JPH0720903B2 - 2-Hydroxy-3-methylenebicyclo [3.3.0 Method for producing octanes - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Application> The present invention relates to a method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octanes using propargylcyclopentanes. More specifically, 9 (O) -methano-
The present invention relates to a method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octanes, which are novel key synthetic intermediates for Δ ^{6 (9α) -prostaglandin} I ₁ .

<Prior Art> Carbacyclin is a prostaglandin (sometimes abbreviated as PG) I ₂ (PGI ₂ ) that is a physiologically active substance in vivo.
It is a prostaglandin I ₂ analogue in which the 9-position oxygen atom is substituted with a methylene group, and is chemically more stable than natural prostaglandin I ₂ having a partial structure of enol ether in the molecule. Therefore, it is a compound useful as a medicine such as an antithrombotic agent. Recently, isocarbacyclin which is a kind of double bond isomers of carbacyclin, i.e., 9 (O) - methano ^{-Δ 6 (9α)} - prostaglandin I ₁ such that, the strongest platelet aggregation Among the homologues It was discovered that it has an inhibitory effect, and it is expected to be applied as a medicine [Ikegami et al., Tetrahedron Letters, 33 , 3493 and 3497 (19
83)].

The present inventors have previously described such 9 (O) -methano-Δ.
2-Hydroxy-3 useful as a key synthetic intermediate for ^{6 (9α) -prostaglandin} I ₁ ^{(isocarbacycline)}
-Patented a patent for methylenebicyclo [3.3.0] octane and its manufacturing method. (See JP-A-62-61937) The outline is as follows.

According to this method, allyl alcohol (C) (2-hydroxy-3-methylenebicyclo [3.3.0] octane) is derived from allyl alcohol (A) in three steps, and the yield during this period is 50. % Means that half of (A) is lost. Therefore, more efficient allyl alcohol (C)
Development of a synthetic method of (6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octanes) is desired.

Further, the present inventors have previously described the following formula [I] as a method for producing the 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octanes. A method of cyclizing propargylcyclopentane represented by the formula ( ₃ ) with a reducing agent using an alkali metal or an alkaline earth metal (see JP-A-62-258330) and a method of cyclizing samarium iodide (SmI ₂ ). Although a patent application has been filed, it is desired to develop a more efficient synthetic method which is an improvement of these methods.

Recently, it has been reported that, by irradiating γ-ethynyl ketones with light, a reductive intramolecular cyclization reaction proceeds to produce 2-methylenecyclopentanols (D.
Belotti et al., J. Org. Chem., 51, 4196, 1986). However, as far as the present inventors know, no reductive intramolecular cyclization reaction of γ-ethynyl aldehydes by light irradiation has been reported.

<Problems to be Solved by the Invention> An object of the present invention is a useful key intermediate of 9 (O) -methano-Δ ^{6 (9α) -prostaglandin} I ₁ class ( ^{isocarbacyclins)} . An object of the present invention is to provide an efficient method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octanes.

The present inventors are useful synthetic key intermediates for 9 (O) -methano-Δ ^{6 (9α) -prostaglandins} I ₁ ^{(isocarbacyclines)} . As a result of diligent research to find out a more efficient production method of 2-hydroxy-3-methylenebicyclo [3.3.0] octanes, a specific propargylcyclopentanone was used, and the objective was to react it with light irradiation. The present inventors have found that 2-hydroxy-3-methylenebicyclo [3.3.0] octanes can be efficiently obtained, and arrived at the present invention.

<Means for Solving the Problem> In the present invention, the following formula [I] is used. The compound represented by the following formula and its enantiomers or propargylcyclopentanes which are a mixture of them in any proportions are subjected to a photoirradiation reaction to cause a cyclization reaction and, if necessary, a deprotection reaction. II] A process for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octane, which is a compound represented by the formula (1) and an enantiomer thereof or a mixture thereof in any ratio, is provided.

In the above formula [I], R ¹¹ and R ²¹ are the same or different and each is a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group or an oxygen atom to which they are bonded (that is, an oxygen atom derived from a hydroxyl group). And represents a group forming an acetal bond or an ester bond.

