GB2347674A - Producing optically active alpha-hydroxylactones - Google Patents
Producing optically active alpha-hydroxylactones Download PDFInfo
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- GB2347674A GB2347674A GB0005346A GB0005346A GB2347674A GB 2347674 A GB2347674 A GB 2347674A GB 0005346 A GB0005346 A GB 0005346A GB 0005346 A GB0005346 A GB 0005346A GB 2347674 A GB2347674 A GB 2347674A
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- butyrolactone
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- C07—ORGANIC CHEMISTRY
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
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Abstract
A method for producing optically active a -hydroxylactones comprises carrying out transesterification reaction of a -acyloxylactones in a mixture of an (R) body and an (S) body in an optional proportion of formula (1) with primary alcohols, in the presence of a lipase originating in Pseudomonas bacteria, to effect resolution of an (R) a -hydroxylactones of formula (2) and an (S) - ester of a -hydroxylactones of formula (3) as antipodes thereof: <EMI ID=1.1 HE=43 WI=144 LX=244 LY=1385 TI=CF> <PC>wherein R<SB>1</SB> represents a hydrogen atom, a C<SB>1-12</SB> alkyl group or an aryl group, and R<SB>2</SB> and R<SB>3</SB> each represent a hydrogen atom or methyl group.
Description
SPECIFICATION
METHOD FOR PRODUCING OPTICALLY a- HYDROXYLACTONES TECHNICAL FIELD
The present invention relates to a method for producing optically active ahydroxylactones which are useful as starting materials for physiologically active substances as optically active compounds and functional materials.
BACKGROUND OF THE INVENTION
An (R)-a-hydroxy-y-butyrolactone which can be produced by a production process for an optically active a-hydroxylactone of the present invention is useful as a starting material for 2,3-epoxysqualene (M. A. Adballah et al., J.
Chem. Soc. Perkin Trans., 1, 888 (1975)).
Further, an (S)-a-hydroxy-r-butyrolactone can readily be converted into an (R)--a-fluoro-r-butyrolactone. This is useful as a starting material for a physiologically active substance of 1 a, 25-dihydroxy-24 (R)-#luorocholecalciferol (S. J. Shiuey et al., J. Org. Chem., , 1040 (1988)).
Optically active compounds are useful as starting materials for physiologically active substances such as medicines and agricultural chemicals or functional materials. However, because of the existence of optical isomers therein, it is an essential condition to use only either one of the antipodes in practical uses. Herein, it is considered that when racemic bodies or compounds of lower optical purity are used, the objective substances may never exhibit enough physiological activity or functionality. Further, it is often known that the exhibition of physiological activity or functionality is inhibited by an antipode, which is not the objective substance.
Accordingly, the higher the optical purity of the preceding optically active compounds is used as the starting materials, the better the exhibition is.
However, very useful as the optically active a-hydroxylactones are, any method for producing an (R) body thereof, effectively and at a high optical purity, is not known.
As production processes for an (R) body of a-hydroxylactones known at present, followings can be mentioned.
(1) A process in which an (R) body is derived from naturally produced malic acid or esters thereof (K. Mori et al., Tetrahedron, 35, 393 (1979), H. Hayashi et al., J. Am. Chem. Soc., 95, 8749 (1973), E. J. Corey et al., J. Am. Chem. Soc., 100, 1942 (1978) and S. J. Shiuey et al., J. Org. Chem., 53, 1040 (1988)). In this process, only one of the carboxyl groups or esters has to be reduced.
However, any effective reducing method is not known, and therefore this process is not necessarily advantageous from an industrial point of view.
(^') Similarly, a process in which L-ascorbic acid is used as a raw material is also known as a technique which uses a natural matter as a raw material (K.
C. Luk et al., Synthesis, S, 226 (1988)). However, this process has very many steps and therefore has a defect that it is not industrially advantageous.
(3) A following process is known as a process for carrying out asymmetric reduction to synthesize a-hydroxylactones. A process in which bread yeast is used to carry out asymmetric reduction to obtain (R)-3-hydroxybutyrolactone has been found (D. Seebach, Synthesis, 1, 37 (1986)), but it has such a defect that the reduction step results in a very inferior efficiency. That is, for example, one kg of bread yeast, one kg of saccharose and water as much as 8 liters are required for treating 35 g of a substrate, and therefore this is not an industrially advantageous process.
