JPH02104542A - Production of 2-hydroxy-3-methylenebicyclo(3.3.0)-octanes - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a novel synthetic intermediate for pharmaceuticals such as antithrombotic agent by cyclizing a specific propargylcyclopentanone compound under photo-irradiation and, as necessary, deprotecting the cyclization reaction product. CONSTITUTION:2-Hydroxy-3-methylenebicyclo[3.3.0]octanes consisting of the compound of formula II (R<1> and R<2> are H, tri-hydrocarbon-silyl, etc.), its enantiomer or their mixture at an arbitrary ratio can be produced by using propargylcyclopentanones consisting of the compound of formula I (R<11> and R<21> are H, tri-hydrocarbon-silyl or form acetal or ester bond together with bonded O; R<3> is H, methyl or vinyl; R<4> is (O-containing) alkyl, phenyl, phonoxy, cycloalkyl, etc.; n is 0 or 1), its enantiomer or their mixture at an arbitrary ratio as a raw material, cyclizing the raw material under photo-irradiation and, as necessary, deprotecting the cyclization reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing 2-hydroxy-3-methylenebicyclo[3,3.0]octanes using propargylcyclopentanes. In more detail, we will discuss 2-hydroxy-3-methylenebicyclo[3,3,0]octanes, which are novel key synthetic intermediates for 9(0)-methano-86(9cx)-prostaglandin 11. Regarding manufacturing methods.

<Prior art> Carbacycline is a bioactive substance prostaglandin (sometimes abbreviated as PG) Iz (P
It is a prostaglandin I2 analog in which the oxygen atom at the 6.9-position of GIz) is substituted with a methylene group, and it is chemically inferior to natural prostaglandin I2, which has an enol ether partial structure in the molecule. Because it is stable, it is a useful compound as a pharmaceutical agent such as an antithrombotic agent. In recent years, isocarbacycline, a type of double bond isomer of carbacycline, namely 9(O)-methano-ΔB(9(
2) - It was discovered that prostaglandin 11 exhibits the strongest platelet aggregation inhibitory effect among its homologues,
It has come to be expected to be applied as a medicine [Ikegami et al., Tetrahedron Letters]
Letters), 33.3493 and 3497
(1983)].

Previously, the present inventors developed such 9(o)-methano-Δ6(9c
2-Hydroxy-3 useful as a key synthetic intermediate of r)-prostaglandin It (isocarbacycline)
-A patent application was filed for methylenebicyclo[3,3.0]octanes and their manufacturing method. (Refer to Japanese Unexamined Patent Publication No. 62-61937.) The outline is as follows.

0R3 (C) According to this method, allyl alcohol (C) (2-hydroxy-3-methylenebicyclo[3,3.0]octanes) is derived from allyl alcohol (8) through three steps. However, the yield during this time is 50%, meaning that half of (A) is lost. This makes allyl alcohol more efficient (
C) Development of a method for synthesizing (6,7-disubstituted-2-hydroxy-3-methylenebicyclo(3,3.0)octanes) is desired.

In addition, the present inventors previously described a method for producing such 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3,3,0]octanes, in which propargylcyclo A method of cyclizing pentanes with a reducing agent using an alkali metal or alkaline earth metal (see JP-A-62-258331)
and filed a patent application for a method for cyclizing samarium iodide (StllI2).

A more efficient synthetic method that improves these methods is desired.

Recently, it has been reported that by irradiating γ-ethynylketones with light, a reductive intramolecular cyclization reaction proceeds, producing -methylenecyclopentanols.

have been reported (D, Be1otti et al., J.
0r(J.

CheIII, 51.4196.1986, etc.). But books! As far as we know, the reductive intramolecular cyclization reaction of γ-[thenyl aldehydes by photoirradiation is I.

Not notified.

<Problems to be Solved by the Invention> The object of the present invention is to provide a useful key intermediate of 9(0)-methano-Δ6(9cr;-prostaglandin II (isocarbaci phosphorus). 2-hydro An object of the present invention is to provide an efficient method for producing cy-3-methylenebicyclo[3,3,03octane 1.

Original The inventors are 9(0)-methano-△6(9(x
)-) It is a useful synthetic key intermediate for prostaglandin h (isocarbacyclins). As a result of intensive research to find a more efficient production method for 2-hydroxy-3-methylenebicyclo[3,3,0]octane, we discovered that a specific propargyl cyclopentanone was used and that it was The present invention was achieved by discovering that the desired 2-hydroxy-3-methylene bisic acid and [3,3,0]octanes can be efficiently obtained by carrying out an irradiation reaction.

