JP4534457B2 - Optically active epoxy compounds and method for producing the same - Google Patents

Description

  The present invention relates to optically active epoxy compounds and a method for producing the same.

  The optically active epoxy compounds of the present invention and the optically active (2S, 3R) -2,3-epoxypropionic acid derivative having a substituent at the 3-position are useful compounds as intermediates for the production of medicines and agrochemicals.

  The present invention also relates to a β-halogenoketone derivative, a method for producing the same, and a method for producing an enone derivative using the same.

  The 3-halogenopropane derivative having a substituent at the 1,3-position and 2-propen-1-one having a substituent at the 1,3-position of the present invention are useful compounds as intermediates for the production of medicines and agricultural chemicals.

  Furthermore, the present invention relates to a method for producing optically active 2,3-epoxy-3-propionic acids and esters thereof having a substituent at the 3-position.

  The optically active 2,3-epoxypropionic acids and esters thereof having a substituent at the 3-position of the present invention are compounds useful as synthetic intermediates for medical and agricultural chemicals as described above.

  As an asymmetric oxidation reaction, an asymmetric oxidation reaction of trans-allyl alcohol using titanium tetraisopropoxide and optically active diethyl tartrate and further using tert-butyl hydroperoxide is known (for example, non-patent literature). 1).

In addition, as a method for producing 2,3-epoxy-3-cyclohexylpropionic acid, optically active cis-2 is obtained by oxidation using RuO ₄ of cis-2,3-epoxy-4-phenyl-butan-1-ol. , 3-epoxy-4-phenyl-butanoic acid is known (for example, see Non-Patent Document 2 and Non-Patent Document 3).

Further, 2,3-epoxy-4-methylpentanoic acid and 2,3-epoxyheptanoic acid are produced by using the corresponding allyl alcohol, titanium tetraisopropoxide and optically active diethyl tartrate, and further tert-butyl hydroperoxide. A method is known in which an asymmetric epoxidation is performed using an oxide and then oxidized to a carboxylic acid using RuO ₄ (see, for example, Patent Document 1).

  1-Phenyl-3-cyclohexyl-2-propen-1-one is described in various known documents (for example, see Patent Document 2).

  It is also known that 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one can be obtained by the reaction of cyclohexanecarboxaldehyde and acetophenone (see, for example, Patent Document 3).

  Furthermore, 3-hydroxy-1-carbonyl compounds (aldol forms) produced by the reaction of a general aldehyde and a ketone easily undergo a dehydration reaction with an acid or a base, and α, β unsaturated ketones or α, β -It is known that unsaturated esters are formed (see Non-Patent Document 4 and the like).

JP 2002-80441 A

Japanese Patent Laid-Open No. 11-80036 International Publication No. 02/041984 Pamphlet K. B. Sharpless, et. al. , J .; Am. Chem. Soc. 109, 5765 (1987) K. B. Sharpless, et. al. , J .; Org. Chem. , 50, 1560 (1985) K. B. Sharpless, et. al. , J .; Org. Chem. 46, 3936 (1981) Herbert O. House, “Modern Synthetic Reactions Second Edition” (1972). A. Benjamin, Inc. p. 632-637

  The conventional asymmetric oxidation reaction has not been satisfactory as an industrial production method. For example, in the conventional asymmetric oxidation reaction of trans-allyl alcohol, since a large amount of oxidant is present in the reaction system during the reaction, there is no problem in the production of a small amount. This is an accompanying method and could not be said to be an industrial production method.

  Further, in the conventional method, in the obtained 1-phenyl-3-cyclohexyl-2-propen-1-one, a side reaction product is generated depending on conditions, and in order to obtain a high-purity target product, silica gel Precise purification by column chromatography or the like is necessary, and it was not an industrial production method.

  As a result of intensive studies on an industrially safe method for producing an optically active epoxy enone derivative, the present inventors have found a method of using the enone derivative of the present invention as a raw material and deriving via a novel intermediate.

  In addition, as a result of intensive studies on an industrial method for producing 1-phenyl-2-propen-1-one having a substituent at the 3-position, the present inventors have found that a reaction of aldehydes with lithium enolate of acetophenone or an aldehyde 1-phenyl-3-hydroxypropan-1-one derivative having a substituent at the 3-position obtained by the reaction of acetylphenone with trimethylsilyl enolate of acetophenone is reacted with hydrogen halide or hydrohalic acid and substituted at the 3-position 1-phenyl-3-halogenopropan-1-one derivative having a group, and subsequently treated with a base, 1-phenylpropene having a substituent at the 3-position with high purity without precise purification by silica gel column chromatography The inventors have found that -1-one can be obtained and have completed the present invention.

That is, the present invention
1. An optically active epoxy enone derivative represented by the following general formula (1):

（式中、Ｒ^１はメチル基、エチル基、又は炭素数３〜１０の分岐、直鎖若しくは環式のアルキル基を表し、Ｒ^２はフェニル基、置換フェニル基又はｔｅｒｔ−ブチル基を表す。）
２．下記一般式（２）

(Wherein R ¹ represents a methyl group, an ethyl group, or a branched, straight-chain or cyclic alkyl group having 3 to 10 carbon atoms, and R ² represents a phenyl group, a substituted phenyl group or a tert-butyl group. )
2. The following general formula (2)

（式中、Ｒ^１はメチル基、エチル基、又は炭素数３〜１０の分岐、直鎖若しくは環式のアルキル基を表し、Ｒ^２はフェニル基、置換フェニル基又はｔｅｒｔ−ブチル基を表す。）
で示されるエノン誘導体を不斉酸化することを特徴とする上記一般式（１）で示される光学活性エポキシエノン誘導体の製造方法、
３．下記一般式（３）で示される光学活性エポキシエステル誘導体、

(Wherein R ¹ represents a methyl group, an ethyl group, or a branched, straight-chain or cyclic alkyl group having 3 to 10 carbon atoms, and R ² represents a phenyl group, a substituted phenyl group or a tert-butyl group. )
A process for producing the optically active epoxy enone derivative represented by the general formula (1), wherein the enone derivative represented by formula (1) is asymmetrically oxidized:
3. An optically active epoxy ester derivative represented by the following general formula (3):

（式中、Ｒ^１はメチル基、エチル基、又は炭素数３〜１０の分岐、直鎖若しくは環式のアルキル基を表し、Ｒ^２はフェニル基、置換フェニル基又はｔｅｒｔ−ブチル基を表す。）
４．上記一般式（１）で示される光学活性エポキシエノン誘導体を酸化剤により酸化することを特徴とする上記一般式（３）で示される光学活性エポキシエステル誘導体の製造方法、
５．上記一般式（３）で示される光学活性エポキシエステル誘導体を加水分解することを特徴とする下記一般式（４）

(Wherein R ¹ represents a methyl group, an ethyl group, or a branched, straight-chain or cyclic alkyl group having 3 to 10 carbon atoms, and R ² represents a phenyl group, a substituted phenyl group or a tert-butyl group. )
4). A method for producing an optically active epoxy ester derivative represented by the general formula (3), wherein the optically active epoxy enone derivative represented by the general formula (1) is oxidized with an oxidizing agent;
5). The following general formula (4), wherein the optically active epoxy ester derivative represented by the general formula (3) is hydrolyzed

（式中、Ｒ^１はメチル基、エチル基、又は炭素数３〜１０の分岐、直鎖若しくは環式のアルキル基を表す。）
で示される３位に置換基を持つ光学活性（２Ｓ，３Ｒ）−２，３−エポキシプロピオン酸誘導体の製造方法。

(In the formula, R ¹ represents a methyl group, an ethyl group, or a branched, linear or cyclic alkyl group having 3 to 10 carbon atoms.)
The manufacturing method of the optically active (2S, 3R) -2,3-epoxypropionic acid derivative which has a substituent in 3-position shown by these.

