JPH0646960B2 - 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.) And the optically active 4-cyclopentenones, and a process for producing the same.

The optically active 4-cyclopentenones of the 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 introduced into a sulfonic acid ester with, for example, paratoluenesulfonic acid or methanesulfonic acid and then reacted with a base, or alternatively sodium acetate, sodium dichloroacetate, trichloroacetic acid. By reacting with soda etc. to form the corresponding ester and then hydrolyzing it to lead to a 2-substituted 4-hydroxy-2-cyclopentenone having a configuration that is opposite to the original configuration, and use it. You can also

The optically active 4-cyclopentenones represented by the above general formula (I) are represented by the general formula (II) (In the formula, R ″ represents an acyl group, and R has the same meaning as described above.) By reacting an esterase produced by a microorganism or an esterase derived from an animal or plant with dl-4-cyclopentenone ester represented by By asymmetric hydrolysis, optically active 4-cyclopentenones in which the substituent R'is a hydrogen atom in the general formula (I) and optically active 4-cyclopentenones in which R'is an acyloxyl group. Can be obtained as a mixture with.

Here, represented by the general formula (II) used as a raw material
dl-4-cyclopentenone esters have the general formula (III) (In the formula, R has the same meaning as described above.) Dl-2-substituted-3-hydroxy-4-cyclopentenones can be easily synthesized by reacting them with an organic carboxylic acid.

The dl-2-substituted-3-hydroxy-4-cyclopentenones are easily obtained, for example, by rearranging furancarbinols, and specific compounds thereof include the following compounds.

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-cyclopentenone.

The organic carboxylic acids include saturated or unsaturated organic carboxylic acid anhydrides and organic carboxylic acid halides, such as acetic anhydride, acetic acid chloride or bromide,
Propionic chloride or bromide, propionic anhydride, butyryl chloride or bromide, caproyl chloride or bromide, caprylic chloride or bromide, stearic chloride or bromide caprinoyl chloride or bromide, dodecanoin chloride or bromide, palmitoyl chloride or bromide, Examples include chloroacetyl chloride or bromide, dichloroacetyl chloride or bromide, and the like.

For the reaction of the dl-2-substituted-3-hydroxy-4-cyclopentenone and the organic carboxylic acid, ordinary esterification conditions are applied, and the reaction is performed using a catalyst in the presence or absence of a solvent. It is carried out by

When a solvent is used in this reaction, the solvent may be, for example, tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane or the like. Solvents such as aromatic hydrocarbons, ethers and halogenated hydrocarbons, which are inert to the reaction, may be used alone or as a mixture. The amount used can be used without particular limitation.

The organic carboxylic acid used in the reaction needs to be 1 equivalent or more with respect to the starting material dl-2-substituted-3-hydroxy-4-cyclopentenone, and the upper limit is not particularly limited, but it is preferably 4 equivalents. .

Examples of the catalyst include organic or inorganic basic substances such as triethylamine, tri-n-butylamine, pyridine, picoline, sodium carbonate, sodium methylate and potassium hydrogencarbonate. The amount used is not particularly limited, but is usually dl-2-substituted-3-hydroxy-4-
It is 1 to 5 equivalents relative to the cyclopentenones.

When an organic amine is used as a solvent, the amine may act as a catalyst.

Further, acids such as toluene sulfonic acid, methane sulfonic acid and sulfuric acid can also be used as a catalyst.

The reaction temperature is usually -20 ° C to 150 ° C, preferably -10 ° C to 120 ° C.

The reaction time is not particularly limited.

By such a reaction, the general formula (I
The dl-4-cyclopentenone esters represented by I) are easily obtained in good yield, and these are easily isolated from the reaction mixture by a usual separation means such as extraction, separation, concentration and distillation. However, when carrying out the method of the present invention, the reaction mixture can be used as it is.

