JPH0761995B2 - Process for producing 2,3-disubstituted-4-substituted cyclopentanones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to 2,3-disubstituted-4-substituted cyclopentanones,
It relates to a method for producing the enantiomer or a mixture thereof.

<Prior Art> Natural prostaglandins (hereinafter abbreviated as PG) are known as local hormones (autocoids) having biologically and pharmacologically high activities. With the aim of developing new drugs by skillfully utilizing these physiological characteristics of PGs, research is being conducted on not only natural PGs but also various derivatives.

Natural PGE ₂ and PGF ₂ α, which are typical compounds of PGE and PGFs, have a uterine smooth muscle contraction action and are provided as the most useful labor-promoting drug. On the other hand, natural PGE ₁ is one of the type 1 prostaglandins, which is a compound having unique biological activities such as platelet aggregation inhibitory action and blood pressure effect action, and has recently been used as a therapeutic agent for peripheral circulation in the medical field. It is a useful natural product.

Conventionally, many methods are known for the production of these PGE and PGF [JBBindla (JBBind
ra) et al., Prostagland Synthesis
din Synthesis), Academic Press (Academic Pr)
ess) (1977)]. Among them, the following methods are typical methods.

(I) Method obtained by biosynthesis from arachidonic acid or dihomo-γ-linolenic acid [B. Sam Elson (B. Sa
Muelsson) et al., Angevante Chemie International Edition in English (Angev.Ch
em.Int.Ed.Engl.) 4, 410 (1965 ) refer] (ii) is a key intermediate Corey (Corey) method via lactone [E. J. Corey (EJCore
y) et al., Journal of the American Chemical Society (J.Amer.Chem.Soc.), 92, 397 (197).
0)] (iii) Method via a 2-substituted-2-cyclopentenone body which is an important intermediate [CJSi (CJSi
h) et al., Journal of the American Chemical Society (J.Amer.Chem.Soc.), 97, (1975).
Reference] (iv) Method for selectively reducing 5,6-dehydro PGE ₂ or PGF ₂ α [ES Ferdinandi (ESFe
rdinandi) et al., Canadian Journal of Chemistry (Can.J.Chem.), 49 , 1070 (1971)],
[See CHLin et al., Prostaglandin, 11 , 377 (1976)] However, in the method (i) obtained by biosynthesis among these methods, polyunsaturated fatty acid as a raw material is used. Is difficult to obtain, and the yield from this is very low, and it is difficult to obtain a product from a by-product. In addition, the methods (ii) to (iv) obtained by chemical synthesis have many steps to obtain a starting material, and even if the starting material is easily obtained, the production of prostaglandins from such a starting material has not yet been completed. It has many steps and therefore has the point to be improved that the overall yield is very low.

In order to overcome these difficulties, a three-component coupling process method was proposed as a direct synthesis method of the PG skeleton, which uses a coupling addition reaction to a 2-cyclopentenone system followed by an enolate trapping process [Gee Stoke ( G.Stock) et al., Journal of the American Chemical Society (J.Amer.Chem.Soc.), 97, 6260 (1975), KGUntch et al., Journal of the Journal. -Organic Chemistry (J.Org.Chem.), 44 , 3755].

However, in this method, enolate is trapped using formaldehyde, which is a low molecular weight compound, and PG skeleton synthesis must be achieved by chemical synthesis via the obtained important intermediate. It has a drawback that the total yield is also low.

On the other hand, the three-component connection process method enables more effective PG
The following proposals have been made to manufacture the skeleton.

(1) JP-A-50-96542, JP-A-50-101337, G-Posner et al., Tetrahedron Letters, 2591 (19)
74) and GH Posner et al., Journal of the American Chemical Society (J. Amer. Chem. Soc.), 97, 107 (1974); The present invention relates to a method for producing 2,3-di-substituted cyclopentanones by conjugate-adding an organocopper compound to pentenone and then alkylating with a halide. In these reports, there are no examples of producing prostaglandins, only examples of model systems are described, and 4-substituted-2
No example is disclosed of preparing 4-substituted-2,3-disubstituted cyclopentanones from -cyclopentenones.

(2) G. W. Patterson, Jr. (JW
Patterson, Jr.) and J Et Fried (JHFri
ed), Journal of the Organic Chemistry (J.Org.Chem.), 39, 2506 (1974); In this report, the method of (1) above is applied to 2-cyclopentenone. It has been successful in the synthesis of 11-deoxy-prostaglandin E _1. However, the possibility of producing 4-substituted-2,3-disubstituted-cyclopentanones from 4-substituted-2-cyclopentenones is not even disclosed.

