Stereoselective Hydrolysis of Substituted Cyclopropanedicarboxylates with Pig Liver Esterase

Abstract

The hydrolysis of the rneso-cyclopropane-l,2-dicarboxylates la-3a, 4, 5a, 6a, and 9, containing various substituents at C(3), and of the rac-3-phenylcyclopropane-1,2-dicarboxylates 7a, Sa, and 10 with pig liver esterase (PLE) is described. The stereoselectivity and absolute configurations of the products were determined. An interpretation of results was attempted on the basis of a recent active-site model for PLE.Introduction. -The efficient synthesis of biologically active compounds, either of natural or unnatural origin, frequently requires chiral synthons. Enzymes as chiral catalysts are now widely used for their preparation [l-41, because it often is rather difficult to introduce centres or chirality or perform regiospecific transformations by the application of purely 'chemical methods'. Especially esterases, such as pig liver esterase (PLE, E.C. 3.1.1.1), a serine hydrolase, have been studied extensively in recent years [5-81. We have used PLE successfully in resolving racemic esters [9] and for the preparation of versatile chirons [5] [6] [9] [lo]. Stability, low costs, and the ability of hydrolyse a wide range of substrates with high stereoselectivity represent additional advantages of this enzyme which operates-without the need for co-enzymes. Until now, more than one hundred different esters, mainly meso-and prochiral-diesters have been subjected to the treatment with PLE [8]. To be able to fully exploit the potential of this enzyme, it is indispensable to understand the factors which are responsible for the specificity. Accordingly, we as well as other research groups have initiated investigations for securing a large number of data on hydrolyses, allowing to gain more insight into the relationship between substrate structure and enzymic activity of PLE. Until recently, it appeared to be very difficult to reach this goal, not only because the physiological role of PLE is unknown [ 1 I], but also because commercially available PLE preparations are mixtures of at least six isoenzymes [12] [ 131 which, however, were found to exhibit essentially the same stereospecificity [14]. These findings justify the attempt to rationalize the results of the hydrolyses by an active-site model which is mainly based on the measured ee values and the absolute configuration of the hydrolysis products. Several approaches to such a model have been reported [14-181. The most recent proposal made by Jones and coworkers which is based on cubic-space descriptors, is at present the most precise published active-site model [19].Here, we report on the results of the hydrolysis of a series of structurally related cyclopropane-l,2-~arboxylates with PLE. These substrates were chosen for the following reasons: I ) The cyclopropane ring provides rigidity. Therefore, only one preferred conformation has to be accounted for the analysis of the substrate/active-site interac-

Kinetic Enzymatic Resolution of Cyclopropane Derivatives

“…[23] By comparison, C 2 -or pseudo-C 2 -symmetric cyclopropanes 2 generally give a decreased selectivity: for different esters 2 E values of E < 10 were observed [18] and also the difluorocyclopropane 3 (E 11) gave only slightly better results. [21] More generally speaking, with compounds where the cyclopropane moiety is the only stereogenic element, the kinetic resolution using hydrolases provides modest selectivities compared to those observed in the desymmetrization of meso compounds: Enantioselectivities (E values [24±28] ) greater than 40 are rarely observed (see Figure 2 for some selected examples 4 ± 15 [29±40] ).…”

Strategies and Tactics for the Synthesis of Oxygenated Natural Products

“…The importance of cyclopropanes is further enhanced by their ability to serve as mechanistic (36-38) and biological (39-41) probes as well as synthetic intermediates (42,43). Although numerous methods for the stereoselective synthesis of cyclopropanes exist (44-46), only recently have there been reports of general techniques for their asymmetric synthesis (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). In connection with our synthetic efforts directed toward ambruticin coupled with our interest in exploiting trisubstituted cyclopropanes as rigid replacements of peptide secondary structure (39)(40)(41), we embarked several years ago on a program to develop novel and efficient methods for the asymmetric synthesis of 1,2,3trisubstituted cyclopropanes.…”

Enantioselective Lactonization of 3,3,6-Trimethyl-4(E)-heptenoic Acid Esters

“…Bicyclic lactones were also obtained by enzymatic desymmetrization of cyclopropane diesters [47,48]. A reaction between optically pure epichlorohydrines with sodium malonate also yields bicyclic lactones with a cyclopropane group and is characterized by good enantioselectivity [49,50]. Last up-to-date review of an asymmetric approach for halolactonization was published by Nolsøe and Hanson in 2014 [30].…”