JPH0811076B2 - Process for producing optically active cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound represented by the general formula (I): (In the formula, R represents a hydrogen atom or a lower alkyl group,
n represents an integer of 4 to 8) and a method for producing an optically active cyclopentenone compound.

<Prior Art> The optically active cyclopentenones represented by the above general formula (I) are useful compounds as intermediates for medicines, agricultural chemicals, etc., and are used as important intermediates of prostaglandin derivatives. You can

Conventionally, the following methods are known as methods for producing such optically active cyclopentenones (I).

1) Tetrahedron Letters, N
o.49,4959 (1973) 2) JACS, 97 , 865 (1975) 3) Acta.Chimica.Academiae.Scientiarum.Hungariae. 1
02 (1) .pp91 ~ 100 (1979) <Problems to be Solved by the Invention> However, these methods are not always satisfactory in terms of yield, optical purity, etc. for the method of 1), for example, and there is a problem that some by-products are produced. However, the method 2) has a problem that the starting triketone body is not easily synthesized and the number of subsequent steps is large, and the method 3) is a starting material (-)-cis-2-. Oxobicyclo [3,3,0] -octa-
Since 6-en-3-ol must be an optically active substance and there are various problems such as a large number of steps, none of them can be said to be an industrially advantageous production method.

From the above, the present inventors have described the above general formula (I).
The present invention has been accomplished as a result of the examination of a method for industrially and easily producing an optically active cyclopentenone represented by the formula (3) at low cost with good yield and high purity.

<Means for Solving the Problems> The present invention has the general formula (III) (In the formula, R represents a hydrogen atom or a lower alkyl group.
n represents an integer of 4 to 8) and a hydroxycyclopentenone is reacted with a lower aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof to simultaneously perform an acylation and a rearrangement reaction. According to the general formula (II) (In the formula, R and n have the same meanings as described above, and R'represents a lower alkyl group which may be substituted with a halogen atom.) A dl-cyclopentenone ester represented by General formula (I) for asymmetric hydrolyzing by acting on
The present invention provides a method for producing an optically active cyclopentenone compound represented by:

Examples of the lower aliphatic carboxylic acid used in the reaction for obtaining the dl-cyclopentenones represented by the general formula (II) include acetic acid, propionic acid, butyric acid, valeric acid, chloroacetic acid, dichloroacetic acid and bromoacetic acid. As the metal salt, lithium salt, sodium salt of these lower aliphatic carboxylic acids,
Examples thereof include potassium salt, calcium salt, copper salt, zinc salt, palladium salt, lead salt, tin salt, manganese salt, and cobalt salt. In this reaction, the amount of the lower aliphatic carboxylic acid used with respect to the starting hydroxycyclopentenones (III) is usually 1 equivalent or more, and the amount of the metal salt used is usually 0.01
˜5 equivalent times or more, preferably 0.01 to 0.5 equivalent times.
The amount of the acid anhydride of the above-mentioned aliphatic carboxylic acid used is at least 1 equivalent of the starting hydroxycyclopentenones (III).

In this reaction, it is very important to use the three components of the above-mentioned aliphatic carboxylic acid, its metal salt and its acid anhydride, and it may be an effective method to omit any of the components. And both isomerization and acylation do not proceed well at the same time.

When a solvent is used in this reaction, examples of the solvent include tetrohydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, Solvents such as aliphatic or aromatic hydrocarbons such as hexane, ethers, halogenated hydrocarbons and the like which are inert to the reaction may be used alone or as a mixture, and the amount thereof is not particularly limited. In addition, an aliphatic carboxylic acid can be used as a solvent.

The reaction temperature is 0 to 150 ° C., preferably 30 to 140 ° C.
Range.

The reaction time is not particularly limited, but is usually 0.5 to 10 hours. When the reaction time becomes long, the dl-cyclopentenone ester represented by the general formula (II) thus formed is partially decomposed, so that unnecessary time extension is not preferable.

As a reaction method, for example, a method of charging hydroxycyclopentenones represented by the general formula (III), an aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof into a reaction vessel at the same time and reacting them is represented by the general formula (III) Aliphatic carboxylic acid and its acid anhydride are added to hydroxycyclopentenones to react with each other, and after a fixed time (usually 0.1 to 5 hours, but not particularly limited), a metal of the aliphatic carboxylic acid is added. Examples thereof include a method of adding a salt and further reacting.

