Meso-diesters, hydrolysis

PLE catalyzes the hydrolysis of a wide range of meso-diesters (Table 2). This reaction is interesting from both theoretical and practical standpoints. Indeed, the analysis of a large range of kinetic data provided sufficient information to create a detailed active site model of PLE (31). From a practical standpoint, selective hydrolysis of y j (9-cyclo-I,2-dicarboxylates leads to chiral synthons that are valuable intermediates for the synthesis of a variety of natural products. 

Table 2. PLE-Catalyzed Hydrolysis of Monocyclic meso-Diesters...

Table 1.2 Influence ofcosolvents on the asymmetric hydrolysis of the meso-diester (3) catalyzed by pig liver esterase.

Esterases, proteases, and some lipases are used in stereoselective hydrolysis of esters bearing a chiral or a prochiral acyl moiety. The substrates are racemic esters and prochiral or meso-diesters. Pig liver esterase (PLE) is the most useful enzyme for this type of reaction, especially for the desymmetrization of prochiral or meso substrates. 

Podophyllotoxin, a plant lignan, is a potent antimitotic agent (Figure 6.61). An enantioselective synthesis of (—)-podophyllotoxin was achieved via the enzymatic desymmetrization of an advanced meso-diacetate, through PPL-mediated diester hydrolysis [157]. 

K. Adachi, S. Kobayashi, M. Ohno, Chiral Synthons by Enantioselective Hydrolysis of meso-Diesters with Pig Liver Esterase Substrate-Stereoselectivity Relationships , Chi-mia 1986, 40, 311-314. 

Optically active aziridines have been prepared in high enantiomeric excess by the enzymatic resolution of meso diesters (94AG(E)599). For example, when the me o-bis(acetoxymethyl)aziridine (56) was subjected to enzymatic hydrolysis with lipase Amano P, the aziridine (57) was obtained in 98% ee (90TL6663). 

Four possible stereoisomers of PHYLPA (72) were synthesized in enantioselective manners by Kobayashi et al. [40] Preparation of one diastereomer of cyclopropane-containing hexadecanoic acid (81) was summarized in Scheme 7, starting with enzymatic hydrolysis of meso diester (74). 

The asymmetric hydrolysis of several cyclic meso-diesters has been accomplished and optically pure monoesters have been obtained. A classical example is the hydrolysis of dimethyl cis-4-cyclohexene-1,2-dicarboxylate, which affords the corresponding nearly optically pure half ester, a versatile synthon for various chiral cyclohexane derivatives (eq 3). ... 

Table 8 Enzymatic Enantioselective Hydrolysis of meso-Diesters or Diacetates...

Construction of the enantiomerically pure cyclopentane unit for 161 hinged on the ability of an enzyme to react preferentially with one of two enantiotopically related functional groups. To this end, the reaction of the meso diester 261 with commercially available pig liver esterase resulted in almost exclusive hydrolysis at the 1/ ester group to afford the mono ester 262 in 92% yield and >99% ee. Reduction to the alcohol was accomplished via the intermediate acid chloride, which was then cyclized to the lactone 263. Oxidative ring opening followed... 

The crucial compound in this strychnine synthesis is azabicyclo[3.2.1]octane 31, which is the substrate for the aza-Cope-Man-nich sequence (Scheme 4). In the preparation of 31, meso-diester 20 is subjected to acetylcholine esterase catalyzed hydrolysis to yield 21 with high enantiomeric purity. Eighteen ensuing steps then provide 31 in 14 % yield. The allylic carbonate obtained from 21 is... 

Ohno has reviewed the work of his group on the enantioselective synthesis of, inter alia, nucleosides, C-nucleosides and carbocyclic nucleoside analogues using chiral synthons derived by asymmetric hydrolysis of meso-diesters with pig liver esterase. Although acyclonucleosldes are not discussed in detail in these volximes, we note an extensive review of the chemistry and antiviral activity of such compounds. ... 

