JPH064552B2 - New method for producing α-methylene ketones - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing α-methylene ketones.
More specifically, it relates to a novel method for producing α-methylene ketones, which comprises contacting α-substituted methyl β-ketocarboxylic acid allyl esters with a platinum group metal salt or complex.

<Prior Art> [alpha] -methylene ketones are not only important structures as key partial structures of natural products showing antitumor activity, but also important compounds as synthetic intermediates of various useful compounds. Methods for obtaining α-methylene ketones from ketones have been studied for a long time, and the aldol reaction and Mannich reaction are well known as the reaction with formaldehyde. However, it is known that the above reaction requires strong conditions such as using a strong base, and the regiospecificity of the product is not good. For example, in the case of a 3-substituted cyclopentanone having a hydroxyl group protected at the 4-position, elimination of the protected hydroxyl group at the 4-position takes precedence due to the use of the strongly basic substance. Therefore, G.Stork et al. Capture the enolate obtained by conjugating an organocopper compound to 2-cyclopentenone having a hydroxyl group protected at the 4-position, and capturing the enolate with formaldehyde to shift the α-position. Hydroxymethylated, then α
-By inducing methylenecyclopentanones,
We have succeeded in securing position specificity and suppressing side reactions such as desorption [Journal of the American Chemical
Society (J. Am. Chem. Soc.), 97, 6260 (1975)
And 97, 4745 (1975)]. If you outline the outline Is. Although this method is an epoch-making method at first glance, it has a drawback in yield and reproducibility of the reaction, and has not reached an industrially completed method.

According to J. Schwantz et al., This difficulty was achieved by using an organozirconium compound as a conjugate addition agent in the presence of a nickel catalyst to improve the subsequent trapping condition of formaldehyde [Journal of the・ American Chemical Society (J.Am.Chem.So
c.), 102, 1333 (1980)] has not yet been established, which is position-specific, simple and reproducible under mild conditions such as neutral and room temperature. In addition to the above-mentioned importance of α-methylene ketones, a new method satisfying such requirements has been desired.

<Objective of the Invention> The present inventors have paid attention to such technical background, and are expected not only to be antitumor drugs themselves but also to be key intermediates for obtaining useful drugs. As a result of earnest research on a method for producing ketones, the present invention has been succeeded in the development of a new production method which is simple, efficient and excellent in practicality.

<Structure and Effect of Invention> In the present invention, the following formula [II] [Wherein, R ¹ and R ² are the same or different and each represents a substituted or unsubstituted C _{1 to} C ₁₀ linear or branched saturated or unsaturated hydrocarbon group, and R ¹ and R ² are bonded to each other. And may form a ring. R ³ is a C _{2 to} C ₁₀ acyl group, C ₂
To C ₁₁ alkoxycarbonyl group, C _{1 to} C ₁₀ sulfonyl group, R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are the same or different and are hydrogen atoms, C _{1 to} C ₁₀ hydrocarbon groups. ，
Alternatively, it represents an aromatic hydrocarbon group. ] The α-substituted methyl β-ketocarboxylic acid allyl ester represented by the following formula [I] is prepared by contacting with a platinum group metal salt or complex in the presence of an inert organic medium. [In the formula, R ¹ and R ² are the same as defined above. ] The manufacturing method of the (alpha)-methylene ketone represented by these is provided.

In the above formula [II], R ¹ and R ² are the same or different,
It represents a substituted or unsubstituted C _{1 to} C ₁₀ linear or branched saturated or unsaturated hydrocarbon group, and R ¹ and R ² may be bonded to each other to form a ring. Such C _{1 to} C ₁₀
Examples of the linear or branched saturated or unsaturated hydrocarbon group of include, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. Linear saturated hydrocarbon group, isopropyl group, isobutyl group, sec-butyl group, t-butyl group, 1-methylbutyl group, 2-methylbutyl group, 3
-Methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, branched saturated hydrocarbon group such as 3,7-dimethyloctyl group, allyl Group, 2-butenyl group, 3-butenyl group, straight-chain unsaturated hydrocarbon group such as propargyl group, isoprenyl group, geranyl group, citronellyl group, branched unsaturated hydrocarbon group such as neryl group. it can.

As a substituent of a C _{1 to} C ₁₀ linear or branched saturated or unsaturated hydrocarbon group, a C _{3 to} C ₁₀ cycloalkyl group,
An optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic hydrocarbon oxy group, a C _{1 to} C ₁₀ alkoxy group, a C _{2 to} C ₁₁ alkoxycarbonyl group, a C _{2 to} C ₁₀ acyl group, C ₂ -C ₁₀ acyloxy group (provided that the compound contains a double bond in the molecule, the substitution position of the C ₂ -C ₁₀ acyloxy group is not limited to the allyl position), α-alkoxy substitution Alkyl group, tri (C ₁ ~
C ₇ ) Hydrocarbon silyl group, nitro group, nitrile group and the like. Examples of the C _{3 to} C ₇ cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like, which may be substituted with an aromatic hydrocarbon group or an aromatic hydrocarbon oxy group. Represents an phenyl group, an α-naphthyl group, a β-naphthyl group, and various anthranyl groups, and the substituent thereof is C described later.
₁ -C ₁₀ alkoxy group, C ₂ -C ₁₁ alkoxycarbonyl group, C ₂ -C ₁₀ acyl group, C ₂ -C ₁₀ acyloxy group, a nitro group, a cyano group or a halogen atom (e.g. fluorine atom, a chlorine atom, Bromine atom, iodine atom, etc.). C ₁ -C ₁₀ alkoxy and C ₂ -C
_As the C ₁ -C ₁₀ alkoxy group of the ₁₁ alkoxycarbonyl group, methoxy group, ethoxy group, isopropoxy group, t
- butoxy group, and a decyloxy group and the like, C ₂ ~
C ₁₀ C ₂ -C acyl group and C ₂ -C ₁₀ acyloxy group
₁₀ acetyl group as the acyl group, a propionyl group, a butyryl group, a pivaloyl group, a hexanoyl group, Deshinoiru group, a benzoyl group, and a naphthoyl group. C
_{As the 1 to} C ₁₀ alkoxy group, C _{2 to} C ₁₁ alkoxycarbonyl group, C _{2 to} C ₁₀ acyl group, and C _{2 to} C ₁₀ acyloxy group, the groups exemplified as the above-mentioned substituents of the aromatic hydrocarbon group are as they are. It can be preferably used. The α-alkoxy-substituted alkyl group refers to a hydroxyl group-protecting group that forms an acetal bond together with the oxygen atom of the hydroxyl group, and examples of such groups include methoxymethyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group, 2- Ethoxy-2-propyl group,
(2-Methoxyethoxy) methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 6,6-dimethyl-3-oxa-2-oxobicyclo [3,1,0] -4 A hexyl group, etc., and the tri (C ₁ -C ₇ ) hydrocarbon silyl group may be a tri (C ₁ -C ₄ ) alkylsilyl group such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group. group, t- butyl diphenyl diphenyl like enyl silyl group (C ₁ ~C ₄₎ alkyl group, Fueniruji such as phenylalanine dimethyl silyl group (C ₁ ~C ₄₎ and the like alkyl or tribenzylsilyl group You can

R ¹ and R ² may be bonded to each other to form a ring, and the number of ring members is 4 to 12 membered ring. Specifically, cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone , Cyclooctanone, and cyclododecanone derivatives. The ring may have a substituted or unsubstituted C _{1 to} C ₁₀ linear or branched, saturated or unsaturated hydrocarbon group as a substituent.

