JPH038328B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, R ¹ is a straight chain, branched or cyclic alkyl group or alkenyl group having 5 to 10 carbon atoms, and R ² is a hydrogen atom, a tetrahydropyranyl group,
Methoxymethyl group, 4-methoxytetrahydropyranyl group, 1-ethoxyethyl group, 1-methyl-
1-methoxyethyl group, t-butyldimethylsilyl group, diphenyl-t-butylsilyl group, benzoyl group or acetyl group, R ³ is a hydrogen atom,
t-butyldimethylsilyl group, benzoyl group, acetyl group, tetrahydropyranyl group, methoxymethyl group, 4-methoxytetrahydropyranyl group,
It is a 1-ethoxyethyl group, a 1-methyl-1-methoxyethyl group, or a diphenyl-t-butylsilyl group, and ^R4 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. ) (3'-alkoxy-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivatives. Represented by the general formula () of the present invention (3'-
Alkoxy-1'-alkenyl)-cis-hycyclo[3.3.0]octene derivatives selectively reduce the double bond of the α-chain and hydrolyze the ester by deprotecting the hydroxyl protecting group. Accordingly, 9(0)-
This can lead to methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ and its analogs (see Reference Examples below). 9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ has a strong platelet aggregation inhibiting effect, and for example, when human platelets are used, its effect is comparable to that of the chemically unstable PGI ₂ . , a compound used as a therapeutic or preventive drug for various cardiovascular diseases. Conventionally, methods for producing 9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ include (a) a method in which PGE ₂ is used as a raw material through 14 steps [Proceedings of the 103rd Annual Meeting of the Pharmaceutical Society of Japan] 156
(1983)] and (b) A method for producing it from 1,3-cyclooctadiene through 19 steps [Pharmaceutical Society of Japan No.
Proceedings of the 103rd Annual Meeting, p. 157 (1983)] is known, but method (a) requires expensive raw materials, method (b) produces the target product as a racemate, and method (a) (b) Both had a drawback that the total yield was very low. The present inventors have discovered that 9(0)-methano-
As a result of intensive research to produce Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ and its analogues, we discovered that the compound of the present invention could serve as an important intermediate to achieve the objective, and completed the present invention. did. Represented by the general formula () of the present invention (3'-
The alkoxy-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivative can be produced according to the following reaction formula. In addition, the protecting group for hydroxyl group in the present invention is a ^{tetrahydropyranyl} group, a methoxymethyl group,
4-methoxytetrahydropyranyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, t-butyldimethylsilyl group, diphenyl-
Examples include t-butylsilyl group, benzoyl group, acetyl group, etc., and as ^R3 , t-butyldimethylsilyl group, benzoyl group, acetyl group,
Tetrahydropyranyl group, methoxymethyl group, 4
Examples include -methoxytetrahydropyranyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, diphenyl-t-butylsilyl group, and the like. (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as above.) [First step] This step methyleneates the allylcyclopentanone derivative represented by the above general formula (). In this way, the allylcyclopentylidene derivative represented by the general formula () is produced. The allylcyclopentanone derivative represented by the above general formula (), which is the raw material for this step, has the general formula (In the formula, R ² represents a hydroxyl group protecting group.) Cyclopentenones represented by the general formula (In the formula, R ¹ is the same as defined above, R ³ represents the same meaning as above, and X is a group

[Second step]

In this step, the hydroxymethylcyclopentane derivative represented by the general formula () is produced by subjecting the allylcyclopentylidene derivative represented by the general formula () obtained in the first step to a hydration reaction. The hydration reaction in this step is carried out by hydroboration and oxidation. In the hydroboration, for example, a hydroboration reagent such as 9-BBN (9-borabicyclo[3,3,1]nonane), dithiamylborane, thexylborane, etc. can be used. The amount of the hydroboration reagent used is usually 1 to 3 equivalents. The reaction is preferably carried out in a solvent, and for example, ether solvents such as tetrahydrofuran, diglyme, and diethyl ether can be used. The reaction proceeds smoothly at -25°C to room temperature. Additionally, the process involves hydroboration followed by oxidation without isolation of the product. For oxidation, for example, an oxidizing agent such as hydrogen peroxide can be used. When hydrogen peroxide is used for oxidation, it is preferable to use it in a basic state, such as sodium hydroxide. The amount of oxidizing agent used is 5 to 15 equivalents. The reaction proceeds smoothly at room temperature to 80°C. In this step, for example, the compound produced by hydroboration using 9-BBN is It is presumed that it has a structure like this. [Third Step] This step oxidizes and dehydrates the hydroxymethylcyclopentane derivative represented by the general formula () obtained in the second step to obtain bicyclo[3.3.0 ] This method produces octenyl aldehyde derivatives. In the oxidation, for example, dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide-sulfur trioxide pyridine complex, etc. can be used. The amount of the oxidizing agent to be used is usually 1 to 5 equivalents. The reaction is preferably carried out in a solvent, and for example, halogenated hydrocarbons such as methylene chloride can be used. The reaction varies depending on the type of oxidizing agent, but at -70℃
