Candida antarctica A lipase

In recent years, a great variety of primary chiral amines have been obtained in enantiomerically pure form through this methodology. A representative example is the KR of some 2-phenylcycloalkanamines that has been performed by means of aminolysis reactions catalyzed by lipases (Scheme 7.17) [34]. Kazlauskas rule has been followed in all cases. The size of the cycle and the stereochemistry of the chiral centers of the amines had a strong influence on both the enantiomeric ratio and the reaction rate of these aminolysis processes. CALB showed excellent enantioselec-tivities toward frans-2-phenylcyclohexanamine in a variety of reaction conditions ( >150), but the reaction was markedly slower and occurred with very poor enantioselectivity with the cis-isomer, whereas Candida antarctica lipase A (GALA) was the best catalyst for the acylation of cis-2-phenylcyclohexanamine ( = 34) and frans-2-phenylcyclopropanamine ( =7). Resolution of both cis- and frans-2-phenyl-cyclopentanamine was efficiently catalyzed by CALB obtaining all stereoisomers with high enantiomeric excess. 

Candida antarctica lipase A (CAL-A, Chirazyme L-5, C2), 100 mg ethyl acetate... 

The rather complex furylvinylcarbinol derivative 76 shown in Scheme 4.28 was required in enantiopure form as a key intermediate in the synthesis of the natural product cneorin. The carbinol moiety is heavily substituted with sterically demanding groups. Therefore attempts to resolve the furylvinylcarbinol with CALB or lipase PS-II led to very slow reactions. However, the rarely used enzyme Candida antarctica lipase A (CALA), which is known to act on sterically hindered substrates offers an alternative. Thus acylation of the furylvinylcarbinol 76 with 2,2,2-trifluoroethyl butanoate catalyzed by CALA (immobilized on celite with sucrose at pH 7.9) furnished the enantiomerically enriched propanoate of S-76 and R-76 (Scheme 4.28) [90]. Small-scale experiments gave E > 300. 

Tertiary alcohols are very unreactive toward hydrolases. There are, however, exceptions. Some enzymes have a certain amino acid motif located in the oxyanion binding pocket that allows the docking of space-demanding alcohols such as tertiary ones into the acylated enzyme [104]. One such hydrolase is Candida antarctica lipase A (CALA), which has been found to catalyze the acylation of the tertiary 2-phenyl-3-butyn-2-ol rac-110 by vinyl acetate in organic solvents. Thus efficient resolution of 110 was achieved in isooctane at room temperature (Scheme 4.34) [105]. 

Scheme 4.39 Candida antarctica lipase A (CALA)-catalyzed ...

Kanerva et al. have also reported DKR of cyanohydrins [22]. In particular, they obtained very good results with Candida antarctica lipase A (CAL-A) as the catalyst for the KR of a variety of substrates for which other enzymes such as CALB or PS-C do not give good results (Scheme 5.9) [22a]. 

Candida antarctica lipase A (CaLA), which was ten times more active in [BMPy][BF4] and [BMIm][ Tf2N] than in diisopropyl ether (DIPE) [54] is an exception. 

TIL Thermomyces lanuginosus lipase, RdL Rhizopus delemar lipase, RnL Rhizopus niveus lipase, MmE Mucor miehei esterase, PsL Pseudomonas sp. lipase, MmL Mucor miehei lipase, RoL Rhizopus orvzae lipase, CaLA Candida antarctica lipase A, CaLB Candida antarctica lipase B, PLE Pig liver esterase, EP Enteropeptidase, PKA Porcine kidney acylase, CE Cholesterol esterase Figure 8.1 (S)-Selective enzyme hits from hydrolase screening. ... 

This methodology was employed to prepare many heterocyclic cyanohydrin acetates in high yields and with excellent enantioselectivities, Candida antarctica lipase A (CAL-A) being the lipase of choice (Scheme 5.7) [23]. A recent detailed study of the reaction conditions revealed that the carrier on which the lipase is immobilised is important generally Celite should be used for aromatic substrates. With Celite R-633 as support for Candida antarctica lipase B (CAL-B)... 

The application of ionic liquids in lipase biocatalysis has not remained entirely restricted to CaLB, PcL or CrL. Other lipases have been used in ionic liquids for ester synthesis such as Candida antarctica lipase A (CaLA) [15,16], Thermomyces lanuginosus lipase [17] (TLL), Rhizomucor miehei lipase (PmL), Pseudomonas fluorescens lipase (PJL) [18], Pig pancreas lipase (PpL) [17] and Alcaligenes sp. lipase (A5 L) [16]. 

Candida antarctica lipase A cyclic (hexanedithiol-sebacate) / corresponding ester monomer [110]... 

