JPH0733352B2 - Process for producing optically active 2-substituted-4-hydroxy-2-cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) (In the formula, R is And XY is CH ₂ -CH ₂ or cis CH = CH, and R'is an alkyl group), and is an optically active 2-substituted-4-hydroxy-2-
The present invention relates to a method for producing cyclopentenones.

Optically Active 2-Substituted-4-Represented by General Formula (I) above
Hydroxy-2-cyclopentenones are useful as intermediates for agricultural chemicals, fragrances, or pharmaceuticals, and can be used as important intermediates for prostaglandin derivatives, for example.

Furthermore, these optically active substances are converted into sulfonic acid esters with, for example, paratoluenesulfonic acid or methanesulfonic acid, and then reacted with a base, or with sodium acetate, sodium dichloroacetate, sodium trichloroacetate or the like. The corresponding ester may be converted to a 2-substituted-4-hydroxy-2-cyclopentenone having a configuration that is opposite to the original coordination by hydrolysis.

Conventionally, as a method for producing the optically active 2-substituted-4-hydroxy-2-cyclopentenones represented by the general formula (I), for example, the following method is known.

1) Tetrahedron Letters., No.49,4959 (1973) 2) J. Am. Chem. Soc., 97 865 (1975) However, the method 1) is not always satisfactory in terms of yield and optical purity, and there is a problem in that some by-products are formed, and the method 2) is a method for producing a triketone body as a raw material. Is not easy, and there are problems that it is not an industrially advantageous method because of the large number of subsequent steps, and any method is unsatisfactory as an industrial production method, An advantageous manufacturing method has been demanded.

From the above, the present inventors have conducted studies to industrially advantageously produce the 2-substituted-4-hydroxy-2-cyclopentenones represented by the general formula (I), and as a result, arrived at the present invention. .

That is, the present invention has the general formula (II) (In the formula, R has the same meaning as described above) and is an optically active 5-substituted-4-hydroxy-2-
A method for producing an optically active 2-substituted-4-hydroxy-2-cyclopentenone represented by the above general formula (I), which comprises rearrangement of cyclopentenone with steric retention. Is.

Here, the optically active 5-substituted-indicated by the general formula (II)
4-hydroxy-2-cyclopentenones have the general formula (III) (In the formula, R has the same meaning as described above, and R ₁ represents an acyloxyl group, provided that the substituent R at the 5-position and the substituent at the 4-position are
R ₁ is trans-coordinated), and can be easily produced by asymmetric hydrolysis of dl-cyclopentenone esters represented by ( ₁ ) using an esterase produced by a microorganism or an esterase derived from animals and plants.

Here, the dl-cyclopentenone ester represented by the general formula (III) used as a starting material is obtained by rearranging a furancarbinol compound as shown in the following formula, for example. It can be easily obtained by further esterifying hydroxy-2-cyclopentenones.

Examples of the esters include acetic acid ester, propionic acid ester, butyric acid ester, valeric acid ester, caprylic acid ester, chloroacetic acid ester, dichloroacetic acid ester, and the like.

The optically active 5-substituted-4-hydroxy-2-cyclopentenones represented by the general formula (II) are microorganisms capable of hydrolyzing dl-cyclopentenone esters represented by the general formula (III). It is carried out by hydrolyzing one of the optically active forms of the esters with esterase or animal and plant esterase.

The esterase-producing microorganism used in this reaction is not particularly limited as long as it is an esterase-producing microorganism that has the ability to asymmetrically hydrolyze dl-cyclopentenone esters. Esterase means a broad sense of esterase including lipase.) Specific examples of such microorganisms include, for example, microorganisms belonging to the following genera.

Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida Genus, Saccharomyces, Rhodotorula, Cryptococcus, Torrlopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, Microorganisms belonging to the genus Achromobacter Examples of microorganisms belonging to each of these genera include the following.