B. Asymmetric Hydrolysis of meso-Diesters and Asymmetric Esterification of meso-D o s... 

The ability of lipases and esterases to achieve asymmetric hydrolysis of meso-diesters is well known, and was reviewed by Ohno and Otsuka [61]. In theory me o-diesters generate the desired optically active monoesters quantitatively. 

Besides fragmentation or rearrangement, the carboxylic acid anions, formed by an enzymatic hydrolysis, can also act as nucleophiles. Kuhn and Tamm used the asymmetric hydrolysis of meso-epoxy diester 8-28 with PLE to synthesize y-lactone... 

Next, Danishefsky s allosamizoline synthesis will be described [143,144]. The key point of their synthetic strategy is the utilization of enzymatic optical resolution to the racemic substrate. As illustrated in O Fig. 8, there are two approaches for the enzymatic optical resolution. One is the enzymatic hydrolysis of a diester [145,146,147], and the other is the enzymatic transacylation of the meso-dk> [148,149,150] (O Fig. 8). In Danishefsky s group, the former route was chosen as the key step. Treatment of diacetate 186 with electric eel acetylcholinesterase provided the monoacetate 187, which was reported by Deardorrf et al. [147]. This work was also applied to the synthesis of PG p2a in Danishefsky s laboratory [151]. On the basis of the success of their synthesis of PG p2a, diacetate 188, which was derived from the 2-alkene-l,4-diol derivative 176, was treated with electric eel acetylcholinesterase as well. Interestingly, this treatment provided the unexpected monoacetate 189 in 95% yield, > 95% ee (O Fig. 8). 

Even a fourth variant is feasible, namely the submission of meso-compounds -these contain stereogenic centers but feature internal elements of symmetry and, hence, are achiral - to a desymmetrization, which in principle generates only one stereoisomer. The classical case is the hydrolysis of a diester to form a half-acid/es-ter as a single antipode. Generation of both optical isomers of synthetically useful 1,2-diol products in good yield and stereoisomeric purity applying this methodology has recently been demonstrated (see Fig. 2.11) [65]. 

Numerous meso-configured or otherwise prochiral substrates, preferentially containing enantiotopic methoxycarbonyl groups, have been converted by a pig liver esterase- or lipase-catalyzed enantioselective hydrolysis in water to chiral monoesters (see Sect. 11.1.1.1.1., Tables 11.1-1 to 11.1-4 and Sect. 11.1.1.1.5, Tables 11.1-10 to 11.1-12). In nearly all cases investigated thus far the pig liver esterase-catalyzed hydrolysis of the substrate diester S terminates at the stage of the enantiomeric monoesters P and ent-P. In this case, where the products P and ent-P are not transformed further, the irreversible enantiotopos-differentiation may be described by the process depicted in Scheme 11.1-10167 691. 

Racemic cis-raonoesters of cyc1opentene-3,5-diol have been previously prepared by the selective acylation of the meso-diol and the copper-mediated addition of carboxylic acid salts to cyclopentadiene monoepoxide. Optically active monoacetates can be accessed by enzymatic hydrolysis of the corresponding diester. The present method offers four principal advantages over the earlier reports (1) it is operationally simple, (2) it requires a much shorter reaction time, (3) it gives better yields, and (4) it has widespread applicability, since reactants other than carboxylic acids may be employed with equally good results. 

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. 

As adumbrated earlier, the hydrolysis of meso-compounds or prochiral compounds can provide optically active intermediates, useful for the synthesis of pharmaceuticals and other high-value materials. A further example is provided by the prochiral diester (17), which is hydrolysed using pie as the catalyst to give the chiral acid (18) (93% e.e., 93% yield). The protected amino acid (18) was converted through a series of conventional chemical steps into the anti-bacterial agent thienamycin. Similarly, the diester (19) provides the hydroxyester (20) on hydrolysis utilizing ppl as the catalyst. Over-reaction can be a problem in this case, and a sample... 

Figure 47 Preparation of chiral synthons for (-)-aristeromycin and (-)-neoplanocin Enzymatic asymmetrical hydrolysis of meso-Qpoxy diester 131.

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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