Prochiral diesters

Table 1.1 Influence ofcosolvents on the asymmetric hydrolysis the prochiral diester (1) catalyzed by pig liver esterase. of...

Figure 2.2 Production of enantiopure compounds using hydrolytic enzymes. In (a) a prochiral diester is hydrolysed to yield predominance (in theory 100%) of one enantiomer. In the next example (b) a raeso-diester is hydrolysed to yield predominance (in theory 100%) of one enantiomer of the monoester. If kj>k2 the (IS, 2i )-enantiomer is formed to the greatest extent. Due to the preference of the enzyme k4>kj and the lower monoester (IR, 2S) will be removed fastest. Hence both steps will lead to an increase of the upper enantiomer at the monoester stage. If the reaction proceeds to completion, however, the result will be another raeio-compound, a diol. In example (c) a racemic secondary ester is resolved by hydrolysis. One monoester is hydrolysed faster than the other and this leads to kinetic resolution.

Recent advances include the use of new chiral bases, extention to substrates other than ketones, and trapping with electrophiles other than silylating reagents and aldehydes. Regarding alternate substrates and electrophiles, the Simpkins group reported alkylation of a prochiral diester with common alkyl halides with >98% ee [46]. Simpkins and coworkers have also demonstrated desym-metrization of cyclic imides, in this case with trapping by silyl groups [47]. 

There are also recent reports of the lipase-catalyzed enantioselective hydrolysis of prochiral diacid derivatives such as 2-substituted malonates, barbiturates, and highly substituted, sterically hindered 1,4-dihydropyridine derivatives using acy-loxymethyl groups to enhance the reaction rate. An example of a prochiral diester hydrolysis is illustrated in eq 10. ... 

Because of the results with numerous prochiral diesters and diols, which have been subjected successfully to hydrolase-catalyzed enantioselective hydrolysis and acylation, respectively, and because of the desire to predict the sense of the asymmetric induction in the conversion of a new substrate, active-site or substrate models have been developed for the hydrolases pig liver esterase171 731, pig pancreas... 

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... 

Desymmetrization of Prochiral Diesters. PLE has been used only relatively infrequently for the resolution of racemic esters, while a-chymotrypsin has played... 

ISJC109R B. M. Trost, Isr. J. Chem., 1997, 37, 109-118. Desym-metrization of Prochiral Diesters Via Transition Metal Catalyzed Reactions. VII... 

Recently, two enantioselective syntheses of (—)-alloyohimbane (82) have been reported. The synthetic route utilized by Riva s group featured an enzymatic hydrolysis as the key step (Scheme 3.8S) (135). Prochiral diester 489 was hydrolyzed with pig liver esterase to provide the hydroxyester (—)-490 in good yield and with a high enantiomeric excess. One carbon homologation of (—)-490 followed by subsequent lactonization generated the bi-cyclic lactone (—)-491. Condensation of (—)-491 with tryptamine afforded tetracyclic lactam (—)-81, an intermediate in Isobe s synthesis of (—)-alloyohimbane ((—)-82). 

A number of examples of monoacylated diols produced by enzymatic hydrolysis of prochiral carboxylates are presented in Table 3. PLE-catalyzed conversions of acycHc diesters strongly depend on the stmcture of the substituent and are usually poor for alkyl derivatives. Lipases are much less sensitive to the stmcture of the side chain the yields and selectivity of the hydrolysis of both alkyl (26) and aryl (24) derivatives are similar. The enzyme selectivity depends not only on the stmcture of the alcohol, but also on the nature of the acyl moiety (48). 

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. 

The first asymmetric synthesis of (—)-Y-jasmolactone, a fruit fiavor constituent, vas achieved via the enantioselective lactonization (desymmetrization) of a prochiral hydroxy diester promoted by porcine pancreas lipase (PPL) (Figure 6.23) [71]. 

Reaction in organic solvent can sometimes provide superior selectivity to that observed in aqueous solution. For example, Keeling et al recently produced enantioenriched a-trifluoromethyl-a-tosyloxymethyl epoxide, a key intermediate in the synthetic route to a series of nonsteroidal glucocorticoid receptor agonist drug candidates, through the enan-tioselective acylation of a prochiral triol using the hpase from Burkholderia cepacia in vinyl butyrate and TBME (Scheme 1.59). In contrast, attempts to access the opposite enantiomer by desymmetrization of the 1,3-diester by lipase-catalysed hydrolysis resulted in rapid hydrolysis to triol under a variety of conditions. 

A phosphate diester of the form R0P020R is prochiral, since one of the non-alkylated oxygen (160) atoms must be replaced to produce chirality. A monoester... 

Prochiral substrate giving prochiral product (i.e., diester — diester). 

Enantioselective enzymatic ester hydrolyses of prochiral trimethylsilyl-substituted diesters of the malonate type have been applied for the synthesis of the related optically active monoesters68. As an example of this particular type of biotransformation, the enantioselective conversion of the diester 82 is illustrated in Scheme 17. Hydrolysis of compound 82 in phosphate buffer, catalyzed by porcine liver esterase (PLE E.C. 3.1.1.1) or horse liver acetonic powder (HLAP), gave the optically active monoester 83 (absolute configuration not reported) in 86% and 49% yield, respectively. The enantiomeric purities... 

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. 