(3) G. Stork and M. Isobe (MI)
sobe), Journal of the American Chemical Society (J.Am.Chem.Soc.), 97,6260 (197)
5); In this report, we succeeded in capturing the enolate obtained by conjugating an organocopper compound to 4-substituted-2-cyclopentenones with monomeric formaldehyde. However, a negative conclusion is reached regarding the alkylation reaction in which the above enolate is captured by an alkylating agent.

(4) JA Noguez and Elle
A Maldonado, Synthetic Communication
s), 6, 39 (1976); In this report, the enolate formed after conjugation of a lithium salt of cyanohydrin with a protected ω chain of prostaglandin to 2-cyclopentenone was introduced. Is trapped with propargyl halides, leading to 11-deoxyprostaglandin derivatives. However, from 4-substituted-2-cyclopentenones, 4-substituted-
Even the possibility is not disclosed for a method for producing 2,3-disubstituted cyclopentanones.

(5) R. Davis and K. Guntch, Journal of the Organic Chemistry (J.Org.Chem.), 44, 3755 (197).
9); In this report, 4-substituted-2-cyclopentenones were conjugated with an organocopper compound having an organic group corresponding to the ω chain of prostaglandins, and the resulting enolate was directly alkylated with allyl halides. It argues that it has made various studies aimed at becoming commercialized, but that they all failed.

(6) AJ Dixon and RJKTaylor, Journal of the Chemical Society (J.Cem.So)
c.), Parkin I, 1407 (1981); According to this report, it has been difficult to progress until now, 2-
We have succeeded in allylating the enolates formed from cyclopentenone and organocopper compounds and obtaining intermediates for 11-deoxyprostaglandin synthesis. However, from 4-substituted-2-cyclopentenones, 4-substituted-
Regarding the method for producing the 2,3-disubstituted cyclopentanones, neither specific examples nor even the possibility thereof are disclosed.

(7) Nishiyama et al., Tetrahedro Letters
n Letters), 25, 233 (1984) and 25, 2487 (1984); In these reports, trimethylsilyllithium or methyllithiotrimethylserialacetate was conjugated to 2-cyclopentenone, followed by addition of tributyltin chloride, and then propalyl. We have succeeded in alkylating enolate with bromide derivatives. However, even in the case of this report, as for the method for producing 4-substituted-2,3-disubstituted cyclopentanones from 4-substituted-2-cyclopentenones, not to mention the possibility Not even disclosed.

The above-mentioned conventional techniques (1) to (7) and other conventional techniques are described in Angewandte Chemie International Edition in English (Angewandte C).
hemie International Edition in English), 23 , No.1
1, November 1984 Pages 847-876 Ryoji Nnyori et al.
Prostaglandin Synthesis by Three Component Coupling
A review titled Three-Component Coupling) is helpful.

<Problems to be Solved by the Invention> An object of the present invention relates to a novel method for producing 2,3-disubstituted-4-substituted cyclopentanones, enantiomers thereof or a mixture thereof.

Another object of the present invention is 2,3-disubstituted-4-, such as PGEs.
It relates to an efficient process for producing substituted cyclopentanones, enantiomers thereof or mixtures thereof.

In order to achieve the object of the present invention, the present inventors previously reacted an organolithium compound represented by the above formula (2) in the presence of a cuprous compound to give an organocopper compound, which was converted into the above formula ( 1-) 4-substituted-2-cyclopentenones, their enantiomers or a mixture thereof in an arbitrary ratio are subjected to a conjugate addition reaction, and then the halides are reacted in the presence of a trihydrocarbon tin halide. A method for producing a 2,3-disubstituted-4-substituted cyclopentanone represented by the above formula (4), an enantiomer thereof, or a mixture thereof in any proportion has been proposed (JP-A-62-81344). reference).

After that, as a result of diligent research on a more efficient and simple method for achieving this object, as a result, an organolithium compound was conjugated-added with a 4-substituted-2-cyclopentenone derivative in the presence of an organozinc compound, and then the resulting activity was produced. It has been found that a 2,3-disubstituted-4-substituted cyclopentanone derivative can be produced by reacting a seed with a halide, and the present invention has been completed.