R ³ represents a sulfonyl group of C ₂ -C ₁₀ acyl group, an alkoxycarbonyl group having C ₂ -C ₁₁ or C ₁ -C _10,. As the C _{2 to} C ₁₀ acyl group and the C _{2 to} C ₁₁ alkoxycarbonyl group, the groups exemplified as the above-mentioned substituents of the aromatic hydrocarbon group can be mentioned as they are, and C ₁
Examples of the -C ₁₀ sulfonyl group include a methanesulfonyl group and a paratoluenesulfonyl group.

R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are the same or different and represent a hydrogen atom, a C _{1 to} C ₁₀ hydrocarbon group, or an aromatic hydrocarbon group, and a C _{1 to} C ₁₀ hydrocarbon group. As the above, the above-mentioned C _{1 to} C ₁₀ linear or branched saturated hydrocarbon group is preferable as it is, and as the aromatic hydrocarbon group, benzene group, naphthalene group and the like are preferable. Basis Specific examples of preferable groups are allyl group (R ^{4 to} R ⁸ are hydrogen atoms), methallyl group (R ⁶ is methyl group, others are hydrogen atoms),
2-butenyl group (R ⁷ or R ⁸ is a methyl group, other is a hydrogen atom), 2-pentenyl group (R ⁷ or R ⁸ is a methyl group, other is a hydrogen atom), cinnamyl group (R ⁷ or R ⁸ is phenyl) Groups and others are hydrogen atoms), among which R ^{4 to} R ⁸
An allyl group in which is a hydrogen atom is most suitable because of its easy availability.

Specific examples of the α-substituted methyl β-ketocarboxylic acid allyl ester represented by the formula [II] include any combination of the groups exemplified above. Among them, the following formula [II ' [In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are the same as defined above, and R ⁹¹ and R ¹⁰¹ are the same or different and each is a hydrogen atom or tri (C _{1 to} C ₇ ). A hydrocarbon silyl group or a group forming an acetal bond with an oxygen atom of a hydroxyl group, R ¹¹ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a vinyl group, and R ¹² may contain an oxygen atom. It represents a substituted or unsubstituted C _{3 to} C ₈ straight-chain or branched saturated or unsaturated hydrocarbon group, and n represents 0 or 1. ] 3,4-Disubstituted-2-substituted methyl-2-allyloxycarbonylcyclopentanones represented by and their stereoisomers or α- which is a mixture thereof at any ratio
The substituted methyl β-ketocarboxylic acid allyl esters are derived by the production method of the present invention into 3,4-disubstituted-2-methylenecyclopentanones useful as key intermediates for the synthesis of various prostaglandin skeletons. Is a group of compounds particularly useful for

In the formula [II ′], R ⁹¹ and R ¹⁰¹ are the same or different and each represents a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group, or a group forming an acetal bond with the oxygen atom of the hydroxyl group. Specific examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group are the same as those mentioned above, and as the group forming an acetal bond with the oxygen atom of the hydroxyl group, the same as the above α-alkoxy-substituted alkyl group. The same groups as exemplified above are mentioned, R ¹¹ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a vinyl group, and the C ₁ -C ₁₀ alkyl group includes a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl group, isobutyl group, sec-butyl group, t-
A butyl group and the like can be mentioned, but a hydrogen atom and a methyl group are particularly preferable as R ¹¹ .

R ¹² represents a substituted or unsubstituted C _{3 to} C ₈ linear or branched, saturated or unsaturated hydrocarbon group which may contain an oxygen atom. Examples of such a group include linear or branched C ₃ -C ₈ alkyl group, alkenyl group, or alkynyl group which may contain an oxygen atom; optionally substituted phenyl group, phenoxy group, or C ₃
To C ₁₀ cycloalkyl group; or C _{1 to} C ₆ alkoxy group, optionally substituted phenyl group, phenoxy group,
Alternatively, a linear or branched C _{1 to} C ₅ alkyl group substituted with a C _{3 to} C ₁₀ cycloalkyl group and the like can be mentioned. Straight or branched chain C ₃ -which may contain oxygen
As the C ₈ alkyl group, alkenyl group or alkynyl group, 2-methoxyethyl group, 2-ethoxyethyl group,
Propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, 1-methyl-1-butyl group, 2-
Methylhexyl group, 2-methyl-2-hexyl group, 2-
Hexyl group, 1,1-dimethylpentyl group, 1,5-dimethyl-4-hexenyl group, 1-butenyl group, 1-butynyl group, 2-butenyl group, 2-butynyl group, etc., preferably propyl group, butyl group , Pentyl group, 1-methyl-1-
Examples thereof include a butyl group, a 2-methyl-1-butyl group, a 1-butenyl group, a 1-butynyl group, a 2-butenyl group and a 2-butynyl group, but a butyl group, a pentyl group, a hexyl group and 1 are particularly preferable. -Methylbutyl group, 1,1-dimethylbutyl group, 2-methylhexyl group, 2-butenyl group,
It is a 2-butynyl group, a cyclopentyl group, or a cyclohexyl group. As the substituent of the optionally substituted phenyl group, phenoxy group, or C ₃ -C ₁₀ cycloalkyl group, for example, halogen atom, hydroxy group, C ₂
To C ₇ acyloxy group, C _{1 to} C ₄ alkyl group optionally substituted with halogen atom, C _{1 to} C ₄ alkoxy group optionally substituted with halogen atom, nitrile group, carboxyl group or (C ₁ ~ etc. C ₆₎ alkoxycarbonyl group. The halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, and particularly preferably a fluorine atom or a chlorine atom. Examples of the C _{2 to} C ₇ acyloxy group include acetoxy group, propionyloxy group, n-butyryloxy group, isobutyryloxy group, n-valeryloxy group, isovaleryloxy group, caproyloxy group, enanthyloxy group or benzoyloxy group. A group can be mentioned.

Examples of the C ₁ -C ₄ alkyl group which may be substituted with halogen include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl, a chloromethyl group, a dichloromethyl group and a trifluoromethyl group. It can be mentioned as a preferable one. The C ₁ -C ₄ alkoxy group which may be substituted with halogen includes, for example, methoxy group, ethoxy group, n-propoxy, isopropoxy group, n-butoxy group, chloromethoxy group, dichloromethoxy group, trifluoromethoxy group. And the like can be mentioned as preferable ones.

Examples of the (C ₁ -C ₆ ) alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group and a 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 ₁₀ cycloalkyl group, the unsubstituted or are substituted by the same substituents as described above, saturated or unsaturated C ₃ -C _10, preferably C ₅ -C ₆ , Particularly preferably C ₆ groups such as cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclohexenyl group, cycloheptyl group, cyclooctyl group,
A cyclodecyl group etc. can be mentioned.

The straight-chain or branched-chain C ₁ -C ₅ alkyl group substituted by a C ₁ -C ₆ alkoxy group, an optionally substituted phenyl group, a phenoxy group, or a C ₃ -C ₁₀ cycloalkyl group is as described above. A group obtained by combining the exemplified groups of the above definitions is directly preferred.

The carbon atom substituted by R ¹¹ and R ¹² in the above formula [II ′] is usually an asymmetric carbon atom, and both isomers of R configuration and S configuration of steric configuration exist. In the invention, all isomers thereof are included, and the dl form also includes a mixture in an arbitrary ratio.