By such a method, the desired dl-cyclopentenone ester represented by the general formula (II) can be obtained from the hydroxycyclopentenone represented by the general formula (III).

The thus obtained dl-cyclopentenone esters (II) is allowed to act on an esterase produced by a microorganism or an esterase derived from animals and plants to hydrolyze one of the optically active substances of the starting dl-cyclopentenone esters (II). As a result, the objective optically active cyclopentenones (I) can be obtained.

The esterase-producing microorganism used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze the dl-cyclopentenone esters represented by the general formula (II), and is not particularly limited. It is not something that will be done.

The esterase in the present invention means an esterase in a broad sense including lipase.

Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Previbacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus,
Examples include microorganisms belonging to Rhizopus, Mucor, Aureopasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, and Achromobacter.

For the culture of the above-mentioned microorganisms, a liquid culture is usually obtained by performing liquid culture according to a conventional method.

For example, sterilized liquid medium [malt extract / yeast extract medium for molds and yeasts] [dissolve 5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract in 1 water, p
H6.5), for bacteria, fructose broth medium (1 g water with 10 g glucose, 5 g peptone, 5 g meat extract and 3 g NaCl)
To pH 7.2)], and inoculate the
The culture may be performed by reciprocal shaking culture at -40 ° C for 1 to 3 days, and if necessary, solid culture may be performed.

Some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include the followings. Pseudomonas lipase [Lipase P (manufactured by Amano Pharmaceuticals)] Aspergillus lipase [lipase AP (manufactured by Amano Pharmaceuticals)], Mucor lipase [lipase MAP (manufactured by Amano Pharmaceuticals)], lipase of Candida cirindrass [lipase MY] (Made by Meito Sangyo)],
Alcaligenes lipase [Lipase PL (Meito Sangyo)], Achromobacter lipase [Lipase AL
(Manufactured by Meito Sangyo Co., Ltd.)], lipase of Arthrobacter genus [(manufactured by Shin Nippon Kagaku Co.)], lipase of chromobacterium genus (manufactured by Toyo Brewing Co.), lipase of Rhizopus dermer [talipase (manufactured by Tanabe Seiyaku)], Rhizopus lipase [Lipase Saiken (Osaka Bacterial Research Institute)].

Also, animal / plant esterase can be used,
Specific examples of these esterases include the following.

Steapsin, pancreatin, pig liver esterase, Wheat Germ esterase.

As the esterase used in this reaction, an enzyme obtained from an animal, a plant or a microorganism is used. The usage forms thereof include a purified enzyme, a crude enzyme, an enzyme-containing material, a microbial culture solution, a culture, a bacterium, and a culture medium. It can be used in various forms such as a liquid and a product obtained by treating them as needed, and an enzyme and a microorganism can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or an immobilized bacterium immobilized on a resin sugar.

The asymmetric hydrolysis reaction of the present invention is carried out by vigorously stirring a mixture of the starting dl-cyclopentenone esters (II) and the enzyme or microorganism in a buffer solution.

As the buffer solution, sodium phosphate which is usually used,
A buffer solution of an inorganic acid salt such as potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate and sodium citrate, etc. is used, and the pH thereof is 8 to 11 in a culture solution of an alkaliphilic bacterium or alkaline esterase, A pH of 5 to 8 is preferable for a culture solution of a non-alkaline microorganism or an esterase having no alkali resistance. The concentration is usually 0.05-2 molar,
It is preferably in the range of 0.05 to 0.5 molar concentration.

The reaction temperature is usually 10 to 60 ° C., and the reaction time is generally 10 to 70 hours, but is not limited thereto.

By such a reaction, one of the optically active dl-cyclopentenone esters (II) is hydrolyzed to produce optically active cyclopentenones represented by the general formula (I). Cyclopentenone esters, which is the other optically active substance of the raw material compounds, remain as a hydrolysis residue as it is, and, in the end, in the asymmetric hydrolysis, the above-mentioned two kinds of hydrolysis products and hydrolysis residues are used. An optically active compound will be obtained at the same time.