~Proceeds smoothly at room temperature. The oxidation product of this step is obtained by adding a tertiary amine such as triethylamine or diisopropylethylamine to the reaction mixture and treating at -70°C to room temperature. Subsequently, this step involves dehydration. Dehydration is carried out in the presence of an acidic catalyst. As acidic catalysts, acid-ammonium salts can be used. Acid-ammonium salt catalysts can be formed from acids and amines. Examples of acids that can be used include trifluoroacetic acid, toluenesulfonic acid, camphorsulfonic acid, and acetic acid. In addition, amines that can be used include dibenzylamine, diethylamine,
Examples include dimethylamine, diisopropylamine, piperidine, pyrrolidine, and piperazine. These acids and amines can be appropriately selected and used in combination, but a catalyst containing a combination of trifluoroacetic acid and dibenzylamine is particularly preferred since the desired product can be obtained in good yield. The amount of catalyst used may be around 0.2 equivalent, but
It is preferable to use about 1 equivalent in order to cause 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℃,
In order to carry out the reaction smoothly, it is preferable to carry out the reaction at a temperature in the range of 50°C to 70°C. [Fourth step] This step involves reacting the bicyclo[3.3.0]octenylaldehyde derivative represented by the general formula () obtained in the third step with 3-carboxypropylphosphonium bromide in the presence of a base. , (3'-alkoxy-1'-alkenyl)-cis-bicyclo [3.3.0] represented by the above general formula ()
This is to produce octene derivatives. This step needs to be carried out in the presence of a base. Potassium t-butoxy, butyl lithium, sodium salt of dimethyl sulfoxide, etc. can be used as the base, but potassium t-butoxy is preferably used in order to carry out the reaction efficiently. The amount of base to be used is usually 1% based on the raw material 3-carboxypropylphosphonium bromide.
~1.2 equivalents are used. To carry out the reaction, use tetrahydrofuran,
Ether solvents such as dimethoxyethane and diethyl ether can be suitably used, but there are no limitations as long as the solvent does not participate in the reaction. The reaction proceeds smoothly by selecting a reaction temperature in the range of 0°C to 50°C. The compound obtained in this step is usually produced as a free carboxylic acid, but for the reaction in the next step, it is isolated as an ester using the conditions of diazomethane or alkyl halide-diazabicycloundecene-acetonitrile. be able to. Conversion into an ester can be carried out using methods that can be easily performed by those skilled in the art. [Fifth Step] This step involves catalytically reducing the (3'-alkoxy-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivative represented by the general formula () obtained in the fourth step. , a bicyclo[3.3.0]octene derivative represented by the above general formula () is produced by selectively reducing only the disubstituted olefin of the α-chain. Examples of catalysts that can be used include palladium catalysts such as palladium-carbon and palladium black, Wilkinson's catalyst, platinum, and nickel, but Wilkinson's catalyst is preferably used in order to carry out the reaction efficiently. It is sufficient to use a so-called catalytic amount of the catalyst. In carrying out this step, hydrogen may be reacted at normal pressure or under increased pressure. It is desirable to use a solvent to carry out the reaction,
For example, alcohol solvents such as methanol and ethanol, ester solvents such as ethyl acetate, and aromatic solvents such as benzene can be used. The reaction proceeds smoothly by selecting a temperature in the range of -25°C to 60°C. The (3'-alkoxy-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivative of the present invention has asymmetric carbon atoms in the molecule; It includes R configuration or S configuration of carbon atoms, or a mixture thereof in any proportion. Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. {2(R)-allyl-3(R)-[3'(S)-t-
Butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone} (707 mg,
A zinc-titanium chloride-methylene bromide reagent (Zn-TiCl ₄ --CH ₂ Br ₂ /THF, 7.48 ml, about 1.3 equivalents) was added to a solution of 1.44 mmol) in methylene chloride (7 ml) at room temperature. After stirring for 30 minutes under the same conditions, the raw materials disappeared, so the reaction solution was poured into a two-layer system of ether and saturated aqueous sodium bicarbonate solution to stop the reaction. Then, the ether layer was separated and further extracted with ether. The combined ether layers were washed with saturated ammonium chloride water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain {2(R)-allyl-3(R)-[3′(S)-t
-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene} (652 mg, 88%)
was obtained as an almost colorless oil. IR (neat): 3080, 2930, 2850, 1650, 1460,
1360, 1250cm ^-1 . NMR δ (CDCl ₃ ) 5.70 (m, 1H), 5.41 (m, 2H), 4.75~5.10
(m, 4H), 4.02 (m, 1H), 3.76 (1H, m),
2.00～2.70(m.6H), 1.40(m, 8H), 0.88(s,
21H), 0.02(s, 12H). Mass m/z: 435 (M ⁺ −57), 421, 393, 323,
303, 289, 229, 147, 75, 73. {2(R)-allyl-3(R)-[3'(S)-t-
Butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene} (700mg,
1.42mmol) to 9-borabicyclo[3,3,1]
THF solution of nonane (9-BBN) (7.10 mmol,
14.2 ml) was added at room temperature and stirred for 3 hours. Next, 6N-NaOH aqueous solution (6.9ml) and 30% _H2O2 were added to the reaction system _.
