KR100462473B1 - Method for the preparation of chiral hydroxy esters by enzyme-metal multi-catalysis - Google Patents

Abstract

The present invention is a compound having a ketone group and an acyloxy group in the molecule at the same time; A hydrogen donor for reducing a ketone group of the compound to an alcoholic group; A metal complex that is a catalyst for promoting both a reaction for reducing a ketone group of the compound with an alcohol and a racemization reaction between two optical isomers of a racemic alcohol formed by the reduction; And it provides a method for synthesizing chiral hydroxy ester by mixing the enzyme catalyzing the reaction of the three-selective transition of the acyl group of the acyloxy group is reduced alcohol group. According to the present invention, chiral hydroxy esters having excellent optical purity characteristics can be obtained in a high synthesis yield through a multi-step catalytic reaction from various substrates having a ketone group and an acyl group in a molecule. Chiral hydroxy esters synthesized according to the process of the invention are very useful as intermediates in the preparation of chiral pesticides, medicines and natural compounds.

Description

Method for the preparation of chiral hydroxy esters by enzyme-metal multi-catalysis

The present invention relates to a method for producing a chiral hydroxy ester, and more particularly, to a method for producing a chiral hydroxy ester having high purity optical activity by multicatalytic action of a combination of an enzyme and a metal catalyst in one reaction vessel. It is about.

Development of a methodology for stereoselectively synthesizing an optically active material having excellent optical purity is one of the most important research fields in organic synthesis, and two methodologies are currently being developed. One is kinetic resolution using an enzyme catalyst and the other is asymmetric synthesis using a metal catalyst. (Wong, C.-H .; Whitesides, GM Enzymes in Synthetic Organic Chemistry ; Pergamon: Oxford, UK, 1994; Noyori, R. Asymmetric Catalysis in Organic Synthesis ; Wiley: New York, 1994.).

The former method of the above-described manufacturing method has the advantage of high optical purity of the product, low cost of the enzyme catalyst, and simple reaction conditions, while having a low yield of 50% or less. In the latter method, the optical purity and the yield are good, but in addition to the metal catalyst, a chiral ligand having a large manufacturing cost must be used, and the reaction conditions are complicated and difficult.

Recently, dynamic kinetic resolution has been proposed, a new methodology that combines enzyme and metal catalysts. (Persson, BA; Larsson, ALE; Ray, ML; Backvall, J.-E. J. Am. Chem. Soc. 1999 , 121 , 1645 .; Lee, DH; Huh, EA; Kim, M.-J. Jung, HM Koh, JH; Park, J. Org. Lett. 2000 , 2 , 2377.). According to this method, an enzyme, which is a catalyst for stereoselective optical cleavage, and a metal catalyst, which is a racemization catalyst, are used together to convert a reaction substrate present in a racemic mixture into a product that exists as one optical isomer. This method has the advantage of a very high yield compared to the optical splitting method using only the above-described enzyme, and has the advantage that it does not require an expensive chiral ligand compared to the asymmetric synthesis method using the metal catalyst described above.

By utilizing the kinetics of the above-mentioned enzymes and metal catalysts, chiral esters can be synthesized from ketones (Jung, HM; Koh, JH; Kim, M.-J .; Park, J. Org. Lett . 2000 , 2 , 409 .; Jung, HM; Koh, JH; Kim, M.-J .; Park, J. Org. Lett . 2000 , 2 , 2487.). In this method, chiral esters are prepared by using enzymes called lipases and ruthenium metal complexes as catalysts, ketones, reducing agents and acyl donors as reactants. This method requires the use of excess acyl donors to improve conversion yield. However, the acyl donor used in excess is not only economically left in large quantities when the reaction is completed, but also has a disadvantage in that it is very difficult to separate and purify the product of the same ester compound, thereby lowering the separation yield.

The technical problem to be achieved by the present invention is to use the acyl donor to eliminate the problems caused by the excess acyl donors raised in the production method for synthesizing chiral esters from ketones by the kinetics of dynamic mixing of the enzyme and metal catalyst. By developing a practical process for preparing chiral esters, the present invention provides a method for producing chiral hydroxy esters, which is particularly excellent in separation yield and optical purity.

