Lipases1

[9001-62-1]  · (MW 30000-100000)

(catalyst for asymmetric transformations of chiral or prochiral alcohols or acids by hydrolysis or esterification reactions1)

Solubility: powder sol aqueous solutions; suspension in organic media.

Form Supplied in: usually a white or brownish powder, but also immobilized on an appropriate support. Lipases from microbial sources are virtually homogeneous in terms of hydrolytic activity, while mammalian and plant lipase preparations contain several interfering enzymes including proteases and esterases.

Analysis of Reagent Purity: assay by titrimetry.2

Handling, Storage, and Precautions: must be stored in a refrigerator at 0-5 °C. Avoid breathing or inhaling dust. Avoid too vigorous stirring.

Lipase General Aspects.

Enzymes are now widely recognized as practical catalysts for asymmetric synthesis.1b,c Lipases are among the most widely applied and versatile biocatalysts in organic synthesis as can be witnessed by a number of recent reviews.1 There are several reasons for this. They are readily available, do not require cofactors, are inexpensive and highly stable, exhibit broad substrate specificity, do not require water-soluble substrates, mechanistically are relatively well understood and, finally, are splendidly suited to retain a high degree of activity in organic media.

More than 20 lipases are now commercially available, either free or immobilized, from animal, plant, and microbial sources.2 Amongst the lipases, the pig pancreatic lipase (PPL), the yeast lipase from Candida cylindracea (rugosa) (CCL), and the bacteria lipases from Pseudomonas fluorescens (cepecia) (PFL) and other unclassified Pseudomonas species (PSL) have been most widely used. The experimental methods are very straightforward and little different in their execution from conventional chemical reactions. Hydrolysis reactions are conducted on the soluble lipase in buffered aqueous solutions, commonly in the presence of an organic cosolvent. In organic media the enzyme is added as a powder or in an immobilized form and the resulting suspension stirred or (better) shaken at approximately 40 °C. The enzyme is removed by filtration.

Since their action toward substrates in terms of chemo-, regio-, and enantioselectivity varies considerably, it is important to have a large selection of lipases to find the right enzyme for a specific reaction by traditional biocatalyst screening. Alternative strategies for improving enantioselectivity of the already existing commercial lipases have been developed,1a,3 including product recycling,4 solvent screening,5 water content control,6 and immobilization. In addition to this, several active site models have been proposed to predict the enantiopreference of certain lipases.1a,7

Lipases have been used in three main types of asymmetric transformations: kinetic resolution of racemic carboxylic acids or alcohols, enantioselective group differentiations of meso dicarboxylic acids or diols, and enantiotopic group differentiation of prochiral dicarboxylic acid and diol derivatives. Hydrolysis has been the most widely used technique, but complementary esterification or transesterification procedures are increasingly coming into use. Lipases are used most frequently in transformations involving chiral alcohols rather than acids, unlike the pig liver esterase (PLE),1a,b,c which is most frequently employed on esters of chiral carboxylic acids. Lipases are also gaining increasing importance in solving problems of regioselectivity of various polyol and carbohydrate compounds.1c,e,f,8 They have found application in stereoselective transformations involving lactonization and oligomerization of hydroxy acids and esters.1e,f Finally, a minor but useful advantage of the lipases is their mildness, which is particularly important in transformations involving labile compounds.1a

The range of nucleophiles that lipases accept is not confined to water or alcohols. There are numerous examples of amines,9 hydrazine,10 phenols,11 and hydrogen peroxide.12 Proteases have frequently been used in biocatalytic transformations involving ester hydrolysis and esterification reactions and their different stereoselection often provides a useful complement to the lipases.1a,c,f

Kinetic resolution of racemic compounds is by far the most common transformation catalyzed by lipases, in which the enzyme discriminates between the two enantiomeric constituents of a racemic mixture. It is important to note that the maximum yield of a kinetic resolution is restricted to 50% for each enantiomer based on the starting material. The prochiral route and transformations involving meso compounds, the meso-trick, have the advantage of potentially obtaining a 100% yield of pure enantiomer. A theoretical quantitative analysis of the kinetics involved in the biocatalytic processes described above has been developed.1a,d,e The enantiomeric ratio (E), an index of enantioselectivity, can be calculated from the extent of conversion and the corresponding enantiomeric excess (ee) values of either the product or the remaining substrate. The results reveal that for an irreversible process, such as hydrolysis, the optimum in both chemical and optical yield for the faster hydrolyzed enantiomer is to be expected near 40% conversion, and for the remaining slower hydrolyzed enantiomer around 60% conversion. For a high enantiomeric ratio (>100), high enantioselectivity is expected for both enantiomers at 50% conversion.

