Enzymatic hydrolysis desymmetrization

The enzymatic hydrolysis of nitriles provides a viable alternative for the generally harsh chemical conditions that are most often used. As a result of the ability of many nitrilehydrolyzing enzymes to give selective monohydrolysis, in the case of dinitriles, additional opportunities such as desymmetrization can be explored. With the previous examples, we have shown that, for several substrate classes, enzymatic desymmetrization of dinitriles is indeed a synthetically viable option. 

Zopiclone is a chiral cyclopyrrolone with hypnotic properties, possessing a pharmaceutical profile of high efficacy and low toxicity, similar to that of benzodiazepines. Zopiclone has been commercialized as a racemic mixture however, the (S)-enantiomer is more active and less toxic than the (R)-enantiomer [11]. Although enzymatic hydrolysis of esters or transesteriflcation processes of alcohols have been widely applied for enzymatic resolution or desymmetrization... 

Scheme 7.16 Desymmetrization of 2-substituted 1,3-propanediol to (S)-monoacetate by enzymatic hydrolysis in 80% organic solvent.

Scheme 14- Synthesis of (-)-paroxetine using an asymmetric desymmetrization of a glutanc ester via enzymatic hydrolysis.

Excellent enantioselectivities are observed in the alkylation of various gem-dicarboxylates with both carbon and heteroatom nucleophiles as summarized in Table 8E.2 [71]. Screening various chiral ligands from the DPPBA module revealed that 1,2-diaminocyclohexane derived ligand 5 gives the best results, and the mnemonic of Figure 8E.8 correctly predicts the enantiomer obtained in this reaction. Notably, the corresponding desymmetrization by enzymatic hydrolysis or acylation is not feasible with these 1,1-diol derivatives. 

Neri et al89 reported the desymmetrization of A-Boc-serinol 98 by the selective monoacetylation using PPL (porcine pancreas lipase) and vinyl acetate as the acylating agent in organic solvent. The mono acetylated product (R)-99 was obtained after 2 hours with 99% ee and isolated in 69% chemical yield. Traces of the diacetylated product 100 were observed. The cyclization of (R)-99 in basic medium afforded the racemic oxazolidinone 101. The latter was subjected to enzymatic hydrolysis in phosphate buffer affording (R)-... 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

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). 

Enzymatic desymmetrization, 275 Enzymatic hydrolysis, 1085 Enzymatic proteins, 3981 Enzymatic treatment, 4032 Enzyme-linked immunosorbent assay... 

A final example shows a process called desymmetrization (Figure 15.25). We start with a raeso-compound (remember this is a molecule that contains asymmetric carbon atoms but is not chiral, because it has a plane of symmetry) with two identical functional groups. Under enzymatic hydrolysis, only one of these reacts, so a chiral compound is produced, and all the material is used, without any need to recycle. The enzyme used in this reaction is electric eel acetylcholinesterase (EEAc). Pig liver esterase is also commonly used, as a relatively crude extract is inexpensive and gives good results. An example is shown in Figure 15.26, in the synthesis of 7 -mevalonolactone, important in the biosynthesis of terpenes and steroids. 

In an asymmetric synthesis, the enantiomeric composition of the product remains constant as the reaction proceeds. In practice, ho vever, many enzymatic desymmetrizations undergo a subsequent kinetic resolution as illustrated in Figure 6.5. For instance, hydrolysis of a prochiral diacetate first gives the chiral monoalcohol monoester, but this product is also a substrate for the hydrolase, resulting in the production of... 

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

Few examples of chemical or enzymatic desymmetrizations of centrosymmetric molecules (point group S2 = Q) have been described [150]. The PLE-catalyzed hydrolysis of a centrosymmetric cyclohexanediacetate gave rise to an enantiomeri-cally pure (>99.5% ee) cyclohexanediol monoacetate in high yield [151] (Figure 6.57). 

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]. 

Biocatalysis plays a central role in the manufacturing of statin side chains (Figure 6.2). A first set of approaches exploits enzymatic desymmetrization reactions, for example, of the methoxyacetyl ester of glutaric acid diethyl ester with commercially available a-chymotrypsin as explored by Ciba SC with a yield of 94% and enantiomeric excess of up to 98% [1]. In the optimized procedure, the substrate was available in a concentration of 1 M at an enzyme/substrate ratio of 7% (wt/wt), and the reaction took approximately a day. The subsequent steps to the final acetonide also involved a pig-liver esterase (PLE) catalyzed selective hydrolysis of the methoxyacetyl group (Figure 6.2a). 

The first enzymatic desymmetrizations of prochiral phosphine oxides was recently reported by Kielbasinski et al.88 Thus, the prochiral bis(methoxycarbonylmethyl)-phenylphosphine oxide 93 was subjected to the PLE-mediated hydrolysis in buffer affording the chiral monoacetate (RJ-94 in 72% ee and 92% chemical yield. In turn, the prochiral bis(hydroxymethyl)phenylphosphine oxide 95 was desymmetrized using either lipase-catalyzed acetylation of 95 with vinyl acetate as acyl donor in organic solvent or hydrolysis of 97 in phosphate buffer and solvent affording the chiral monoacetate 96 with up to 79% ee and 76% chemical yield. 

Enzymatic resolution has been successfully applied to the preparation of optically active gem-difluorocyclopropanes (see Scheme 12.4). We succeeded in the first optical resolution of racemic gm-difluorocyclopropane diacetate, trans-43, through lipase-catalyzed enantiomer-specific hydrolysis to give (R,R)-(-)-44 with >99% ee (see equation 9, Scheme 12.4) [4a], We also applied lipase-catalyzed optical resolution to an efficient preparation of monoacetate cw-46 from prochiral diacetate m-45 (see equation 10, Scheme 12.4) [4a], Kirihara et al. reported the successful desymmetrization of diacetate 47 by lipase-catalyzed enantiomer-selective hydrolysis to afford monoacetate (R)-48, which was further transformed to enantiopure amino acid 15 (see equation 11, Scheme 12.4) [19]. We demonstrated that the lipase-catalyzed enantiomer-specific hydrolysis was useful for bis-gem-difluorocyclopropane 49. Thus, optically pure diacetate (R,S,S,R)-49 and (S,R,R,S)-diol 50, were obtained in good yields, while meso-49 was converted to the single monoacetate enantiomer (R,S,R,S)-51 via efficient desymmetrization (see equation 12, Scheme 12.4) [4b, 4e], Since these mono- and bis-gm-difluorocyclopropanes have two hydroxymethyl groups to modify, a variety of compounds can be prepared using them as building blocks [4, 22],... 

Chiral ligand 651 is obtained from the appropriate natural amino-acid phenylalanine, whereas the corresponding derivatives of valine or leucine proved to be slightly less effective [46], Axially prochiral, enantiotopic, biaryl-2,6-diols have been converted to the respective chiral compounds via enzymatic desymmetrization. Thus Pseudomonas cepacia lipase (PCL) catalysed the atropisomerically-selective hydrolysis of diacetate 654 to give monoacetate 655 in 67% yield and 96% e. e. [47], Scheme 24. 

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