In order to achieve the above technical problem, in the present invention, a compound having a ketone group and an acyloxy group in the molecule at the same time; A hydrogen donor for reducing a ketone group of the compound to an alcoholic group; A metal complex that is a catalyst for promoting both a reaction in which a ketone group of the compound is reduced to an alcoholic group and a racemization reaction between two optical isomers of a racemic alcohol formed by the reduction; And a method of preparing a chiral hydroxy ester by mixing an organic solvent with an enzyme catalyzing a reaction in which an acyl group of the acyloxy group is stereoselectively transferred to a reduced alcohol group.

The compound having a ketone group and an acyloxy group in the molecule at the same time is represented by the formula (2), the chiral hydroxy ester is represented by the formula (1).

Wherein R ₁ and R ₃ are each independently a substituted or unsubstituted C 1 -C 15 alkyl group, a substituted or unsubstituted C 1 -C 15 alkenyl group, a substituted or unsubstituted C 1 -C 15 alkynyl group , Substituted or unsubstituted C6-C15 aryl group, substituted or unsubstituted C4-C15 heteroaryl group, substituted or unsubstituted C4-C15 cycloalkyl group, substituted or unsubstituted C4-C15 Is a heterocycloalkyl group, an unsubstituted or substituted C1-C15 heteroarylalkyl group, R ₂ is a substituted or unsubstituted C1-C15 alkylene group, a substituted or unsubstituted C6-C15 Arylene group, substituted or unsubstituted C4-C15 heteroarylene group, substituted or unsubstituted C4-C15 cycloalkylene group, substituted or unsubstituted C4-C15 heterocycloalkylene group, unsubstituted or substituted C1-C15 heteroarylalkylene group selected from the group consisting of The groups R ₁ and R ₂ , R ₂ and R ₃ or R ₁ and R ₃ may be connected to each other.

According to one embodiment of the invention, the metal complex is a ruthenium complex represented by the formula (3).

Wherein Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ are independently of each other hydrogen, a substituted or unsubstituted C 1 -C 10 alkyl group, substituted or unsubstituted C6-C15 aryl group or substituted or unsubstituted C1-C15 heteroaryl group.

Hereinafter, the present invention will be described in more detail.

The present invention provides synthesis by intramolecular asymmetric reduction acyl transfer reactions that occur in multiple stages by multi-catalysis in which enzymes and metal compounds participate as catalysts.

First, as a substrate, between two optical isomers of a compound represented by the formula (2) having a ketone group and an acyl group in the molecule, a reaction of reducing the ketone group of the compound represented by the formula (2), and a racemic alcohol formed by the reduction A ruthenium complex represented by the formula (3) for promoting a racemization reaction, a hydrogen donor for reducing the ketone group of the compound represented by the formula (2), and an enzyme for selectively acylating one enantiomer of the racemic alcohol After mixing, the solvent is added and mixed thereto.

After oxygen is removed from the mixture and purged with an inert gas, the reaction mixture is stirred at 0-100 ° C. to complete the reaction of the substrate with ruthenium complex, lipase and hydrogen donor. Subsequently, the reaction mixture is worked up and purified to obtain a chiral hydroxy ester of Chemical Formula 1.

<Formula 1>

<Formula 2>

Wherein R ₁ and R ₃ are each independently a substituted or unsubstituted C 1 -C 15 alkyl group, a substituted or unsubstituted C 1 -C 15 alkenyl group, a substituted or unsubstituted C 1 -C 15 alkynyl group , Substituted or unsubstituted C6-C15 aryl group, substituted or unsubstituted C4-C15 heteroaryl group, substituted or unsubstituted C4-C15 cycloalkyl group, substituted or unsubstituted C4-C15 A heterocycloalkyl group, an unsubstituted or substituted C1-C15 heteroarylalkyl group,

R ₂ is substituted or unsubstituted C1-C15 alkylene group, substituted or unsubstituted C6-C15 arylene group, substituted or unsubstituted C4-C15 heteroarylene group, substituted or unsubstituted C4 -C15 cycloalkylene group, substituted or unsubstituted C4-C15 heterocycloalkylene group, unsubstituted or substituted C1-C15 heteroarylalkylene group,

R ₁ and R ₂ , R ₂ and R ₃ or R ₁ and R ₃ may be connected to each other. Specific examples of such linked forms include substituted or unsubstituted C7-C20 fused rings or substituted or unsubstituted C5-C20 heterofused rings.

