Prochiral glutarates

Alcoholysis of prochiral glutaric anhydrides under the usual conditions gives, with moderate selectivities, the monoesters 3-8. 

Our final example is that of cyclic anhydrides, namely prochiral 3-sub-stituted glutaric anhydrides (7.101, R = Me, Et, or Pr). When incubated with lipase in an inert solvent in the presence of an alcohol (methanol, butan-l-ol, etc.), these compounds underwent nucleophilic ring opening with formation of a hemiester (7.102) of (/ -configuration (60-90% ee) [180]. This product enantioselectivity and, of course, the lack of reactivity in the absence of lipase show the enzymatic nature of the reaction. 

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... 

The known desymmetrization of prochiral 3-substituted glutarates via enzymatic hydrolysis [65] has been optimized by chemists at Ciba Speciality Chemicals for the synthesis on a large scale [66]. The a-chymotrypsin-catalyzed process is characterized by a high substrate concentration of 285 g L and an isolated yield of 94% product with an ee of 98.2% (route C). 

A limited number of prochiral malonates and glutarates are hydrolyzed by a-chymotrypsin to the corresponding monoesters with synthetically useful enantiose-lectivities(l-9) (Table 11.1-7). 

Complications arise when two esters of different acids are present or when acylation occurs on the aglycone. One must then rely on partial hydrolysis. The tactics are examplified hy the Entada saponins which contain C2 and Cjq acids (89). The acetate was selectively removed hy 0.025 % K2CO3 while both adds were removed by 1 % KOH. Comparison of C NMR spectra of the parent compound and of derivatives allowed determination of the points of acylation. The dicrotalic (3-hydroxy 3-methyl glutaric add) esters of the tubeistemosides and related compoimds (29-32) provide more complicated examples where the double anchoring of the diadd transforms a prochiral carbon atom into a center of chirality. 

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. 

M.J. Homan, R. Vail, B. Morgan, V. Sabesan, C. Levy, D.R. Dodds, A. Zaks, Enzymatic hydrolysis of a prochiral 3-substituted glutarate ester, an intermediate in the synthesis of an NKl/ NK2 dual antagonist, Adv. Synth. Catal. 343 (6-7) (2001) 744-749. 

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