The tri (C ₁ ~C ₇₎ hydrocarbon silyl group include a trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tri (C ₁ ~, such as t- butyldimethyl group
C ₄ ) alkylsilyl group, diphenyl (C ₁ -C ₄ ) alkylsilyl group such as t-butyldiphenylsilyl group, di (C ₁ -C ₄ ) alkylphenyl group such as dimethylphenyl group, or tribenzylsilyl group A group and a triphenylsilyl group can be mentioned as preferable ones. A tri (C ₁ -C ₄ ) alkylsilyl group, a diphenyl (C ₁ -C ₄ ) alkylsilyl group and a phenyldi (C ₁ -C ₄ ) alkylsilyl group are preferable, and a t-butyldimethylsilyl group is particularly preferable.

Examples of the group that forms an acetal bond with an oxygen atom derived from a hydroxyl group include, for example, methoxymethyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2-propyl group, (2-methoxy (Ethoxy) methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hex-
4-yl group may be mentioned. 2-tetrahydropyranyl group, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl, 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1. [0] Hex-4-yl is particularly preferred.
Of these, a 2-tetrahydropyranyl group is particularly preferable.

Examples of the group that forms an ester bond with an oxygen atom derived from a hydroxyl group include a formyl group, an acetyl group, a propionyl group, a butanoyl group, and a pentanoyl group (C ₁ to
C ₅₎ alkanoyl group; a benzoyl group, and a substituted or unsubstituted benzoyl group such as a toluyl group.
An acetyl group and a benzoyl group are particularly preferable.

It is to be understood that these silyl groups, groups forming acetal bonds and ester bonds are protecting groups for hydroxyl groups. These protecting groups can be easily removed in the final product stage to give free hydroxyl groups useful as drugs. Therefore, the hydroxyl-protecting group having such properties can be used as a substitute for the silyl group or the group forming an acetal bond or an ester bond. Since the cyclization reaction of the present invention can also be carried out neutrally, such protecting groups can be stably present during the reaction, and thus essentially there is no need to limit the protecting groups.

In the above formula [I], R ³ represents a hydrogen atom, a methyl group, or a vinyl group.

In the above formula [I], R ⁴ is a linear or branched C _{3 to} C ₈ alkyl group, alkenyl group or alkynyl group; phenyl group; C _{3 to} C ₁₀ cycloalkyl group; or C _{1 to} C ₆ alkoxy group, phenyl Group, a straight chain or branched chain C ₁ ~ substituted with a phenoxy group or a C ₃ ~ C ₁₀ cycloalkyl group
Represents a C ₅ alkyl group.

As a straight-chain or branched-chain C ₃ -C ₈ alkyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, 2
-Hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group, 2-methylhexyl group, 2,2
-A dimethylhexyl group etc. can be mentioned. Butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2
-Methylpentyl group and 2-methylhexyl group are preferred.
Also, 2-methoxyethyl group as R ^4, even those using 2-ethoxyethyl group and the like as a reference example.

Examples of the straight-chain or branched-chain C ₃ -C ₈ alkenyl group such as 1-Buchirubiniru, 2-propyl allyl, 2-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-hexenyl, 1,4-dimethyl -3-Pentenyl, 5-heptenyl, 1-methyl-5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl and the like are preferable.

As the linear or branched C ₃ -C ₈ alkyl group, for example, 2-butyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl is preferable.

Examples of the cycloalkyl group C ₃ -C _10, can be, for example, cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclohexenyl group, cycloheptyl group, cyclooctyl group, etc. cyclodecyl. A cyclopentyl group and a cyclohexyl group are preferred. A phenyl group of R ⁴ or a C _{3 to} C ₁₀ cycloalkyl group is further substituted with a halogen atom, a protected hydroxyl group (eg, a silyloxy group, a C _{1 to} C ₆ alkoxy group, etc.), a C _{1 to} C ₄ alkyl group, etc. Those that have been substituted are also listed as reference examples.

In the linear or branched C ₁ -C ₅ alkyl group substituted with a C ₁ -C ₆ alkoxy group, a phenyl group, a phenoxy group or a C ₃ -C ₁₀ cycloalkyl group, the C ₁ -C ₆ alkoxy group is Examples thereof include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butoxy group, t-butoxy group and hexyloxy group. Examples of the linear or branched C _{1 to} C ₅ alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group and a pentyl group. can Note that substitution of linear or branched C ₁ -C ₅ substituent serving phenyl alkyl group, a phenoxy group or a C ₃ -C ₁₀ cycloalkyl group, exemplified for further phenyl group R ^4, such as described above The thing having a group is also mentioned as a reference example. Examples of R ³ include butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl, 2-methylpentyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, cyclopentylmethyl and cyclohexylmethyl groups. It can be mentioned as a preferable one. In addition, the substituent may be bonded to any position thereof.

