Lipases prochiral compounds

Prochiral Compounds. The enantiodifferentiation of prochi-ral compounds by lipase-catalyzed hydrolysis and transesterification reactions is fairly common, with prochiral 1,3-diols most frequently employed as substrates. Recent reports of asymmetric hydrolysis include diesters of 2-substituted 1,3-propanediols and 2-0-protected glycerol derivatives. The asymmetric transesterification of prochiral diols such as 2-0-benzylglycerol and various other 2-substituted 1,3-propanediol derivatives is also fairly common, most frequently with Vinyl Acetate as an irreversible acyl transfer agent. 

Die synthesis of enantiomerically pure inteimediates and active products is a major requiiement for the pharmaceutical industry. Hydrolytic biocatalysts such as esterases, lipases and proteases aie employed for the preparation of enantiopure compounds from racemic precursors, prochiral compounds, and diastereomeric mixtures. Hydrolytic enzymes alsocatalyze reverse hydrolysis and thus offer access to both enantiomers of a specific compound. Examples aie the use of enol esters as trani-esterification reagents and the combination of hydi olytic enzymes with racemization catalysts. 

In kinetic resolutions (Scheme 3.2-3.5) it is often the case that one of the products is required, while the other is not and must be discarded or recycled (e.g. racemised). Such operations can be wasteful or expensive. On the other hand, the biotransformation of wcso-compounds or prochiral compounds allows for the possibility of preparing an optically pure compound in quantitative yield. In Scheme 3.7, two examples of the use of meso-compounds are described. The diester (11) is made up of a complex dicarboxylic acid unit derivatised as the dimethyl ester. Pig liver esterase catalyses the hydrolysis of one of the ester groups to give the acid (12) (95% e.e.) in 96% yield. This compound is an excellent precursor of the natural product neplanocin. Note that the acid (12) is not a substrate for pie, and thus the reaction stops at the half-way stage. The compound (13), like (11), possesses a plane of symmetry. Hydrolysis catalysed by porcine pancreatic lipase (ppl) affords the alcohol (14) (>98% e.e.) in quantitative yield. The latter compound has been used to make fluorocarbocyclic adenosine (C -adenosine), a stable analogue of the naturally occurring nucleoside adenosine. 

Substituted-1,3-propanediols are a special class of prochiral compounds that can be efficiently asynunetrized by the lipase-catalyzed reactions. Using this procedure it is... 

Our final example is that of cyclic anhydrides, namely prochiral 3-sub-stituted glutaric anhydrides (7.101, R = Me, Et, or Pr). When incubated with lipase in an inert solvent in the presence of an alcohol (methanol, butan-l-ol, etc.), these compounds underwent nucleophilic ring opening with formation of a hemiester (7.102) of (/ -configuration (60-90% ee) [180]. This product enantioselectivity and, of course, the lack of reactivity in the absence of lipase show the enzymatic nature of the reaction. 

It is generally believed that selectivity of hydrolytic enzymes strongly depends on the proximity of the chiral center to the reacting carbonyl group, and only a few examples of successful resolutions exist for compounds that have the chiral center removed by more than three bonds. A noticeable exception to this rule is the enantioselective hydrolysis by Pseudomonasfluorescens lipase (PFL) of racemic dithioacetal (5) that has a prochiral center four bonds away from the reactive carboxylate (24). The monoester (6) is obtained in 89% yield and 98% ee. 

Asymmetric synthesis with lipases and esterases can basically be performed by two different approaches - the desymmetrization of prochiral or meso compounds and the enzymatic kinetic resolution of racemic mixtures. The main bottleneck of kinetic resolutions, product yields of maximum 50%, can be overcome if an in situ racemization of the starting material is possible. In this case all starting material can theoretically be converted to the desired product [34],... 

The proper stereochemistry was achieved by enzyme catalyzed desymmetrization of the prochiral 1,3-diol 30. Candida antarctica lipase (CAL)-catalyzed transesterification yielded the monoacetate 31, which gave rise to the methyl with the proper stereochemistry 32. The generation of the desired chiral epoxide 35 was achieved by asymmetric dihydroxylation employing AD-mix-a,42 followed by epoxide formation. Base-catalyzed etherification yielded the mixture of the enantiopure (+)-heliannuol A and (-)-heliannuol D. Unfortunately these compounds correspond to the opposite d/l series and correspond to the enantiomers of the natural products (-)-heliannuol A and (+)-heliannuol D (Fig. 5.6.A). 

A prochiral diol can be converted into enantiomeric compounds as shown by the example in Scheme 7.5. Catalyzed by a hydrolytic enzyme like a lipase, it can be enantioselectively acetylated by vinyl acetate in organic solvent to yield a mixture of monoacetates. The chiral monoacetates will be formed at unequal rates and also react further at unequal rates. It is usually anticipated that if kj > k2, then k4 > ky and, moreover, that the ratio ki/ki is constant throughout the reaction [4c],... 

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-trkk, 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. - The enantiomeric ratio ( ), 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. 

