Esterification, lipase-catalyzed enantioselective

R)-3-Phenoxybutanoic acid and the corresponding butyl (S)-ester were obtained by Burkholderia cepacia lipase-catalyzed enantioselective esterification of the racemic acid with 1-butanol in hexane containing anhydrous sodium sulfate to remove the water produced during the reaction (Figure 6.17) [64]. 

Martins, J. F. de Carvalho, I.B. de Sampaio, T. C. Barreiros, S. Lipase-Catalyzed Enantioselective Esterification of Glycidol in Supercritical Carbon Dioxide. Enzyme Microb. Technol. 1994, 16, 785-790. 

Shang, C-S. Hsu, C-S. Lipase-catalyzed enantioselective esterification of (S)-naproxen hydroxyalkyl ester in organic media. Biotechnology Letters 2003, 25 413-416. 

A subfield in this area is using SCFs to control the stereoselectivity of biologically active chiral compounds. For example, supercritical CO2 has been used to do the lipase-catalyzed enantioselective esterification of ibuprofen. Enantiomeric purities exceeding 90% at an ibuprofen conversion of 25% have been reported [20]. 

Lipase-catalyzed enantioselective esterification of racemic ibuprofen coupled with pervaporation... 

Won K, Hong JK, Kim KJ, and Moon SJ. Lipase catalyzed enantioselective esterification of racemic ibuprofen coupled with pervaporation. Proc. Biochem. 2006 41(2) 264—269. 

Martins JF, de Carvalho IB, de Sampaio TC, Barreiros S. Lipase-catalyzed enantioselective esterification of glycidol in supercritical carbon dioxide. Enzyme Microb Technol 1994 16 785-790. 

The solution was found by using an approach which is closely related to the dynamic resolution of cyanohydrins, i.e., a lipase-catalyzed enantioselective esterification employing vinyl acetate as acyl donor [236]. Thus, dynamic resolution was attempted by making use of the inherent instability of the racemic substrate, which - being a hemithioacetal - is in equilibrium with the... 

W/O microemulsions have also been shown to be an effective system for the lipase-catalyzed enantioselective esterifications of racemic substrates [115,117]. It has been reported that the reaction rate for the esterification of the (-)-enantiomer of menthol with fatty acids catalyzed by P. simplicissimum lipase in AOT-based systems is seven times faster than the esterification rate of the (H-)-enantiomer... 

In an alternative approach to prepare the chiral side-chain of Captopril and Zofenopril, the lipase-catalyzed enantioselective esterification of racemic 3-benzoylthio-2-mefhylpropanoic add 37 in an organic solvent was demonstrated to yield (k)-methyl ester 38 and unreaded add enriched in the desired (S)-37a [91]. Using lipase PS-30 with toluene as solvent and methanol as nucleophile, the desired (S)-37a was obtained in 37% yield (maximum theoretical yield is 50%) with 97% ee. The amounts of water and the concentration of... 

The third group of target molecules comprises chiral carboxylic acid and their derivatives esters, amides and nitriles. Enantiomerically pure esters are prepared in an analogous manner to the enantiomerically pure alcohols discussed earlier [i.e. by esterase- or lipase-catalyzed hydrolysis or (trans)esterification]. However, these reactions are not very interesting in the present context of cascade reactions. Amides can be produced by enantioselective ammoniolysis of esters or even the... 

When water molecules interact with an enzyme, it is natural that conformational changes can occur, which in turn can cause changes in the selectivity of the enzyme. Since enantioselectivity of enzymes is of major importance for many applications, it is a common task to investigate how to choose reaction conditions providing the maximal enantioselectivity. As might be expected, because water can interact with enzymes in many ways, it is difficult to generalize the effects. In some studies of lipase-catalyzed esterification reactions, no effects of water activity on enantioselectivity were observed [30]. In a similar study, no effects were observed in most cases, while the enantioselectivity of one lipase-catalyzed reaction decreased... 

It is known that enantioselectivity of enzymes depends on many different parameters such as temperature, substrate structure, reaction medium, and presence of water. Enantiopreference of enzymes can be greatly affected, even reversed, by changing the reaction solvent. Such an example was reported by Ueji et al. in 1992 for Candida cylindracea lipase-catalyzed esterification of ( )-2-phenoxy propionic acid with 1-butanol [29]. 

As an example of the use of SC-CO2 in an enzymatic reaction, the lipase-catalyzed esterification of oleic acid with racemic ( )-citronellol should be mentioned. At 31 °C and 8.4 MPa, the (—)-(5)-ester is formed enantioselectively in SC-CO2 with an optical purity of nearly 100% [924]. The reaction rate is enhanced by increasing pressure, i.e. by increasing the solvation capability or solvent polarity of SC-CO2. A linear correlation has been found between reaction rate and the solvatoehromie solvent polarity parameter 1(30) see Section 7.4 for the definition of t(30). 

An enzyme-catalyzed enantioselective esterification of racemic LA 3 with -alcohols containing one to eight carbon atoms in hexane as a solvent, using Candida rugosa lipase <1997TA337>, has been described (Scheme 24). The best selectivity at 30% conversion was obtained with -hexanol, yielding the (3)-ester 176 with 72% ee, along with (K)-lipoic acid (20% ee) this decreased with -octanol (58% ee for an ester and 24% for acid) and there was a drastic drop... 

Lipase (CrL)-catalyzed enantioselective esterification of ibuprofen takes place with approximately double E value (24) in [BMIM][PFg] in comparison to 13 in... 

