JPH064557B2 - Process for producing 2,3-disubstituted-4-substituted cyclopentanones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Application> The present invention relates to a method for producing a 2,3-disubstituted-4-substituted cyclopentanone, an enantiomer thereof, 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 a new drug by skillfully utilizing these physiological characteristics of PGs, studies have been conducted on not only natural PGs but also various derivatives.

PGE, natural PGE ₂ , which is a typical compound of PGFs,
PGF ₂ α has a uterine smooth muscle contraction action and is provided as a most useful labor-promoting drug. On the other hand, natural P
GE ₁ is one of the type 1 prostaglandins, is a compound having specific biological activities such as an inhibitory effect on platelet aggregation and an antihypertensive effect, and is useful as a therapeutic agent for peripheral circulation in the medical field in recent years. It is a natural product.

Conventionally, many methods are known for producing these PGE and PGFs [JB Bindra et al., Prostaglandin Synthesis, Academics. Press (Academic Press) (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 Ingredients (Angev. C)
hem. Int. Ed. Engl.) 4 , 410 (1965)] (ii) Method via an important intermediate, Corey lactone [EJ Corey (EJ Core
y) et al., Journal of the American Chemical Society (J. Amer. Chem. Soc.), 92 , 3
97 (1970)] (iii) Method via a 2-substituted-2-cyclopentenone body which is an important intermediate [CJ Si (CJ Si
h) et al., Journal of the American Chemical Society (J. Amer. Chem. Soc.), 97 , 8
65 (1975)] (iv) Method for selectively reducing 5,6-dehydro-PGE ₂ or PGF ₂ α [ES Ferdinandi et al., Canadian International Journal of・ Chemistry (Can. J. Chem.), 49 , 10
70 (1971)], [C. Etch Lin (C.
H. Lin) et al., Prostaglandin,
11 , 377 (1976)] However, among these methods, the method obtained by biosynthesis
In (i), the polyunsaturated fatty acid that is the raw material is difficult to obtain, and the yield from this is very low, and it is difficult to purify and obtain the by-product. Further, in the methods (ii) to (iv) obtained by chemical synthesis, there are many steps for obtaining the starting material, while even if the starting material is easily obtained, the production of prostaglandins from such starting material Still goes through many steps and therefore the overall yield is very low and has some points to be improved.

In order to overcome these difficulties, a three-component coupling process method was proposed as a direct synthesis method of the PG skeleton using the capture process of Elenote following the conjugate addition reaction to the 2-cyclopentenone system [Gee Stoke ( G. Stock) et al., Journal of the American Chemical Society (J. Amer. Chem. Soc.), 97 , 6262 (197).
5). K.G.Untch et al., Journal of the Organic Chemistry (J.
Org. Chem.), 44 , 3755].

However, in this method, capture of elenote is carried out 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, P can be more efficiently
The following proposals have also been made to manufacture the G skeleton.

(1) JP-A-50-96542, JP-A-50-1
No. 01337, G. Etch Posner (GH
Posner) et al., Tetrahedron Letters
Letters), 2591 (1974), and G.H. Posner et al., Journal of the American Chemical Society (J. Amer. Chem. Soc.), 9.
7, 107 (1974); all of these reports are methods for producing 2,3-disubstituted cyclopentanones by conjugate addition of an organocopper compound to 2-cyclopentenone and then alkylation with a halide. It is about. In these reports, there are no examples of producing plastaglandins, only examples of model systems are described, and 4-substituted-
No example of preparing 4-substituted-2,3-disubstituted cyclopentanones from 2-cyclopentenones is disclosed.

(2) G. Davry Patterson Giunia (JWP
atterson, Jr) and J. Etsch Fleet (JHFrie)
d), Journal of the Organism Chemistry (J. Org. Chem.), 39, 2506 (1974); In this report, the method of (1) above was applied to 2-cyclopentenone. -Successful synthesis of deoxyprostaglandin E ₁ . However, even the possibility of producing 4-substituted-2,3-disubstituted-cyclopentanones from 4-substituted-2-cyclopentenones is not disclosed.

(3) G.Stork and M.Is
ob), Journal of the American Chemicals
Society (J. Am. Chem. Soc.), 97, 6260
(1975); In this report, the enolate obtained by conjugate-adding an organocopper compound to 4-substituted-2-cyclopentenones has been successfully captured with monomelic formaldehyde. However, a negative conclusion has been reached regarding the alkylation reaction in which the above enolate is captured by an alkylating agent.

(4) J.A. Noguez and L.A. Maldonando, Synthetic Communic
ations), 6, 39 (1976); In this report, the enolate formed after conjugation of a lithium salt of cyanohydrin protected with a portion corresponding to the ω chain of prostaglandin to 2-cyclopentenone was introduced. Is trapped with propargyl halides, leading to an 11-deoxyprostaglandin derivative. However, even the possibility of producing 4-substituted-2,3-disubstituted-cyclopentanones from 4-substituted-2-cyclopentenones is not disclosed.

(5) R. Davis and K. Gunch, J. Org. Chem., 44, 3755
(1979); In this report, an organocopper compound having an organic group corresponding to the ω chain of a prostaglandin was conjugated and added to a 4-substituted-2-cyclopentenone, and the produced enolate was directly added by an allyl halide. He discusses various investigations aimed at alkylation, but all of them were unsuccessful.

(6) AJ Dixon (AJ Dixon) and RJK Taylor (RJK Taylo)
r), Journal of the Chemical Society (J. Chem. Soc.), Parkin I, 140
7 (1981); According to this report, it has been difficult to proceed until now, 2-
The allylation of enolate formed from cyclopentenone and an organocopper compound has been challenged, and an intermediate for 11-deoxyprostaglandin synthesis has been successfully obtained. However, regarding the method for producing 4-substituted-2,3-disubstituted cyclopentanones from 4-substituted-2-cyclopentenones, specific examples thereof and even the possibility thereof are disclosed. Absent.

(7) Nishiyama et al., Tetrahedron Letters, 25, 223 (1984)
And 25,2487 (1984); in these reports, trimethylsilyllithium or methyllithiotrimethylsilylacetate was conjugated to 2-cyclopentenone, followed by addition of tributyltin chloride, followed by alkylation of enolate with propargyl bromide derivative. Have been successful. 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 its possibility. Nothing is disclosed.

The above-mentioned conventional techniques (1) to (7) and other conventional techniques are described in Angewandte Chemie International Edition in Ingredients.
International Edition in English), 23 , No.1
Prostaglandin Synthesis by Ryoji Noyori et al., November 1984 pages 847-876.
Bi-Three Component Coupling (Prostagl
A review entitled andin Synthesis by 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 invention is 2,3-disubstituted-such as PGEs.
The present invention relates to an efficient method for producing 4-substituted cyclopentanones, enantiomers thereof or a mixture thereof.

Still another object of the present invention is to produce 2,3-disubstituted-4-substituted cyclopentanones and the like, which cannot be produced by conventional lithium enolate or copper enolate, via tin enolate. Based on our finding that it can be produced by the following method, a method for easily producing the 2,3-disubstituted-4-substituted cyclopentanones in one step or single pot with high yield is provided. Especially.

Still another object of the present invention is to subject a 4-substituted-2-cyclopentenone to a conjugate addition reaction with an organic copper compound, and convert the resulting copper enolate into a tin enolate to directly react with an alkyl halide or alkenyl halide. Based on our findings that we can
It is to provide a novel method for producing 2,3-disubstituted-4-substituted cyclopentanones in a step or single pot.

<Means for Solving Problems> Still other objects and advantages of the present invention will be apparent from the following description.

According to the present invention, the above objects and advantages of the present invention include (A) the following formula (1) [Here, R ² is a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a group which represents an acetal bond with R ² O. ] A 4-substituted-2-cycloentenone represented by the following formula, its enantiomer or a mixture thereof at an arbitrary ratio is represented by the following formula (2) R _B -Li ... (2) [where R _B is substituted or it represents the unsubstituted C ₂ -C ₁₀ alkyl or alkenyl group. ] And an organic lithium compound represented by the following formula (3) Cu-Q ... (3) [wherein Q represents a halogen atom, a cyano group, a phenylthio group or a 1-pentynyl group. ] The organic copper compound produced from the copper compound represented by the formula (4) is subjected to a conjugate addition reaction, and then (B) the produced enolate intermediate is added to the following formula (4) R ₃ SnY ... (4) [where R is They are the same or different from each other and represent C _{1 to} C ₄ lower alkyl, C _{3 to} C ₇ cycloalkyl, phenyl or a halogen atom, Y represents a halogen atom or a triflate group, provided that 2 to 3 R's are halogen at the same time. It cannot be an atom. The presence of an organotin compound represented by] the following formula _{(5) X-CH 2 -Z} -R A ......... (5) [Here, Z is an ethylene group, an ethynylene group, trans -
It represents a vinylene group or a cis-vinylene group, R _A represents a hydrogen atom, and X represents a halogen atom or a tosyl group. ] Reacting with a halide represented by the following formula (6) [Here, the definitions of R _A , R _B , Z and R ² are the same as above. ] A 2,3-disubstituted-4-substituted cyclopentanone represented by the following formula, its enantiomer, or a mixture thereof in any proportion is achieved.

