Enantioselectivity racemic substrate

Quantitative Analysis of Selectivity. One of the principal synthetic values of enzymes stems from their unique enantioselectivity, ie, abihty to discriminate between enantiomers of a racemic pair. Detailed quantitative analysis of kinetic resolutions of enantiomers relating the extent of conversion of racemic substrate (c), enantiomeric excess (ee), and the enantiomeric ratio (E) has been described in an excellent series of articles (7,15,16). 

The enantioselectivity of biocatalytic reactions is normally expressed as the enantiomeric ratio or the E value [la], a biochemical constant intrinsic to each enzyme that, contrary to enantiomeric excess, is independent of the extent of conversion. In an enzymatic resolution of a racemic substrate, the E value can be considered equal to the ratio of the rates of reaction for the two enantiomers, when the conversion is close to zero. More precisely, the value is defined as the ratio between the specificity constants (k st/Ku) for tho two enantiomers and can be obtained by determination of the k<-at and Km of a given enzyme for the two individual enantiomers. 

As outlined above, enantioconvergent processes require two separate reaction pathways in order to transform a racemic substrate into a single product enantiomer. This is accomplished by employing a catalyst, which transforms one of the substrate enantiomers to the product with retention of configuration. Concurrently, another catalyst, with opposite enantioselectivity and opposite regioselectivity, transforms the other substrate enantiomer with inversion of configuration (Figure 5.24). 

The resolution of a racemic substrate can be achieved with a range of hydrolases including lipases and esterases. Among them, two commercially available Upases, Candida antarctica lipase B (CALB trade name, Novozym-435) and Pseudomonas cepacia lipase (PCL trade name. Lipase PS-C), are particularly useful because they have broad substrate specificity and high enantioselectivity. They display satisfactory activity and good stability in organic media. In particular, CALB is highly thermostable so that it can be used at elevated temperature up to 100 °C. 

Enantioselective enzyme-catalyzed reactions may involve the transformation of a prochiral substrate into a chiral product, in which case the selectivity is measured by the enantiomeric excess (ee). The transformations can also involve kinetic resolution of racemic substrates, in which case enantioselectivity is measured by the selectivity factor E reflecting the relative rates of reaction of the R)- and (5)-enantiomer. 

Except for the disaccharide synthesis, in which introduction of natural sugars produced optically active diastereoisomers at the dihydropyran ring stage, most transformations leading to sugars was done with racemic substrates. Alcohol 3 was resolved into enantiomers by crystallization of its 6-O-camphanyl ester and subsequent hydrolysis. Recent discoveries of enantioselective catalysts and reagents permit one to obtain basic... 

The rabbit FruA discriminates the enantiomers of its natural substrate with a 20 1 preference for D-GA3P (12) over its L-antipode [202], Assistance from anionic binding was revealed by a study on a homologous series of carboxylated 2-hydroxyaldehydes which showed optimum enantioselectivity when the distance of the charged group equaled that of 12 (Scheme 15, Fig. 11) [299], The resolution of racemic substrates is not, however, generally useful since the kinetic enantioselectivity for nonionic aldehydes is rather low [202], 3-Azido substituents (69) can lead to an up to 9-fold preference of enantiomers in kinetically controlled experiments [300] while hydroxyl (70 preference for the... 

The first strategy involves discrimination between enantiotopic leaving groups (Type A). In the second approach, two enantiomers of a racemic substrate converge into a meso-n-al y complex wherein preferential attack of the nucleophile at one of either allylic termini leads to asymmetric induction, a process that may be referred to as a dynamic kinetic enantioselective transformation (Type B). The third requires differentiation between two enantiotopic transition... 

If the substrate contains two identical substituents at one terminus of the allylic position such as shown in Scheme 8E.26, the it-allyl intermediate can undergo enantioface exchange via the formation of a a-palladium species at that terminus. This process should occur faster than the nucleophilic addition, which is the enantio-determining step (fc, > 2[Nu ] and 2[Nu ]). Thus, enantioselection can be derived from the relative rate of the nucleophilic addition to each diastereomer the relative stabilities of the two diastereomeric complexes need not have a direct effect on the enantioselectivity (Curtin-Hammett conditions). Although the achiral allylic isomer 120 is expected to follow the same kinetic pathway as the racemic substrate 119, the difference between the results from the two systems often gives an indication as to the origin of enantioselection—complexation or ionization versus nucleophilic addition. 

