Esters enzymatic resolution

Carboxylic acids from carboxylic acid esters Enzymatic resolution of racemates... 

One approach called enzymatic resolution, involves treating a racemic mixture with an enzyme that catalyzes the reaction of only one of the enantiomers Some of the most commonly used ones are lipases and esterases enzymes that catalyze the hydrol ysis of esters In a typical procedure one enantiomer of the acetate ester of a racemic alcohol undergoes hydrolysis and the other is left unchanged when hydrolyzed m the presence of an esterase from hog liver... 

High yields of the enantiomerically pure alcohol and enantiomerically pure ester are reg ularly achieved The growing interest m chiral drugs (see the boxed essay on this topic p 296) has stimulated the development of large scale enzymatic resolution as a com mercial process... 

Fig. 7-19. Enzymatic resolution and separation of ibuprofen sulphonmethyl ester.

Figure A8.10 Enzymatic resolution of D,L-amlno acid esters.

Figure A8.11 Enzymatic resolution of N-acetyl-D,L-amino add esters.

The enzymatic resolution of esters via aminolysis or ammonolysis processes represents an efficient alternative to the resolution of substrates by transesterification... 

Here, we have selected a few representative examples of the enzymatic resolution of esters by aminolysis or ammonolysis reactions. On the other hand, the enzymatic acylation of racemic amines is also of great utility for the preparation of optically pure... 

Scheme 7.25 Enzymatic resolution of pipecolic methyl esters.

Fumaric acid to L-aspartic acid, L-aspartic acid to L-alanine Enzymatic resolution of methyl ester of (+/-) trans 4- methoxy-... 

Scheme 6. Substrate modulation in enzymatic resolution of a proline ester...

The three-step procedure described for the preparation of the illustrated crotylsilanes is initiated with the hydrosilation of rac-3-butyn-2-ol. This procedure is significantly improved with respect to the positional selectivity of the hydrosilation resulting in exclusive formation of the racemic (E)-vinylsilane, and as a result the present procedure is much more amenable to scale-up than those previously described in the literature.8 The enzymatic resolution of the racemic secondary allylic alcohol (vinylsilane) has also been reported using commercially available lipase extracts. The use of a Johnson ortho ester Claisen rearrangement affords the (E)-crotylsilanes 4 in nearly enantiomerically pure form. 

Other examples of efficient enzymatic resolutions by reaction at a remote position from stereocentres have been reported, such as the lipase-catalysed resolution of a synthetic intermediate of escitalopram." This property of enzymes has also been effectively used to resolve sterically hindered compounds by the introduction of a tether so that the enzyme-catalysed reaction can be performed at an artificially created, but less hindered, remote location. An example is the resolution of tertiary alcohols by the introduction of a glyoxylate ester. 

The enzymatic resolution of racemic substrates now is a well-established approach for the synthesis of single enantiomers [1, 2]. A representative example is the kinetic resoluhon of secondary alcohols via lipase-catalyzed transesterification for the preparation of enantiomericaUy enriched alcohols and esters [3], The enzymatic resolution in general is straightforward and satisfactory in terms of optical purity, but it has an intrinsic Hmitation in that the theoretical maximum yield of a desirable enantiomer cannot exceed 50%. Accordingly, additional processes such as isolation, racemization and recycling of unwanted isomers are required to obtain the desirable isomer in a higher yield (Scheme 1.1). 

Another example showing the utility of 1 is the asymmetric hydrogenation of vinyl esters which usually are used as acyl donors in enzymatic resolution. In this transformation, vinyl esters are converted to ketones which then undergo asymmetric reductive acylation to give chiral esters as described in Scheme 1.13. The overall reaction thus corresponds to the asymmetric hydrogenation of vinyl ester to the corresponding alkyl esters. 

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... 

The second-resolution approach relied on enzymatic resolution of acetate esters 62 (Scheme 4.7) (Hayakawa et ah, 1991). The sequence opened with the alkylation of 2,3-difluoro-6-nitrophenol (59) with l-acetoxychloro-2-propane (60) to deliver ether 61. Reduction of the nitro group of 61 gave an intermediate anihne that cyclized to give racemic benzoxazine 62 in 62% yield. A variety of lipases were then examined for the resolution. The best results arose from use of LPL Amano 3, derived from P. aeruginosa, which gave a ratio of 73 23 in favor of the desired (—)-enantiomer. Benzoylation of the enantiomerically-enriched mixture followed by chromatography of the aryl amides delivered enantiomerically pure 63. 

M.D. Truppo, M. Journet, A. Shafree, J.C. Moore, Optimization and scale-up of a lipase-catalyzed enzymatic resolution of an indole ester intermediate for a prostaglandin D2 (DP) receptor antagonist targeting allergic rhinitis, Org. Proc. Res. Dev. 10 (2006) 592. 

Reduction in the presence of methanolic sodium methoxide produces the corresponding A -acetylphenylalanine methyl ester as the final product. °° ° Enzymatic resolution of A -acetylphenylalanine methyl ester then gives phenylalanine in high enantiomeric purity. Magnesium in methanol has also been used to produce nearly quantitative yields of the M-acetylphenylalanine methyl ester without isolation of the intermediate saturated oxazolone. ° ... 