In the above formula [II '], n represents 0 or 1. That is, when n is 0, the 3,4-disubstituted-2-substituted methyl-2-allyloxycarbonylcyclopentanones represented by the formula [II ′] are represented by the following formula [II′-0] [Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹¹ ,
R ¹⁰¹ , R ¹¹ and R ¹² are as defined above. ] When n is 1, the 3,4-disubstituted-2-substituted methyl-2-allyloxycarbonylcyclopentanones represented by the formula [II '] are represented by the following formula [II'-
1] [Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹¹ ,
R ¹⁰¹ , R ¹¹ and R ¹² are the same as defined above. ] It is a structure represented by.

The α-substituted methyl β-ketocarboxylic acid allyl esters represented by the above formulas [II] and [II ′] are prepared by reacting the corresponding α-hydroxymethyl β-ketocarboxylic acid allyl esters by the method known per se. Under,
It can be easily obtained by reacting with carboxylic acid anhydride, carboxylic acid halide, chloroformic acid esters, organic sulfonic acid halides and the like. The α-hydroxymethyl β-ketocarboxylic acid allyl ester is prepared by a method proposed by the present inventors (Tsuji et al., Journal of Organic Chemistry (J. Org. Chem.), 1985 , 50, 3416).
The corresponding β-ketocarboxylic acid allyl ester can be easily produced by reacting an aqueous formaldehyde solution in the presence of a base such as potassium hydrogen carbonate.

The method of the present invention comprises the thus-obtained formula [II] or [II '
It is carried out by contacting an α-substituted methyl β-ketocarboxylic acid allyl ester represented by with a platinum group metal salt or complex in the presence of an inert organic medium.

Examples of the platinum group metal include metals such as ruthenium, rhodium, palladium and platinum. Of these, palladium is particularly preferable. The platinum group metal is usually used in the form of a salt or complex, but it is particularly preferably used in the form of a phosphine complex. As a method of preparing such a phosphine complex, a method of previously forming a complex with a platinum group metal with a phosphine and a method of adding a phosphine ligand in a reaction system to a platinum group metal salt- or complex containing no phosphine to activate There is a method of forming a phosphine complex as a seed, and both are preferably used.

Examples of such phosphine complexes and phosphine-free platinum group metal salts or complexes include ruthenium compounds such as dihydrotetrakis (triphenylphosphine) ruthenium, ruthenium acetylacetonate, dichlorotetrakis (triphenylphosphine) ruthenium, and chlorotris (triphenyl). Rhodiums such as phosphine) rhodium, hydrotetrakis (triphenylphosphine) rhodium and rhodium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium acetate, bis (acetylacetonato) palladium, tris (Dibenzylideneacetone) dipalladium chloroform complex, palladiums such as tris (tribenzylideneacetone) tripalladium, tetrakis (triphenylphosphine) ) Platinum and platinum such as platinum acetylacetonate can be mentioned, but among them, palladium complex is preferable, and tris (dibenzylideneacetone) dipalladium, chloroform complex to which an appropriate amount of phosphine ligand is added and tetrakis (triphenyl). Phosphine) palladium and the like are particularly preferable.

When such a complex is prepared in the reaction system, an organic acid palladium salt such as palladium acetate, palladium propionate, palladium butyrate or palladium benzoate, or an inorganic acid palladium salt such as palladium chloride, palladium sulfate or palladium nitrate is used as a ligand. It is carried out by contacting with a reducing agent such as sodium hydride, lithium aluminum hydride, or hydrogen in the presence of to generate active species in the reaction system. As such a ligand,
For example, triethylphosphine, tributylphosphine, tricyclohexylphosphine, 4-methyl-1-
Trialkylphosphines such as phospha-3,5,8-trioxabicyclo [2.2.2] octane, triaromatic hydrocarbon phosphines such as triphenylphosphine, triethylphosphite, triisopropylphosphine Phyto, triphenylphosphite, 4-ethyl-1
-Phospha-2,6,7-trioxabicyclo [2.2.2] octane and other phosphites, 1,2-diphenylphosphinoethane, 1,3-diphenylphosphinopropane, 1,4-diphenyl Examples of the ligand include phosphine bidentate ligands such as phenylphosphinobutane, and triphenylphosphine is particularly preferable.

It should be noted that the amount of the ligand may be added in excess to the platinum group metal salt or complex, and it has been found that this addition amount has a delicate influence on the reaction mode of the present invention. That is, the platinum group metal salt or complex used is 0.001 to 30 mol%, preferably 0.01 to 30 mol% with respect to the α-substituted methyl β-ketocarboxylic acid allyl ester represented by the formula [II] or [II ′]. -20 mol%, more preferably 0.1-10 mol%, usually 1-5 mol%, but when the reaction scale becomes an industrial large scale, 1 mol% or less Is enough. The amount of the ligand used is 0.1 to 50 times by mole, preferably 1 to 10 times by mole, and particularly preferably 2 to 5 times by mole, and usually 4 times by mole, with respect to the platinum group metal. .

The method of the present invention is carried out in the presence of an inert organic medium.
Examples of the inert organic medium include ether mediums such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane, aromatic hydrocarbons such as benzene and toluene, or acetonitrile, propionitrile, dimethyl sulfoxide, N. , N-dimethylformamide and the like are used, and tetrahydrofuran and acetonitrile are particularly preferable. The amount of the inert organic medium used may be an amount sufficient for the reaction to proceed smoothly, and is usually 1 to 100 times, preferably 2 to 30 times the volume of the raw material. The reaction is usually preferably carried out under an atmosphere of an inert gas such as nitrogen or argon.

The reaction temperature varies depending on the type and amount of the platinum group metal salt or complex used, and the type of inert organic medium.
78 ° C to the boiling point of the inert organic medium used, preferably -2
A temperature range of 0 ° C to 60 ° C, particularly preferably 0 ° C to room temperature is adopted. The reaction time also depends on the type and amount of platinum group metal salt or complex used, the type of inert organic medium, and the reaction temperature, and the end point of the reaction is determined by tracing with gas chromatography or thin layer chromatography. Usually, the reaction is completed within 1 hour to several hours at a reaction temperature near room temperature.

After completion of the reaction, the α-methylene ketones represented by the above formula [I] or [I ′] can be added with water which may contain an electrolyte such as sodium chloride or ammonium chloride by a conventional method, hexane. The compound of the formula [I] or [I '], which is the target compound, is obtained by separating and purifying using a separating means such as extraction with a solvent such as ether, ethyl acetate, washing, drying, separation, concentration, distillation after concentration, and chromatography. The α-methylene ketones represented can be isolated.

Of the products thus obtained, the α-methylene ketones represented by the formula [I ′] may have a protected hydroxyl group in the molecule. These protected hydroxyl groups are converted to free hydroxyl groups by subjecting them to a deprotection reaction, if necessary. The deprotected α-methylene ketones represented by the formula [I ′] are themselves a group of compounds expected to have physiological activities such as antitumor activity, and such protective groups for hydroxyl groups (R ⁹¹ and R ¹⁰¹ ) When the protecting group is a group that forms an acetal bond together with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin is used as a catalyst to remove water. It is preferably carried out by using ethyl erythryl as a reaction solvent. Reaction is usually -78 ° C to +30
It is carried out in the temperature range of ° C for about 10 minutes to 3 days. Also,
When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, the above-mentioned reaction is carried out using, for example, acetic acid, tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid or hydrogen fluoride-pyridine as a catalyst. It is carried out in the reaction solvent at the same temperature for a similar time.