<Formula 3>

Wherein Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ are independently of each other hydrogen, a substituted or unsubstituted C 1 -C 10 alkyl group, substituted or unsubstituted C6-C15 aryl group or substituted or unsubstituted C1-C15 heteroaryl group.

The compound of Formula 2 has a ketone group and an acyl group in the molecule at the same time, and is represented by Formula 4 or 5 in particular.

Wherein R ₄ is a C1-C10 alkyl group or an alkyl group substituted with a hetero atom, R ₅ is a C1-C5 alkyl group, a hetero atom substituted alkyl group, a C2-C5 alkenyl group or a C2-C5 alkynyl group, n is an integer of 0 to 10, m is an integer of 1 to 6, X is a halogen atom, an alkyl group of C1-C5, an alkenyl group of C2-C5, an alkynyl group of C2-C5, an alkoxy group of C1-C5, Nitro group, amide group, sulfonyl group or at least one thioalkoxy group, Is a C6-C10 aryl group or a C1-C10 heteroaryl group.

Specific examples of the compound of Formula 4 or 5 include a compound of Formulas 4a to 4d and a compound of Formulas 5a to 5d.

<Formula 4a>

<Formula 4b>

<Formula 4c>

<Formula 4d>

<Formula 5a>

<Formula 5b>

<Formula 5c>

<Formula 5d>

The definitions of terms used in the present invention and specific examples thereof are as follows.

In the above formulas, specific examples of the unsubstituted C 1 -C 15 alkyl group include methyl, ethyl, propyl, isobutyl, sec-butyl, pentyl, iso-amyl, hexyl, and the like, and at least one hydrogen atom of the alkyl group. Is a halogen atom, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonic acid group or salt thereof, phosphoric acid or salt thereof, or alkyl group, alkenyl group, alkynyl group of C1-C15 , C1-C15 heteroalkyl group, C6-C15 aryl group, C6-C15 arylalkyl group, C6-C15 heteroaryl group, or C6-C15 heteroarylalkyl group.

The unsubstituted C1-C15 alkenyl group or alkynyl group means that it contains a carbon double bond or a triple bond in the middle or the end of the alkyl group as defined above. Examples are ethylene, propylene, butylene, hexylene, acetylene and the like. At least one hydrogen atom of these alkenyl or alkynyl groups may be a halogen atom, a hydroxy group, a nitro group, a cyano group, an amino group, an amidino group, a hydrazine, a hydrazone, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, a phosphoric acid or a salt thereof, Or C1-C15 alkyl group, alkenyl group, alkynyl group, C1-C15 heteroalkyl group, C6-C15 aryl group, C6-C15 arylalkyl group, C1-C15 heteroaryl group, or C6-C15 heteroarylalkyl group It may be substituted by.

Specific examples of the unsubstituted C1-C15 alkylene group include methylene, ethylene, propylene, isobutylene, sec-butylene, pentylene, iso-amylene, hexylene and the like, and one of the alkylene groups The above hydrogen atoms are halogen atom, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonic acid group or salt thereof, phosphoric acid or salt thereof, or alkyl group or alkenyl group of C1-C15. , An alkynyl group, a C1-C15 heteroalkyl group, a C6-C15 aryl group, a C6-C15 arylalkyl group, a C1-C15 heteroaryl group, or a C6-C15 heteroarylalkyl group.

The heteroalkyl group means that the alkyl group as defined above contains a nitrogen atom, a sulfur atom, an oxygen atom or a person atom. Examples include methoxy, ethoxy, propoxy, butoxy and t-butoxy, and examples having substituents include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoro Haloalkoxy radicals such as oxy and fluoropropoxy. At least one hydrogen atom of these heteroalkyl groups may be a halogen atom, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonic acid group or salt thereof, phosphoric acid or salt thereof, or C1- To be substituted with a C15 alkyl group, an alkenyl group, an alkynyl group, a C1-C15 heteroalkyl group, a C6-C15 aryl group, a C6-C15 arylalkyl group, a C6-C15 heteroaryl group, or a C6-C15 heteroarylalkyl group Can be.

The aryl group used alone or in combination means a carbocyclic aromatic system having 6 to 30 carbon atoms containing one or more rings, which rings may be attached or fused together in a pendant manner. The term aryl includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferred aryl is phenyl or naphthyl. The aryl group may have substituents such as hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino. In addition, at least one hydrogen atom of the aryl group may be a halogen atom, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonic acid group or salt thereof, phosphoric acid or salt thereof, or C1-C15. Alkyl group, alkenyl group, alkynyl group, C1-C15 heteroalkyl group, C6-C15 aryl group, C6-C15 arylalkyl group, C6-C15 heteroaryl group, or C6-C15 heteroarylalkyl group have.