Slowly add the aqueous solution (5.8 ml) dropwise at room temperature, and then
The mixture was stirred for 2 hours. The reaction solution was extracted with ether, and the ether layer was washed with an aqueous sodium thiosulfate solution and water. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give {1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3
(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-
butyldimethylsilyloxycyclopentane}
(502 mg, 67%) was obtained as a colorless oil. IR (neat): 3350, 2930, 2850, 1460, 1360,
1250cm ^-1 . NMR δ (CDCl ₃ ) 5.38 (m, 2H), 3.96 (m, 2H), 3.59 (m,
4H), 2.83 (m, 1H) 2.16 (m, 3H), 1.10~
1.80 (m, 15H), 0.87 (s, 21H), 0.04 (s,
12H) Mass m/z: 471 (M ⁺ -57), 453, 396, 379,
339, 325, 321, 247, 229, 75, 73. DMSO (0.83 ml,
A methylene chloride solution (4 ml) of 11.7 mmol) was added over 5 minutes at -78°C, and the mixture was stirred under the same conditions for 15 minutes. To this {1(S)-hydroxymethyl-2(S)
-(3'-Hydroxypropyl)-3(S)-[3'(S
)
-t-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxycyclopentane} (475mg,
A solution of 0.900 mmol) in methylene chloride (3 ml) was added dropwise, and the mixture was further stirred at -78°C for 15 minutes. Add triethylamine (2.50ml, 18.0mmol) under the same conditions,
The cooling bath was removed and stirred for 15 minutes. Methylene chloride was distilled off under reduced pressure, and benzene (8
ml) and dibenzylamine trifluoroacetate (220 mg, 0.900 mmol) and stirred at 70°C for 4 hours. The reaction solution was diluted with ether and diluted with ammonium chloride aqueous solution, saturated sodium hydrogen carbonate aqueous solution, and saturated brine. It was washed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel chromatography to obtain {3-formyl-6(S)-[3'(S)-t-butyldimethylsilyl] Oxy-1'-trans-octenyl]-7(R)-
t-Butyldimethylsilyloxy-(1S,5S)-
cis-bicyclo[3.3.0]oct-2-ene}
(441 mg, 97%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1680, 1460, 1360,
1250cm ^-1 . NMR δ (CDCl ₃ ) 9.82 (s, 1H), 6.73 (bs, 1H), 5.48 (m,
2H), 4.08 (m, 1H), 3,76 (m, 1H),
3.24 (m, 1H), 1.10~2.80 (m, 14H), 0.87,
0.90 (2s, 21H), 0.03 (s, 12H). Mass m/z: 449 (M ⁺ −57), 435, 359, 339,
317, 303, 202, 73. 3-Carboxypropyltriphenylphosphonium bromide (321 mg, 0.748 mmol) in THF
(3.0 ml), t-butoxypotassium (167 mg, 1.49 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. {3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7 was added to the resulting red-orange ylide solution.