Thus, 3,4-disubstituted-2 represented by the above formula [I ']
-Methylenecyclopentanones and their stereoisomers or α-methylene ketones which are a mixture thereof at any ratio can be obtained. The formula [II 'which is a starting material for the production of the present α-methylene ketones is obtained. ] 4,4-Disubstituted-2-substituted methyl-2-allyloxycarbonylcyclopentanone and its stereoisomer or a mixture of them in any proportion, α-substituted methyl β-ketocarboxylic acid allyl esters Is a novel substance group and is useful as an important key intermediate for reaching a useful compound group represented by the formula [I '] of the final product by the method of the present invention. That is, the following formula [II ′] [Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹¹ ,
R ¹⁰¹ , R ¹¹ , R ¹² and n are the same as defined above. ] 3,4-Disubstituted-2-substituted methyl-2-allyloxycarbonylcyclopentanones represented by and their stereoisomers or α- which is a mixture thereof at any ratio
It is a substituted methyl β-ketocarboxylic acid allyl ester.

In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹¹ , R ¹⁰¹ ,
R ¹¹ , R ¹² and n are the same as defined above, and the same groups as those mentioned above are preferably mentioned. Among them, particularly preferable groups are R ³ as acetyl group, propionyl group or benzoyl group, respectively. An acyl group such as a group, an methoxycarbonyl group, an ethoxycarbonyl group, an alkoxycarbonyl group such as an isobutyloxycarbonyl group, an organic sulfonyl group such as a methanesulfonyl group or a paratoluenesulfonyl group, and R ⁴ , R ⁵ ,
R ⁶ , R ⁷ and R ⁸ are each preferably a hydrogen atom, and R ⁹¹ ,
R ¹⁰¹ is the same or different and is preferably a hydrogen atom, t-butyldimethylsilyl group, trimethylsilyl group, 2-tetrahydropyranyl group, 1-ethoxyethyl group, (2-methoxyethoxy) methyl group or the like, and R ¹¹ is a hydrogen atom. Alternatively, a methyl group is preferable, and R ¹² is butyl group, pentyl group, hexyl group, 1-methylbutyl group, 1,1-dimethylbutyl group, 2-methylhexyl group, 2-butenyl group, 2
A -butynyl group, a cyclopentyl group, a cyclohexyl group or the like is preferable, and n is 0 or 1 and both are preferable.

Further, the compound having the three-dimensional structure represented by the formula [II '] is the most preferable isomer since it is completely the same as the three-dimensional structure of natural prostaglandin, but in the present invention, the stereoisomer or its It should be understood that it also includes mixtures in any proportion.

In exemplifying the specific examples of the compound represented by the formula [II ′], the following formula [II ″] [In the formula, R ¹¹ , R ¹² , and n are the same as defined above. ] 3,4-disubstituted-2-hydroxymethyl-2 represented by
-Carboxycyclopentanones are exemplified above as a basic mother nucleus, and the compounds of the present invention are exemplified as derivatives of the mother nucleus.

1-1) Specific examples of the basic mother nucleus of the compound in which n is 0 include (01) (3R, 4R) -3-[(S)-(E) -3-hydroxy-1-octenyl] -4- Hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (02) (3R, 4R) -3-[(S)-(E) -3-hydroxy-1-nonenyl] -4-hydroxy-2-hydroxymethyl 2-Carboxycyclopentanone (03) (3R, 4R) -3-[(S)-(E) -3-Hydroxy-1-decenyl] -4-hydroxy-2-hydroxymethyl-2-carboxycyclopenta Non (04) (3R, 4R) -3-[(3S, 5S)-(E)-
3-Hydroxy-5-methyl-1-nonenyl] -4-hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (05) (3R, 4R) -3-[(3S, 5R)-(E)-
3-Hydroxy-5-methyl-1-nonenyl] -4-hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (06) (3R, 4R) -3-[(S)-(E) -3- Hydroxy-4-methyl-1-octenyl] -4-hydroxy-
2-Hydroxymethyl-2-carboxycyclopentanone (07) (3R, 4R) -3-[(S)-(E) -3-hydroxy-4,4-dimethyl-1-octenyl] -4-hydroxy- 2-Hydroxymethyl-2-carboxycyclopentanone (08) (3R, 4R) -3-[(S)-(E) -3-hydroxy-3-cyclopentyl-1-propenyl] -4-hydroxy-2- Hydroxymethyl-2-carboxycyclopentanone (09) (3R, 4R) -3-[(S)-(E) -3-hydroxy-3-cyclohexyl-1-propenyl] -4-hydroxy-2-hydroxymethyl 2-Carboxycyclopentanone (10) (3R, 4R) -3-[(S)-(E) -3-Hydroxy-3-cyclopentyl-1-butenyl] -4-hydroxy-2-hydroxymethyl-2 -Carboxycyclopentano (11) (3R, 4R) -3-[(S)-(E) -3-Hydroxy-5-phenoxy-1-pentenyl] -4-hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (12 ) (3R, 4R) -3-[(E) -3-hydroxy-
3-Methyl-1-octenyl] -4-hydroxy-2-
Hydroxymethyl-2-carboxycyclopentanone (13) (3R, 4R) -3-[(E) -3-hydroxy-
3-Vinyl-1-octenyl] -4-hydroxy-2-
Hydroxymethyl-2-carboxycyclopentanone (14) (01) to (13) (3S, 4S) isomers (15) (01) to (13) enantiomers 1-2) n is 0 Specific examples of the 3,4-disubstituted-2-substituted methyl-2-allyloxycarbonylcyclolopentanones of the invention include (101) (01) to (15) which are 2-acetoxymethyl groups. Group in which the 2-carboxy group is a 2-allyloxycarbonyl group (hereinafter, the above-mentioned derivative is abbreviated as 2-acetyl allyl ester) (102) 2-acetyl of (01) to (15) 2-methyl-2 of the body
-Propenyl ester (103) (01) to (15) 2-acetyl 2-butenyl ester (104) (01) to (15) 2-acetyl 1-methyl-2
-Propenyl ester (105) (01) to (15) 2-acetyl geranyl ester (106) (01) to (15) 2-acetyl cinnamyl ester (107) (01) to (15) 2-propionyl allyl ester (108) (01) to (15) 2-butyryl allyl ester (109) (01) to (15) 2-pivaloyl allyl ester (110) (01) To (15) 2-benzoyl allyl ester (111) (01) to (15) 2-naphthoyl allyl ester (112) (01) to (15) 2-methoxycarbonyl allyl ester ( 113) (01) to (15) 2-methoxycarbonyl 2-
Methyl-2-propenyl ester (114) (01) to (15) 2-methoxycarbonyl 2-
Butenyl ester (115) (01) to (15) 2-methoxycarbonyl cinnamyl ester (116) (01) to (15) 2-ethoxycarbonyl allyl ester (117) (01) to ( (15) 2-isobutyloxycarbonyl allyl ester (118) (01) to (15) 2-methanesulfonyl allyl ester (119) (01) to (15) 2-paratoluenesulfonyl allyl Esters (120) (101) to (119) 4,3'-bis (t-butyldimethylsilyl) ether (121) (101) to (119) 4-t-butyldimethylsilyl-3'-trimethylsilyl ether (122) (101) to (119) 4,3'-bis (2-tetrahydropyranyl) ether (123) (101) to (119) 4-t-butyldimethylsilyl-3 '-(2- Tetrahydropyranyl) ether (124) (101) to (119) 4- (2-tetrahydropyranyl) -3'-t-butyldimethylsilyl ether 4- (2-tetrahydropyranyl) -3'-trimethylsilyl ether of (125) (101) to (119) and the like.