The arylalkyl group means that some of the hydrogen atoms in the aryl group as defined above are substituted with radicals such as lower alkyl, for example methyl, ethyl, propyl and the like. For example benzyl, phenylethyl and the like. At least one hydrogen atom of the arylalkyl group may be a halogen atom, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonic acid group or salt thereof, phosphoric acid or salt thereof, or C1-C15 Alkyl group, alkenyl group, alkynyl group, C1-C15 heteroalkyl group, C6-C15 aryl group, C6-C15 arylalkyl group, C6-C15 heteroaryl group, or C6-C15 heteroarylalkyl group have.

The heteroaryl group includes 1, 2, 3 or 4 heteroatoms selected from N, O, P or S, and has 5 to 15 monovalent monocyclic or bicyclic aromatic radicals in which the remaining ring atoms are C. Means. The term also refers to monovalent monocyclic or bicyclic aromatic radicals in which heteroatoms in the ring are oxidized or quaternized, for example to form N-oxides or quaternary salts. Representative examples include thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, Benzisoxazolyl, Benzimidazolyl, Triazolyl, Pyrazolyl, Pyrrolyl, Indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl, Pyrazinonil, Pyridazino Nil, pyrimidinyl, oxazoloyl, and their corresponding N-oxides (eg, pyridyl N-oxides, quinolinyl N-oxides), quaternary salts thereof, and the like, and the like. Do not. At least one hydrogen atom of the hetero atom may be a halogen atom, a hydroxy group, a nitro group, a cyano group, an amino group, an amidino group, a hydrazine, a hydrazone, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, a phosphoric acid or a salt thereof, or C1-C15 Alkyl group, alkenyl group, alkynyl group, C1-C15 heteroalkyl group, C6-C15 aryl group, C6-C15 arylalkyl group, C6-C15 heteroaryl group, or C6-C15 heteroarylalkyl group have.

The heteroarylalkyl group means that a part of the hydrogen atoms of the heteroaryl group is substituted with an alkyl group. At least one hydrogen atom of the heteroarylalkyl group may be a halogen atom, a hydroxy group, a nitro group, a cyano group, an amino group, an amidino group, a hydrazine, a hydrazone, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, a phosphoric acid or a salt thereof, or C1- To be substituted with a C15 alkyl group, an alkenyl group, an alkynyl group, a C1-C15 heteroalkyl group, a C6-C15 aryl group, a C6-C15 arylalkyl group, a C6-C15 heteroaryl group, or a C6-C15 heteroarylalkyl group Can be.

The cycloalkyl group refers to a monovalent monocyclic radical having 4 to 30 carbon atoms. At least one hydrogen atom of the cycloalkyl group may be a halogen atom, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonic acid group or salt thereof, phosphoric acid or salt thereof, or C1- To be substituted with a C15 alkyl group, an alkenyl group, an alkynyl group, a C1-C15 heteroalkyl group, a C6-C15 aryl group, a C6-C15 arylalkyl group, a C6-C15 heteroaryl group, or a C6-C15 heteroarylalkyl group Can be.

The heterocycloalkyl group refers to a monovalent monocyclic radical having 5 to 15 ring atoms containing 1, 2, 3 or 4 heteroatoms selected from N, O, P or S, and the remaining ring atoms being C. It means that a part of the hydrogen atoms of the cycloalkyl group is substituted with an alkyl group. At least one hydrogen atom of the cycloalkyl group may be a halogen atom, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonic acid group or salt thereof, phosphoric acid or salt thereof, or C1-C15 Alkyl group, alkenyl group, alkynyl group, C1-C15 heteroalkyl group, C6-C15 aryl group, C6-C15 arylalkyl group, C6-C15 heteroaryl group, or C6-C15 heteroarylalkyl group have.

In the present invention, the ruthenium complex of formula (3) reduces the ketone group possessed by the compound of formula (2) and simultaneously promotes the racemization reaction of the alcohol obtained by the reduction reaction, in particular, Y ₁ to Y ₈ are all It is preferable that it is a phenyl group or a methyl group. And the content of the ruthenium complex is preferably 0.01 to 0.05 moles, more preferably 0.02 to 0.04 moles based on 1 mole of the compound represented by the formula (2). If the content of the ruthenium complex is less than 0.01 mole, the reaction is too slow. If the content of the ruthenium complex exceeds 0.05 mole, the production cost of the chiral ester is increased, which is not preferable.