(4) Known as well is a process in which optically active 4-methyl-1, 4 dihydropyridine is used to subject prochiral ketone to asymmetric reduction to thereby obtain optically active pantolactone (A. I. Meyers, Tetrahedron Lett.
29, 5617 (1988)). This process has a defect that it has an optical purity as low as or less than 72 % ee and therefore is not practical.
(5) Processes in which lipase is used to carry out optical resolution are known.
Reported as one of them is a process in which asymmetric transesterification is carried out with a lipase to obtain an (R)-or (S)-pantolactone (H. S.
Bevinakatti, J. Org. Chem., 54, 2453 (1989)). According to this process, both antipodes can be obtained, and hence it looks to be excellent. However, it has a problem that the (R) body has an optical purity as low as 70 % ee.
(6) It is disclosed in Laid-Open Japanese Patent Publication No. Hei 7-51090 by the present inventors that a-or 3-hydroxylactones are esterified with a lipase to carry out optical resolution. In this process, however, an (R) body having an optical purity as low as 94 % ee can only be obtained in one-path reaction. Accordingly, should a higher optical purity be required for the alcohols, it has a problem that the steps described in the above patent gazette have to be repeated plural times.
DISCLOSURE OF THE INVENTION
An object of the present invention is to overcome the above defects of the prior art and to provide a method for producing optically active ahydroxylactones with a high purity by a simple operation and in high yield.
The inventors of the present invention carried out research to solve the problems described above and found that only optically active (R)-a- hydroxylactones can selectively be obtained by carrying out transesterification
reaction of a-acyloxylactones which are mixtures of an (R) body and (S) body in an optional proportion with primary alcohols, in the presence of a lipase
originating in Pseudomonas bacteria, and the present invention has been
achieved.
That is, the present invention is characterized in a method for producing
optically active a-hydroxylactones comprising carrying out transesterification reactionof a-acyloxylactones in a mixture of an (R) body and (S) body in an
optional proportion and are represented by the general formula (1) with
primary alcohols, in the presence of a lipase originating in Pseudomonas
bacteria, to effect resolution of an (R) body of a-hydroxylactones represented by the general formula (2) and an (S)-ester body of a-hydroxylactones represented by the general formula (3) as antipodes thereof
wherein Ri represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms or an aryl group, and R2 and R3 each represent a hydrogen atom or a methyl group.
METHOD FOR CARRYING OUT OF THE INVENTION
In the method for producing optically active a-hydroxylactones of the present invention, water is not positively added to the reaction zone. This scarcely brings about side reactions such as hydrolysis of raw material esters and ring-opening of lactones. Further, after the reaction is finished, the used lipase, which is soluble in water, can readily be removed and be used repeatedly.
Further, because of the reaction carried out under the condition of less moisture content, microorganisms do not propagate, and therefore specific
apparats, preservatives and sterilizing treatment, etc., are not required.
Furthermore, for the production of the optically active a-hydroxylactones of the present invention, the substrates can be used in the same or greater concentration than that of the conventional organic synthesis.
