JPH0784409B2 - Cis-bicyclo [4.3.0] nonene derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention is represented by the following general formula (I). [In the formula, R ¹ represents a CO ₂ R ³ group (in the group, R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 12 carbon atoms), and A represents —CH ₂ CH ₂ CH _{2. 2 - -CH 2 CH 2 CH 2} CH 2 - or -CH = CHCH ₂ CH ₂ - and is, R ² is a hydrogen atom, a trimethylsilyl group, triethylsilyl group, tribenzylsilyl group, t- butyl dimethyl silyl group, diphenyl It represents a -t-butylsilyl group, a p-methoxybenzyl group, a 1-methyl-1-methoxyethyl group, a benzyl group, a tetrahydropyranyl group, a 1-ethoxyethyl group or a methoxymethyl group. The double bond in the substituent represented by A is E or Z or a mixture thereof]. Cis-bicyclo (4.3.
0] relates to a nonene derivative. The cis-bicyclo [4.3.0] nonene derivative represented by the general formula (I) can be a useful intermediate for prostacyclin analogs.

[Conventional technology]

Prostacyclin (hereinafter referred to as PGI ₂ ) is known as a natural physiologically active substance and has a structure represented by the following formula: Its chemical name is (5Z, 13E)-(9α, 11α, 15S) -6,9-epoxy-11,15-dihydroxyprosta-5,13-dienoic acid. PGI ₂ is present in the arterial wall, and has a strong platelet aggregation inhibitory action and peripheral arterial smooth muscle relaxing action [Nature, 263 , 663 (1976)]. PGI ₂ exhibiting such an action is useful for prevention and treatment of cerebral thrombosis, myocardial infarction, and acute angina induced by increased platelet aggregation and increased thrombotic tendency, and is useful for prevention and treatment of arteriosclerotic diseases. It is expected to be applicable and is expected to be developed as a so-called blood flow improving drug.

In addition, prostaglandins containing PGI ₂ are known to have gastric mucosa protective action and gastric mucosal blood flow increasing action ['83 Inflammation Seminar "Prostaglandin" Proceedings 50 pages (sponsored by the Japanese Academy of Inflammation)] It is expected that PGI ₂ showing such an action can be applied to the prevention and treatment of gastrointestinal ulcer typified by gastric ulcer.

However, PGI ₂ is a very unstable substance, which impedes its practical application as a medicine.

In order to solve this obstacle, studies have been conducted on stable analogs in which the oxygen atom between the 6th and 9th carbon atoms of PGI ₂ is replaced with a carbon atom. A carbacycle compound represented by the general formula (III) represented by OP-41483 [JP-A-54-130543] [JP-A-54-130543] 9 (O) -methano- represented by the chemical formula (IV) All of Δ ⁶ -PGI ₁ [JP-A-56-32436] are chemically stable PGI ₂ related compounds. Further, 9 (O) -methano-Δ in which the 5-position double bond of 9 (O) -methanoprostacyclin (carbacycline) was moved to the 6 (9α) position.
^{6 (9α)} -PGI ₁ (isocarbacycline, chemical formula (V)) is also chemically sufficiently stable and has been reported as a PGI ₂ related compound having a strong physiological activity [JP-A-59].
−137445].

Compounds represented by the following general formulas (VI and VII) are used as key intermediates for synthesizing such chemically stable PGI ₂ analog compounds.

[Problems to be Solved by the Invention] As a result of extensive research conducted by the present inventors for the purpose of providing prostacyclins having stable and excellent pharmacological properties, which hardly decompose at room temperature, The inventors have found that the cis-bicyclo [4.3.0] nonene derivative represented by the general formula (I) can be an important intermediate for synthesizing an excellent stable prostacyclin analog, and completed the present invention.

[Means for solving problems]

The present invention is a cis-bicyclo [4.3.0] nonene derivative represented by the general formula (I).

Examples of R ¹ in the present invention include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group and the like, and as the protection of the hydroxyl group of R ^2, a trimethylsilyl group, a triethylsilyl group,
Tribenzylsilyl group, t-butylmethylsilyl group, diphenyl-t-butylsilyl group, p-methoxybenzyl group, 1-methyl-1-methoxyethyl group, benzinl group, tetrahydropyranyl group, 1-etoxyethyl group,
A methoxymethyl group etc. can be illustrated. The cis-bicyclo [4.3.0] nonene derivative represented by the general formula (I) is a novel stable prostacyclin analog having a high physiological activity by introducing an ω-chain by a Witting reaction after oxidizing a primary hydroxyl group into an aldehyde. Can be derived (see the reference example below).

The cis-bicyclo [4.3.0] nonene derivative represented by the general formula (I) of the present invention can be produced according to the following reaction formula.

R ⁸ in the following formula is a hydroxyl-protecting group, and as the hydroxyl-protecting group for R ⁸ , t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, diphenyl-t-butylsilyl group, tribenzylsilyl group, p Examples thereof include -methoxybenzyl group, 1-methyl-1-methoxyethyl group, benzyl group and the like.

[First Step] In this step, the lactol derivative represented by the general formula (VII) is subjected to Wittig reaction to produce the α, β-unsaturated ester derivative represented by the general formula (IX). . The lactol body represented by the general formula (VIII) can be easily obtained by reduction of corey lactone (see Reference Example below). The Wittig reaction in this step is
It is carried out using a stable ylide such as methoxycarbonylmethylenetriphenylphosphorane or ethoxycarbonylmethylenetriphenylphosphorane in an aromatic hydrocarbon such as toluene or benzene. The amount of stable ylide used is usually 1-2.
It is equivalent, and the reaction proceeds smoothly at 50 ° C to 130 ° C.

[Second Step] In this step, the α-β-unsaturated ester derivative represented by the general formula (IX) obtained in the first step is reduced to give the hydroxy-ester represented by the general formula (X). The body is manufactured. This reduction reaction uses 5% palladium /
Carbon / 10% palladium / carbon, can be carried out under hydrogen at 1 atm in the presence of Wilkinson's complex. As the solvent, ethanol, methanol, benzene, ethyl acetate or the like can be used, and the reduction reaction easily proceeds at 0 ° C to 50 ° C in the presence of these solvents.

[Third Step] In this step, the hydroxy-ester derivative represented by the general formula (X) obtained in the second step is oxidized to produce a cyclopentanone derivative represented by the general formula (IX). It is a thing. This oxidation reaction easily proceeds by using a Collins reagent or pyridium chlorochromate in a halogenated hydrocarbon solvent such as methylene chloride.
The Swern oxidation reaction can also be used as a simpler reaction from the experimental procedure. Swern oxidation reaction is 2 in methylene chloride
~ 3 equivalents of oxalyl chloride, 4-5 equivalents of DMSO, 10
It can be done with ~ 15 equivalents of triethylamine. The reaction temperature can be selected in the range of -78 ° C to room temperature.

[Fourth Step] In this step, the exo-methylene derivative represented by the general formula (XII) is obtained by methyleneating the cyclopentanone derivative represented by the general formula (XI) obtained in the third step. It is manufactured. For this methyleneation reaction,
A reagent prepared from zinc-methylene bromide-titanium tetrachloride in tetrahydrofuran is used. The methyleneation reaction is carried out in a halogenated hydrocarbon solvent such as methylene chloride, and the reaction temperature can be selected in the range of 0 ° C to 50 ° C.

