Racemic deracemization

Subsequently Turner and coworkers were able to show that the Asn336Ser variant possessed broad substrate specificity, with the ability to oxidize a wide range of chiral amines of interest [19]. They also discovered a second mutation, Ile246Met, which conferred enhanced activity toward chiral secondary amines as exemplified by the deracemization of racemic 1-methyltetrahydroisoquinoline (MTQ) (9) (Figure 5.9)[20j. 

In a related approach, Adam ef al. used glycolate oxidase with D-lactate dehydrogenase for the deracemization of a wide range of racemic a-hydroxy acids (20) (Figure 5.13) [23]. 

It is well known that certain microorganisms are able to effect the deracemization of racemic secondary alcohols with a high yield of enantiomerically enriched compounds. These deracemization processes often involve two different alcohol dehydrogenases with complementary enantiospedficity. In this context Porto ef al. [24] have shown that various fungi, induding Aspergillus terreus CCT 3320 and A. terreus CCT 4083, are able to deracemize ortho- and meta-fluorophenyl-l-ethanol in good... 

Chadha et al, have published a series of papers on the deracemization of P-hydroxyesters using whole cells of Candida parapsilosis. For example, deracemization of racemic ethyl 2-hydroxy-4-phenylbutanoic acid (22 R = H) yielded the (S) enantiomer in 85-90% yield and >99% ee (Figure 5.15) [26]. 

Carnell et al. discovered that whole cells of Cunninghamella echinulata NRRL1384 were able to deracemize racemic N-(l-hydroxy-l-phenylethyl)benzamide (24) to produce the (R) enantiomer (Figure 5.17) [30]. The deracemization involves fast, highly (S)-selective oxidation, followed by slower, partially (R)-selective reduction of the ketone (25). Optimization by removing competing extracellular amidase/prote-ase activity resulted in 82% yield and 92% ee. 

An alternative approach to the microbial deracemization of secondary alcohols is to use two different microorganisms with complementary stereoselectivity. Fantin et al. studied the stereoinversion of several secondary alcohols using the culture supernatants of two microorganisms, namely Bacillus stearothermophilus and Yarrowia lipolytica (Figure 5.18) [31]. The authors tested three main systems for deracemization. First, they used the supernatant from cultures of B. stearothermophilus, to which they added Y. lipolytica cells and the racemic alcohols. Secondly, they used the culture supernatant of Y. lipolytica and added B. stearothermophilus cells and the racemic alcohols. Finally, they resuspended the cells of both organisms in phosphate buffer and added the racemic alcohols. The best results were obtained in the first system with 6-penten-2-ol (26) (100% ee and 100% yield). The phosphate buffer system gave... 

Faber et al. have reported a novel process for the overall deracemization of racemic mandelic acid derivatives using a combination of an enantioselective lipase and a mandelate racemase activity from Lactobacillus paracasei (Figure 5.19) [32]. 

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... 

For the deracemization of phenylethanol derivatives using G. candidum under aerobic conditions (Figure 8.41b), the (S)-specific enzyme was reversible and (R) enzyme was irreversible, so (R)-alcohol accumulated when the cell and racemic alcohols were mixed [31b,c]. Para-substituted phenylethanol derivatives gave better results than meta-substituted derivatives. Sphingomonas was used for... 

Biooxidative deracemization of racemic sec-alcohols to single enantiomers [47,48] is complementary to combined metal-assisted lipase-mediated strategies [49,50]. In general, deracemization can be realized by either an enantioconvergent, a dynamic kinetic resolution, or a stereoinversion process. The latter concept is particularly appealing, as only half of the substrate needs to be converted, as the remaining half already represents the product with correct stereochemistry. 

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. 

For example, the racemic thioester 57 was placed in contact with a certain optically active amide. After 28 days the solution contained 89% of one enantiomer and 11% of the other. To effect the deracemization two conditions are necessary (1) the enantiomers must complex differently with... 