<Structure and Effect of Invention> In the present invention, the following formula (1) is used. A 4-substituted-2-cyclopentenone represented by the following formula, its enantiomer or a mixture thereof in any ratio is represented by the following formula (2): An organic lithium compound represented in, reacted in the presence of an organic zinc compound, then the active species generated in the system, the following equation _{(3) X-CH 2 -Y} -R 6 ... (3) Represented by the following formula (4), characterized by reacting halides There is provided a novel method for producing a 2,3-disubstituted-4-substituted cyclopentanone represented by the following formula, its enantiomer or a mixture thereof in any ratio.

The 4-substituted-2-cyclopentenones used as a raw material in the present invention are represented by the above formula (1). In the formula (1), R ² is a tri (C ₁ -C ₇ ) hydrocarbon silyl group or 1
- an alkoxy-substituted (C ₁ ~C ₅₎ alkyl group.

The tri (C ₁ ~C ₇₎ hydrocarbon silyl group, such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t- butyl tri (C ₁ ~, such as dimethylsilyl group
C ₄ ) alkylsilyl, diphenylmethylsilyl, diphenyl (C ₁ -C ₄ ) alkylsilyl such as t-butyldiphenylsilyl group, phenyldi (C ₁ -C ₄ ) alkylsilyl such as phenyldimethylsilyl or tribenzylsilyl A group etc. can be mentioned as a preferable thing. Of these, the t-butyldimethylsilyl group is particularly preferable.

Examples of the ₁ -alkoxy-substituted (C ₁ -C ₅ ) alkyl group include methoxymethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl, 1-ethoxy-1-methylethyl,
Mention is made of (2-methoxyethoxy) methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hex-4-yl group. be able to. Of these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 1-methoxy-1
The -methylethyl, (2-methoxyethoxy) methyl or 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hex-4-yl group is particularly preferred.

Specific examples of the compound represented by the above formula (1) will be apparent based on the above definition of R ² and the specific examples thereof.

The enantiomer of the compound represented by the above formula (1) has the following formula (1 ′) [Here, the definition of R ² is the same as the above formula (1). ]] Is represented.

The 4-substituted-cyclopentenones used as the starting material of the present invention can be compounds represented by the above formulas (1) and (1 ′) and a mixture of these compounds in any ratio. Equimolar mixtures of the compounds of the formulas (1) and (1 ′) are racemic, and when one of the compounds is more than the other, the mixture shows a degree of light rotation depending on their mixing ratio.

The other starting material in the production method of the present invention is the organolithium compound represented by the above formula (2). Such an organolithium compound can be prepared, for example, by a known method, by reacting a corresponding iodine compound with t-butyllithium,
Alternatively, it can be easily produced by reacting a corresponding trihydrocarbon tin compound with n-butyllithium.

In the formula (2), R ³ represents a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a 1-alkoxy-substituted (C ₁ -C ₅ ) alkyl group, R ⁴ represents a hydrogen atom or a methyl group, R ⁵ is a linear or branched (C _{3 to} C ₁₀ ) alkyl group, a linear or branched (C _{3 to} C ₁₀ ) armenyl group, a linear or branched (C _{3 to} C ₁₀ ) alkyl group, or substituted Alternatively, it represents an unsubstituted (C ₃ -C ₁₀ ) cycloalkyl group, and n represents 0 or 1.

The tri (C ₁ ~C ₇₎ hydrocarbon silyl group or a 1-alkoxy-substituted (C ₁ ~C ₅₎ alkyl group R ^3, above, groups exemplified in R ² is likewise preferably cited.

R ⁴ represents a hydrogen atom or a methyl group, and when n is 0, R ⁴ is preferably a hydrogen atom, and when n is 1, R ⁴ is preferably a methyl group.

Examples of the straight-chain or branched-chain (C ₃ ~C ₁₀₎ alkyl group R ⁵ n-propyl, n- butyl, n- pentyl, n- hexyl, n
-Heptyl, n-octyl, n-nonyl, n-decyl, 1-methylpentyl, 1-methylhexyl, 1,1-dimethylpentyl, 2-methylpentyl, 2-methylhexyl, 5-methylhexyl, 2,5 -Dimethylhexyl group and the like, preferably n-butyl, n-pentyl, n-hexyl, (R)
-Or (S)-or (RS) -1-methylpentyl, (R)-or (S)-or (RS) -2-methylhexyl group and the like can be mentioned.

