Enantioselectivity solvent engineering

Using solid/gas reactors to improve enzyme enantioselectivity by solvent engineering and changing reaction conditions... 

The structure of lipases has been shown to be similar in both water and hydrophobic solvents and binding of solvent molecules other than water has been observed. Rates of reaction and enantioselectivity have been altered by changing the solvent in a process called solvent engineering. 

The experimental evidences that medium engineering might represent an efficient method to modify or improve enzyme selectivity (alternative to protein engineering and to the time-consuming search for new catalysts) were immediately matched by the search for a sound rationale of this phenomenon. The different hypotheses formulated to try to rationalize the effects of the solvent on enzymatic enantioselectivity can be grouped into three different classes. The first hypothesis suggests that... 

As shown in this chapter, by focusing on the modulation of enzyme selectivity by medium engineering, quite simple modifications of the solvent composition can really have significant effects on the performances of the biocatalysts. The main drawback remains the lack of reliable predictive models. Despite the significant research efforts (particularly in the last decade), it is likely that a reasonable foresight of the enantioselective outcome of an enzymatic transformation will continue to be based solely on a careful analysis of the increasingly numerous literature reports. 

In order to get good results in a kinetic resolution, E must be high, preferably well above 30 [66]. However, in organic media the enantioselectivity of an enzyme can depend strongly on parameters such as temperature and solvent, so medium engineering is often a fast and highly effective tool to increase E. 

Despite the fact that solvent effects on enzyme enantioselectivity appear to resist our efforts to rationalize their outcome using commonly accepted solvent descriptors, the effects are certainly there. An impressive example is provided in a report on the successful resolution of ds/trans-( 1 R,5 R)-bicyclo[3.2.0]hept-6-ylidene-acetate ethyl esters, intermediates in the synthesis of GABA (y-aminobutyric acid) analogs, by the Pfizer Bio transformations and Global R D groups (Scheme 2.2) [136]. From a screening protocol, CaLB was identified as a reactive catalyst for the hydrolysis of the racemic mixture of / //-os lor enantiomers with approximately equal activity for the ds- and tmns-isomers and a rather modest (E = 2.7) preference for the /Z-(lR,5R)-enantiomers. Application of medium engineering resulted in a phenomenal increase in the enantioselectivity (addition of 40% acetone, E > 200), while the ds- and trans-isomers were still converted at an almost equal rate. 

It is the most exciting and significant feature that the substrate specificity, enantioselectivity and regioselectivity can be profoundly affected by nature of solvents in which the enzyme molecule exists. This phenomenon has opened an alternative approach for changing specificity and selectivity of an enzyme other than both screening from nature and protein engineering in the field of synthetic organic chemistry. The ability of enzymes to discriminate... 

Numerous studies have demonstrated the solvent influence on enzyme enan-tioselectivity, and sometimes the enantiopreference may even be reversed by medium engineering. For instance, the enantioselectivity of asymmetric reduction of prochiral ketones catalyzed by T. ethanolicus ADH can be controlled by changing the reaction medium containing either organic solvents or ionic liquids [93]. Reversal of the enantioselectivity was reported for S. cerevisiae-catalyzed reduction of hydrophobic phenyl w-propyl ketone by means of the... 

---