JP3094597B2 - Method for producing optically active cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] The present invention relates to a prostaglandin and the like.
Active Cyclopentenones Useful as Intermediates of Cyclopentenones
[9]A method for producing the same. [0002] [Prior art]Has an ester group at the side chain terminalOptically active
Cyclopentenones[9]As a method of producing
Of cyclopentenone and acylating agent with pig pancreas lipper
Reaction in the presence of an enzyme such as
Active Cyclopentenone Esters and Optically Active Cyclope
An ester derivative was obtained, and after separation, the ester was hydrolyzed.
Decomposition, the alcohol undergoes steric inversion and hydrolysis to give light
Method for Obtaining Biologically Active Cyclopentenones (JP-A-2-1
67098) are known. However, this method
Is the same as the racemic cyclopentenone
5-9 days using a large amount of enzyme over weight
The reaction must be performed for a long period of time, and the hydrolysis yield
Is not always high, and is not always
Was not satisfactory. [0003] SUMMARY OF THE INVENTION The present inventors have studied optical activity
Cyclopentenones[9]More efficient manufacturing
After a thorough study to find out, racemic cyclopentenone
Reaction with the acylating agent
Use of a specific enzyme called lipase derived from
This allows efficient reaction in a short time even with a small amount of enzyme.
Not only can it be
Clopentenone esters and optically active cyclopente
To obtain non-derivatives,
Stereoinversion of Highly Optically Active Cyclopentenone Derivatives
Method and efficient hydrolysis method
Higher yield and higher selection from racemic cyclopentenones
AlternativelyAnd efficientlyOptically active cyclopentenones
[9]The present invention was found by finding a method for producing. [0004] That is, the present invention provides a compound represented by the following general formula:
[1] Of cyclopentenones and unsaturated alcohols
C2-4Carboxylic acid ester
Reaction in the presence of a lipase derived from
[2] Optically active cyclopentenone derivatives represented by
Equation [3] Of optically active cyclopentenone esters represented by
And then the optically active cyclopentenone derivative
[2] and optically active cyclopentenone esters
With the mixture of [3]General formula [5] (Where R _Three Is a hydrogen atom or an alkyl having 1 to 3 carbon atoms
Represents a group. ), General formula
[4] (Where R_TwoRepresents an alkyl group. Azo represented by)
DicarboxylateLeAnd general formula [6] (Where R_FourIs a lower alkyl group or a lower alkoxy group
Or a phenyl group optionally substituted with a halogen atom,
Or lower alkyl group, lower alkoxy group or halo
A cyclohexyl group which may be substituted with
I forgot. Phosphines represented by)Under the coexistence ofLet it react
And the general formula [7] Optically active ester derivative and optically active cyclo
A mixture of pentenone esters [3] is obtained,
Optically active ester derivative [7] and optically active cyclopen
A mixture of tenone esters [3] and a compound of the general formula [8] (Wherein, R represents the same meaning as described above)
Characterized in that it reacts with alcohol in the presence of an acid catalyst.
General formula [9] A method for producing an optically active cyclopentenone represented by
Cyclopentenones [1] and unsaturated alcoholcarbon
Number 2-4Carboxylic acid ester and Arthrobacter
Reaction in the presence of lipase derived from the genus
Shown by clopentenone derivative [2] and general formula [3]
A mixture of optically active cyclopentenone esters
And then separating the mixture to obtain an optically active cyclo
Pentenone derivative [2]With carboxylic acids [5],
Zodicarboxylic acid ester [4]And phosphines [6]
Under the coexistence ofReact to obtain an optically active ester derivative [7]
And then an optically active ester derivative [7]
Coal [8] is reacted in the presence of an acid catalyst
For producing optically active cyclopentenones [9]
Process, cyclopentenones [1], unsaturated alcohol
OfC2-4Carboxylic acid ester
Reacted in the presence of a lipase derived from Robacter,
Optically active cyclopentenone derivative [2] and optically active
A mixture of cyclopentenone esters [3] was obtained.
Optically active cyclopenteno obtained by separating the mixture with
Ester [3] and alcohol [8] in the presence of an acid catalyst.
Optically active cyclope characterized by reacting in the presence
The present invention relates to a method for producing an intenone [9]. Hereinafter, the present invention will be described in detail. First,
Clopentenones [1] and unsaturated alcoholCarbon number
2-4Carboxylic acid esters and Arthrobacter
Reaction in the presence of lipase derived from
Clopentenone derivative [2] and optically active cyclopen
A method for obtaining a mixture of tenone esters [3]
I will tell. In the reaction, the starting material represented by the general formula [1] is used.
Examples of the cyclopentenone to be used include, for example, 2-alco
Xycarbonylalkyl-4-hydroxy-2-cyclo
Pentenone, 2-alkoxycarbonylalkenyl-4
-Hydroxy-2-cyclopentenone, 2-alkoxy
Carbonylalkynyl-4-hydroxy-2-cyclope
For example, entenone can be used. These are for example,
Furan and alkoxycarbonylalkynes (or
Coxycarbonylalkanes, alkoxycarbonyla
With trifluoroacetic anhydride in the presence of trifluoroacetic anhydride.