  6). A 3-halogenopropan-1-one derivative having a substituent at the 1,3-position represented by the following general formula (5);

（式中、Ｒ^１はメチル基、エチル基、又は炭素数３〜１０の分岐、直鎖若しくは環式のアルキル基を表し、Ｒ^２はフェニル基、置換フェニル基又はｔｅｒｔ−ブチル基を表し、Ｘはフッ素原子、塩素原子、臭素原子又はヨウ素原子を表す。）
７．下記一般式（６）

(Wherein R ¹ represents a methyl group, an ethyl group, or a branched, straight-chain or cyclic alkyl group having 3 to 10 carbon atoms, R ² represents a phenyl group, a substituted phenyl group or a tert-butyl group; X represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.)
7). The following general formula (6)

（式中、Ｒ^１はメチル基、エチル基、又は炭素数３〜１０の分岐、直鎖若しくは環式のアルキル基を表し、Ｒ^２はフェニル基、置換フェニル基又はｔｅｒｔ−ブチル基を表す。）
で示されるβ−ヒドロキシケトン誘導体をハロゲン化水素又はハロゲン化水素酸と反応させることを特徴とする上記一般式（５）で示される１，３位に置換基を持つ３−ハロゲノプロパン−１−オン誘導体の製造方法、並びに
８．上記一般式（５）で示される１，３位に置換基を持つ３−ハロゲノプロパン−１−オン誘導体を、塩基で処理することを特徴とする下記一般式（２）

(Wherein R ¹ represents a methyl group, an ethyl group, or a branched, straight-chain or cyclic alkyl group having 3 to 10 carbon atoms, and R ² represents a phenyl group, a substituted phenyl group or a tert-butyl group. )
A 3-halogenopropane-1-substituted one having a substituent at the 1,3-position represented by the general formula (5), wherein the β-hydroxyketone derivative represented by the formula (3) is reacted with hydrogen halide or hydrohalic acid. 7. Method for producing on-derivative, and A 3-halogenopropan-1-one derivative having a substituent at the 1,3-position represented by the general formula (5) is treated with a base, and the following general formula (2)

（式中、Ｒ^１はメチル基、エチル基、又は炭素数３〜１０の分岐、直鎖若しくは環式のアルキル基を表し、Ｒ^２はフェニル基、置換フェニル基又はｔｅｒｔ−ブチル基を表す。）
で示されるα，β−不飽和ケトン誘導体の製造方法、
である。

(Wherein R ¹ represents a methyl group, an ethyl group, or a branched, straight-chain or cyclic alkyl group having 3 to 10 carbon atoms, and R ² represents a phenyl group, a substituted phenyl group or a tert-butyl group. )
A process for producing an α, β-unsaturated ketone derivative represented by:
It is.

  Hereinafter, the present invention will be described in detail.

  First, the optically active epoxy compounds of the present invention and the production method thereof will be described.

In the optically active epoxy enone derivative represented by the general formula (1) of the present invention, the substituent R ¹ represents a methyl group, an ethyl group, or a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms. Specific examples include a cyclohexyl group, an isopropyl group, and an n-butyl group. The substituent R ² represents a phenyl group, a substituted phenyl group, or a tert-butyl group, and specific examples thereof include a phenyl group, a 4-methoxyphenyl group, and a tert-butyl group.

  Specific examples of the optically active epoxy enone derivative represented by the general formula (1) of the present invention include (2S, 3R) -2,3-epoxy-1-phenylbutan-1-one, (2S, 3R). ) -2,3-epoxy-1-phenylpentan-1-one, (2S, 3R) -2,3-epoxy-1-phenyl-4-methylpentan-1-one, (2S, 3R) -2, 3-epoxy-1-phenylhexan-1-one, (2S, 3R) -2,3-epoxy-1-phenylheptan-1-one, (2S, 3R) -2,3-epoxy-1-phenyl Octane-1-one, (2S, 3R) -2,3-epoxy-1-phenylnonan-1-one, (2S, 3R) -2,3-epoxy-1-phenyldecan-1-one, (2S , 3R) -2,3-epoxy-1-phenyl Decan-1-one, (2S, 3R) -2,3-epoxy-1-phenyldodecan-1-one, (2S, 3R) -2,3-epoxy-1-phenyl-4,4-dimethylpentane- 1-one, (2S, 3R) -2,3-epoxy-1-phenyl-3-cyclohexylpropan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylbutan-1-one (2S, 3R) -2,3-epoxy-1-tert-butylpentan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butyl-4-methylpentan-1-one (2S, 3R) -2,3-epoxy-1-tert-butylhexan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylheptan-1-one, (2S , 3R) -2,3-epoxy -1-tert-butyloctane-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylnonan-1-one, (2S, 3R) -2,3-epoxy-1-tert- Butyldecan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylundecan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butyldodecane-1- ON, (2S, 3R) -2,3-epoxy-1-tert-butyl-4,4-dimethylpentan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butyl-3 -Cyclohexylpropan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) butan-1-one, (2S, 3R) -2,3-epoxy-1- (4 -Methoxyphenyl) pe Ntan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) -4-methylpentan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) hexan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) heptan-1-one, (2S, 3R) -2,3-epoxy -1- (4-methoxyphenyl) octane-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) nonan-1-one, (2S, 3R) -2,3 -Epoxy-1- (4-methoxyphenyl) decan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) undecan-1-one, (2S, 3R) -2 , 3-Epoxy-1- (4-methoxyphenyl) do Can-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) -4,4-dimethylpentan-1-one, (2S, 3R) -2,3-epoxy- 1- (4-methoxyphenyl) -3-cyclohexylpropan-1-one and the like can be mentioned.

  The optically active epoxy enone derivative represented by the general formula (1) of the present invention can be produced, for example, by asymmetric oxidation of the enone derivative represented by the general formula (2).

In the enone derivative represented by the general formula (2) of the present invention, the substituent R ¹ represents a methyl group, an ethyl group, or a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms. Examples include cyclohexyl group, isopropyl group, n-butyl group and the like. The substituent R ² represents a phenyl group, a substituted phenyl group, or a tert-butyl group, and specific examples thereof include a phenyl group, a 4-methoxyphenyl group, and a tert-butyl group.

  Although it does not specifically limit as a preparation method of the enone derivative shown by the said General formula (2) of this invention, For example, it can prepare by cross-aldol reaction of aldehydes and acetophenone. Specifically, it may be prepared by reacting acetophenone or silyl enol ether of methyl tert-butyl ketone or lithium enolate with an aldehyde, and then dehydrating the generated aldol derivative with an acid or the like. In order to obtain a product, it may be prepared by a method via β-haloketones substituted at the 1,3-position described later.

  In preparing the epoxy enone derivative represented by the above general formula (1) of the present invention, lanthanoid triisopropoxide, (R) -1,1-bi-2-naphthol, triphenylphosphine oxide and cumene hydro It is preferable to perform an asymmetric oxidation reaction with cumene hydroperoxide using a peroxide catalyst.

  In the present invention, the lanthanoid triisopropoxide applicable to the asymmetric oxidation reaction is not particularly limited as long as it is a rare earth metal alkoxide, but preferably lanthanum triisopropoxide, ytterbium triisopropoxide. And lanthanum triisopropoxide is particularly preferred.

  In the present invention, as the lanthanoid triisoproposide used for the asymmetric oxidation reaction, those prepared by any production method can be used and are not particularly limited. The amount of lanthanoid triisoproposide used is usually 0.1 mol% to 30 mol% with respect to the enone derivative represented by the general formula (2) used in the reaction.

  In the present invention, the amount of (R) -1,1′-bi-2-naphthol used in the asymmetric oxidation reaction is usually 1 to 2 times the molar amount of lanthanum isopropoxide used in the reaction. The molar amount is preferably 1 to 1.5 times.

  In the present invention, the amount of triphenylphosphine oxide used in the asymmetric oxidation reaction is 1 to 5 times, preferably 1.1 to 3 times the amount of lanthanum triisopropoxide used in the reaction. use.

  In the present invention, the amount of cumene hydroperoxide or tert-butyl hydroperoxide used in the asymmetric oxidation reaction is usually 1 to 4 moles with respect to lanthanum isopropoxide at the time of catalyst formation, and further during the reaction. It is usually used in an amount of 1 to 2 times the molar amount of the enone derivative represented by the general formula (1) to be used.

  In the present invention, for the asymmetric oxidation reaction, a catalyst solution comprising lanthanoid triisopropoxide, (R) -1,1-bi-2-naphthol, triphenylphosphine oxide and cumene hydroperoxide is prepared in advance. The substrate and cumene hydroperoxide or tert-butyl hydroperoxide may be mixed and supplied to the catalyst solution to carry out the reaction, or the substrate and cumene hydroperoxide or tert-butyl hydroperoxide may be separately reacted in the catalyst solution. The reaction may be carried out by supplying to

  In the present invention, during the asymmetric oxidation reaction, an appropriate amount of zeolite such as molecular sieves-4A, molecular sieves-3A or the like in powder or molded form may be used as necessary to keep the system anhydrous.

  In the present invention, specific examples of the solvent applicable to the asymmetric oxidation reaction include ethers such as tetrahydrofuran (hereinafter abbreviated as THF), diethyl ether, diisopropyl ether, and aromatics such as benzene, toluene, ethylbenzene, and xylene. Examples include hydrocarbons, and ethers are preferable, and THF is particularly preferable.

  In the present invention, the reaction temperature of the asymmetric oxidation reaction can be carried out by a reaction of −30 ° C. to 30 ° C. In order to obtain the optically active epoxy enone derivative represented by the general formula (1) with high optical purity. For this, it is preferable to carry out at -10 to 20 ° C.