To avoid the problems shown above, a new approach has been developed. It is called deracemization and consists in the transformation of a racemic substrate into one enantiomer of the product. In other words, it means that one enantiomer of... 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

To obtain a better understanding of the reaction mechanism, some compounds that are considered to he intermediates were subjected to the reaction. Various reaction courses can be considered as illustrated in Fig. 21. Path A a-Methyltropic acid is oxidized to a-phenyl-a-methylmalonic acid. Then, the malonate is converted to optically active a-phenylpropionate hy arylmalonate decarboxylase. In order to confirm this assumption, incubation of the malonic acid with Rhodococcus sp. was carried out. The result obtained was the total recovery of the substrate, indicating that no decarboxylase is present in this bacterium. Path B a-Methyltropic acid is converted to racemic a-phenylpropionic acid, which is deracemized to optically active propionic acid. To examine the possibility of this route, racemic a-phenylpropionic acid was subjected to the reaction to observe... 

Although decarboxylation reaction seems to be a simple one-carbon removing reaction, it is demonstrated that this reaction is a unique and useful reaction in the preparation of optically active carboxylic acids. If the starting material is a racemic carboxylic acid, the optically active compound can be obtained via symmetrization by chemical carboxylation followed by asymmetrization via enzymatic reaction. Accordingly, the whole process can be said as chemicoenzymatic deracemization (Fig. 24). 

The deracemization of lactate, in principle, is also interesting. In this process, pyruvate is reduced at the cathode to racemic lactate which is reoxidized to pyruvate by the cheap L-lactate dehydrogenase combined with the anodic... 

Chiral Lewis acids are also applicable in the deracemization of racemic allene dicarboxylates 289. Treatment of dimethylallene-l,3-dicarboxylate 289 with a chiral organoeuropium reagent, (+)-Eu(hfc)3, gave the corresponding optically active allene in 79% ee (Scheme 4.76) [118]. Unfortunately the chiral allene could not be isolated from the reaction mixture without loss of its optical purity. 

Asymmetric synthesis can refer to any process which accesses homochiral products. We will focus on asymmetric synthesis from racemic or prochiral starting materials in the presence of an enantioselective catalyst (enzyme). There are four general methodologies commonly applied kinetic resolution, dynamic kinetic resolution, deracemization and... 

Figure 11.1 Enzymatic deracemization of racemic amines via a two-step, one-pot process utilizing an enantioselective amine oxidase in combination with ammonia-borane.

The use of D-AAO from the yeast Rhodotorula gracilis to deracemize naphthyl amino acids has been studied in some detail by the groups of Servi and Pollegioni, who compared the kinetic properties of the enzyme with racemic 1- and 2-naphthylalanine (1 and 2) and 1- and 2-naphthylglycine (3 and 4). 

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... 

Medici et al. have used a combined sequential oxidation-reduction to access a range of imsaturated secondary alcohols from their racemates [7] (Scheme 1). Here the S-alcohol 2 is oxidized by B. stereothermophilus which is displaying Prelog specificity leaving the l -enantiomer untouched. The other microorganism, Y. lipolytica contains an anti-Prelog dehydrogenase which is therefore able to reduce the ketone 1 to the l -alcohol 2. Thus the combination of the two steps effects a net deracemization of substrate 2. 

J )-Mandelic acid 3 is a useful chiral synthon for the production of pharmaceuticals such as semi-synthetic penecillins, cephalosporins and antiobesity agents and many methods have been reported for the preparation of the optically pure material. A method to deracemize the racemate which is readily available on a large scale was developed by Ohta et al. using a combination of two biotransformations. The method consists of enantioselective oxidation of (S)-... 

The results actually showed a deracemization of the racemic hydroxyester 10 as opposed to enantioselective hydrolysis with formation of optically pure (R)-hydroxyester 10 and only 20 % loss in mass balance. Small quantities of ethyl 3-oxobutanoate 9 (<5%) were also detected throughout the reaction, leading the authors to suggest a multiple oxidation-reduction system with one dehydrogenase enzyme (DH-2) catalysing the irreversible reduction to the (R)-hydroxy-ester (Scheme 5). 

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