Enzymatic hydrolysis of chiral esters

Enzymatic Hydrolysis of Chiral Esters Using Lipase or Esterase... 

Use as chiral auxiliary. Whitcscll1 has reviewed use of this chiral alcohol (1), particularly as compared with that of (-)-menthol and (lR)-(+)-8-phenylmcnthol. One advantage is that both enantiomers of 1 are available by resolution of trans-2-phcnyl-cyclohcxanol by means of enzymatic hydrolysis of the esters and that 2-substitutcd cyclohexanols arc readily available. Although this chiral auxiliary was used originally for control of enc reactions of glyoxylatcs, it is also useful for asymmetric alkylation of enolatcs, and for control of various cycloaddition reactions. 

A practical aspect of the use of enzymes for the preparation of chiral synthons is the fact that one can use enzymes such as lipases either in hydrolytic conditions or in organic solvents, and the most suitable method is a compromise between the solubility of the compound, the efficiency of the process, and the maximum enantioselection that can be achieved. In Scheme 65 two of these cases are presented [278,244] where esterification and hydrolysis can be compared. Interestingly, an opposite configuration of products is obtained when enzymatic hydrolysis of the ester or esterification of the alcohol is carried out. 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

Analogous to the reactions of chiral alcohols, enantiomerically pure amines can be prepared by (D)KR of the racemate via enzymatic acylation. In the case of alcohols the subsequent hydrolysis of the ester product to the enantiomerically pure alcohol is trivial and is generally not even mentioned. In contrast, the product of enzymatic acylation of an amine is an amide and hydrolysis of an amide is by no means trivial, often requiring forcing conditions. 

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... 

Figure 12 Synthesis of chiral synthon for thromboxane A2 antagonist (A) stereoselective microbial oxidation of (exo,exo)-7-oxabicyclo[2.2. l]heptane-2,3-dimethanol (36) to the corresponding lactol (33) and lactone (34) (B) asymmetric enzymatic hydrolysis of (exo,exo)-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol, diacetate (37) to the corresponding S-(—)-monoacetate ester (38).

The oxidation of chiral imines with peracids and the oxidation of achiral imines with chiral peracids to give optically active A-alkyl oxaziridines has been reviewed <84MI 112-01 >. The resolution of chiral A-alkyloxaziridine-3,3-dicarboxylic esters through the enzymatic hydrolysis of the racemic diesters, in moderate ees, has been reported <88CC1614>. 

FIGURE 16.10 Preparation of the chiral C-13 paclitaxel side-chain synthon. (A) Enantio-selective microbial reduction of 2-keto-3-(Al-benzoylamino)-3-phenyl propionic acid ethyl ester 36. (B) Enantioselective enzymatic hydrolysis of cw-3-(acetyloxy)-4-phenyl-2-azetid-inone 38. 

Chiral hydroxyesters would be accessible via enzymatic hydrolysis of their acyloxy esters, but a disadvantage which is commonly encountered in such resolutions is an undesired side reaction involving the hydrolysis of the carboxyl ester moiety which leads to the formation of hydroxyacids as byproducts. Thus, low... 

Synthesis of chiral compounds by enzymatic hydrolysis of esters... 

Various optically active compoimds have been synthesized by enzymatic hydrolysis of esters. - Some examples are shown in Fig. 10.21. The kinetic resolution of racemic esters afforded an intermediate in the synthesis of a j8-blocker (Fig. 10.21(a)) and phosphodiesterase inhibitor (Fig. 10.21(b)).Useful chiral acids can be obtained through the resolution of meso esters by pig liver esterase-catalyzed hydrolysis (Fig. 10.21(c)). 

In addition to the previously mentioned chirons, albeit with less frequency, a variety of other chiral precursors have been used in the synthesis of natural 5,6-dihydropyrones [3]. Some of them have been prepared with the aid of enzymes. For example, a synthesis of both enantiomers of the natural dihydropyrone rugulactone was based on the enzymatic resolution of the racemic ester 37, obtained in four steps from 1,3-propanediol (Scheme 2.8) [lOh]. Thus, enzymatic hydrolysis of 37 was best catalyzed by a lipase isolated from Candida rugosa and afforded optically enriched (ii)-ester 38 and (S)-alcohol 39. Saponification of 38 was followed by desilylation and selective oxidation of the primary alcohol function to yield aldehyde 40. Still-Gennari olefination of 40 provided Z-a,fl-enoate 41, easily cycUzed to lactone... 

Tetrahydroisoquinolines bearing a chiral center at the Cl position constitute a structural motif found in many biologically active compounds. For instance, (5)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 114 is a precursor of the natural product (5)-calycotomine (Scheme 57.31). Kanerva, Fiilbp, et al. have described the preparation of both enantiomers of 114 by enzymatic hydrolysis of the ethyl ester derivative rac-113. Considering this substrate undergoes spontaneous racemization in an aqueous medium, these authors carried out an exhaustive study of the reaction variables in order to find the optimal conditions and thus achieve the DKR of this substrate. Two enzymes with opposite enantiopreferences were used CAL-B and... 

Figure 14 Synthesis of chiral synthon for thromboxane A2 antagonist Asymmetrical enzymatic hydrolysis of (cxo,cxo)-7-oxabicyclo[2.2.1]heptane 2,3-dimethanol, diacetate ester 50.

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