The method of the present invention is, as described above, 4-substituted-2-cyclopentenones (1), an enantiomer or a mixture thereof, and an organocopper compound produced from an organolithium compound (2) and a copper compound (3). And a conjugated addition reaction step (A), and a step (B) of reacting the enolate intermediate produced in step (A) with a halide (5) in the presence of an organotin compound (4).

The 4-substituted-2-cyclopentenones used as a raw material in the present invention are represented by the above formula (1). Formula (1)
R ² represents a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a group forming an acetal bond (OR ² ) with the oxygen atom of the hydroxyl group.

Tri (C ₁ -C ₇₎ hydrocarbon silyl group, such as trimethylsilyl, triethylsilyl, triisopropylsilyl, such as t- butyldimethylsilyl group tri (C ₁
~ C ₄ ) alkylsilyl, diphenylmethylsilyl, t
-Diphenyl (C _1-
Preferable examples include C ₄ ) alkylsilyl, phenyldi (C ₁ -C ₄ ) alkylsilyl groups such as phenyldimethyl, and tribenzylsilyl groups. Of these, the t-butyldimethylsilyl group is particularly preferable.

Examples of the group forming an acetal bond with the oxygen atom of the hydroxyl group include methoxyethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2-ethoxy-2-.
Propyl, (2-methoxyethoxy) methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2
An -oxobicyclo [3.1.0] hex-4-yl group may be mentioned. Among these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl, (2-methoxyethoxy) methyl or 6,6-dimethyl-3-oxa-2
The -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 from the definition of R ² and its specific examples.

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 in the step (A) can be compounds represented by the above formulas (1) and (1) ′ and a mixture of these compounds in any ratio. An equimolar mixture of compounds of formulas (1) and (1) 'is a tesemide, and when one is more than the other, the mixture shows optical rotation depending on their mixing ratio.

R _B in the organolithium compound of formula (2) represents a substituted or unsubstituted C ₂ -C ₁₀ alkyl group or alkenyl group.

The unsubstituted C ₂ -C ₁₀ alkyl group may be linear or branched and includes, for example, ethyl group, propyl group, butyl group, isobutyl group, sec-butyl group, t-butyl group. Examples thereof include a group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group.

C ₂ -C ₁₀ alkenyl group unsubstituted may be filed with a thickness be linear or branched, for example, a vinyl group, a 1-propenyl group, 1-Budeniru group, a 1-pentenyl group, 1-hexenyl Group, 1-heptenyl group, 1-octenyl group, 1-
Examples thereof include nonyl group and 1-decyl group. These are E
It may be in any isomeric form, i.e.

When R _B is a substituted C _{2 to} C ₁₀ alkyl group, examples of the substituent include a C _{3 to} C ₇ cycloalkyl group, a vinyl group, a C _{2 to} C ₄ alkynyl group, a phenyl group and a phenoxy group (these The phenyl and phenoxy groups are fluoro,
A methyl, trifluoromethyl or trifluoromethoxy group), a C ₁ -C ₄ lower alkoxy group or a group represented by the formula OR ² (wherein R ² has the same definition as above) Can be mentioned.

When R _B is a substituted C _{2 to} C ₁₀ alkenyl group, the substituent is, for example, a C _{1 to} C ₄ lower alkyl group, C
_{3 to} C ₇ cycloalkyl group, C _{2 to} C ₄ alkynyl group, phenyl group, phenoxy group (the phenyl group and phenoxy group may be substituted with fluoro, methyl, trifluoromethyl or trifluoromethoxy), C ₁
To C ₄ lower alkoxy group or a group represented by OR ² (wherein the definition of R ² is the same as above).

Examples of the above-mentioned substituents include, for example, lower alkyl groups such as methyl group, ethyl group, propyl group and butyl group;
Vinyl group; cyclopentyl, C ₃ -C ₇ cycloalkyl groups such as cyclohexyl group ethynyl group, propargyl group, 1-butynyl, such as 1-propynyl C ₂ -C ₄ alkynyl group; phenyl, fluoro-phenylalanine, tolyl, trifluoromethyl-phenylalanine, trifluoromethoxy phenylalanine, phenoxy, fluoro phenoxyethanol, methylphenoxy, trifluoromethyl phenoxyethanol, trifluoromethoxy phenoxyethanol; methoxy, ethoxy, propoxy, such as butoxy C ₁ -C ₄ Lower alkoxy can be mentioned. A specific example of the case where the substituent is OR ² is represented by the formula (1)
Is clear from the example described above. Specific examples of the organolithium compound (2) having such a substituted or unsubstituted C _{2 to} C ₁₀ alkyl group or alkenyl group will be apparent from the specific examples of R _B as described above. Among them, particularly preferred is the following formula (2) -A [Here, R ³ is a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a group that represents an acetal bond by OR ³ . ] It is a compound represented by.

The reason why the organolithium compound represented by the above formula (2) -A is particularly preferable is that it is a part of the skeleton of natural prostaglandins, which is the same.

On the other hand, Q in the copper compound of formula (3) represents a halogen atom such as chlorine atom, bromine atom, iodine atom, cyano group, phenylthio group, or 1-pentynyl group.

Examples of these copper compounds are self-evident from the definition of Q above.

In the conjugate addition reaction step (A) of the present invention, the organocopper compound produced from the organolithium compound (2) and the copper compound (3) is used as described above.

To obtain an organocopper compound from an organolithium compound of the formula (2) and a copper compound of the formula (3), reference can be made to, for example, the literature G. E. Posner, Organic Reacion (Or
ganic Reaction), vol. 19 , 1 (1972); Noyori et al.
Tetrahedron Letters,
21, 1247 (1980), 23, 4057 (198
2), 23, 5563 (1982), 24, 1187.
(1983), 24, 4103 (1983), 25, 1
383 (1984) and Israeli Journal of Chemistry (Isr. J. Chem.), 24, 118.
(1984).

These documents are cited as the description of the present specification. For example, an inert medium such as hydrocarbons such as pentane, hexane and heptane and ethers such as diethyl ether and dimethoxyethane is used, in which the organolithium compound and the copper salt are reacted at room temperature to -78 ° C. Within a few hours,
For example, the reaction is carried out at -78 ° C for 0.5 hour. The conjugated addition reaction in the step (A) is preferably a trivalent organic phosphorus compound, for example, toluarylphosphine (eg, triethylphosphine, tributylphosphine, etc.), trialkylphosphite (eg, trimethylphosphine). (Phite, triethyl phosphite, triisopropyl phosphite, tri-n-butyl phosphite, etc.), hexamethylphosphorus triamide, triphenyl phosphine, etc. are used. When these compounds are used, this conjugate addition reaction proceeds smoothly. Particularly, tributylphosphine and hexamethylphosphorus triamide are preferably used.

In the step (A) of the method of the present invention, the 4-substituted-2-cyclopentenones represented by the formula (1) are the above-mentioned organic copper compounds,
It is advantageously carried out by reacting in the presence of a trivalent organophosphorus compound and an aprotic inert organic medium.

The 4-substituted-2-cyclopentenones and the organocopper compound undergo stoichiometrically equimolar reaction, but usually 4-
0.5 to 1 mol of the substituted-2-cyclopentenones
To 2.0 mol times, preferably 0.8 to 1.5 mol times, and particularly preferably 1.0 to 1.3 mol times of the organic copper compound is used.

The reaction temperature in step (A) is, for example, −100 ° C. to 20 ° C.
C., particularly preferably a temperature range of about −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 an organic medium. An inert aprotic organic medium which is liquid at the reaction temperature and does not react with the reaction reagent is preferably used.

As such an aprotic inert organic medium, for example,
Saturated hydrocarbons such as pentane, hexane, heptane, cyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene; Ether solvents such as diethyl ether, tetrahydroplan, dioxane, dimethoxyethane, diethylene glycol dimesyl ether; Other hexa Methylphosphoric triamide (HMP), N,
N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), dimethylsulfoxide,
Examples include so-called aprotic polar solvents such as sulfolane and N-methylpyrrolidone. These can also be used as a mixed solvent of two or more kinds. Further, as the aprotic inert organic medium, the inert medium used for producing the organic copper compound may be used as it is. That is, in this case, the 4-substituted-2-cyclopentenones may be added to the reaction system for producing the organocopper compound to carry out the reaction. The amount of the organic medium used may be an amount sufficient to smoothly proceed the reaction. Normal,
1 to 100 times by weight, preferably 2 to 20 times by weight of 4-substituted-2-cyclopentenones are used.

The trivalent organophosphorus compound can be allowed to be present at the time of the above-mentioned preparation of the organocopper compound, and 4-substituted-in the system.
It is also possible to carry out the reaction by adding 2-cyclopentenones.

Thus, in the step (A) of the method of the present invention, R _B which is the organic group moiety of the organocopper compound is added to the 3-position of the 4-substituted-2-cyclopentenones in the reaction system. The so-called conjugated addition enolate is formed.

In the method of the present invention, the conjugated addition enolate is reacted with the halide represented by the formula (5) in the presence of the organotin compound represented by the formula (4).