Let (AlCoxycarbonyl) -1-oxo-1-free
Rualkynes (or corresponding alkanes, alkenes
), And the compound is reduced to give (alkoxy carbonyl)
) -1-hydroxy-1-furylalkynes (or
Corresponding alkanes and alkenes) and water solvent
Isomerization while controlling pH in the system
Can be synthesized. Also, 2-alkoxycarboni
Lualkynyl-4-hydroxy-2-cyclopentenone
Is partially hydrogenated to give 2-alkoxycarbonylalkenyl
To be 4-hydroxy-2-cyclopentenone
In the same manner as above,
2-hydroxy-2-cyclopentenone to 2-a
Lucoxycarbonylalkyl-4-hydroxy-2-si
Clopentenone, 2-alkoxycarbonylalkynyl
-2-Hydroxy-2-cyclopentenone to 2-al
Coxycarbonylalkyl-4-hydroxy-2-cycl
Lopentenone can also be synthesized(Japanese Patent Application No. 3-12310
issue). The unsaturated alcohol usedCarbon number 2-4
ofAs the carboxylic acid ester, for example, vinyl acetate
G, vinyl propionate, vinyl valerate, isop
Lopenyl acetate, isopropenyl propionate,
Isopropenyl valerate and the like.
The amount to be used is usually 0.5 to cyclopentenones [1].
It is at least molar, preferably at least 2 molar. In addition,
Of saturated alcoholC2-4Carboxylic acid ester
It can also be used as a solvent. [0007] The enzyme is derived from the genus Arthrobacter.
Lipase is used, in the form of a purified enzyme,
Adsorbed on diatomaceous earth, fixed on bead glass, etc.
Various types, such as those made into the form, can be used. Yeast
The amount of element is usually 0.1 to the amount of cyclopentenone [1].
01 to 1 times by weight, preferably 0.03 to 0.5 times by weight,
More preferably, it is 0.05 to 0.2 times by weight. In the reaction, a solvent may be used.
And the solvent is the above-mentioned unsaturated alcohol.carbon
Number 2-4Other than carboxylic acid esters, for example, hexane,
Heptane, benzene, toluene, dichloromethane, chloroform
Aliphatic hydrocarbons such as roform and dibutyl ether, and fragrances
Single group hydrocarbons, halogenated hydrocarbons, ethers, etc.
Or a mixture can be mentioned. The amount used is shik
Usually 0.5 to 10 times the weight of lopentenones [1]
It is. The reaction temperature is usually from 10 to 50 ° C.
The time is usually sufficient for 0.5 to 50 hours. Inference of reaction
Transfer can be carried out, for example, with a liquid crystal with a filler for the optically active compound.
Cyclopentenone derivatives using chromatography
Tracking by measuring the optical purity of [2]
It can also determine the end point of the reaction.
Normal (especially not necessarily for optically active compounds)
Using liquid chromatography, etc.,
Lopentenones [1] and / or optically active cyclope
Entenone derivative [2]) and esters (optically active cyclo
Pentenone esters [3])
The reaction end point can be determined when the ratio becomes approximately 1: 1.
You. After completion of the reaction, hexane and
Butane, benzene, toluene, dichloromethane, chloro
Form, chlorobenzene, dichloroethane, ethyl acetate
Or aromatic hydrocarbons such as ethyl ether
Element, ether, ketone, ester, halogenated hydrocarbon
The enzyme is filtered off, and the filtrate is concentrated.
The optically active cyclopentenone derivative
[2] and optically active cyclopentenone esters
The mixture of [3] can be obtained. And even more
By applying normal chromatography to light
Optically active cyclopentenone derivative [2]
It can also be separated into lopentenone esters [3]
You. Next, the optical activity obtained by the above-described reaction is described.
Cyclopentenone derivative [2] and optically active cyclo
With a mixture of pentenone esters [3]Carboxylic acids
[5] andAzodicarboxylic acid ester [4]And hos
Fins [6]Under the coexistence ofReact to the optically active
Derivative [7] and optically active cyclopentenone ester
A method for obtaining a mixture of the class [3] will be described. The azodicarbon used in the reaction
Examples of the acid ester [4] include azodicarboxylic acid diacid
Methyl ester, azodicarboxylic acid diethyl ester,
Azodicarboxylic acid dipropyl ester, azodicarboxylic acid
Acid dibutyl ester and the like.
Usually, 1 relative to the optically active cyclopentenone derivative [2].
The molar ratio is 1 to 3 times, preferably 1 to 2.5 times. Cal
As the boric acid [8], for example, formic acid, acetic acid, propion
Acid, butanoic acid, and the like.
The active cyclopentenone derivative [2] is usually 1 to 4
The molar ratio is preferably 1 to 3 molar times. Phosphines
Are, for example, triphenylphosphine, trichloro
Rophenylphosphine, tolylphosphine, tri-
Methoxyphenylphosphine, tricyclohexylphos
Fins and the like can be used.