[Fifth Step] This step is the same as the general formula (XII) obtained in the fifth step.
The hydroxymethylcyclopentane derivative represented by the general formula (XIII) is produced by hydrating the exo-methylene derivative represented by The hydration reaction in this step is carried out by hydroboration and oxidation. Upon hydroboration, a hydroboration agent such as 9-BBN (9-borabicyclo [3.3.1] nonane) or thexylborane can be used. The hydroboration reagent is usually used in an amount of 1 to 1.5 equivalents. It is desirable to carry out the reaction in a solvent, for example, an ether solvent such as tetrahydrofuran, diglyme or diethyl ether can be used.
The reaction proceeds smoothly at -25 ° C to room temperature. In addition, the process involves hydroboration followed by oxidation without isolation of the product. For the oxidation, an oxidizing agent such as hydrogen peroxide can be used. When oxidation is performed using hydrogen peroxide, it is preferable to use it in a basic state such as sodium hydroxide. The amount of the oxidizing agent used is 5 to 15 equivalents, and the reaction proceeds smoothly at room temperature to 60 ° C.

[Sixth Step] This step is the same as the above-mentioned general formula (XII) obtained in the fifth step.
The hydroxymethylcyclopentane derivative represented by the formula (1) is reduced to produce the diol body represented by the general formula (XIV). The reduction reaction can be carried out using a reducing agent such as lithium aluminate hydride in an ether solvent such as tetrahydrofuran or ether. The reaction temperature can be selected in the range of 0 ° C to 40 ° C.

[Seventh Step] This step is the same as the above-mentioned general formula (XIV) obtained in the sixth step.
The 6-membered ring enal represented by the general formula (XV) is produced by subjecting the diol represented by the formula (3) to oxidation and subsequent aldol condensation accompanied by dehydration.

In the oxidation, for example, dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-sulfur trioxide pyridine complex or the like can be used. The oxidizing agent may be used in an amount of usually 1 to 5 equivalents.

It is desirable to carry out the reaction in a solvent,
For example, halogenated hydrocarbon such as methylene chloride can be used.

The reaction proceeds smoothly at -70 ° C to room temperature, though it depends on the type of oxidant.

The oxidation product in this step is obtained by adding a tertiary amine such as triethylamine or diisopropylethylamine to the reaction product and treating at -70 ° C to room temperature.

After completion of the oxidation reaction, the product was subjected to the next dehydration reaction without isolation.

The dehydration reaction is performed by heating the product obtained by the oxidation reaction in the presence of an acidic catalyst. An acid-ammonium salt can be used as the acidic catalyst. Acid-ammonium salt catalysts can be formed from acids and amines. Examples of the acid that can be used include trifluoroacetic acid, toluenesulfonic acid, camphorsulfonic acid, acetic acid and the like. Further, as usable amines, dibenzylamine, diethylamine, dimethylamine, diisopropylamine, piperidine, pyrrolidine,
Examples thereof include piperazine. These acids and amines can be appropriately selected and used in combination, and in particular, a catalyst in which trifluoroacetic acid and dibenzylamine are combined is preferable in that the desired product can be obtained in good yield. The catalyst may be used in an amount of about 0.2 equivalent, but it is preferable to use about 1 equivalent in order to allow the reaction to proceed rapidly.

In carrying out the reaction, it is desirable to use a solvent, and aromatic hydrocarbons such as benzene, toluene and xylene can be used.

The reaction temperature can be selected from room temperature to 100 ° C, but it is preferable to carry out the reaction in the range of 50 ° C to 70 ° C for smooth reaction.

The cis-bicyclo [4.3.0] nonene derivative represented by the general formula (I) is produced from the 6-membered ring enal represented by the general formula (XV) by two routes.

[Step 8] In this step, the 6-membered ring enal represented by the general formula (XV) is methyleneated to produce a conjugated diene represented by the general formula (XVI). The methyleneation reaction can be carried out using an ylide prepared with a base such as methyltriphenylphosphonium bromide and a potassium salt of t-butyl alcohol in an ether solvent such as tetrahydrofuran. The reaction temperature is 0 ° C to
50 ° C can be selected.

[Ninth Step] This step is the same as the general formula (XVI) obtained in the eighth step.
The primary dihydric alcohol represented by the above general formula (XVII) is produced by selectively hydroborating the conjugated diene represented by the formula (1) and then performing an oxidation reaction. For this hydroboration, a hydroborating agent such as disiamilborane or 9-BBN can be used. It is desirable to carry out the reaction in a solvent, for example, an ether solvent such as tetrahydrofuran, diglyme or diethyl ether can be used. In the oxidation after hydroboration, an oxidizing agent such as hydrogen peroxide can be used under basic conditions.

[10th step] This step is the same as the above-mentioned general formula (XVII) obtained in the 9th step.
The aldehyde represented by the above general formula (XVIII) is produced by oxidizing the primary alcohol represented by. In this oxidation reaction, a halogenated hydrocarbon solvent such as methylene chloride can be used, and Collins reagent, pyridinium chlorochromate, Swern oxidation and the like can be used. The reaction temperature can be selected from -78 ° C to 50 ° C.

[Eleventh Step] This step is the same as the general formula (XVII) obtained in the tenth step.
The α, β-unsaturated ester represented by the general formula (XIX) is produced by subjecting the aldehyde represented by I) to Wittig reaction.

This Wittig reaction is carried out using a stable ylide such as carbomethoxymethylenetriphenylphosphorane or carboethoxymethylenetriphenylphosphorane in an aromatic hydrocarbon such as toluene or benzene. The amount of the stable ylide used is usually 1 to 2 equivalents, and the reaction proceeds smoothly at 50 ° C to 130 ° C.

[Twelfth Step] This step is the same as the general formula (XIX) obtained in the eleventh step.
The α, β-unsaturated ester represented by is selectively reduced to produce the ester represented by the general formula (XX). This reduction reaction can be carried out using a reducing agent such as lithium tri-sec-butylborohydride or copper (I) hydride in an ether solvent such as tetrahydrofuran. The reaction temperature can be selected from -78 ° C to 0 ° C.

[Thirteenth Step] In this step, the protecting group for the primary hydroxyl group of the ester represented by the general formula (XX) obtained in the twelfth step is selectively deprotected to give the compound represented by the general formula (I). Ω-chain-primary alcohol production. The reaction conditions of this deprotection reaction differ depending on the kind of R ⁸ , but when R ⁸ is a trialkylsilyl group such as t-butyldimethylsilyl and R ² is an acetal-type protecting group such as a tetrahydropyranyl group, tetrahydrofuran is used. The condition of medium tetra-n-butylammonium fluoride can be used.

[Step 14] In this step, the 6-membered ring enal represented by the general formula (XV) is subjected to a Wittig reaction, and then the carboxyl group is protected to give the 1,3-diene represented by the general formula (XXI). Is manufactured.

In this Wittig reaction, an ylide prepared from 3-carboxypropyltriphenylphosphonium bromide and potassium salt of t-butyl alcohol can be used.
As the reaction solvent, an ether solvent such as tetrahydrofuran can be used, and the reaction temperature can be selected from -78 ° C to 50 ° C. In this step, the product obtained by the Wittig reaction is subsequently esterified. When R ³ is methyl, the conditions of diazomethane in ether and the reaction conditions of potassium carbonate-methyl iodide in acetone can be used.

[Fifteenth Step] In this step, the 1,3-diene represented by the general formula (XXI) is selectively reduced to produce the monoene represented by the general formula (XXI). This selective reduction uses a catalytic reduction reaction, and the hydrogen pressure used for the catalytic reduction reaction is usually 1 atm. As the reduction catalyst, 5% palladium / carbon, 10% palladium / carbon, Wulkinson complex can be used. The reducing solvent is methanol,
A wide range of ethanol, benzene, ethyl acetate and the like can be selected, and similarly, a wide range of reaction temperatures of -78 ° C to 50 ° C can be selected.