Means for Solving the Problem> 1 In the present invention, the following formula [I] Clothes HC> Kuki
The following method is characterized in that propargylcyclopentanes, which are a compound represented by OR, its enantiomer, or a mixture thereof in any proportion, are subjected to a cyclization reaction by photoirradiation reaction, and are also subjected to a deprotection reaction if necessary. A method for producing 2-hydroxy-3-methylenebicyclo[3,3,0]octanes, which are a compound represented by the formula [n]O R2 and its enantiomer, or a mixture thereof in any proportion, is provided.

In the above formula [I], R11 and R21 are the same or different, and together with a hydrogen atom, a tri(C+ to Cy) hydrocarbon silyl group, or an oxygen atom to which they are bonded (i.e., an oxygen atom derived from a hydroxyl group), an acetal bond or Represents a group that forms an ester bond.

Examples of the tri(C+ to C7) hydrocarbon silyl group include tri(C+ to C4) alkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, and t-butyldimethyl group, and t-butyldiphenylsilyl group. diphenyl(C+~C4)alkylsilyl group such as di(C+~C4) group, di(C+~C4) group such as dimethylphenyl group,
4) Preferred examples include an alkylphenyl group, a tribenzylsilyl group, and a triphenylsilyl group. Tri(C+-C4)alkylsilyl, diphenyl(C+-C4)alkylsilyl, and phenyldi(C+-C4)alkylsilyl groups are preferred, and t-butyldimethylsilyl group is particularly preferred.

Examples of the group that forms an acetal bond with an oxygen atom derived from a hydroxyl group include a methoxymethyl group, a 1-ethoxyethyl group, a 2-methoxy-2-propyl group, and a 2-ethoxy-2-propyl group.

(2-methoxyethoxy)methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-titrahydrofuranyl group, or 6,6-dimethyl-3-oxa-
A 2-oxobicyclo[3°1.0]hex-4-yl group can be mentioned. 2-tetrahydropyranyl group,
2-tetrahydrofuranyl, 1-ethoxyethyl, 2-
Particularly preferred are ethoxy-2-propyl, (2-methoxyethoxy)methyl, 6°6-dimethyl-3-oxa-2-oxobicyclo[3,1,0]kis-4-yl.

Among them, 2-tetrahydropyranyl group is particularly preferred.

Examples of groups that form an ester bond with an oxygen atom derived from a hydroxyl group include (C+
-Cs) Alkanoyl group: Substituted or unsubstituted benzoyl groups such as benzoyl group and tolyl group can be mentioned. Acetyl group.

Particularly preferred is a benzoyl group.

It should be understood that these silyl groups, acetal bond-forming groups, and ester bond-forming groups are hydroxyl group-protecting groups. These protecting groups can be easily removed in the final product stage to provide free hydroxyl groups useful as pharmaceuticals. Therefore, a hydroxyl group-protecting group having such properties can be used in place of a silyl group or a group forming an acetal bond or an ester bond. Since the cyclization reaction of the present invention can also be carried out in a neutral state, such a protecting group can exist stably during the reaction, and therefore there is no need to essentially limit the protecting group.

In the above formula [I], R3 is a hydrogen atom or a methyl group.

Or it represents a vinyl group.

In the above formula [I], R4 is a straight-chain or branched C3-C8 alkyl group, alkenyl group or alkynyl group that may contain an oxygen atom: a substituted or unsubstituted phenyl group: @a substituted or unsubstituted phenoxy group: Substituted or unsubstituted 03-CIO cycloalkyl group: or C
1-C6 alkoxy group; straight chain or branched C1-C5 substituted with an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted 03-Coo cycloalkyl group Represents an alkyl group.

Straight chain or branched chain C3 to C8 that may contain oxygen
Alkyl groups include 2-methoxyethyl group, 2-ethoxyethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2
Examples include -hexyl group, 2-methylbutyl group, 2-methylpentyl group, 2-methylhexyl group, and 2,2-dimethylhexyl group. 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.