Rhodotorula minuta IFO−0387, IFO−0412, Rhodotorul
a rubra IFO−0870, Rhodotolura minuta var texe
nsis IFO−0879, Trichoderma Iongibrachiatum IFO
−4847, Candida krusei out−6007, Candida cylindr
acea, Candida tropicalis PK 233, Candida utilu
s IFO-1086, Pseudomonas fragi IFO-3458, Pseudom
onas putida IFO-12996, Pseudomonas fluorescens
IFO-3903, Pseudomonas aeruginosa aeruginosa I
FO-3080, Bacillus cereus IFO-3466, Bacillus sub
tilis ATCC-6638 Bacillus pulmilus IFO-12092,
Bacillus subtilis var niger IFO-3108, Nocardia
uniformis subtsuyanarenus ATCC-21806, Nocardia
uniformis IFO-13072, Chromobacterium chocolatu
m IFO-3758, Chromobacterium iodinum IFO-3558, F
lavobacterinm arbonescens IFO-3750, Flavobacteri
um heparinum IFO-12017 Rizopus chinensis IFO
−4768, Mucor javanicus IFO−4572, Aspergillus ni
ger ATCC-9642, Alcaligenes faecalis IFOM12669, T
orulopsis candida IFO-0768, Corynebacterium sep
edonicum IFO-13768, Saccaromyces rouxii IFO-05
05, Arthrobacter simplex IFO-3530, Streptomyces
grisens IFO-3356, Brevibacterium ammoniagenes I
FO-12072, Brevibacterium divaricatum ATCC-1402
0, Micrococcus varians IFO−3765, Micrococcus Iut
eus IFO−3066, Enterobacter cloacae IFO−3320, Co
nynebacterium ezui ATCC 7699, Lacto bacillus c
asei IFO 3322, Cryptococcus albidus IFO−0378, P
ihia polimorpha IFO-1166, penicillium frezuenta
ns IFO 5692, Aureobasidium pullulans IFO 4464,
Actinomucor elegans IFO 4022 Hansenula anomal
a var ciferrii out 6095, Hansenula anomala IF
O-0118, Achromobacter parvulus IFO-13181, Achrom
Cultivation of the bacterium sinplex IFO-12069, the above-mentioned microorganism is usually carried out by liquid culture according to a conventional method to obtain a culture solution. For example, sterilized liquid medium [malt extract / dairy extract medium for molds and yeasts (5 g of water, 1 g of peptone, 10 g of glucose, 3 g of malt extract)
g, yeast extract 3g to pH 6.5), and for bacteria use sweetened broth medium (water 1g glucose 10g, peptone 5)
g, meat extract 5 g, and Nacl 3 g are dissolved to adjust the pH to 7.2)], and the microorganism is inoculated, and the reciprocal shaking culture is usually performed at 20 to 40 ° C. for 1 to 3 days. Moreover, you may perform solid culture as needed.

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 (manufactured by Amano Pharmaceuticals) Aspergillus lipase (lipase AP
(Manufactured by Amano Pharmaceutical Co., Ltd.), lipase M-Ap of genus Mucor (manufactured by Amano Pharmaceutical Co., Ltd.), lipase of Candida syrindasse (lipase MY (manufactured by Meito Sangyo)) lipase of genus Alcaligenes (lipase PL (manufactured by Meito Sangyo)) , Achromobacter lipase (Lipase AL (Meito Sangyo)), Arthrobacter lipase (Nippon Kagaku), Chromobacterium lipase (Toyo Brewing), Rhizopus delemar lipase (Taripase) (Manufactured by Tabe Seiyaku Co., Ltd.), lipase of the genus Rhizopus (Lipase Saiken (Osaka Bacterial Research Institute)) Further, animal / plant esterases can also be used, and specific esterases thereof include the following. it can.

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

Esterase (hydrolase) used in this reaction,
As the use form of the enzyme obtained from animals, plants and microorganisms, there are various forms such as purified enzyme, crude enzyme, enzyme-containing product, microbial culture solution, culture, fungus body, culture oral liquid and processed products thereof. It can be used as necessary, and the enzyme and the microorganism can be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

This hydrolysis reaction is carried out by vigorously stirring the dl-cyclopentenone ester and the 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 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.

In addition, at the time of hydrolysis, in addition to the buffer solution, it is possible to use an organic solvent which is inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, and dichloromethane, and by using these, asymmetric hydrolysis is advantageously carried out. be able to.

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 such as methyl isobutyl ketone, ethyl acetate, and ethyl ether are subjected to an extraction treatment, The solvent is distilled off from the layer, and then the concentrated residue is further distilled or treated by column chromatography to obtain optically active 5-substituted-4-hydroxy-2-cyclopentenones and the hydrolysis residue. Each active 5-substituted-4-acyloxy-2-cyclopentenone can be isolated.