After completion of such hydrolysis reaction, the hydrolysis product and the hydrolysis residue are separated from the reaction solution by subjecting the hydrolysis reaction solution to extraction treatment with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, etc. After distilling off the solvent, the concentrated residue is further distilled, treated by column chromatography, or redissolved in an appropriate solvent and then recrystallized separately. The product, an optically active cyclopentenone represented by the general formula (I), and the above-mentioned optically active cyclopentenones among the raw material compounds, which are hydrolysis residues, are optically active antipodes. It can be separated from cyclopentenone esters.

The optically active cyclopentenone ester obtained here is further hydrolyzed as necessary, and the optically active cyclopentenone obtained above is converted to an enantiomer optically active cyclopentenone. You can also

When a lipase belonging to the genus Pseudomonas or the genus Arthrobacter is used as the lipase in this asymmetric hydrolysis reaction, optically active cyclopentenones can be obtained with a relatively high optical purity.

In addition, at the time of this asymmetric hydrolysis, in addition to the buffer solution, toluene,
It is also possible to use an organic solvent inert to the reaction such as chloroform, methyl isobutyl ketone, or dichloromethane.
By using these, asymmetric hydrolysis can be advantageously performed.

The hydroxycyclopentenones represented by the general formula (III) which are the starting materials in the above reaction are represented by the general formula (V) (In the formula, R and n have the same meanings as described above), a furancarbinol compound represented by the following formula was used in a solvent mainly containing water while maintaining the pH of the reaction solution at 3.5 to 6 with or without the presence of a catalyst. It can be easily produced by rearrangement in the presence.

Examples of the furancarbinol compound used in this reaction include α- (alkoxycarbonylalkyl) furancarbinol such as α- (methoxycarbonylalkyl) furancarbinol, α- (ethoxycarbonylalkyl) furancarbinol, α- (butoxycarbonyl). Examples thereof include alkyl) furan carbinol and α- (hydroxycarbonylalkyl) furan carbinol.

The solvent used in this reaction is a solvent containing water as a main solvent, and is water alone or a mixed solvent containing water as a main component in which a small amount of another organic solvent is mixed with water. Here, other organic solvents include, for example, ethylene glycol, 1,8
-Aliphatic or aromatic hydrocarbons such as propanediol, methanol, ethanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, ethyl acetate, acetic acid, dichloromethane, toluene, dimethyl ether, alcohols, fatty acids, ethers, esters, halogenated hydrocarbons. A solvent inert to the reaction such as However, generally, there is no particular advantage in coexisting these organic solvents with water.

This reaction does not necessarily require a catalyst, but its use is effective because the addition of the catalyst improves the reaction rate and increases the reaction rate.

When a catalyst is used in this reaction, examples of the catalyst include various metal salts, organic quaternary ammonium salts, surfactants, alcohols and the like.

Examples of various metal salts include sodium, potassium,
Examples include phosphates, sulfates, chlorides, bromides, oxides, organic fatty acid salts, organic sulfonates of magnesium, zinc, iron, calcium, manganese, cobalt, aluminum and the like, and organic quaternary ammonium salts. Examples include tetrabutylammonium bromide, benzyltrimethylammonium chloride, tricaprylmethylammonium chloride, dodecyltrimethylammonium chloride,
Caprylbenzyldimethylammonium chloride and the like, and surfactants include higher fatty acid salts, polyoxyethylene alkylphenol ethers, higher aliphatic alcohols, and the like. Examples of the alcohol include methanol, ethanol, and ethylene glycol exemplified above as the solvent. And the like are also used as catalysts, and these are used alone or as a mixture.

When a catalyst is used, the amount used is usually 1/200 to 5 with respect to the furancarbinol compound represented by the general formula (V).
Although it is in the range of double weight, it is applicable even outside this range.

The catalyst used here can be recovered and reused after completion of the reaction.

The reaction pH is preferably in the range of 3.5 to 6, more preferably in the range of 3.5 to 5.5.