2-1) Specific examples of the basic mother nucleus of the compound in which n is 1 include (51) (3R, 4R) -3-[(S)-(E) -4-hydroxy-1-octenyl] -4- Hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (52) (3R, 4R) -3-[(R)-(E) -4-hydroxy-1-octenyl] -4-hydroxy-2-hydroxymethyl -2-Carboxycyclopentanone (53) (3R, 4R) -3-[(E) -4-hydroxy-
1-nonenyl] -4-hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (54) (3R, 4R) -3-[(E) -4-hydroxy-
1-decenyl] -4-hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (55) (3R, 4R) -3-[(E) -4-hydroxy-
4-Cyclopentyl-1-butenyl] -4-hydroxymethyl-2-carboxycyclopentanone (56) (3R, 4R) -3-[(E) -4-hydroxy-
4-Methyl-1-octenyl] -4-hydroxy-2-
Hydroxymethyl-2-carboxycyclopentanone (57) (3R, 4R) -3-[(S)-(E) -4-hydroxy-4-methyl-1-octenyl] -4-hydroxy-
2-Hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (58) (3R, 4R) -3-[(R)-(E) -4-hydroxy-4-methyl-1-octenyl] -4- Hydroxy-
2-Hydroxymethyl-2-carboxycyclopentanone (59) (3R, 4R) -3-[(1E, 5Z) -4-hydroxy-4-methyl-1,5-octadienyl] -4-
Hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (60) (3R, 4R) -3-[(E) -4-hydroxy-
4-Methyloct-1-en-5-ynyl] -4-hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (61) (3R, 4R) -3-[(E) -4-hydroxy-
4-Vinyl-1-octenyl] -4-hydroxy-2-
Hydroxymethyl-2-carboxycyclopentanone (62) (3R, 4R) -3-[(E) -4-hydroxy-
5-phenoxy-1-propenyl] -4-hydroxy-
2-Hydroxymethyl-2-carboxycyclopentanone (63) (3R, 4R) -3-[(1E) -4-hydroxy-
1,8-Dimethyl-1,7-nonadienyl] -4-hydroxy-2-hydroxymethyl-2-carboxycyclopentanone (64) (51) to (63) (3S, 4S) isomers (65) ( 51) to (63) enantiomers 2-2) Specific examples of the 3,4-disubstituted-2-substituted methyl-2-allyloxycarbonylcyclopentanones of the present invention in which n is 1 are (151) Derivatives in which the 2-hydroxymethyl group of (51) to (65) is a 2-acetoxymethyl group and the 2-carboxy group is a 2-allyloxycarbonyl group (hereinafter, the above-mentioned derivative is referred to as a 2-acetyl allyl ester). (152) (51) to (65) of 2-acetyl 2-methyl-2
-Propenyl ester (153) (51) to (65) 2-acetyl 2-butenyl ester (154) (51) to (65) 2-acetyl 1-methyl-2
-Propenyl ester (155) (51) to (65) 2-acetyl geranyl ester (156) (51) to (65) 2-acetyl cinnamyl ester (157) (51) to (65) 2-propionyl allyl ester (158) (51) to (65) 2-butyryl allyl ester (159) (51) to (65) 2-pivaloyl allyl ester (160) (51) ~ (65) 2-benzoyl allyl ester (161) (51) ~ (65) 2-naphthoyl allyl ester (162) (51) ~ (65) 2-methoxycarbonyl allyl ester ( 163) 2-of the 2-methoxycarbonyl compound of (51) to (65)
Methyl-2-propenyl ester (164) (51) to (65) 2-methoxycarbonyl 2-
Butenyl ester (165) (51) to (65) 2-methoxycarbonyl cinnamyl ester (166) (51) to (65) 2-ethoxycarbonyl allyl ester (167) (51) to ( Allyl ester of 2-isobutyloxycarbonyl compound of (65) (168) Allyl ester of 2-methanesulfonyl compound of (51) to (65) (169) Allyl ester of 2-paratoluenesulfonyl compound of (51) to (65) Esters (170) (151) to (169) 4,4'-bis (t-butyldimethylsilyl) ether (171) (151) to (169) 4-t-butyldimethylsilyl-4'-trimethylsilyl ether (172) (151) to (169) 4,4'-bis (2-tetrahydropyranyl) ether (173) (151) to (169) 4-t-butyldimethylsilyl-4 '-(2- Tetrahydropyranyl) ether (174) (151) to (169) 4- (2-tetrahydropyranyl) -4'-t-butyldimethylsilyl ether 4- (2-tetrahydropyranyl) -4'-trimethylsilyl ether of (175) (151) to (169) can be mentioned, but not limited thereto.

3,4-disubstituted represented by the formula [II ′] exemplified here
The 2-substituted methyl-2-allyloxycarbonylcyclopentanones are 3,4-disubstituted-2 by a method similar to the method for producing the α-substituted methyl β-ketocarboxylic acid allyl esters represented by the above formula [II]. -Hydroxymethyl-2
-Allyloxycarbonylcyclopentanones are easily obtained by reacting with carboxylic acid anhydrides, carboxylic acid halides, chloroformates, organic sulfonic acid halides, etc. in the presence of a base by a method known per se. To be The 3,4-disubstituted-2-hydroxymethyl-2-allyloxycarbonylcyclopentanones are also shown in the literature (Jiro Tsuji et al., J. Org. Chem., 1985 , 5).
0,3416) to easily produce the corresponding 3,4-disubstituted-2-allyloxycarbonylcyclopentanones by reacting an aqueous formaldehyde solution in the presence of a base such as potassium hydrogen carbonate. You can

The production of such 3,4-disubstituted-2-allyloxycarbonylcyclopentanones was carried out by a method separately proposed by the present inventors [Hari et al., Chemical and Pharmaceutical Bulletin (Chem.Pharm.Bull. ., 33 (5), 1815 (198
5)] and (Japanese Patent Application Laid-Open No. 59-44336), but the main points of the production method will be introduced in the following reaction scheme. [In the scheme, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹¹ ,
R ¹⁰¹ , R ¹¹ , R ¹² and n are the same as defined above. ] Is shown.

Further, among the α-methylene ketones represented by the general formula [I] obtained by the method of the present invention, 3,4-disubstituted-2-substituted methyl-2-allyloxy represented by the above formula [II '] is used. 3,4-Disubstituted-2-methylenecyclopenta represented by the above formula [I '] derived from the carbonyl cyclopentanones and stereoisomers thereof or a mixture thereof in arbitrary proportions by the method of the present invention. As far as the present inventors know, the nonones and the stereoisomers thereof or a mixture thereof in any ratio are known compounds in which n is 0, R ¹¹ is a hydrogen atom, and R ¹² is a pentyl group. G.Stork et al., Journal of the American Chemical Society (J.Am.Chem.Soc.), 97, 6260 (1975) and G. Schyubarz (J. Schwartz) et al., Jiya Naru Of
The American Chemical Society (J.Am.Che
m.Soc.), 102, 1333 (1980)).
All others are new compounds. Moreover, the 3,4-disubstituted-2-methylenecyclopentanones represented by the above formula [I '] and stereoisomers thereof or a mixture thereof in any proportion are useful as key intermediates for various prostaglandin derivatives. Rather, [e.g., supra, Hari et al., Chemical and Pharmacological Bulletin (Chem.Pharm.Bull.), 33 (5), 1815 (1985), G. Stork et al. , Journal of the
American Chemical Society (J.Am.Chem.So
c.), 97, 6260 (1975), etc.], and the compound group in which R ⁹ and R ¹⁰ in the formula [I ′] are both hydrogen atoms is expected to have physiological effects such as antitumor activity. From this viewpoint, it is a useful compound group. That is, according to the production method of the present invention, the following formula [I '] [In the formula, R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group, or a group forming an acetal bond with the oxygen atom of the hydrogen group,
¹¹ , R ¹² and n are the same as defined above. ] 3,4-Disubstituted-2-methylenecyclopentanones represented by the formula and α-methylene ketones which are stereoisomers thereof or a mixture thereof at any ratio are provided.