In formula (4) representing the organotin compound, three Rs are the same or different and each represents C ₁ -C ₄ lower alkyl, C ₃ -C ₇ cycloalkyl, phenyl or halogen atom. However, no two or three Rs are halogen atoms at the same time.

Examples of the organotin compound are tri (C ₁ -C ₄ ) alkyltin such as trimethyltin chloride, trimethyltin bromide, triethyltin bromide, tripropyltin chloride, tributyltin chloride, tributyltin bromide, etc., according to the definition of R above. Chloride; tri (C ₁ -C ₄ ) alkyltin bromide; dialkyltin dihalide such as dimethyltin dichloride, diethyltin dichloride, dibutyltin dichloride; tributyltin triflate; tricyclohexyltin chloride, tricyclohexyltin bromide,
Tricyclopentyl dibutyltin Puromaido, tri tri (C ₃ ~C _7), such as cyclopentyl dibutyltin dichloride cycloalkyl tin halides; triphenyl tin chloride; dicyclohexyl tin dichloride, di-and di-cyclopentyl dilaurate dichloride (C ₃ ~C ₇₎ cycloalkyl tin Dihalides; diphenyltin dihalides such as diphenyltin dichloride and diphenyltin bromide; or triphenyltin triflate and tricyclohexyltin triflate.

Among these, those in which three R's in formula (4) are the same or different and are a butyl group, a cyclohexyl group or a phenyl group are preferable, and for example, tributyltin chloride, triphenyltin chloride and tricyclohexyl chloride are particularly preferable.

The halide used in step (B) is represented by the above formula (5).

_{X-CH 2 -Z-R A} ......... (5) formula (5), X is a halogen atom or a tosyl group, Z is an ethylene, ethynylene group, trans - vinylene group or cis - vinylene group, phenylene group In the formula, R _A is a hydrogen atom. As another reference example, a substituted or unsubstituted C ₁ -C ₇ alkyl group or alkenyl group can be mentioned.

In the substituted or unsubstituted C ₁ -C ₇ alkyl group or alkenyl group in the definition of _{RA in} the above formula (5), the unsubstituted C ₁ -C ₇ alkyl group may be linear or branched. It may have a chain form, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-
Examples thereof include a butyl group, a t-butyl group, a pentyl group, a hexyl group, and a heptyl group.

The unsubstituted C ₁ -C ₇ alkenyl group may be linear or branched, and is a group in which the carbon atom of the group Z is directly bonded to form a double bond. For example, = CH ₂ or the carbon atom of the group Z may be an alkenyl group bonded by a single bond.

Examples of such an unsubstituted C ₁ -C ₇ alkenyl group include vinyl group, 1-propenyl group, 1-butenyl group, 1
-Pentenyl group, 1-hexenyl group, 1-heptenyl group, 2-propenyl group, 2-butenyl group, 2-pentenyl, 2-hexenyl group, 2-heptenyl group, 3-butenyl group, 3-pentenyl group, 3- Examples thereof include a hexenyl group and a 3-heptenyl group. These may be in the E form and in any isomeric form of the E form.

Examples of the substituent in the substituted C _{1 to} C ₇ alkyl group include a C _{3 to} C ₇ cycloalkyl group, a vinyl group, a C _{2 to} C ₄ alkynyl group, a phenyl group and a phenoxy group (these phenyl and phenoxy groups are fluoro). , Optionally substituted with a methyl, trifluoromethyl or trifluoromethoxy group), a C ₁ -C ₄ lower alkoxy group or a group represented by OR ² (wherein R ² has the same definition as above),
C ₁ -C ₄ lower acyloxy group; oxo group or C ₁ ~
A C ₄ lower alkoxycarbonyl group may be mentioned.

Examples of the substituent in the substituted C ₁ -C ₇ alkenyl group include C ₁ -C ₄ lower alkyl group, C ₃ -C ₇ cycloalkyl group, C ₂ -C ₄ alkynyl group, phenyl group, phenoxy group (these The phenyl and phenoxy groups may be substituted with fluoro, methyl, trifluoromethyl or trifluoromethoxy), C ₁ -C ₄ lower alkoxy groups have the formula OR ² (wherein R ^{2 is} as defined above). A C ₁ -C ₄ lower acyloxy group; an oxo group or a C ₁ -C ₄ lower alkoxycarbonyl group.

Examples of the above-mentioned substituents include, for example, lower alkyl groups such as methyl group, ethyl group, propyl group and butyl group;
Vinyl group; cyclopentyl, C ₃ -C ₇ cycloalkyl groups such as cyclohexyl group ethynyl group, propargyl group, 1-butynyl, such as 1-propynyl C ₂ -C ₄ alkynyl group; phenyl, fluoro-phenylalanine, tolyl, trifluoromethyl-phenylalanine, trifluoromethoxy phenylalanine, phenoxy, fluoro phenoxyethanol, methylphenoxy, trifluoromethyl phenoxyethanol, trifluoromethoxy phenoxyethanol; methoxy, ethoxy, propoxy, such as butoxy C ₁ -C ₄ lower alkoxy; lower acyloxy groups such as acetooxy group and propionyloxy group; oxo group; and lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and t-butoxycarbonyl group. Specific examples where the substituent is OR ² are apparent from the examples described above for formula (1).

Among the halides of the above formula (5), the following formula (5) -1 [Here, the definition of X is the same as the above formula (5), and R ¹ is C
₁ -C ₁₀ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C ₃ -C ₇ cycloalkyl group or a substituted or unsubstituted phenyl (C ₁ -C ₂₎ alkyl group, n 1 Is an integer from 9 to 9. Compounds represented by], or the following formula _{(5) -2 X-CH 2} -Z'-R 'A ......... (5) -2 [wherein the definition of X are the same as the above formula, Z' Represents an ethynylene group, a trans-vinylene group or a cis-vinylene group, a phenylene group or a phenyleneoxa group,
R ′ _A has a substituent —COOR ¹ (R
¹ definition C ₁ ~ had it occurred substituted is as defined above)
Represents a C ₇ alkenyl group. ] The compound represented by the following is mentioned as a preferable reference example.

In formulas (5) -1 and (5) -2, X is a halogen atom, R ¹ is a C _{1 to} C ₁₀ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C _{3 to} C ₇ A cycloalkyl group or a substituted or unsubstituted phenyl (C _1-
A C ₂₎ alkyl group.

The C ₁ -C ₁₀ alkyl group may be linear or branched and is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-
Examples thereof include a butyl group, a t-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group.

Examples of the substituent of the substituted or unsubstituted phenyl group include a halogen atom, a protected hydroxy group, C _2-
C ₇ acyloxy group, C ₁ -C ₄ alkyl group optionally substituted by halogen atom, C ₁ -C ₄ alkoxy group optionally substituted by halogen atom, nitrile group, or (C
Such as ₁ -C ₆₎ alkoxycarbonyl group. The halogen atom is preferably fluorine, chlorine or bromine, and particularly preferably fluorine or chlorine. Examples of the C _{2 to} C ₇ acyloxy group include an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group, an isovaleryloxy group, a caproyloxy group, an enanthyloxy group, or a benzoyloxy group. Can be raised.

Examples of the C ₁ -C ₄ alkyl group which may be substituted with a halogen atom include a mesyl group, an ethyl group, a propyl group,
Preferred examples include isopropyl group, butyl group, chloromethyl group, dichloromethyl group and trifluoromethyl group. As the C ₁ -C ₄ alkoxy group which may be substituted with a halogen atom, for example, methoxy group, ethoxy group, propoxy group, butoxy group, chloromethoxy group, dichloromethoxy group, trifluoromethoxy group and the like are preferable. I can give you.
Examples of the (C ₁ -C ₆ ) alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, t
Examples thereof include butoxycarbonyl group and hexyloxycarbonyl group.

The substituted phenyl group can have 1 to 3 substituents, preferably 1 substituent as described above.

The substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a unsubstituted or are substituted by the same substituents as described above, saturated or C ₃ -C ₇ unsaturated, preferably C ₅
To C ₆ , particularly preferably C ₆ groups such as cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclohexenyl group, cycloheptyl group and the like.

Examples of the substituted or unsubstituted phenyl (C ₁ -C ₂ ) alkyl group include a benzyl group, an α-phenethyl group and a β-phenethyl group which are substituted or unsubstituted by the same substituents as described above. can give.

In the above formula (5) -1, n is an integer of 1-9.

In the above formula (5) -2, Z ′ is an ethynylene group. Is.

In the above formula (5) -2, R _'A is a group Z' closest position substituent from (-COOR ^1, wherein the R ¹ definition is the same as above) had it occurred substituted a C ₁ -C ₇ alkenyl group.

C ₁ -C ₇ alkenyl group, for example, 1-propenyl (-C =
C-CH _3), and, if Z 'is an ethynylene group, -
Z'-R _'A is a -CH = CH-CH = CH- CH 2 -COOR 1.

In step (B) of the method of the present invention, the conjugated addition enolate produced in step (A) and present in the system and the halide (formulas (5), (5) -1 and (5) -2) are converted into Reaction) is carried out. In the reaction, the organotin compound may be first added to the reaction system in which the organocopper compound is conjugated and added to the 4-substituted-2-cyclopentenones, and then diluted with the aprotic organic medium. It is carried out by adding the halide of the above formula (5).