Modifying the parent phosphinooxazoline 38 to ligand 57, exciting improvement in the regio- and enantioselectivity has been realized (entries 1 and 2) [151,152]. Similar enantio- and regioselectivities obtained from the reaction of the racemic substrate 125 suggest a facile... 

Enantioselective enzymatic ester hydrolyses have also been used for the preparation of optically active silicon compounds with the silicon atom as the center of chirality. An example of this is the kinetic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-(SiR,CR/SiS,CS)-79 with porcine liver esterase (PLE E.C. 3.1.1.1) (Scheme 16)65. Under preparative conditions, the optically active l-silacyclohexan-2-ol (SiS,CS)-80 was obtained as an almost enantiomerically pure product (enantiomeric purity >96% ee) in ca 60% yield [relative to (SiS,CS )-79 in the racemic substrate]. The biotransformation product could be easily separated from the nonhydrolyzed substrate by column chromatography on silica gel. 

To evaluate the enantioselectivity of the reaction, usually, enantiomeric excess, ee, of products is used. However, when a racemic substrate is reacted, ee of the product as well as that for the substrate changes depending on the conversion as shown in Figure 5(a). To evaluate the enantioselectivity of this type of reaction, the ratio of the specificity constants of the enantiomers, E-value, was introduced (Figure 5(b)).5 The methods of the calculation of E for the reaction of racemates is shown in Figure 5(c). 

P-Chiral phosphine an p the corresponding racemic substrate (Figure 17).18 hpase-catalyzed optical resou rugosa (CRL) was used for the enantioselective... 

Substituted aliphatic and aromatic a-keto ethers (Scheme 18.5) are also amenable to enantioselective hydrogenation catalyzed by cinchona-modified Pt catalysts.25 However, as opposed to the prochiral ketones discussed earlier, kinetic resolution is observed for these chiral substrates. At conversions of 20A2%, ee s of 91-98% were obtained when starting with a racemic substrate (see Table 18.5). It is somewhat surprising that a-keto ethers without substituent in the a-position, such as methoxy acetone, reacted very slowly or not at all and led to very low enantioselectivities,6 and from the results described earlier for a-ketoacetals, the same is expected if 2 substituents are present. 

Another example of a highly regio- and enantiospccific microbial Baeyer-Villiger reaction is the transformation of racemic bicyclic ketone 17 by Acinetobacter TD 63433. This leads to chiral lactones 18 and 19 which are of particular interest as synthons for prostaglandin synthesis. Interestingly, each enantiomer of the racemic substrate reacts with a different regioselectivity for the oxygen atom insertion, and the enantioselectivity of the reaction is excellent. 

The simplest enantioselective process is the reaction of a racemic substrate with two identical substituents at the allylic termini (Scheme 10). Here, the enantioselectivity originates from regioselective nucleophilic attack at the two enantiotopic termini of the allyl system. If a C2-symmetric ligand is used, only one allyl-Pd intermediate has to be considered (if we disregard syn-anti isomerism) and an analysis of the possible regioselectivity-determining factors becomes relatively straightforward. 

If nucleophilic attack constitutes the stereoselective step, special substitution patterns of the intermediate rc-allylpalladium complex are suitable for enantioselective catalysis, Racemic substrates with identical substituents in positions 1 and 3 give rise to chiral complexes incorporating a meso-n- y ligand. In this case, enantioselectivity is determined by discrimination of the nucleophile for the diastereotopic termini of the allylic system. 

Only the geometry of the rt-allyl ligand in the intermediate metal complex determines the enantioselectivity. Racemization cannot occur via anti attack of a free palladium(O) species onto the xc-allyl complex. A stereoscrambling T-a-n rearrangement is rather unlikely, since it would involve the unfavorable formation of a cr-bond from palladium to a tertiary carbon atom. Ionization of the allylic ester is under stereoelectronic control. In particular, the C —X bond has to be orientated orthogonal to the plane of the double bond. Two enantiomeric conformers of the allylic substrate which are in rapid equilibrium meet this requirement. The chiral palladiuni(O) complex discriminates between these enantiomeric conformers, whose conversion to the corresponding jt-allyl complexes occurs at markedly different rates. 

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