Usually 1 to 3 mol based on the clopentenone derivative [2]
Times, preferably 1 to 2.5 times. As a reaction method, for example, an optically active cyclo
Pentenone derivative [2] and optically active cyclopenteno
Mixtures of esters [3], phosphines [6] and
Carboxylic acid and azodicarboxylic acid ester
Can be added. The smell of the reaction
In some cases, a solvent can be used.
For example, hexane, heptane, toluene, dichloromethane,
Chloroform, dibutyl ether, tetrahydrofura
, Dioxane, acetone, cyclohexanone, acetate
Chill, ethyl acetate, triethylamine, dimethylform
Aliphatic hydrocarbons such as amides and dimethyl sulfoxide
Aromatic hydrocarbons, halogenated hydrocarbons, ethers, keto
Amines, esters, amines, formamides, sulfo
Oxides and the like, which may be used alone or in combination.
Can be used as a compound. The amount used is optical activity
With respect to the soluble cyclopentenone derivative [2].
20 times the weight. The reaction temperature is usually from 0 to 60 ° C.
You. The reaction time is usually sufficient for 0.5 to 30 hours,
With the disappearance of the optically active cyclopentenone derivative [2]
It can be the end point of the reaction. After the reaction is completed, filter and concentrate
Normal post-treatment operations such as extraction,
The optically active ester derivative [7] and light
To obtain a mixture of biologically active cyclopentenone esters [3].
Column chromatography, liquid chromatography
Purification by chromatography such as chromatography
However, it is generally possible to use the crude
Can be An optically active cyclopentenone derivative
Optically active cyclope represented by [2] and general formula [3]
Optical activity obtained by separating a mixture of
Cyclopentenone derivative [2] andCarboxylic acids [5]
AndAzodicarboxylic acid ester [4]And phosphine
Class [6]Under the coexistence ofReaction to induce optically active ester
The method for obtaining the isomer [7] is also described in the optically active
Lopentenone derivative [2] and optically active cyclopente
Derivation of optically active ester from a mixture of non-esters [3]
Conductor [7] and optically active cyclopentenone esters
It can be carried out in the same manner as in the method for obtaining the mixture of [3]. The optically active ester derivative obtained above
[7] and optically active cyclopentenone esters [3]
Of a mixture of the above with an alcohol [8] in the presence of an acid catalyst
Optically active cyclopentenones [9]
A method for obtaining the following will be described. The alcohol used in the reaction
[8] includes, for example, methanol, ethanol, n-
Propanol, isopropanol, n-butanol,
Sobutanol, t-butanol, n-pentanol, i
Linear or branched such as sopentanol and hexanol
Aliphatic alcohols. Its usage
Represents an optically active ester derivative [7] and an optically active cyclo
Usually, 0.1% of the mixture of the pentenone esters [3] is used.
5 to 10 times by weight. As the acid catalyst, hydrochloric acid, nitric acid, phosphoric acid,
Phosphoric acid, sulfuric acid, hydrobromic acid, toluenesulfonic acid,
Examples of common inorganic and organic acids such as tansulfonic acid
Can be. The acid catalyst is an aqueous solution such as an aqueous hydrochloric acid solution,
Acid anhydride, hydrogen chloride gas, toluenesulfonic acid, etc.
It can be used in various forms, such as in a state close to it
You. Usually used as an aqueous solution. Acid catalyst and aqueous solution
When used as an acid, the acid concentration is usually 10% or less.
Above, preferably 15% to 80%. Of course, the type of acid
Is usually determined by the upper limit, for example, aqueous hydrochloric acid
35-37% for liquid, 46-4 for aqueous hydrogen bromide
7%, 60-70% for phosphoric acid or nitric acid, etc.
The concentration up to the upper limit is the concentration that can be used normally. The acid
The amount of the catalyst used depends on the optically active ester derivative [7]
To a mixture of biologically active cyclopentenone esters [3]
And usually 0.05 to 3 times the weight of the acid catalyst used.
It is set appropriately according to the type and concentration. In the reaction, a solvent may be used.
Examples of the solvent include alcohol [8] and te.
Trahydrofuran, dioxane, acetone, benzene,
Toluene, dimethyl sulfoxide, dimethylformamide
Hexane, diethyl ether, dichloromethane,
Alcohols such as roloform, aliphatic or aromatic carbonized
Hydrogen, ether, ketone, halogenated hydrocarbon, form
Examples of solvents inert to the reaction, such as amides and sulfoxides
These can be used alone or in combination
it can. Preferably, tetrahydrofuran, dioxa
Water-soluble solvents such as acetone, acetone, and dimethylformamide
And alcohol [8].
For example, alcohol [8] can be mentioned. reaction
The temperature is usually -10 to 80C, preferably 0 to 60C.
It is. The reaction time is usually within 12 hours. reaction
After completion, charge the reaction solution in ice water, extract, wash, and concentrate.
The optically active
Cyclopentenones can be obtained in high purity and high yield,
By distillation, column chromatography, etc.