The enzyme uses a biocatalyst that promotes an acyl transfer reaction, among which lipase is used. Lipase is a hydrolase of esters, which selectively acylates one enantiomer of racemic alcohol to produce chiral esters with excellent optical purity. Specific examples of such lipases include Pseudomonas cepacia lipase (LPS), Candida antarctica lipase (CAL), and Candida rugosa lipase (CRL), but Pseudomonas sepacia lipase (CRL) is immobilized. Pseudomonas cepacia lipase or immobilized Candida anthatiga lipase ratio ( Candida rugosa lipase B) is preferred. The amount of immobilized lipase is 0.5 to 20 mg, in particular 1 to 10 mg per mmol of the substrate.

The hydrogen donor serves to reduce the ketone group of the compound of formula 2 to alcohol under the catalyst of the ruthenium complex of formula 3. As the hydrogen donor, at least one selected from the group consisting of hydrogen, formic acid and alcohols represented by the formula (6) is used.

Wherein R ′ and R ″ are each independently a linear or branched C 1 -C 10 alkyl group, a C 6 -C 15 aryl group or a C 1 -C 15 hetero aryl group.

The alcohol represented by the formula (6) is preferably a compound having an alkyl side chain so as to have low enzyme reactivity, examples of which include 2,4-dimethyl-3-pentanol, 2,6-dimethyl-4-heptanol, and the like. have.

In the present invention, the hydrogen donor is more preferable in view of ease of removal, particularly after obtaining a chiral ester whose target is hydrogen under atmospheric pressure. The content of the hydrogen donor is preferably 1 to 50 moles based on 1 mole of the compound of Formula 2.

The solvent is not particularly limited, but enzymatic catalysis such as lipase is usually influenced by the solvent in terms of synthesis yield and stereoselectivity of the product, so benzene, toluene, hexane, tetrahydrofuran, dioxane, C2-C10 Preference is given to using aprotic solvents such as dialkyl ethers of diethyl ether, C3-C10 alkyl acetates of ethyl acetate, acetonitrile, acetone, dichloromethane, chloroform and carbon tetrachloride. And the content of the solvent is adjusted to the solution of the substance to be dissolved in the concentration range of 0.2 to 0.4M.

The temperature of the reaction varies depending on the ruthenium catalyst used, but is preferably made at 50-100 ° C., in particular at 70-80 ° C. If the reaction temperature is less than 50 ℃, the rate of racemization reaction is slow, if it exceeds 100 ℃ it is not preferable because the enzyme loses the activity quickly.

Scheme 1 shows a multi-stage reaction route according to a preferred embodiment of the present invention.

As shown in Scheme 1, the ruthenium compound of Formula 3 (when Y ₁ -Y ₈ are all phenyl), which is a metal catalyst, and a lipase, which is an enzyme catalyst, in the presence of hydrogen as the substrate of Formula 4a is a reducing agent, Converted to the final product of 1a.

The product obtained according to the above scheme is very useful as an intermediate in the preparation of chiral medicaments such as rivastigmine (trade name, Exelon).

Hereinafter, the present invention will be described with reference to the following examples, but the present invention is not limited only to the following examples.

Example 1

A compound of formula 4 (0.6 mmol), a ruthenium complex of formula 3 (Y ₁ to Y all phenyl) (0.012 mmol), and immobilized lipase (5 mg) were mixed in 1.5 mL of toluene, and the argon gas was purged to remove oxygen. It was. The reaction vessel was then filled with hydrogen gas at atmospheric pressure and the reaction mixture was stirred at room temperature for 72 hours. After the reaction was completed, column chromatography was performed to obtain a chiral hydroxy ester represented by Chemical Formula 1a.

Example 2-8

Chiral hydroxy esters of the following Chemical Formulas 1b to 1h were obtained in the same manner as in Example 1, except that the compounds of Chemical Formulas 4b to 4d and the compounds of Chemical Formulas 5a to 5d were used instead of the compounds of Chemical Formula 4a, respectively.