[16th step] This step is the above-mentioned general formula (XXII) obtained in the 15th step.
The primary hydroxyl-protecting group of the monoene represented by the formula (1) is selectively deprotected to produce the ω'-chain-primary alcohol represented by the general formula (I). The reaction conditions of this deprotection reaction varies depending on the kind of R ^8, in such a trialkylsilyl group R ⁸ is t- butyldimethylsilyl, R ²
When is an acetal-type protecting group such as a tetrahydropyranyl group, the condition of tetra-n-butylammonium fluoride in tetrahydrofuran can be used.

[Seventeenth Step] This step is the same as the one represented by the general formula (XXI) obtained in the fourteenth step.
By selectively deprotecting the protective group for the primary hydroxyl group of the 1,3-diene represented by the formula, ω'-represented by the general formula (I)
Chain-produces primary alcohol. The reaction conditions of this deprotection reaction varies depending on the kind of R ^8, R ⁸ is t
When a trialkylsilyl group such as -butyldimethylsilyl and R ² is an acetal type protecting group such as a tetrahydropyranyl group, the condition of tetra-n-butylammonium fluoride in tetrahydrofuran can be used.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples.

Reference example 1 Under an argon atmosphere, [2-oxa-3-oxo-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxy-cis-bicyclo [3.3.0] octane] (10 g, 27 mmol) was added. Toluene (80m
l) and cooled to -78 ° C. Diisobutylaluminum hydride (1M toluene solution 40.5 ml, 40.5 mmol) was added, and the mixture was stirred at -78 ° C for 60 minutes. Methanol was added at −78 ° C. until generation of hydrogen was not observed, and the temperature was raised to room temperature. Saturated saline was added, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off [2-oxa-
3-Hydroxy-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxy-cis-bicyclo [3.3.0] octane] (10.1 g, 100
%) Was obtained.

IR (neat): 3430, 2950, 2860, 835 cm ⁻¹ . NMR (CDCl ₃ ) δ: 5.70-5.30 (m, 1H), 4.85-4.55 (m, 2
H), 4.40-3.25 (m, 5H), 0.90 (s, 9H). Mass m / z (%): 213 (5), 159 (17), 85 (100), 75
(19), 73 (13). Reference example 2 Under an argon atmosphere, [2-oxa-3-hydroxy-6
-Exo-t-butyldimethylsilyloxymethyl-7
-Endo-tetrahydropyranyloxy-cis-bicyclo [3.3.0] octane] (10.1 g, 27 mmol) was added to toluene (1
00 ml). (Methoxycarbonylmethylene) triphenylphosphorane (11.7g, 35mmol) was added at 60 ℃.
It was stirred for 12 hours. After cooling, the solvent was distilled off and the obtained residue was subjected to silica gel column chromatography (ether: n-
Purified by hexane = 1: 2), [2α- (3-methoxycarbonyl-2-propenyl) -3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol] (10.9 g , 94%)
Got

IR (neat): 3530, 2960, 2875, 1730, 1660, 840 cm ^-1 . NMR (CDCl ₃ ) δ: 7.06 (m, 1H), 5.95 (d, J = 15Hz, 1H),
4.66 (bs, 1H), 3.70 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6
H). Mass m / z (%): 211 (1), 159 (37), 85 (100), 75
(26), 73 (18), 43 (9). Reference example 3 [2α- (3-methoxycarbonyl-2-propenyl)
-3β-t-butyldimethylsilyloxymethyl-4α
-Tetrahydropyranyloxy-1α-cyclopentanol] (7.0 g, 16.4 mmol) was dissolved in methanol (50 ml). 10% Palladium / carbon (700 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hr. The catalyst was filtered off and the solvent of the filtrate was distilled off [2α- (3-methoxycarbonylpropyl) -3β-t-butyldimethylsilyloxymethyl-
4α-Tetrahydropyranyloxy-1α-cyclopentanol] (6.5 g, 93%) was obtained.

IR (neat): 3530, 2940, 2850, 1738, 830 cm ^-1 NMR (CDCl ₃ ) δ: 4.76 (bs, 1H), 3.66 (s, 3H), 0.90 (s,
9H), 0.05 (s, 6H). Mass m / z (%): 257 (10), 211 (1), 165 (29), 159
(62), 119 (11), 85 (100), 75 (28), 73 (22), 43 (1
2). Reference example 4 Oxalyl chloride (3.8ml, 43.5mm) under argon atmosphere
ol) was dissolved in methylne chloride (30 ml). A solution of dimethyl sulfoxide (6.5 ml, 90.6 mmol) in methylene chloride (30 ml) was added at −78 ° C. After stirring at -78 ° C for 30 minutes, [2α-
(3-Methoxycarbonylpropyl) -3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol] (6.5 g, 15.
1 m-mol) methylene chloride solvent (50 ml) was added. −78
After stirring for 30 minutes at ℃, triethylamine (31.3ml, 226.5mm
ol) was added and the temperature was raised to room temperature. Water was added and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ether: n-hexane = 1: 2) [2α- (3-methoxycarbonylpropyl) -3β-t-butyldimethylsilyloxymethyl]. -4α-Tetrahydropyranyloxy-1-cyclopentanol] (6.2 g, 95%) was obtained.

IR (neat): 2900, 2810, 1730, 820 cm ^-1 NMR (CDCl ₃ ) δ: 4.63 (bs, 1H), 3.66 (s, 3H), 0.90 (s,
9H), 0.05 (s, 6H). Mass m / z (%): 209 (2), 159 (28), 85 (100), 75
(29), 73 (29), 43 (3), 41 (22). Reference example 5 Under an argon atmosphere, [2α- (3-methoxycarbonylpropyl) -3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentanone] (10 g, 23 mmol) was added to methylene chloride (100 ml).
Dissolved in at room temperature zinc - it was added until starting material disappeared by titanium tetrachloride reagent _{[(Zn-CH 2 Br 2 -TiCl} 4) / THF ] was TLC - methylene bromide. The reaction solution was poured into a mixed solution of saturated aqueous sodium hydrogen carbonate (500 ml) and ether (500 ml). The mixture was added and filtered through Celite. After separating the ether layer, the aqueous layer was further extracted with ether. The ether layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ether: n-hexane = 1: 6) [2
α- (3-methoxycarbonylpropyl) -3β-t-
Butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene] (7.6 g, 7
6%).

IR (neat): 2900, 2800, 1730, 1645, 1240, 820 cm ^-1 . NMR (CDCl ₃ ) δ: 4.83 (d, 2H), 4.63 (bs, 1H), 3.80 (s,
3H), 0.90 (s, 9H), 0.05 (s, 6H). Mass m / z (%): 193 (18), 159 (41), 85 (100), 75
(37), 73 (31), 43 (15). Reference example 6 Under an argon atmosphere, [2α- (3-methoxycarbonylpropyl) -3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene] (7.5 g, 17.6 mmol) was added to THF (70 ml). Dissolved in. THF solution of disiamilborane (0.9M,
43 ml, 38.7 mmol) was added dropwise. After stirring at 0 ° C. for 1 hour, 6N aqueous sodium hydroxide solution (25.5 ml, 153 mmol) and
30% hydrogen peroxide solution (22 ml, 194 mmol) was added. After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off [1
α-Hydroxymethyl-2α- (3-methoxycarbonylpropyl) -3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane] (7.8 g, 100%) was obtained.