Under almost anhydrous conditions in organic medium,1e,f lipases can be used in the reverse mode for direct ester synthesis from carboxylic acids and alcohols, as well as transesterifications (acyl transfer reactions) which can be divided into alcoholysis (ester and alcohol), acidolysis (ester and acid), and interesterification (ester-ester interchange). The direct esterification and alcoholysis in particular have been most frequently used in asymmetric transformations involving lipases. The parameters that influence enzymatic catalysis in organic solvents have been intensively studied and discussed.1a,e,f

Besides ester synthesis being favored over hydrolysis, there are several major advantages of undertaking biocatalytic reactions in anhydrous media: increased solubility of nonpolar substrates, ease of product and enzyme recovery, enhanced thermal stability of enzymes and substrate specificity, and enantioselectivity regulation by the solvent. The main disadvantages include lower catalytic activity in organic media and reversibility, which limits the yield and works against the kinetic resolution, lowering the enantioselectivity of such processes. There are several strategies available to overcome these problems.1a,e,f Enol esters, such as vinyl or isopropenyl esters, are by far the most commonly used acyl transfer agents to ensure irreversibility by tautomerization of the enol leaving group.13,14 Anhydrides,15 S-phenyl thioacetate,16 acyloxypyridines,17 and oximes18 have also been applied in a similar manner as acyl donors. Active trifluoro-19 and trichloroethyl20 esters have similarly been used to suppress the reversibility by speeding the acyl-enzyme formation and generating the weakly nucleophilic trifluoro- or trichloroethanol. Primary alcohols have also been used as acyl acceptors in transesterifications (deacylations) involving esters of more bulky and less nucleophilic secondary alcohols.21

Kinetic Resolution by Hydrolysis.

Until very recently, kinetic resolution of racemic alcohols as ester derivatives was by far the most common type of asymmetric transformations involving lipases.1a There are number of examples involving acyclic secondary alcohols, such as the glyceraldehyde derivative in eq 122 and various related alkyl- and aryloxy substituted chloride and tosylate glycerol derivatives.22,23

A wide variety of other alcohol substrates has been resolved,1a including aryl substituted secondary alcohols,20,24 a-alkyl-b-hydroxy esters,25 b-hydroxy nitriles,26 and fluoroorganic compounds.27 Active chloroacetate esters are commonly used to speed up the hydrolysis reactions, as exemplified in eq 2.28 Primary acyclic alcohols possessing a stereogenic center that have been resolved include 2,3-epoxy alcohols,29,30 2-amino alcohols,31 and crown ethers.32

Lipase-catalyzed asymmetric hydrolysis has also been conducted on numerous monocyclic, variously substituted five-, six-, and seven-membered cycloalkane and cycloalkene secondary alcohols and diols.1a More recent reports include cis-4-acetoxyflavan,33 substituted cyclopentenones,34 and the 1,2-bis(hydroxymethyl)cyclobutanol derivative exemplified in eq 3.35

Various bicyclic racemic alcohols have been resolved by asymmetric hydrolysis of their corresponding esters. Generally, the exo isomers appear to be far inferior substrates compared with the endo substrates.1a Eq 4 illustrates the resolution of a bicyclic derivative of the Corey lactone type.36

There are also several reports on the enantioselective hydrolysis of bicyclic secondary alcohols possessing the bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane framework.37 Again, with this type of substrate the lipases appear to exhibit strong preference for the endo isomers with the (R)-configured esters preferentially hydrolyzed.