As specific examples of a-acyloxylactones of above general formula (1), a formyloxy-r-butyrolactone, a-acetoxy-r-butyrolactone, a-propionyloxy-r- butyrolactone, a-butyryloxy-7-butyrolactone, a-valeryloxy-r- butyrolactone, a-hexanoyloxy-r-butyrolactone, ct-heptanoyloxy-r- butyrolactone, a-octanoyloxy-r-butyrolactone, cc-nonanoyloxy-T- butyrolactone, a-decanoyloxy-r-butyrolactone, a-undecanoyloxy-r- butyrolactone, a-dodecanoyloxy-r-butyrolactone, a-benzoyloxy-rbutyrolactone, α-formylox-ss, ss'-dimethyl-γ-butyrolactone, a-acetoxy-ss, ss'-dimethyl-γbutyrolactone, α-propionyloxy-ss,ss'-dimethyl-γ- butyrolactone, α-butyry6loxy-ss,ss'-dimethyl-γbutyrolactone, α-valerylox- 3, ss'-dimethyl-γ-butyrolactone, α-hexanoylox-ss,ss'-dimethyl-γ butyrolactone, a-heptanoyloxy-j6, ss'-dimethyl-γ-butyrolactone, α- octanoyloxy- ss'-dimethyl-r-butyrolactone, a-nonanoyloxy-ss, a'-dimethyl r-butyrolactone, a-decanoyloxy- ss,ss'-dimethyl-γ-butyrolactone, a undecanoyloxy-ss, ss'-dimethyl-γ-butyrolactone, α-dodecanoyloxy-ss,ss'- dimethyl-γ-butyrolactone and a-benzoyloxy-ss, ss'-dimethyl-r-butyrolactone can be mentioned, and also a-formyloxy-r-butyrolactone, α-acetoxy-γ- butyrolactone, a-propionyloxy-r-butyrolactone, α-formyloxy-ss, ss' c'imethyl-r-butyrolactone, a-acetoxy-a, 3'-dimethyl-r-butyrolactone and a -propionyloxy-ss,ss'-dimethyl-γ-butyrolactone can be mentioned.
Further, primary alcohols used for transesterification reaction in the method for producing optically active a-hydroxylactones of the present invention may be any commercially available one so far as it is easily obtainable.
As specific examples of the alcohols, methanol, ethanol, n-propanol, nbutanol, isobutyl alcohol, n-amyl alcohol, 1-hexanol, benzyl alcohol, ethylene glycol, propanediol, butanediol, glycerin, 2-methoxy-ethanol, 1-hydroxy-2- methoxy-propane, 1-hydroxy-3-methoxy-propane, 1-hydroxy-2-methoxy- butane, 1-hydroxy-3-methoxy-butane, 1-hydroxy-4-methoxy-butane, 1-hydroxy- 2-methoxy-pentane, 1-hydroxy-3-methoxy-pentane, 1-hydroxy-4-methoxypentane, l-hydroxy-5-methoxy-pentane, 1-hydroxy-2-methoxy-hexane, 1- hydroxy-3-methoxy-hexane, 1-hydroxy-4-methoxy-hexane, 1-hydroxy-5- methoxy-hexane, 1-hydroxy-6-methoxy-hexane, 2-ethoxy-ethanol, 1-hydroxy-2 ethoxy-propane, 1-hydroxy-3-ethoxy-propane, 1-hydroxy-2-ethoxy-butane, 1- hydroxy-3-ethoxy-butane, 1-hydroxy-4-ethoxy-butane, 1-hydroxy-2-ethoxypentane, 1-hydroxy-3-ethoxy-pentane, 1-hydroxy-4-ethoxy-pentane, 1-hydroxy 5-ethoxy-pentane, 1-hydroxy-2-ethoxy-hexane, 1-hydroxy-3-ethoxy-hexane, 1- hydroxy-4-ethoxy-hexane, 1-hydroxy-5-ethoxy-hexane, 1-hydroxy-6-ethoxy- hexane, 2-propoxy-ethanol, 1-hydroxy-2-propoxy-propane, 1-hydroxy-3- propoxy-propane, 1-hydroxy-2-propoxy-butane, 1-hydroxy-3-propoxy-butane, 1 hydroxy-4-propoxy-butane, 1-hydroxy-2-propoxy-pentane, 1-hydroxy-3 propoxy-pentane, 1-hydroxy-4-propoxy-pentane, 1-hydroxy-5-propoxy-pentane, l-hydroxy-2-propoxy-hexane, 1-hydroxy-3-propoxy-hexane, 1-hydroxy-4 propoxy-hexane, 1-hydroxy-5-propoxy-hexane, 1-hydroxy-6-propoxy-hexane, 2butoxy-ethanol, 1-hydroxy-2-butoxy-propane, 1-hydroxy-3-butoxy-propane, 1 hydroxy-2-butoxy-butane, 1-hydroxy-3-butoxy-butane, 1-hydroxy-4-butoxy- butane, 1-hydroxy-2-butoxy-pentane, 1-hydroxy-3-butoxy-pentane, 1-hydroxy- 4-butoxy-pentane, 1-hydroxy-5-butoxy-pentane, 1-hydroxy-2-butoxy-hexane, 1 hydroxy-3-butoxy-hexane, 1-hydroxy-4butoxy-hexane, 1-hydroxy-5-butow y- hexane, 1-hydroxy-6-butoxy-hexane, 2-pentoxy-ethanol, 1-hydroxy-2-pentoxypropane, 1-hydroxy-3-pentoxy-propane, 1-hydroxy-2-pentoxy-butane, 1hydroxy-3-pentoxy-butane, 1-hydroxy-4-pentoxy-butane, 1-hydroxy-2-pentoxypentane, 1-hydroxy-3-pentoxy-pentane, 1-hydroxy-4-pentoxy-pentane, 1hydroxy-5-pentoxy-pentane, 1-hydroxy-2-pentoxy-hexane, 1-hydroxy-3- pentoxy-hexane, 1-hydroxy-4-pentoxy-hexane, 1-hydroxy-5-pentoxy-hexane and 1-hydroxy-6-pentoxy-hexane can be mentioned. Among them, methanol, ethanol, propanol, butanol and ethylene glycol are preferred.