Examples of the acid used to maintain the pH include, for example, common inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, acetic acid, propionic acid, toluenesulfonic acid, and methanesulfonic acid, and organic acids. Examples of the alkali include caustic soda, potassium carbonate, sodium hydrogen carbonate, phosphoric acid 1
Examples include ordinary inorganic bases and organic bases such as potassium hydrogen and organic amines.

Alternatively, a buffer solution containing the above-mentioned acid-base combination may be used, and examples thereof include potassium monohydrogen phosphate-phosphoric acid, sodium acetate-acetic acid, sodium acetate phosphoric acid, phthalic acid-potassium carbonate, and potassium monohydrogen phosphate-hydrochloric acid. , Potassium dihydrogen phosphate-potassium hydrogen carbonate, succinic acid-sodium hydrogen carbonate, and the like.

Generally, it is more preferable to avoid strong acids such as hydrochloric acid and hydrobromic acid and strong alkalis such as caustic soda and caustic potash as acids or alkalis used for pH adjustment.

The reaction temperature is in the range of 0 to 200 ° C, preferably 20
It is in the range of ~ 160 ° C.

In this reaction, at the same time as the hydroxycyclopentenones represented by the general formula (III), the general formula (I
V) (In the formula, R represents a hydrogen atom or a lower alkyl group.
Represents an integer of 4 to 8), and a hydroxycyclopentenone compound represented by the formula (3) is partially produced and is usually obtained as a mixture thereof.

In the reaction for obtaining the dl-cyclopentenone esters represented by the general formula (II) from the hydroxycyclopentenones represented by the general formula (III), the hydroxycyclopentane represented by the general formula (III) is obtained from the above mixture. Although the pentenones may be separated by an appropriate means and then used as a reaction raw material, a mixture with the hydroxycyclopentenone compound represented by the general formula (IV) can be used as it is.

In the above reaction, when the mixture is used as a reaction raw material as it is, the hydroxycyclopentenones (III) undergo acylation and rearrangement reaction at the same time, but the hydroxycyclopentenone compound represented by the general formula (IV) is Since only the acyl compound proceeds to form dl-cyclopentenone esters represented by the general formula (II), there is no problem in the progress of the reaction, and from the industrial point of view, the above mixture should be used as a reaction raw material as it is. Is advantageous.

<Effect of the Invention> Thus, according to the method of the present invention, the optically active cyclopentenones represented by the general formula (I) can be obtained in good yield, good purity and industrially advantageously.

<Examples> Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to the Examples.

Example 1 In a four-necked flask equipped with a stirrer and a thermometer, 2- (1-
(Hydroxy-7-methoxycarbonylheptyl) -furan 114 g, 4560 g of water, 3.8 g of potassium monohydrogen phosphate and a buffered aqueous solution adjusted to pH 4.2 with phosphoric acid were charged, and a raw material was prepared at 100 ° C. under a nitrogen stream. Continue stirring until no more.

After completion of the reaction, the reaction mixture was cooled, extracted twice with 600 ml of methyl isobutyl ketone and separated, and the methyl isobutyl ketone was distilled off from the obtained organic layer to give 3-hydroxy-2- (6-methoxycarbonyl). Hexyl) -4-cyclopentenone and 4-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone were obtained as a mixture in an amount of 92 g (yield 80.7%).

17.0 g of acetic acid, 5.1 g of acetic anhydride and 0.29 g of anhydrous sodium acetate are added to 12.0 g of the above mixture, and heated at 120 ° C. for 4 hours. Check the reaction solution by gas chromatography,
The reaction was terminated after confirming that no reaction raw material was detected in the reaction solution. The reaction solution is concentrated under reduced pressure, 200 ml of toluene and 100 ml of water are added to the concentrated residue, and the layers are separated to obtain an organic layer. The organic layer is washed with 8% heavy soda water and then with water. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated to give 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 18.1 g (yield 98
%) Was obtained.

bp. 180-185 ° C / 0.6mmHg 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 4g, dichloromethane 2ml,
Pseudomonas lipase (amanolipase "P") 40
Charge 100 ml of 0 mg and 0.3 molar phosphate buffer (pH 7.5) to the flask and stir vigorously at 25-30 ° C for 13 hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of toluene. The combined organic layers were concentrated under reduced pressure, and the concentrated residue was 3.98 g.
I got

