Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Reexamination Certificate
2000-02-17
2002-04-02
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
Reexamination Certificate
active
06365398
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a process for the preparation of stereoisomeric carboxylic acid esters consisting of an acid and an alcohol component each having at least one chiral center, at least one stereoisomer of the carboxylic acid ester being present in an excess.
Stereoisomerically pure carboxylic acid esters having at least two chiral centers are important precursors of biologically active substances, such as natural substances, drugs and crop protection agents. An economical preparation process is therefore of great importance.
It is known to prepare optically pure alcohols by transesterification of the racemic alcohols using achiral alkyl carboxylates in an organic solvent in the presence of carboxyl esterases (Klibanov et al., J. Am. Chem. Soc. 1984, 106, 2687-2692). To increase the reaction rate and to shift the reaction equilibrium, it has proven very useful to employ activated achiral carboxylic acid esters, in particular enol esters, oxime esters or anhydrides. Frequently employed acyl donors are vinyl esters and, among these, especially vinyl acetates (see Degueil-Castaing et al., Tetrahedron Lett., 1987, 28, 953-954; Wang et al., J. Am. Chem. Soc., 1988, 110, 7200-7205; Laumen et al., J. Chem. Soc., Chem. Commun., 1988, 1459-1461), oxime esters and, among them, especially 2-propanoneoximyl acetate and cyclohexanoneoximyl acetate (A. Ghogare, G. S. Kumar, J. Chem. Soc., Chem. Commun. 1989, 1533-1535; J. Chem. Soc., Chem. Commun. 1990, 134-135) or anhydrides (D. Bianchi, P. Cesti, E. Battistel, J. Org. Chem. 1988, 53, 5531-5534; J. H. Xu, T. Kawamoto, A. Tanaka, Appl. Microbiol. Biotechnol. 1995, 43, 639-643).
It is furthermore known to prepare optically active carboxylic acids by reacting their racemic esters with achiral alcohols in organic solvents in the presence of lipases (see Holmberg et al., Appl. Microbiol. Biotechnol., 1992, 35, 572-578; Persichetti et al., Tetrahedron Lett., 1996, 37, 6507-6510; Ozegowski et al., Liebigs Ann. 1994, 215-217).
It is furthermore known to prepare stereoisomerically enriched amides by reacting racemic ethyl 2-chloropropionate with racemic amines in the presence of lipases (R. Brieva, J. Chem. Soc., Chem. Commun. 1990, 1386-1387).
It is furthermore known to prepare a mixture of four stereoisomeric esters by reaction of a meso-diol with racemic 2,2,2-trifluoroethyl 2-chloropropanate in organic solvents in the presence of a lipase (F. Theil et al., Tetrahedron Lett. 1992, 33, 3457-3460). The process has the disadvantage that although the reaction times are short only low diastereomer excesses (3.6% de to 51.5% de) are achieved.
The preparation of stereoisomerically enriched carboxylic acid esters by conversion of racemic carboxylic acids using racemic alcohols in organic solvents in the presence of a lipase is known from two publications: P. W. Fowler et al. describe the reaction of racemic p-chlorophenoxypropanoic acid with a racemic bicycloheptenol (J. Chem. Soc., Chem. Commun. 1991, 453-454). The process has the disadvantage that although the diastereomer excesses are higher (16% de to 72% de), in spite of high reaction times only a low conversion and a low enantioselectivity (E(alcohol)=5.8 to 26.7; E(carboxylic acid)=1.3 to 15.7) are achieved, E being understood as meaning the enantioselectivity as defined by Sih et al. (J. Am. Chem. Soc. 1982, 104, 7294-7299). Although the use of the acetylated racemic bicycloheptenol leads to an increase in selectivity, in spite of still greater reaction times even lower conversions are achieved. Chen et al. describe the reaction of racemic, chlorinated phenoxypropionic acids with racemic phenylalkanols. The process has the disadvantage that in spite of high reaction times only low conversions and, apart from one exception (E(acid)=108), only low enantioselectivities E(alcohol)=1.0 to 13.6; E(carboxylic acid)=2.1 to 35.6) are achieved. Therefore only low diastereoselectivities are also achieved.