The optically active 5-substituted-4-acyloxy-2-cyclopentenones recovered here are further hydrolyzed,
It can be used as a raw material for producing a symmetrical body.

The optically active 2-substituted-4-hydroxy-2-cyclopentenones represented by the general formula (I) are the optically active 5-substituted-4-hydroxy-2-cyclopentenones obtained by the above-mentioned method.
It is produced by rearranging 4-hydroxy-2-cyclopentenones in the presence of a base or a catalyst while maintaining the steric structure.

Incidentally, no optically active 5-substituted-4-hydroxy-2-cyclopentenones represented by the general formula (II), which is a raw material of this reaction step, have been known so far, and only Tetrahedoron as a dl-form is known. Letters., 1131 to 1134 (177), but the literature does not describe the configuration of the 4-position hydroxyl group and the 5-position substituent.
Of course, even the possibility of optical activity and its separation is not described, and the possibility that the separated optically active substance is rearranged while retaining the steric structure, or the 2-substitution obtained by rearranging the steric substance while retaining the steric structure is possible. There is no description about the configuration of -4-hydroxy-2-cyclopentenones or even its recognition.

On the other hand, as stereoisomers of the optically active 5-substituted-4-hydroxy-2-cyclopentenones represented by the above general formula (II), there are Acta Chemie Academiae Scientiarum.
The following method is described in Hungaricae, Tomus 102 (1), PP91-100 (1979).

However, the compound of the formula (IV) has a different stereoconfiguration from the optically active 5-substituted-4-hydroxy-2-cyclopentenones represented by the general formula (II). The starting material, (−)-Cis-2-oxobicyclo [3.3.0] -oct-6-en-3-ol, must be optically active and requires many steps up to (IV). , Not always a satisfactory method.

As described above, the optically active 5-substituted-4-hydroxy-2-cyclopentenones represented by the general formula (II), which is a raw material in the present invention, are compounds synthesized by a method which has not been known so far. Then, the present inventors have also clarified the configuration for the first time.

When rearranging such an optically active 5-substituted-4-hydroxy-2-cyclopentenone while maintaining its steric structure, the rearrangement can be carried out while keeping the optical purity as high as possible, that is, by reducing racemization as much as possible. It is necessary, and for that purpose, it is preferable to carry out under appropriate conditions with respect to the base or catalyst used, temperature and the like.

Examples of the solvent used in this rearrangement reaction include:
Aliphatic or aromatic hydrocarbons such as water, tetrahydrofuran, dioxane, acetone, benzene, toluene, ethyl acetate, chlorobenzene, peptane, dichloromethane, dichloroethane, diethyl ether, cyclohexane, ethers, ketones, esters, halogenated hydrocarbons, etc. Solvents inert to the reaction are used alone or as a mixture.

Examples of the base or catalyst used in this reaction include organic tertiary amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N'-dimethylpiperazine, pyridine and lutidine, metals such as alumina and silica gel. Inorganic bases such as oxides, caustic soda, caustic potash, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium monohydrogenphosphate, and basic buffer solutions such as carbonate base buffer solutions are suitable, and these may be used alone or in combination of two kinds. Used above.

The amount of such a base or catalyst used is not particularly limited, but it is usually 0.05 to 60 times by mole with respect to the optically active 4-cyclopentenone alcohol as a raw material, and the organic tertiary
The primary amine and basic buffer can also be used as a solvent.

The reaction temperature is in the range of −20 to 130 ° C., the solvent used,
It is appropriately selected depending on the base or catalyst.

For example, when the reaction is carried out in the absence of water as a solvent, racemization is unlikely to occur, so the reaction can be carried out within the range of -10 to 90 ° C. In the case of an organic tertiary amine-water mixed system, the range of -10 to 50 ° C is preferable, and the range of -20 to 30 ° C is preferable for the rearrangement reaction with water alone or under strong basicity.

The reaction time is not particularly limited.

From the reaction mixture thus obtained, extraction, liquid separation,
The objective optically active 2-substituted-4-hydroxy-2-cyclopentenones represented by the general formula (I) can be obtained with good optical purity and good yield by general operations such as concentration and distillation. it can.