(R)-t-butyldimethylsilyloxy-(1S,
A solution of 5S)-cis-bicyclo[3.3.0]oct-2-ene} (189 mg, 0.374 mmol) in THF (1.5 ml) was added and stirred for 30 minutes. The reaction solution was diluted with ether, and after confirming acidity (PH≈4) with a 10% aqueous HCl solution, the ether layer was separated. After further extraction with ether, the ether layers were combined, washed with saturated NaCl water, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was dissolved in a small amount of ether and converted into methyl ester with an ether solution of diazomethane. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-
[3'(S)-t-butyldimethylsilyloxy-
1'trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (194mg, 88%)
was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1750, 1460, 1360,
1250cm ^-1 . NMR δ (CDCl ₃ ) 6.27 (d, J=16Hz, 2/5H, trons), 6.02
(d, J=11Hz, 3/5H, cis), 5.51 (m,
4H), 4.07 (m, 1H), 3.70 (m, 1H), 3.69
(s, 3H), 2.97 (m, 1H), 1.10~2.70
(m.16H), 0.87, 0.90 (2S, 21H), 0.03
(s.12H). Mass m/z: 590 (M ⁺ ), 534, 533, 519,
458, 427, 401, 301, 75, 73. [α] ²⁰ _D = -37° (c = 0.614, CHCl ₃ ) {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)
-t-butyldimethylsilyloxy- (1S, 5S)
-cis-bicyclo[3.3.0]oct-2-ene}
(31mg, 0.05mM) in THF (0.5ml) and tetrabutylammonium fluoride THF solution (0.16mg, 0.05mM).
ml, 1M solution) was added thereto, and the mixture was stirred at room temperature for 15 hours.
After stopping the reaction with saturated ammonium chloride water,
THF was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel chromatography, and {3-
(4'-methoxycarbonyl-1'-butenyl)-6
(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (15
mg) obtained as a colorless caramel (79%). IR (neat): 3400, 2950, 1742 cm ^-1 . NMR δ (CDCl ₃ ) 6.30 (d, J = 16Hz 1/3H, trans), 6.02 (d, J = 11Hz, 2/3H, cis), 5.60 (m , 3H), 5.40 (m, 1H), 4.10 (m, 1H), 3.80 (m,
1H), 3.70 (s, 3H), 3.02 (m, 1H) [α] ²⁰ _D = -35° (c = 0.466, MeOH) Mass m/z (%): 362 (7, M ⁺ ), 344 ( 44),
326 (19), 300 (37), 220 (54), 168 (41), 178
(55), 43(100). {3-(4'-methoxycarbonyl-1'-butenyl-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,
5S)-cis-bicyclo[3.3.0]oct-2-ene} (15mg, 0.04mM) was dissolved in methanol (0.3ml). A 10% aqueous sodium hydroxide solution (0.3 ml) was added at 0°C. After stirring at 0°C for 16 hours, the mixture was neutralized with a 10% aqueous hydrochloric acid solution while cooling. After distilling off methanol under reduced pressure, the pH was adjusted to 3 to 4 and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give {3-(4'-carboxy-1'-butenyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]- 7(R)-hydroxy-(1S,
5S)-cis-bicyclo[3.3.0]oct-2-ene (14 mg, 100%) was obtained as a colorless caramel. IR (neat): 3350, 1720, 1090, 970 cm ^-1 . NMR δ (CDCl ₃ ) 6.34 (d, J = 16 Hz, 1/3 H), 6.06 (d, J = 11 Hz, 2/3 H), 5.65 (m , 3H), 5.45 (m, 1H), 3.10 (m, 1H). {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)
-t-butyldimethylsilyloxy- (1S, 5S)
-cis-bicyclo[3.3.0]oct-2-ene}
(48mg, 0.081mM) in benzene (0.9ml) solution
RhCl(Ph ₃ P) ₃ (10 mg) was added, and the mixture was stirred at room temperature for 1 hour and at 45° C. for 1.5 hours under a hydrogen stream (atmospheric pressure). After removing the catalyst using a short silica gel column, the resulting residue was purified again using silica gel column chromatography to obtain 45 mg of a colorless oil. A THF solution of tetrabutylammonium fluoride (0.8 ml, IM concentration) was added to this and stirred at room temperature for 12 hours to remove silyl ether. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain {3-(4'-methoxycarbonibutyl)-6
(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (20
mg, 69%). IR (neat): 3400, 2970, 2930, 2870, 1742cm
^-1 . NMR δ (CDCl ₃ ) 5.60 (m, 2H), 5.33 (bs, 1H), 4.12 (m,
1H), 3.80 (m, 1H), 3.69 (s, 3H), 3.00
(m, 1H). Mass m/z: 346 (M ⁺ −H ₂ O), 328, 315,
302, 275, 247, 232, 199, 193, 180, 179. {3-(4'-methoxycarbonylbutyl)-6