It is believed that the organotin compound reacts stoichiometrically equimolarly with the enolate produced by the conjugate addition to newly produce tin enolate, but usually the 4-substituted-2- 0.8-1.5 mole times with respect to 1 mole of cyclopentenones, particularly preferably 1.0-
1.2 molar times are used.

The reaction temperature is −100 ° C. to 0 ° C., preferably −78 ° C.
A temperature range of about 20 ° C is adopted. Reaction time is usually 1
Time is enough.

The halide of the formula (5) reacts stoichiometrically equimolar with the enolate formed by the conjugate addition, but is usually 0. 1 relative to the 4-substituted-2-cyclopentenone initially used. 8 to 5.0 molar times, particularly preferably 1.0 to 2.0
It is used in a molar amount.

The reaction temperature is −100 ° C. to 0 ° C., preferably −78 ° C.
A temperature range of about 20 ° C is adopted. The reaction time varies depending on the type of halide used and the reaction temperature. Usually -7
The reaction is terminated by reacting at 8 ° C to -30 ° C for about 1 to 50 hours, and the end point of the reaction is efficiently determined by tracing by thin layer chromatography or the like.

The alkylation reaction (step (B)) with the halide (5) in the method of the present invention is preferably carried out in the presence of the aprotic polar solvent, especially hexamethylphosphoric triamide, and often gives good results. give. After the reaction, it is separated and purified by a usual means (post-treatment, extraction, washing, chromatography, distillation, or a combination thereof).

Thus, according to the present invention, the following formula (6) [Here, the definitions of R _A , R _B , R ² and Z are the same as above. ] 2,3-disubstituted-4-substituted cyclopentanones represented by the following formula (6) ′ [Here, the definitions of R _A , R _B , R ² and Z are the same as above. ] The enantiomer represented by or a mixture thereof in any ratio can be produced.

Among the compounds represented by the above formula (6), the following formula (6) -1 [Here, the definitions of R ¹ , R ² , R ³ and Z are the same as above. ] The compound represented by is a preferable compound.

In the above formula (6) -1, the compound in which Z is a cis-vinylene group has a PGE ₂ skeleton, the compound in which Z is an ethynylene group has a 5,6-dehydro PGE ₂ skeleton, and Z
The compound in which is ethylene has a PGE ₁ skeleton.
The present invention should be fully evaluated as a production method capable of providing such useful compounds.

In order to show the usefulness of the compound produced by the method of the present invention, a 5,6-dehydro PGE ₂ derivative is used as a starting material to produce PGE ₂ , E ₁ , F ₂ α, F ₁ α, D ₂ , D ₁ and I ₂ . The flow charts below are shown in the flow chart.

In the above flow chart, Red means reduction, Cy means cyclization, depro means deprotection, pro means protection and OX means oxidation.

The following Reference Examples 19 to 23 specifically show a part of the above induction reaction. Other conversion reactions have already been reported by some of the inventors.

Further, one of the features of the method of the present invention is that all the reactions used proceed in a stereospecific manner.
From the starting material having the configuration represented by (1), the above formula
A compound having a configuration represented by (5) (including (6) -1) is obtained, and the enantiomer of the formula (6) ′ is obtained from the enantiomer of the formula (1) ′. Therefore, from the mixture of these arbitrary ratios, the mixture of the target substance reflecting the ratio can be obtained. Further, the organolithium compound of the formulas (2)-(A) contains asymmetric carbon and therefore includes two kinds of optical isomers. Any optically active substance or a mixture of them in any proportion can be used. Of these, the above formula
The compound having the configuration represented by (6) -1 is a particularly useful stereoisomer because it has the same configuration as natural prostaglandins.

<Examples> The present invention will be described in more detail with reference to Examples below, but the present invention is not limited thereto.

Reference Example 1 (2R, 3R, 4R) -3-butyl-4-t-butyl-
Dimethylsilyloxy-2- (2-octynyl) cyclopentanone (i) Cuprous iodide (99.1 mg, 0.52 mmol) was weighed into a 30 ml reaction tube substituted with argon, and the inside of the tube was dried under reduced pressure, and then replaced with argon again. Dry tetrahydrofuran (2 ml) and tributylphosphine (0.337 ml, 1.35 mmol) were added thereto, and the mixture was stirred at 20 ° C. to form a uniform solution. After cooling the solution to -78 ° C, n-butyllithium (1.60M, 0.325ml,
0.52 mmol) was added, and the mixture was stirred at -78 ° C for 10 minutes.
Then, a solution of (R) -4-t-butyldimethylsiloxy-2-cyclopentenone (100 mg, 0.471 mmol) in tetrahydrofuran (2 ml) was added dropwise at -78 ° C over 10 minutes. Further, wash the container with 0.5 ml of tetrahydrofuran, drop this washing solution in the same manner, and
Stir for 0 minutes. Then, hexamethylphosphoric triamide (1 ml) was added and stirring was continued at -78 ° C for 40 minutes. Then tributyltin chloride (0.14m
(1, 0.520 mmol) was added, and the temperature was raised to -40 ° C.
1-iodo-2-octyne (184 mg, 0.78 mmol)
Tetrahydrofuran solution (1 ml) was added and the mixture was stirred for 2 hours. After ether (5 ml) was added to the reaction solution, it was washed successively with saturated ammonium chloride aqueous solution (5 ml), saturated potassium thiocyanate aqueous solution (5 ml) and saturated saline solution (5 ml),
The separated organic layer was dried over anhydrous sodium sulfate.
The crude product obtained by concentration under reduced pressure and silica gel column chromatography (Merck 77734, 6% water content, 2
0 g; hexane: ethyl acetate = 30: 1) for separation, and (2R, 3R, 4R) -3-butyl-4-t-butyldimethylsiloxy-2- (2-octynyl) cyclopentanone (88. 1 mg, 0.233 mmol, 49%) was obtained.

TCL; Rf = 0.39 (hexane: ethyl acetate = 10:
1) IR (liquid film); 1750, 1460, 1247, 1098, 83
4, 771 cm ^-1 .

NMR (CDCl ₃ ) δ; 0.05 and 0.09 (s, 6, SiCH ₃ ×, respectively)
2), 0.89 (s, 15 , SiC (CH 3) 3, CH 3 × 2), 1.1~1.7 (m, 12, CH 2 × 6), 1.8~2.4 ( m, 5, CH ₂ C≡C × 2, CH ×
1), 2.4 to 2.8 (m, 3, CH ₂ CO × 2, CHCO), 4.05 (dd, 1, J = 13.0 and 6.4 Hz, CHOS
i).

¹³ C NMR (CDCl ₃ ) δ; -4.9, -4.5, 13.9 (for two), 18.
6, 19.1, 22.1, 22.9, 25.7 (for 4) 28.7, 29.0, 31.0, 31.7, 47.
7, 48.6, 52.5, 73.3, 77.0, 81.9, 21
5.4.

MS (75eV; m / e) ; 378 (M +), 321 (M + -C 4 H 9).

(ii) Cuprous iodide (198 mg, 1.04 mmol) was weighed into a 150 ml reaction tube purged with argon, and the inside of the tube was dried under reduced pressure, and then purged with argon again. Dry tetrahydrofuran (10 ml) and tributylphosphine (0.673 ml, 2.70 mmol) were added thereto, and the mixture was stirred at 19 ° C to give a uniform solution. After cooling the solution to -78 ° C, n-butyllithium (1.60M, 0.647ml,
1.04 mmol) was added, and the mixture was stirred at -78 ° C for 10 minutes.
Then, a tetrahydrofuran (15 ml) solution of (R) -4-t-butyldimethylsiloxy-2-cyclopentenone (200 mg, 0.942 mmol) was added dropwise at −78 ° C. over 0.8 hours using a syringe drive. Further, the container was washed with 2 ml of tetrahydrofuran, and this washing solution was dropped in the same manner, followed by stirring at -78 ° C for 10 minutes. Then add hexamethylphosphoric triamide (2 ml)-
Stirring was continued at 78 ° C for 40 minutes. Then, tributyltin chloride (0.28 ml, 1.04 mmol) was added, and the temperature was raised to -30 ° C to obtain 1-bromo-2-octyne (197).
A tetrahydrofuran (2 ml) solution of (mg, 1.04 mmol) was added and the mixture was stirred for 17.5 hours. Ether (1
0 ml) and then saturated aqueous ammonium chloride solution (10
ml), a saturated aqueous solution of potassium thiocyanate (10 ml), and saturated saline (10 ml) in that order, and the separated organic layer was dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was subjected to silica gel column chromatography (Merck 7734, 6% water content, 40 g; hexane: ethyl acetate = 30: 1) for separation, and the product was obtained in (i). Consistent with product (2R, 3R, 4R) -3-butyl-
4-t-butyldimethylsiloxy-2- (2-octynyl) cyclopentanone (58.8 mg, 0.155 mmol,
16%).