  The reaction time of the asymmetric oxidation reaction of the present invention varies depending on the substrate concentration, catalyst amount, catalyst concentration, and reaction temperature, but the reaction is usually completed within 0.5 to 24 hours after the addition of the substrate.

  The post-treatment of the asymmetric oxidation reaction of the present invention is not particularly limited. Usually, after adding a saturated aqueous ammonium chloride solution to decompose the catalyst, excess cumene hydroperoxide is converted into an aqueous sodium sulfite solution. The target optically active epoxy enone represented by the above general formula (1) can be obtained by subsequent decomposition with a silica gel column chromatography and the like.

In the above general formula (3) of the present invention, the substituent R ¹ represents a methyl group, an ethyl group, or a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, specifically, a cyclohexyl group. , Isopropyl group, n-butyl group and the like. The substituent R ² represents a phenyl group, a substituted phenyl group, or a tert-butyl group, and specific examples thereof include a phenyl group, a 4-methoxyphenyl group, and a tert-butyl group.

  Specific examples of the optically active epoxy ester derivative represented by the general formula (3) of the present invention include phenyl (2S, 3R) -2,3-epoxybutyrate, phenyl (2S, 3R) -2,3. -Epoxypentanoate, phenyl (2S, 3R) -2,3-epoxy-4-methylpentanoate, phenyl (2S, 3R) -2,3-epoxyhexanoate, phenyl (2S, 3R) -2 , 3-epoxyheptanoate, phenyl (2S, 3R) -2,3-epoxyoctanoate, phenyl (2S, 3R) -2,3-epoxynonanoate, phenyl (2S, 3R) -2,3- Epoxy decanoate, phenyl (2S, 3R) -2,3-epoxyundecanoate, phenyl (2S, 3R) -2,3-epoxydodecanoate Phenyl (2S, 3R) -2,3-epoxy-4,4-dimethylpentanoate, phenyl (2S, 3R) -2,3-epoxy-3-cyclohexylpropionate, tert-butyl (2S, 3R) -2,3-epoxybutanoate, tert-butyl (2S, 3R) -2,3-epoxybutylpentanoate, tert-butyl (2S, 3R) -2,3-epoxy-4-methylpentanoate Tert-butyl (2S, 3R) -2,3-epoxyhexanoate, tert-butyl (2S, 3R) -2,3-epoxyheptanoate, tert-butyl (2S, 3R) -2,3-epoxy Octanoate, tert-butyl (2S, 3R) -2,3-epoxynonanoate, tert-butyl (2S, 3R) -2,3- Poxydecanoate, tert-butyl (2S, 3R) -2,3-epoxy-undecanoate, tert-butyl (2S, 3R) -2,3-epoxydodecanoate, tert-butyl (2S, 3R) -2 , 3-epoxy-butyl-4,4-dimethylpentanoate, tert-butyl (2S, 3R) -2,3-epoxy-3-cyclohexylpropionate, 4-methoxyphenyl (2S, 3R) -2, 3-epoxy-1-butanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxypentanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxy-4-methylpentanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxyhexanoate, 4-methoxyphenyl (2S, 3R) -2 3-epoxyheptanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxyoctanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxynonanoate, 4-methoxyphenyl (2S , 3R) -2,3-epoxydecanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxyundecanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxide decanoate 4-methoxyphenyl (2S, 3R) -2,3-epoxy-4,4-dimethylpentanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxy-3-cyclohexylpropionate, etc. Can be mentioned.

  The method for producing the optically active epoxy ester derivative represented by the above general formula (3) of the present invention is not particularly limited. For example, the optically active epoxy enone derivative represented by the above general formula (1) is converted into an oxidizing agent. Can be obtained by oxidation reaction.

  In the production of the optically active epoxy ester derivative represented by the general formula (3) of the present invention, the applicable oxidizing agent is not particularly limited. Specifically, potassium persulfate, hydrogen peroxide, Examples include peracetic acid, excess acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, cumene hydroperoxide and the like, and m-chloroperbenzoic acid is preferred from the viewpoint of safety and operability.

  The oxidizing agent used in the production of the optically active epoxy ester derivative represented by the general formula (3) of the present invention is usually 1 to 1 with respect to the optically active epoxy enone derivative represented by the general formula (1) used in the reaction. A 10-fold molar amount is used.

  The solvent used for the production of the optically active epoxy ester derivative represented by the general formula (3) of the present invention is not particularly limited as long as it is an inert solvent for the reaction. -Dichloroethane, chloroform, benzene, toluene, ethylbenzene, etc. are used and used in an amount of 5 to 100 times by weight with respect to the epoxy enone represented by the general formula (1) used in the reaction. Moreover, you may further add pH adjusters, such as sodium carbonate, sodium hydrogencarbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid, as needed.

  The reaction temperature and time in the production of the optically active epoxy ester derivative represented by the general formula (3) of the present invention vary depending on the type of the epoxy enone derivative represented by the general formula (1) used in the reaction, and are particularly illusion. Although not intended, the reaction is usually completed in a temperature range of 0 to 60 ° C. in 1 to 48 hours. Further, when the raw material remains, after reacting for a predetermined time, an oxidizing agent may be further added, or a reaction may be further performed after removing a decomposition product of the oxidizing agent.

  The post-treatment after the production of the optically active epoxy ester derivative represented by the above general formula (3) of the present invention is not particularly limited, but it is usually washed with an alkaline aqueous solution such as saturated sodium bicarbonate water, and then silica gel. The desired product is obtained by purification by column chromatography or the like.

  In the present invention, (2S, 3R) -2,3-epoxy-3-cyclohexyl represented by the above general formula (4) is obtained by hydrolyzing the optically active epoxy ester derivative represented by the above general formula (3). Propionic acid is obtained. Specifically, a predetermined amount of alkali metal hydroxide or alkaline earth metal hydroxide is reacted in toluene, methanol, water-methanol mixed solvent or water-methanol-toluene mixed solvent.

In the above general formula (4) of the present invention, the substituent R ¹ represents a methyl group, an ethyl group, or a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, specifically, a cyclohexyl group. , Isopropyl group, n-butyl group and the like.

  Specifically, the alkali metal hydroxide used in the production of the (2S, 3R) -2,3-epoxypropionic acid substituted at the 3-position represented by the general formula (4) of the present invention is water. Examples thereof include lithium oxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, strontium hydroxide and the like, and the amount used is an optical represented by the above general formula (3) used in the reaction. The molar amount is usually 1 to 20 times that of the active epoxy ester derivative.

  The amount of the solvent used in the production of the (2S, 3R) -2,3-epoxypropionic acid substituted at the 3-position represented by the general formula (4) of the present invention is the above general formula (3) used in the reaction. Is usually used in an amount of 1 to 40 times by weight based on the optically active epoxy ester derivative represented by In addition, when using the mixed solvent, the ratio of the mixed solvent is not particularly limited as long as the optically active epoxy ester derivative used in the reaction is dissolved.

  The reaction temperature and time for producing the (2S, 3R) -2,3-epoxypropionic acids substituted at the 3-position represented by the general formula (4) of the present invention are not particularly limited. The reaction is completed at -5 ° C to 30 ° C for 1 to 12 hours.

  The post-treatment after the production of the (2S, 3R) -2,3-epoxypropionic acid substituted at the 3-position represented by the general formula (4) of the present invention is not particularly limited. After distilling off the solvent, oil-soluble impurities are extracted and removed with ethers or halogenated hydrocarbon solvents, etc., and then the pH is adjusted to 4 or less by adding an acid such as hydrochloric acid, such as ethyl acetate or diethyl ether. Extraction with ethers, drying, and concentration can yield the desired optically active (2S, 3R) -2,3-epoxy-3-propionic acid.

  Next, the β-halogenoketone derivative of the present invention, a method for producing the same, and a method for producing an enone derivative using the same will be described.

In the above general formula (5) of the present invention, the substituent R ¹ represents a methyl group, an ethyl group, or a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, specifically, a cyclohexyl group. , Isopropyl group, n-butyl group and the like. The substituent R ² represents a phenyl group, a substituted phenyl group, or a tert-butyl group, and specific examples thereof include a phenyl group, a 4-methoxyphenyl group, and a tert-butyl group. Moreover, the substituent X represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and among these, a chlorine atom is preferably used.