In the formula, R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group, or a group forming an acetal bond with the oxygen atom of the hydroxyl group, and the above-mentioned specific examples are suitable as they are. Can be given to. R ¹¹ , R ¹² , and n are the same as defined above. Among them, particularly preferable groups are: when n is 1, R ⁹ and R ¹⁰ are the same or different and are hydrogen atom, t-butyldimethylsilyl group,
Trimethylsilyl group, 2-tetrahydropyranyl group, 1
-Ethoxyethyl group, (2-methoxyethoxy) methyl group and the like are preferable, R ¹¹ is preferably a hydrogen atom or a methyl group, and R ¹² is butyl group, pentyl group, hexyl group, 1
-Methylbutyl group, 1,1-dimethylbutyl group, 2-methylhexyl group, 2-butenyl group, 2-butynyl group, cyclopentyl group, cyclohexyl group and the like are preferable. Further, when n is 0, the case where R ¹² is a pentyl group is excluded from the range in consideration of the presence of the above-mentioned known compound, and therefore R ⁹ and R ¹⁰ are the same or different, and a hydrogen atom, t-
Butyldimethylsilyl group, trimethylsilyl group, 2-tetrahydropyranyl group, 1-ethoxyethyl group, (2-
Methoxyethoxy) methyl group and the like are preferable, R ¹¹ is preferably a hydrogen atom or a methyl group, and R ¹² is butyl group, hexyl group, 1-methylbutyl group, 1,1-dimethylbutyl group, 2-methylhexyl group, 2- Butenyl group, 2-butynyl group, cyclopentyl group, cyclohexyl group and the like are preferable.

Specific examples of the compound represented by the formula [I '] are as follows: 1) Specific examples of the compound in which n is 0 (201) (3R, 4R) -3-[(S)-(E) -3-hydroxy -1-Nonenyl] -4-hydroxy-2-methylenecyclopentanone (202) (3R, 4R) -3-[(S)-(E) -3-hydroxy-1-decenyl] -4-hydroxy-2 -Methylenecyclopentanone (203) (3R, 4R) -3-[(3S, 5S)-(E)-
3-Hydroxy-5-methyl-1-nonenyl] -4-hydroxy-2-methylenecyclopentanone (204) (3R, 4R) -3-[(3S, 5R)-(E)-
3-Hydroxy-5-methyl-1-nonenyl] -4-hydroxy-2-methylenecyclopentanone (205) (3R, 4R) -3-[(S)-(E) -3-hydroxy-4-methyl -1-octenyl] -4-hydroxy-2-methylenecyclopentanone (206) (3R, 4R) -3-[(S)-(E) -3-hydroxy-4,4-dimethyl-1-octenyl] -4-Hydroxy-2-methylenecyclopentanone (207) (3R, 4R) -3-[(S)-(E) -3-hydroxy-3-cyclopentyl-1-propenyl] -4-hydroxy-2- Methylenecyclopentanone (208) (3R, 4R) -3-[(S)-(E) -3-Hydroxy-3-cyclohexyl-1-propenyl] -4-hydroxy-2-methylenecyclopentanone (209) (3R, 4R) -3-[(S)-(E) -3-hydroxy-4-cyclo Nethyl-1-butenyl] -4-hydroxy-2-methylenecyclopentanone (210) (3R, 4R) -3-[(S)-(E) -3-hydroxy-5-phenoxy-1-pentenyl]- 4-Hydroxy-2-methylenecyclopentanone (211) (3R, 4R) -3-[(E) -3-hydroxy-
3-Methyl-1-octenyl] -4-hydroxy-2-
Methylenecyclopentanone (212) (3R, 4R) -3-[(E) -3-hydroxy-
3-Vinyl-1-octenyl] -4-hydroxy-2-
Methylenecyclopentanone (213) (201) to (212) (3S, 3S) isomer (214) (201) to (212) enantiomer (215) (201) to (214) 4,3 ' -Bis (t-butyldimethylsilyl) ether (216) (201) to (214) 4-t-butyldimethylsilyl-3'-trimethylsilyl ether (217) (201) to (214) 4,3'- Bis (2-tetrahydropyranyl) ether (218) (201)-(214) 4-t-butyldimethylsilyl-3 '-(2-tetrahydropyranyl) ether (219) (201)-(214) 4- (2-tetrahydropyranyl) -3'-t-butyldimethylsilyl ether (220) (201) to (214) such as 4- (2-tetrahydropyranyl) -3'-trimethylsilyl ether may be mentioned. it can.

2) Specific examples of compounds in which n is 1 (301) (3R, 4R) -3-[(S)-(E) -4-hydroxy-1-octenyl] -4-hydroxy-2-methylenecyclopentanone (302) (3R, 4R) -3-[(R)-(E) -4-Hydroxy-1-octenyl] -4-hydroxy-2-methylenecyclopentanone (303) (3R, 4R) -3- [(E) -4-hydroxy-
1-nonenyl] -4-hydroxy-2-methylenecyclopentanone (304) (3R, 4R) -3-[(E) -4-hydroxy-
1-decenyl] -4-hydroxy-2-methylenecyclopentanone (305) (3R, 4R) -3-[(E) -4-hydroxy-
4-Cyclopentyl-1-butenyl] -4-hydroxy-2-methylenecyclopentanone (306) (3R, 4R) -3-[(E) -4-hydroxy-
4-Methyl-1-octenyl] -4-hydroxy-2-
Methylenecyclopentanone (307) (3R, 4R) -3-[(S)-(E) -4-hydroxy-4-methyl-1-octenyl] -4-hydroxy-2-methylenecyclopentanone (308) (3R, 4R) -3-[(R)-(E) -4-Hydroxy-4-methyl-1-octenyl] -4-hydroxy-2-methylenecyclopentanone (309) (3R, 4R) -3 -[(1E, 5Z) -4-
Hydroxy-4-methyl-1,5-octadienyl] -4
-Hydroxy-2-methylenecyclopentanone (310) (3R, 4R) -3-[(E) -4-hydroxy-
4-Methyloct-1-en-5-ynyl] -4-hydroxy-2-methylenecyclopentanone (311) (3R, 4R) -3-[(E) -4-hydroxy-
4-Vinyl-1-octenyl] -4-hydroxy-2-
Methylenecyclopentanone (312) (3R, 4R) -3-[(E) -4-hydroxy-
5-phenoxy-1-propenyl] -4-hydroxy-
2-Methylenecyclopentanone (313) (3R, 4R) -3-[(1E) -4-hydroxy-1,8-dimethyl-1,7-nonadienyl] -4-hydroxy-2-methylenecyclopentanone ( 314) (301) to (313) (3S, 4S) isomers (315) (301) to (313) enantiomers (316) (301) to (315) 4,4'-bis (t- Butyldimethylsilyl) ether (317) (301) to (315) 4-t-butyldimethylsilyl-4′-trimethylsilyl ether (318) (301) to (315) 4,4′-bis (2-tetrahydro) Pyranyl) ether (319) (301) to (315) 4-t-butyldimethylsilyl-4 '-(2-tetrahydropyranyl) ether (320) (301) to (315) 4- (2- Tetrahydropyranyl) -4'-t-butyldimethylsilyl ether (321) (301) to (315) such as 4- (2-tetrahydropyranyl) -4'-trimethylsilyl ether. Although it is Rukoto, but is not limited thereto.