Synthesis yield and optical purity of the chiral ester according to Example 1-8 were measured and shown in Table 1 below. Herein, the synthetic yield of chiral ester was analyzed using ¹ H-NMR, and optical purity was analyzed using high performance liquid chromatography (Chromatography) equipped with chiral column.

division temperament product yield(%) Optical purity of the product (%) Example 1 4a 1a 91 99 Example 2 4b 1b 90 98 Example 3 4c 1c 92 95 Example 4 4d 1d 90 98 Example 5 5a 1e 94 93 Example 6 5b 1f 93 97 Example 7 5c 1 g 88 89 Example 8 5d 1h 87 99

As can be seen from Table 1, according to Examples 1-8, a compound having a ketone group and an acyloxy group in the molecule at the same time, a lipase for promoting a ruthenium complex and an acyl transfer reaction to simultaneously undergo a reduction reaction and a racemization reaction When mixed and reacted under hydrogen gas, a chiral hydroxy ester having excellent optical purity was prepared in a high synthetic yield through a multi-step route.

According to the present invention, chiral hydroxy esters having excellent optical purity characteristics can be obtained in a high synthetic yield from various substrates having a ketone group and an acyloxy group in the molecule. The present invention has demonstrated that multi-step synthesis of chiral compounds by multicatalysis of enzymes and metals can easily proceed in one reactor. Chiral hydroxy esters synthesized according to the process of the invention are very useful as intermediates in the preparation of chiral pesticides, medicines and natural compounds. In particular, the chiral hydroxy esters of formula 1a synthesized according to the process of the present invention are very useful as intermediates in the preparation of chiral medicines such as rivastigmine (trade name, Exelon).

Claims (9)

A compound represented by formula (4) or (5) having a ketone group and an acyloxy group in the molecule at the same time; A hydrogen donor for reducing a ketone group of the compound to an alcoholic group; A metal complex that is a catalyst for promoting both a reaction in which a ketone group of the compound is reduced to an alcoholic group and a racemization reaction between two optical isomers of a racemic alcohol formed by the reduction; And a method of preparing a chiral hydroxy ester represented by Chemical Formula 1 by mixing an enzyme catalyzing a reaction in which the acyl group of the acyloxy group is stereoselectively transferred to an alcohol group reduced with an organic solvent. <Formula 4> <Formula 5> Wherein R ₄ is a C1-C10 alkyl group or a C1-C10 alkyl group substituted with a hetero atom, R ₅ is a C1-C5 alkyl group, a hetero atom substituted C1-C5 alkyl group, a C2-C5 alkenyl group or C2-C5 is an alkynyl group, n is an integer from 0 to 10, m is an integer from 1 to 6, X is a halogen atom, an alkyl group of C1-C5, an alkenyl group of C2-C5, an alkynyl group of C2-C5 , C1-C5 alkoxy group, nitro group, amide group, sulfonyl group or one or more thioalkoxy group, Is a C6-C10 aryl group or a C1-C10 heteroaryl group. delete delete The method of claim 1, wherein the metal complex is represented by Formula 3; <Formula 3> Wherein Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ are independently of each other hydrogen, a substituted or unsubstituted C 1 -C 10 alkyl group, substituted or unsubstituted C6-C15 aryl group or substituted or unsubstituted C1-C15 heteroaryl group. The method for preparing chiral hydroxy ester according to claim 4, wherein in the ruthenium complex of Formula 3, Y ₁ to Y ₈ are all phenyl groups or methyl groups. The method for preparing chiral hydroxy ester according to claim 4, wherein the ruthenium complex of Formula 3 is 0.01 to 0.05 mole based on 1 mole of the compound represented by Formula 4 or 5. The method of claim 1, wherein the hydrogen donor is at least one selected from the group consisting of hydrogen, formic acid, and alcohol represented by the formula (6). <Formula 6> Wherein R ′ and R ″ are each independently a linear or branched C 1 -C 10 alkyl group, a C 6 -C 15 aryl group or a C 1 -C 15 hetero aryl group. The method for producing chiral hydroxy ester according to claim 7, wherein when the hydrogen donor is used as hydrogen, the pressure of hydrogen is atmospheric pressure. According to claim 1, wherein the enzyme is composed of Pseudomonas cepacia lipase (LPS) of the lipase family, Candida antarctica lipase (CAL) and Candida rugosa lipase (CRL) Method of producing a chiral hydroxy ester, characterized in that at least one selected from the group.