In the above [I], n represents 0 or 1.

In the formula [II], R ¹ and R ² 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 or an ester bond with the oxygen atom of the hydroxyl group. Here tri (C ₁ ~C ₇₎
Examples of the group that forms an acetal bond or an ester bond with the hydrocarbon silyl group and the oxygen atom of the hydroxyl group are the same as those in the case of the above formula [I].

The wavelength of light used in the photoirradiation cyclization reaction using the propargyl cyclopentane represented by the above formula [I] as a raw material is usually preferably in the range of 200 to 400 nm, more preferably 220 to 300 nm or a uniform wavelength or a certain width. A range of wavelengths is used. As a light source satisfying such a condition, for example, a low-pressure mercury lamp, a medium-pressure mercury lamp, a high-pressure mercury lamp, a tungsten-halogen lamp, a mercury-xenon lamp, a flash lamp, a laser and the like are preferably used, but a mercury low-pressure lamp is particularly preferable. Is used. If necessary, filters such as Vycor glass filter may be used. (New Experimental Chemistry Course 14-V.p261
6-2620, edited by The Chemical Society of Japan, Maruzen et al.) As a reaction device, any device generally used for light irradiation reaction may be used (Katsuyuki Ogura, Kagaku to Kogyo, 41 , 325, 1988).
Year; New Experimental Chemistry Course 14-V.p2620-2622, edited by The Chemical Society of Japan, Maruzen et al.). For example, an external irradiation type such as a merry-go-round type or various internal irradiation type devices are used. The reaction may also be carried out in the presence of a photosensitizer.

Examples of the solvent for the photocyclization reaction include acetonitrile; alcohol solvents such as methanol, ethanol and isopropanol; hydrocarbon solvents such as hexane, cyclohexane and benzene; ether, tetrahydrofuran,
An ether solvent such as dioxane; a halogen solvent such as chloroform, methylene chloride, carbon tetrachloride; an organic polar solvent such as hexamethylphosphoric triamide, dimethylformamide, dimethylsulfoxide, and a mixed solvent thereof at an arbitrary ratio are used. However, preferably, acetonitrile, hexamethylphosphoric triamide or the like is used. Generally, the photocyclization reaction is preferably carried out in the presence of amines. Examples of the amines used include alkylamines such as triethylamine, diisopropylethylamine, diethylamine, diisopropylamine, t-butylamine, and aromatic amines such as aniline and dimethylaniline. Triethylamine is preferably used. . The amine is used in an amount of 0 to 500 equivalents, preferably 1 to 20 equivalents, relative to the raw material propargylcyclopentane represented by the above formula (I). The cyclization reaction generally does not proceed in the absence of the amines, but when a solvent excited by light irradiation such as hexamethylphosphoric triamide is used as a solvent, the amine In such a case, the reaction is generally performed in the absence of the amines because the reaction proceeds without the presence of the amines.

The reaction temperature is in the range of -100 to 60 ° C, preferably -30 to 40 ° C. The reaction time varies depending on the strength of the lamp used, the number of lamps, the wavelength and the equipment used, but is usually 0.
It is 1 to 24 hours, preferably 0.5 to 5 hours. The concentration of the propargyl cyclopentane represented by the above formula (I) in the solution in the photocyclization reaction is 10 ⁻⁴ M to 1 M (M = mol / l)
However, it is preferably about 10 ^{−3 to} 0.5 M. In addition, methanol, ethanol, isopropanol, t
-The photocyclization reaction may be carried out by adding a proton source such as butanol.

The reaction solution thus obtained can be taken out from the reaction system as a crude product by distilling off the solvent as it is, or by passing it through silica gel, Florisil, etc. as it is, and then distilling off the solution under reduced pressure. Further, after adding saturated ammonium chloride water, water, etc., extraction with an organic solvent or the like can also be carried out as a crude product from the reaction system. The crude product can be purified by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, and recrystallization, if desired.

Necessary when the 7'-position and the 6'-position 3'-position (or 4'-position) of 2-hydroxy-3-methylenebicyclo [3.3.0] octane represented by the above formula [II] is a protected hydroxyl group. Depending on the case, it can be converted into a free hydroxyl group by deprotection.