(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (10
mg, 0.027 mmol) was dissolved in methanol (0.3 ml). 10% aqueous sodium hydroxide solution (0.2
ml) was added. After stirring at 0°C for 9 hours, under cooling,
% aqueous hydrochloric acid solution. After distilling off methanol under reduced pressure, the pH was adjusted to 3 to 4 and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give [9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ ] (10 mg,
100%). IR (neat): 3350, 2910, 2850, 1700, 1450,
1250cm ^-1 . NMR δ (CDCl ₃ ) 5.60 (m, 2H), 5.31 (bs, 1H), 4.11 (m,
1H), 3.80 (m, 1H), 3.00 (m, 1H), 0.90
(t, J=6Hz, 3H). Mass (CI, NH ₃ ) m/z: 368 (M ⁺ +NH ₄ ) Melting point: 73-79°C [α] ²⁰ _D = +16° (c = 0.25, MeOH). {2(R)-allyl-3(R)-[3'(S)-t-
butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone} (354 mg, 0.72 mmol) in methylene chloride (7 ml)
Add zinc-titanium chloride-methylene bromide reagent (Zn- _TiCl4 - _{CH2Br2 /} THF, 3.74
ml, approximately 1.3 equivalents) was added. After stirring for 30 minutes under the same conditions, the raw materials disappeared, so the reaction solution was poured into a two-layer system of ether and saturated aqueous sodium bicarbonate solution to stop the reaction. Then, the ether layer was separated and further extracted with ether. The combined ether layers were washed with saturated ammonium chloride water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain {2(R)-allyl-3(R)-
[3'(S)-t-butyldimethylsilyloxy-
3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene) (326 mg, 88%) was obtained as an almost colorless oil. IR (neat): 3078, 2930, 2850, 1648, 1460,
1360, 1247cm ^-1 . NMR δ (CDCl ₃ ) 5.70 (m, 1H), 5.40 (m, 2H), 4.70~5.05
(m, 4H), 4.02 (m, 1H), 3.76 (1H, m),
2.00-2.60 (m, 6H), 1.38 (m, 9H), 0.88
(s, 18H), 0.02 (s, 12H). Mass m/z: 433 (M ⁺ -57), 419, 391 {2(R)-allyl-3(R)-[3'(S)-t-
Butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene} (698 mg, 1.42 mmol) was added to 9-borabicyclo[3,3 , 1] A THF solution (7.10 mmol, 14.2 ml) of nonane (9-BBN) was added at room temperature and stirred for 3 hours. Next, 6N-NaOH aqueous solution (6.9
ml) and 30% H ₂ O ₂ aqueous solution (5.8 ml) were slowly added dropwise at room temperature, and the mixture was stirred at 60°C for 2 hours. The reaction solution was extracted with ether, and the ether layer was washed with an aqueous sodium thiosulfate solution and water. After drying over anhydrous magnesium sulfate, the solvent was distilled off, the residue was purified by silica gel column chromatography, and {1(S)-
Hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4( R)-t-butyldimethylsilyloxycyclopentane} (442 mg, 59%) was obtained as a colorless oil. IR (neat): 3345, 2920, 2850, 1456, 1360,
1246cm ^-1 . NMR δ (CDCl ₃ ) 5.35 (m, 2H), 3.95 (m, 2H), 3.59 (m,
4H), 2.16 (m, 4H), 1.10~1.80 (m, 16H),
0.87 (s, 18H), 0.04 (s, 12H). Mass m/z: 469 (M ⁺ -57), 451, 394, 377. DMSO (0.83 ml,
11.7 mmol) in methylene chloride (4 ml) at -78
The mixture was added over 5 minutes at ℃ and stirred for 15 minutes under the same conditions. To this {1(S)-hydroxymethyl-2(S)
-(3'-Hydroxypropyl)-3(S)-[3'(S
)
-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)
-t-butyldimethylsilyloxycyclopentane} (473 mg, 0.900 mmol) in methylene chloride (3
ml) solution was added dropwise and stirred for an additional 15 minutes at -78°C. Under the same conditions, triethylamine (2.50ml,
18.0 mmol) was added, the cooling bath was removed, and the mixture was stirred for 15 minutes. Methylene chloride was distilled off under reduced pressure, and to the resulting residue were added benzene (8 ml) and trifluoroacetate of dibenzylamine (220 mg, 0.900 mmol), and the mixture was stirred at 70°C for 4 hours. The reaction solution was diluted with ether, washed with an aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent,
The residue was purified by silica gel column chromatography to give {3-formyl-6(S)-[3'(S)-t