  Specific examples of 3-halogenopropan-1-ones substituted at the 1,3-positions represented by the general formula (5) of the present invention include 3-fluoro-1-phenylbutan-1-one, 3-chloro-1-phenylbutan-1-one, 3-bromo-1-phenylbutan-1-one, 3-iodo-1-phenylbutan-1-one, 3-fluoro-1-phenylpentane-1- ON, 3-chloro-1-phenylpentan-1-one, 3-bromo-1-phenylpentan-1-one, 3-iodo-1-phenylpentan-1-one, 3-fluoro-1-phenyl-4 -Methylpentan-1-one, 3-chloro-1-phenyl-4-methylpentan-1-one, 3-bromo-1-phenyl-4-methylpentan-1-one, 3-iodo-1-phenyl- 4-methylpen 1-one, 3-fluoro-1-phenylhexan-1-one, 3-chloro-1-phenylhexan-1-one, 3-bromo-1-phenylhexan-1-one, 3- Iodo-1-phenylhexan-1-one, 3-fluoro-1-phenylheptan-1-one, 3-chloro-1-phenylheptan-1-one, 3-bromo-1-phenylheptan-1-one 3-iodo-1-phenylheptan-1-one, 3-fluoro-1-phenyloctane-1-one, 3-chloro-1-phenyloctane-1-one, 3-bromo-1-phenyloctane-1 -One, 3-iodo-1-phenyloctane-1-one, 3-fluoro-1-phenylnonan-1-one, 3-chloro-1-phenylnonan-1-one, 3-bromo-1-phenylnonane 1-one, 3-iodo-1-phenylnonan-1-one, 3-fluoro-1-phenyldecan-1-one, 3-chloro-1-phenyldecan-1-one, 3-bromo-1-phenyl Decan-1-one, 3-iodo-1-phenyldecan-1-one, 3-fluoro-1-phenylundecan-1-one, 3-chloro-1-phenylundecan-1-one, 3-bromo-1 -Phenylundecan-1-one, 3-iodo-1-phenylundecan-1-one, 3-fluoro-1-phenyldodecan-1-one, 3-chloro-1-phenyldodecan-1-one, 3-bromo -1-phenyldodecan-1-one, 3-iodo-1-phenyldodecan-1-one, 3-fluoro-1-phenyl-4,4-dimethylpentan-1-one, 3-chloro-1- Phenyl-4,4-dimethylpentan-1-one, 3-bromo-1-phenyl-4,4-dimethylpentan-1-one, 3-iodo-1-phenyl-4,4-dimethylpentan-1-one 3-fluoro-1-phenyl-3-cyclohexylpropan-1-one, 3-chloro-1-phenyl-3-cyclohexylpropan-1-one, 3-bromo-1-phenyl-3-cyclohexylpropane-1- ON, 3-iodo-1-phenyl-3-cyclohexylpropan-1-one, 3-fluoro-1-tert-butylbutan-1-one, 3-chloro-1-tert-butylbutan-1-one, 3-bromo -1-tert-butylbutan-1-one, 3-iodo-1-tert-butylbutan-1-one, 3-fluoro-1-tert-butylpe Tan-1-one, 3-chloro-1-tert-butylpentan-1-one, 3-bromo-1-tert-butylpentan-1-one, 3-iodo-1-tert-butylpentan-1-one 3-fluoro-1-tert-butyl-4-methylpentan-1-one, 3-chloro-1-tert-butyl-4-methylpentan-1-one, 3-bromo-1-tert-butyl-4 -Methylpentan-1-one, 3-iodo-1-tert-butyl-4-methylpentan-1-one, 3-fluoro-1-tert-butylhexan-1-one, 3-chloro-1-tert -Butylhexan-1-one, 3-Bromo-1-tert-butylhexan-1-one, 3-iodo-1-tert-butylhexan-1-one, 3-fluoro-1-ter -Butylheptan-1-one, 3-chloro-1-tert-butylheptan-1-one, 3-bromo-1-tert-butylheptan-1-one, 3-iodo-1-tert-butylheptane-1 -One, 3-fluoro-1-tert-butyloctane-1-one, 3-chloro-1-tert-butyloctane-1-one, 3-bromo-1-tert-butyloctane-1-one, 3- Iodo-1-tert-butyloctane-1-one, 3-fluoro-1-tert-butylnonan-1-one, 3-chloro-1-tert-butylnonan-1-one, 3-bromo-1-tert-butylnonane -1-one, 3-iodo-1-tert-butylnonan-1-one, 3-fluoro-1-tert-butyldecan-1-one, 3-chloro-1-t tert-Butyldecan-1-one, 3-bromo-1-tert-butyldecan-1-one, 3-iodo-1-tert-butyldecan-1-one, 3-fluoro-1-tert-butylundecan-1-one 3-chloro-1-tert-butylundecan-1-one, 3-bromo-1-tert-butylundecan-1-one, 3-iodo-1-tert-butylundecan-1-one, 3-fluoro- 1-tert-butyldodecan-1-one, 3-chloro-1-tert-butyldodecan-1-one, 3-bromo-1-tert-butyldodecan-1-one, 3-iodo-1-tert-butyl Dodecan-1-one, 3-fluoro-1-tert-butyl-4,4-dimethylpentan-1-one, 3-chloro-1-tert-butyl- , 4-Dimethylpentan-1-one, 3-bromo-1-tert-butyl-4,4-dimethylpentan-1-one, 3-iodo-1-tert-butyl-4,4-dimethylpentane-1- ON, 3-fluoro-1-tert-butyl-3-cyclohexylpropan-1-one, 3-chloro-1-tert-butyl-3-cyclohexylpropan-1-one, 3-bromo-1-tert-butyl- 3-cyclohexylpropan-1-one, 3-iodo-1-tert-butyl-3-cyclohexylpropan-1-one, 3-fluoro-1- (4-methoxyphenyl) butan-1-one, 3-chloro- 1- (4-methoxyphenyl) butan-1-one, 3-bromo-1- (4-methoxyphenyl) butan-1-one, 3-iodo-1- (4-me Xylphenyl) butan-1-one, 3-fluoro-1- (4-methoxyphenyl) pentan-1-one, 3-chloro-1- (4-methoxyphenyl) pentan-1-one, 3-bromo-1- (4-methoxyphenyl) pentan-1-one, 3-iodo-1- (4-methoxyphenyl) pentan-1-one, 3-fluoro-1- (4-methoxyphenyl) -4-methylpentane-1- ON, 3-chloro-1- (4-methoxyphenyl) -4-methylpentan-1-one, 3-bromo-1- (4-methoxyphenyl) -4-methylpentan-1-one, 3-iodo- 1- (4-methoxyphenyl) -4-methylpentan-1-one, 3-fluoro-1- (4-methoxyphenyl) hexan-1-one, 3-chloro-1- (4-methoxyphenyl) Hexan-1-one, 3-bromo-1- (4-methoxyphenyl) hexan-1-one, 3-iodo-1- (4-methoxyphenyl) hexan-1-one, 3-fluoro-1 -(4-methoxyphenyl) heptan-1-one, 3-chloro-1- (4-methoxyphenyl) heptan-1-one, 3-bromo-1- (4-methoxyphenyl) heptan-1-one, 3 -Iodo-1- (4-methoxyphenyl) heptan-1-one, 3-fluoro-1- (4-methoxyphenyl) octane-1-one, 3-chloro-1- (4-methoxyphenyl) octane-1 -One, 3-bromo-1- (4-methoxyphenyl) octane-1-one, 3-iodo-1- (4-methoxyphenyl) octane-1-one, 3-fluoro-1- (4-methoxyphenyl) ) Nan-1-one, 3-chloro-1- (4-methoxyphenyl) nonan-1-one, 3-bromo-1- (4-methoxyphenyl) nonan-1-one, 3-iodo-1- (4 -Methoxyphenyl) nonan-1-one, 3-fluoro-1- (4-methoxyphenyl) decan-1-one, 3-chloro-1- (4-methoxyphenyl) decan-1-one, 3-bromo- 1- (4-methoxyphenyl) decan-1-one, 3-iodo-1- (4-methoxyphenyl) decan-1-one, 3-fluoro-1- (4-methoxyphenyl) undecan-1-one, 3-chloro-1- (4-methoxyphenyl) undecan-1-one, 3-bromo-1- (4-methoxyphenyl) undecan-1-one, 3-iodo-1- (4-methoxyphenyl) undecane- -One, 3-fluoro-1- (4-methoxyphenyl) dodecan-1-one, 3-chloro-1- (4-methoxyphenyl) dodecan-1-one, 3-bromo-1- (4-methoxyphenyl) ) Dodecan-1-one, 3-iodo-1- (4-methoxyphenyl) dodecan-1-one, 3-fluoro-1- (4-methoxyphenyl) -4,4-dimethylpentan-1-one, 3 -Chloro-1- (4-methoxyphenyl) -4,4-dimethylpentan-1-one, 3-bromo-1- (4-methoxyphenyl) -4,4-dimethylpentan-1-one, 3-iodo -1- (4-methoxyphenyl) -4,4-dimethylpentan-1-one, 3-fluoro-1- (4-methoxyphenyl) -3-cyclohexylpropan-1-one, 3-chloro-1- ( 4 -Methoxyphenyl) -3-cyclohexylpropan-1-one, 3-bromo-1- (4-methoxyphenyl) -3-cyclohexylpropan-1-one, 3-iodo-1- (4-methoxyphenyl) -3 -Cyclohexylpropan-1-one and the like.