Various chiral acids have also been resolved by lipase-catalyzed asymmetric hydrolysis.1a The reports include variously a-substituted acids3,38 as well as the tertiary a-benzyloxy ester exemplified in eq 5.39 Remethylation and repeated hydrolysis afforded the (S)-enantiomer in eq 5 optically pure. More recent examples include esters of glycidic acid,40 b-aryl-b-hydroxy acid,41 and sulfinyl alkanoates.42

Kinetic Resolution by Transesterification.

Asymmetric transformation involving acylation of chiral alcohols is by far the most common example of kinetic resolution by lipase-catalyzed transesterification, most commonly with irreversible vinyl esters.1a,15 This field is now becoming the most widely applied technique involving lipases. Recent reports of the numerous secondary alcohol substrates include various monocyclic (eq 6)43 and acyclic44 compounds, cyanohydrins,45 sulfones,46 and glycals,47 to name a few.

There are also several reports of enantioselective transesterification involving primary alcohols possessing stereogenic centers by similar acylation procedures, such as 2,3-epoxy alcohols (eq 7),48 norbornene-derived iodolactones,49 and 1,3-propanediols.50

Enantioselective lipase-catalyzed transesterification involving deacylation of esters of racemic primary or secondary alcohols with primary alcohols, most frequently n-butanol, serving as an acyl acceptor, is fairly common.1a Recent examples include esters of amino alcohols,51 isoserine,52 chlorohydrins,53 and various tosyloxybutanoate esters (eq 8).54

Kinetic resolution involving acidolysis of esters of racemic secondary alcohols and acids or transesterification of chiral acids does not have many examples in the literature.1a

Kinetic Resolution by Direct Esterification.

This is the least common strategy for kinetic resolution and is most commonly executed on racemic alcohols with carboxylic acids in organic solvents.1a Reports include several alicyclic secondary alcohols such as menthol55 and various aliphatic secondary alcohols.56 Kinetic resolution of a variety of racemic saturated, unsaturated, and a-substituted carboxylic acids has also been effected by direct esterification with various alcohols.20,57

In addition to this, there are several reports of asymmetric esterification of racemic alcohols with anhydrides as acyl donors. Examples include various primary and secondary alcohols,15 bicyclic secondary alcohols of the norbornane type,58 amino alcohols,59 and ferrocenes.60 This is exemplified in eq 9 for 1-phenylethanol.15

Prochiral Compounds.

The enantiodifferentiation of prochiral compounds by lipase-catalyzed hydrolysis and transesterification reactions is fairly common, with prochiral 1,3-diols most frequently employed as substrates.1a Recent reports of asymmetric hydrolysis include diesters of 2-substituted 1,3-propanediols61 and 2-O-protected glycerol derivatives.8 The asymmetric transesterification of prochiral diols such as 2-O-benzylglycerol8,13a and various other 2-substituted 1,3-propanediol derivatives13b,62 is also fairly common, most frequently with Vinyl Acetate as an irreversible acyl transfer agent.

There are also recent reports of the lipase-catalyzed enantioselective hydrolysis of prochiral diacid derivatives such as 2-substituted malonates,63 barbiturates,64 and highly substituted, sterically hindered 1,4-dihydropyridine derivatives using acyloxymethyl groups to enhance the reaction rate.65 An example of a prochiral diester hydrolysis is illustrated in eq 10.66

Meso Compounds.

Although pig liver esterase is by far the most suitable enzyme for asymmetric transformations involving meso compounds, especially diacids, there are several reports on the lipase-catalyzed hydrolysis and transesterification reactions of cyclic diol derivatives.1a The former includes variously substituted cycloalkene diacetates, cyclohexylidene protected erythritol diacetate,67 piperidine derivatives,68 and the exo-acetonide in eq 11.69 Complementary results are clearly demonstrated in eqs 11 and 12 for the hydrolysis and esterification processes.

The asymmetric transesterification of cyclic meso-diols, usually with vinyl acetate as an irreversible acyl transfer agent, includes monocyclic cycloalkene diol derivatives,70 bicyclic diols,71 such as the exo-acetonide in eq 12,69 bicyclic diols of the norbornyl type,72 and organometallic 1,2-bis(hydroxymethyl)ferrocene possessing planar chirality.73

Regioselective Biotransformations with Lipases.