Removal of the protective group of the hydroxyl group, when the protective group is a group forming an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, p-toluenesulfonic acid, a pyridinium salt of p-toluenesulfonic acid or a cation exchange resin, etc. Is used as a catalyst, and water, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile or the like is used as a reaction solvent. Reaction is usually -78 ℃ to + 50 ℃
It is carried out in the temperature range of 10 minutes to 3 days. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, for example, acetic acid, p-toluenesulfonic acid, a pyridinium salt of p-toluenesulfonic acid, tetrabutylammonium fluoride, cesium fluoride, It is carried out in the presence of hydrogen fluoride and pyridine-hydrogen fluoride in the reaction solvent as described above at the same temperature and for the same time. When the protecting group is a group that forms an ester bond with the oxygen atom of the hydroxyl group, for example, an aqueous solution of sodium hydroxide, potassium hydroxide, calcium hydroxide or a water-alcohol mixed solution,
Or sodium methoxide, potassium methoxide,
It can be carried out by hydrolysis in a methanol or ethanol solution containing sodium ethoxide.

In addition, in the compounds represented by the above formulas [I] and [II], the cyclopentane ring and the bicyclo [3.3.0] octane ring themselves and the carbons to which the substituents bonded to these rings are attached are asymmetric. Although stereoisomers exist due to the environment, the present invention includes any stereoisomers, and a mixture of stereoisomers in any proportion thereof may be used. Further, the compound represented by the formula represents all of these stereoisomers and a mixture of these isomers at an arbitrary ratio, and a compound having a stereostructure represented by the formula is most preferred.

The propargylcyclopentanes represented by the above formula [I] used in this reaction have the following formula [III] Oxidize propargyl cyclopentane represented by
If necessary, it can be obtained by deprotecting in the same manner as described above. Any oxidation method may be used as long as it can oxidize an alcohol into an aldehyde.
Swern Oxidation with Acrylic Chloride-Dimethyl Sulfoxide-Triethylamine
ncuso et al., J. Org. Chem., 44, 4148, 1979, etc.), pyridinium chlorochromate (PCC; EJCorey
Et al., Tetrahedron Lett., P. 2647, 1975, etc.), pyridinium dichromate (PDC; EJ Corey et al., Tetrahedro
n Lett., page 399, 1979, etc.) are preferably used.

The amount of the oxidizing agent used is 0.8 to 20 times, preferably 0.8 to 20 times that of the raw material cyclopentane represented by the formula [III].
It is carried out using 1.2 to 2 equivalents of the oxidizing agent. The reaction temperature and the solvent greatly differ depending on the oxidizing agent used, and in the case of swern oxidation, it is carried out at about -60 ° C to room temperature, mainly using dichloromethane as a solvent, and in the case of PCC and PDC, it is -20 ° C.
It is carried out mainly at a temperature of about ℃ to room temperature using dichloromethane as a solvent. The reaction time depends on the reaction conditions,
It usually takes about 10 minutes to 6 hours.

The propargyl cyclopentanes represented by the above formula [III] have the following formula [IV] The propargylcyclopentane represented by can be obtained by the hydroboration reaction and the subsequent oxidation reaction, or when R ⁵ is a trimethylsilyl group, further selectively deprotecting R ⁵ . The hydroboration reaction can be carried out by a usual method. [Organic Reactions, 13
Volume, Chapter I, John Willie and Sons (Joh
n, Wiley & Sons Inc.) New York, 1963; New Experimental Chemistry Lecture, Synthesis and Reactions of Organic Compounds I, P497-505, Maruzen et al. ] As a hydroboration reagent, disiamilborane ((CH ₂ ) ₂ CHCH (CH ₃ ) BH), 9-borabicyclo [3.
3.1] Nonane (9-BBN), dialkylboranes such as dicyclohexylborane and diisopinocanphenylborane, and disubstituted boranes such as catecholborane and dihaloborane can be used, but preferably disiamilborane and 9-borabicyclo [3.3.1. ] Nonane (9-BBN) is used. Hydrogen peroxide-sodium hydroxide, trimethylamine oxide, air oxidation and the like can be used as the oxidizing agent used in the oxidation reaction subsequent to hydroboration, but hydrogen peroxide-sodium hydroxide is particularly preferable. The amount of the hydroboration reagent used is stoichiometrically equimolar to the cyclopentanes represented by the formula [IV], and the reaction proceeds, but usually 0.5 to 5 times the molar amount of the starting compound is used. . The reaction temperature is −100 to 50 ° C., preferably −2
It is about 0 ° C to room temperature. The reaction time varies depending on the reaction temperature, but is usually 10 minutes to 20 hours, preferably about 30 minutes to 5 hours. The reaction is usually performed in the presence of an organic medium.
The medium used is an inert aprotic organic medium which does not react with the reaction reagent, preferably an ether solvent such as tetrahydrofuran, diethyl ether, diglyme or triglyme, and particularly preferably tetrahydrofuran. Alkylborane produced by the hydroboration reaction is usually not isolated but is oxidized by directly adding an oxidizing agent to the reaction system to give the following formula [III ′] Is led to the alcoholic body represented by. When hydrogen peroxide is used as an oxidizing agent, a base such as sodium hydroxide is used at the same time. Hydrogen peroxide may be used in any concentration, but a concentration of around 30% is generally used. The amount of hydrogen peroxide used is 0.5 to 50 times mol, preferably 3 to 10 times mol, of the hydroboration reagent used. Although sodium hydroxide can be used as it is or as an aqueous solution, an aqueous solution having a concentration of 1 to 10 N is generally used. The amount used is 0.5 to 50 times mol, preferably 3 to 10 times mol of the hydroboration reagent. The reaction temperature at this time is 0 ° C to 100 ° C, preferably 40 ° C to 70 ° C. The reaction time is 5 minutes to 5 hours, preferably 20 minutes to 1 hour. When trimethylamine oxide is used as an oxidizing agent, it is usually used in an amount of 0.5 to 50 times mol, preferably 3 to 10 times mol, of the hydroboration reagent.