  The 1,3-position substituted 3-halogenopropan-1-ones represented by the general formula (5) of the present invention are substituted, for example, at the 1,3-position represented by the general formula (6). 3-Hydroxypropan-1-ones can be obtained by reacting with hydrogen halide or hydrohalic acid in a solvent inert to the reaction.

In the above general formula (6) of the present invention, the substituent R ¹ represents a methyl group, an ethyl group, or a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, specifically, a cyclohexyl group. , Isopropyl group, n-butyl group and the like. The substituent R ² represents a phenyl group, a substituted phenyl group, or a tert-butyl group, and specific examples thereof include a phenyl group, a 4-methoxyphenyl group, and a tert-butyl group.

  In the method of the present invention, 3-hydroxypropan-1-ones substituted at the 1,3-position represented by the general formula (6) can be prepared by a conventionally known method. For example, a method of reacting aldehydes with lithium enolate of acetophenone prepared beforehand from acetophenone and lithium diisopropylamide in tetrahydrofuran (hereinafter abbreviated as THF) at −60 ° C. or lower, silyl enol ether of aldehydes and acetophenone Can be easily prepared by a reaction of -20 ° C. to room temperature in a halogenated hydrocarbon solvent such as dichloromethane in the presence of titanium (IV) chloride. The obtained 1,3-substituted 3-hydroxypropan-1-ones may be purified and used in the method of the present invention, or used in the method of the present invention without purification. Is also possible.

  In the method of the present invention, the hydrogen halide or hydrohalic acid used in the production of 3-halogenopropan-1-ones substituted at the 1,3-position represented by the general formula (5) is as follows: For example, anhydrous hydrogen halide, 5-36 wt% aqueous hydrohalic acid solution, a mixture of hydrogen halide and hydrohalic acid, a solution in which hydrogen halide is dissolved in an organic solvent, and the like can be mentioned. For example, in the case of producing 3-halogenopropan-1-ones substituted at the 1,3-position, anhydrous hydrogen chloride, a 5-36 wt% hydrochloric acid aqueous solution, a mixture of hydrogen chloride and hydrochloric acid, hydrogen chloride A solution or the like dissolved in an organic solvent may be used. The hydrogen halide or hydrohalic acid is usually used in an amount of 1 to 100 times the molar amount of 3-hydroxypropan-1-one substituted at the 1,3-position used for the reaction.

  In the method of the present invention, as a hydrogen halide or hydrohalic acid applicable in the production of 3-halogenopropan-1-ones substituted at the 1,3-positions represented by the general formula (5), Specific examples include hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like.

  Any solvent that is inert to the reaction can be used for the production of 3-halogenopropan-1-ones substituted at the 1,3-position represented by the general formula (5) of the present invention. Specifically, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, and xylene, aliphatic hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane, diethyl ether, diisopropyl ether, Examples thereof include ethers such as THF, and halogenated aromatic hydrocarbons such as chlorobenzene and o-chlorobenzene. Of these, dichloromethane, toluene, and THF are preferable, and the amount used is usually 3 to 100 times by weight with respect to 3-hydroxypropan-1-one substituted at the 1,3-position used for the reaction. Use amount.

  In the method of the present invention, the reaction temperature and time for producing 3-halogenopropan-1-ones substituted at the 1,3-positions represented by the general formula (5) are usually from −40 ° C. to 30 ° C. The reaction is carried out in the temperature range of 1 to 12 hours.

  In the method of the present invention, as a post-treatment after the production of 3-halogenopropan-1-ones substituted at the 1,3-positions, a large amount of water is added, followed by liquid separation, and then with an aqueous sodium bicarbonate solution. By washing and concentration, crude 3-halogenopropan-1-ones substituted at the 1,3-position can be obtained. The obtained crude 3-halogenopropan-1-ones substituted at the 1,3-position can be used in the next reaction without purification by silica gel column chromatography, but they can be purified if necessary. No problem.

  In the present invention, the method for producing the enone derivative represented by the general formula (2) is a 3-halogenopropane-1-substituted at the 1,3-position represented by the general formula (5) after crude or purified. A method can be used in which ONs are treated with a base in a solvent inert to the reaction.

  In the method of the present invention, the base applicable in the production of the enone derivative represented by the general formula (2) is not particularly limited, but specifically, triethylamine, pyridine, 4-dimethylamino Amines such as pyridine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like Examples include alkali metal hydroxides, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate, and 3-halogenopropane substituted at the 1,3-position represented by the general formula (5) used in the reaction. The molar amount is usually 1 to 10 times that of 1-ones. Moreover, when using alkali metal hydroxide or alkali metal carbonate, solid may be used as it is or may be used as an aqueous solution. Further, when an alkali metal hydroxide or an alkali metal carbonate is used, a phase transfer catalyst such as a crown ether or an ammonium salt may be used as necessary.

  In the method of the present invention, the solvent applicable to the production of the enone derivative represented by the general formula (2) is not particularly limited as long as it is inert to the reaction. Specifically, Aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, aliphatic hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, ethers such as diethyl ether, diisopropyl ether, THF, chlorobenzene, o-chlorobenzene, etc. And halogenated aromatic hydrocarbons. Of these, dichloromethane, toluene, and THF are preferable, and the amount used is relative to 3-halogenopropan-1-ones substituted at the 1,3-positions represented by the above general formula (5) used in the reaction. Usually 3 to 100 times by weight is used.

  In the method of the present invention, the reaction temperature and time for producing the enone derivative represented by the above general formula (2) vary depending on the type of solvent used in the reaction and the type of base, and are not particularly limited. Usually, the reaction is completed in a reaction for 1 to 24 hours in a temperature range of 10 to 70 ° C.

  In the method of the present invention, the post-treatment after the production of the enone derivative represented by the general formula (2) is carried out by removing excess bases with an acid, washing with water, drying and concentrating, and then using a small amount of silica gel for coloring components. By removing, the enone derivative represented by the general formula (2), which is the target product, can be obtained with high purity.

  According to the present invention, optically active (2S, 3R) -2,3-epoxy-3-propionic acid and a novel intermediate thereof, and an industrially safer production method thereof are provided.

  In the present invention, (R) -1,1′-bi-2-naphthol used as a catalyst component in the asymmetric oxidation reaction is replaced with (S) -1,1′-bi-2-naphthol. This makes it possible to prepare (2R, 3S) isomers which are optically contrasted with the compounds of the present invention.

  Furthermore, according to the method of the present invention, a method for obtaining a highly pure enone derivative substituted at the 1,3-position via a novel intermediate is provided, and the present invention is very significant industrially.

  EXAMPLES Hereinafter, the optically active epoxy compounds of the present invention and the production method thereof will be specifically described by way of examples. However, the present invention is not limited only to these examples. In addition, about the analysis of the compound, it implemented using the following apparatus.

⁽¹ H-NMR and ¹³ C-NMR measurement)
Uses Varian Gemini-200.

(Infrared absorption measurement)
Use Perkin Elmer 2000FT-IR.

(Mass spectrometry)
Use Hitachi M-80B.

(Specific rotation)
SEPA-300 manufactured by HORIBA, Ltd. is used.

Reference example 1
A 2000 ml three-necked flask equipped with a dropping funnel and a stirrer was purged with nitrogen, and diisopropylamine (98.3 g, 971 mmol) and THF (540 ml) were charged into the flask and cooled to -70 ° C. Next, n-butyllithium (15% hexane solution, 394 g, 922 mmol) was added dropwise thereto over 10 minutes, and the mixture was further stirred at the same temperature for 1 hour. Subsequently, acetophenone (116.7 g, 971 mmol) was added dropwise to the same reaction solution at the same temperature. After stirring at the same temperature for 3 hours, cyclohexanecarboxaldehyde (99.0 g, 883 mmol) was added, and the reaction was further performed for 2 hours. It was.

  After completion of the reaction, the reaction solution was added to a saturated aqueous ammonium chloride solution (287 g) cooled to 0 ° C., extracted with ethyl acetate (890 ml × 2), and concentrated to obtain a crude aldol derivative.

  The obtained aldol derivative and dichloromethane (2000 ml) were charged into a 200 ml three-necked flask equipped with a dropping funnel and a stirring bar, cooled to 0 ° C., and concentrated sulfuric acid (100 g, 1.01 mol) was added thereto. The reaction was performed at room temperature for 1 hour.

  After completion of the reaction, washing with water (500 ml × 2 times), washing with saturated aqueous sodium bicarbonate (200 ml × 4 times), liquid separation, drying, concentration, followed by silica gel column chromatography (hexane / ethyl acetate = 100/0 to 90/10, The product 1-phenyl-3-cyclohexyl-2-propen-1-one (156.5 g, 730 mmol) was obtained (yield 83%).

