Candida antarctica lipase dynamic kinetic resolution

The use of an enzyme in a cascade using nanoencapsulation has also been demonstrated [23]. In this case, the dynamic kinetic resolution (DKR) of secondary alcohols was achieved with an acidic zeolite and an incompatible enzyme, Candida antarctica lipase B (CALB) (Scheme 5.8). 

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris-... 

Table n.1-24. Lipase-catalyzed dynamic kinetic resolution (PCL Pseudomonas cepacia lipase, PPL pig pancreatic lipase, ANL Aspergillus n/ger lipase, MML Mucormieheilipase, CAL-B Candida antarctica B lipase, PSL Pseudomonas sp. lipase, PFL Pseudomoasfluorescens lipase, CAL Candida antarctica lipase, not specified). 

Dynamic resolution of various sec-alcohols was achieved by coupling a Candida antarctica lipase-catalyzed acyl transfer to in-situ racemization based on a second-generation transition metal complex (Scheme 3.17) [237]. In accordance with the Kazlauskas rule (Scheme 2.49) (/ )-acetate esters were obtained in excellent optical purity and chemical yields were far beyond the 50% limit set for classical kinetic resolution. This strategy is highly flexible and is also applicable to mixtures of functional scc-alcohols [238-241] and rac- and mcso-diols [242, 243]. In order to access products of opposite configuration, the protease subtilisin, which shows opposite enantiopreference to that of lipases (Fig. 2.12), was employed in a dynamic transition-metal-protease combo-catalysis [244, 245]. 

Engstroem, K., Shakeri, M., and Baeckvall, J.-E. (2011) Dynamic kinetic resolution of p-amino esters by a heterogeneous system of a palladium nanocatalyst and Candida antarctica lipase A. Eur. J. Org. Chem., 2011 (10), 1827-1830, S1827/1-S1827/5. 

Shakeri, M., Engstrom, K., Sandstrom, A. G., and BackvaU, J.-E. (2010). Highly enantiose-lective resolution of beta-amino esters by Candida antarctica lipase A immobilized in mesoceUular foam Application to dynamic kinetic resolution. ChemCatChem, 2, 534-538. 

Engstrom K, Shaken M, Backvall J-E. Dynamic kinetic resolution of -amino esters by a heterogeneous system of a palladium nanocatalyst and Candida antarctica lipase A. Eur. 

The combination of a resin and covalently supported IL with SCCO2 was also used in the KR and dynamic kinetic resolution (DKR) of 1-phenylethanol with vinyl propionate catalyzed by Candida antarctica lipase B (CALB) [125]. The IL molecule covalently supported on Merrifield resin was realized through the reaction of 1-butyl imidazole with chloromethylated resin. Subsequently, NTf2 was introduced via ion exchange. Under improved conditions, the conversion of 1-phenylethanol was 50% with 99.9% ee to the product. In order to develop a more efficient process, the KR of 1-phenylethanol was tested on a flow system, and it remained stable for 6 days with 99% ee Moreover, by combing two fixed-bed reactors loaded with the supported enzyme (biocatalytic reactor, CALB-SILLP (SILLP, supported ionic liquid-like phase) 11, 150 mg) and an additional one with an acid zeolite (chemical racemization catalyst, 100 mg). Figure 2.40, the DKR of 1-phenylethanol... 

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