Reference Example 2 11,15-bis (t-butyldimethylsilyl) -5,
6-dehydroprostaglandin E ₂ methyl ester (i) Arrange the reaction tube (E, 3
S) -3-t-Butyldimethylsiloxy-1-iodo-
After adding a solution of 1-octene (354 mg, 0.961 mmol) in dry ether (5 ml) and cooling to -95 ° C, t-
Butyl lithium (1.77M, 1.09ml, 1.92mm
ol) was added dropwise and the mixture was stirred at -95 to -78 ° C for 3 hours. In another 30 ml eggplant-shaped flask, cuprous iodide (183 mg,
0.961 mmol) was weighed, the inside of the tube was dried under reduced pressure, and then the atmosphere was replaced with argon again. Tetrahydrofuron (4ml) and tributylphosphine (0.62ml,
(2.50 mmol) was added and the mixture was stirred at 21 ° C. to form a uniform solution. This homogeneous solution was added all at once to the alkenyllithium solution prepared above under pressure of argon using a stainless steel tube, and the container was further washed with tetrahydrofuran (4 ml), and this solution was also added dropwise, and then at -78 ° C for 5 minutes. It was stirred. Then (R) -4-t-butyldimethylsiloxy-2-cyclopentenone (200 mg, 0.942 mmo
A solution of l) in tetrahydrofuran (15 ml) was added dropwise at -78 ° C over 1 hour using a syringe drive. Further, the container was washed with 2 ml of tetrahydrofuran, and this washing solution was also dropped in the same manner, followed by stirring at -78 ° C for 1 hour. Then, hexamethylphosphoric triamide (2 ml) was added and stirring was continued at -78 ° C for 40 minutes. Then, tributyltin chloride (0.26 ml, 0.961 mmol) was added, and the temperature was raised to -45 ° C, and 1-iodo-6-methoxycarbonyl-2-hexyne (276 mg, 1.04 mmol).
Tetrahydrofuran solution (2 ml) was added and the mixture was stirred for 1 hour. After adding ether (20 ml) to the reaction solution, it was washed successively with saturated ammonium chloride aqueous solution (30 ml), saturated potassium thiocyanate aqueous solution (30 ml) and saturated saline (30 ml), and the separated organic layer was dried over anhydrous sodium sulfate. Dried. The crude product obtained by concentration under reduced pressure and silica gel column chromatography (Merck 7734, 6%
Water content, 40 g; hexane: ethyl acetate = 40: 1) for separation, and 11,15-bis (t-butyldimethylsilyl) -5,6-dehydroprostaglandin E ₂ methyl ester (105.6 mg, 0) 178 mmol, 19%)
Got

TCL: Rf = 0.50 (ethyl acetate-hexane = 1: 1
5) IR (liquid ^{film); 1746,1246,827,761cm -1 1 H NMR (} CDCl 3 -CCl 4 = 1: 1) δ; 0.04 and 0.06 (each s, 12, SiCH ₃
× 2), 0.89 (s, 18, SiC (CH ₃ ) ₃ × 2), 0.92 (t, 1, J = 6.5 Hz, 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 x 2, and CH ₂ ), 3.65 (s, 3, OCH ₃ ), 4.05 (m, 2, CHOSi x 2), 5.4-5.7 (m, 2, vinyl) ¹³ C NMR (CDCl ₃ ) δ; -4.7, -4.5 (for two), -4.2, 13.
6, 14.0, 16.9, 18.0, 18.2, 22.
6, 24.2, 25.0, 25.8 (3 pieces), 25.9 (3 pieces), 31.9, 32.7, 38.
6, 47.7, 51.4, 51.9, 52.9, 72.
7, 73.1, 77.3, 80.8, 128.2, 13
6.8, 173.4, 213.4 [α] ▲ ²¹ _D ▼; -13.9 ° ( C 1.59, CH ₃ OH) (ii) In a 150 ml reaction tube purged with argon ( E , 3
S ) -3-t-Butyldimethylsiloxy-1-iodo-
After adding a solution of 1-octene (354 mg, 0.961 mmol) in dry ether (5 ml) and cooling to -95 ° C, t-
Butyl lithium (1.77M, 1.09ml, 1.92mm
ol) was added dropwise and the mixture was stirred at -95 to -78 ° C for 3 hours. Separately, in a 30 ml eggplant-shaped flask, cuprous iodide (183 mg,
0.961 mmol) was weighed, the inside of the tube was dried under reduced pressure, and then the atmosphere was replaced with argon again. In it, tetrahydrofuran (4 ml) and tributylphosphine (0.62 ml,
(2.50 mmol) was added and the mixture was stirred at 24 ° C. to form a uniform solution. This homogeneous solution was added to the alkenyllithium solution prepared above under a pressure of argon using a stainless steel tube all at once, and the container was further washed with tetrahydrofuran (2 ml). This solution was also added dropwise, and then at -78 ° C for 5 minutes. It was stirred. Then (R) -4-t-butyldimethylsiloxy-2-cyclopentenone (200 mg, 0.942 mmo
A solution of l) in tetrahydrofuran (10 ml) was added dropwise at -78 ° C over 30 minutes using a syringe drive. Further, the container was washed with 2 ml of tetrahydrofuran, and this washing solution was dropped in the same manner, followed by stirring at -78 ° C for 10 minutes.
Then, tributyltin chloride (0.26 ml, 0.
961 mmol) was added and the mixture was stirred at -78 ° C for 1 hour. Then 1-iodo-6-methoxycarbonyl-2-hexyne (276 mg, 1.04 mmol) in tetrahydrofuran (2
solution) and stirred for 20 minutes, then hexamethylphosphoric triamide (0.9 ml) was added and the stirring was continued at -78 ° C for 15 minutes. Then, the temperature was raised to -45 ° C., the mixture was stirred for 30 minutes, hexamethylphosphoric triamide (0.9 ml) was further added, and the mixture was stirred for 1 hour and 30 minutes. Saturated aqueous ammonium chloride solution (30 ml) was added to the reaction mixture and shaken vigorously, then the organic layer and the aqueous layer were separated, and the organic layer was saturated aqueous potassium thiocyanate solution (30 ml) and saturated saline solution (30 ml).
ml) and then dried over anhydrous sodium sulfate.
The crude product obtained by concentration under reduced pressure was subjected to silica gel column chromatography (Merck 7734, 6% water content,
40 g, 1:40 ethyl acetate-hexane) and separated, 11,15-bis (t-butyldimethylsilyl)-
There was obtained 5,6-dehydroprostaglandin E ₂ methyl ester (173.9 mg, 0.293 mmol, 31%).
The various spectra of this product were the same as in (i).

(iii) Add (E) -1-to a 150 ml reaction tube purged with argon.
Iodo-3-t-butylsiloxy-1-octene (59
3.1 mg, 1.61 × 10 ⁻³ mol) and 6 ml of dry ether were taken, cooled to −95 ° C. and stirred. T-Butyllithium (1.72 ml, 3.22 × 10 ⁻³ mol) was added thereto with a syringe and stirred for 3 hours at −95 to −78 ° C. Separately, a 30 ml eggplant type flask was prepared and iodinated. Cuprous acid (306.6 mg, 1.61 × 10 ^-3 mol) was taken, and the inside of the tube was heated and dried under reduced pressure and then replaced with argon.
F6ml and tributylphosphine (1.04ml, 4.19x1)
0 ^-3 mol) was added and a homogeneous solution was stirred at room temperature (23 ° C.). This was cooled to −78 ° C., added to the previously prepared solution of vinyl lithium under a pressure of argon with a stainless steel tube at once, and the container was rinsed with 6 ml of dry THF and added. After stirring at −78 ° C. for 10 minutes, 4-t-butyldimethylsiloxy-2-cyclopentenone (32
5.6 mg, 1.53 × 10 ^-3 mol) in THF (12 m
l) was added dropwise over 1 hour. The container was rinsed with 1 ml of THF and then stirred for 10 minutes. HMPA (1.5m
l) was added and stirred for 30 minutes, then Ph ₃ SnCl (627.
A THF solution (2 ml) of 6 mg, 1.61 × 10 ⁻³ mol) was added. After the temperature was raised to -30 ° C, 1-iodo-6-carbomethoxy-2-hexyne (814.2 mg, 3.06 x 10 ^-3
(mol) HMPA solution was added, and the mixture was stirred at −30 ° C. for 4 hours and 30 minutes. After leaving it at -27 ° C for 13 hours,
A saturated aqueous solution of ammonium chloride (20 ml) was added and shaken vigorously. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with ether (20 ml × 2). The ether layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After that, it was concentrated under reduced pressure and subjected to silica gel column chromatography (Merck 7734 50 g, 1: 6).
0 = ethyl acetate: hexane, 600 ml → 1: 20 ethyl acetate: hexane, 200 ml), dl-11,15-bis (t-butyldimethylsilyl) -5,6-dehydroprostaglandin E ₂ methyl ester (542. 1 mg, yield 59.7
%) Was obtained.