Examples of the straight-chain or branched-chain (C ₃ ~C ₁₀₎ alkenyl group R ⁵ 2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 4-hexenyl, 2-methyl-4-hexenyl,
2,6-dimethyl-5-heptenyl group and the like can be mentioned.

Examples of the straight-chain or branched-chain (C ₃ ~C ₁₀₎ alkynyl group R ⁵ 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 4-hexynyl, 2-octynyl, 5-decynyl, 1
-Methyl-3-pentynyl, 1-methyl-3-hexynyl, 2-methyl-4-hexynyl groups and the like can be mentioned.

Examples of the substituted or unsubstituted (C ₃ -C ₁₀ ) cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, (C ₁ -C ₅ ) alkylcyclopentyl, (C ₁ -C _4). ) Alkylcyclohexyl, dimethylcyclopentyl, dimethylcyclohexyl, chlorocyclopentyl, bromocyclohexyl, iodocyclopentyl, fluorocyclohexyl groups and the like can be mentioned, with preference given to cyclopentyl and cyclohexyl groups.

The organolithium compound represented by the above formula (2) has an asymmetric carbon in the molecule, but in the method of the present invention, the R-form or the S-form or a mixture thereof in any ratio can be contained. Specific examples of such an organolithium compound include
It will be apparent from the above specific examples of R ³ , R ⁴ , and R ⁵ . Among them, a preferable example of the formula (2) by a particularly preferable combination is the following formula (2 ′). The organolithium compound represented by the formula (3) is preferred, and the S configuration is particularly desirable for the configuration of the asymmetric carbon.

The reason why the organolithium compound represented by the above formula (2 ′) is particularly preferable is that it is consistent with a part of the skeleton of natural prostaglandins.

In the production method of the present invention, first, 4-substituted-2-cyclopentenones represented by the above formula (1), enantiomers thereof or a mixture thereof at an arbitrary ratio (hereinafter, this compound group is referred to as the above formula (1) ), Which is represented by 4-substituted-2-cyclopentenones) and an organolithium compound represented by the above formula (2) in the presence of an organozinc compound. To be

Examples of the organozinc compound include di (C ₁ -C ₆ ) hydrocarbon zinc, and among them, dimethyl zinc, diethyl zinc, diphenyl zinc and the like are preferably used. Among them, dimethyl zinc is particularly preferably used. The organozinc compound is used in an amount of 0.01 to 5 mol times, preferably 0.1 to 3 mol times, and particularly preferably 0.5 to 1.5 mol times the amount of the organolithium compound represented by the above formula (2). To be done. The embodiment is usually carried out by adding a separately prepared organozinc compound to a reaction solution prepared by preparing an organolithium solution and bringing them into sufficient contact. As the organic solvent used at this time, the organic solvent used when the organolithium compound is prepared is preferably used as it is. For example, hydrocarbons such as pentane, hexane, heptane, diethyl ether, dimethoxyethane, and tetrahydrofuran. Such as ethers, aromatic hydrocarbons such as benzene and toluene, or a mixed solvent system thereof. The amount of the organic solvent used may be an amount sufficient for the reaction to proceed smoothly, and usually,
It is used in a range of 1 to 100 times the volume of the reactant.

The reaction temperature is usually -10 when adjusting the organolithium compound.
It is carried out at 0 ° C to -60 ° C, preferably near -78 ° C, and the contact between the organolithium compound and the organozinc compound is -100 ° C to 2
It is carried out at 0 ° C., preferably around 0 ° C. Contact time is 0
One hour or less is sufficient in the vicinity of ° C.

The production method of the present invention proceeds by adding a 4-substituted-2-cyclopentenone represented by the formula (1) to the mixture of the organolithium compound and the organozinc compound thus obtained.

The 4-substituted-2-cyclopentenones and the organolithium compound are stoichiometrically equimolar, but
For 1 mol of 4-substituted-2-cyclopentenones, 0.
The organolithium compound is used in an amount of 5 to 2.0 mole times, preferably 0.8 to 1.5 mole times, and particularly preferably 0.9 to 1.3 mole times.

As the reaction temperature, for example, a temperature range of −100 ° C. to 20 ° C., particularly preferably −78 ° C. to 0 ° C. is adopted. The reaction time varies depending on the reaction temperature, but usually the reaction proceeds sufficiently if the reaction is carried out at -78 ° C to -20 ° C for about 1 hour.

