Chiral acyl donors lipase-catalyzed resolution

The resolution of chiral amines via lipase-catalyzed enantioselective acylation is now a major industrial process, but interest in adopting ionic liquid reaction media has been surprisingly scant. Interestingly, acids could be used as the acyl donor (Figure 10.15) rather than the usual activated ester in a range ofionic liquids. CaLB was employed as the biocatalyst, and water was removed to shift the equilibrium toward the product [130, 131]. The highest rates were found in [BMMIm][TfO], [EMIm][TfO], and [EMIm][BF4]. 

The improvement of the enantioselectivity E in kinetic resolution of a primary alcohol (10) through lipase-catalyzed transesterification was studied using a chiral acyl donor 11. The combination of the lipase, solvent and acyl donor was effective for the enantioselectivity.62... 

Scheme 3 A Lipase-catalyzed resolution of a chiral acyl acceptor. B The scheme shows the competition tetween two enantiomeric alcohols (HOR and HOS) and water for the acyl enzyme (RiCOO-Enz). The nucleophile (HOR2) released from the acyl donor is supposed to tautomerize, evaporate, or otherwise leave the system. The substrates competing for the enzyme (HO-Enz) are the acyl donor (R1COOR2), the products formed during the catalysis (R,COOR and R,COOS), and any formed acid (RjCOOH). The enantiomeric alcohol moieties R and S are shown in boldface.

Scheme 4 A Lipase-catalyzed resolution of a chiral acyl donor (RCOOH and SCOOH) by esterification or hydrolysis (the reverse reaction). B The reaction goes through two diastereomeric acyl enzymes (RCOO-Enz and SCOO-Enz). The enantiomeric acyl groups R and S are shown in boldface.

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]. 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

Primary alcohols have been successfully used as substrates for lipases. Monterde et. Al60 reported the resolution of the chiral auxiliary 2-methoxy-2-phenylethanol 1 via Candida antarctica lipase B (CAL-B)-catalyzed acylation using either vinyl acetate (R=H) or isopropenyl acetate (R= CH3) as acyl donor (cf. fig. 8) and the alkoxycarbonylation using diallyl carbonate as the alkoxycarbonylation agent in THF at 30 °C (cf. fig. 9). 

Using a resolution process, chiral alcohol i -(+)-57 was also prepared by the lipase-catalyzed stereoselective acetylation of racemic 57 in organic solvent [85]. Various lipases were evaluated among which lipase PS-30 (Amano International Enzyme Co.) and BMS lipase efficiently catalyzed the acetylation of the undesired enantiomer of racemic 57 to yield S-(—)-acetylated product 60 and unreacted desired R-(+)-57 (Fig. 17). A reaction yield of 49 M% (theoretical maximum yield is 50 M%) and an e.e. of 98.5% were obtained for J -(+)-57 when the reaction was conducted in toluene as solvent in the presence of isopropenyl acetate as acyl donor. In methyl ethyl ketone at 50 g/L substrate concentration, a reaction yield of 46 M% (theoretical maximum yield is 50 M%) and optical purity of 96.4% were obtained for R-(+)-57. 

Numerous examples exist on the kinetic resolution of chiral acyl acceptors. Among other compounds primary and secondary alcohols, various amines, and peroxides have been resolved. Representative examples are shown in Scheme 7. The secondary alcohol 2-octanol was resolved using S-ethyl octanethioate as acyl donor and C. antarctica lipase B [12]. The alkyl peroxide was acylated with isopropenyl acetate using P. cepacia lipase [87]. The primary amine was resolved by C. antarctica lipase B-catalyzed acylation of ethyl octanoate at reduced pressure [88]. The primary alcohol was successfully resolved by acylation of vinyl acetate at — 40 C [89]. 

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