IR (liquid film); 1746,1246,827,767 cm ^-1 Reference Example 3 11,15-bis (t-butyldimethylsilyl) prostaglandin E ₂ methyl ester (i) Arrange the reaction tube (E, 3
S) -3-t-Butyldimethylsiloxy-1-iodo-
After adding a solution of 1-octene (354 mg, 0.961 mmol) in dry ether (5 ml) and cooling to -95 ° C, t-
Butyl lithium (1.77M, 1.09ml, 1.92mm
ol) was added dropwise and the mixture was stirred at -95 to -78 ° C for 3 hours. Separately, in a 30 ml eggplant-shaped flask, cuprous iodide (183 mg,
0.961 mmol) was weighed, the inside of the tube was dried under reduced pressure, and then the atmosphere was replaced with argon again. In it, tetrahydrofuran (4 ml) and tributylphosphine (0.62 ml,
(2.50 mmol) was added and the mixture was stirred at 29 ° C. to form a uniform solution. This homogeneous solution was added all at once to the previously prepared alkenyllithium aqueous solution under pressure of argon using a stainless steel tube, and the container was washed with tetrahydrofuran (2 ml), and this solution was also added dropwise, and then at -78 ° C for 5 minutes. It was stirred. Then (R) -4-t-butyldimethylsiloxy-2-cyclopentenone (200 mg, 0.942 mm
A solution of ol) in tetrahydrofuran (10 ml) was added dropwise at -78 ° C over 30 minutes using a syringe drive. Further, the container was washed with 2 ml of tetrahydrofuran, and this washing solution was dropped in the same manner, followed by stirring at -78 ° C for 10 minutes.
Then tributyltin chloride (0.26 ml, 0.9
61 mmol) was added and the mixture was stirred at −78 ° C. for 30 minutes. Hexamethylphosphoric triamide (1.8 ml) was then added, followed by (Z) -1-iodo-6-methoxycarbonyl-
A solution of 2-hexene (279 mg, 1.04 mmol) in tetrahydrofuran (2 ml) was added, the temperature was raised to -45 ° C, and the mixture was stirred for 2 hours. Saturated ammonium chloride aqueous solution (4
(0 ml) and vigorously shaken, the organic layer and the aqueous layer are separated, and the organic layer is saturated aqueous potassium thiocyanate solution (40 m
l) and a saturated saline solution (40 ml) were successively washed, and dried over anhydrous sodium sulfate. Silica gel column chromatography (Merck 7734, 40 g, 1:20 ethyl acetate-hexane).
And separated to give 11,15-bis (t-butyldimethylsilyl) prostaglandin E ₂ methyl ester (1
42.5 mg, 0.239 mmol, 25%) was obtained.

TLC; Rf = 0.58 (ethyl acetate-hexane = 1: 1
5) IR (liquid ^{film); 1734,1243,1000,964,927, 828,768cm -1 1 H} NMR (CDCl 3) δ; 0.03 and 0.06 (each s, 12, SiCH ₃
× 4), 0.8-1.0 (m, 21, C-CH ₃ × 7), 1.2-1.5 (m, 8, CH ₂ × 4), 1.6-2.9 ( m, 12, CH ₂ CO × 2, CH ₂ C = ×
2, CH × 2, and CH ₂ ), 3.67 (s, 3, OCH ₃ ), 4.06 (m, 2, CHOSi × 2), 5.37 (m, 2, vinyl), 5.54 (M, 2, vinyl) [α] ▲ ²¹ _D ▼; 52.7 ° ( C 1.28, CH ₃ OH) (ii) In a 150 ml reaction tube purged with argon, (E) -1-
Iodo-3-t-butyldimethylsiloxy-1-octene (593.1 mg, 1.61 × 10 ⁻³ mol) and 6 ml of dry ether are taken, cooled to −95 ° C. and stirred. T-Butyllithium (1.72 ml, 3.22 × 10 ^-3)
(mol) was stirred with a syringe at -95 to -78 ° C for 3 hours. Separately, a 30 ml eggplant-shaped flask was prepared, cuprous iodide (306.6 mg, 1.61 × 10 ⁻³ mol) was taken, the inside of the tube was heated and dried under reduced pressure, and then the atmosphere was replaced with argon. To this, dry THF 6 ml and tributylphosphine (1.04 ml,
4.19 × 10 ⁻³ mol) was added, and the mixture was stirred at room temperature (25 ° C.) to give a uniform solution. This was cooled to −78 ° C., and the previously adjusted vinyl lithium was added to the solution all at once under pressure of argon with a stainless steel tube, and the container was rinsed with 6 ml of dry THF and added. After stirring at −78 ° C. for 10 minutes,
A solution of 4-t-butyldimethylsiloxy-2-cyclopentenone (325.6 mg, 1.53 × 10 ⁻³ mol) in THF (12 ml) was added dropwise over 1 hour. The container was rinsed with 1 ml of THF, added, and stirred for 10 minutes. HMP
After adding A (1.5 ml) and stirring for 30 minutes, Ph ₃ SnC
l (627.6 mg, 1.61 × 10 ⁻³ mol) THF (2
ml) was added. After heating to -30 ° C, (Z) -1-iodine-
A HMPA solution of 6-carbomethoxy-2-hexene (1.231 g, 4.59 × 10 ⁻³ mol) was added, and the mixture was stirred at −30 ° C. for 3 hours. Subsequently, the mixture was allowed to stand at -27 ° C for 97.9 hours, saturated aqueous ammonium chloride solution (20 ml) was added, and the mixture was vigorously shaken.
After separating the organic layer and the aqueous layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After that, it was concentrated under reduced pressure, and then chromatographed (Merck 77345 g, 1:
5 = Ethyl vinegar: Hexane), highly polar substances (Bu ₃ P, Ph)
₃ SnCl) was removed, and then silica gel column chromatography (Merck 7734 50 g, 1:60 = ethyl acetate: hexane, 780 ml → 1:20 = ethyl acetate: hexane, 600
ml), and dl-11,15-bis (t-butyldimethylsilyl) prostaglandin E ₂ methyl ester (6
47 mg, yield 71%) was obtained.

IR (liquid film); 1743,1243,1000,964,927,828,768 cm ^-1 Reference Example 4 11,15-bis (t-butyldimethylsilyl) prostaglandin E ₁ methyl ester (E, 3S) -3 in a 150 ml reaction tube with argon substitution.
Tert-Butyldimethylsiloxy-1-iodo-1-octene (607.8 mg, 1.65 × 10 ⁻³ mol) and 6 ml of dry ether were weighed, cooled to −95 ° C. and stirred.
T-Butyllithium (1.92M, 1.72m)
l, 3.30 × 10 ⁻³ mol) was added using a syringe,
The mixture was stirred at 95 to -78 ° C for 3 hours. Separately, a 30 ml eggplant-shaped flask was prepared, and cuprous iodide (314.2 mg, 1.
(65 × 10 ⁻³ mol) was weighed, the reaction system was heated and dried under reduced pressure, and the atmosphere was replaced with argon. In this, dry THF (6
ml) and tributylphosphine (1.07 ml, 4.29x)
10 ⁻³ mol) was added and the mixture was stirred at room temperature to form a uniform solution.
This solution was cooled to −78 ° C., and added to the solution of vinyllithium prepared above under a pressure of argon with a stainless steel tube at once, and the container was washed with 6 ml of dry THF, and this washing solution was also added. After stirring at -78 ° C for 10 minutes, (R) -4
A THF solution (12 ml) of -t-butyldimethylsiloxy-2-cyclopentenone (318.5 mg, 1.50 x 10 ^-3 mol) was added dropwise over 1 hour. 1 ml TH
After flushing the vessel with F and adding, the reaction mixture was stirred for 10 minutes. To this reaction mixture was added 1.5 ml of hexamethylphosphoric triamide (HMPA), and the mixture was stirred for 30 minutes and then triphenyl tin chloride (643.2 mg,
A solution of 1.65 × 10 ⁻³ mol) in THF (2 ml) was added. After heating the reaction solution to -20 ° C, methyl 6-iodohexanoate (2.0882 mg, 7.73 x 10 ^-3 mol)
HMPA solution (2.87 ml) was added at 16 ° C at -20 ° C.
Stir for hours. After completion of the reaction, saturated aqueous ammonium chloride solution (20 ml) was added, and the mixture was shaken well and then separated into an organic layer and an aqueous layer, and the aqueous layer was extracted with ether (2 × 20 ml). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. After passing through a desiccant and concentrating under reduced pressure, it was subjected to silica gel column chromatography (Me
rck 7734 5 g, 1: 5 ethyl acetate-hexane). The resulting concentrated crude product was subjected to silica gel column chromatography (Merck 7734 50 g; ethyl acetate: hexane = 1: 1).
60,900 ml → ethyl acetate: hexane = 1: 20,6
(00 ml), 178.7 mg (20%) of 11,1
5-bis (t-butyldimethylsilyl) plastaglandin E ₁ methyl ester was obtained.

TLC: Rf = 0.52 (ethyl acetate-hexane = 1: 1
5) ¹ H NMR (CDCl ₃ ) δ: 5.6-5.4 (m, 2H), 4.2-3.8.
(M, 2H), 3.66 (s, 3H), 2.64 (dd, 1H, J = 72, 18.4Hz), 2.4-1.8 (m, 4H), 1.7-1. .0
(M), 1.0-0.8 (m, 21H), 0.1-0.0
(M) IR (neat): 1750 cm ^-1 Example 1 (2R, 3R, 4R) -2-allyl-4-t-butyldimethylsilyloxy-3-[(E, 3S) -3-t-butyldimethyl Silyloxy-1-octenyl] cyclopentenone In the same manufacturing method as in Reference Example 3, (Z) -1-iodo-6
Carried out using allyl iodide instead of methoxycarbonyl-2-hexene (2R, 3R, 4R)-
2-allyl-4-t-butyldimethylsilyloxy-3
-[(E, 3S) -3-t-butyldimethylsilyloxy-1-octenyl] cyclopentanone was obtained.

