JPH0691836B2 - Process for producing optically active cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) (In the formula, R ′ represents a hydrogen atom or an acyl group, and R represents an alkyl group, an alkenyl group or an alkynyl group.
The substituent R at the 2-position and the substituent OR 'at the 3-position are in cis coordination) and an optically active 4-cyclopentenone and a method for producing the same.

The optically active 4-cyclopentenones of the above general formula (I) are novel compounds synthesized by the present inventors for the first time, and the compounds themselves are useful as intermediates for agricultural chemicals, fragrances or pharmaceuticals. For example, in the above formula, when R'is a hydrogen atom, for example, 1-2-substituted-3-hydroxy-4-cyclopentenone is rearranged while retaining the steric structure, then a 2-substituted- having a R (+) coordination It can be 4-hydroxy-2-cyclopentenone, which can be used as an important intermediate for prostaglandin derivatives.

Furthermore, the optically active substance obtained by the above rearrangement is converted into a sulfonic acid ester by, for example, paratoluenesulfonic acid chloride or methanesulfonic acid chloride, and then reacted with a base, or alternatively sodium acetate or sodium dichloroacetate. , 2-chloro-4-sodium trichloroacetate and the like to give the corresponding ester, followed by hydrolysis to give 2-substituted 4-
It can also be used by introducing it into hydroxy-2-cyclopentenone.

The optically active 4-cyclopentenones represented by the above general formula (I) are represented by the general formula (II) (Wherein R ″ is an acyl group and R has the same meaning as described above, provided that the substituent R at the 2-position and the acyloxy group at the 3-position are in cis coordination). An optically active 4-cyclopentene in which the substituent R'is a hydrogen atom in the general formula (I) is obtained by asymmetric hydrolysis of a cyclopentenone ester with an esterase produced by a microorganism or an esterase derived from an animal or plant. It can be obtained as a mixture of tenones and optically active 4-cyclopentenones in which R'is an acyloxyl group.

Here, dl represented by the general formula (II) used as a raw material
For example, -4-cyclopentenone esters are obtained by rearranging a furancarbinol compound as shown below, and transforming the resulting dl-2-substituted-3-hydroxy-4-cyclopentenones with an organic carboxylic acid. It can be synthesized by reacting an acid to form an ester, and then contacting with a base to epi-form the substituent at the 2-position to form a cis-coordinate, and if necessary, separate from the trans-coordination.

As such dl-4-cyclopentenone esters,
The substituent R at the 2-position and the hydroxyl group at the 3-position are in cis coordination, for example, 3-hydroxy-2-methyl-4-cyclopentenone, 2-ethyl-3-hydroxy-4-cyclopentenone, 3- Hydroxy-2-n-propyl-4-cyclopentenone, 2-isopropyl-3-hydroxy-4-
Cyclopentenone, 3-hydroxy-2-n-butyl-
4-cyclopentenone, 2-isobutyl-3-hydroxy-4-cyclopentenone, 3-hydroxy-2-n-
Pentyl-4-cyclopentenone, 2-isopentyl-
3-hydroxy-4-cyclopentenone, 3-hydroxy-2-n-hexyl-4-cyclopentenone, 3-hydroxy-2-n-heptyl-4-cyclopentenone,
2-allyl-3-hydroxy-4-cyclopentenone,
2- (2-cis-butenyl) -3-hydroxy-4-cyclopentenone, 2- (ω-butenyl) -3-hydroxy-4-cyclopentenone, 2- (2-cis-pentenyl) -3- Hydroxy-4-cyclopentenone, 3-hydroxy-2- (2-trans-pentenyl) -4-cyclopentenone, 2- (3-cis-hexenyl) -3-
Hydroxy-4-cyclopentenone, 3-hydroxy-
2-propargyl-4-cyclopentenone, 3-hydroxy-2- (2-pentynyl) -4-cyclopentenone, 3-hydroxy-2- (α-methylallyl) -4-
Dl-2-substituted-3-hydroxy- such as cyclopentenone
Examples of saturated or unsaturated organic carboxylic acid esters of 4-cyclopentenones include carboxylic acids such as acetic acid, propionic acid, lactic acid, valeric acid, caprylic acid,
Examples include stearic acid, dodecanoic acid, palmitic acid, chloroacetic acid and dichloroacetic acid.

Such asymmetric hydrolysis of dl-4-cyclopentenone esters is caused by the action of an esterase produced by a microorganism or an esterase derived from animals and plants to hydrolyze one of the optically active substances of the raw material dl-4-cyclopentenone esters. It is done by disassembling.

The esterase-producing microorganism used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze the dl-4-cyclopentenone esters represented by the general formula (II). It is not particularly limited.