You can also. Also,,lightA chemically active ester derivative [7],
To react alcohol [8] in the presence of an acid catalyst
Therefore, a method for obtaining an optically active cyclopentenone [9]
And optically active cyclopentenone derivatives [2] and optical
Separation of a mixture of active cyclopentenone esters [3]
Active cyclopentenone esters obtained by
[3] is reacted with alcohol [8] in the presence of an acid catalyst.
Optically active cyclopentenones [9]
The method for obtaining the optically active ester derivative
[7] and optically active cyclopentenone esters
Optically active cyclopentenones from the mixture of [3]
It can be carried out in the same manner as in the method for obtaining [9]. [0019] According to the method of the present invention, Arthrobacta
-Use of a specific enzyme called lipase derived from the genus
Optically active racemates from racemic cyclopentenones
Clopentenones can be obtained with high yield and high selectivity.
You.In addition, light obtained from racemic cyclopentenones
Active Cyclopentenone Esters and Optically Active Cycles
If each of the Lopentenone derivatives is not separated
To obtain only optically active cyclopentenones
Can be. [0020] The present invention will be described in more detail with reference to the following examples.
As will be described, the present invention is not limited to the embodiments. Example 1 (1) Structural formula 2- (6-methoxycarbonylhexyl) -4-hydr of
Roxy-2-cyclopentenone [1-1] 4.0 g,
0.5 g of Luthobacter lipase (Shin Nippon Chemical)
And a mixture of 50 ml of vinyl acetate at 25 ° C.
And stirred. On the way, the reaction solution was subjected to liquid chromatography.
Checked. 14 hours after the start of stirring, 2- (6-me
(Toxicarbonylhexyl) -4 (S) -hydroxy-
The optical purity of 2-cyclopentenone [2-1] is 98.5.
% Ee, the reaction was stopped, and
Pase was removed by filtration, and the filtration residue was washed with ethyl acetate and filtered.
Then, the mixture was concentrated under reduced pressure together with the filtrate. Concentrated residue4.
48 g were obtained. 2.24 g of the obtained concentrated residue
Separation and purification by column chromatography, [2-1] 0.94 g
(Optical purity 98.8% ee) and 4 (R) -acetoxy
-2- (6-methoxycarbonylhexyl) -2-cycl
1.24 g (90% ee) of Lopentenone [3-1]
I got each. In addition, compounds [2-1], [2-2], [2
-3], [2-4], [2-5], [9-1], [9-
2], [9-3], [9-4] and [9-5] optics
Purity was measured using an optically active column (Sumipax OA-450).
0: manufactured by Sumitomo Chemical Co., Ltd.) with compounds [3-1], [3-2],
The optical purity of [3-3], [3-4] and [3-5] is
Optically active column (Chiralcel OD: Daicel)
) Was measured by liquid chromatography
Specified. (2) 2.24 g of the concentrated residue obtained in (1) was
Dissolve in 15 ml of anhydrous THF,
2.05 g of phenylphosphine and 0.4 g of formic acid were added.
I got it. Then, at 10 ° C or less, diethyl azodicarboxylate
Add 1.36 g of steal and add 2 hours at 10 ° C, then room temperature
For 15 hours. Reaction liquid chromatography
After checking the disappearance of [2-1], the reaction mixture was
After concentration under reduced pressure, t-butyl methyl ether 30 was added to the residue.
ml of hexane and then 50 ml of hexane to remove insolubles.
It was removed by filtration. The filtrate is concentrated and 4 (R)
-Formyloxy-2- (6-methoxycarbonylhexyl)
Sil) -2-cyclopentenone [7-1] and [3-
1) was obtained. (3) [7-1] and [3] obtained in (2)
9 g of methanol and 3 g of 30% sulfuric acid
Was added and reacted at 40 ° C. for 5 hours. After the reaction,
Cool the reaction solution to 10 ° C or less, and p with 10% caustic soda water.
After adjusting H to 4.0, methanol was distilled off under reduced pressure.
The residue was extracted by adding 30 ml of ethyl acetate, and the organic layer was washed with water.
I washed. The obtained organic layer is concentrated under reduced pressure, and the residue is
Purified by muchromatography, 4 (R) -hydroxy-2-
(6-methoxycarbonylhexyl) -2-cyclopen
1.92 g of Tenon [9-1] (optical purity 94.0% e
e) was obtained. Embodiment 2 1.0 g of [3-1] obtained in Example 1 (1), 35% salt
0.3 g of acid water and 5 ml of methanol were added at 40 to 45 ° C.
Reacted for hours. After the reaction, cool the reaction solution to 10 ° C or less.
The pH was adjusted to 4.0 with 10% sodium hydroxide solution and then decreased.
The methanol was distilled off under pressure. Ethyl acetate 10m to the residue
The organic layer was washed with water. Organic layer obtained
Was concentrated under reduced pressure, and [9-1] 0.83 g (optical purity 9
0.0% ee) was obtained. Embodiment 3 (1) 0.5 g of [2-1] obtained in Example 1 (1)
Phenylphosphine 1.1 g, formic acid 0.2 g, THF1
After adding 0 ml and cooling to 10 ° C or less, azodicarboxylic acid
0.73 g of diethyl ester was added and the mixture was added at 10 ° C. for 2 hours.