IR (neat): 3450, 2930, 2850, 835 cm ^-1 . NMR (CDCl ₃ ) δ: 4.66 (bs, 1H), 3.66 (s, 3H), 0.90 (s,
9H), 0.05 (s, 6H). Mass m / z (%): 285 (15), 255 (9), 193 (30), 159
(54), 85 (100), 57 (100), 43 (52). Reference example 7 Lithium aluminum hydride (3.34 g, 88 mmol) was suspended in THF (70 ml) under an argon atmosphere. below freezing,
A THF solution (100 ml) of [1α-hydroxymethyl-2α- (3-methoxycarbonylpropyl) -3α-t-butylmethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane] (7.8 g, 17.6 mmol) was added dropwise. did. After stirring for 30 minutes under ice cooling, sodium sulfate 10
The hydrate was added and the mixture was filtered through Celite. The solvent was distilled off and the residue was subjected to silica gel column chromatography (ether).
Purified by [1α-hydroxymethyl-2α- (4-
Hydroxybutyl) -3β-t-butylmethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane] (6.8 g, 93%) was obtained.

IR (neat): 3420, 2935, 2850, 1730, 830 cm ^-1 NMR (CDCl ₃ ) δ: 4.63 (bs, 1H), 4.10 (m, 1H), 0.90 (s,
9H), 0.05 (s, 6H). Mass m / z (%): 331 (M ⁺ −85,3), 275 (4), 183
(8), 159 (35), 85 (100), 41 (31). Reference example 8 Oxalyl chloride (9ml, 105.6mmo under argon atmosphere)
l) was dissolved in methylene chloride (70 ml). At −78 ° C., dimethyl sulfoxide (16.2 ml, 228.8 mmol) in methylene chloride (40 ml) was added. After stirring at -78 ° C for 30 minutes, [1α-
Hydroxymethyl-2α- (4-hydroxybutyl)-
3β-t-butyldimethylsilyloxymethyl-4α-
Tetrahydropyranyloxycyclopentane] (6.8 g, 1
A solution of 6.4 mmol) in methylene chloride (40 ml) was added. −78
After stirring at ℃ for 30 minutes, triethylamine (73ml, 528mmol)
Was added and the temperature was raised to room temperature. The methylene chloride was distilled off. Benzene (150 ml) and dibenzylammonium trifluoroacetate (51 g, 1
6.4 mmol) was added and the mixture was stirred at 60 ° C. for 5 hours. After allowing to cool, water was added and the mixture was extracted with ether. The ether layer was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate, and water. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography (ether: n-
Hexane = 1: 4) and purified [3-formyl-7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] ( 3g, 46%).

IR (neat): 2950, 2870, 1680, 1630, 835 cm ^-1 . NMR (CDCl ₃ ) δ: 9.43 (s, 1H), 6.70 (bs, 1H), 4.63 (b
s, 1H), 0.90 (s, 9H), 0.05 (s, 6H). Mass m / z (%): 309 (M ⁺ −85, trace), 159 (33), 85
(100), 75 (26), 73 (10), 57 (14). Reference example 9 Methyltriphenylphosphonium bromide (449mg,
1.14 mmol) was suspended in THF (5 ml). To this, a THF solution (2 ml) of potassium t-butoxide (140 mg, 1.14 mmol) was added at room temperature. After stirring for 10 minutes, [3-formyl-
7-exo-t-butyldimethylsilyloxymethyl-
8-Endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (150 mg, 0.38 mmol) T
The HF solution (2 ml) was added and the mixture was stirred at room temperature for 30 minutes. After adding a saturated ammonium chloride aqueous solution, the mixture was extracted with ether.
The ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ether: n-hexane = 1: 1).
15) and then [3-ethenyl-7-exo-t-
Butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (139 mg, 93%) was obtained.

IR (neat): 2950,2875,1640,1605,1475,1260,1200,840,
780 cm ^-1 .NMR (CDCl ₃ ) δ: 6.33 (dd, J = 11.6Hz, 1H), 5.66 (bs, 1
H), 5.03 (d, J = 20Hz, 1H), 4.88 (d, J = 11.6Hz, 1H), 4.
60 (bs, 1H), 0.90 (s, 9H), 0.05 (s, 6H). Mass m / z (%): 374 (M ⁺ −H ₂ O, trace), 308 (7), 251
(18), 205 (3), 159 (77), 85 (100), 57 (19). Reference example 10 Under an argon atmosphere, [3-ethenyl-7-exo-t-
Butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (245 mg, 0.63 mmol) was dissolved in THF (4 ml), and the mixture was stirred at 0 ° C. Ruborane in THF (0.91M, 1.7
(ml, 1.58 mmol) was added dropwise and the mixture was stirred at 0 ° C. for 1 hour. 0 ° C
At 6 N sodium hydroxide solution (1.13 ml, 6.78 mmol) and 3
After adding 0% hydrogen peroxide solution (0.94 ml, 8.29 mol), the mixture was stirred at room temperature for 1 hour. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated saline. After drying over anhydrous magnesium sulfate,
The solvent was distilled off. The residue was purified by silica gel column chromatography (ether: n-hexane = 1: 3) to give [3- (2-hydroxyethyl) -7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyl. Oxy-cis-bicyclo [4.3.0] non-2-ene] (259 mg, 100%) was obtained.

IR (neat): 3450,2930,2860,1475,1255,1200,835,775cm
_{^{. -1 NMR (CDCl 3) δ}} : 5.40 (bs, 1H), 4.56 (bs, 1H), 0.90
(S, 9H), 0.05 (s, 6H). Mass m / z (%): 410 (M ⁺ , trace), 326 (7), 269
(9), 177 (44), 159 (91), 85 (100), 41 (30). Reference example 11 Chromic acid (610 mg, 6.1 mmol) was suspended in methylene chloride (10 ml) under an argon atmosphere, and pyridine (1 ml, 12.2 mmol) was added dropwise. After stirring at room temperature for 15 minutes, [3- (2-hydroxyethyl) -7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] nona-2. -En] (259
A methylene chloride solution (10 ml) of (mg, 0.61 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was diluted with ether, filtered by flow lysyl column chromatography (ether), and washed with ether. After distilling off the solvent,
Pyridine was sufficiently distilled off with a vacuum pump. Silica gel column chromatography (ether: n-hexane = 1:
Purified by 5) [3- (1-formylmethyl) -7-
Exo-t-butyldimethylsilyloxymethyl-8-
Endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (180 mg, 73%) was obtained.

IR (neat): 2950,2850,1730,1475,1255,1200,835,775cm
_{^{. -1 NMR (CDCl 3) δ}} : 9.56 (t, 1H), 5.50 (bs, 1H), 4.55 (b
s, 1H), 2.94 (d, 1H), 0.90 (s, 9H), 0.05 (s, 6H). Mass m / z (%): 324 (M ⁺ −84,4), 267 (27), 249 (1
3), 159 (100), 85 (100). Reference example 12 [3- (1-formylmethyl) -7 under an argon atmosphere
-Exo-t-butyldimethylsilyloxymethyl-8
-Endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (180 mg, 0.44 mmol) was dissolved in toluene (1.5 ml). (Methoxycarbonylmethylene) triphenylphosphorane (220 mg, 0.66 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ether: n-hexane = 1: 4) [3- (3-methoxycarbonyl-2-propenyl) -7-exo-t-butyldimethylsilyl. Oxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-
En] (201 mg, 98%) was obtained.