Enzymes can also be used in sc carbon dioxide.185 A Pseudomonas lipase immobilized on silica gel gave better conversions and enantioselectivity in the acetylation of racemic alcohols with acetic anhydride than when used in organic solvents.186 The lipase-catalyzed esterification of glycidol gave 83% enantioselectivity, which is as favorable as when the reaction is run in organic solvents.187 An immobilized lipase has been used in the ethanolysis of cod liver oil.188 Another immobilized lipase has been used to convert oleic acid to various esters.189 The use of a lipase in sc carbon dioxide for analyses of fats in foods cuts solvent use by 98%.190 Polyesters have been made enzymatically in carbon dioxide.191... 

Microwave radiation increased the rate 1- to 14-fold and the ee 3- to 9-fold (up to 92% ee for one isomer and 96% ee for the other) in the lipase-catalyzed esterification of an alcohol with vinyl acetate.34 Ultrasound increased the rate 7-to 83-fold. Directed evolution can occasionally be used to improve the enantioselectivity of lipases. A lipase for the hydrolysis of racemic p-nitrophenyl 2-methyldecanoate that gave 2% ee was run through four generations of error-prone polymerase chain reactions to raise the selectivity to 81% ee.35... 

Water activity of the reaction medium plays a central role in lipase catalyzed reactions (Berglund 2001). Different authors have described and demonstrated the usefulness of controlling water activity on lipase performance. In esterification reactions on cyclohexane media, the reaction rate increased with water activity in the low activity range however, it reached a maximum at a value of 0.84 and a subsequent increase in water activity led to a decrease in the reaction rate (Mat-sumoto et al. 2001). Results on the effect of water activity on enantioselectivity of lipases are rather contradictory (Berglund 2001). However, very good papers have been published in tuning lipase enantioselectivity by reaction medium engineering (Wehtje and Adlercreutz 1997 Matsumoto et al. 2001 Bomscheuer 2002). 

Moreover, the enantioselective synthesis of ibuprofen esters catalyzed by Candida cylindracea lipase was also studied in a similar system [115]. The enanti-oselectivity displayed by the lipase was much higher in AOT/isooctane microemulsions than in isooctane. The use of lipases to prepare large quantities of an optically enriched product has also been demonstrated in CTAB-based microemulsions [89]. Resolution of ( )-menthol by C. cylindracea lipase-catalyzed esterification with propionic anhydride in a nonionic reverse micellar system in an ultraiiltration manbrane reactor has been recently described [117]. 

Matsuda,T.,Kanamaru,R.,Watanabe, K., Kamitanaka, T., Harada, T, and Nakamura, K. (2003) Control of enantioselectivity of lipase-catalyzed esterification in supercritical carbon dioxide by tuning the pressure and temperature. Tetrahedron Asymmetry,... 

Chiral cyanohydrins were also obtained by a lipase PS-catalyzed enantioselective esterification of racemic cyanohydrins with enol esters [114]. The lipase PS was furthermore applied for the preparation of (S)-l-acetoxy-2-arylpropionitriles by asymmetric hy-... 

The alcohol used as cosubstrate in lipase reactions with chiral acyl donors may act as an enantioselective inhibitor that will be detrimental to the enantiomeric excess. This has been reported for C. rugosa lipase-catalyzed kinetic resolution by esterification of 2-meth-ylalkanoic acids (Scheme 17) [134]. 

Scheme 19 Mechanism of sequential lipase-catalyzed hydrolysis-esterification in situ. The chiral alcohol (HOR, HOS) will be involved in two enantioselective steps, i.e., first in the hydrolysis A, and then in the deacylation step of the esterification B [147].

Martins et al. [52] investigated the enantioselective esterification of glycidol with butyric acid at 35°C and 140 bar. They received a enantiomeric excess of (5)-glycidyl butyrate with lipase from porcine pancreas of 72-82%. The conversions were between 11% and 23%. With immobilized lipase they optimize the enantiomeric excess to 88-90% e.e. and a conversion of 20%. The e.e. of the substrate was 20%. In his dissertation, Bomscheuer [83] described the lipase-catalyzed transesterification of 3-hydroxymethyloc-tanoate with cyclohexyl acetate in organic solvents and supercritical GO2 (40°C/100 bar). After 400 h reaction time the author yielded 20% substrate and 96% product e.e. The... 

The functions of chiral drugs in human body are closely related to their configurations. It has been reported that the R- and S-isomers of ibuprofen have quite different biological activities and toxicides. So it is imperative to prepare enan-tiomerically pure ibuprofen. Song el al. conducted a study on the lipase-catalyzed esterification of racemic ibuprofen with octanol in AOT reverse micelles [108,109] and found that the esterification is enantioselective and the main product is the corresponding S (-H)-ibuprofen ester, with the conversion yield and the enantiomer excess being about 36% and 0.9732, respectively. The water content and the concentration of AOT in the medium affected the conversion yield, but they had little influence on the enantiomeric excess (Table 15.7). Also, it was found that the chain lengths of alcohols affected both the rate of the reaction and the enantiomeric excess of the products. 

Enantioselective enzymatic esterifications of trimethylsilyl-substituted alcohols with racemic 2-(4-chlorophenoxy)propanoic acid in water-saturated benzene, catalyzed by the Candida cylindracea lipase OF 360 CCL OF 360 E.C. 3.1.1.3) have been used to prepare (—)-2-(4-chlorophenoxy)propanoic acid76,77. As shown in Scheme 23, the (trimethylsilyl)alkanols 95, 97 and 99 were converted enantioselectively into the corresponding (trimethylsilyl)alkyl (+)-2-(4-chlorophenoxy)propanoates 96, 98 and 100. The enantiomeric purity of the remaining (—)-2-(4-chlorophenoxy)propanoic acid was 95.8% ee (95), 76.1% ee (97) and 77.5% ee (99). 

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