The reaction was further performed at room temperature for 15 hours. Liquid chromatographic reaction
Check by torography to confirm disappearance of [2-1]
Thereafter, the reaction solution was concentrated under reduced pressure, and t-butylmethyl was added to the residue.
Add 15 ml of ether and 25 ml of hexane to precipitate
The crystals were removed by filtration. Concentrate the filtrate as a residue
[7-1] was obtained. (2) 5 g of methanol was added to the residue obtained in (1).
And 1 g of 50% sulfuric acid, and reacted at 35 ° C. for 6 hours.
I let you. After completion of the reaction, post-treatment and purification were performed according to Example 1 (3).
Then, [9-1] 0.48 g (optical purity 98.5% ee)
I got Comparative Example 1 Shoe instead of Arthrobacter lipase 0.50g
Domonas lipase (Amano P: manufactured by Shin Nippon Chemical)
25 g and the reaction scale was set to half that of Example 1.
The reaction was carried out in the same manner as in Example 1 except for the above. Compound [2-1]
The optical purity of 98.5% ee exceeded 18.5% after the start of the reaction.
Seven hours later. After that, the same post-processing and
0.60 g of the compound [2-1] (optical purity
98.7% ee) and 1.63 g of compound [3-1] (4
2.2% ee) were obtained in each case. Comparative Example 2 Pig pancreas instead of 0.50 g of Arthrobacter lipase
Lipase (manufactured by Sigma: No. L-3126) was added to 2
g, and the reaction scale is halved in Example 1
The reaction was carried out in the same manner as in Example 1. 24 hours after the start of the reaction
At this time, alcohol / ester = 63/37,
The optical purity of the product [2-1] was 70% ee. further
Add 0.6 g of swine pancreatic lipase, 72 hours after the start of the reaction
The reaction was continued until the optical purity of the compound [2-1] was 7
It only rose to 7% ee. Embodiment 4 (1) Structural formula 2- (6-methoxycarbonyl-3-cis-hexenic)
L) -4-hydroxy-2-cyclopentenone [1-
2] 2.38 g, Arthrobacter lipase (New Japan
0.28 g of vinyl acetate and 24 ml of vinyl acetate
The mixture was kept at 25 ° C. and stirred. On the way, the reaction liquid is
It was checked by chromatography. 13 after the start of the reaction
The reaction was stopped by time. At this time, 2- (6-methoxycarbo)
Nil-3-cishexenyl) -4 (S) -hydroxy-
The optical purity of 2-cyclopentenone [2-2] is 99.8.
% Ee. After completion of the reaction, follow the procedure of Example 1 (1).
The treatment operation was performed to obtain 2.72 g of a concentrated residue. Got
1.36 g of the concentrated residue was separated and purified by column chromatography.
Then, [2-2] 0.54 g (optical purity 99.8% e
e) and 2- (6-methoxycarbonyl-3-cishex)
(Cenyl) -4 (R) -acetoxy-2-cyclopenteno
[3-2] 0.77 g (88% ee) was obtained, respectively.
Was. (2) 1.36 g of the concentrated residue obtained in (1)
Add 8 ml of anhydrous THF and 2 ml of dichloromethane and dissolve
And triphenylphosphine 1.07
g and formic acid 0.23 g. Then azo at 10 ° C or less
1.36 g of diethyl dicarboxylate was added, and 10
The reaction was carried out at a temperature lower than or equal to 2 ° C. for 2 hours and at room temperature for 16 hours. Anti
The reaction solution was checked by liquid chromatography, and [2-
After confirming the disappearance of 2], the reaction solution was concentrated under reduced pressure, and
t-butyl methyl ether 15 ml, hexane 25 ml
Was added, and the precipitated crystals were removed by filtration. Concentrate the filtrate
And 4 (R) -formyloxy-2- (6-methoxyca)
Rubonyl-3-cishexenyl) -2-cyclopenteno
Thus, a mixture of [7-2] and [3-2] was obtained. (3) [7-1] and [3] obtained in (2)
-1] in 5 ml of methanol and 0.5 m of THF.
l and 1.5 g of 40% sulfuric acid at 40 ° C. for 6 hours
Reacted. After the reaction, cool the reaction solution to 10 ° C or less.
The pH was adjusted to 4.0 with 10% sodium hydroxide solution and then decreased.
The solvent was distilled off under pressure. Hereinafter, according to Example 1 (3)
After treatment and purification, 4 (R) -hydroxy-2- (6-
Methoxycarbonyl-3-cishexenyl) -2-cycl
1.13 g of lopentenone [9-2] (optical purity 93.4)
% Ee). Comparative Example 3 Shoe instead of 0.28 g of Arthrobacter lipase
Domonas lipase (Amano P: manufactured by Shin Nippon Chemical)
The reaction scale was set to 1/2 of that of Example 4 using 14 g.