<Analysis results>
Melting point: 50-51 ° C
MS (m / z) = 214 [M +]
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.08-1.48 (m, 5H), 1.60-1.98 (m, 5H), 2.12-2.38 (m, 1H), 6 .82 (d, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.8, 3.3 Hz, 1H), 7.38-7.61 (m, 3H), 7.86- 7.98 (m, 2H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 25.8, 26.0, 31.9, 41.0, 123.3, 128.3, 128.4, 132.4, 138.1, 154.7, 191.1
IR (KBr): 2921, 2943, 1663, 1614, 1443, 1365, 1273, 1234, 1019, 985, 692 cm ⁻¹ .

Example 1
A 2000 ml three-necked flask equipped with a dropping funnel and a stirrer was purged with nitrogen, and then dried molecular sieves 4A (200 g), (R) -1,1′-bi-2-naphthol (5.98 g, 20. 9 mmol), triphenylphosphine oxide (15.84 g, 56.9 mmol) and THF (950 ml) were charged and dissolved. Subsequently, a solution of lanthanum triisopropoxide (6.0 g, 19.0 mmol) in THF (40 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour, and then cumene hydroperoxide (80% concentration, 6.1 g, 32). 0.1 mmol) was added, followed by stirring at room temperature for 2 hours.

  After confirming that the reaction solution was green, it was cooled to 0 ° C. and 1-phenyl-3-cyclohexyl-2-propen-1-one (203.3 g, 949 mmol) in THF (457 ml) prepared in a separate container. The solution was placed in a dropping funnel and dropped over 1 hour, and then further reacted at the same temperature for 4 hours.

  After completion of the reaction, saturated aqueous ammonium chloride solution (400 ml) was added, 5% aqueous sodium sulfite solution (225 ml) was added, filtration, liquid separation, and the aqueous layer were extracted with dichloromethane (200 ml × 2 times), concentrated, and silica gel column chromatography. (2S, 3R) -1-phenyl-2,3-epoxy-3-cyclohexylpropan-1-one of the target product by purification with (hexane / ethyl acetate = 100/0 to 95/5, vol / vol) (174.8 g, 759 mmol) was obtained (yield 80%).

<Analysis results>
MS (m / z) = 230 [M +]
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06-1.58 (m, 6H), 1.61-2.00 (m, 5H), 2.96 (dd, J = 3.3, 1.. 0 Hz, 1H), 4.09 (d, J = 1.0 Hz, 1H), 7.44-7.67 (m, 3H), 7.97-8.07 (m, 2H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 25.4, 25.6, 26.1, 29.0, 29.5, 40.1, 56.4, 64.2, 128.1, 128.7, 133.6, 135.5, 194.6
IR (KBr): 2927, 2853, 1690, 1598, 1580, 1450, 1230, 902, 703, 666 cm ⁻¹
Specific rotation [α] _D ²⁰ = −4.6 ° (C = 1.11, CHCl ₃ )
HPLC: Daicel-made Chiralcel OB-H (4.6 mm ID × 250 mm L), hexane / isopropanol = 9/1 (vol ratio), 1.0 ml / min, UV = 254 nm, 6.9 min (2S, 3R), 7.7 min (2R, 3S), 98.0% ee.

Example 2
(2S, 3R) -1-phenyl-2,3-epoxy-3-cyclohexylpropan-1-one (40.5 g, 176 mmol) obtained in Example 1 in a 2000 ml eggplant-shaped flask equipped with a Liebig condenser, m-Chloroperbenzoic acid (70% purity, 130 g, 527 mmol) and toluene (850 ml) were charged and reacted at 55 ° C. for 12 hours.

  After completion of the reaction, the reaction mixture was cooled to room temperature, the precipitate was filtered, and m-chloroperbenzoic acid (70% purity, 87 g, 353 mmol) was further added to the reaction solution, followed by reaction at 55 ° C. for 12 hours.

  After completion of the reaction, the mixture was cooled to room temperature, the excess m-chloroperbenzoic acid was decomposed with a 5% aqueous sodium sulfite solution (500 g), the precipitate was filtered, washed with saturated aqueous sodium bicarbonate (200 ml × 6 times), and silica gel column chromatography. (Hexane / ethyl acetate = 100/0 to 95/5, vol / vol) to purify the target phenyl (2S, 3R) -2,3-epoxy-3-cyclohexylpropionate (34.7 g, 141 mmol) (yield 80%).

<Analysis results>
Melting point: 59-60 ° C
MS (m / z) = 246 [M +]
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.05-1.52 (m, 6H), 1.61-1.97 (m, 5H), 3.15 (dd, J = 3.2, 1.. 0 Hz, 1 H), 3.50 (d, J = 1.0 Hz, 1 H), 7.08-7.45 (m, 5 H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 25.4, 25.6, 26.1, 28.8, 29.3, 39.5, 51.9, 63.0, 121.1, 126.1, 129.4, 150.1, 168.0
IR (KBr): 2931, 2848, 1769, 1483, 1449, 1242, 1184, 1172, 1156, 972, 881, 777, 722, 690 cm ⁻¹
Specific rotation [α] _D ²⁰ = + 13.5 ° (C = 1.08, CHCl ₃ )
HPLC: Daicel Chiralcel OD-H (4.6 mm ID × 250 mm L), hexane / isopropanol = 9/1 (vol ratio), 1.0 ml / min, UV = 254 nm, 5.6 min (2R, 3S), 7.3 min (2S, 3R),> 99.0% ee.

Example 3
To a 2000 ml three-necked flask equipped with a dropping funnel and a stirrer, phenyl (2S, 3R) -2,3-epoxy-3-cyclohexylpropionate (54.0 g, 219 mmol) and methanol obtained in Example 2 were added. (437 ml) was charged and cooled to 0 ° C. Next, 4% aqueous sodium hydroxide solution (250 g, 250 mmol) was added to this over 1 hour, and the reaction was further carried out at the same temperature for 2 hours.

  After completion of the reaction, sodium dihydrogen phosphate dihydrate (3.42 g) was added, the solvent was distilled off, water (250 ml) was added, extracted with dichloromethane (50 ml × 4 times), and then dibasic phosphate. Sodium hydrogen dihydrate (116 g) was added, followed by extraction with ethyl acetate (50 ml × 4 times), followed by addition of 10% aqueous hydrochloric acid (200 ml) to adjust the pH to 3, followed by ethyl acetate (50 ml × 3 (Times) Extraction, drying and concentration gave crude (2S, 3R) -2,3-epoxy-3-cyclohexylpropionic acid (20.5 g). The obtained crude product was recrystallized with n-heptane / toluene = 2/1 (vol / vol) to give (2S, 3R) -2,3-epoxy-3-cyclohexylpropionic acid (18. 0 g, 106 mmol) was obtained (yield 48%).

<Analysis results>
Melting point: 64-65 ° C
MS (m / z) = 170 [M +]
¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.98-1.48 (m, 6H), 1.56-1.94 (m, 5H), 3.03 (dd, J = 3.1, 1.. 0 Hz, 1H), 3.32 (d, J = 1.0 Hz, 1H), 10.85-11.23 (br, 1H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 25.4, 25.5, 26.0, 28.7, 29.2, 39.4, 51.4, 63.1, 175.2
IR (KBr): 3009, 2929, 2851, 1715, 1638, 1448, 1252, 902, 882, 678 cm ⁻¹
Specific rotation [α] _D ²⁰ = + 20.8 ° (C = 1.04, CHCl ₃ )
HPLC: Daicel Chiralcel OD-H (4.6 mm ID × 250 mm L), hexane / isopropanol / trifluoroacetic acid = 95/5 / 0.5 (vol ratio), 1.0 ml / min, UV = 210 nm, 6.5 min ( 2R, 3S), 7.2 min (2S, 3R),> 99.0% ee.

Example 4
The same operation as in Example 1 was carried out except that 1-phenyl-3-cyclohexyl-2-propen-1-one was replaced with 1-phenyl-4-methyl-2-penten-1-one, ( 2S, 3R) -2,3-epoxy-1-phenyl-4-methylpentan-1-one was obtained with a yield of 92% and an optical purity of 96%.

<Analysis results>
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.07 (d, J = 7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 1.62-1.84 (m, 1H), 2.97 (dd, J = 6.6, 1.8 Hz, 1H), 4.07 (d, J = 1.8 Hz, 1H), 7.48-7.66 (m, 3H), 8.02-8.08 (m, 2H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 18.4, 19.0, 30.7, 56.6, 65.1, 128.2, 128.8, 133.7, 194.6
MASS (m / z) = 190 [M +]
IR (KBr) 3062, 2965, 2872, 1692, 1598, 1470, 1450, 1367, 1285, 1230, 1180, 1075, 943, 891, 831, 697, 665 cm ⁻¹
Specific rotation [α] _D ²⁰ = −24.0 ° (C = 1.00, CHCl ₃ )
Analysis Calculated _{C 12 H 14 O 2: C} , 75.76; H, 7.42
Measurement: C, 75.68; H, 7.39.