As of an enzyme applied to the method for producing optically a- hydroxylactones of the present invention, a lipase originating in Pseudomonas bacteria, more particularly the one originating in Pseudomonas fluorescens bacteria can be suitably used.
As commercially available lipase originating in Pseudomonas fluorescens bacteria, Lipase PS manufactured by Amano Pharmaceutical Co.,
Ltd., Lipase PS CI manufactured by Amano Pharmaceutical Co., Ltd. and
Lipase PS CII manufactured by Amano Pharmaceutical Co., Ltd., can be mentioned.
The following description illustrates the present invention more specifically.
In the method for producing optically active a-hydroxylactones of the present invention, a mixture of an (R) body and an (S) body represented by the general formula (1), to be used as a raw material, can easily be produced by conventional synthetic methods for organic chemicals. As such methods, those in which bromine of a-bromo-r-butyrolactolle, which is commercially available, is subjected to substitution by an acetoxy group by nucleophilic substitution reaction, or a-hydroxy-r-butyrolactone, which is commercially available, is subjected to esterification are mentioned, but the present invention shb U not be restricted to them.
In the method for producing optically active a-hydroxylactones of the present invention, the reaction may be carried out by mixing a racemic compound or other mixture of (R) and (S) compounds in any proportion with one or more primary alcohols to efficiently contact it with the lipase. Both the racemic compound or other mixture and the primary alcohol (s) can be used without any specific treatment in this reaction.
In the method of producing optically active a-hydroxylactones of the present invention, the reaction in which the racemic compound or other mixture is mixed with a primary alcohol to carry out transesterification may be carried out in the absence of a solvent, but in order to mix the racemic compound with the primary alcohols, to contact it efficiently with the lipase, the reaction is preferably carried out in such a solvent as ester; linear, branched or cyclic alkane having 5 to 12 carbon atoms; aromatic hydrocarbon having 6 to 12 carbon atoms; or ether.
As specific examples of the solvent, methyl formate, ethyl formate, propyl formate, butyl formate, pentyl formate, hexyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, hexyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, pentyl propionate, hexyl propionate, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, cyclopentane, cyclohexane, cycloheptane, methylcyclopentane, ethylcyclopentane, propylcyclopentane, butylcyclopentane, methylcyclohexane, ethylcyclohexane, butylcyclohexane, benzene, toluene, xylene, ethylbenzene, pyridine, furan, pyrrole, diethyl ether, dipropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, methyl ethyl ether, methyl propyl ether, methyl butyl ether, methyl pentyl ether, methyl hexyl ether, ethyl propyl ether, ethyl butyl ether, ethyl pentyl ether, ethyl hexyl ether, propyl butyl ether, propyl pentyl ether, propyl hexyl ether, pentyl hexyl ether and tetrahydrofuran are mentioned, and ethyl acetate and isopropyl ether are preferred.
The solvent is preferably used 0.5 to 50 times as much as the racemic compound represented by the general formula (1) based on the volume thereof, and in particular preferably 1 to 10 times.
The transesterification reaction is preferably carried out at a temperature of 0 to 80 C, in particular preferably 15 to 50 C.