Straight chain or branched chain C3~ which may contain an oxygen atom
Examples of the C8 alkenyl group include 1-butylvinyl,
2-propylaryl, 2-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-hexenyl, 1,
4-dimethyl-3-pentenyl, 5-hebutenyl, 1-
Methyl-5-hexenyl, 6-methyl-5-hebutenyl, 2,6-dimethyl-5-hebutenyl and the like are preferred.

Straight chain or branched chain that may contain oxygen atoms @Cx~
Preferred examples of the C8 alkyl group include 2-butyl, 2-pentynyl, 3-pentynyl, 1"-methyl-2-pentynyl, and 1-methyl-3-pentynyl.

Substituted phenyl group, substituted phenoxy group, or 03-C
Examples of the substituent of the +o-substituted cycloalkyl group include a halogen atom, a protected hydroxyl group (for example, a silyloxy group, aC+ to C6 alkoxy group, etc.), and an 01 to C4 alkyl group. Examples of the cycloalkyl group of 03 to C+o include cyclopropyl group, cyclopentyl group, :! /chlorhexyl group, cyclohexenyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, etc. Cyclopentyl group and cyclohexyl group are preferred.

01-C6 alkoxy group, optionally substituted phenyl group, optionally substituted phenoxy group, or optionally substituted phenoxy group.

or a straight chain or branched chain C1 to C5 substituted with an optionally substituted 03 to Coo cycloalkyl group
In the alkyl group, examples of the 01-C6 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group,
Isopropyloxy group.

Examples include butoxy group, t-butoxy group, hexyloxy group, and the like. As the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted 03-C+o cycloalkyl group, the same ones as mentioned above can be mentioned. Examples of straight chain or branched C+-Cs alkyl groups include methyl group,
Ethyl group.

Examples include propyl group, isopropyl group, butyl group, isobutyl group, 5ec-butyl group, t-butyl group, and pentyl group. Examples of R3 include butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl, 2-methylpentyl, and cyclopentyl.

Preferred examples include cyclohexyl, phenyl, phenoxy, cyclopentylmethyl, and cyclohexylmethyl groups. Note that the substituent may be bonded to any position thereof.

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

In the above formula [II], R1 and R2 are the same or different and represent a group that forms an acetal bond or an ester bond with a hydrogen atom, a tri(C+ to C7>hydrocarbon silyl group, or an oxygen atom of a hydroxyl group. C+~C7>Hydrocarbon The group forming an acetal bond or ester bond with the oxygen atom of the silyl group and hydroxyl group includes the same groups as in the above formula [I].

The wavelength of the light used in the photoirradiation cyclization reaction using the propargylcyclopentanes represented by the above formula [I] as a raw material is usually preferably in the range of 200 to 400 m, more preferably a uniform wavelength of 220 to 3001 m, or A wide range of wavelengths is used.

Examples of light sources that meet these conditions include low-pressure mercury lamps, medium-pressure mercury lamps, high-pressure mercury lamps, and tungsten lamps.
Halogen lamps, mercury-xenon lamps, flash lamps, lasers, etc. are preferably used, and mercury low-pressure lamps are particularly preferably used. Further, filters such as a Vycor glass filter may be used if necessary. (New Experimental Chemistry Course Volume 14-V, 92616-26
20. (Reference: Chemical Society of Japan, edited by Maruzen et al.) Any reactor that is commonly used for light irradiation reactions may be used (Katsuyuki Ogura, Chemistry and Industry, 41, 325.
1988: New Experimental Chemistry Course Volume 14-V, I) 262
0-2622. Edited by the Chemical Society of Japan, see Maruzen et al.). For example, external irradiation type devices such as a merry-go-round type, and various internal irradiation type devices are used. The reaction may also be carried out in the presence of a photosensitizer.

The solvent for the photolayering reaction includes, for example, acetonitrile; alcohol solvents such as methanol, ethanol, and isopropanol; hydrocarbon solvents such as hexane, cyclohexane, and benzene; ether solvents such as ether, tetrahydrofuran, and dioxane; Halogenated solvents such as chloroform, methylene chloride, and carbon tetrachloride; organic polar solvents such as hexamethylphosphoric triamide, dimethylformamide, and dimethyl sulfoxide; and mixed solvents thereof in arbitrary proportions are used, but preferably acetonitrile, Hexamethylphosphoric triamide and the like are used. The photolayer reaction is generally preferably carried out in the presence of amines. Examples of the amines used include triethylamine.