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 3) to give 4R (+)-hydroxy-2- (6-
Methoxycarbonylhexyl) -2-cyclopentenone
1.01g [▲ [α] ²⁰ _D ▼ + 15.1 ° (c = 1, methanol)
(88% ee), m.p 58 ° C.] and 4S (−)-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 2.60 g [▲
[Α] ²⁰ _D ▼ -73.1 ° (c = 1, methanol), m.p 41 ° C]
I got

Example 2 In a four-necked flask equipped with a stirrer and a thermometer, 2- (1-
(Hydroxy-7-methoxycarbonylheptyl) -furan 114 g, 4560 g of water, 3.8 g of potassium monohydrogen phosphate and a buffered aqueous solution adjusted to pH 4.2 with phosphoric acid were charged, and a raw material was prepared at 100 ° C. under a nitrogen stream. Continue stirring until no more.

After completion of the reaction, the reaction mixture was cooled, extracted twice with 600 ml of methyl isobutyl ketone and separated, and the methyl isobutyl ketone was distilled off from the obtained organic layer to give 3-hydroxy-2- (6-methoxycarbonyl). Hexyl) -4-cyclopentenone and 4-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone were obtained as a mixture in an amount of 92 g (yield 80.7%).

17.0 g of acetic acid, 5.1 g of acetic anhydride and 0.29 g of anhydrous sodium acetate are added to 12.0 g of the above mixture, and heated at 120 ° C. for 4 hours. Check the reaction solution by gas chromatography,
The reaction was terminated after confirming that no reaction raw material was detected in the reaction solution. The reaction solution is concentrated under reduced pressure, 200 ml of toluene and 100 ml of water are added to the concentrated residue, and the layers are separated to obtain an organic layer. The organic layer is washed with 8% heavy soda water and then with water. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated to give 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 18.1 g (yield 98
%) Was obtained.

bp.180-185 ° C / 0.6 mmHg 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 4 g, 0.3 molar phosphate buffer (pH 7.5) 100 ml and Pseudomonas lipase (amanolipase " P ") 400 mg are charged into a flask and vigorously stirred at 40 ° C for 5 hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of toluene. The combined organic layers were concentrated under reduced pressure and the concentration residue was 8.98 g.
I got

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 3) to give 4R (+)-hydroxy-2- (6-
Methoxycarbonylhexyl) -2-cyclopentenone
0.98g [▲ [α] ²⁰ _D ▼ + 14.9 ° (c = 1, methanol)
(86.7% ee)] and 4S (−)-acetoxy-2- (6-
Methoxycarbonylhexyl) -2-cyclopentenone
2.66 g [▲ [α] ²⁰ _D ▼ -73.5 ° (c = 1, methanol)] were obtained.

Example 3 34.0 g of acetic acid, 10.2 g of acetic anhydride and 0.6 g of anhydrous sodium acetate were added to 24.0 g of 3-hydroxy-2- (6-methoxycarbonylhexyl) -4-cyclopentenone, and the mixture was heated at 120 ° C. for 4 hours. . The reaction solution was checked by gas chromatography, and it was confirmed that no reaction raw material was detected in the reaction solution, and the reaction was terminated.

The reaction mixture was concentrated under reduced pressure, and 400 ml of toluene was added to the concentrated residue.
And 200 ml of water are added, and the layers are separated to obtain an organic layer. The organic layer is washed with 8% heavy soda water and then with water. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated to 4
-Acetoxy-2- (6-methoxycarbonylhexyl)
86.2 g (yield 98%) of 2--2-cyclopentenone was obtained.

bp. 180-185 ° C / 0.6mmHg 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 4g, dichloromethane 2ml,
0.3 molar phosphate buffer (pH 7.5) 100ml and Pseudomonas lipase (amanolipase "P") 400m
Charge g into a flask and stir vigorously at 25-30 ° C for 13 hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of toluene. The combined organic layers were concentrated under reduced pressure and the concentration residue was 8.98 g.
I got

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 8) to give 4R (+)-hydroxy-2- (6-
Methoxycarbonylhexyl) -2-cyclopentenone
0.98g ▲ [α] ²⁰ _D ▼ + 15.1 ° (c = 1, methanol) (88
% Ee)] and 4S (−)-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone (2.66 g) [▲ [α] ²⁰ _D ▼ -73.5 ° (c = 1, methanol)] It was

Example 4 To 12 g of 3-hydroxy-2- (6-methoxycarbonylhexyl) -4-cyclopentenone, 27 g of chloroacetic acid, 8.5 g of anhydrous chloroacetic acid and 0.4 g of anhydrous sodium chloroacetate were added, and heated at 120 ° C. for 4 hours. To do.