Enzymatic resolution has been successfully applied to the preparation of optically active gem-difluorocyclopropanes (see Scheme 12.4). We succeeded in the first optical resolution of racemic gm-difluorocyclopropane diacetate, trans-43, through lipase-catalyzed enantiomer-specific hydrolysis to give (R,R)-(-)-44 with >99% ee (see equation 9, Scheme 12.4) [4a], We also applied lipase-catalyzed optical resolution to an efficient preparation of monoacetate cw-46 from prochiral diacetate m-45 (see equation 10, Scheme 12.4) [4a], Kirihara et al. reported the successful desymmetrization of diacetate 47 by lipase-catalyzed enantiomer-selective hydrolysis to afford monoacetate (R)-48, which was further transformed to enantiopure amino acid 15 (see equation 11, Scheme 12.4) [19]. We demonstrated that the lipase-catalyzed enantiomer-specific hydrolysis was useful for bis-gem-difluorocyclopropane 49. Thus, optically pure diacetate (R,S,S,R)-49 and (S,R,R,S)-diol 50, were obtained in good yields, while meso-49 was converted to the single monoacetate enantiomer (R,S,R,S)-51 via efficient desymmetrization (see equation 12, Scheme 12.4) [4b, 4e], Since these mono- and bis-gm-difluorocyclopropanes have two hydroxymethyl groups to modify, a variety of compounds can be prepared using them as building blocks [4, 22],... 

Only a very few acyclic prochiral acylated diols have been subjected with moderate success to pig liver esterase-catalyzed hydrolysis with formation of the corresponding chiral monoacetates (1-3) (Table 11.1-4). For this kind of compounds, lipases are the hydrolases of choice. 

The biocatalytic acetylation of prochiral bis(hydroxymethyl)phenylphosphine oxide 277 and the biocatalytic hydrolysis of prochiral bisfmethoxycarbonylmethyl) phenylphosphine oxide 279 was subjected to hydrolysis in a phosphate buffer in the presence of several hydrolases (PLE, PPL, AHS, Amano-AK, and Amano-PS), of which only porcine liver esterase (PLE) proved to be efficient. The best results were attained with Pseudomonas fluorescens lipase (PFL) in chloroform which allowed the compound 278 to be obtained in yields up to 76% and with ee up to 79%. Absolute configuration of the (5)-278 was determined by means of chemical correlation to the earlier described compound (/ )-282, as shown in Scheme 91 [185]. 

Wiktelius D, Johansson MJ, Luthman K, Kann N (2005) A biocatalytic route to P-chirogenic compounds by lipase-catalyzed desymmetrization of a prochiral phosphine-borane. Org Lett 7 4991 994... 

Chiral ligand 651 is obtained from the appropriate natural amino-acid phenylalanine, whereas the corresponding derivatives of valine or leucine proved to be slightly less effective [46], Axially prochiral, enantiotopic, biaryl-2,6-diols have been converted to the respective chiral compounds via enzymatic desymmetrization. Thus Pseudomonas cepacia lipase (PCL) catalysed the atropisomerically-selective hydrolysis of diacetate 654 to give monoacetate 655 in 67% yield and 96% e. e. [47], Scheme 24. 

Desymmetrization of Prochiral and wieso-Diols. Chiral 1,3-propanediol derivatives are useful building blocks for the preparation of enantiomerically pure bioactive compounds such as phospholipids [176], platelet activating factor (PAF), PAF-antagonists [177], and renin inhibitors [178]. A simple access to these syn-thons starts from 2-substituted 1,3-propanediols (Scheme 3.8). Depending on the substituent R in position 2, (/ )- or (5)-monoesters were obtained in excellent optical purities using Pseudomonas sp. lipase (PSL) [179-182]. The last three entries demonstrate an enhancement in selectivity upon lowering the reaction temperature [183]. 

For recent extensive reviews on biotransformations with lipases, see Kazlauskas and Bom-scheuer [77], Johnson [78], Rubin and Dennis [79], Itoh et al. [80], and Boland et al. [81]. The most widespread and frequently used biocatalytic reaction involving chiral compounds is kinetic resolution of racemates. Other biocatalytic stereoselective methods, although less frequently used, are asymmetrization of prochiral and meso compounds. These will be briefly discussed in Secs. C and D, respectively. 

Similarly as for prochiral substrates, many of the lipase-catalyzed asymmetrizations of meso compounds are accompanied by a second reaction step that usually enhances the enantiomeric excess of the product. This second step is a kinetic resolution. For example, in the hydrolysis of a m o-diester, die reaction usually does not stop at the monoester stage (Scheme 15). The two enantiomeric monoesters will react further giving the same me o-diol. This second step usually favors the minor monoester enantiomer and therefore leads to an increase of the enantiomeric excess of the major monc ster, but a decrease in the yield. This has been illustrated and described by Wang et al. for the lipase-catalyzed hydrolysis of meso-l,5-diacetoxy-cw-2,4-dimethylpentane [117]. The monoacetate was afforded in 89.7% e.e. 

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