An optimal and economic enzyme-catalyzed preparation of stereoisomeric carboxylic acid esters consisting of an acid and an alcohol component each having at least one chiral center should advantageously fulfil a number of conditions, such as, for example,
1. a high enantioselectivity, in each case based on the acid and alcohol components,
2. a high diastereoselectivity,
3. good space-time yield (short reaction times, high conversions based on one enantiomer, high starting material and product concentrations),
4. high substrate spectrum of the enzyme,
5. high chemical yield of the desired product,
6. low amounts of catalyst (amounts of enzyme),
7. easy purification of the synthesis products,
8. good solubility of starting material and product under the reaction conditions,
9. inexpensive synthesis (easily preparable starting materials, good handleability of the starting materials, solvents, reagents and enzymes).
The object of the present invention is therefore to remedy the outlined deficiencies of the prior art and to provide an improved process which as much as possible fulfils the conditions described above.
BRIEF SUMMARY OF THE INVENTION
Accordingly, we have found that this object is achieved by a process for the preparation of stereoisomeric carboxylic acid esters, consisting of a carboxylic acid and an alcohol component each having at least one chiral center, at least one stereoisomer of the carboxylic acid ester being present in an excess, in which a racemic carboxylic acid ester is reacted with a racemic alcohol in the presence of a carboxyl ester hydrolase (EC 3.1.1) (Enzyme Nomenclature 1992, NC-IUBMB, Academic Press, Inc., San Diego). The preparation of the stereoisomeric carboxylic acid ester, where at least one stereoisomer of the carboxylic acid ester is present in an excess, is thus carried out by transesterification of a racemic carboxylic acid ester with a racemic alcohol in the presence of a carboxyl ester hydrolase (EC 3.1.1).
DETAILED DESCRIPTION OF THE INVENTION
The process according to the invention leads to an advantageous increase in the reaction rate and the conversion with a simultaneous increase in the enantioselectivity and the diastereoselectivity of the enzymes used (carboxyl ester hydrolases). High diastereomer excesses and enantioselectivities can thus be achieved with high reaction conversions and short reaction times.
At about 50% conversion, diastereomer excesses of at least 50% de, preferably at least 55% de, are achieved. The enantioselectivity (E) for the alcohol is advantageously at least 30, preferably 80, particularly preferably greater than 100. Stereoisomeric carboxylic acid esters consisting of a carboxylic acid and an alcohol component each having at least one chiral center are understood as meaning all possible stereoisomers of a carboxylic acid ester, the carboxylic acid and the alcohol component in each case containing at least one chiral center.
At least one chiral center is understood as meaning 1 to 3, preferably 1 or 2 chiral centers, particularly preferably 1 chiral center for the carboxylic acid and the alcohol component in each case. For i chiral centers in the total molecule of the carboxylic acid ester, 2
i
possible stereoisomers of the carboxylic acid ester result.
Accordingly, the racemic carboxylic acid ester and the racemic alcohol each have at least one chiral center. In principle, racemic alcohols and racemic carboxylic acid esters which each have at least one chiral center with a large structural breadth are accessible to the process according to the invention.
In a preferred embodiment of the process, the racemic carboxylic acid ester used is an activated racemic carboxylic acid ester. An activated racemic carboxylic acid ester is understood as meaning a racemic carboxylic acid ester which contains one component with a hydroxyl group as a leaving group which has better leaving group properties than ethanol in the transfer of the racemic acyl group (acid components) of the racemic carboxylic acid ester to an alcohol. The leaving group of the activated racemic carboxylic aci
Bornscheuer Uwe
Henke Erik
Yang Hong
BASF - Aktiengesellschaft
Keil & Weinkauf
Saucier Sandra E.
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