Both chiral compounds have been prepared by enantioselective reduction of ethyl-5-oxohexanoate 71 and 5-oxohexanenitrile 72 by Pichia methanolica SC 16116. Reaction yields of 80%-90% and more than 95% EEs were obtained for each chiral compound. In an alternate approach, the enzymatic resolution of racemic 5-hydroxy-hexane nitrile 73 by enzymatic succinylation was demonstrated using immobilized lipase PS-30 to obtain (S)-5-hydroxyhexanenitrile 69 in 35% yield (maximum yield is 50%). (S)-5-Acetoxy-hexanenitrile 74 was prepared by enantioselective enzymatic hydrolysis of racemic 5-acetoxyhexanenitrile 75 by Candida antarctica lipase. A reaction yield of 42% and an EE of more than 99% were obtained [96]. 

MartineUe M, Holmquist M, Hult K (1995) On the interfacial activation of Candida antarctica lipase A and B as compared with Humicola lanuginose lipase. Biochim Biophys Acta 1258 272-276... 

S)-dapoxetine Gotor 2 out of 4 Step 4 Selective amidation with Candida antarctica lipase A... 

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. 

On the other hand, DKR was used for the preparation of a series of novel ( + )-10-alkyl-phenothiazin-3-ylcyanomethyl acetates on the basis of a similar methodology to that used in Scheme 3.24.The use of Candida antarctica lipase A allowed excellent enantioselectivities to be obtained, as depicted in Scheme 3.26. 

Another example of DKR of amines was reported by Kanerva s group in 2004. In this case, the DKR of the methyl esters of proline and pipecolic acid was based on the acylation of the secondary amino group of the amino esters with vinyl butanoate by Candida antarctica lipase A. Acetaldehyde, used as a racemising agent, was released in situ from vinyl butanoate in the presence of TEA, allowing proline and pipecolic add methyl esters to be acylated in the forms of highly enantiopure butanamides (Scheme 3.51). 

More recently, BackvalFs group reported the DKR of the jS-amino ester, ethyl 3-amino-3-phenylpropanoate, using Candida antarctica lipase A (CAL-A) immobilised in mesocellular foam (GamP-MCF) in combination with the methoxy analogue of Shvo s catalyst at 90°C. It was shown that the use of 2,4-dimethyl-3-pentanol as a hydrogen donor allowed side product formation to be suppressed. Thus, the reaction performed in the presence of trifluoroethyl butyrate as the acyl donor provided the corresponding (5)-amide in 85% yield and 89% ee. 

A method that has been successfully applied to the resolution of p-amino acids is N-acylation or N-acyl hydrolysis. Enantioselective N-acylation of p-amino esters in an organic solvent has been carried out using Candida antarctica lipase A (CAL-A) lipase, while enantioselective hydrolysis of N-acyl p-amino acids in aqueous medium has been catalyzed by aminoacylase (Scheme 14.2). 

Gedey, S., Liljeblad, A., Ldzdr, L., Ftilop, F., and Kanerva, L.T. (2001) Preparation of highly enantiopure P-amino esters by Candida antarctica lipase A. Tetrahedron Asymmetry, 12, 105-110. 

L.T. (2002) Candida Antarctica lipase a — a powerful catalyst for the resolution of heteroaromatic p-amino esters. Tetrahedron Asymmetry, 13, 2383-2388. 

In the same area, the DKR of p-amino esters, including aliphatic, aromatic as well as heteroaromatic ones, was performed hy Backvall et al, using a palladium nanocatalyst [Pd°/AlO(OH)] in combination with immobilised Candida antarctica lipase A (CALA/GAmP-MCF), providing the corresponding chiral amides in both excellent yields and enantioselectivities, as shown in Scheme 8.75. ... 

More recently, interest in the immobilization of catalysts has increased. Candida antarctica lipase A (CALA) immobilized in mesoceUular foam (MCF) showed a dramatic increase in the enantioselectivity, as well as an improved thermostability of the enzyme. The immobilized enzyme (CALA/GAmp-MCF) was combined with the para-methoxyphenyl derivative of the Shvo catalyst, in an efficient DKR of 3-amino-3-phenylpropanoate at 90°C (24) [90]. The chiral acy-lated p-amino ester was obtained in 85% yield and with an ee value of 89%. 

Lipases are a family of enzymes which catalyze cleavage of ester bonds between organic alcohols and fatty acids (Lowe, 2002 Reis et al 2009). They have distinctive stmctural characteristics responsible for different kinetic behavior. For example, human pancreatic lipase (hPL) (Reis et al 2009), Candida antarctica lipase A (GALA) (Ericsson et al, 2007)... 

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. 

---