Desymmetrization of Diesters

This methodology avoids the inherent 50% yield limit of KR and the difficult separations often encountered in the resolution of racemates. The potential of enzymes, especially lipases, to catalyze the aminolysis and ammonolysis of prochiral 

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For desymmetrization of diesters 3 via their hydrolysis in water, pig Hver esterase [12], o -chymotrypsin [12, 13a], and Candida antarctica Hpase (CAL-B) [14] were successfully used. However, further studies showed that respective anhydrides 5 can be used as substrates for enzyme-catalyzed desymmetrization in organic solvents [15]. The desired monoesters 4 were obtained in high yield in this way, using immobilized enzymes Novozym 435 or Chirazyme L-2 (Scheme 5.3). After the reaction, enzymes were filtered off, organic solvents were evaporated, and the crude products were crystalHzed. This was a much simpler experimental procedure in which control of the reaction progress was not necessary, and aU problems associated with extraction of products from aqueous phase and their further purification were omitted [15]. 

The crucial step for the eastern part was the desymmetrization of diester 432. This was accomplished with lypozyme TL in 100 g quantities. 

In another signiflcant example published in the same period, Guanti and coworkers described the desymmetrization of the meso cydohexene diester (3) to give the hemiester (4), whose enantiomeric excess increased from 55 to 96% when moving from plain buffer to the same buffer containing 10% v/v t-BuOH (Scheme 1.2 and Table 1.2 [8]). 

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. 

Several lipases were more efficient than PLE and subtilisin Carlsberg for the desymmetrization of an N-t-butoxycarbonyl (Boc) meso-piperidine diester (Figure 6.13). The (3R)-monoester was converted into optically pure isogalactofagomme, a potent galactosidase inhibitor [60]. 

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]. 

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]. 

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. 

In 1992, Trost and his co-workers investigated desymmetrization of cyclic w j-o-diesters with lithium sulfonyl-methylenenitronate as a nucleophile in the presence of Trost s ligand 118, where the corresponding cyclic compounds are obtained with an excellent enantioselectivity via intramolecular cyclization (Scheme 15),103,103a Asymmetric cyclopropanation and lactone annulation are achieved according to this protocol (Scheme Nitroalkanes can also be employed as carbon-centered nucleophiles in lieu of malonates (Scheme 17). ... 

For a new potential -3-receptor agonist a pig liver esterase-based enantioselec-tive synthesis was devised (Scheme 6.18). The substituted malonic acid diester was hydrolysed at pH 7.2 and yielded 86% of the (S)-monoester with an ee of 97% [62]. This reaction immediately demonstrates the great advantage of starting with a symmetric molecule. The enzyme very efficiently desymmetrizes the diester and excellent yields with high optical purities are obtained. No extra steps are necessary and no additional chemicals need to be added. 

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. 

Similarly, the two chemically identical groups X, positioned on carbon atoms of opposite (/ ,5)-configuration in a weso-substrate, can react at different rates in a hydrolase-catalyzed reaction (Scheme 2.4). So, the optically inactive meso-substrate is transformed into an optically active product due to the transformation of one of the reactive groups from X into Y along with the destruction of the plane of symmetry within the substrate. Numerous open-chain or cyclic c/s-weso-diesters have been transformed into chiral monoesters by this technique [30]. Again, for dicarboxylates the reaction usually stops after the first step at the carboxylate monoester stage, whereas two hydrolytic steps are usually observed with diacetoxy esters [31]. The theoretical yield of chiral product from single-step reactions based on an enantioface or enantiotopos differentiation or a desymmetrization of meso-compounds is always 100%. 

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

As shown in Scheme 2.27, the prochiral center may be moved from the site of the reaction into the (3-position. Thus, chiral recognition by PLE [214-218] and a-chymotrypsin [219-222] is retained during the desymmetrization of prochiral 3-substituted glutaric diesters. Whole cells of Acinetobacter lowfii and Arthrobac-ter spp. have also been used as a source for esterase activity [223] and, once again, depending on the substitutional pattern on carbon-3, the desymmetrization can lead to both enantiomeric products. 

Scheme 2.32 Desymmetrization of W-conlaining cyclic mcio-diester by porcine liver esterase...

Resolution of Racemic Esters. Although PLE-catalyzed resolution of racemic esters have been performed less often as compared to the desymmetrization of prochiral and me,so-diesters, it can be a valuable technique. 

Scheme 2.54 Desymmetrization of prochiral 1,3-propanediol diesters by porcine pancreatic...

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]. 

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... 

Back TG, Wulff JE. A stereodivergent synthesis of virantmycin by an enzyme-mediated diester desymmetrization and a highly hindered aryl amination. Angew. Chem. Int. Ed. 2004 43(47) 6493-6496. 

Subsequently, diester 19 was subjected to desymmetrization through the use of an enzymatic process before its transformation to 20. 

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