−
Butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-
Butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3,3,0.]oct-2-ene}
(385 mg, 85%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1675, 1450, 1360,
1250cm ^-1 . NMR δ (CDCl ₃ ) 9.82 (s, 1H), 6.72 (bs, 1H), 5.45 (m,
2H), 4.05 (m, 1H), 3.76 (m, 1H), 3.23
(m, 1H), 1.10~2.80 (m, 15H), 0.87,
0.90 (2s, 18H), 0.03 (s, 12H). Mass m/z: 447 (M ⁺ -57), 433, 357, 337,
315, 301, 200, 71. 3-Carboxypropyltriphenylphosphonium bromide (321 mg, 0.748 mmol) in THF
(3.0 ml), t-butoxypotassium (167 mg, 1.49 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. {3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R) was added to the obtained reddish-orange ylide solution. -t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3,
3,0.]Oct-2-ene} (189mg,
A solution of 0.374 mmol) in THF (1.5 ml) was added and stirred for 30 minutes. Dilute the reaction solution with ether to 10%
After confirming acidity (PH≒4) with an aqueous HCl solution, the ether layer was separated. After further extraction with ether, the ether layers were combined, washed with saturated NaCl water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was dissolved in a small amount of ether, and methyl ester was obtained with an ether solution of diazomethane. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t
−
Butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-
Butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (175mg,
80%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1745, 1460, 1358,
1240cm ^-1 . NMR δ (CDCl ₃ ) 6.25 (d, J=16Hz, 2/5H, trans), 6.01
(d, J=11Hz, 3/5H, cis), 5.50 (m,
4H), 4.07 (m, 1H), 3.69 (m, 1H), 3.68
(s, 3H), 2.98 (m, 1H), 1.10~2.70 (m,
17H), 0.87, 0.90 (2s, 18H), 0.03(s,
12H). Mass m/z: 588 (M ⁺ ), 532, 531, 517 [α] ²⁰ _D = -37° (c = 1.618, CHCl ₃ ) {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-
propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]
Oct-2-ene} (81mg, 0.14mM) in THF
(1.5 ml) A tetrabutylammonium fluoride THF solution (0.42 ml, IM solution) was added to the solution, and the mixture was stirred at room temperature for 16 hours. After stopping the reaction with saturated ammonium chloride water, THF was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-Cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-
Bicyclo[3.3.0]oct-2-ene} (49mg,
100%) was obtained as a colorless caramel. IR (neat): 3400, 1740, 1430, 1160, 1090,
965cm ^-1 . NMR δ (CDCl ₃ ) 6.22 (d, J=16Hz, 1/3H, trans), 5.95 (d, J=11Hz, 2/3H, cis), 5.13~5.74 (m, 4H, olefin Nick proton), 3.66
(s, 3H), 3.50-4.00 (m, 2H), 3.02 (m,
1H). Mass m/z: 360 (M ⁺ ), 342 (M ⁺ −H ₂ O),
324 (M ⁺ −2H ₂ O), 298, 273. [α] ²⁰ _D = −30° (c = 1.16, MeOH). {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)
-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (50mg, 0.14mM) was dissolved in methanol (1.1ml). A 10% aqueous sodium hydroxide solution (1.1 ml) was added at 0°C. 0℃
After stirring for 18 hours, the mixture was neutralized with a 10% aqueous hydrochloric acid solution under cooling. After distilling off methanol under reduced pressure, the pH was adjusted to 3 to 4 and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give {3-(4'-carboxy-1'-butenyl)-6(S)-[3'(S)-
Hydroxy-1'-cyclopentyl-1'-trans-
propenyl]-7(R)-hydroxy-(1S,5S)-
cis-bicyclo[3.3.0]oct-2-ene} (43
mg, 86%) was obtained as a colorless caramel. IR (neat): 3350, 1715, 1085, 970 cm ^-1 . NMR δ (CDCl ₃ ) 6.32 (d, J = 16 Hz, 1/3 H), 6.04 (d, J = 12 Hz, 2/3 H), 5.64 (m , 3H), 5.44 (m, 1H), 3.10 (m, 1H). {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-
propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]
RhCl( _Ph3P ) ₃ (10mg) was added to a solution of oct-2-ene (47mg, 0.081mM) in benzene (0.9ml),