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

Raw Material Production Example 1 A flask is charged with 1,000 ml of water and 0.2 g of 2 potassium hydrogen phosphate, and the pH is adjusted to 4.2 with 5% phosphoric acid.

To this, 20 g of 2- (ω-methoxycarbonylhexyl) -furfuryl alcohol was added, and the mixture was heated with stirring for 12 hours.

After completion of the reaction, extraction is performed twice with 200 ml of toluene. The organic layer is concentrated under reduced pressure to obtain a concentrated residue (19.8 g).

19.8 g of this concentrated residue are dissolved in 100 ml of dichloromethane and 30 ml of pyridine are added. 13.1 g of acetyl chloride is added over 2 hours while keeping the internal temperature at 0 to 10 ° C. After incubating at the same temperature for 1 hour, react at 25-30 ° C for 3 hours.

After completion of the reaction, the organic layer was washed with water, 1% dilute hydrochloric acid, 1% aqueous sodium hydrogen carbonate and water successively, dried over magnesium sulfate and concentrated under reduced pressure to obtain 23.1 g of a concentrated residue.

This was purified by silica gel column chromatography using a mixed solution of toluene: ethyl acetate (5: 2), and 4-acetoxy-5- (ω-methoxycarbonylhexyl)-
97.5 g of 2-cyclopentenone are obtained.

▲ n ²⁰ _D ▼ 1.4809 Example 1 100 ml of 0.8M phosphate buffer (pH 7.5), 4-acetoxy-5- (ω-methoxycarbonylhexyl) -2-cyclopentenone was placed in a flask equipped with a stirrer and a thermometer. Four
g, 2 ml of dichloromethane, and 240 mg of Pseudomonas lipase (amanolipase "P") were charged, and the mixture was kept at 30 ° C for 15
Stir vigorously for hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of toluene.
The organic layers are combined and concentrated under reduced pressure to obtain 38.5 g of a concentrated residue.

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 2), and l-4-hydroxy-5- (ω-methoxycarbonylhexyl) -2-cyclopentenone 1.27 g ▲ [α] ²⁰ _D ▼ -16.3 ° (c = 1, CHCl ₃ ) mp 48 ° C. and d-4-acetoxy-5- (ω-methoxycarbonylhexyl) -2-cyclopentenone 2.33 g ▲ [α] ²⁰ _D ▼ + 27.2 ° ( c = 1, CHCl ₃ ) ▲ n ²⁰ _D ▼ 1.4826 was obtained.

1 g of 1-4-hydroxy-5- (ω-methoxycarbonylhexyl) -2-cyclopentenone obtained here was stirred with 20 g of alumina in 50 ml of toluene at 30 ° C. for 24 hours.

After completion of the reaction, alumina is separated and the liquid is concentrated.

The concentrated residue was further purified by silica gel column chromatography with toluene-ethyl acetate (5: 4) to obtain 0.91 g of 4R (+)-hydroxy-2- (ω-methoxycarbonylhexyl) -2-cyclopentenone.

▲ [α] ²⁰ _D ▼ 16.2 ° (c = 1, methanol) mp 59 ° C

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Claims (2)

[Claims] 1. A general formula (In the formula, R is And XY is CH ₂ -CH ₂ or cis CH = CH, and R'is an alkyl group.) Is an optically active 5-substituted-4-hydroxy-2-
A general formula characterized by rearranging cyclopentenones with steric retention (In the formula, R has the same meaning as described above.) The optically active 2-substituted-4-hydroxy-2-
A method for producing cyclopentenones. 2. General formula (In the formula, R is In a substituent represented, shows the X-Y is CH ₂ -CH ₂ or cis CH = CH and R 'is an alkyl group. R ₁ represents an acyloxyl group. However, the substituent R at the 5-position and the substituent R _{1 at the} 4-position are trans-coordinated. ) The dl-cyclopentenone ester represented by the general formula is asymmetrically hydrolyzed using an esterase produced by a microorganism or an esterase derived from an animal or plant. (In the formula, R has the same meaning as above.) The optically active 5-substituted-4-hydroxy-2-
A general formula characterized in that cyclopentenones are obtained and rearranged while retaining a steric structure. (In the formula, R has the same meaning as described above.) The optically active 2-substituted-4-hydroxy-2-
Method for producing cyclopentenones.