IR (neat): 2910,2840,1720,1640,1455,1420,1190,825,
765 cm ^-1 .NMR (CDCl ₃ ) δ: 6.60 (dt, J = 16.7Hz, 1H), 5.84 (d, J =
16.7Hz, 1H), 5.42 (bs, 1H), 4.60 (bs, 1H), 3.71 (s, 3
H), 2.80 (d, 2H), 0.90 (s, 9H), 0.05 (s, 6H). Mass m / z (%): 380 (M ⁺ −84,13), 323 (24), 231 (3
4), 199 (8), 159 (100), 85 (100), 57 (33). Reference example 13 In an argon atmosphere, cuprous bromide (1 g, 7 mmol) was added to THF (3 m
l). Viride (70% toluene solution, 1.97 ml, 14 mmol) was added dropwise at -20 ° C, and the mixture was stirred for 30 minutes. -78 ° C
2-butanol (1.4 ml, 15.8 mmol) and [3- (3
-Methoxycarbonyl-2-propenyl) -7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.
[0] Nona-2-ene] (201 mg, 0.43 mmol) in THF (8 m
l) was added. The mixture was stirred at -20 ° C for 1 hour and 30 minutes. Water and a saturated ammonium chloride aqueous solution were added to the reaction solution, and the mixture was diluted with ether. The mixture was stirred at room temperature until the aqueous layer turned blue, then extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ether: n-hexane = 1: 5) [3- ( 3-Methoxycarbonylpropyl) -7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (200 mg, 100%) was obtained. It was

IR (neat): 2900,2830,1735,1455,1425,1225,1195,830,
775 cm ^-1 .NMR (CDCl ₃ ) δ: 5.30 (bs, 1H), 4.62 (bs, 1H), 3.56
(S, 3H), 0.90 (s, 9H), 0.05 (s, 6H). Mass m / z (%): 466 (M ⁺ , trance), 382 (2), 325
(7), 233 (13), 201 (12), 159 (34), 85 (100), 28
(twenty three). Example 1 Under an argon atmosphere, [3- (3-methoxycarbonylpropyl) -7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-
Cis-bicyclo [4.3.0] non-2-ene] (200 mg, 0.4
3 mmol) was dissolved in THF (2.5 ml). Tetra-n-butylammonium fluoride (1M THF solution, 0.86ml, 0.86mm
ol) was added and the mixture was stirred at room temperature for 24 hours. After adding saturated saline, the mixture was extracted with ether, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ether: n-hexane = 3: 1) to give [3- (3-methoxycarbonylpropyl) -7-exo-hydroxymethyl-8-endo-tetrahydropyranyloxy-cis. -Bicyclo [4.3.0] non-2-ene] (154 mg, 100%) was obtained.

IR (neat): 3500, 2950, 2870, 1740, 1440, 1200 cm ^-1 NMR (CDCl ₃ ) δ: 5.32 (bs, 1H), 4.62 (bs, 1H), 3.65
(S, 3H). Mass m / z (%): 352 (M ⁺ , trance), 268 (7), 219 (1
1), 131 (9), 85 (100), 41 (16). Reference example 14 Under an argon atmosphere, [3- (3-methoxycarbonylpropyl) -7-exo-hydroxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.
[0] Nona-2-ene] (60 mg, 0.17 mmol) was dissolved in dimethyl sulfoxide (2 ml). Triethylamine (0.11m
l, 1.02mmol) and sulfur trioxide-pyridine complex (162mg,
1.02 mmol) in dimethyl sulfoxide solution (2 ml) was added, and the mixture was stirred at room temperature for 1 hour. Ice water was added, extracted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and [3- (3-methoxycarbonylpropyl) -7-exo-formyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.
3.0] Nona-2-ene] (57 mg, 96%) was obtained.

On the other hand, sodium hydride (60% oil, 16 mg, 0.4 mmol) was washed with pentane under an argon atmosphere and suspended in THF (2 ml). A THF solution (10 ml) of dimethyl (2-oxoheptyl) phosphonate (118 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. A solution of [3- (3-methoxycarbonylpropyl) -7-exo-formyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (57 mg) in THF (3 ml) was added. The mixture was stirred at room temperature for 1 hour. After adding a saturated ammonium chloride aqueous solution, extraction was performed with ether, and the ether layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ether: n-hexane = 1: 2) [3-
(3-Methoxycarbonylpropyl) -7-exo-
(3-oxo-trans-1-octenyl) -8-endo-tetrohydropyranyloxy-cis-bicyclo [4.
3.0] Nona-2-ene] (62 mg, 84%) was obtained.

IR (neat): 2930,2860,1740,1690,1670,1620,1430,120
0,1025,865,730 cm ^-1 .NMR (CDCl ₃ ) δ: 6.80 (m, 1H), 6.16 (dd, J = 16.7Hz, 1
H), 5.33 (bs, 1H), 4.60 (m, 1H), 3,65 (s, 3H), 0.90
(T, 3H). Mass m / z (%): 344 (13), 318 (8), 248 (7), 166
(36), 85 (100), 57 (21). Reference example 15 In the same manner as in Reference Example 14, dimethyl (2-oxo-3,7
By reaction with -dimethyl-5-heptynyl) phosphonate [3- (3-methoxycarbonylpropyl) -7-
Exo- (3-oxo-4-methyl-trans-1-nonene-6-ynyl) -8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene]
(84%) was synthesized. The spectrum data is shown.

IR (neat): 2950,2900,1740,1700,1675,1630,1440,121
0,1040 cm ^-1 .NMR (CDCl ₃ ) δ: 6.63 (m, 1H), 6.23 (dd, J = 16.7,4Hz, 1
H), 5.30 (bs, 1H), 4.56 (m, 1H), 3,63 (s, 3H), 1.23−
1.00 (m, 6H). Reference example 16 Under an argon atmosphere, [3- (3-methoxycarbonylpropyl) -7-exo- (3-oxo-trans-1-
Octenyl) -8-endo-tetrahydroxy-cis-
Bicyclo [4.3.0] non-2-ene] (46 mg, 0.14 mmol)
Was dissolved in methanol (3 ml). Cool to −25 ° C. and add excess sodium borohydride. After stirring for 20 minutes at -25 ° C, excess acetone was added. After returning to room temperature,
A saturated ammonium chloride aqueous solution was added, and methanol and acetone were distilled off under reduced pressure. The residual aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to remove [3- (3-methoxycarbonylpropyl) -7-exo- (3-hydroxy-trans-1-octenyl)-
8-Endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (47 mg, 100%) was obtained.

IR (neat): 3450,2930,2860,1740,1200,1030,910,730cm
^-1 . NMR (CDCl ₃ ) δ: 5.60 (m, 2H), 5.30 (bs, 1H), 4.66 (b
s, 1H), 3.33 (s, 3H), 0.88 (t, 3H). Mass m / z (%): 346 (7), 302 (22), 279 (3), 149
(21), 85 (100), 57 (21). Reference example 17 [3- (3-Methoxycarbonylpropyl) -7-exo- (3-hydroxy-4-methyl-trans-1-nonen-6-ynyl) -8-endo-tetrahydropyranyl was prepared in the same manner as in Reference Example 16. Oxy-cis-bicyclo (4.
3.0] Nona-2-ene] (78.1%) was synthesized. The spectrum data is shown.

IR (neat): 3400, 2950, 2900, 1750, 1200, 1020 cm ^-1 NMR (CDCl ₃ ) δ: 5.60 (m, 2H), 5.33 (bs, 1H), 4.63 (b
s, 1H), 3.33 (s, 3H), 1.33-0.96 (m, 6H). Reference example 18 [3- (3-Methoxycarbonylpropyl) -7-exo- (3-hydroxy-trans-1-octenyl)-
7-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (45 mg, 0.1 mmol) was mixed with acetic acid: THF: water (0.7 ml) (3: 1: 1, volume ratio). Dissolve in liquid,
The mixture was stirred at 50 ° C for 2 hours. After cooling, it was neutralized with diluted saturated aqueous sodium hydrogen carbonate with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium acetate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ether: n-hexane = 5: 1) to give a more polar fraction [3- (3-methoxycarbonylpropyl) -7. -Exo- (3α-hydroxy-
Trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene] (9 mg, 25
%) And less polar polar function [3- (3
-Methoxycarbonylpropyl) -7-exo- (3β
-Hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-
En] (12 mg, 25%) was obtained. The spectrum data of the α-epimer is shown below. The same applies to the spectrum of the β-epimer body.