The reaction mixture was concentrated under reduced pressure, and 400 ml of toluene was added to the concentrated residue.
And 200 ml of water are added, and the layers are separated to obtain an organic layer. The organic layer is washed with 8% heavy soda water and then with water. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated to 4
-Chloroacetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone is obtained.

4-chloroacetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 4g, dichloromethane
2 ml, 0.3 molar phosphate buffer (pH 7.5) 100 ml and Arthrobacter lipase (Nippon Kagaku) 300 mg
Is charged into a flask and vigorously stirred at 25 to 30 ° C for 13 hours.

After completion of the reaction, the reaction solution was extracted twice with toluene, the organic layers were combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography and then subjected to 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl). ) -2-Cyclopentenone is obtained.

Example 5 Acetic acid 8 was added to 52.5 g (0.25 mol) of 3-hydroxy-2- (4-methoxycarbonylbutyl) -4-cyclopentenone.
5.5g, acetic anhydride 25.5g and potassium acetate 1.7g are added, and it heats at 120 degreeC for 4 hours. The reaction solution is concentrated under reduced pressure, 800 ml of toluene and 400 ml of water are added to the concentrated residue, and the layers are separated to obtain an organic layer. After washing the organic layer with 8% heavy water,
Wash further with water. The obtained organic layer is dried over anhydrous magnesium sulfate and then concentrated to obtain 4-acetoxy-2- (4-methoxycarbonylbutyl) -2-cyclopentenone.

4-Acetoxy-2- (4-methoxycarbonylbutyl) -2-cyclopentenone was asymmetrically hydrolyzed according to Example 3, and 4R (+)-hydroxy-2- as a hydrolysis product.
(4-Methoxycarbonylbutyl) -2-cyclopentenone is obtained.

Example 6 3-hydroxy-2- (6-ethoxycarbonylhexyl) -4-cyclopentenone (12.7 g) and sodium acetate 2.1
g, 5.1 g of acetic anhydride and 40 g of acetic acid are added, and the mixture is heated at 110 ° C. for 4 hours. After completion of the reaction, post-treatment was carried out according to Example 5,
14.9 g (yield 95.1%) of 4-acetoxy-2- (6-ethoxycarbonylhexyl) -2-cyclopentenone was obtained.

bp.189-198 ° C / 0.5 mmHg or less, asymmetric hydrolysis was carried out according to Example 3, and 4R (+)-hydroxy-2- (6-ethoxycarbonylhexyl) -2-cyclopentenone was used as a hydrolysis product. obtain.

Example 7 To 12.0 g of 3-hydroxy-2- (6-methoxycarbonylhexyl) -4-cyclopentenone was added 17.0 g of acetic acid, 5.1 g of acetic anhydride and 0.29 g of sodium acetate, and the mixture was heated at 120 ° C. for 4 hours. The reaction solution was checked by gas chromatography, and it was confirmed that no reaction raw material was detected in the reaction solution, and the reaction was terminated. The reaction solution is concentrated under reduced pressure, 200 ml of toluene and 100 ml of water are added to the concentrated residue, and the layers are separated to obtain an organic layer. The organic layer is washed with 8% heavy soda water and then with water. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated to give 18.1 g of 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone (yield 9
8%).

bp.180-185 ° C / 0.6mmHg 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 4g, 0.3 molar phosphate buffer (pH 7.5) 100ml, Chromobacterium lipase (Toyo A mixture of 300 mg of brewed lipase LP) is vigorously stirred at 40 ° C. for 5 hours.