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, Rhodotoru
la rubra IFO-0870, Rhodotolura minuta var texensi
s IFO-0879, Trichoderma longibrachiatum IFO-484
7, Candida Krusei out−6007, Candida cylindracea, Candida tropicalis PK 233, Candida ut
ilus IFO-1086, Pseudomonas fragi IFO-3458, Pseudomonas putida IFO-12996, Pseudomonas fluorescens IFO-3903, Pseu
domonas aeruginosa IFO-3080, Bacillus cereus IFO
-3466, Bacillus subtilis ATCC-6638, Bacillus pulmilus IFO-12092, Bacillus subtilis var niger IFO-310
8, Nocardia uniformis subtsuya-narenus ATCC-2180
6, Nocardia uniformis IFO-13072, Chromobacterium chocolatum IFO-3758, Chromobacterium iodinum IFO-3558, Flavobacterinm arbonescens IFO-3750, Flavobacterium heparinum IFO-12017, Rizopus chinensis IFO-4768, Mucor javanicus IFO-4572, Aspergill. Alcaligenes faecalis IFO-12669, Torulopsis candida IFO-0768, Corynebacterium sepedonicum IFO-13768, Saccaromyces rouxii IFO-0505, Arthrobacter simplex IFO-3530, Streptomyces grisens IFO-3356, Brevibacterium divaricarum IFO-12070, BreCC IFO-3765, Micrococcus luteus IFO-3066, Enterobacter cloacae IFO-3320, Corynebacterium equi ATCC-7699, Lacto bacillus casei IFO-3322, Cryptococcus albidus IFO-0378, Pihia polimorpha IFO-1166, Penicillium frequentans IFOsidium pull, AFO-5692 −4464, Actinomucor elegans IFO−4022, Hansenula anomala var ciferrii out 6095, Hansenula anomala IFO -0118, Achromobacter parvuius IFO-13181, Achromobacter sinplex IFO-12069, and the like are exemplified. For the culture of the above-mentioned microorganism, a liquid culture is usually carried out according to a conventional method to obtain a culture solution.

For example, sterilized liquid medium [for molds, yeasts, malt extract. Yeast extract medium (5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract are dissolved in 1 water to make pH 6.5), and for bacteria, sweetened broth medium (10 g of glucose in 1 water, 5 g of peptone, meat extract) 5 g Nacl 3 g is dissolved and pH is adjusted to 7.2)], and the microorganisms are inoculated, and the culture is usually performed by reciprocal shaking culture at 20 to 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.

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. Cylindrace lipase [Lipase MY (manufactured by Meito Sangyo)], Alcaligenes lipase [Lipase PL
(Manufactured by Meito Sangyo Co., Ltd.)], lipase of Achromobacter genus [lipase AL (manufactured by Meito Sangyo)], lipase of genus Arthrobacter [lipase-combined BSL (purified joint liquor)], lipase of chromobacterium (toyo) Brewed), Rhizopus.
Derema lipase [Talipase (Tanabe Seiyaku)], Rhizopus lipase [Lipase Saiken (Osaka Bacterial Research Institute)].

Also, animals. 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. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

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 the pH thereof is an alkalophilic bacterium. The pH of the culture broth or the alkaline esterase is preferably 8 to 11, and the pH of the culture broth of a non-alkalophilic microorganism or the esterase having no alkali tolerance is preferably 5 to 8. Concentration is usually 0.05-2
M, preferably 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 is not limited thereto.

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-cyclopetenone in which the substituent R ′ is a hydrogen atom is produced, and on the other hand, a general formula ( In I), the substituent R'is an acyloxyl group, and is an optically active 2-substituted-3-acyloxyl-
4-Cyclopentenone remains as a hydrolysis residue as it is, and eventually, 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 never been known so far,
2-substituted-3-hydroxy-4-cyclopentenone dl
Tctrahedron Letter, NO.39, 3555-355 as a unit
8 (1976) describes that the pair is (1).

However, the specific description and separation of the pair (1) of the optically active substances are not described at all, and even the possibility thereof is not described. Of course, the separated optically active substances retain the steric structure. The possibility of rearrangement,
Nothing is known about the configuration of 2-substituted-4-hydroxy-2-cyclopentenone obtained by rearrangement while maintaining the configuration.

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

Example 1 dl-3-hydroxy-2-n-penter-4-cyclopentenone was placed in a flask equipped with a stirrer and a thermometer.
8 g, p-toluenesulfonic acid 0.1 g and acetic anhydride 33.6 g were charged, and stirring was continued at 100 ° C. for 2 hours.

After completion of the reaction, acetic anhydride is distilled off under reduced pressure, and the residue is extracted with toluene. Wash the toluene layer with 1% sodium bicarbonate solution,
Wash further with water.

Toluene was distilled off from the organic layer, and dl-3-acetoxy-
2-n-pentyl-4-cyclopentenone 19.5 lg
Yield 93%) was obtained.

(Bp 105-110 ° C / 0.2-0.5 mmHg) dl-
3-acetoxy-2-n-pentyl-4-cyclopentenone 5 g and lipase P-30A (manufactured by Amano Pharmaceutical Co., Ltd.) 10
200 mg of 0.1 M phosphate buffer (pH 7.0) 200
Stir vigorously in ml 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 l-3-hydroxy-2-n-pentyl-4-cyclopentenone. 1.8 g (yield 45%)
{Optical rotation α] _D ²⁰ -53.3 ° (c = 1, chloroform), refractive index ▲ n ²⁵ _D ▼ 1.4692} and d-3-acetoxy-2-n-pentyl-4-cyclopentenone 2.54 g
{Optical rotation ▲ α] ²⁰ _D ▼ + 112.0 ° (c = 1, chloroform) and refractive index ▲ n ²⁵ _D ▼ 1.4621} were obtained.