Diisopropylethylamine, diethylamine.

Alkylamines such as diisopropylamine and t-butylamine, aromatic amines such as aniline and dimethylaniline, etc. are used, but triethylamine is preferably used. The amount of the amines to be used is determined based on the above formula (
It is used in an amount of 0 to 500 equivalents, preferably 1 to 20 equivalents, relative to the propargylcyclopentane represented by I). The cyclization reaction does not proceed in the absence of the amine, but if a solvent that is excited by light irradiation, such as hexamethylphosphoric triamide, is used as a solvent, the cyclization reaction will not proceed in the absence of the amine. Since the reaction proceeds without the presence of amines, in such cases the reaction is generally carried out in the absence of the amines.

The reaction temperature is -100 to 60°C, preferably -30 to 40°C.
A temperature range of about °C is adopted. The reaction time varies depending on the intensity and number of lamps used, the wavelength, and the equipment used, but is usually 0.1 to 24 hours, preferably 0.5 to 5 hours. In the photostratification reaction, the concentration of propargylcyclopentanes represented by the above formula (I>) in the solution is 10-
It is about 4M to 1M (M=0101/l), but
Preferably it is about 1G-3 to 0.5M. Note that methanol and ethanol are used in the reaction system.

The photostratification reaction may be carried out by adding a proton source such as inpropatol or t-butanol.

The reaction solution thus obtained can be taken out from the reaction system as a crude product by directly removing the solvent under reduced pressure, or by directly filtering it through silica gel, Floriseal, etc., and then removing the furnace liquid under reduced pressure. . Also, saturated ammonium chloride water.

It can also be taken out from the reaction system as a crude product by adding water or the like and then performing extraction with an organic solvent. The crude product is subjected to column chromatography or thin layer chromatography, if desired.

It can be purified by purification means such as liquid chromatography and recrystallization.

In the case where the 7th and 6th positions of the 2-hydroxy-3-methylenebicyclo[3,3,0]octanes represented by the above formula [I] have a protected hydroxyl group at the 3° (or 4°) position, , if necessary, can be deprotected to form a free hydroxyl group.

When the protecting group is a group that forms a 7-cetal bond with the oxygen atom of the hydroxyl group, removal of the protecting group of the hydroxyl group may be performed using, for example, acetic acid, p-toluenesulfonic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation. This reaction is suitably carried out using an exchange resin or the like as a catalyst and, for example, water, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, etc. as a reaction solvent. The reaction is usually -78℃~
It is carried out for about 10 minutes to 3 days at a temperature range of 150°C.

In addition, when the protecting group is a tri(C+ to C7) hydrocarbon silyl group, for example, acetic acid, p-toluenesulfonic acid, p-
It is carried out in the presence of the pyridinium salt of toluenesulfonic acid, tetrabutylammonium fluoride, cesium fluoride, hydrogen fluoride, pyridine-hydrogen fluoride in the reaction solvent as described above at similar temperatures and for similar times.

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 or a water-alcohol mixed solution of sodium hydroxide, potassium hydroxide, calcium hydroxide, or sodium methoxide, potassium methoxide, sodium This can be carried out by hydrolysis in a methanol or ethanol solution containing ethoxide.

In addition, in the compounds represented by the above formulas [I] and [II], the carbon atoms to which the cyclopentane ring and bicyclo[3,3°0]octane ring themselves and the substituents bonded to these rings are unbound. Although stereoisomers exist due to the homogeneous environment, the present invention includes any stereoisomers, and mixtures of these stereoisomers in arbitrary proportions are also acceptable. In addition, the compound represented by the formula includes all of these stereoisomers and mixtures of these isomers in arbitrary proportions, but compounds having the three-dimensional structure represented by the formula are most preferred. .

The propargyl cyclopentanes represented by the above formula [I] used in this reaction are obtained by oxidizing the propargyl cyclopentanes represented by the following formula [I11] and, if necessary, deprotecting them by the same method as described above) q
can be done. Any method that oxidizes alcohol to aldehyde may be used as such an oxidation method, but Swern oxidation using oxalic acid chloride dimethyl sulfoxide-triethylamine is suitable.
; A.J., Mancuso et al.

J, Org, CheRl, vol. 44, 4148
Page, 1979, etc.), pyridinium chlorochromate (PCC: E, J, C0rey et al., Tetr
ahedrOn Lett,, 2847 pages.