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, Brevibacterium, Cydudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus,
Examples of microorganisms belonging to Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, and Achromobacter, more specifically, Rhodotorula minuta IFO-0387, IFO −0412, Rhodotorul
a rubra IFO-0870, Rhodotolura minuta var texensis
IFO-0879, Trichoderma longibrachiatum IFO-4847,
Candida krusei out−6007, Candida cylindracea, Ca
ndida tropicalis PK 233, Candida utilus IFO-1086,
Pseudomonas fragi IFO−3458, Pseudomonas putida I
FO-12996, Pseudomonas fluorescens IFO-3903, Pseu
domonas aeruginosa IFO-3080, Bacillus cereus IFO
−3466, Bacillus subtilis ATCC-6638, Bacillus pul
milus IFO−12092, Bacillus subtilis var niger IFO
−3108, Nocardia uniformis subtsuyanarenus ATCC−2
1806, Nocardia uniformis IFO−13072, Chromobacteri
um chocolatum IFO-3758, Chromobacterium iodinum I
FO-3558, Flavobacterinm arbonescens IFO-3750, Fl
avobacterium heparinum IFO-12017, Rizopus chinens
is IFO−4768, Mucor javanicus IFO−4572, Aspergill
us niger ATCC−9642, Alcaligenes faecalis IFO−126
69, Torulopsis candida IFO-0768, Corynebacterium
sepedonicum IFO−13763, Saccaromyces rouxii IFO−0
505, Arthrobacter simplex IFO-3530, Streptomyces
grisens IFO-3356, Brevibacterium ammoniagenes IFO
−12072, Brevibacterium divaricarum ATCC−14020, M
icrococcus varians IFO−3765, Micrococcus luteus I
FO-3066, Enterobacter cloacae IFO-3320, Coryneba
cterium equi ATCC−7699, Lacto bacillus casei IFO
−3322, Cryptococcus albidus IFO−0378, Pihia poli
morpha IFO-1166, Penicillium frequentans IFO-569
2, Aureobasidium pullulans IFO−4464, Actinomucor
elegans IFO-4022, Hansenula anomala var ciferrii
out 6095, Hansenula anomala IFO−0118, Achromobact
er parvuius IFO-13181, Achromobacter sinplex IFO
-12069 and the like are exemplified.

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, a sterilized liquid medium [malt extract / yeast extract medium for molds and yeasts (5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract dissolved in 1 water, pH
6.5), and for bacteria, a broth containing sugar (10 g of glucose, 5 g of peptone, 5 g of meat extract and 3 g of Nacl 3 g are dissolved in 1 of water to have a pH of 7.2)] and the microorganism is inoculated, usually at 20 to 40 ° C.
The culture may be performed by reciprocal shaking culture 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.

Lipase of the genus Cichudomonas (manufactured by Amano Pharmaceuticals) Lipase of the genus Aspergillus [lipase AP (manufactured by Amano Pharmaceuticals)], lipase AP of the genus Mucor (manufactured by Amano Pharmaceuticals)], Candida
Cylindracee lipase [Lipase MY (Meito Sangyo)], Alcaligenes lipase [Lipase PL (Meito Sangyo)], Achromobacter lipase [Lipase AL (Meito Sangyo)], Arthrobacter Lipase [lipase joint BSL (purified joint liquor)], chromobacterium lipase (manufactured by Toyo Brewing Co., Ltd.), rhizopus derema lipase [talipase (manufactured by Tanabe Seiyaku]], lipase lipase [lipase Saiken (Osaka bacterium) Institute)].

Animal / plant esterases can also be used, and specific esterases thereof include the following.

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

As the esterase used in this reaction, an enzyme obtained from an animal, a plant or a microorganism is used, and its usage forms include a purified enzyme, a crude enzyme, an enzyme-containing material, a microorganism culture solution, a culture, a bacterium, 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.

The asymmetric hydrolysis reaction of the present invention is usually carried out by vigorously stirring a mixture of the starting dl-4-cyclopentenone esters and the above enzyme or microorganism in a buffer solution.

As the buffer solution, a commonly used buffer solution of an inorganic acid salt such as sodium phosphate or potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate or sodium citrate, etc. is used, and its pH is an alkalophilic bacterium. PH of 8 to 11 for the culture solution and alkaline esterase, and for the culture solution of microorganisms that are not alkalophilic and esterase that does not have alkali tolerance
A pH of 5-8 is preferred. The concentration is usually 0.05 to 2M, preferably
It is in the range of 0.05 to 0.5M.

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

By this reaction, one of the optically active dl-4-cyclopentenone esters is hydrolyzed,
In the general formula (I), an optically active 2-substituted-3-hydroxy-4-cyclopentenone in which the substituent R ′ is a hydrogen atom is produced, and on the other hand, an optically active 2-substituted-3-hydroxy-4-cyclopentenone which is the other optically active substance of the starting compounds is generally used. An optically active 2-substituted-3-acyloxyl-4 wherein the substituent R ′ in the formula (I) is an acyloxyl group.
-Cyclopentenone remains as a hydrolysis residue as it is, and in the method of the present invention, the above two kinds of optically active compounds are simultaneously obtained as a hydrolysis product and a hydrolysis residue.