Asymmetrization of a prochiral dicarboxylic acid diester catalyzed by lipases, where the stereo center of the product is located on the acyl side, becomes a single-step process because the polar carboxylic acid and/or amide formed are not well accepted as substrates by the Upase. One example is the enantioselective hydrolysis or ammonolysis of diethyl 3-hydroxyglutarate, as shown in Scheme 7.4, a reaction which leads to the formation of a precursor for the important chiral side chain of atorvastatin, lipitor [40, 41]. The S-enantiomer was formed with high e.e. (98%), but unfortunately this is the undesired enantiomer for the production of the pharmaceutically important product. Only a-chymotrypsin gave a predominance of the... 

Pig Liver Esterase (PLE). This is the more used car-boxylesterase (carboxylic-ester hydrolase, EC 3.1.1.1, CAS 9016-18-6) which physiologically catalyzes the hydrolysis of carboxylic acid esters to the free acid anion and alcohol. PLE is a serine hydrolase which has been widely used for the preparation of chiral synthons and these applications have been fully reviewed. An active-site model for interpreting and predicting the specificity of the enzyme has been published. In the pioneering studies of the enzyme applications field, PLE was used for the chiral synthesis of mevalonolactone. Prochiral 3-substituted glutaric acid diesters... 

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. 

Prochiral y-hydroxy diesters underwent enantioselective lactonization with PPL to afford the (S)-lactone in a highly enantioselective fashion (eq 17). Formation of macrocyclic lactones by the condensation of diacids or diesters with diols, leading to mono- and dilactones, linear oligomeric esters, or high molecular weight optically active polymers, depending upon type of substrates as well as reaction conditions, has also been described. 

Although prochiral or chiral alcohols and carboxylic acid esters initially served as the primary classes of substrates, compounds susceptible to processing via these two routes now encompass diols, a- and 3-hydroxy acids, cyanohydrins, chlorohydrins, diesters, lactones, amines, diamines, amino alcohols, and a-and 3-amino acid derivatives. Gotor and Arroyo have reviewed the use of biocatalysts for the preparation of pharma-eeutical intermediates and fine ehemieals. Some specific examples are indieated below. 

We are concerned with the absolute stereochemistry of the product does epoxidation give 5a or 5b Does the Diels-Alder reaction give 7a or 7b There is also a small group of prochiral tetrahedral carbon atoms with enantiotopic functional groups such as the diester 8 or the diene 9. We shall meet examples of all these (and more ) in this chapter. 

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. 

Chiral monoesters, obtained either from a prochiral diol or diester, may be converted by a suitable series of chemoselective transformation to either enantiomer of a given target compound (enantiodivergent synthesis) (Scheme 11.1-13)110 40l... 

Table 11.7-1. Pig liver esterase-catalyzed enantiotopos-differentiating hydrolysis of prochiral cyclic dicarboxylic acid diesters in aqueous solution.

Table 11.1-12. Lipase-catalyzed enantiotopos-differentiating hydrolysis of prochiral acyclic and cyclic dicarboxylic acid diesters in aqueous solution (CCL Candida cylindracea lipase, PPL pig pancreas lipase, PSL Pseudomonas sp. lipase, CVL Chromobacterium viscosum lipase,...

A limited number of acyclic and cyclic prochiral dicarboxylic acid diesters were found to be good substrates for hydrolysis catalyzed by lipases (Table 11.1-12). Notable examples which give a good illustration of the potential of hydrolases as well as of the trial and error approach one relies on to a certain extent are the dithio acetal derivative 9 and the fluoro alkyl malonates 1-8. The dithio monoester 9 is obtained with different lipases with high enantioselectivities and yields despite its remote chiral center. Candida cylindracea lipase is the enzyme of choice for the synthesis of fluoro alkyl malonates with small alkyl groups. An astonishing observation was... 

A sensitive probe applied to understand the nature of the reaction mechanism of group transfer is the stereochemistry of the overall reaction. The reaction at a phosphoryl center normally is a degenerate question, since a monosubstituted phosphate ester or anhydride is proprochiral at the phosphate center. Phosphate centers at a diester or disubstituted anhydride are prochiral. Two related methods to analyze the stereochemistry at a phosphate center have been developed by the generation of chirality at the phosphorus center. The first approach was developed by Usher et al. (24) and gave rise to the formation of isotopi-cally chiral [ 0, 0]thiophosphate esters and anhydrides (I). Isotopically chiral [ 0, 0, 0]phosphates (II) have also been synthesized and the absolute configurations determined. Two primary problems must first be addressed with respect to both of the methods that have been developed the synthesis of the isotopically pure chiral thiophosphates and phosphates and the analysis of the isotopic chirality of the products. An example of the chiral starting substrates, as developed for ATP, is schematically demonstrated. Ad = adenosine. 

Scheme 2.13 shows a few examples of resolutions and desymmetrization using esterases. Entry 1 shows the partial resolution of a chiral ester using a crude enzyme source. The enantioselectivity is only moderate. Entries 2 to 5 are examples of desymmetrization, in which prochiral ester groups are selectively hydrolyzed. Entries 6 and 7 are examples of selective hydrolysis of unsaturated esters that lead to isomeric monoesters. These cases are examples of diastereoselectivity. In Entry 8, the f ,f -enantiomer of a racemic diester is selectively hydrolyzed. In all these cases, the... 

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