Meso compounds, lipases

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],... 

Enantiomerically pure cyclopropanes are a frequent motif in the structure of natural products. Their synthesis is often demanding and many approaches have been made [50, 51]. Porcine pancreatic lipase (PPL) was used for the stereoselective desymmetrization of a cyclopropane dibutanoate (Fig. 2). The asymmetric hydrolysis of the meso compound yielded the corresponding enantiopure alcohol almost quantitatively. The intermediate obtained was successfully applied in the total synthesis of dictyopterenes A and C, sexual pheromones of brown algae [52], and constanolactones (see below) [53]. 

For the resolution of cyanopentafluorophenylethanol with lipase, (he reaction temperature was decreased to improve the enantioselectivities (Figure 15(b)). The ameso comPounds were conducted to obtain fluorinated amino, . "UIC. 1 > e)). Esterification of meso alcohol gave the corresponding W-ammo acid, whereas the hydrolysis gave the corresponding(5)-product. 

Chiral diols have also been prepared starting from meso-compounds [68-71]. Since meso-compounds are, in essence, symmetric molecules, the same applies as for the other symmetric starting materials. Indeed, this is exactly what was found Even though the stereocenters of the protected heptane tetrol are far away from the ester groups that are to be hydrolysed stereoselectively, this is what happens [69, 70]. The high selectivity is partly due to the fact that the secondary alcohol groups are protected as a cyclic acetal, giving additional structural information to the enzyme (Scheme 6.20 A). A cyclic acetal also provides additional structural information in the enantioselective hydrolysis of a pentane tetrol derivative (Scheme 6.20 B) [71]. In both cases Pseudomonas fluorescens lipase (PFL) proved to be the enzyme of choice. 

Evolution of a lipase for the stereoselective hydrolysis of a meso-compound... 

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. 

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. The former includes variously substituted cycloalkene diacetates, cyclohexylidene protected erythri-tol diacetate, piperidine derivatives, and the exo-acetonide in eq 11. Complementary results are clearly demonstrated in eq 11 and eq 12 for the hydrolysis and esterification processes. 

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. 

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. 

Compound 168 is a key intermediate for the synthesis of prostaglandin or prostacyclin compounds. Scheme 5-50 shows its preparation via a retro Diels-Alder reaction and subsequent treatment. Using enzyme-catalyzed acetylation, Liu et al.80 succeeded in the asymmetric synthesis of enantiomerically pure (+)/ (—)-156 and (—)-168 from the meso-Aio 164. When treated with vinyl acetate, meso-diol 164 can be selectively acetylated to give (+)-165 in the presence of Candida cyclindracea lipase (CCL). The yield for the reaction is 81%, and the enantiomeric excess of the product is 98.3%. 

With a good route to the key meso diol 128 in hand, the authors turned their attention to desymmetrization, using the known asymmetric hydrolysis of meso diacetates by Lipase AK (Scheme 23). The meso diol 128 was first converted to diacetate 140, and then hydrolyzed with Lipase AK to cleave selectively one of the two acetates, producing chiral hydroxyester 141. Oxidation, cleavage of the acetate, and lactonization yielded the (3S,4.R) lactone 129. The corresponding lactol (3S,4 )-130 was found to be the enantiomer of the compound produced in the HLADH synthesis. 

The authors then used a modification of their Lipase-AK route to produce the natural enantiomer, as described in detail in the chapter by Kenji Mori in this volume. Instead of using the enzyme to execute a stereoselective monohydrolysis of meso diacetate 140, the enzyme was used to esterify selectively one of the hydroxy groups of meso diol 128, resulting in the antipodal hydroxyester. After oxidation of the free hydroxyl to the acid, and recrystallization of its salt with (JR)-l-naphthylethylamine, the purified acid was then carried through the remaining steps to furnish the chiral pheromone compound (see the chapter by Kenji Mori in this volume). 

Starting with tropone 330, the azido compound 331 was first synthesized, as shown in Scheme 55. Then, compound 331 was chemoselectively reduced to unsaturated amine 332 by Lindlar catalyst, and this material was elaborated to the meso carbamate 333, ready for enzymatic asymmetrization. Treatment of 333 with Amano P-30 lipase in the presence of isopropenyl acetate resulted in formation of the enantiomerically pure (>98% ee) monoacetate 334, the common intermediate to both calystegines 337 and ent-337. Using conventional chemistry, elaboration of the functional groups within tropane 334... 

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],... 

A recent synthesis of both (+)- and (-)-enantiomers of calystegine Aj has been achieved, commencing from the 6-azido derivative of meso-2-cycloheptene-1,4-diol [57]. The amine derived from this compound was protected as the benzyl carbamate (47) and subjected to asymmetrization using Pseudomonas cepacia lipase to give the mono-acetate (48). The product of this reaction was ... 

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