The reaction was carried out in the same manner as in Example 4 except for the above. Compound [2-2]
The optical purity of 98.5% ee exceeded 18.5% after the start of the reaction.
Six hours later. After that, the same post-processing and
And 0.40 g of the compound [2-2] (optical purity
98.6% ee) and 0.75 g of compound [3-2] (5
0.5% ee) were each obtained. Comparative Example 4 Porcine pancreas instead of 0.28 g of Arthrobacter lipase
Lipase (manufactured by Sigma: No. L-3126)
1.19 g was used, and the reaction scale was set to half that of Example 4.
The reaction was carried out in the same manner as in Example 4 except for the reaction. 7 after the start of the reaction
At 5 hours, alcohol / ester = 63/37
The optical purity of the compound [2-2] was 40% ee.
Was. Further, add 0.3g of pig pancreatic lipase and start the reaction
The reaction was continued for 130 hours thereafter. At this time, alcohol / d
The steal was 50/50. After that, the same as in Example 4
Post-treatment and purification operations were performed to obtain 0.58 g of the compound [2-2].
(Optical purity 50% ee) and compound [3-2] 0.75
g were obtained. Embodiment 5 (1) 0.48 g of [2-2] obtained in Example 4 (1),
1.05 g of triphenylphosphine, 0.22 g of formic acid and
Charge 8 ml of THF, cool to 5 ° C.,
0.7 g of acid diethyl ester is added at 10 ° C. or lower.
Reaction at ４15 ° C. for 4 hours and further at room temperature for 15 hours
Was. After completion of the reaction, the reaction solution was concentrated. Hereinafter, Example 3
Post-treatment according to (1), and 4 (R) -formyloxy-2
-(6-methoxycarbonyl-3-cishexenyl)-
0.55 g of 2-cyclopentenone [7-2] was obtained. (2) 5.0 g of [7-2] obtained in (1)
0.15 g of 30% hydrochloric acid solution at 40-45 ° C for 5 hours
I responded. Hereinafter, post-treatment and purification were performed according to Example 3 (2).
And [9-2] 0.45 g (optical purity 98.9%)
Obtained. Embodiment 6 0.5 g of [3-2] obtained in Example 4, 0.1% of 35% hydrochloric acid
5 g and 2 ml of methanol are reacted at 40 to 45 ° C. for 4 hours.
did. Thereafter, post-treatment and purification were performed in the same manner as in Example 2, and 2-
(6-methoxycarbonyl-3-cishexenyl) -4
0.41 g of (R) -hydroxy-2-cyclopentenone
(Optical purity: 88.2%). Embodiment 7 (1) Structural formula Of 4-hydroxy- (6-methoxycarbonyl-3-he
(Xynyl) -2-cyclopentenone [1-3] 2.36
g, Arthrobacter lipase (Shin Nippon Chemical Co., Ltd.)
24 g, vinyl acetate 20 ml and hexane 3 m
1 of the mixture was kept at 20 ° C. and stirred. On the way, the reaction solution
Check by liquid chromatography and check 4 (R) -A
Sethoxy-2- (6-methoxycarbonyl-3-hexyl
Nyl) -2-cyclopentenone [3-3] and 4 (S)-
Hydroxy- (6-methoxycarbonyl-3-hexini
L) -2-cyclopentenone [2-3]
The reaction was terminated at the time of about 1: 1 and was performed according to Example 1 (1).
After work-up, a mixture of [3-3] and [2-3] 2.6
2 g were obtained. (2) [3-3] obtained in (1) and [2-
3) in a mixture of 15 ml of THF and triphenylphosphine.
2.62 g of formic acid and 0.46 g of formic acid were added and the reaction solution was brought to 5 ° C.
Cool and at the same temperature azodicarboxylic acid diethyl ester
Add 1.4 g, at 5-10 ° C for 4 hours, and at room temperature
Stirred for 20 hours. After completion of the reaction, according to Example 1 (2)
After post-treatment, 4 (R) -formyloxy-2- (6-
Methoxycarbonyl-3-hexynyl) -2-cyclope
2.70 mixture of nonenones [7-3] and [3-3]
g was obtained. (3) [7-3] and [3] obtained in (2)
13 ml of methanol and 30% sulfuric acid
3 g was added and reacted at 40 ° C. for 5 hours. End of reaction
Then, the pH was adjusted to 4.5 with caustic soda water, and
Post-treatment and purification were carried out according to Example 1 (3), and 4 (R) -hydroxy
C- (6-methoxycarbonyl-3-hexynyl) -2
2.26 g of cyclopentenone [9-3] (optical purity 9
1% ee) was obtained. Embodiment 8 (1) Structural formula Of 4-hydroxy-2- (6-methoxycarbonyl-2)
-Hexynyl) -2-cyclopentenone [1-4] 2.
36 g, Arthrobacter lipase (Nippon Chemical)
A mixture of 0.4 g and 23 ml of vinyl acetate was mixed with 3
It was kept at 0 ° C. and stirred. On the way, check the reaction solution,
(S) -hydroxy-2- (6-methoxycarbonyl-
2-hexynyl) -2-cyclopentenone [2-4]
The reaction was stopped when the optical purity exceeded 98% ee.