The mixture was stirred at room temperature for 1 hour and at 45°C for 1.5 hours under a hydrogen stream (atmospheric pressure). After removing the catalyst using a short silica gel column, the resulting residue was purified again using silica gel column chromatography to obtain 42 mg of a colorless oil. A THF solution of tetrabutylammonium fluoride (0.8 ml, 1M concentration) was added to this, and the mixture was stirred at room temperature for 12 hours to remove the silyl ether. After evaporating the solvent, the residue was purified by silica gel column chromatography to give {3-(4'-methoxycarbonylbutyl)-6(S)-[3'(S)-hydroxy-3'
−
Cyclopentyl-1'-trans-propenyl]-
7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (17 mg, 60%) was obtained as a colorless viscous oil. IR (neat): 3400, 2960, 2880, 1740 cm ^-1 . NMR δ (CDCl ₃ ) 5.61 (2H, m), 5.32 (1H, bs), 3.85 (2H,
m), 3.67 (3H, s), 3,00 (1H, m), 1.10
~2.60 (26H, m). Mass m/z: 344 (M ⁺ -18), 326 (M ⁺ -36),
300, 275, 243, 232, 225, 199, 193, 183,
181, 180, 179, 141, 119, 117, 105, 93,
91, 81, 79, 69, 67, 55, 41. {3-(4'-methoxycarbonylbutyl)-6
(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octo-2 -ene} (10 mg, 0.027 mmol) was dissolved in methanol (0.3 ml). A 10% aqueous sodium hydroxide solution (0.2 ml) was added at 0°C. After stirring at 0° C. for 9 hours, the mixture was neutralized with a 10% aqueous hydrochloric acid solution while cooling. After distilling off methanol under reduced pressure, the pH was adjusted to 3 to 4 and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give {3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-
3′-cyclopentyl-1′-transpropenyl]
-7(R)-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (10mg, 100%)
was obtained as a colorless solid. When this was recrystallized from ethyl acetate-hexane, a colorless powder with a melting point of 115-116°C was obtained. IR (KBr): 3430 (OH), 2960, 1700, 1655 cm ^-1 . NMR δ (CDCl ₃ ) 5.60 (2H, m), 5.32 (1H, bs), 3.90 (2H,
m), 3,00 (1H, m), 1.00~2.70 (25H,
m). Mass (Cl, NH ₃ ) m/z: 366 (M ⁺ +NH ₄ ) {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,
RhCl(Ph ₃ P) ₃ (5 mg) was added to a solution of 5S)-cis-bicyclo[3.3.0]oct-2-ene} (15 mg, 0.041 mM) in benzene (0.5 ml), and the mixture was heated under a hydrogen stream (normal pressure). ), stirred at room temperature for 1 hour and at 45°C for 1.5 hours. After removing the catalyst using a short silica gel column, the resulting residue was purified again using silica gel column chromatography to obtain 9 mg of a colorless oil. This was dissolved in methanol (0.2ml). A 10% aqueous sodium hydroxide solution (0.1 ml) was added at 0°C. 0℃
After stirring for 9 hours, the mixture was neutralized with a 10% aqueous hydrochloric acid solution under cooling. After distilling off methanol under reduced pressure, the pH was adjusted to 3 to 4 and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give {3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R) -Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (9 mg) was obtained as a colorless solid.
The spectral data are consistent with those obtained in Reference Example 5. {3-(4'-carboxy-1'-butenyl)-6
(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (14
mg, 0.041mM) in benzene (0.5ml).
(Ph ₃ P) ₃ (5 mg) was added, and the mixture was stirred at room temperature for 1 hour and at 45° C. for 1.5 hours under a hydrogen stream (atmospheric pressure). After removing the catalyst using a short silica gel column, the resulting residue was purified again using silica gel column chromatography to obtain 6 mg of {3-(4'-carboxybutyl)-6
(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} is colorless. Obtained as a solid. The spectral data are consistent with those obtained in Reference Example 5. {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)
-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (15mg, 0.041mM)
RhCl(Ph ₃ P) ₃ (5 mg) in benzene (0.5 ml) solution
and incubate for 1 hour at room temperature under hydrogen flow (atmospheric pressure) at 45°C.