The reaction is advantageously carried out in the presence of organic solvents. An inert aprotic organic solvent that is liquid at the reaction temperature and does not react with the reaction reagent is preferably used.

Suitable examples of the aprotic inert organic solvent include the organic solvents mentioned above, and hexamethylphosphoric triamide (HMPA), N, N-dimethylformamide (DMF), N, N -Dimethylacetamide (D
MAC), dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, and so-called aprotic polar solvents such as 1,3-dimethyl-2-imidazolidinone.
These can also be used as a mixed solvent of two or more kinds. Further, as the aprotic inert organic solvent, the inert solvent used for producing the organolithium compound may be used as it is. That is, in this case, the organolithium compound may be produced, and then the 4-substituted-2-cyclopentenones may be added to the reaction system to which the organozinc compound has been added to carry out the reaction. The organic solvent may be used in an amount sufficient for the reaction to proceed smoothly, but it is usually used in an amount of 1 to 100 times, preferably 3 to 30 times the volume of the reactant.

The reaction temperature is -100 ° C to 0 ° C, preferably -78 ° C to -30.
° C, particularly preferably carried out in the range of -78 ° C to -40 ° C,
The reaction time is within a few hours when the reaction temperature is around -78 ° C.

Thus, in the steps up to this point of the method of the present invention, a substituent that is an organic moiety derived from an organolithium compound is introduced into the reaction system at the 3-position of the 4-substituted-2-cyclopentenones as the starting material. The generated anion active species are formed. In the method of the present invention, the halides represented by the formula (3) are then added to the anion active species to form the 2,3-represented by the formula (4).
The production of di-substituted-4-substituted cyclopentanones is achieved. The halides used in this step are represented by the following formula (3).

X—CH ₂ —Y—R ⁶ (3) In the above formula (3), X represents a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, Y represents an ethylene group, an ethynylene group, a trans-vinylene group, Alternatively, it represents a cis-vinylene group, and R ⁶ represents a hydrogen atom, a trimethylsilyl group, or a (C ₁ -C ₇ ) alkyl group optionally substituted with a (C ₁ -C ₁₀ ) alkoxycarbonyl group. Where (C ₁ ~
The C ₁₀ ) alkoxycarbonyl group means a group having 1 to 10 carbon atoms other than carbonyl carbon.

Among the halogen atoms represented by X, a bromine atom, an iodine atom, particularly an iodine atom is preferable, and among the groups represented by Y, an ethynylene group and a cis-vinylene group are preferable.
The R ⁶ (C ₁ ~C ₁₀₎ alkoxy optionally substituted with a carbonyl group (C ₁ ~C ₇₎ alkyl group (C ₁ ~C ₇₎ alkyl moieties branched be straight It may be in the form of, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and heptyl groups.

The (C ₁ -C ₇ ) alkyl group may be, for example, (C ₁ -C ₇ ).
C ₄₎ alkoxy groups, 1-alkoxy-substituted (C ₁ ~C ₅₎ alkyl group, tri (C ₁ ~C ₇₎ hydrocarbon silyl group, also those which are substituted by (C ₂ ~C ₆₎ acyloxy Reference Take as an example.

1-alkoxy substituted (C ₁ -C ₅ ) alkyl group, tri (C ₁ -C ₅ )
Specific examples of the C ₇ ) hydrocarbon silyl group include the groups exemplified for R ² and R ^{3 as} they are. Examples of the (C ₁ -C ₄ ) alkoxy group include methoxy, ethoxy, propoxy, butoxy groups, and examples of the (C ₂ -C ₆ ) acyloxy group include acetoxy, propionyloxy, benzoyloxy groups and the like. As the (C ₁ -C ₁₀ ) alkoxycarbonyl group, for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxyarbonyl, butoxycarbonyl, phenoxycarbonyl, hexyloxycarbonyl, cyclohexyloxycarbonyl, decyloxycarbonyl group and the like can be mentioned. Preferred examples include:

Among the halides represented by the above formula (3), the following formula (3 ′) The halide represented by is particularly preferable because the product when it is used is a prostaglandin analog skeleton.

In the above formula (3 ′), X has the same definition as above,
A similar group is preferably exemplified, and Y'represents an ethynylene group or a cis-vinylene group. m represents an integer from 1 to 5, 3 is most preferable, R ¹ represents a (C ₁ -C ₁₀ ) alkyl group, examples of which are the above-mentioned (C ₁ -C ₁₀ ) alkoxycarbonyl groups. Corresponding to (C ₁ ~
C ₁₀ ) alkyl groups.