As described above, the method for producing α-methylene ketones by contacting α-substituted methyl β-ketocarboxylic acid allyl esters with a platinum group metal salt or complex as described in detail in the present invention is as follows. It has various characteristics. That is, 1) α-methylene ketones can be produced from β-ketocarboxylic acid allyl esters in a position-specific and good yield.

2) It is an industrially advantageous production method because the reaction proceeds at neutral temperature and room temperature and there are few side reactions.

3) In particular, in the case of application to derivative synthesis for the purpose of synthesizing a prostaglandin skeleton, the conventional method for trapping formalin of enolate [G.Stork et al., Journal of the American Chemical. Society of Science (J. Am. Chem. Soc.), 97, 6260 (1975)] is difficult to obtain with good reproducibility. The α-methylenecyclopentanone derivative represented by the formula [I '] has good reproducibility. It can be produced in high yield, and has come to be highlighted again as an intermediate for the synthesis of various prostaglandins.

4) The produced α-methylenecyclopentanones are themselves useful as a group of compounds expected to exhibit antitumor activity.

Hereinafter, the present invention will be described in more detail with reference to Examples.
The present invention is not limited to these.

Examples 1 to 6 Representative Experimental Examples: α-Substituted methyl β-ketonecarboxylic acid allyl esters (1.0 mmol) were dissolved in 3.0 ml of a solvent (tetrahydrofuran or acetonitrile), and tris (dibenzylideneacetone) was dissolved therein. ) Dipalladium (o) chloroform complex (5mol%) and triphenylphosphine (20mol
%) Was added, and the reaction was performed at room temperature for 8 to 25 minutes while monitoring the disappearance of the raw materials by thin layer chromatography. After the reaction was completed, saturated saline was added, hexane was added to the resulting mixture for extraction, the separated organic layer was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and then over-concentrated to obtain a crude product. . The gas chromatograph (G
The GLC yield was determined by LC) analysis, and in some cases, the product was isolated by a separation means such as distillation or column chromatography, and the isolated yield was calculated. Examples 1-6
The starting materials, products, and yields are listed in Table 1, the spectral data of the starting materials are listed in Table 2, and the spectral data of the products are listed in Table 3.

Example 7 dl-4-t-butyldimethylsilyloxy-3-[(RS)-
(E) -4-Methyl-4-trimethylsilyloxy-1-
Octenyl] -2-allyloxycarbonylcyclopentanone (1.95 g, 3.82 mmol) was dissolved in 1.5 ml of alcohol, and potassium hydrogen carbonate (42
mg, 0.42 mmol) and then 37% formalin aqueous solution (1.0 ml) were added at 0 ° C, and the mixture was stirred at 0 ° C for 15 minutes,
Stir at room temperature for 10 minutes. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to the reaction solution, the mixture was extracted with ether, the obtained organic layer was dried over anhydrous magnesium sulfate, and then concentrated over time to obtain 2.18 g of a crude product. This was separated by silica gel column chromatography (hexane: ethyl acetate = 9: 1), and dl-4-t-butyldimethylsilyloxy-3-[(RS)-(E) -4-methyl was isolated. -4
-Trimethylsilyloxy-1-octenyl] -2-allyloxycarbonyl-2-hydroxymethylcyclopentanone (1.60 g, 2.96 mmol, 77%) was obtained.

NMR (CDCl ₃ ) δ: 0.04 (6H, s), 0.09 (9H, s), 0.85 (12H), 1.1 to 1.5 (6H, m), 1.13 (3H , S), 1.8 to 3.4 (6H, m), 3.5 to 4.4 (3H, m), 4.4 to 4.7 (2H,
m), 4.9-6.0 (5H, m).

IR (liquid film): 3500, 3100, 1760, 1735, 1650, 1250, 1105, 1060, 860, 840, 775, 750 cm ^-1 .

MS: 541 (M + 1), 525, 173.

Example 8 Dl-4-t-butyldimethylsilyloxy-3-[(RS)-(E) -4-methyl-4-trimethylsilyloxy-1-octenyl] -2-allyloxycarbonyl-2 obtained in Example 7 -Hydroxymethylcyclopentanone (1.22 g, 2.26 mmol) in acetic anhydride (3.0 m
l) and pyridine (3.0 ml) were added, and the mixture was stirred at room temperature for 15 hours. After adding ethanol (3.0 ml), adding toluene (50 ml) and concentrating under reduced pressure, the crude product obtained was subjected to silica gel column chromatography (hexane: ethyl acetate = 19: 1) to give the product. Is separated and dl-4-t
-Butyldimethylsilyloxy-3-[(RS)-(E) -4
-Methyl-4-trimethylsilyloxy-1-octenyl] -2-allyloxycarbonyl-2-acetoxymethylcyclopentanone (1.06 g, 1.82 mmol, 8
1%) was obtained.

NMR (CDCl ₃ ) δ: 0.04 (6H, s), 0.09 (9H, s), 0.87
(12H), 1.0 to 1.5 (6H, m), 1.13 (3H,
s), 1.98 and 2.001 (total 3H, s × 2),
2.0-3.7 (5H, m), 3.7-4.2 (1H,
m), 4.2 to 4.5 (2H, m), 4.45 to 4.70 (2H, m), 4.9 to 6.2 (5H,
m).

IR (liquid film): 1760, 1740, 1250, 1225, 1100, 1050, 840, 775 cm ^-1 .

MS: 525,173.

Example 9 Dl-4-t-butyldimethylsilyloxy-3 [(RS)-(E) -4-methyl-4-trimethylsilyloxy-1-octenyl] -2-allyloxycarbonyl-2-obtained in Example 8 Acetoxymethylcyclopentanone (6
58 mg, 1.13 mmol) was dissolved in 5 ml of acetonitrile and in this solution triphenylphosphine (59 mg,
0.23 mmol) and tetrakis (triphenylphosphine) palladium (o) (65 mg, 0.056 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, the same as the post-treatment method described in the representative experimental examples of Examples 1 to 6, 67
0 mg of crude product was obtained, which was subjected to silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain dl-4-t-butyldimethylsilyloxy-3-.
[(RS)-(E) -4-Methyl-4-trimethylsilyloxy-1-octenyl] -2-methylenecyclopentanone (305 mg, 0.70 mmol, 62%) was obtained.

NMR (CDCl ₃ ) δ: 0.04 (6H, s), 0.09 (9H, s), 0.87 (12H), 1.0 to 1.5 (6H, m), 1.14 (3H , S), 1.8 to 2.7 (4H, m), 3.0 to 3.5 (1H, m), 3.7 to 4.3 (1H,
m), 5.15 to 5.35 (1H, m), 5.0 to 5.9 (2H,
m), 6.0-6.2 (1H, m).

IR (liquid film): 3050, 1735, 1640, 1460, 1375, 1250, 1120, 1060, 1005, 880, 860, 835, 775, 750 cm ^-1 .

MS: 381 (M-57).

Example 10 By the same method as in Example 7, (2R, 3R, 4R) -4
-T-butyldimethylsilyloxy-3-[(3S, 5
S)-(E) -3-t-butyldimethylsilyloxy-5
-Methyl-1-nonenyl] -2-allyloxycarbonylcyclopentanone as a starting material (3R, 4R)-
4-t-butyldimethylsilyloxy-3-[(3S,
5S)-(E) -3-t-butyldimethylsilyloxy-
5-Methyl-1-nonenyl] -2-hydroxymethyl-
2-Allyloxycarbonylcyclopentanone was obtained.
Yield 74%.