1915), pyridinium dichromate (P
D C: E, J., Corey et al., Tetrahed
roll Lett.

399, 1979, etc.) are preferably used.

The amount of the oxidizing agent to be used is 0.8 to 20 times, preferably 1.2 to 2 times the amount of the cyclopentane represented by formula [III] as the raw material.

The reaction temperature and solvent vary greatly depending on the oxidizing agent used; in the case of Swern oxidation, the temperature is between -BO''C and room temperature, and dichloromethane is mainly used as the solvent, and in the case of PCC and PDC, the temperature is between 0°C and room temperature. The reaction is carried out mainly using dichloromethane as a solvent.The reaction time varies depending on the reaction conditions, but is usually about 10 minutes to 6 hours.

The propargyl cyclopentanes represented by the above formula [1[1] can be obtained by a hydroboration reaction and a subsequent oxidation reaction of the propargyl cyclopentanes represented by the following formula [IV].
When is a trimethylsilyl group, it can be obtained by selectively deprotecting the silane. The hydroboration reaction can be carried out using conventional techniques. [
organic reaction
ctting), 13 volumes.

Chapter 1. John Wiley & Sons Inc.
) New York, 1963: New Experimental Chemistry Course, Synthesis and Reactions of Organic Compounds■.

P497-505. See round neck etc. ] As a hydroboration reagent, dialkylborane such as dicyamylborane ((CH2)z CHCH(CH3)BH), 9-borabicyclo[3,3,1]nonane (9-BBN>, dicyclohexylborane, diisopinocamphenylborane) and catecholborane.

Disubstituted borane such as dihaloborane can be used, but preferably dicyamylborane and 9-borabicyclo[3,3,13nonane (9-BBN>) are used as the oxidizing agent used in the oxidation reaction following hydroboration. Although hydrogen peroxide-sodium hydroxide, trimethylamine oxide, air oxidation, etc. can be used, hydrogen peroxide-sodium hydroxide is particularly preferred.The amount of the hydroboration reagent used is cyclopentanes represented by formula [IV] The reaction proceeds stoichiometrically in equimolar amounts, but usually 0.5 to 5 times the mole relative to the starting material compound is used.The reaction temperature is -100 to 50 degrees Celsius, preferably 10 to 0 degrees Celsius. The temperature is about room temperature.The reaction time varies depending on the reaction temperature, but is usually 10 minutes to 20 hours, preferably 30 minutes to
It takes about 5 hours. The reaction is usually carried out in the presence of an Il-containing medium. The medium used is an inert aprotic organic medium that does not react with the reaction reagent, preferably an ether type solvent such as tetrahydrofuran, diethyl ether, diglyme, triglyme, etc., with tetrahydrofuran being particularly preferred. Alkylboranes produced by hydroboration reactions are usually not isolated.
By directly adding an oxidizing agent to the reaction system, it is oxidized and led to an alcohol represented by the following formula [■°]. When hydrogen peroxide is used as an oxidizing agent, a base such as sodium hydroxide is used at the same time. Hydrogen peroxide can be used at any concentration, but a concentration of around 30% is commonly used.The amount of hydrogen peroxide used is 0.5 to 50 times the mole of the hydroboration reagent used. Preferably 3 to 10 times the molar amount.Sodium hydroxide can be used as such or as an aqueous solution;
Use an aqueous solution of the specified concentration. The amount used is 0.5 to 50 times the mole of the hydroboration reagent, preferably 3 to 50 times the mole of the hydroboration reagent.
It is 10 times the molar amount. The reaction temperature at this time is 0°C to 100°C.
℃, preferably 40℃ to 70℃.

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, preferably 3 to 10 times, the amount of the hydroboration reagent.

The product thus obtained can be taken out from the reaction system as a crude product by quenching, extraction, etc. according to a conventional method. The crude product may be subjected to column chromatography, thin layer chromatography, or liquid chromatography as required.

It can be purified by purification means such as recrystallization.

The compound represented by the above formula [II[] is the above formula [■°]
It can also be obtained by selectively deprotecting compounds in which R5 is a trimethylsilyl group among the compounds represented by the formula. This deprotection reaction of the acetylene terminal can be carried out by a conventional method [Stricon Reagent for Organic Synthesis].
gents for Organic Synthesis
s), Reactivity and 5truct
ureconcepts organic chemistry
story volume 14, chapter 9゜spr+n
ger-ver+ag, 1983] As deprotection reaction reagents, sodium methoxide-methanol, silver nitrate-
those using ethanol-water and potassium cyanide-water;
Potassium hydroxide water, potassium fluoride-methanol, etc. are used.