The reaction can be carried out in an air atmosphere but is preferably carried out in an atmosphere of an inert gas such as nitrogen, argon, helium or xenon.
In the method for producing optically active a-hydroxylactones of the present invention, and after the asymmetrical transesterification thereof is finished, the lipase can be removed from the reaction zone by an ordinary operation.
After the removal, the lipase, should it be fixed on a suitable supporter, can also be used readily and repeatedly. The reaction solution obtained after removing the lipase is then subjected to a conventional method such as distillation, column chromatography and extraction to separate it into an optically active alcohol and ester which is an antipode thereof. Further, the optically active ester thus obtained can be subjected to de-carbonic acid reaction under a mild condition containing no Lewis base or Broensted base to thereby turn into an optically active alcohol which is an antipode of the alcohol above mentioned.
In the method for producing optically active a-hydroxylactones of the present invention, silica, silica having a methylated surface, alumina or magnesia can be used as specified examples of the supporter for the lipase, but the supporter is never be limited to those examples as far as the lipase could be fixed thereon. This fixing is, in general, carried out by an electrostatic interaction between a part having a polarity present on a filler surface and a polar amino acid residue present on a protein surface, or by a hydrophobic interaction between a hydrophobic part present or introduced on the filler and a hydrophobic group on the protein surface.
The following examples illustrate the present invention more specifically, but these are not intended as a definition of the limits of the present invention.
In the examples, the optical purity was determined by means of a liquid chromatograph apparatus equipped with Chiral Cell OD manufactured by
Daicel Co., Ltd.
Example 1 a-Acetoxy-r-butyrolactone (a compound represented by the general formula (1) wherein R, = CH3, R2 = H and R3 = H) was optically resolved as follows.
One g of racemic a-acetoxy--r-butyrolacto'ne, 1.0 2. of n-propanol, o ethyl acetate as a solvent and 0.5 g of Lipase PS manufactured by Amano
Pharmaceutical Co., Ltd. as a lipase were mixed and stirred at 25 C for 24 hours under an argon atmosphere. The lipase was removed by suction filtration, and then an extraction operation was carried out in waterchloroform. This provided (R)-a-hydroxy-r-butyrolactone and an ester which was an antipode thereof.
Conversion rate of (R)-a-acetoxy-r-butyrolactone : 88 %
Optical purity of (R)-a-hydroxy-r-butyrolactone : 100 % ee
Example 2
Optical resolution was carried out according to Example 1, except that the solvent was changed from 2.0 g of ethyl acetate to 2.0 g of isopropyl ether.
Conversion rate of (R)--acetoxy-r-butyrolactone : 93 %
Optical purity of (R)-a-hydroxy-r-butyrolactone : 100 % ee
Example 3
Optical resolution was carried out according to Example 1, except that the solvent was changed from 2.0 g of ethyl acetate to 2.0 g of n-hexane.
Conversion rate of (R)-a-acetoxy-r-butyrolactone : 87 % Optical purity of (R)-a-hydroxy-r-butyrolactone : 100 % ee
Example 4
Optical resolution was carried out according to Example 1, except that the lipase was changed from 0.5 g of Lipase PS manufactured by Amano
Pharmaceutical Co., Ltd. to 0.5 g of Lipase PS CI manufactured by Amano
Pharmaceutical Co., Ltd.
Conversion rate of (R)-a-acetoxy-r-butyrolactone : 97 %
Optical purity of (R)-a-hydroxy-T-butyrolactone : 100 % ee
Example 5
Optical resolution was carried out according to Example 1, except that the lipase was changed from 0.5 g of Lipase PS manufactured by Amano
Pharmaceutical Co., Ltd. to 0.5 g of Lipase PS CII manufactured by Amano
Pharmaceutical Co., Ltd.
Conversion rate of (R)-a-acetoxy-r-butyrolactone : 94 %
Optical purity of (R)-ce-hydroxy-t-butyrolactone : 100 % ee
Example 6 a-Acetoxy-r-butyrolactone rich in an (R) body (a compound represented by the general formula (1) wherein Ri = CH3, R2 = H and R3 = H) was optically resolved as follows.