NMR (CDCl ₃ ) δ: 0.05 (12H, s), 0.87 (24H), 1.1 to 1.5 (9H, m), 1.8 to 3.4 (4H,
m), 3.5-4.4 (4H, m), 4.4-4.7 (2H,
m), 4.9-6.1 (5H, m).

IR (liquid film): 3500, 3100, 1760, 1735, 1650, 1250, 1105, 1060, 860, 840, 775, 750 cm ^-1 .

MS: 597 (M + 1), 539.

Example 11 (3R, 4R) -4-t-butyldimethylsilyloxy-3-[(3S, 5S)-(E)-obtained in Example 10
3-t-butyldimethylsilyloxy-5-methyl-1
-Nonenyl] -2-hydroxymethyl-2-allyloxycarbonylcyclopentanone was acetylated in the same manner as in Example 8 to give (3R, 4R) -4-t-butyldimethylsilyloxy-3-[(3S, 5S)-(E) -3-
t-Butyldimethylsilyloxy-5-methyl-1-nonenyl] -2-acetoxymethyl-2-allyloxycarbonylcyclopentanone was obtained. Yield 87%.

NMR (CDCl ₃ ) δ: 0.06 (12H, s), 0.87 (24H), 1.1
~ 1.5 (9H, m), 2.03 (3H, s), 1.9
~ 3.5 (3H, m), 3.7-4.2 (2H, m),
4.2-4.6 (2H, m), 4.45-4.70 (2
H, m), 4.9-6.2 (5H, m).

IR (liquid film): 1760, 1740, 1250, 1225, 1100,
1050, 840, 775 cm ^-1 .

MS: 581 (M-57).

Example 12 (3R, 4R) -4-t-butyldimethylsilyloxy-3-[(3S, 5S)-(E)-obtained in Example 11
3-t-butyldimethylsilyloxy-5-methyl-1
-Nonenyl] -2-acetoxymethyl-2-allyloxycarbonylcyclopentanone was reacted under the same reaction conditions as in Example 9 to give (3R, 4R) -4-t-butyldimethylsilyloxy-3- [ (3S, 5S)-(E)-
3-t-butyldimethylsilyloxy-5-methyl-1
-Nonenyl] -2-methylenecyclopentanone was obtained.
Yield 49%.

_{NMR (CDCl 3) δ: 0.05} (12H, s), 0.87 (24), 1.1~
1.5 (9H, m), 1.8 to 2.7 (2H, m),
3.0-3.5 (1H, m), 3.7-4.2 (2H,
m), 5.15-5.35 (1H, m), 5.4-5.
6 (2H, m), 6.0-6.2 (1H, m).

IR (liquid film): 3050, 1735, 1640, 1460, 1375,
1250, 1120, 1060, 1005, 880, 8
60,835,775,750 cm ^-1 .

MS: 437 (M-57).

Example 13 (3R, 4R) -4-t-butyldimethylsilyloxy-3-[(3S, 5S)-(E) -obtained in Example 12
3-t-butyldimethylsilyloxy-5-methyl-1
-Nonenyl] -2-methylenecyclopentanone (235
mg, 0.39 mmol) was dissolved in 10 ml of acetonitrile, pyridine (0.1 ml) and then hydrogen fluoride-pyridine (0.2 ml) were added at room temperature, and the mixture was stirred for 5 hours. Aqueous sodium hydrogen carbonate was added to the reaction solution for neutralization, and the mixture was extracted 3 times with ethyl acetate. The separated organic layer was washed successively with aqueous potassium hydrogen sulfate and brine, dried over magnesium sulfate, and concentrated to give a crude product. Silica gel column chromatography (hexane: ethyl acetate =
1: 3) and separated to give (3R, 4R) -4-hydroxy-3-[(3S, 5S)-(E) -3-hydroxy-
5-Methyl-1-nonenyl] -2-methylenecyclopentanone (85 mg, 0.32 mmol, 83%) was obtained.

_{NMR (CDCl 3) δ: 0.87} (6H, m), 1.1~1.5 (9H, m),
1.8-2.7 (4H, m), 3.0-3.5 (1H,
m), 3.7-4.2 (2H, m), 5.15-5.3
5 (1H, m), 5.4 to 5.6 (2H, m), 6.0
~ 6.2 (1H, m).

IR (liquid film): 3400, 3050, 1730, 1640, 1250,
1110, 1060, 880, 750 cm ^-1 .

MS: 248 (M-18), 230 (M-18 x 2).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location B01J 31/24 X 7821-4G C07B 61/00 300

Claims (8)

[Claims] 1. The following formula [II] [Wherein, R ¹ and R ² are the same or different and each represents a substituted or unsubstituted C _{1 to} C ₁₀ linear or branched saturated or unsaturated hydrocarbon group, and R ¹ and R ² are bonded to each other. And may form a ring. R ³ is a C _{2 to} C ₁₀ acyl group, C ₂
To C ₁₁ alkoxycarbonyl group, C _{1 to} C ₁₀ sulfonyl group, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and are hydrogen atoms, C _{1 to} C ₁₀ hydrocarbon groups, Alternatively, it represents an aromatic hydrocarbon group. ] The α-substituted methyl β-ketocarboxylic acid allyl ester represented by the formula [I] below is characterized by contacting with a platinum group metal salt or complex in the presence of an inert organic medium. [In the formula, R ¹ and R ² are the same as defined above. ] The manufacturing method of the alpha-methylene ketone represented by these. 2. A process for producing an α-methylene ketone according to claim 1, wherein R ³ is a C ₂ -C ₁₀ acyl group. 3. The method for producing an α-methylene ketone according to claim 1, wherein R ³ is a C _{2 to} C ₁₁ alkoxycarbonyl group. 4. The method for producing an α-methylene ketone according to claim _{1, wherein} R ³ is a C ₁ -C ₁₀ sulfonyl group. 5. The method for producing an α-methylene ketone according to claim 1, wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen atoms. 6. The method for producing α-methylene ketones according to any one of claims 1 to 5, wherein the platinum group metal is palladium. 7. A platinum group metal is a phosphine or phosphite complex of palladium.
Item 10. A method for producing an α-methylene ketone according to any one of items. 8. The following formula [II '] [Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as defined above, and R ⁹¹ and R ¹⁰¹ are the same or different and each is a hydrogen atom or tri (C ₁ -C ₇ ) carbonization. A hydrogen silyl group or a group which forms an acetal bond with an oxygen atom of a hydroxyl group, R ¹¹ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a vinyl group, and R ¹² may contain an oxygen atom. It represents a substituted or unsubstituted C ₃ -C ₈ linear or branched saturated or unsaturated hydrocarbon group, and n represents 0 or 1. ] 3,4-Disubstituted-2-substituted methyl-2-allyloxycarbonylcyclopentanones represented by and their stereoisomers or a mixture thereof in any proportions α-
Substituted methyl β-ketocarboxylic acid allyl esters are brought into contact with a platinum group metal salt or complex in the presence of an inert organic medium and optionally subjected to a deprotection reaction to give formula [I] represented by the following formula [I ′] [Wherein R ⁹ and R ¹¹ are the same or different and represent a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group, or a group forming an acetal bond with an oxygen atom of a hydroxyl group, and R 9
¹¹ , R ¹² and n are the same as defined above. ] The 3,4-disubstituted-2-methylenecyclopentanone represented by the formula and the α-methylene ketone which is a stereoisomer thereof or a mixture thereof at any ratio is produced. A method for producing α-methylene ketones.