Kinetic deracemization

Scheme 18.52 Kinetic deracemization of adenallene (155) by enzyme-catalysed deamination [147] (ADA= adenosine deaminase Tf=trifluoromethanesulfonyl).

Enzyme-catalyzed kinetic deracemization of unsaturated GABA derivatives ... 

Figure 5.1 Schematic illustration of (a) dynamic kinetic resolution, (b) deracemization, and (c) enantioconvergent processes.

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. 

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]. 

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... 

Unlike kinetic resolution, catalytic desymmetrization and asymmetrization can afford enantiopure products in theoretical yields of 100 % and are more generally applicable than DKR or deracemization techniques. 

This section will only discuss examples of catalytic kinetic resolution, DKR, desymmetrization and asymmetrization. Deracemization will not be considered because, although an important developing technology, examples of its application to the production of chiral late-stage intermediates in API production have yet to appear. 

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). 

DYNAMIC INSTABILITY DEPOLYMERIZATION, END-WISE MICROTUBULE TREADMILLING POLYMERIZATION RANDOM SCISSION KINETICS DEPOLYMERIZATION, END-WISE Deracemization,... 

Substituted acrylates (which reseitible the enamide substrates employed 1n asymmetric hydrogenation) may be deracemized by reduction with an optically active catalyst, especially DIPAMPRh . Selectivity ratios of 12 1 to 22 1 have been obtained for a variety of reactants with compounds of reasonable volatility, separation of starting material and product may be effected by preparative GLC. Recovered starting material can then be reduced with an achiral catalyst to give the optically pure anti product. Examples of kinetic resolutions by this method are given in Table II. More recently very successful kinetic resolutions of allylic alcohols have been carried out with Ru(BINAP) catalysts. 

During the past few years great efforts have been made to overcome the 50% threshold of enzyme-catalyzed KRs. Among the methods developed, deracemization processes have attracted considerable attention. Deracemizations are processes during which a racemate is converted into a non-racemic product in 100% theoretical yield without intermediate separation of materials [5]. This chapter aims to provide a summary of chemoenzymatic dynamic kinetic resolutions (DKRs) and chemoenzymatic cyclic deracemizations. 

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. 

Likewise, conversions where a reactant is unstable should be linked with the previous step to keep the yield as high as possible, and conversions where the product is unstable should be linked with the following step to keep the yield as high as possible. In addition, reactions requiring deracemization to take advantage of the unreacted enantiomer will also benefit from one-pot operation to improve the yield. In each of these cases it is an increase in the thermodynamic yield of product on substrate rather than any kinetic advantage that is gained. 

Kroutil, W., and Faber, K. 1998. Deracemization of compounds possessing a sec-alcohol or -amino group through a cyclic oxidation-reduction sequence a kinetic treatment. Tetrahedron Asymm., 9(16), 2901-2913. 

Turner, N. J. 2004. Enzyme catalyzed deracemization and dynamic kinetic resolution reactions. Curr. Op. Chem. Biol., 8(2), 114-119. 

In Scheme 1 the respective rate constants of thermal interconversion of R and S(k), R and S (k ), and of deactivation of R and S (B) are equal. If this were not so, spontaneous or nonpolarized-light induced deracemization would occur, which never has been observed. The interconversion rates of Pr and Ps(k3 and k 3 ) may be different, if the products are diasteromers. If the ground state enantiomerization is slow compared to the other reactions then the kinetics of independent parallel reactions apply if not, those of dependent parallel reactions. 

The two more common strategies for achieving such an objective are deracemization by stereoinversion or deracemization by dynamic kinetic resoluhon DKR (Scheme 13.1). 

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... 

Unhke a kinetic resolution process, where in principle both enantiomers of the same compound can be obtained, a deracemization process gives access to one single enantiomer. The possibihty of securing the enantiomer of opposite configuration depends on the availability of the enzymes involved frequently enzymes with complementary stereopreferences are not available. 

In order to extend the two-enzyme system to other 2-hydroxy acids, a racemase with a broader activity was found in Lactobacillus paracasei. This was exploited for deracemization of 2-hydroxy-4-phenylbutanoic acid and 3-phenyllactic acid, which are important synthetic intermediates. In addition, in this case the procedure requires a kinetic resolution step and a successive racemization step. O-Acetyl derivatives of the absolute (S)-configuration can be obtained in two successive repeating cycles. Yields are around 60%. Of course the 0-acetyl derivatives of opposite configuration can be obtained when the lipase-catalyzed reaction is apphed in the hydrolysis direction. Obtaining the O-acetyl derivatives of the absolute (R)-configuration requires an additional acetylation step of the initially resolved and racemized (S)-hydroxy acid [12]. 

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