Pase was removed by filtration. Hereinafter, according to Example 1 (1)
[2-4] (optical purity 98% ee) and
4 (R) -acetoxy-2- (6-methoxycarbonyl
-2-hexynyl) -2-cyclopentenone [3-4]
2.66 g of a mixture having an optical purity of 92% ee was obtained. (2) [2-4] (optical purity) obtained in (1)
98% ee) and [3-4] (optical purity 92% ee)
1.33 g of triphenylphosphine 1.3
1 g, formic acid 0.39 g and THF 10 ml were added, and 5
0.87 g of diethyl azodicarboxylate
At room temperature for 5 hours and at room temperature for 18 hours.
I responded. After completion of the reaction, the reaction solution was concentrated, and t-butyl
Triphenylphosphine thiol in butyl ether and hexane
The oxide was removed by filtration, and the following procedure was followed according to Example 1 (2).
After post-treatment and purification, 4 (R) -formyloxy-2-
(6-methoxycarbonyl-2-hexynyl) -2-si
Mixture of Clopentenone [7-4] and [3-4]
1.48 g were obtained. (3) [7-4] and [3] obtained in (2)
-4] to 1.48 g of the mixture, methanol 6 g, 30%
1.48 g of sulfuric acid was added and reacted at 40 ° C. for 5 hours.
After completion of the reaction, the reaction solution was adjusted to pH 4.5 with caustic soda water.
And methanol was distilled off under reduced pressure. Residue in ethyl acetate
After extraction and washing with water, the organic layer is concentrated and
Purified by chromatography, 4 (R) -hydroxy-2- (6-
Methoxycarbonyl-2-hexynyl) -2-cyclope
1.12 g (94.8% e of optical purity)
e) was obtained. Embodiment 9 (1) [2-4] and [3-
1.33 g of the mixture of 4) was separated and purified by column chromatography.
Then, 0.55 g of [2-4] was obtained. (2) 0.47 g of [2-4] obtained in (1)
1.00 g of triphenylphosphine, 0.2 g of formic acid,
Add 3 ml of dichloromethane and azodical at 5 ° C or less.
0.70 g of boronic acid diethyl ester was added, and
Incubate for 5 hours. After completion of the reaction, the reaction mixture is concentrated and
Purification by muchromatography gave [7-4] 0.52 g
Was. (3) 0.5 g of [7-4] obtained in (2),
2.5 ml of methanol and 0.7 g of 30% sulfuric acid were added, and 3
The reaction was performed at 0 to 35 ° C for 3 hours. Hereinafter, Example 7 (3)
After-treatment and purification were carried out according to the procedures described in [9-4] 0.44 g.
(Optical purity 97.7% ee) was obtained. Embodiment 10 (1) Structural formula Of 4-hydroxy-2- (6-methoxycarbonyl-2)
-Cishexenyl) -2-cyclopentenone [1-5]
2.38 g, Arthrobacter lipase (Shin Nippon Chemical
Liquid mixture of 0.4 g and 23 ml of vinyl acetate
Was kept at 30 ° C. and stirred. Check the reaction solution on the way
And 4 (S) -hydroxy-2- (6-methoxycarbo
Nyl-2-cishexenyl) -2-cyclopentenone
When the optical purity of [2-5] exceeds 98% ee,
I stopped responding. Hereinafter, post-treatment and purification according to Example 1 (1)
[2-5] (optical purity 98.2% ee) and 4
(R) -acetoxy-2- (6-methoxycarbonyl-
2-cishexenyl) -2-cyclopentenone [3-
5] 2.60 g of a mixture of (optical purity 91.2% ee)
Obtained. (2) [2-5] (optical purity) obtained in (1)
98.2% ee) and [3-5] (optical purity 91.2%).
% Ee) to 2.60 g of the mixture of
3.04 g, formic acid 0.46 g and THF 10.4 m
l and 0.1 g of triethylamine, and then 5 ° C or lower.
Under the conditions, 1.74 g of diethyl azodicarboxylate was added.
For 5 hours at 5 to 10 ° C and 10 hours at room temperature
I responded. T-Butyl methyl ether, hexa
After that, post-processing is performed according to Example 1 (2).
4 (R) -formyloxy-2- (6-methoxyca)
Rubonyl-2-cishexenyl) -2-cyclopenteno
2.82 g of a mixture of [7-5] and [3-5] was obtained.
Was. (3) [7-5] and [3] obtained in (2)
-5] to 2.82 g of the mixture, 9 g of methanol and 40%
2.1 g of sulfuric acid was added and reacted at 40 ° C. for 4 hours. Less than
The post-treatment was carried out in the same manner as in Example 1 (3) to give 4 (R) -hydro
Xy-2- (6-methoxycarbonyl-2-cishexe
2.26 g of nyl) -2-cyclopentenone [9-5]
(Optical purity 94.3% ee) was obtained. Production Example 1 6-methoxycarbonyl-1-carboxy-cis-3-
Hexene 25.1 g, furan 13.8 g (0.20 mol) and black
To a mixture of 100 ml of roform at room temperature
15.5 g (0.074 mol) of acid anhydride was added, and at 20 to 25 ° C.
