [42] are being used with great utility in asymmetric synthesis. 

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... 

The approach can be coupled with other methods to prepare amino acids, such as to access [3-substituted a-amino acids. The methodology gives a way to prepare all four possible isomers of (3-aryl a-amino acids by a combination of asymmetric hydrogenation and the use of the deracem-ization process to invert the a-center (Scheme 9.36)." "°... 

Deracemization via Biocatalytic Stereoinversion. Racemic secondary alcohols may be converted into a single enantiomer via stereoinversion which proceeds through a two-step redox sequence (Scheme 2.130) [38, 941, 942] In a first step, one enantiomer from the racemic mixture is selectively oxidized to the corresponding ketone while the other enantiomer remains unaffected. Then, the ketone is reduced in a second subsequent step by another redox-enzyme displaying opposite stereochemical preference. Overall, this process constitutes a deracemization technique, which leads to the formation of a single enantiomer in 100% theoretical yield... 

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