One gram of a-Acetoxy-r-butyrolactone rich in an (R) body (85 % ee), 1.0 g of n-propanol, 2.0 g of ethyl acetate and 0.5 g of Lipase PS manufactured by
Amano Pharmaceutical Co., Ltd. were mixed and stirred at 25 C for 24 hours under an argon atmosphere. The lipase was removed by suction filtration, and then an isolation operation was carried out with a silica gel column. This provided (R)-a-hydroxy-r-butyrolactone and an ester which was an antipode thereof.
Conversion rate of (O-a-acetoxy-r-butyrolactone : 89 %
Optical purity of (R)-a-hydroxy-r-butyrolactone : 100 % ee
Example 7 a-Acetoxy-r-butyrolactone rich in an (S) body (a compound represented by the general formula (1) wherein R, = CH3, R2 = H and R3 = H) was optically resolved as follows.
One gram of a-acetoxy-7-butyrolactone rich in an (S) body (70 % ee), 1.0 g of n-propanol, 1.4 g of isopropyl ether and 0.5 g of Lipase PS manufactured by Amano Pharmaceutical Co., Ltd. were mixed and stirred at 25 C for 24 hours under an argon atmosphere. The lipase was removed by suction filtration, and then an isolation operation was carried out with a silica gel column. This provided (R)-a-hydroxy-r-butyrolactone and an ester which was an antipode thereof :
Conversion rate of (R)-a-acetoxy-r-butyrolactone : 94 %
Optical purity of (R)-a-hydroxy-r-butyrolactone : 99 % ee
Example 8 a-Propoxycarbonyl-r-butyrolactone (a compound represented by the general formula (1) wherein Ri = C2 Hs, R2 = H and R3 = H) was optically resolved as follows.
Optical resolution was carried out according to Example 1, except that the substrate was changed from 1.0 g of a-acetoxy-r-butyrolactone to 1.1 g of a- prop oxycarbonyl-r-butyrolactone as above.
Conversion rate of (R)-a-propoxycarbonyl-r-butyrolactone : 95 %
Optical purity of (R)-a-hydroxy-r-butyrolactone : 99 % ee
Example 9
Optical resolution was carried out according to Example 1, except that the primary alcohol was changed from n-propanol to n-butanol.
Conversion rate of (R)-a-acetoxy-r-butyrolactone : 87 %
Optical purity of (O-a-hydroxy-r-butyrolactone : 100 % ee
Comparative Example 1 a-Acetoxy-r-butyrolactone rich in an (R) body (a compound represented by the general formula (1) wherein Ri = CH3, R2 = H and R3 = H) was hydrolyzed as follows.
Ten grams of a-acetoxy-- (-butyrolactone rich in an (R) body (98 % ee), 15 ml of 1M phosphoric acid buffer of pH 7.2 and 0.1 g of Lipase PS manufactured by Amano Pharmaceutical Co., Ltd. were mixed and stirred at 25 C for 28 hours under an argon atmosphere. The lipase was removed by suction filtration, and then a conversion rate to a-hydroxy-r-butyrolactone and an optical purity of a-hydroxy-7-butyrolactone were determined.
Conversion rate of (R)-a-acetoxy-r-butyrolactone : 94 %
Optical purity of (R)-a-hydroxy-r-butyrolactone : 16.5 % ee
Comparative Example 2 a-Acetoxy-ss, ss'-dimethyl-r-butyrolactone (a compound represented by the general formula (1) wherein Ri = CH3, R2 = CH3 and Ps = CH3) was optically resolved with lipase originating in yeast bacteria as follows.
α-Acetoxy-ss, ss'-dimethyl-r-butyrolactone (2.34 g), 45 ml of isopropyl ether, 4.4 g of n-butanol and 3.0 g of lipase originating in yeast bacteria were mixed and stirred for 14 days.
Conversion rate of a-acetoxy-ss, ss'-dimethyl-r-butyrolactone : 34 % Optical purity of α-hydroxy-ss,ss'-dimethyl-γ-butyrolactone: 70% ee Comparative Example 3
a-Acetoxy-r-butyrolactone (a compound represented by the general formula (1) wherein R, = CH3, R, = H and R3 = CH3) was optically resolved with lipase originating in yeast bacteria as follows. a-Acetoxy-r-butyrolactone (1.84 g), 45 ml of isopropyl ether, 3.6 g of n- propanol and 3.0 g of lipase originating in yeast bacteria were mixed and stirred for 7 days. After stirring is finished, the products, without any purification, were allowed to a gas chromatography method and a liquid chromatography method, and a conversion rate and an optical purity were determined thereby.