IR (neat): 3410, 2980, 2940, 1742 cm ^-1 . NMR (CDCl ₃ ) δ: 5.57 (m, 2H), 5.36 (bs, 1H), 3.69 (s,
3H), 0.89 (m, 3H). Mass m / z (%): 346 (M ⁺ −H ₂ O, 13), 302 (36), 149,
(100), 79 (12), 43 (86). Reference example 19 [3- (3-methoxycarbonylpropyl) -7-exo- (3α-hydroxy-4-] was prepared in the same manner as in Reference Example 18.
Methyl-trans-1-nonene-6-ynyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] nona-2
-Ene] (44%) and its β-epimer (31%) were synthesized. The spectral data of an α-epimer body is shown. β
The same for the spectra of the epimers.

IR (neat): 3400, 2930, 2870, 1740 cm ^-1 . NMR (CDCl ₃ ) δ: 5.63 (m, 2H), 5.30 (bs, 1H), 3.30 (s,
3H), 1.23-0.88 (m, 6H). Reference example 20 Under an argon atmosphere, [3- (3-methoxycarbonylpropyl) -7-exo- (3α-hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis-
Bicyclo [4.3.0] non-2-ene] (9 mg, 0.025 mmol)
Was dissolved in methanol (0.2 ml). At 0 ° C., 10% aqueous sodium hydroxide solution (0.2 ml) was added, and the mixture was stirred overnight. After neutralizing with 1N hydrochloric acid solution at 0 ° C., methanol was distilled off, and the residual aqueous layer was adjusted to pH 4 with 1N hydrochloric acid solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to remove [3- (3-carboxypropyl) -7-exo- (3α-hydroxy-trans-1-octenyl) -8-endo-hydroxybicyclo [4.3.0] non-2-ene] ( 8.9 mg, 100%) was obtained.

IR (neat): 3375, 2970, 2860, 1720, 1125 cm ^-1 . NMR (CDCl ₃ ) δ: 5.60 (m, 2H), 5.35 (bs, 1H), 0.90 (t,
3H). Mass m / z (%): 332 (M ⁺ −H ₂ O, 10), 288 (18), 218 (1
0), 208 (13), 138 (50), 91 (53), 43 (100). Similarly, the 15β-epimer is also hydrolyzed to [3- (3-
Carboxypropyl) -7-exo- (3β-hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene] was obtained. Spectral data (IR, NMR, Mass) is [3- (3-
Data similar to carboxypropyl) -7-exo- (3α-hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene].

Reference example 21 In the same manner as in Reference Example 20, [3- (3-carboxypropyl) -7-exo- (3α-hydroxy-4-methyl-
Trans-1-nonene-6-ynyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene]
(97%) and its β-epimer (98%) were synthesized.
The spectral data of an α-epimer body is shown. The same applies to the spectrum of the β-epimer body.

IR (neat): 3370, 2940, 2850, 1710, 1450 cm ^-1 . NMR (CDCl ₃ ) δ: 5.60 (m, 2H), 5.30 (bs, 1H), 1.03-0.
88 (t, 6H). Reference example 22 Under an argon atmosphere, 3-carboxypropyltriphenylphosphonium bromide (1.1 g, 2.5 mmol) was added to THF (10 m
l). Potassium t-butoxide (560mg, 5mmol)
THF solution (10 ml) was added, and the mixture was stirred at room temperature for 20 minutes. There [3-formyl-7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene]
(200 mg, 0.5 mmol) in THF (5 ml) was added dropwise at room temperature to 3
Stir for 0 minutes. Add saturated ammonium chloride solution,
The reaction solution was adjusted to pH 5 to 4 with a 10% aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Add ether to the residue,
An ether solution of diazomethane was added at 0 ° C. By thin layer chromatography [3- (4-carboxy-1-
After confirming the disappearance of the spot of butenyl) -7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene], a small amount of formic acid was added. In addition, the mixture was immediately washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The residue obtained by drying over anhydrous magnesium sulfate and distilling off the solvent was subjected to silica gel column chromatography (ether: n-hexane = 1: 1).
4) and then [3- (4-methoxycarbonyl-
1-butynyl) -7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (210
mg, 88%) was obtained. The isomer ratio of the (Z) -form and the (E) -form was 2: 1.

IR (neat): 2950,2860,1740,1430,1255,1200,1030,835c
m ^-1 .NMR (CDCl ₃ ) δ: 6.12 (d, J = 16.5Hz, 1 / 3H, trans), 5.96
(D, J = 12Hz, 2 / 3H, cis), 5.63 (bs, 1H), 5.30 (m, 1H),
4.65 (bs, 1H), 3.70 (s, 3H), 0.90 (s, 9H). Mass m / z (%): 479 (M ⁺ −1, trace), 337 (12), 245
(14), 213 (9), 159 (34), 85 (100), 57 (17). Example 2 Under an argon atmosphere, [3- (4-methoxycarbonyl-
1-butenyl) -7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (160
mg, 0.33 mmol) was dissolved in THF (0.5 ml). Tetra-n
-Butyl ammonium fluoride (1M THF solution, 0.68 ml,
0.68 mmol) was added and the mixture was stirred at room temperature for 24 hours. After adding saturated saline, the mixture was extracted with ether, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ether: n-hexane = 1: 1) to give [3- (4-methoxycarbonyl-1-butenyl) -7-exo-hydroxymethyl-8-endo-tetrahydropyranyl. Oxy-cis-bicyclo (4.3.0)
Nona-2-ene] (108 mg, 90%) was obtained.

IR (neat): 3490,2950,2880,1740,1435,1200,1020,865c
m ^-1 .NMR (CDCl ₃ ) δ: 6.30 (d, J = 16.5Hz, 1 / 3H, trans), 5.83
(D, J = 12Hz, 2 / 3H, cis), 5.60 (bs, 1H), 5.30 (m, 1H),
4.68 (m, 1H), 3.70 (s, 3H). Mass m / z (%): 364 (M ⁺ trace), 280 (15), 199
(5), 117 (11), 85 (100), 28 (29). Reference example 23 Under an argon atmosphere, [3- (4-methoxycarbonyl-
1-butenyl) -7-exo-hydroxymethyl-8-
Endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (108 mg, 0.3 mmol) was dissolved in dimethyl sulfoxide (2 ml). A solution of triethylamine (0.25 ml, 1.8 mmol) and sulfur trioxide-pyridine complex (286 mg, 1.8 mmol) in dimethyl sulfoxide (2 ml)
Was added, and the mixture was stirred at room temperature for 1 hour and 10 minutes. Ice water was added, extracted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and [3- (4
-Methoxycarbonyl-1-butenyl) -7-exo-
Formyl-8-endo-tetrahydropyranyloxy-
Cis-bicyclo [4.3.0] non-2-ene] (106 mg, 100
%) Was obtained. On the other hand, sodium hydride (oil 60%, 18 mg,
0.45 mmol) was washed with pentane under an argon atmosphere,
Suspended in THF (5 ml). Dimethyl (2-oxoheptyl) phosphonate (133 mg, 0.6 mmol) in THF (5 ml)
Was added, and the mixture was stirred at room temperature for 40 minutes. [3- (4-methoxycarbonyl-1-butenyl) -7-exo-formyl-
8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (106 mg) in THF (5
ml) was added and the mixture was stirred at room temperature for 40 minutes. After adding a saturated ammonium chloride aqueous solution, the mixture was extracted with ether, and the ether layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the obtained residue was subjected to silica gel column chromatography (ether: n-hexane = 1: 3).
Purified by [3- (4-methoxycarbonyl-1-butenyl) -7-exo- (3-oxo-trans-1-
Octenyl) -8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (112m
g, 84%) was obtained.