Yield 71%.

¹ H NMR (CDCl ₃ ) δ: 0.07 (12H, s), 0.85 (21H,
s), 1.1 to 1.5 (8H, m), 1.6 to 2.8 (6
H, m), 3.8 to 4.3 (2H, m), 4.75 to 5.60.
(5H IR (liquid film): 3100, 1745, 1255, 1110, 96
5, 910, 875, 835, 810, 770 cm ^-1 .

MS (m / e): 494, 479, 437, 379. Example 2 (2R, 3R, 4R) -4-t-butyldimethylsilyloxy-3-[(E, 3S) -3-t-butyldimethylsilyloxy-1-octenyl] -2- (2-propynyl) Cyclopentanone (2R, 3R, 4R) -4 was carried out in the same manner as in Reference Example 2, except that propargyl iodide was used instead of 1-iodo-6-methoxycarbonyl-2-hexyne.
-T-butyldimethylsilyloxy-3-[(E, 3
S) -3-t-Butyldimethylsilyloxy-1-octenyl] -2- (2-propynyl) cyclopentanone was obtained. Yield 65%.

¹ H NMR (CDCl ₃ ) δ: 0.06 (12H, s), 0.87 (21H), 1.0 to 1.7 (8H, m), 1.8 to 3.0 (7
H, m), 3.7 to 4.2 (2H, m), 5.3 to 5.6 (2
H, m).

IR (liquid film): 3330, 1755, 1255, 1155, 112
0, 1090, 1005, 965, 880, 835, 775 cm ^-1 .

Reference Examples 5-14 11,15-Bis (t-butyldimethylsilyloxy)
Prostaglandin E ₂ methyl esters The following compound was synthesized by the same production method as in Reference Example 3 (yield 19 to 67%).

Reference Example 5: 11,15-bis (t-butyldimethylsilyl) -17
(R), 20-Dimethylprostaglandin E ₂ methyl ester Reference Example 6: 11,15-bis (t-butyldimethylsilyl) -17
(S), 20-Dimethylprostaglandin E ₂ methyl ester Reference Example 7: 11,15-bis (t-butyldimethylsilyl) -1
6,17,18,19,20-Pentanol-15-cyclopentyl prostaglandin E ₂ methyl ester Reference Example 8: 11,15-bis (t-butyldimethylsilyl) -1
6,17,18,19,20- Pentanoru -15- cyclohexyl prostaglandin E ₂ methyl ester Example 9: 11,15- bis (t-butyldimethylsilyl) -15
- methyl prostaglandin E ₂ methyl ester Example 10: 11,15- bis (t-butyldimethylsilyl) -1
6,16- dimethyl prostaglandin E ₂ methyl ester Example 11: 11,15- bis (t-butyldimethylsilyl) -20
- isopropylidene-17-methyl-prostaglandin E ₂ methyl ester Example 12: 11,15- bis (t-butyldimethylsilyl) -1
8,18,19,19-Tetradehydro-16-methylprostaglandin E ₂ methyl ester Reference Example 13: 11,15-bis (t-butyldimethylsilyl) -1
8,19,20-Trinor-17-phenylprostaglandin E ₂ methyl ester Reference Example 14: 11- (t-butyldimethylsilyl) -15-deoxy-16-trimethylsilyloxy-16-vinylprostaglandin E ₂ Methyl Ester Characteristic spectral data for these compounds are listed in Table 1.

Reference Examples 15 and 16 11,15-bis (t-butyldimethylsilyloxy)
Prostaglandin E ₂ derivative The following compounds were synthesized in the same manner as in Reference Example 1 and Reference Examples 5 to 14 (yield 35 to 49%).

Reference Example 15: 11,15-bis (t-butyldimethylsilyl) -2,
3-dehydro-17,18,19,20-tetranor-
16- [3- (α, α, α-trifluoromethyl) phenoxy] prostaglandin E ₂ methyl ester Reference Example 16: 11,15-bis (t-butyldimethylsilyl) -4,
5-6- characteristic spectrum data of trinor-3,7-inter -m- phenylene-3-oxa-prostaglandin E ₂ methyl ester These compounds are listed in Table 1.

The following compounds were synthesized by the same method as in Reference Example 17, 18 prostaglandin E ₁ methyl ester derivative Reference Example 4 (17-32% yield).

Reference Example 17: 11- (t-butyldimethylsilyl) -15-deoxy-16-methyl-16-trimethylsilyloxy prostaglandin E ₁ methyl ester Example ^{18: (4Z) - △ 4} -11- (t- butyl Dimethylsilyl)
-15-Deoxy-16-methyl-16-trimethylsilyloxyplastaglandin E ₁ methyl ester Characteristic spectral data for these compounds are listed in Table 1.

Reference Example 19 11,15-bis (t-butyldimethylsilyl) prostaglandin E ₂ methyl ester 11,15-bis (t-butyldimethylsilyl) -5,
6-Dehydroprostaglandin E ₂ methyl ester (48.2 mg, 0.081 mmol) and synthetic quinoline (25 mg) were dissolved in benzene (2.5 ml) and cyclohexane (2.5 ml) was added, followed by 5% Pd-BaSO 4. ₄ (25m
g) was added, and the mixture was stirred under a hydrogen atmosphere at 25 ° C. for 3 hours, then, synthetic quinoline (50 mg) and 5% Pd—BaSO ₄ (5
0 mg) was added, and the mixture was stirred at 40 ° C. for 4.5 hours. After passing the catalyst, the mixture was washed with ethyl acetate, combined and concentrated under reduced pressure.

It was subjected to silica gel column chromatography (8 g, ether-hexane = 1: 10), the collected fractions were concentrated under reduced pressure, and the residue was further reduced under a vacuum pump under reduced pressure (<4 mmHg).
Left for 7 hours, 11,15-bis (t-
Butyldimethylsilyl) prostaglandin E ₂ methyl ester (41.8 mg, 87%) was obtained.

TCL: Rf = 0.58 (ethyl acetate-hexane = 1: 1
5) IR (liquid ^{film); 1743,1243,1000,964,927, 828,768cm -1 1 H} NMR (CDCl 3) δ; 0.03 and 0.06 (each s, 12, SiCH ₃
× 4), 0.8-1.0 (m, 21, C-CH ₃ × 7), 1.2-1.5 (m, 8, CH ₂ × 4), 1.6-2.9 ( m, 12, CH ₂ CO × 2, CH ₂ C = ×
2, CH × 2, and CH ₂ ), 3.67 (s, 3, OCH ₃ ), 4.06 (m, 2, CH
OSi x 2), 5.37 (m, 2, vinyl), 5.54 (m, 2,
Vinyl) [α] ▲ ²¹ _D ▼; 52.7 ° ( C 1.28, CH ₃ OH) This compound was completely in agreement with the protected disilyl derivative of 11,15 derived from (-)-PGE ₂ . .

Reference Example 20 Prostaglandin E ₂ methyl ester 11,15-Bis (t-butyldimethylsilyl) prostaglandin E ₂ methyl ester (40 mg, 0.067 m
(mol) was dissolved in anhydrous acetonitrile (8 ml), HF-pyridine (0.1 ml) was added at 0 ° C., the mixture was stirred at 24 ° C. for 30 minutes, and HF-pyridine (0.4 ml) was further added.
Stir for hours. After pouring into a saturated aqueous NaHCO ₃ solution (20 ml), the mixture was extracted with ethyl acetate three times (30 ml × 3). The combined extracts were dried over Na ₂ SO _{4 and then} concentrated under reduced pressure. To remove pyridine in the residue, toluene was added and the mixture was further concentrated under reduced pressure. After leaving it for a while under reduced pressure (<4 mmHg) in a vacuum pump, it was chromatographed on silica gel (2 g, ethyl acetate-
Hexane (1: 1) → (1: 0) gradient) was used to obtain (−)-PGE ₂ methyl ester (24.1 mg, 98%).

TLC; Rf = 0.29 (ethyl acetate - cyclohexane - THF = 6: 3: 1 ) IR ( liquid ^{film); 3680-3080,1744,970cm -1 1 H NMR (} CDCl 3) δ: 0.90 (t , 1, J = 6.5 Hz, CH ₃ ), 1.1-2.9 (m, 20, CH ₂ CO × 2, CH ₂ × 5, CH ₂ C = × 2, CH × 2), 3. 08 (br, 1, OH), 3.66 (s, 3, OC
H ₃ ), 4.06 (m, 3, CHO × 2 and OH), 5.34 (m, 1, vinyl), 5.70 (m, 1,
Vinyl) ¹³ C NMR (CDCl ₃ ) δ: 14.0, 22.6, 24.7, 25.1, 26.
6, 31.7, 33.5, 37.3, 46.1, 51.5, 53.
7, 54.5, 72.0, 73.0, 126.6, 130.8, 1
31.5, 136.8, 174.0, 214.1 [α] ▲ ²¹ _D ▼; -71.7 ° ( C 1.043, CH ₃ O
H) Reference Example 21 11,15-bis (t-butyldimethylsilyl) -5,
6-prostaglandin F ₂ α methyl ester Diisobutyl aluminum hydride (1 equivalent) /
A solution of 2,6-di-t-butyl-4-methylphenol (2 equivalents) in toluene (0.192M soln, 2.24 ml,
0.43 mmol) at -78 ° C with 11,15-bis (t-
Butyldimethylsilyl) -5,6-dehydroprostaglandin E ₂ methyl ester (25.5 mg, 0.043 m
Toluene solution (1 ml) of (mol) was added.

