Improvement of enantioselectivity

These examples are part of a broader design scheme to combine catalytic metal complexes with a protein as chiral scaffold to obtain a hybrid catalyst combining the catalytic potential of the metal complex with the enantioselectivity and evolvability of the protein host [11]. One of the first examples of such systems combined a biotinylated rhodium complex with avidin to obtain an enantioselective hydrogenation catalyst [28]. Most significantly, it has been shovm that mutation-based improvements of enantioselectivity are possible in these hybrid catalysts as for enzymes (Figure 3.7) [29]. 

Figure 8.18 Acetone treatment of Geotrichum candidum for the improvement of enantioselectivity [14].

Esterases have a catalytic function and mechanism similar to those of lipases, but some structural aspects and the range of substrates differ 7-11). Most important, they lack the so-called lid prominent in almost all lipases. Nevertheless, one can expect that the lessons learned from the directed evolution of lipases also apply to esterases. So far, few efforts have been investigated in the directed evolution of enantioselective esterases, although earlier work by Arnold 17,32,139) had shown that the activity of esterases as catalysts in the hydrolysis of achiral esters can be enhanced. The first example involving the improvement of enantioselectivity concerned the hydrolytic kinetic resolution of the sterically hindered ester rac-19 catalyzed by the esterase from P. fluorescens (PFE) 140). 

They showed that despite the fact that lower activities were generally observed, significant improvements of enantioselectivity in the oxidation of thioanisole by PAMO and EtaA could be induced by the addition of short-chain alcohols such as methanol and ethanol. Remarkably, methanol was able to cause a reversal of PAMO enantiopreference in the case of several substrates. Reversal of enantio-preference was also observed with EtaA when using t-BuOMe. The authors hypothesize that in these enzymes solvents exert their influence on enantioselectivity by binding in or near the enzyme active site and, depending on their structure, interfere with the association of the substrate. 

Because of the high potential of alkaloid-based alkylations for synthesis of amino acids, several groups focused on the further enantiomeric enrichment of the products [20]. In addition to product isolation issues, a specific goal of those contributions was improvement of enantioselectivity to ee values of at least 99% ee during downstream-processing (e.g. by crystallization). For pharmaceutical applications high enantioselectivity of >99% ee is required for optically active a-amino acid products. 

The alkaloid-catalyzed addition of alcohols to prochiral ketenes is one of the very first examples of catalytic asymmetric synthesis. In pioneering work by Pracejus in the 1960s quite remarkable 76% ee was achieved and it was not until 1999 that substantial improvement of enantioselectivity in catalytic asymmetric addition of O- and N-nucleophiles to prochiral ketenes was reported. In particular, the chiral... 

Tsugawa, W., Nakamura, H., Sode, K., Ohuchi, S. (2000). Improvement of enantioselectivity of chiral organophosphate insecticide hydrolysis by bacterial phosphotriesterase. Appl. Biochem. Biotechnol. 84-6 311-17. 

For enantioseparation on CSPs in CEC, nonstereospecific interactions, expressed as 4>K, contribute only to the denominator as shown in Eq. (1), indicating that any nonstereospecific interaction with the stationary phase is detrimental to the chiral separation. This conclusion is identical to that obtained from most theoretical models in HPLC. However, for separation with a chiral mobile phase, (pK appears in both the numerator and denominator [Eq. (2)]. A suitable (f)K is advantageous to the improvement of enantioselectivity in this separation mode. It is interesting to compare the enantioselectivity in conventional capillary electrophoresis with that in CEC. For the chiral separation of salsolinols using /3-CyD as a chiral selector in conventional capillary electrophoresis, a plate number of 178,464 is required for a resolution of 1.5. With CEC (i.e., 4>K = 10), the required plate number is only 5976 for the same resolution [10]. For PD-CEC, the column plate number is sacrificed due to the introduction of hydrodynamic flow, but the increased selectivity markedly reduces the requirement for the column efficiency. 

Shibata, T., Gilheany, D. G., Blackburn, B. K., Sharpless, K. B. Ligand-based improvement of enantioselectivity in the catalytic asymmetric dihydroxylation of dialkyl-substituted olefins. Tetrahedron Lett. 1990, 31, 3817-3820. 

Fluorine substituents on the aromatic ring in chiral quaternary ammonium salts also play an important role for the improvement of enantioselectivity in asymmetric alkylations of the Schiff base of glycine esters in an aqueous biphase system. Dolling first demonstrated asymmetric methylation of indanone (44) by cinchonidine ammonium salt (43) (Scheme 5.12) [18]. 

Figure 15-11. Improvement of enantioselectivity by substituting iodide at the para position yeast reduction followed by dehalogenation (dh)[6S1.

Y.M. Chung, H.K. Rhee, Design of Sdica-Supported Dendritic Chiral Catalysts for the Improvement of Enantioselective Addition of Diethylzinc to Benzaldehyde, Catalysis Letters 82, 249, 2002. 

We were particularly fascinated by the small and simple compound olean and attempted its asymmetric synthesis via a Brpnsted acid-catalyzed cycUzation of the corresponding hydroxyenolether substrate [57], However, only low enantios-electivity could be obtained (Scheme 19). We faced a similar failure with the construction of the even smaller 5,5-spiroacetal (Scheme 20). Silver salts were also tested as catalysts however, this only resulted in a reduced reaction rate. It is likely that the corresponding acid, which can be formed via an HVAg" exchange with the substrate or water, is the actual catalyst. Although the acid-catalyzed spiroacetalization reactions were very facile at room temperature, lowering the temperature did not result in an improvement of enantioselectivity. 

Besides aUylsUanes or stannanes, allyl boron species have found widespread apphcations in synthesis. The Roush crotylation is a very well-estabhshed method with a broad substrate scope, and is therefore commonly used in organic synthesis [73]. The following example depicts a reversal in enantioselectivity induced by a cobalt complex present in the substrate. Roush et al. reported that the use of metal carbonyl complexes as substrate surrogates led to an improvement of enantioselectivity in the asymmetric crotylation of the respective aldehydes. These results were attributed to electronic effects exerted by the metal complexes that stabilize the transition state of the crotylation reaction (Scheme 3.47) [74]. 

The recognition mechanism is based on the formation of a cyclodextrin-enantiomer inclusion complex, which is stabilized partially by hydrophobic and ion pairing interactions. The increasing polarity of the solvent system was shown to stabilize this complex. The influence of CS concentration in the stationary phase on enantioselectivity has also been studied. The increase of the CS/racemate molar ratio from 10- to 160-fold resulted in an improvement of enantioselectivity and resolution. 

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