IR (neat): 2940,2880,1740,1700,1675,1625,1430,120
0,1030 cm ^-1 .NMR (CDCl ₃ ) δ: 6.81 (m, 1H), 6.22 (dd, J = 16.5,3Hz, 1
H), 6.08 (d, J = 15Hz, 1 / 3H trans), 5.82 (d, J = 12Hz,
2 / 3H cis), 5.56 (bs, 1H), 5.30 (m, 1H), 4.62 (m, 1
H), 3.70 (s, 3H), 0.88 (t, 3H). Mass m / z (%): 376 (8), 332 (12), 85 (100), 57
(18), 55 (13), 41 (2). Reference example 24 Under an argon atmosphere, [3- (4-methoxycarbonyl-
1-butenyl) -7-exo- (3-oxa-trans-1-octenyl) -8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene]
(110 mg, 0.24 mmol) was dissolved in methanol (2 ml).
Cool to −25 ° C. and add excess sodium borohydride. After stirring at -25 ° C for 30 minutes, a small amount of acetone and a saturated aqueous solution of ammonium chloride were added, and methanol and acetone were distilled off under reduced pressure. The residual aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off [3-
(4-Methoxycarbonyl-1-butenyl) -7-exo- (3-hydroxy-trans-1-octenyl)-
8-Endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (112 mg, 100%) was obtained.

^{IR (neat):. 3450,2900,2850,1738,1430,1200,1020cm -1} NMR (CDCl 3) δ: 6.11 (d, J = 16.5Hz, 1 / 3H, trans), 5.82
(D, J = 12Hz, 2 / 3H, cis), 5.58 (m, 3H), 5.25 (m, 1H),
4.68 (bs, 1H), 3.70 (s, 3H), 0.88 (t, 3H). Mass m / z (%): 422 (M ⁺ −H ₂ O, trace), 358 (10), 314
(11), 234 (31), 150 (21), 85 (100), 41 (42). Reference example 25 [3- (4-methoxycarbonyl-1-butenyl) -7
-Exo- (3-hydroxy-trans-1-octenyl) -8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene (112 mg, 0.24 mmo
l) was dissolved in a mixed solution of acetic acid: water: THF (2 ml) (3: 1: 1, volume ratio) and stirred at 50 ° C. for 4 hours and 30 minutes. After cooling, it was diluted with ethyl acetate and neutralized with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ether: n-hexane = 5: 1) to give [3- (4-methoxycarbonyl-1-butenyl) as a highly polar fraction. ) -7-exo- (3
α-Hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] nona-2
-Ene] (34 mg, 38%) and [3- (4-methoxycarbonyl-1-butenyl) -7-exo- (3β-hydroxy-trans-1 as a less polar fraction.
-Octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene] (26 mg, 26%) respectively was obtained. The spectrum data of the α-epimer is shown below. The same applies to the spectrum of the β-epimer body.

IR (neat): 3400, 2950, 2880, 1745, 1440, 740 cm ^-1 . NMR (CDCl ₃ ) δ: 6.06 (d, J = 16Hz, 1 / 3H, trans), 5.81
(D, J = 12Hz, 2 / 3H, cis), 5.53 (m, 3H), 5.25 (m, 1H),
3.70 (s, 3H), 0.86 (t, 3H). Mass m / z (%): 358 (M ⁺ −H ₂ O, 19), 314 (11), 244,
(28), 227 (9), 117 (45) 91 (59), 43 (100). Reference example 26 Under an argon atmosphere, [3- (4-methoxycarbonyl-
1-butenyl) -7-exo- (3α-hydroxy-trans-1-octenyl) -8-endo-hydroxy-
Cis-bicyclo [4.3.0] non-2-ene] (30 mg, 0.08
mmo) was dissolved in methanol (0.7 ml). 10% at 0 ° C
Aqueous sodium hydroxide solution (0.7 ml) was added, and the mixture was stirred overnight. After neutralizing with 1N hydrochloric acid solution at 0 ° C., methanol was distilled off, and the residual aqueous layer was adjusted to pH 4 with 1N hydrochloric acid solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to remove [3- (4-carboxy-1-butenyl) -7-exo- (3α-hydroxy-
Trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene] (28 mg, 97
%) Was obtained.

IR (neat): 3375, 2950, 2870, 1720, 1440, 1120, 965 cm ^-1 . NMR (CDCl ₃ ) δ: 6.10 (d, J = 16Hz, 1 / 3H, trans), 5.85
(D, J = 12Hz, 2 / 3H, cis), 5.63 (m, 3H), 5.40-5.13 (m,
3H), 0.90 (t, 3H). Mass m / z (%): 344 (M ⁺ −H ₂ O, 12), 300 (12), 230 (1
2), 220 (15), 150 (48), 91 (56), 43 (100). Similarly, the 15β-epimer is also hydrolyzed to [3- (4-
Carboxy-1-butenyl) -7-exo- (3β-hydroxy-trans-1-octenyl) -8-endo-
Hydroxy-cis-bicyclo [4.3.0] non-2-ene] was obtained. Spectral data (IR, NMR, Mass)
[3- (4-Carboxy-1-butenyl) -7-exo- (3α-hydroxy-trans-1-octenyl)-
Similar to the data for 8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene].

Reference example 27 [3- (4-methoxycarbonyl-1-butenyl) -7
-Exo-t-butyldimethylsilyloxymethyl-8
-Endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (190 mg, 0.4 mmol) was dissolved in methanol (5 ml). 10% palladium / carbon (60m
A methanol solution (5 ml) of g) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes in a hydrogen atmosphere. The catalyst was filtered off and the solvent of the filtrate was distilled off. The residue was purified by silica gel chromatography (ether: n-hexane = 1: 8), [3- (4
-Methoxycarbonylbutyl) -7-exo-t-butyldimethylsilyloxymethyl-8-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (187 mg, 97%) was obtained.

IR (neat): 2930, 2850, 1740, 1200, 835 cm ^-1 . NMR (CDCl ₃ ) δ: 5.35 (bs, 1H), 4.63 (bs, 1H), 3.66
(S, 3H), 0.90 (s, 9H). Mass m / z (%): 339 (8), 247 (12), 159 (28), 85
(100), 75 (17). Example 3 Under an argon atmosphere, [3- (4-methoxycarbonylbutyl) -7-exo-t-butylcymethylsilyloxymethyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene ] (93mg, 0.19mm
ol) was dissolved in THF (3 ml). Tetra-n-butylammonium fluoride (1M in THF, 0.48ml, 0.48mmol)
Was added, and the mixture was stirred at room temperature for 13 hours. After adding saturated saline, the mixture was extracted with ether, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ether: n-hexane = 3: 1) to give [3- (4-methoxycarbonylbutyl) -7-exo-hydroxymethyl-8-endo-tetrahydropyranyloxy-cis. -Bicyclo [4.3.0] non-2-ene] (62 mg, 89%) was obtained.