After completion of the reaction, the reaction solution was extracted twice with toluene, the organic layers were combined and concentrated under reduced pressure, and the obtained residue was purified by column chromatography and then 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl). -2-Cyclopentenone 0.99g [▲
[Α] ²⁰ _D ▼ + 13.9 ° (c = 1, methanol) (81.2% e
e)] and 4S (-)-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 1.4 g [▲
[Α] ²⁰ _D ▼ -69.0 ° (c = 1, methanol)] was obtained.

Example 8 To 12.0 g of 3-hydroxy-2- (6-butoxycarbonylhexyl) -4-cyclopentenone, 14.5 g of acetic acid, 4.3 g of acetic anhydride and 0.25 g of anhydrous sodium acetate are added, and heated at 120 ° C. for 4 hours. . The reaction solution is concentrated under reduced pressure, 200 ml of toluene and 100 ml of water are added to the concentrated residue, and the layers are separated to obtain an organic layer. The organic layer is washed with 8% aqueous sodium hydrogen carbonate and then with water.

After drying the obtained organic layer with anhydrous magnesium sulfate,
Concentrate to give 4-acetoxy-2- (6-butoxycarbonylhexyl) -2-cyclopentenone.

This 4-acetoxy-2- (6-butoxycarbonylhexyl) -2-cyclopentenone was asymmetrically hydrolyzed according to Example 3 to give 4R (+)-hydroxy-2- (6-butoxy) as a hydrolysis product. Carbonylhexyl) -2-cyclopentenone is obtained.

Example 9 12 g of 3-hydroxy-2- (6-methoxycarbonylhexyl) -4-cyclopentenone, 17.2 g of acetic acid and acetic anhydride
Add 5.1 g and anhydrous sodium acetate 0.3 g, and stir at 120 ° C. for 4 hours.

The reaction mixture was concentrated under reduced pressure, and 400 ml of toluene was added to the concentrated residue.
And 200 ml of water are added, and the layers are separated to obtain an organic layer. The organic layer is washed with 8% aqueous sodium hydrogen carbonate and then with water. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated to give 4-acetoxy-2- (6-methoxycarbonylhexyl) -2.
13.4 g of cyclopentenone were obtained.

Obtained 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 4 g, 0.3 molar phosphate buffer (pH 7.5) 100 ml and Arthrobacter lipase (Nippon Kagaku) 300 mg Is charged into a flask and vigorously stirred at 25 to 30 ° C for 13 hours.

After completion of the reaction, the reaction solution was extracted twice with toluene, the organic layers were combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography and then subjected to 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl). ) -2-Cyclopentenone 1.2 g [▲
[Α] ²⁰ _D ▼ + 15.8 ° (c = 1, methanol), 92.3% ee]
I got

In the asymmetric hydrolytic reaction of the above example, dichloromethane
When the reaction was performed in exactly the same manner except that 2 ml was further added, 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 1.21 g [▲ [α]
²⁰ _D ▼ + 16.1 ° (c = 1, methanol), 94.8% ee] was obtained.

Claims (2)

[Claims] 1. A general formula (III) (In the formula, R represents a hydrogen atom or a lower alkyl group.
Represents an integer of 4 to 8. ) By reacting hydroxycyclopentenones with a lower aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof to simultaneously carry out an acylation reaction and a rearrangement reaction. (Wherein R and n have the same meanings as described above, and R'represents a lower alkyl group which may be substituted with a halogen atom), dl-cyclopentenone ester represented by General formula (I) characterized in that (In the formula, R and n are the same as the above), and a method for producing an optically active cyclopentenone. 2. General formula (V) (In the formula, R represents a hydrogen atom or a lower alkyl group.
Is an integer of 4 to 8) and is rearranged in the presence or absence of a catalyst while maintaining the pH of the reaction solution at 3.5 to 6 in a solvent mainly containing water. General formula (III) (Wherein R and n are the same as those described above), and the resulting cyclocyclopentenones are reacted with a lower aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof to carry out an acylation and rearrangement reaction. By simultaneously performing the general formula (II) (Wherein R and n have the same meanings as described above, and R ′ represents a lower alkyl group which may be substituted with a halogen atom), dl-cyclopentenone ester represented by General formula (I) characterized by acting to cause asymmetric hydrolysis (In the formula, R and n are the same as the above), and a method for producing an optically active cyclopentenone.