Conversion rate of a-acetoxy-r-butyrolactone : 25 %
Optical purity of a-hydroxy-r-butyrolactone : 60 % ee
BENEFITS OF THE INVENTION
Benefits of the invention can be listed as follows: (1) Water need not be positively added to the reaction zone or system, and therefore ; the moisture content present in the reaction system can be small. Accordingly, the racemization velocity of an objective alcohol which is caused by an advance in unnecessary hydrolysis of an ester and cleavage reaction velocity of lactone which is a side reaction can both be reduced to such an extent that they can be neglected.
(2) Little presence of free moisture in the system makes it easy to recover and use repeatedly the lipase that is soluble in water.
(3) The reaction, which can be carried out at a relatively low temperature, does not require any specific apparats.
(4) Optically almost pure antipodes can be obtained by a one-pass reaction.
(5) A buffer solution is not required, so that a salt strength does not become a factor for regulation of concentration of a reaction solution. Accordingly, concentration of the substrate can be elevated even when the present invention is in a biochemical reaction. This does not require a reactor having an extremely large capacity for the substrate. Further, the efficiency of concentration in purifying the reaction products can be raised to a large extent.
As described above, by the present invention, optically active ahydroxylactones with a high purity can be produced by a simple operation and in high yield, and the optically active compounds thus produced are suitable. as starting materials for various useful compounds.
Claims (6)
- CLAIMS : 1. A method for producing optically active a-hydroxylactones comprising carrying out a transesterification reaction of a mixture of (R) and (S) a- acyloxylactones represented by the general formula (1) with a primary alcohol, in the presence of a lipase originating in Pseudomonas bacteria, to produce an (R) K- hydroxylactone represented by the general formula (2) and an (S)-ester of an cc- hydroxylactone represented by the general formula (3) as an antipode thereof :wherein Ri represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms or an aryl group, and Ra and Rg each represent a hydrogen atom or methyl group.
- 2. A method according to claim 1, wherein the transesterification reaction is carried out in the substantial absence of moisture.
- 3. A method according to claim 1 or 2, wherein the transesterification reaction is carried out in the presence of a solvent.
- 4. A method according to claim 3, wherein the solvent is n-hexane, ethyl acetate or isopropyl ether.
- 5. A method for producing optically active a-hydroxylactones substa-ntiai. as hereinbefore described with reference to any of examples 1 to 9 hereof.
- 6. An optically active a-hydroxylactone when produced by a method according to any of claims 1 to 5.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP06222299A JP4196470B2 (en) | 1999-03-09 | 1999-03-09 | Process for producing optically active α-hydroxylactones |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB0005346D0 GB0005346D0 (en) | 2000-04-26 |
| GB2347674A true GB2347674A (en) | 2000-09-13 |
Family
ID=13193921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0005346A Withdrawn GB2347674A (en) | 1999-03-09 | 2000-03-06 | Producing optically active alpha-hydroxylactones |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP4196470B2 (en) |
| GB (1) | GB2347674A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001018231A2 (en) * | 1999-09-08 | 2001-03-15 | Lonza Ag | METHOD FOR PRODUCING (R) OR (S)-HYDROXY-η-BUTYROLACTONE |
-
1999
- 1999-03-09 JP JP06222299A patent/JP4196470B2/en not_active Expired - Fee Related
-
2000
- 2000-03-06 GB GB0005346A patent/GB2347674A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001018231A2 (en) * | 1999-09-08 | 2001-03-15 | Lonza Ag | METHOD FOR PRODUCING (R) OR (S)-HYDROXY-η-BUTYROLACTONE |
| WO2001018231A3 (en) * | 1999-09-08 | 2001-09-13 | Lonza Ag | METHOD FOR PRODUCING (R) OR (S)-HYDROXY-η-BUTYROLACTONE |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000253897A (en) | 2000-09-19 |
| GB0005346D0 (en) | 2000-04-26 |
| JP4196470B2 (en) | 2008-12-17 |
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