Kinetic fast-reacting enantiomer

A kinetic resolution depends on the fact that the two enantiomers of a racemic substrate react at different rates with the enzyme. The process is outlined in Figure 6.1, assuming that the (S) substrate is the fast-reacting enantiomer (ks > ka) and Kic = 0-In ideal cases, only one enantiomer is consumed and the reaction ceases at 50% conversion. In most cases, both enantiomers are transformed and the enantiomeric composition ofthe product and the remaining starting material varies with the extent... 

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]. 

Dynamic kinetic resolution (DKR) is an extension to the kinetic resolution process, in which an enantioselective catalyst is usually used in tandem with a chemoselective catalyst. The chemoselective catalyst is used to racemize the starting material of the kinetic resolution process whilst leaving the product unchanged. As a consequence, the enantioselective catalyst is constantly supplied with fresh fast-reacting enantiomer so that the process can be driven to theoretical yields of up to 100 %. There are special cases where the starting material spontaneously racemizes under the reaction conditions and so a second catalyst is not required. 

The enantioselective esterification of 2-arylpropionic acids catalysed by a lipase was discussed earlier.26 Steady-state kinetics of the Pseudomonas cepacia lipase-catalysed hydrolysis of five analogous chiral and achiral esters (R)- and (.S )-(235 R1 = Me, R2 = H), (R)- and (reaction mixtures of water-insoluble substrates.212 The Km values were all die same and the apparent kcat values reflected the binding abilities of the alcoholate ions for the fast-reacting enantiomers. All the substrates are believed to be... 

Precatalysts 41a-c and 44 were activated with MAO and tested for kinetic resolution. Tetradecane was used as a solvent for these polymerizations at 25 °C. Kinetic resolution was reported by using stereoselectivity factors, or values, where s = (rate of fast reacting enantiomer)/(rate of slow reacting enantiomer). Experimentally, s may be calculated by using the following equation s = ln[(l -c)(l -ee)]/ln[(l - c)(l-fee)], where ee is the enantiomeric excess of the recovered olefin and c is the fraction conversion. If no kinetic resolution is achieved, s = 1. The authors assayed the fraction conversion, c, by gas chromatography (GC) analysis of two aliquots for each polymerization run (1) an aliquot removed immediately before the start of polymerization (i.e., immediately before the addition of zirconocene catalyst) and (2) an aliquot removed after the desired conversion was reached in all cases, tetradecane was used as the internal standard. 

One reason to choose acylation in an organic solvent over hydrolysis in water is to get the desired enantiomer in either the alcohol or ester form. A kinetic resolution of an alcohol yields one enantiomer as the alcohol and the other as the ester. Although the same enantiomer is favored in both hydrolysis and acylation, in hydrolysis the fast-reacting enantiomer is the product alcohol, whereas... 

ScheniB 7 Examples of lipase-catalyzed kinetic resolution by deacylation of an acyl enzyme (RiCOO-Enz). The chiral acyl acceptors are a secondary alcohol [12], a j roxide [87], a primary amine [88], and a primary alcohol [89]. The fast-reacting enantiomers are shown. 

Scheme 4.1 Enantioselective kinetic resolution of a racemate. = rate constants for the individual enantiomers of the substrate, E = enantiomeric ratio, i.e., the ratio between the specificity constants kat/Km for the fast and slow reacting enantiomer. If a racemate is used as substrate, then these concentrations are equal at the start (i.e. zero conversion), and hence E = kR/ks.

The resolution of rac-20 represents a less common form of catalytic kinetic resolution (parallel kinetic resolution) [9]. In conventional kinetic resolution, one substrate enantiomer reacts preferably to leave behind the unreacted isomer in high optical purity (e.g., rac-18 (k)-19 in Scheme 4). In this instance, both starting material enantiomers undergo catalytic alkylation to give constitutional isomers. Since both enantiomers are consumed simultaneously, as the reaction proceeds, the amount of slow enantiomer (relative to the unreacted fast enantiomer) does not increase. Therefore, product ee remains high, even at relatively high conversions. 

By far the commonest reaction used in kinetic resolution by enzymes is ester formation or hydrolysis. Normally one enantiomer of the ester is formed or hydrolysed leaving the other untouched so one has the easy job of separating an ester from either an acid or an alcohol. There are broadly two kinds of enzymes that do this job. Lipases hydrolyse esters of chiral alcohols with achiral acids such as 119 while esterases hydrolyse esters of chiral acids and achiral alcohols such as 122. Be warned this definition is by no mans hard and fast If the unreacted component (120 or 123) is wanted, the reaction is run to just over 50% completion, to ensure complete destruction of the unwanted enantiomer, while if the reacted component (121 or 124) is wanted it is best to stop short of 50% completion so that little of the unwanted enantiomer reacts. 

As can be concluded on the basis of Figure 9, only one of the enantiomers reacts in the best case of kinetic resolution. The reaction in the initially racemic mixture [S + S ] then stops at 50% conversion giving 50% of the enantiopure product [P ] and 50% of the enantiopure substrate Enzyme- or chemocat-alyzed racemization of the less reactive enantiomer in situ allows kinetic resolution to be changed to dynamic kinetic resolution when the substrate racemizes fast compared with the product formed and when the enzyme and the product p ) stable under the racemization conditions (Fig. 10). In dynamic kinetic resolution, a racemic mixture is transformed into the product enantiomer with 100% theoretical yield. Since 2003, a kind of revolution has been occurring in the development of dynamic kinetic resolution methods through enzymatic transesterification reactions (15). 

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