The product thus obtained can be taken out from the reaction system as a crude product by carrying out quenching, extraction and the like according to a usual method. The crude product can be purified by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, recrystallization and the like, if desired.

The compound represented by the above formula [III] can also be obtained by selectively deprotecting the compound represented by the above formula [III ′] in which R ⁵ is a trimethylsilyl group. This acetylene terminal deprotection reaction can be carried out by a conventional method [Silicon Reagents for Organic Synthesis].
ic Synthesis), Reactivity and Structure Concepts O
rganic Chemistry Volume 14, Chapter 9, Springer-Verlag, 19
1983] As a deprotection reaction reagent, sodium methoxide-
Methanol, silver nitrate-ethanol-water and potassium cyanide-water, potassium hydroxide water, potassium fluoride-methanol, etc. are used.

The propargyl cyclopentanes represented by the above formula [IV] are represented by the following formula [V] The propargyl cyclopentanone represented by the formula: methyleneating agent prepared from titanium tetrachloride-zinc-dibromomethane (L. Lombardo et al., Tetrahedron letters, 23, 42)
Page 93, 1982), using a methyleneating agent prepared from titanium tetrachloride-zinc-jodomethane (Nozaki, K. et al., Tetrahedron Letters, 26, 5581, 1985) or other methyleneating agent. It can be obtained by methyleneation.

The methyleneating agent prepared from titanium tetrachloride-zinc-dibromomethane is 1 g of dibromomethane, and a mixture of 0.5 g to 2 g of titanium tetrachloride and 0.8 to 2.5 g of zinc is stirred in tetrahydrofuran at 0 ° C for 5 hours to 3 days. It means the one left unattended.

The methyleneating agent prepared from titanium tetrachloride-zinc-jodomethane is a mixture of 0.1-0.2 g of titanium tetrachloride and 0.3-0.6 g of zinc per 1 g of joodomethane, and the mixture is stirred at 25 ° C for 30 minutes in tetrahydrofuran. Represents what was done.

The reaction between the cyclopentanone represented by the above formula [V] and the methyleneating agent is carried out in the presence of an organic medium, and is a liquid at the reaction temperature and does not react with the reaction reagent. An organic medium is used. Preferred examples of such a medium include halogenated hydrocarbons such as dichloromethane, dichloroethane, and tetrachloroethane. The amount of the organic medium used may be an amount sufficient for the reaction to proceed smoothly, and is usually 1 to 200 times the volume of the raw material, preferably 5 to 50 times the volume. Reaction temperature is -20 ℃
It is carried out at 70 ° C, preferably 0 ° C to 50 ° C. The reaction time is
Finish in 10 minutes to 24 hours. The product thus obtained is quenched with saturated aqueous sodium hydrogen carbonate and can be taken out from the reaction system by extraction or the like. The crude product can be purified by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, recrystallization and the like, if desired.

The propargyl cyclopentanones represented by the above formula [V] are prepared according to the method of Noyori et al. (Ryoji Noyori et al., Journal.
Of American Chemical Society, Volume 107, 3
348, 1985), and can be obtained by carrying out a three-component ligation reaction as shown below.