Example 2 13.8 g of dl-2-allyl-3-hydroxy-4-cyclopentenone and 0.1 g of toluenesulfonic acid were placed in a flask.
Then, 27.6 g of acetic anhydride is charged and heated at 90 to 100 ° C. for 3 hours. Hereinafter, post-treatment according to Example 1,
Purification yielded 16 g of dl-3-acetoxy-2-allyl-4-cyclopentenone (89% yield). (Bp80-
85 ° C./0.6 to 1 mmHg) dl-3-acetoxy-2-allyl-4-cyclopentenone 5.5 g and lipase PL (Meito Sangyo Co., Ltd.) 0.2 g
250 ml of 0.1M phosphate buffer (pH 7.0)
Stir vigorously at 25-35 ° C for 24 hours. After completion of the reaction, post-treatment and purification were carried out in accordance with Example 1 to give 1-2-allyl-3-hydroxy-4-cyclopentenone 1.68.
g (yield 40%) {▲ α] ²⁰ _D ▼ -28.2 ° (c =
1, chloroform), ▲ n ²⁵ _D ▼ 1.5048} and d-
2-acetoxy-2-allyl-4-cyclopentenone (2.86 g) ({α) ²⁰ _D ▼ + 68.8 ° (c = 1, chloroform), ▲ n ²⁵ _D ▼ 1.4824} was obtained.

Example 3 3 g of dl-3-acetoxy-2-n-pentyl-4-diclopentenone and lipase combined BSL (combined liquor purification)
150 mg of 0.1M phosphate buffer (pH 7.0) 1
Stir vigorously in 20 ml at 30 ° C. for 20 hours. After completion of the reaction, post-treatment and purification were carried out in accordance with Example 1, l-3-hydroxy-2-n-pentyl-4-cyclopentenone 1.
01 g (yield 42%) {▲ α] ²⁰ _D ▼ -51.6 ° (c
= 1, chloroform), ▲ n ²⁵ _D ▼ 1.4701} and d
-3-acetoxy-2-n-pentyl-4-cyclopentenone 1.54 g {▲ α] ²⁰ _D ▼ + 107.5 ° (c =
1, chloroform), ▲ n ²⁵ _D ▼ 1.4609} was obtained.

Example 4 3 g of dl-3-acetoxy-2-propargyl-4-cyclopentenone and Lipase M-AP (manufactured by Amano Pharmaceutical Co., Ltd.) 5
0 mg of 0.1M phosphate buffer (pH 6.0) 100
Stir vigorously in ml at 25-35 ° C. for 20 hours. After completion of the reaction, the reaction solution is extracted 3 times with 50 ml of hexane. The hexane layer was evaporated under reduced pressure to remove the solvent, and the concentrated residue was subjected to column chromatography with a mixed solution of ethyl acetate: toluene = 1: 10 to give 1.68 g of d-3-acetoxy-2-propargyl-4-cyclopentenone. {▲ α] ²⁰ _D ▼ + 82.9 ° (c = 1, chloroform), ▲ n ²⁵ _D ▼ 1.5042} were obtained.

Further, the remaining aqueous layer extracted with hexane is extracted four times with 50 ml of methyl isobutyl ketone. The methyl isobutyl ketone layers are combined and the solvent is distilled off under reduced pressure.

0.99 g of l-3-hydroxy-2-propargyl-4-cyclopentenone are obtained.

Yield 42.2% {▲ α] ²⁰ _D ▼ -42.6 ° (c = 1,
Chloroform), ▲ n ²⁵ _D ▼ 1.5258]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-57-38741 (JP, A) JP-A-57-188538 (JP, A) JP-A-58-31994 (JP, A) JP-A-58- 47495 (JP, A) Tetrahedron, 35 (1979) P. 135-138 Tetrahedron, 39 (1972) P. 213-220 Pharmaceutical Journal 92 (1972) P. 213-220

Claims (1)

[Claims] 1. A general formula (In the formula, R ″ represents an acyl group, and R represents an alkyl group, an alkenyl group or an alkynyl group.) To a dl-4-cyclopentenone ester represented by the following formula:
A general formula characterized by asymmetric hydrolysis by the action of esterase produced by microorganisms or esterase derived from animals and plants (In the formula, R ′ represents a hydrogen atom or an acyl group, and R has the same meaning as described above.) A process for producing an optically active 4-cyclopentenone compound.