IR (neat): 3450, 2930, 2850, 1740, 1020 cm ^-1 . NMR (CDCl ₃ ) δ: 5.35 (bs, 1H), 4.65 (bs, 1H), 3.66
(S, 3H). Mass m / z (%): 366 (M ⁺ , trace), 282 (5), 85 (10
0), 65 (11), 57 (10), 41 (11). Reference example 28 Under an argon atmosphere, [3- (4-methoxycarbonylbutyl) -7-exo-hydroxymethyl-8-endo-
Tetrahydropyranyloxy-cis-bicyclo (4.3.
[0] Nona-2-ene] (51 mg, 0.14 mmol) was dissolved in dimethyl sulfoxide (3 ml). Triethylamine (0.12m
l, 0.84mmol) and sulfur trioxide-pyridine complex (133mg,
0.84 mmol) of dimethyl sulfoxide solution (2 ml) was added, and the mixture was stirred at room temperature for 1 hour. Ice water was added, extracted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and [3- (4-methoxycarbonylbutyl) -7-exo-formyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.
0] Nona-2-ene] (53 mg, 100%) was obtained.

On the other hand, sodium hydride (oil 60%, 9.2mg, 0.23mmol)
Was washed with pentane and suspended in THF (2 ml). Dimethyl (2-oxoheptyl) phosphonate (62mg, 0.28mmo
1) THF solution (3 ml) was added, and the mixture was stirred at room temperature for 40 minutes.
[3- (4-Methoxycarbonylbutyl) -7-exo-formyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (53 mg)
THF solution (3 ml) was added and the mixture was stirred at room temperature for 1 hour. After adding a saturated ammonium chloride aqueous solution, extraction was performed with ether, and the ether layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ether: n-hexane = 1: 3) to give [3- (4-methoxycarbonylbutyl) -7- Exo- (3-oxo-trans-1-octenyl) -8-endo-tetrahydropyranyloxy-cis-bicycyclo [4.3.0] non-2-ene] (51 mg, 80%) was obtained.

IR (neat): 2930,2880,1740,1700,1675,1625,1200,1030
cm ^-1 .NMR (CDCl ₃ ) δ: 6.83 (m, 1H), 6.20 (dd, J = 15,3.5Hz, 1
H), 5.33 (bs, 1H), 4.65 (m, 1H), 3.70 (s, 3H). Mass m / z (%): 376 (10), 312 (13), 85 (100), 67
(16), 57 (20), 43 (21), 41 (20). Reference example 29 Under an argon atmosphere, [3- (4-methoxycarbonylbutyl) -7-exo- (3-oxo-trans-1-octenyl) -8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] nona- 2-ene] (120 mg,
0.26 mmol) was dissolved in methanol (5 ml). Cool to −25 ° C. and add excess sodium borohydride. −25
After stirring for 30 minutes at ° C, excess acetone was added. After returning to room temperature, a saturated aqueous solution of ammonium chloride was added, and methanol and acetone were distilled off under reduced pressure. The residual aqueous layer was extracted with ethyl acetate and dried over anhydrous magnesium sulfate,
The solvent was distilled off to give [3- (4-methoxycarbonylbutyl) -7-exo- (3-hydroxy-trans-1-
Octenyl) -8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (118
mg, 98%) was obtained.

IR (neat): 3450, 2930, 2850, 1740, 1020 cm ^-1 . NMR (CDCl ₃ ) δ: 5.58 (m, 2H), 5.31 (bs, 1H), 4.67 (b
s, 1H), 3.66 (s, 3H), 0.86 (t, 3H). Mass m / z (%): 444 (M ⁺ −H ₂ O, trace), 316 (13), 85
(100), 67 (12), 57 (18), 55 (10), 43 (17), 41 (2
0). Reference example 30 [3- (4-Methoxycarbonylbutyl) -7-exo- (3-hydroxy-trans-1-octenyl) -8
-Endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (115 mg, 0.25 mmol) acetic acid: water: THF (2.5 ml) (3: 1: 1, volume ratio) mixture And was stirred at 50-55 ° C for 4 hours. After cooling, it was diluted with ethyl acetate and neutralized with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ether) to give [3- (4-methoxycarbonylbutyl) -7-exo- (3α-hydroxy- Transformer-1
-Octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene] (42 mg, 44%) and [3- (4-methoxycarbonylbutyl) -7- as the less polar fraction. Exo- (3β-hydroxy-
Trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene] (29 mg, 31
%) Respectively. The spectrum data of the α-epimer is shown below. The same applies to the spectrum of the β-epimer body.

IR (neat): 3400, 2940, 2870, 1740 cm ^-1 . NMR (CDCl ₃ ): 5.56 (m, 2H), 5.33 (bs, 1H), 4.10 (m, 1
H), 3.68 (s, 3H), 0.88 (t, 3H). Mass m / z (%): 358 (M ⁺ −H ₂ O, 21), 342 (18), 329
(9), 316 (75), 289 (15), 261 (11), 246 (32), 199
(17), 193 (20), 179 (27). Reference example 31 Under an argon atmosphere, [3- (4-methoxycarbonylbutyl) -7-exo- (3α-hydroxy-trans-
1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene] (38 mg, 0.1 mmol) was dissolved in methanol (1 ml). A 10% aqueous sodium hydroxide solution (1 ml) was added at 0 ° C., and the mixture was stirred overnight. 0 ° C
Then, after neutralizing with 1N hydrochloric acid solution, the methanol was distilled off,
The residual aqueous layer was adjusted to pH 4 with a 1N hydrochloric acid solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation [3- (4-carboxybutyl)
-7-exo- (3α-hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene] (35 mg, 96%) was obtained.

^{IR (neat):. 3350,2950,2850,1720,1450cm -1} NMR (CDCl 3): 5.60 (m, 2H), 5.33 (bs, 1H), 3.73 (s, 3
H), 0.88 (t, 3H). Mass m / z (%): 346 (M ⁺ −H ₂ O, 10), 302 (17), 232 (1
4), 91 (50), 43 (100). Similarly, the 15β-epimer is also hydrolyzed to [3- (4-
Carboxybutyl) -7-exo- (3β-hydroxy-trans-1-octenyl) -8-hydroxy-cis-bicyclo [4.3.0] non-2-ene] was obtained. Data (IR, NMR, Mass) are [3- (4-carboxybutyl)-
Similar to the data for 7-exo- (3α-hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene.

Test Example 3- (4-Carboxy-1-butenyl) -7-exo- (3α-hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis- synthesized by the above method
Bicyclo [4.3.0] non-2-ene, 3- (3-carboxypropyl) -7-exo-3- (3α-hydroxy-4-methyl-trans-1-nonene-6-ynyl)-
8-endo-hydroxy-cis-bicyclo [4.3.0] non-2-ene and 3- (4-carboxybutyl) -7
-Exo- (3α-hydroxy-trans-1-octenyl) -8-endo-hydroxy-cis-bicyclo [4.
3.0] Nona-2-ene exhibits the following rabbit platelet aggregation inhibitory action.

As the platelet aggregating agent, as shown in Table 1, ADP or collagen was used.

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ represents a CO ₂ R ³ group (in the group, R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 12 carbon atoms), and A represents —CH ₂ CH ₂ CH ₂ --CH ₂ CH ₂ CH ₂ CH ₂ --or --CH = CHCH ₂ CH _2- , R ² is a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, a tribenzylsilyl group, a t-butyldimethylsilyl group, It represents a diphenyl-t-butylsilyl group, a p-methoxybenzyl group, a 1-methyl-1-methoxyethyl group, a benzyl group, a tetrahydropyranyl group, a 1-ethoxyethyl group or a methoxymethyl group. The double bond in the substituent represented by A is E or Z or a mixture thereof].