Thus, the hydroxy-3-methylenebicyclo [3.3.
[0] Octanes are useful as isocarbacycline, which is useful as a drug such as the antithrombotic agent described above, that is, an intermediate of 9 (O) -methano-Δ ^{6 (9α) -prostaglandin} I ₁ . That is, hydroxy-3 of the formula [II]
-Methylenebicyclo [3.3.0] octanes (provided that R ¹ , R ²
Each represent R ¹² and R ²² as defined above) and react with the organolithium compound at the γ-position of the allyl alcohol in a position-selective manner to the above-mentioned isocarbacycline, namely 9 (O) -methano-Δ. ^{6 (9α) -prostaglandin}
It is a useful key intermediate capable of constructing an I ₁ skeleton (see JP-A-62-61937).

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

An external irradiation type merry-go-round type light irradiation device was used as a light reaction device (Rayonet Photo-Chemical Reactor; T).
he Southern New England Ultraviolet Company). The lamp is a low-pressure mercury lamp (Rayonet Photochemical Reacti
on Lamp, 2537Å, 16) were used. In the examples, -OZ ₁
Represents t-butyldimethylsilyloxy group, and -OZ ₂
Represents a trimethylsilyloxy group.

Example 1 102 mg (0.20 mmol) of the aldehyde compound (compound i) is dissolved in 5.8 ml of acetonitrile and placed in a quartz glass tube having a diameter of 1 lcm. After bubbling nitrogen for 30 minutes, triethylamine 14
3 μl (1.03 mmol) was added, and light irradiation was carried out for 2 hours with the light irradiation device. The solvent was distilled off under reduced pressure and the obtained crude product was purified by silica gel column chromatography to give 5
73 mg (72% yield) (1
S, 2RS, 5R, 6R, 7R) -2-Hydroxy-3-methylene-6
-{(E, 3'S) -3'-t-butyldimethylsilyloxy-1'-octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octane (compound ii) was obtained.

Example 2 In the same manner as in Example 1, the following product was obtained from the following starting materials.

Example 3 Aldehyde compound (compound iii) 110 mg (0.21 mmol) was dissolved in hexamethylphosphoric triamide 4 ml and put in a quartz glass tube having a diameter of 1 cm, and nitrogen was bubbled for 20 minutes. This was set in the light irradiation device and light irradiation was performed for 2.5 hours. After adding water and extracting twice with ether, the combined organic layers were washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 77 mg (yield 70%) of (1S, 2RS, 5R, 6R, 7R) -2 in the 5% ethyl acetate-hexane eluate.
-Hydroxy-3-methylene-6-{(E, 3'S, 5'S)
-3'-t-Butyldimethylsilyloxy-5'-methyl-1'-nonenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octane (compound iv) was obtained.

Spectral data are shown in Example 2.

Example 4 In the same manner as in Example 3, the following product was obtained from the following starting materials.

The spectral data are shown in Example 1 and Example 2.

Claims (8)

[Claims] 1. The following formula [I]: The compound represented by the following formula and its enantiomers or propargylcyclopentanes which are a mixture of them in any proportions are subjected to a photoirradiation reaction to cause a cyclization reaction and, if necessary, a deprotection reaction. II] A method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octane, which is a compound represented by the formula (1) and an enantiomer thereof or a mixture thereof in any ratio. 2. In the above formula [I], R ¹ and R ² are both t-.
The method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octane according to claim 1, which is a butyldimethylsilyl group. 3. The method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octane according to claim 1 or 2, wherein R ³ in the above formula [I] is a hydrogen atom or a methyl group. 4. In the above formula [I], R ⁴ is an n-butyl group, n
A method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octane according to any one of claims 1 to 3, which is a -pentyl group, a cyclopentyl group, a cyclohexyl group or a 2-methylhexyl group. 5. The light irradiation reaction is carried out in the presence of amines.
2-Hydroxy-3 according to any one of claims 1 to 4.
-A method for producing methylenebicyclo [3.3.0] octanes. 6. The 2-hydroxy-3 according to claim 5, wherein the amine is triethylamine or dimethylaniline.
-A method for producing methylenebicyclo [3.3.0] octanes. 7. The reaction solvent is acetonitrile.
7. The method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octane according to any one of 1 to 6. 8. The method for producing 2-hydroxy-3-methylenebicyclo [3.3.0] octanes according to claim 1, wherein the reaction solvent is hexamethylphosphoric triamide.