Example 5
In the same manner as in Example 2 except that (2S, 3R) -2,3-epoxy-1-phenyl-4-methylpentan-1-one obtained in Example 4 was used, phenyl (2S, 3R)- 2,3-epoxy-4-methylpentanoate was obtained with a yield of 68%.

<Analysis results>
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.62-1.84 (m, 1H), 3.14 (dd, J = 6.2, 1.8 Hz, 1H), 4.48 (d, J = 1.8 Hz, 1H), 7.10-7.34 (m, 5H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 18.3, 18.8, 30.1, 52.0, 63.9, 121.2, 125.3, 126.2, 128.2, 129.0, 129.5, 167.9
MASS (m / z) = 206 [M +]
IR (KBr) 2967, 2874, 1774, 1754, 1593, 1493, 1451, 1353, 1266, 1194, 1169, 969, 895, 713, 688 cm ⁻¹
Specific rotation [α] _D ²⁰ = −6.2 ° (C = 1.00, CHCl ₃ )
Analysis Calculated _{C 12 H 14 O 3: C} , 69.88; H, 6.84
Measurement: C, 70.01; H, 6.66.

Example 6
The phenyl (2S, 3R) -2,3-epoxy-4-methylpentanoate obtained in Example 5 was reacted in the same manner as in Example 3 (2S, 3R) -2,3-epoxy-4. -Obtained methylpentanoic acid in 85% yield.

<Analysis results>
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.00 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 1.59-1.78 (m, 1H), 3.03 (dd, J = 5.6, 1.8 Hz, 1H), 3.31 (d, J = 1.8 Hz, 1H), 11.1 (bs, 1H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 18.1, 18.7, 30.1, 51.6, 64.0, 175.2
MASS (m / z) = 152 [M +]
IR (KBr) 3050, 2968, 1725, 1452, 1369, 1284, 1220, 895, 821, 666 cm ⁻¹
Specific rotation [α] _D ²⁰ = + 2.7 ° (C = 1.00, CHCl ₃ )
Analysis Calculated _{C 6 H 10 O 3: C} , 55.37; H, 7.74
Measurement: C, 55.22; H, 7.58.

Example 7
The same operation as in Example 1 was carried out except that 1-phenyl-3-cyclohexyl-2-propen-1-one was replaced with 1-phenyl-2-hepten-1-one, and (2S, 3R ) -2,3-epoxy-1-phenylheptan-1-one was obtained in 89% yield and 92% optical purity.

<Analysis results>
¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (r, J = 7.0 Hz, 3H), 1.40-1.84 (m, 6H), 3.14 (dt, J = 5.8, 1.8Hz, 1H), 4.02 (d, J = 1.8Hz, 1H), 7.48-7.66 (m, 3H), 8.02-8.08 (m, 2H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 14.0, 22.5, 28.0, 31.7, 57.5, 60.1, 128.2, 128.5, 128.8, 133.7, 194.6
MASS (m / z) = 204 [M +]
IR (KBr) 2959, 2993, 2872, 1690, 1598, 1450, 1426, 1231, 1002, 937, 906, 765, 735, 699 cm ⁻¹
Specific rotation [α] _D ²⁰ = + 7.3 ° (C = 1.00, CHCl ₃ )
Analysis Calculated _{C 13 H 16 O 2: C} , 76.44; H, 7.90
Measurement: C, 76.68; H, 7.9.

Example 8
In the same manner as in Example 2, except that (2S, 3R) -2,3-epoxy-1-phenylheptan-1-one obtained in Example 7 was used, phenyl (2S, 3R) -2,3- Epoxyheptanoate was obtained with a yield of 65%.

<Analysis results>
¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (t, J = 7.2 Hz, 3H), 1.33-1.82 (m, 1H), 3.33 (dt, J = 6.2) 1.8Hz, 1H), 3.44 (d, J = 1.8Hz, 1H), 7.06-7.48 (m, 5H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 14.0, 22.5, 27.9, 31.2, 53.0, 59.0, 121.2, 125.3, 126.2, 128.2 128.4, 129.0, 129.5, 129.8, 167.8
MASS (m / z) = 220 [M +]
IR (KBr) 2958, 2933, 2873, 1773, 1753, 1593, 1493, 1455, 1344, 1266, 1194, 1169, 1108, 1070, 1026, 956, 688 cm ⁻¹
Specific rotation [α] _D ²⁰ = + 15.4 ° (C = 1.00, CHCl ₃ )
Analysis Calculated _{C 13 H 16 O 3: C} , 70.89; H, 7.32
Measurement: C, 70.76; H, 7.56.

Example 9
The phenyl (2S, 3R) -2,3-epoxyheptanonoate obtained in Example 8 was reacted in the same manner as in Example 3 to obtain (2S, 3R) -2,3-epoxyheptanoic acid in a yield of 72. %.

<Analysis results>
¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.92 (t, J = 7.0 Hz, 3H), 1.26-1.72 (m, 6H), 3.19 (m, 1H), 3.25 (Bs, 1H), 9.66 (bs, 1H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 13.9, 22.4, 27.8, 31.2, 52.8, 59.0, 174.6
MASS (m / z) = 144 [M +]
IR (KBr) 3070, 2959, 2935, 2874, 1736, 1460, 1378, 1243, 1046, 901, 667 cm ⁻¹
Specific rotation [α] _D ²⁰ = + 20.4 ° (C = 1.00, CHCl ₃ )
Analysis Calculated _{C 7 H 12 O 3: C} , 58.32; H, 8.39
Measurement: C, 58.12; H, 8.21.

  Hereinafter, although the example demonstrates the β-halogenoketone derivative of the present invention, the production method thereof, and the production method of the enone derivative using the same, the present invention is not limited to these examples. In addition, about the analysis of the compound, it implemented using the apparatus shown below.

⁽¹ H-NMR and ¹³ C-NMR measurement)
Uses Varian Gemini-200.

(Purity measurement by HPLC)
Tosoh CCPM, Tosoh TSKgel80TQA (4.6 mm ID × 150 mmL), Tosoh UV-8020 detector (UV = 254 nm), eluent: acetonitrile / water = 9/1 (vol / vol), measured at 1 ml / min.

Preparation Example 1
A 2000 ml three-necked flask equipped with a dropping funnel and a stirrer was purged with nitrogen, and diisopropylamine (98.3 g, 971 mmol) and THF (540 ml) were charged into the flask and cooled to -70 ° C. Next, n-butyllithium (15% hexane solution, 394 g, 922 mmol) was added dropwise thereto over 10 minutes, and the mixture was further stirred at the same temperature for 1 hour. Subsequently, acetophenone (116.7 g, 971 mmol) was added dropwise to the same reaction solution at the same temperature. After stirring at the same temperature for 3 hours, cyclohexanecarboxaldehyde (99.0 g, 883 mmol) was added, and the reaction was further performed for 2 hours. It was.

  After completion of the reaction, the reaction solution was added to a saturated aqueous ammonium chloride solution (287 g) cooled to 0 ° C., extracted with ethyl acetate (890 ml × 2), concentrated, and then crude 1-phenyl-3-hydroxy-3-cyclohexyl. Propan-1-one was obtained (194.8 g, 855 mmol).

Example 10
1-Phenyl-3-hydroxy-3-cyclohexylpropan-1-one (93.5 g, 402 mmol) obtained in Preparation Example 1 and dichloromethane (850 g) in a 2000 ml three-necked flask equipped with a dropping funnel and a stirring bar ) And cooled to −10 ° C., 36% hydrochloric acid (180 g, 1.78 mol) was added dropwise thereto over 30 minutes, and the reaction was further carried out at the same temperature for 2 hours.

  After completion of the reaction, water (700 ml) was added, stirred, separated, washed with saturated aqueous sodium hydrogen carbonate (250 ml × 3 times), and concentrated to give 1-phenyl-3-chloro-3-cyclohexylpropane-1. -On (95.9 g, 382 mmol) was obtained in 95% yield.

<Analysis results>
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.08-1.51 (5H, m), 1.58-1.95 (6H, m), 3.23 (1H, dd, J = 4.4 Hz, 16.8 Hz), 3.56 (1 H, dd, J = 8.8 Hz, 16.8 Hz), 4.52 (1 H, ddd, J = 4.4 Hz, 4.4 Hz, 8.8 Hz), 7.42 −7.65 (3H, m), 7.96 (2H, d, J = 7.0 Hz).

Example 11
The procedure was carried out except that 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one obtained by the same production method as in Preparation Example 1 was used as a raw material, and 36% hydrochloric acid (180 g) was replaced with 15% hydrochloric acid (250 ml). The same reaction and post-treatment operation as in Example 10 were carried out to obtain the desired product 1-phenyl-3-chloro-3-cyclohexylpropan-1-one (92.0 g, 366 mmol) in a yield of 91%.