Stirred at ℃ for 1.5 hours. After removing the catalyst using a short silica gel column, the resulting residue was purified again using silica gel column chromatography to obtain 8 mg of colorless viscous oil. Add this to methanol (0.2ml)
dissolved in A 10% aqueous sodium hydroxide solution (0.1 ml) was added at 0°C. After stirring at 0° C. for 9 hours, the mixture was neutralized with a 10% aqueous hydrochloric acid solution while cooling. After distilling off methanol under reduced pressure, the pH was adjusted to 3 to 4 and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give {3-(4'-carboxybutyl)-6(S)
-[3'(S)-hydroxy-3'-cyclopentyl-
1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (8 mg) was obtained as a colorless solid. The spectral data are consistent with those obtained in Reference Example 10. {3-(4'-carboxy-1'-butenyl)-6
(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octo-2 -ene} (14 mg, 0.041 mM) in benzene (0.5 ml) was added RhCl(Ph ₃ P) ₃ (5 mg), and the mixture was stirred at room temperature for 1 hour and at 45°C for 1.5 hours under a hydrogen stream (normal pressure). . After removing the catalyst using a short silica gel column, the resulting residue was purified again using silica gel column chromatography to obtain 7 mg of {3-(4'-carboxybutyl)-6(S)-[3'(S) -Hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} was obtained as a colorless solid. The spectral data are consistent with those obtained in Reference Example 10. {2
(R)-Allyl-3(R)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-
4(R)-tetrahydropyranyloxy-1-cyclopentanone} (868 mg, 2 mmol) to {3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl ]-7(R)
-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3,3,0.]oct-2-ene}
(446 mg, total yield 50%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1680 cm ^-1 . NMR δ (CDCl ₃ ) 9.81 (s, 1H), 6.75 (bs, 1H), 5.44 (m,
2H), 4.50 (m, 2H), 3.20-4.10 (m, 7H). Mdss m/z: 446 (M ⁺ ), 361. By exactly the same reaction procedure as in Example 1, {3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-
Tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (446mg,
1mmol) from {3-(4'-methoxycarbonyl-
1'butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans--octenyl]-
7(R)-tetrahydropyranyloxy-(1S,
5S)-cis-bicyclo[3.3.0]oct-2-ene} (477 mg, 90%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1745cm ^-1 . NMR δ (CDCl ₃ ) 6.25 (d, J = 16Hz, 1/3H, trans), 6.02
(d, J=11Hz, 2/3H, cis), 5.50 (m,
4H), 4.60 (m, 2H), 3.40~4.10 (m, 6H),
3.69 (s, 3H), 2.97 (m, 1H), 0.87 (t, J
=7Hz, 3H). Mass m/z: 530 (M ⁺ ), 499, 445. {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy −(1S,5S)−cis−
Bicyclo[3.3.0]oct-2-ene} (470mg,
0.89mmol) in acetic acid (4.7ml), water (1.6ml), THF
(1.6 ml) of a mixed solvent and heated at an external temperature of 45°C for 6 hours. After acetic acid was distilled off under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)
−
Hydroxy-1'-trans-octenyl]-7
(R)-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (261 mg) was obtained as a colorless caramel (81%). Various spectral data matched the spectral data of the substance obtained in Example 2. {2
(R)-Allyl-3(R)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-tetrahydropyranyloxy-1-cyclopenta Non} (864mg,
2mmol) from {3-formyl-6(S)-[3'(S)
-Tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-
Bicyclo[3.3.0]oct-2-ene} (408mg,
(46% overall yield) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1680 cm ^-1 . NMR δ (CDCl ₃ ) 9.81 (s, 1H), 6.74 (bs, 1H), 5.45 (m,
2H), 4.48 (m, 2H), 3.20-4.10 (m, 7H). Mass m/z: 444 (M ⁺ ), 359. By the same reaction procedure as in Example 4, {3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydro {3-
(4'-methoxycarbonyl-1'-butenyl)-6
(S)-[3'(S)-tetrahydropyranyloxy-
3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-
(1S,5S)-cis-bicyclo[3.3.0]octo-2
-ene} (447 mg, 92%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1744cm ^-1 . NMR δ (CDCl ₃ ) 6.24 (d, J = 16Hz, 1/3H, trans), 6.01
(d, J=11Hz, 2/3H, cis), 5.50 (m,
4H), 4.60 (m, 2H), 3.50-4.10 (m, 6H),
3.68 (s, 3H), 2.98 (m, 1H). Mass m/z: 528 (M ⁺ ), 497, 443. {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R) -tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octo-
2-ene} (500 mg, 0.95 mmol) in acetic acid (4.7 ml),
Dissolved in a mixed solvent of water (1.6ml) and THF (1.6ml),
It was heated at an external temperature of 45°C for 6 hours. After acetic acid was distilled off under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography.
{3-(4'-methoxycarbonyl-1'-butenyl)
-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-
Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]
Oct-2-ene} (308 mg, 90%) was obtained as a colorless caramel. Various spectral data matched the spectral data of the substance obtained in Example 5.

Claims (1)

[Claims] 1. General formula A (3'-alkoxy-1'-alkenyl) ^-cis -bicyclo[3,3,0]octene derivative represented by group or alkenyl group, R ² is a hydrogen atom, a tetrahydropyranyl group,
Methoxymethyl group, 4-methoxytetrahydropyranyl group, 1-ethoxyethyl group, 1-methyl-
1-methoxyethyl group, t-butyldimethylsilyl group, diphenyl-t-butylsilyl group, benzoyl group or acetyl group, R ³ is a hydrogen atom,
t-butyldimethylsilyl group, benzoyl group, acetyl group, tetrahydropyranyl group, methoxymethyl group, 4-methoxytetrahydropyranyl group,
It is a 1-ethoxyethyl group, a 1-methyl-1-methoxyethyl group, or a diphenyl-t-butylsilyl group, and ^R4 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.