After stirring at −78 ° C. for 2 hours, the temperature was raised and the mixture was stirred at −25 to −20 ° C. for 3 hours. A saturated aqueous sodium hydrogen tartrate solution (10 ml) was added, and the mixture was vigorously shaken.

It was extracted with ethyl acetate three times (20 + 10 + 10 ml) at room temperature, combined, dried over Na ₂ SO _{4 and} concentrated under reduced pressure.

It was subjected to silica gel column chromatography (5 g, ethyl acetate-hexane = 5: 1), and 11,15-bis (t
-Butyldimethylsilyl) -5,6-dehydroprostaglandin F ₂ α methyl ester (23.5 mg, 92%,
A low polarity component) was obtained.

TCL; Rf = 0.29 (ethyl acetate-hexane = 1: 1
5) IR (liquid film); 3640-3080, 1745, 1247, 102
0, 970, 930, 830, 770 cm ^{-1 1} H NMR (CDCl ₃ ) δ; 0.02 and 0.05 (s, 12, SiCH ₃ respectively)
× 4), 0.7-1.0 (m, 21, C-CH ₃ × 7), 2.1-3.5 (m, 20, CH ₂ CO, CH ₂ × 6, CH ₂ C≡ × 2, CH × 2), 3.69 (d, 1, J = 8.3 Hz, OH), 3.67 (s, 3, OCH ₃ ), 4.00 and 4.24 (br, 3, CHO ×) 3), 5.40 (m, 2, vinyl) [α] ▲ ²¹ _D ▼; + 0.37 ° ( C 0.715, CH ₃ O
H) Reference example 22 11,15-bis (t-butyldimethylsilyl) prostaglandin F ₂ α methyl ester 11,15-bis (t-butyldimethylsilyl) -5,
6-dehydroprostaglandin F ₂ α-methyl ester (28.7 mg, 0.048 mmol) was dissolved in benzene (1 ml), cyclohexane (1 ml) and Lindlar's catalyst (28.7 mg) were added, and then under a hydrogen atmosphere, 22 ~ 2
The mixture was stirred at 3.5 ° C for 12 hours. The catalyst was passed over, washed with ethyl acetate, combined and concentrated under reduced pressure.

Silica gel column chromatography (6 g, ethyl acetate-hexane-benzene = 1: 15: 2) was applied to 1
1,15-Bis (t-butyldimethylsilyl) prostaglandin F ₂ α methyl ester (23.2 mg, 81%)
Got

TCL; Rf = 0.32 (ethyl acetate-hexane = 1: 1
5) IR (liquid film); 3610-3280, 1745, 1250, 100
0, 970, 938, 830, 770 cm ^{-1 1} H NMR (CDCl ₃ ) δ: 0.03 and 0.05 (s, 12, SiCH ₃ respectively)
× 4), 0.8-1.0 (m, 21, C-CH 3 × 7), 1.2-2.4 (m, 20, CH 2 CO, CH 2 × 6, CH 2 C = × 2, CH × 2), 2.69 (d, 1, J = 9.5 Hz, OH), 3.67 (s, 3, OCH ₃ ), 4.05 (br, 3, CHO × 3), 5 40 (m, 2, vinyl) [α] ▲ ²¹ _D ▼; + 12.3 ° ( C 1.037, CH ₃ O
H) Reference Example 23 Prostaglandin F ₂ α methyl ester 11,15-Bis (t-butyldimethylsilyl) prostaglandin F ₂ α methyl ester (21 mg, 0.035
mmol) in acetic acid (1 ml) and H ₂ O (0.33 ml),
THF (0.1 ml) was added, and the mixture was stirred at 55 ° C for 1.5 hr. The mixture was transferred to a large container, toluene was added, and concentration under reduced pressure was repeated several times to remove acetic acid and H ₂ O. The residue was subjected to silica gel column chromatography (3 g, ethyl acetate-hexane (1: 1) → (1: 0) gradient),
(+)-PGF ₂ α methyl ester (11 mg, 85%) was obtained.

TCL; Rf = 0.2 (ethyl acetate-cyclohexane-
THF = 6: 3: 1) IR (liquid film); 3640-3040, 1738, 1435, 116.
0, 1116, 1042, 1020, 968, 858cm
^{-1 1} H NMR (CDCl ₃ ) δ; 0.89 (t, 3, J = 6.5 Hz, CH ₃ ), 1.2-2.4 (m, 20, CH ₂ CO, CH ₂ × 6). CH ₂ C = × 2, CH × 2), 2.57 (br, 1, OH), 3.29 (br, 1, O)
H), 3.69 (s, 3, OCH ₃ ), 4.03 (brm, 3, C
HO x 3), 5.3-5.6 (m, 2, vinyl) ¹³ C NMR (CDCl ₃ ) δ; 14.0, 22.6, 24.8, 25.2, 25.
6, 26.6, 31.8, 33.5, 37.3, 43.0, 50.
5, 51.6, 55.8, 72.9, 73.0, 78.0, 12
9.1, 129.6, 132.6, 135.3, 174.3 [α] ▲ ²¹ _D ▼; + 31.4 ° ( C 0.423, CH ₃ O
H) The spectrum of the synthesized product (IR, ¹ HNMR, ¹³ CNM
R, TLC) was derived from (+)-PGF ₂ α, and (+)-PGF ₂ αmeth
It was a perfect match with yl ester.

Claims (5)

[Claims] Claim: (A) The following formula (1) [Here, R ² is tri (C ₁ -C ₇ ) is a hydrocarbon silyl group or R ² O is a group representing an acetal bond. ] The 4-substituted-2-cyclopentenones represented by the formula, their enantiomers or a mixture of them in any proportion are represented by the following formula (2) RB-Li ... (2) [where RB is a substituted or unsubstituted It represents a C ₂ -C ₁₀ alkyl or alkenyl group. ] And an organic lithium compound represented by the following formula (3) Cu-Q ... (3) [wherein Q represents a halogen atom, a cyano group, a phenylthio group or a 1-pentynyl group. ] The organic copper compound produced from the copper compound represented by the formula (4) is subjected to a conjugate addition reaction, and then (B) the enolate intermediate produced is added to the following formula (4) R ₃ SnY (4) [where R are the same as each other. Alternatively, it represents C ₁ -C ₄ lower alkyl, C ₃ -C ₇ cycloalkyl, phenyl or a halogen atom, and Y represents a halogen atom or a triflate group. However, two to three R cannot be halogen atoms at the same time. The presence of an organotin compound represented by, the following formula _{(5) X-CH 2 -Z} -RA ... (5) [ wherein, Z is an ethylene group, an ethynylene group, trans -
It represents a vinylene group or a cis-vinylene group, a phenylene group, a phenyleneoxa group, RA represents a hydrogen atom, and X represents a halogen atom or a tosyl group. ] The halide represented by is reacted. Formula (6) below [Here, the definitions of RA, RB, Z and R ² are the same as above. ] The manufacturing method of the 2, 3- di-substituted 4- substituted cyclopentanone represented by these, its enantiomer, or the mixture of them in arbitrary ratios. 2. An organolithium compound of the above formula (2) is represented by the above formula.
In (2), RB is a substituted or unsubstituted C _{2 to} C ₁₀ alkenyl group, and the substituent is a C _{1 to} C ₄ lower alkyl group, a C _{3 to} C ₇ cycloalkyl group, a C _{2 to} C ₄ alkynyl group. Group, phenyl group, phenoxy group (these phenyl group and phenoxy group may be substituted with a fluoromethyl, trifluoromethyl or trifluoromethoxy group), C ₁ -C ₄ lower alkoxy group or formula OR ² (here Wherein R ² is the same as defined above). 3. The organolithium compound of the above formula (2) is represented by the above formula.
In (2), RB is a substituted or unsubstituted C ₂ -C ₁₀ alkyl group, and the substituent is a C ₃ -C ₇ cycloalkyl group, vinyl group, C ₂ -C ₄ alkynyl group, phenyl group, phenoxy group. A group (these phenyl and phenoxy groups may be substituted with a fluoromethyl, trifluoromethyl or trifluoromethoxy group), C ₁ -C ₄
The method according to claim 1, which is a lower alkoxy group or a group represented by the formula OR ² (wherein R ^{2 is} as defined above). 4. The organolithium compound of the above formula (2) has the following formula:
(2) -A [Here, R ³ is a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a group that represents an acetal bond by OR ³ . ] The method as described in any one of Claim 1- Claim 3 represented by these. 5. An organotin compound represented by the above formula (4), wherein R in the above formula (4) is the same or different and is a butyl group, a cyclohexyl group or a phenyl group. Item 5. The method according to any one of items 4 to 4.