Example 12
Using 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one obtained by the same production method as in Preparation Example 1 as a raw material, hydrochloric acid (180 g) was replaced with hydrogen chloride gas (20 ° C., 12300 ml, 511 mmol), Except that the reaction was carried out at −20 ° C., the same reaction and post-treatment operations as in Example 10 were carried out to obtain the target 1-phenyl-3-chloro-3-cyclohexylpropan-1-one (97.1 g, 407 mmol). The yield was 96%.

Example 13
A 1000 ml three-necked flask equipped with a dropping funnel and a stirrer was charged with 1-phenyl-3-chloro-3-cyclohexylpropan-1-one (50 g, 199 mmol) obtained in Example 10 and dichloromethane (300 g). Cooled to 0 ° C. Next, triethylamine (30 g, 296 mmol) was added dropwise thereto over 1 hour, followed by heating to 45 ° C. and reaction at the same temperature for 4 hours.

  After completion of the reaction, cooling to room temperature, washing with water (150 ml), washing with 1N hydrochloric acid (150 ml × 2 times), washing with saturated aqueous sodium bicarbonate (240 ml × 2 times), drying and concentrating to give crude 1-phenyl-3- Cyclohexyl-2-propen-1-one was obtained. Further, purification was carried out with a short column packed with silica gel (50 g) to obtain the target 1-phenyl-3-cyclohexyl-2-propen-1-one (40.6 g, 189 mmol) (yield 95%). The purity measurement result by HPLC was 97%.

Example 14
Using 1-phenyl-3-chloro-3-cyclohexylpropan-1-one obtained by the same production method as in Example 10, triethylamine (30 g, 296 mmol) was replaced with 4-dimethylaminopyridine (26.9 g, 220 mmol), The same reaction operation and post-treatment were performed as in Example 13, except that the reaction temperature was 20 ° C.

  The obtained 1-phenyl-3-cyclohexyl-2-propen-1-one (41.5 g, 193 mmol) was in a yield of 97% and HPLC purity was 98%.

Example 15
Using 1-phenyl-3-chloro-3-cyclohexylpropan-1-one obtained by the same production method as in Example 11, triethylamine (30 g, 296 mmol) was added to sodium carbonate (53.0 g, 500 mmol), 18-crown. The same reaction operation and post-treatment were performed as in Example 13, except that -6-ether (2 g) and the reaction temperature were 50 ° C.

  The obtained 1-phenyl-3-cyclohexyl-2-propen-1-one (39.7 g, 185 mmol) had a yield of 93% and an HPLC purity of 94%.

Example 16
1-phenyl-4-methyl-3-hydroxypentan-1-one prepared with 2-methylpropanal and acetophenone according to Preparation Example 1 was reacted in the same manner as in Example 10 to give 1-phenyl-4-methyl- 3-Chloropentan-1-one was obtained in 92% yield.

<Analysis results>
¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.05 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 2.09 (m, 1H), 3 .21 (dd, J = 16.0, 4.2 Hz, 1H), 3.59 (dd, J = 16.0, 8.0 Hz, 1H), 4.58 (m, 1H), 7.46− 7.66 (m, 3H), 7.92-8.04 (m, 2H)
MASS (m / z) = 210 [M +]
Analysis Calculated _{C 12 H 15 ClO: C,} 68.40; H, 7.18
Measurement: C, 68.43; H, 7.17.

Example 17
The 1-phenyl-4-methyl-3-hydroxypentan-1-one obtained in Example 16 was reacted in the same manner as in Example 13 to give 1-phenyl-4-methyl-2-penten-1-one. The yield was 89% and the purity was 96%.

<Analysis results>
¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.13 (d, J = 6.8 Hz, 6H), 2.48-2.66 (m, 1H), 6.82 (d, J = 7.9 Hz, 1H), 7.04 (dd, J = 15.8, 6.6 Hz, 1H), 7.42-7.59 (m, 3H), 7.90-7.99 (m, 2H)
¹³ C-NMR (CDCl ₃ ) δ 21.5, 31.6, 123.1, 128.2, 128.4, 128.5, 132.5, 138.1, 155.9, 191.2
MASS (m / z) = 174 [M +]
IR (KBr) 3060, 2963, 2870, 1670, 1621, 1465, 1447, 1354, 1304, 1270, 1217, 1018, 983, 960, 772, 697, 660 cm ⁻¹
Elemental analysis; Calculated _{C 12 H 14 O: C,} 82.72; H, 8.10
Measurement: C, 82.78; H, 8.20.

Example 18
1-phenyl-3-hydroxyheptan-1-one prepared with n-pentanal and acetophenone according to Preparation Example 1 was reacted in the same manner as in Example 10 to give 1-phenyl-3-chloroheptan-1-one. The yield was 92%.

<Analysis results>
¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.93 (t, J = 6.8 Hz, 3H), 1.30-1.95 (m, 6H), 3.27 (dd, J = 18.0, 3.2 Hz, 1 H), 3.59 (dd, J = 18.0, 3.2 Hz, 1 H), 4.58 (m, 1 H), 7.44-7.64 (m, 3 H), 7. 95-8.06 (m, 2H)
MASS (m / z) = 224 [M +]
Analysis Calculated _{C 13 H 17 ClO: C,} 69.48; H, 7.62
Measurement: C, 69.45; H, 7.60.

Example 19
The 1-phenyl-4-methyl-3-chloroheptan-1-one obtained in Example 18 was reacted in the same manner as in Example 13 to obtain 1-phenyl-2-hepten-1-one in a yield of 85. %, Purity 98%.

<Analysis results>
¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.93 (t, J = 6.8 Hz, 3H), 1.32-1.57 (m, 4H), 2.26 (m, 2H), 6.70 (D, J = 14.0 Hz, 1H), 7.04 (dt, J = 14.0, 6.6 Hz, 1H), 7.42-7.59 (m, 3H), 7.88-7. 99 (m, 2H)
¹³ C-NMR (CDCl ₃ ) δ 13.9, 22.4, 30.4, 32.6, 125.8, 128.2, 128.4, 128.5, 132.5, 138.0, 150. 0, 190.8
MASS (m / z) = 188 [M +]
IR (KBr) 3060, 2958, 2930, 2872, 1671, 1621, 1448, 1358, 1282, 1265, 1223, 1004, 983, 924, 760, 693 cm ⁻¹
Elemental analysis; Calculated _{C 13 H 16 O: C,} 82.94; H, 8.57
Measurement: C, 82.78; H, 8.40.

Comparative Example 1
Using 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one (50 g, 215 mmol) obtained in Example 10, 36% hydrochloric acid was replaced with concentrated sulfuric acid (100 g, 1.01 mol) at 0 ° C. The reaction was performed for 2 hours.

  After completion of the reaction, washing with water (500 ml × 2 times), washing with saturated aqueous sodium hydrogen carbonate (200 ml × 4 times), liquid separation, drying, and concentration gave crude 1-phenyl-3-cyclohexyl-2-propane-1- Got on.

The obtained crude 1-phenyl-3-cyclohexyl-2-propan-1-one was purified by silica gel column chromatography using silica gel (50 g) to obtain the desired product 1-phenyl-3-cyclohexyl-2-propane-1. -On (36.3 g, 169 mmol) was obtained, which had a low purity of 83% in HPLC measurement.

Claims (4)

The following general formula (2)

(Wherein R ¹ represents a methyl group, an ethyl group, or a branched, straight-chain or cyclic alkyl group having 3 to 10 carbon atoms, and R ² represents a phenyl group, a substituted phenyl group or a tert-butyl group. )
In the presence of a catalyst comprising lanthanoid triisopropoxide, (R) -1,1′-bi-2-naphthol and triphenylphosphine oxide. The following general formula (1) characterized by asymmetric oxidation with an oxide

(Wherein R ¹ represents a methyl group, an ethyl group, or a branched, straight-chain or cyclic alkyl group having 3 to 10 carbon atoms, and R ² represents a phenyl group, a substituted phenyl group or a tert-butyl group. )
A process for producing the optically active epoxy enone derivative described in 1. The method for producing an optically active epoxy enone derivative according to claim 1, wherein the substituent R ¹ in the general formulas (1) and (2) is a cyclohexyl group, an isopropyl group or an n-butyl group. . In general formulas (1) and (2), the substituents R ^2, a phenyl group, optics according to claim 1 or claim 2 characterized in that it is a 4-methoxyphenyl group or a tert- butyl group A method for producing an active epoxy enone derivative. The method for producing an optically active epoxy enone derivative according to any one of claims 1 to 3, wherein the lanthanoid triisopropoxide is lanthanum triisopropoxide.