Propargyl cyclopentanones represented by the above formula [IV] can be prepared using a methylenating agent (L, Lombardo et al., Tetrahedron Letters) prepared from titanium tetrachloride-zinc-dibromomethane. , vol. 23, p. 4293, 1982)
.

Methylenating agent prepared from titanium tetrachloride-zinc-short methane (Nozaki et al., Tetrahedron Letters, 26
Vol., p. 5581, 1985) or by methylenation using other methylenating agents.

The methylenating agent prepared from titanium tetrachloride-zinc-dibromomethane is a mixture of 0.8 to 2.5 g of titanium tetrachloride, 5a12a, and zinc per 1 g of dibromomethane in tetrahydrofuran at 0°C for 5 to 3 hours. Represents a product that has been stirred and left for several days.

The methylenating agent prepared from titanium tetrachloride-zinc-short methane is a mixture of titanium tetrachloride 0.1 to 0.2 (J) and zinc 0.3 to 0.69 in tetrahydrofuran per 1 g of short methane. 25°C for 30 minutes.

The reaction between the cyclopentanones represented by the above formula [V] and the methylenating agent is carried out in the presence of an organic medium, and the reaction @
An inert, aprotic organic medium that is liquid at low temperatures and does not react with the reaction reagents is used. Preferred examples of such a medium include halogenated hydrocarbons such as dichloromethane, dichloroethane, and tetrachloroethane. The amount of organic medium to be used is sufficient as long as it allows the reaction to proceed smoothly, and is usually 1 to 200 times the volume of the raw materials, preferably 5 to 50 times the volume. The reaction temperature is -2
It is carried out at a temperature of 0°C to 70°C, preferably 01 to 50°C.

The reaction time is 10 minutes to 24 hours. The product thus obtained is quenched with saturated aqueous sodium bicarbonate and can be extracted from the reaction system by extraction or the like. The crude product can be purified by purification means such as column chromatography, thin layer chromatography, liquid chromatography, recrystallization, etc., if desired.

Propargyl cyclopentanones represented by the above formula [V] were prepared according to the method of Noyori et al. (Ryoji Noyori et al.

Journal of American φChemical Science, Volume 107, Page 3348, 1985),
It can be obtained by performing a three-component ligation reaction as shown below.

Hydroxy-3-methylenebicyclo[3,3
, 0] Octanes are the isocarbacyclines, 9(0)-
It is useful as an intermediate for methano-Δ6(9cr)-prostaglandin 11. That is, [Hydroxy-3-methylenebicyclo3.3.0 ]octanes of the formula [I[] (where R+ and R2 are R12 and R22 as defined above, respectively)
) is regioselectively reacted with an organolithium compound at the γ-position of its allyl alcohol to form the above-mentioned isocarbacycline, i.e., 9(0)-methano-Δ6(
9cx) - a useful key intermediate capable of constructing the prostaglandin 11 skeleton (Japanese Patent Application Laid-Open No. 62-6193
(See Publication No. 7).

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

The photoreaction device used an external irradiation type merry-go-round light irradiation device (Rayonet Photo-ch
chemical reactor; The 5outh
ern New England Ultraviole
t Company). The lamp is a low pressure mercury lamp (Ra
yonet Photochemical React
ion Lamp, 2537 people, 16 lamps). In the examples, -02+ represents a t-butyldimethylsilyloxy group, and -072 represents a trimethylsilyloxy group.

Example 1 Z+ OOZ+ (Compound i) Z+ OOZ+ (Compound ii) Aldehyde (Compound i) 102ma (0,2
0 mmol) in 5.8 d of acetonitrile and placed in a quartz glass tube with a diameter of 'l ICIII. After bubbling nitrogen for 30 min, triethylamine 143 tll
(1.03 mmol) was added, and light irradiation was performed for 2 hours using the light irradiation device.

When the solvent was distilled off under reduced pressure and the resulting crude product was purified by silica gel column chromatography, 73 rna (yield 72%) of (Is,
2R3, 5R, 6R, 7R) -2-hydroxy-3
-methylene-6-((E, 3°5)-3°-t-butyldimethylsilyloxy-1゛-octenyl)-7-t-
Butyldimethylsilyloxybicyclo[3°3.0]octane (compound ii) was obtained.