After the completion of such a hydrolysis reaction, in order to separate the hydrolysis product and the hydrolysis residue from the reaction solution, the hydrolysis reaction solution is treated with, for example, methyl isobutyl ketone, ethyl acetate,
Extraction treatment with a solvent such as ethyl ether, the solvent is distilled off from the organic layer and then the concentrated residue is further distilled, or it is carried out by a method such as column chromatography.
As a result, the optically active 2-substituted-indicated by the general formula (I)
3-hydroxy-4-cyclopentenone and optically active 2
The -substituted-3-acyloxyl-4-cyclopentenones can be separated.

The optically active 2-substituted-3-acyloxyl-4-cyclopentenone obtained here can be further hydrolyzed and used as a raw material for producing a symmetric body.

Incidentally, the optically active 4-cyclopentenones represented by the general formula (I) of the present invention have not been known at all in the past, and the trans isomer as a dl isomer has a Tctrahedron Letter, No. 39, 35.
55-3558 (1976) describes that the pair is (1).

The activator (1) is described in JP-A-60-78585. However, regarding the cis configuration (2), the possibility of its formation has not been mentioned at all, and its existence has not been known. Therefore, the specific physical properties and usefulness of the optically active substance are not known at all, and of course the separated optically active substance may undergo rearrangement while retaining the steric structure, or may be obtained by rearranging while maintaining the steric condition. Nothing is known about the configuration of 2-substituted-4-hydroxy-2-cyclopentenones.

In addition, dl- having a cis-coordinate, which is a raw material in the present invention
The 4-cyclopentenone esters have a substrate specificity for an enzyme which is particularly excellent as compared with that of trans-coordination, so that the optical purity of the obtained optically active 4-cyclopentenones is extremely high.

Hereinafter, the present invention will be described with reference to examples.

Example 1 A flask equipped with a stirrer and a thermometer was charged with 13.8 g of dl-2-allyl-3-hydroxy-4-cyclopentenone, 0.1 g of toluenesulfonic acid and 27.6 g of acetic anhydride, and 90
Heat at -100 ° C for 3 hours. After completion of the reaction, acetic anhydride is distilled off under reduced pressure, and the residue is extracted with toluene. The toluene layer is washed with 1% sodium hydrogen carbonate solution and further washed with water. Toluene is distilled off from the organic layer to obtain a concentrated residue.

To this concentrated residue was added triethylamine 0.5g, and at 30 ℃
Stir for 20 hours.

The reaction solution is dissolved in toluene and washed with N-HCl water.
After washing with water, toluene was distilled off from the organic layer, and the residue was purified by chromatography to obtain dl-3-acetoxy-2-allyl-4-.
6 g of cyclopentenone was obtained. (▲ n ²⁰ _D ▼ 1.4817) 5 g of dl-3-acetoxy-2-allyl-4-cyclopentenone and 0.2 g of Arthrobacter lipase (manufactured by Shin Nippon Kagaku Co.) were added to 0.1 M phosphate buffer (pH 7.0). In 200 ml,
Stir vigorously at 25-35 ° C for 20 hours. After completion of the reaction, the reaction solution is extracted 4 times with 50 ml of methyl isobutyl ketone.
The solvent was distilled off from the obtained organic layer, and the concentrated residue was purified by column chromatography with a mixed solution of ethyl acetate: toluene = 3: 5 to give 1.67 g of l-2-allyl-3-hydroxy-4-cyclopentenone. (Yield 43.6%) {▲ [α] ²⁰ _D ▼ -148.7 °
(C = 1, chloroform), ▲ n ²⁵ _D ▼ 1.5075, optical purity 100% (separation of optical isomers by SUMIPAX OA-4100 manufactured by Sumika Chemical Analysis Center)} and d-3-acetoxy-2-allyl-4-. cyclopentenone 2.75 g {▲ [α] ²⁰ _D ▼ + 132.
3 ° (C = 1, chloroform), ▲ n ²⁵ _D ▼ 1.4822} was obtained.

Claims (1)

[Claims] 1. A general formula (In the formula, R ″ represents an acyl group, R represents an alkyl group, an alkenyl group, or an alkynyl group. However, the substituent R at the 2-position and the substituent OR ′ at the 3-position are in cis coordination) A general formula characterized by asymmetrically hydrolyzing the indicated d1-4-cyclopentenone esters with an esterase produced by a microorganism or an esterase derived from an animal or plant. (In the formula, R ′ represents a hydrogen atom or an acyl group, and R has the same meaning as described above, provided that the substituent R at the 2-position and 3-
The substituent OR 'at the position is cis-coordinated), and a process for producing optically active 4-cyclopentenones.