Further, in the halides represented by the above formula (3), Y
Is a vinylene group, R ⁶ is a hydrogen atom, Y is an ethynylene group, R ⁶ is a hydrogen atom halides, Y is an ethynylene group, R ⁶ is a trimethylsilyl group halides This is a preferred embodiment because the product used is an intermediate raw material for the prostaglandin analog.

In the latter half of the process of the present invention, the anion activity in which a substituent is introduced into the 3-position of the 4-substituted-2-cyclopentenones produced in the reaction system and existing in the system as described above is used. The reaction is carried out by reacting the seed as it is with the halides represented by the above formula (3) in the system.

The halides of formula (3) react stoichiometrically in equimolar amounts with the anion active species generated by the conjugate addition,
Usually, it is used in an amount of 0.8 to 10.0 mol times, particularly preferably 1.0 to 6.0 mol times, relative to the 4-substituted-2-cyclopentenone used first.

The reaction temperature is -100 ° C to 0 ° C, preferably -78 ° C to -20 ° C.
A range of temperatures is used. The reaction time varies depending on the type of halides used and the reaction temperature. Normally, -78 ℃
The reaction is terminated by allowing it to react at -30 ° C for about 1 to 50 hours, and it is efficient to determine the end point of the reaction by tracing by thin layer chromatography or the like.

In the method of the present invention, the step of alkylating an anion active species with a halide (3) is carried out by the above-mentioned aprotic polar solvent, especially hexamethylphosphoric triamide, N.
It is preferably carried out in the presence of -methylpyrrolidone, 1,3-dimethyl-2-imidazolidone, and often gives good results. After the reaction, the usual means (post-treatment, extraction, washing,
Separation and purification by chromatography, distillation, or a combination thereof.

Thus, according to the present invention, the following formula (4) 2,3-disubstituted-4-substituted cyclopentanones represented by the following formula (4 ') The enantiomer represented by or a mixture thereof in any proportion can be produced.

Among the compounds represented by the above formula (4), the following formula (4 ″) The compound represented by is the most preferred compound.

In the above formula (4 ″), a compound in which Y ′ is a cis-vinylene group and m is 3 has a prostaglandin E ₂ skeleton, and a compound in which Y ′ is an ethynylene group and m is 3 is 5 It has a 6,6-didehydroplastaglandin E ₂ skeleton, and the latter 5,6-didehydroprostaglandin E ₂ is a natural PGE ₁ , PGE ₂ , PGF ₁ α, PGF ₂ α, PGD ₁ , PGD ₂ and PGI
It has already been shown that each of the _two can be induced (Noyori et al., Angewandte Chemie International Edition in English (Angewandte Chemie
Inter-national Edition in English), 23,847,198
Four). Moreover, since the important intermediate of prostaglandin synthesis can be produced as described above, the present invention should be sufficiently evaluated as a production method capable of providing such a useful compound.

Further, one of the features of the method of the present invention is that all the reactions used proceed stereospecifically. Therefore, from the starting material having the configuration represented by the above formula (1), the above formula (4) ( A compound having a steric configuration represented by (including (4 ″)) is obtained, and a mirror image pair represented by the above formula (4 ′) is obtained from the enantiomer of the above formula (1). From the mixture in any proportion, the target mixture reflecting the proportion is obtained, and the organolithium compound of the formula (2) (including (2 ′)) contains an asymmetric carbon. Therefore, although there are two kinds of optical isomers, any of the optically active isomers or a mixture of them at an arbitrary ratio can be used in the production method of the present invention. ) The compound with the configuration represented by A particularly useful stereoisomers because it possesses prostaglandin same configuration and such.

As described above, the formula (1) is used as described in detail for the manufacturing method of the present invention.
Of 4-substituted-2-cyclopentenones of formula (2) with an organolithium compound of formula (2) in the presence of an organozinc compound to generate anion active species as halides of formula (3). The method for producing the 2,3-disubstituted-4-substituted cyclopentanones of formula (4) has the following features. That is, (1) unlike the method via an organic copper compound, it is not necessary to use a phosphine compound as a ligand.

(2) Do not use heavy metals.

(3) Experiment operation is simple.

And the like, which is an industrially useful manufacturing method.