CDα3 NMR (δTMS) 0-0.1 (12H), 0.8-1.0 (21 old,
3.6-4.0 (Iff, m).

3.9-4.5 (2H, +n), 4.96 (IH, b
s).

5.08 (IH, bs), 5.48 (2H, III)
.

eat IR(λWaS) 3350, 1258.968.835.775 cm-
+;Mass (L E I s, m/e)451
(M-tBLl), 319.305 Example 2 In the same manner as in Example 1, the following product was obtained from the following starting material.

Starting Material Product Example 3 Z+OZ+0' (Compound 1i) Z+O'Z+O: (Compound iv) Aldehyde (Compound iii) 110 mg (0
, 21 mmol) was dissolved in hexamethylphosphoric triamide 4d and placed in a quartz glass tube with a diameter of 1 cm.
Bubble nitrogen for 0 minutes. This was set in the light irradiation device, and light irradiation was performed for 2.5 hours. Water was added, extracted twice with ether, and the combined organic layers were washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. When the obtained crude product was purified by silica gel column chromatography, 77 mg (
(1s, 2R3 with a yield of 10%).

5R, 6R, 7R) -2-hydroxy-3-methylene-6-((E, 3°S, 5'S) -3'-t-
1 q of butyldimethylsilyloxy-5°-methyl-1′-nonenyl)-7-t-butyldimethylsilyloxybicyclo[3,3,0]octane (compound iv).

Spectral data are shown in Example 2.

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

Starting materials Product

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I] In the formula, R^1^1 and R^2^1 are the same or different,
Hydrogen atom, tri(C_1-C_7) hydrocarbon silyl group,
or a group that forms an acetal bond or an ester bond with the oxygen atom to which they are bonded, and R^
3 represents a hydrogen atom, methyl group or vinyl group, R^
4 is a straight chain or branched chain C that may contain an oxygen atom
_3~C_8 Alkyl group, alkenyl group or alkynyl group; Substituted or unsubstituted phenyl group Substituted or unsubstituted phenoxy group; Substituted or unsubstituted C_3~
Straight chain or branched chain substituted with a C_1_0 cycloalkyl group or a C_1 to C_6 alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C_3 to C_1_0 cycloalkyl group Chain C_1 to C_5 represents an alkyl group, and n represents 0 or 1. The compound represented by the following formula [ II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...
[II] In the formula, R^1 and R^2 are the same or different and form an acetal bond or an ester bond with a hydrogen atom, a tri(C_1-C_7) hydrocarbon silyl group, or an oxygen atom to which they are bonded. Represents a group, R^3, R^
4 and n are the same as defined above. A method for producing 2-hydroxy-3-methylenebicyclo[3.3.0]octane, which is a compound represented by the following formula, its enantiomer, or a mixture thereof in any proportion. 2. In the above formula [I], both R^1 and R^2 are t
-butyldimethylsilyl group, the method for producing 2-hydroxy-3-methylenebicyclo[3.3.0]octanes according to claim 1. 3. The method for producing 2-hydroxy-3-methylenebicyclo[3.3.0]octanes according to claim 1 or 2, wherein in the above formula [I], R^3 is a hydrogen atom or a methyl group. 4. In the above formula [I], R^4 is n-butyl group, n
-pentyl group, cyclopentyl group, cyclohexyl group or 2-methylhexyl group, 2-hydroxy-3-methylenebicyclo[
3.3.0] Method for producing octanes. 5.Claim 1, wherein the light irradiation reaction is carried out in the presence of amines.
4. The method for producing 2-hydroxy-3-methylenebicyclo[3.3.0]octanes according to any one of items 4 to 4. 6. The method for producing 2-hydroxy-3-methylenebicyclo[3.3.0]octanes according to claim 5, wherein the amine is triethylamine or dimethylaniline. 7. The method for producing 2-hydroxy-3-methylenebicyclo[3.3.0]octanes according to any one of claims 1 to 6, wherein the reaction solvent is acetonitrile. 8. The method for producing 2-hydroxy-3-methylenebicyclo[3.3.0]octanes according to any one of claims 1 to 4, wherein the reaction solvent is hexamethylphosphoric triamide.