Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Patent
1994-03-29
1996-08-13
Wityshyn, Michael G.
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
435135, 435136, C12P 4100
Patent
active
055455581
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for preparing chiral .alpha.-hydroxyketones, and esters thereof, by hydrolyzing esters of said .alpha.-hydroxyketones with an enzyme that has a specificity for one enantiomer, or by esterifying said .alpha.-hydroxyketones with an esterifying agent in the presence of an enzyme that favors the esterification of one enantiomer, leaving the other enantiomer unchanged.
BACKGROUND
Chiral .alpha.-hydroxyketones are useful in the preparation of antimicrobials, for example: antifungals of the type described by Saji et al., "The 28th Interscience Conference on Antimicrobial Agents and Chemotherapy", Los Angeles, Oct. (1988), p. 140; and anti-fungal and anti-bacterials, such as: (+)-(2S,3S)-2-(2,4-difluoro-phenyl)-3-methylsulfonyl-1-(1,2,4-triazol-1-yl )-butan-2-ol and (-)-(2R,3R)-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1,2,4-triazol-1-yl) -butan-2-ol, as disclosed by Konosu et al., Chem. Pharm. Bull. 1990, 38, 2476.
The preparation of chiral .alpha.-hydroxyketones and their derivatives by chemical methods is described in co-owned, co-pending U.S. application Ser. No. 07/676,042, filed Mar. 27, 1991. It is mainly by chemical methods that the literature teaches the synthesis of chiral .alpha.-hydroxyketones, e.g: Davis et al., J. Org. Chem., 1991, Vol. 56, pp 1143-1145; and Davis et al., J. Am. Chem. Soc., 1988, Vol. 110, pp. 8477-8482. However, Chenecert et al., Chemistry Letters, 1988, pp. 1191-1192, and Konishi et al., Chemistry Letters, 1985, pp. 1111-1112, show microbial synthesis of chiral .alpha.-hydroxyketones by reduction of diketones; and Matsumoto et al., Tetrahedron Lett. 1990, pp. 7163-7166, shows the enzymatic synthesis of chiral .alpha.-hydroxyketones by hydrolysis of enol esters.
Bianchi et al., Tetrahedron, 1989, Vol. 45, pp. 869-876, have shown that .alpha.-hydroxy aldehydes can be prepared by enzymatic hydrolysis of corresponding esters using lipases, such as from Pseudomonas species. However, the results obtained using aldehydes cannot be extrapolated to .alpha.-hydroxy ketones due to the greater steric effects inherent in the latter.
The asymmetric hydrolysis of .alpha.-acetoxyacylphenones by enzyme-mediated hydrolysis using a whole organism is disclosed by Ohta et al., Chem Letters, 1986, pp. 1169-1172 and by Yuki Gosei Yankuhin, in Japanese Patent Publication No. J6-2208298. Problems with the use of a whole organism include: low yields and/or slow reaction rates due to poor transport of the substrate or product across the cell membrane; poisoning of the organism by the substrate or the product; difficulties isolating the desired product from other products; and low yields due metabolism of the substrate or product through the action of other enzymes.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of a chiral .alpha.-hydroxyketone or an ester of a chiral .alpha.-hydroxyketone, comprising: selectively hydrolyzing an ester of a racemic .alpha.-hydroxyketone with an enzyme that has a specificity for one enantiomer, or selectively esterifying a racemic .alpha.-hydroxyketone with an esterifying agent in the presence of an enzyme that favors the formation of one enantiomeric ester, optionally racemizing unchanged enantiomers and recycling the resulting racemate through the selective hydrolysis, or esterification, as described above; and isolating said chiral .alpha.-hydroxyketone or ester thereof.
Preferred is a process wherein the .alpha.-hydroxyketone, or ester thereof, is a compound of the formula ##STR1## wherein: R is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl or substitute
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Saucier Sandra
Schering Corporation
Thompson Paul A.
Wityshyn Michael G.
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