Table 5 shows selected examples of the enzymatic resolution of esters with various structures. As discussed above, enhancement of the optical purity was... 

The corresponding syzz-isomer was, on the other hand, prepared from the potassium permanganate-mediated oxidation of trifluorocrotonate 10, derived from -hydroxy-butyrate. In this procedure, the diol ester with syn relative configuration was the only product detected. After acetylation, syn-11 was employed as a substrate for the enzymatic resolution affording both (2S,3S)-11... 

Enantioselective enzymatic transesterifications have been used as a complementary method to enantioselective enzymatic ester hydrolyses. The first example of this particular type of biotransformation is the synthesis of the optically active 2-acetoxy-l-silacyclohexane (5 )-78 (Scheme 19). This compound was obtained by an enantioselective transesterification of the racemic l-silacyclohexan-2-ol rac-43 with triacetin (acetate source) in isooctane, catalyzed by a crude lipase preparation from Candida cylindracea (CCL, E.C. 3.1.1.3)62. After terminating the reaction at 52% conversion (relative to total amount of substrate rac-43), the product (S)-78 was separated from the nonreacted substrate by column chromatography on silica gel and isolated in 92% yield (relative to total amount of converted rac-43) with an enantiomeric purity of 95% ee. The remaining l-silacyclohexan-2-ol (/ )-43 was obtained in 76% yield (relative to total amount of nonconverted rac-43) with an enantiomeric purity of 96% ee. Repeated recrystallization of (R)-43 led to an improvement of enantiomeric purity by up to >98% ee. Compound (R)-43 has already earlier been prepared by an enantioselective microbial reduction of the l-silacyclohexan-2-one 42 (see Scheme 8)53. The l-silacyclohexan-2-ol (R)-43 is the antipode of compound (.S j-43 which was obtained by a kinetic enzymatic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-78 (see Scheme 15)62. For further enantioselective enzymatic transesterifications of racemic organosilicon substrates, with a carbon atom as the center of chirality, see References 64 and 70-72. 

One example is the optically active amino acid derivative (S)-20n which contains a bipyridyl substituent (Scheme 3.14). The alkylation reaction in the presence of the cinchona alkaloid catalyst 33 proceeds with 53% ee (83% yield of (S)-20n) and gave the desired enantiomerically pure a-amino acid ester (S)-20n in >99% ee after re-crystallization [43]. Subsequent hydrolysis of the optically pure (S)-20n furnished the desired unprotected a-amino acid 35. A different purification method, subsequent enzymatic resolution, reported by Bowler et al., furnished the a-amino acid product 35 with enantioselectivity of 95% ee [44],... 

The overall process for this enzymatic resolution is compared with the conventional chemical process in Fig. 14. The enzymatic process can skip several tedious steps which are necessary in chemical resolution and this is a considerable practical advantage. There have been several reports on the application of enzymatic asymmetric hydrolysis to the optical resolution of pantolactone [141, 142], In these cases, esterified substrates, such as O-acetyl or O-formyl pantolactone, and lipases were used as the starting materials and catalysts, respectively. Since the lactonase of F. oxysporum hydrolyzes the intramolecular ester bond of pantolactone, it is not necessary to modify the substrate, pantolactone. This is one of the practical advantages of this enzyme. 

Inure et al94 reported the enzymatic resolution of trans-10-Azido-9-acetoxy-9,10-dihydrophenanthrene 111 in gram-scale using Candida cyclindracea lipase-catalyzed enantioselective hydrolysis in phosphate buffer. The substrate 111 (the ester) was obtained in 89 % yield and 83 % ee while the product 112 (the alcohol) was obtained in 90 % yield and 98 % ee. 

The first enzymatic resolution of 1,3,2-dioxathiolane A-dioxides (cyclic sulfites) was achieved via lipase-catalyzed acylation with vinyl butyrate (Equation 17) <1999TA4755>. For the air-alcohol, 91% ee has been observed after 21% conversion for the ester. However, the enantioselectivity is too low for the resolution of the trans-alcohol <1999TA4755>. 

A)-alcohol (7) by Sphingomonas paucimobilis SC 16113 (Fig. 6) (2) the enzymatic resolution of racemic (a-methyl)phenylalanine amide (8) and a-(4-methoxyphenyl)alanine amide (10) by amidase from Mycobacterium neoaurum ATCC 25795 to prepare the corresponding (S)-amino acids (9) and (11), and (3) the asymmetric hydrolysis of methyl-(4-methoxyphenyl)-propanedioic acid, diethyl ester (12), to the corresponding (X)-monoester (13) by pig liver esterase (Fig. 7). 

A variety of methods exists for the synthesis of optically active amino acids including asymmetric synthesis92-100 and classic and enzymatic resolutions.101-104 However, most of these methods are not readily applicable to the preparation of a,a-disubstituted amino acids as a result of poor stereoselectivity and lower activity at the a-carbon. Attempts to resolve the racemic 2-amino-2-ethylhexanoic acid and its ester through classic resolution failed. Several approaches for the asymmetric synthesis of the amino acid were evaluated including alkylation of 2-aminobutyric acid... 

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