Meso-diester

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. 

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. 

G. Sabbioni, J. B. Jones, Enzymes in Organic Synthesis. 39. Preparations of Chiral Cyclic Acid-Esters and Bicyclic Lactones via Stereoselective Pig Liver Esterase Catalyzed Hydrolyses of Cyclic meso Diesters ,./. Org. Chem. 1987, 52, 4565 - 4570. 

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). 

The formation of dimethyl succinates is stereospecific, syn addition of the two carbomethoxy functions taking place, as illustrated by the dicarboxylation of (Z)-2-butene to the meso diester and ( )-2-butene to the ( )-diester (equations 64 and 65). This occurs since the alkene insertion to yield intermediate (23) is syn and the CO insertion (23) — (24) takes place with retention of configuration at carbon. 

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). 

This step is necessary to retrieve the slightly water-soluble product diester that migrates into the aqueous layer during the wash process. The meso-diester is easily detected in the water phase by TLC analysis (see Note 5). 

In the 1980 s there was a great increase in the development and use of enzymatic procedures by synthetic chemists.6 Previously regarded more as scientific curiosities of limited scope than of practical utility, biological-chemical transformations are now used regularly by synthetic chemists. The ability to induce optical activity in molecules where none existed before is the most useful property of these chiral catalysts. Hydrolase enzymes are generally preferred over other kinds of enzymes for transformations of this nature because they are more easily handled and do not require cofactors for activity. In cases where enantiotopic differentiation between ester functions is desired, prochiral meso diesters are more efficient substrates than racemic esters. In the former case it is possible for all starting material to be converted into a single enantiomer, whereas in the latter example only enzymatic resolution is possible. 

In addition to cyclic allylic substrates, malonate nucleophiles have been used in reactions with both symmetrical" and unsymmetrical" acyclic systems, and with geminal dicarboxylates. Malonates and Meldrum s acid have also been used as nucleophiles in the desymmetrization of meso diesters. 

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... 

Another group of meso diesters are the acyclic compounds 30 and 31. Pig liver esterase is good at forming the mono-ester 33 and this compound can be transformed by selective reduction into either 32 or 34. These lactones are enantiomers so that either series may be entered from the same meso starting material.12 In addition the precarious chirality of 33 is more secure in the lactones. 

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. ... 

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