The reaction was performed for 24 hours. After the completion of the reaction, the reaction solution was diluted with 5% sodium carbonate.
Pour into 200 ml of water and separate the organic layer.
And washed. By concentrating the organic layer, 1-oxo-
1-furyl-7-methoxycarbonyl-cis-4-hep
14.5 g (yield 91%) of ten was obtained. Production Example 2 Next, 1-oxo-1-furyl-7-metho obtained in Production Example 1
12.8 g of xycarbonyl-cis-4-heptene (0.054
Is dissolved in 100 ml of methanol and 50 ml of chloroform
And add 20.4 g (0.054 mol) of sodium borohydride to 10
Added at -20 ° C. After keeping at the same temperature for 2 hours,
Was poured into ice and extracted with toluene. After separating the organic layer,
After washing with water and concentrating the organic layer, 1-hydroxy
Ci-1-furyl-7-methoxycarbonyl-cis-4-
12.3 g of heptene (96% yield) were obtained. Production Example 3 Next, 1-hydroxy-1-furyl-7- obtained in Production Example 2
11.3 g of methoxycarbonyl-cis-4-heptene (0.047
Mol) Add 473 g of water and 0.34 g of acetic acid and add 5% KOH water
PH is adjusted to 4.3 and the raw material runs out at 100 ° C
Until heated. 2- (6-methoxyca) is contained in the reaction system.
Rubonyl-3-cishexenyl) -4-hydroxy-2
-Cyclopentenone [1-2] and 2- (6-methoxy)
(Cicarbonyl-3-cishexenyl) -3-hydroxy
-2-cyclopentenone (producing ratio 65:35) is present
Was. Next, the pH of the reaction solution was raised to 7.0, and 2-
(6-methoxycarbonyl-3-cishexenyl) -3
Until hydroxy-2-cyclopentenone disappears.
The reaction was continued for another 10 hours. After the reaction is completed, the reaction solution is
Extracted twice with 300 ml of ethyl. Concentrate the organic layer and obtain
The obtained residue was chromatographed with toluene: ethyl acetate = 5: 3.
Purified. 2- (6-methoxycarbonyl-3-cis
Hexenyl) -4-hydroxy-2-cyclopentenone
[1-2] 7.97 g (yield 71%) was obtained. n_D ²⁰  1.
5023

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI C07C69 / 738 C07C69 / 738A JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C12P 41/00 C07C 45/67 C07C 49/707 BIOSIS (DIALOG) CA (STN)

Claims (3)

(57) [Claims] 1. The general formula [1] Of cyclopentenones and unsaturated alcohols
Reacting with a carboxylic acid ester having 2 to 4 carbon atoms in the presence of a lipase derived from Arthrobacter; And an optically active cyclopentenone derivative represented by the general formula [3]: And a mixture of the optically active cyclopentenone derivative [2] and the optically active cyclopentenone ester [3].
General formula [5] (Wherein R ₃ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) with a carboxylic acid represented by the general formula [4]: (Wherein, R ₂ represents an alkyl group.) Azodicarboxylate ester le general and formula represented by [6] (Wherein R ₄ is a lower alkyl group, a lower alkoxy group or a phenyl group optionally substituted with a halogen atom,
Or a cycloalkyl group which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom. Is reacted in the presence of a phosphine represented by the general formula [7] And a mixture of the optically active ester derivative [7] and the optically active cyclopentenone ester [3] represented by the following general formula: [8] (Wherein, R represents the same meaning as described above), which is reacted with an alcohol represented by the following general formula [9]: A method for producing an optically active cyclopentenone represented by the formula: 2. An optically active cyclopentenone, which comprises reacting a cyclopentenone [1] with a carboxylic acid ester of an unsaturated alcohol having 2 to 4 carbon atoms in the presence of a lipase derived from Arthrobacter. A mixture of the derivative [2] and the optically active cyclopentenone ester represented by the general formula [3] is obtained. Then, the optically active cyclopentenone derivative [2] obtained by separating the mixture and a carboxylic acid [5] are obtained. the co azodicarboxylate ester (4)及 beauty phosphines [6]
It is reacted under presence to give an optically active ester derivative [7], then the optically active ester derivative (7), optically active, characterized by reacting an alcohol [8] in the presence of an acid catalyst cyclo A method for producing a pentenone [9]. 3. An optically active cyclopentenone, which comprises reacting a cyclopentenone [1] with a carboxylic acid ester of an unsaturated alcohol having 2 to 4 carbon atoms in the presence of a lipase derived from Arthrobacter. A mixture of the derivative [2] and the optically active cyclopentenone ester [3] is obtained. Then, the optically active cyclopentenone ester [3] obtained by separating the mixture and the alcohol [8] are reacted with an acid catalyst. A process for producing an optically active cyclopentenone [9], which is carried out below.