Lipases are gaining increasing importance in solving problems of regioselectivity of various polyol and carbohydrate compounds.1a,c,e,f,8 A variety of diols or the corresponding acetates as well as polyhydric phenol acetates74 have been acylated or deacylated in a highly regioselective manner in high yields by lipase-catalyzed transesterification reactions. Regioselective direct esterification of aliphatic 1,2-diols75 and inositol derivatives76 using anhydrides as acylating agents has recently been reported. Primary hydroxyl groups are exclusively transformed, as would be anticipated on steric grounds. One example of a highly regioselective and at the same time highly enantioselective hydrolysis of a racemic diester is demonstrated in eq 13.77

There are also several reports on highly regioselective transesterification of various steroid derivatives, one example being displayed in eq 14 in which butyration occurred exclusively at the 3b-hydroxyl group by Chromobacterium viscosum lipase (CVL).78 Opposite regioselectivity toward the 17b-hydroxyl group was observed with subtilisin protease.78

There are numerous examples of highly regioselective lipase-catalyzed hydrolysis and acylation/deacylation processes involving monosaccharide and carbohydrate derivatives.1a,f,8 Usually, the biotransformation processes occur preferentially and in many cases exclusively on the primary hydroxyl group (eq 15),79 but highly regioselective transformations have also been described on secondary alcoholic groups for various carbohydrate derivatives possessing an acyl or alkyl protection on the primary hydroxyl moiety. Recent reports include highly regioselective acetylation of pyranosidic and furanosidic monosaccharide derivatives80 and alkoxycarbonylation of nucleosides with oxime carbonates.18

Lactonization and Polycondensation.

The lipase-catalyzed intramolecular transesterification of a range of o-hydroxy esters has been investigated extensively1a,e,f and was observed to be very dependent on the chain length of the substrate (eq 16).

For longer-chain hydroxy esters (n = 13, 14) the corresponding macrolide was accomplished in high yield with very little diolide formed (diolide increased considerably with lower n). With medium-sized hydroxy esters the product profile became considerably more complex, consisting of a complex mixture of di-, tri-, tetra-, and pentalactones.28,81 Shorter-chain unsubstituted b-, d-, and ε-hydroxy esters almost exclusively underwent intermolecular transesterification to afford the corresponding oligomers. d-Substituted d-hydroxy esters82 and g-hydroxy esters83 underwent lactonization with a high degree of enantioselectivity.

Prochiral g-hydroxy diesters underwent enantioselective lactonization with PPL to afford the (S)-lactone in a highly enantioselective fashion (eq 17).83a Formation of macrocyclic lactones by the condensation of diacids or diesters with diols, leading to mono- and dilactones,84 linear oligomeric esters, or high molecular weight optically active polymers,85 depending upon type of substrates as well as reaction conditions, has also been described.

Mildness and Miscellaneous Reactions.

The mildness of the lipases has been particularly well suited in transformations involving labile compounds that are likely to undergo decomposition when conventional chemical methods are applied,1a such as the long-chain polyunsaturated o-3-type fatty acids86 and highly labile prostaglandin precursor derivatives.87 Under mild conditions, lipase was exploited to hydrolyze the peracetal protected hydroperoxy derivative in eq 18 to afford the corresponding acid without affecting the peracetal protection moiety.88

Various miscellaneous lipase-catalyzed reactions have been reported,1a including lipase-mediated epoxidation of alkenes,12 transamidation,89 thiotransesterification of thioesters for the preparation of optically active thiols,90 regio- and chemoselective peptide acylation,91 lactamization,92 and highly enantioselective hydrolysis of racemic oxazolin-5-ones which undergo a rapid keto-enol tautomerism to afford optically pure amino acids, thus exceeding the 50% yield limit.93

Finally, lipases are able to differentiate enantiotopic faces of appropriately substituted enol esters to afford optically active ketones,94 indicating that simultaneously upon hydrolysis of the acyl group, protonation occurs from one specified side of the double bond of the enol ester without formation of an enol intermediate (eq 19).94a


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Gudmundur G. Haraldsson

University of Iceland, Reykjavik, Iceland



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