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

Example 1 5,6 Jidehidoru -11,15-0- bis (t-butyldimethylsilyl) prostaglandin E ₂ methyl ester (S, E) -3- (t-
A solution of butyldimethylsilyloxy) -1- (tributylstannyl) -1-octene (570.1 mg, 1.07 mmol) in dry tetrahydrofuran (5 ml) was added, and the mixture was cooled to −78 ° C. and then n-butyllithium (1.55M hexane). Solution, 0.692 ml,
1.07 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 40 minutes. Dimethyl zinc (2.88M toluene solution, 0.372 ml, 1.
(07 mmol) was added and the reaction mixture was warmed to 0 ° C. This was stirred at 0 ° C for 15 minutes and then cooled to -78 ° C. A solution of (R) -4-t-butyldimethylsilyloxy) -2-cyclopentenone (209.7 mg, 0.987 mmol) in tetrahydrofuran (9 ml) was added to this reaction solution at -78 ° C for 40 minutes using a liquid delivery pump. Was dropped. The reaction mixture was stirred at -78 ° C for 15
After stirring for minutes, hexamethylphosphoric triamide (0.343 ml, 1.97 mmol) was added and stirring was continued at -78 ° C for 30 minutes. Then, a hexamethylphosphoric triamide (1.37 ml, 7.9 mmol) solution of methyl 7-iodo-5-heptate (1316 mg, 4.95 mmol) was added to this solution at -78 ° C.
It was stirred for 1 hour. After bringing the cooling bath to −50 ° C., stirring was continued for 22 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution (30 ml) to terminate the reaction, then the organic layer was separated and washed with saturated brine (30 ml). The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated to give an oily crude product. This product was subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1).
The product fraction was obtained by subjecting to silica gel chromatography (silica gel 15 g, hexane: ethyl acetate = 50: 1 to 18: 1) to give the title compound (376.5 mg, 0.632 mmol, 64).
%) Was obtained.

TLC: Rf = 0.50 (ethyl acetate - hexane = 1: 5) IR (liquid ^{film); 1746,1246,827,761cm -1 1 H NMR (} CD Cl 3 -C Cl 4, 1: 1) δ; 0.04 and 0.06 (S, 12, SiCH ₃ × 2), 0.89 (s, 18, SiC (CH ₃ ) ₃ × 2), 0.92 (t, z, J = 6.5HZ, CH ₃ ), 1.1-1.5 (m, 8 , CH ₂ × 4), 1.7−2.9 (m, 12, CH ₂ CO × 2, CH ₂ C≡ × 2, CH × 2, and CH ₂ ), 3.65 (s, 3, OCH ₃ ), 4.05 (m , 2, CHOSi × 2), 5.4-5.7 (m, 2, vinyl). ¹³ C NMR (CD Cl ₃ ) δ; −4.7, −4.5 (for two), −4.2,13.6,14.0,16.9,18.0,1
8.2,22.6,24.2,25.0,25.8 (3 pieces), 25.9 (3 pieces), 3
1.9,32.7,38.6,47.7,51.4,51.9,52.9,72.7,73.1,77.3,8
0.8,128.2,136.8,173.4,213.4. ▲ [α] ²¹ _D ▼; -13.9 ° ( C 1.59, CH ₃ OH) Example 2 By the same method as in Example 1, (±)-(E) -3- (T
-Butyldimethylsilyloxy) -1- (tributylstannyl) -1-octene and (±) -4- (t-butyldimethysilyloxy) -2-cyclopentenone, and (±) -5 , 6-Didehydro-11,15-0-bis (t
- was obtained butyldimethylsilyl) prostaglandin E ₂ methyl ester and its diastereoisomers. Yield 64
%.

Claims (4)

[Claims] 1. The following formula (1) A 4-substituted-2-cyclopentenone represented by the following formula, its enantiomer or a mixture thereof in any ratio is represented by the following formula (2): The organolithium compound represented by the formula (3) is reacted with an organozinc compound in the presence of an organozinc compound. Represented by the following formula (4), characterized by reacting halides A method for producing a 2,3-disubstituted-4-substituted cyclopentanone represented by, an enantiomer thereof, or a mixture thereof in any proportion. 2. An organolithium compound of the above formula (2) is represented by the following formula (2 ') The manufacturing method according to claim 1, represented by: 3. The organic zinc compound is dimethyl zinc, diethyl zinc, or diphenyl zinc.
The manufacturing method described. 4. A halide represented by the above formula (3) is represented by the following formula (3 '). The manufacturing method according to claim 1, represented by: