JPH0359900B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is useful as a synthetic intermediate for carbacycline derivatives. general formula [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group protecting group, and R ² represents a formyl group or a

[Formula] represents a group (in the formula, R ³ represents an optionally substituted alkyl group, alkenyl group, alkynyl group, or an optionally substituted cycloalkyl group), Ar represents an aryl group, and Y represents a sulfur atom or a selenium atom, and Z represents an oxygen atom or a protecting group for a carbonyl group. ] This invention relates to a novel bicyclo[3.3.0]octane derivative having the following formula and a method for producing the same. Carbacycline derivatives are compounds that are being researched and developed as therapeutic agents for thrombotic diseases, etc., and the conventional synthesis method involves reducing a 15-keto compound to obtain a mixture of 15α- and β-coordinated hydroxy isomers. 15α-hydroxy compounds with excellent physiological activity have been produced by separating and purifying the 15α-hydroxy compounds. As a result of the progress, the present invention was completed by discovering that the compound having the above general formula () is an important synthetic intermediate thereof. In the general formula (), the hydroxyl-protecting group for ^R1 is not particularly limited as long as it is a hydroxyl-protecting group commonly used in this field; for example, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl. , n-butoxymethyl, methylthiomethyl, ethylthiomethyl, n
-Propylthiomethyl, isopropylthiomethyl, n-butylthiomethyl, benzyloxymethyl, p-nitrobenzyloxymethyl, p-bromobenzyloxymethyl, 2,2,2-trichloroethyl, 2,2,2-tribromo Ethyl, 1-
An alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms as a substituent such as methoxyethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2-methoxy-2-butyl group,
or a trihalogenomethyl group, an alkyl group having 1 to 4 carbon atoms having an aralkyloxy group at the α-position; a 2-methoxyethoxymethyl group; a 4-methoxytetrahydrothiopyran-4-yl group;

[Formula] Group (in the formula, n represents an integer of 3 to 5); trimethylsilyl, trimethylsilyl, triethylsilyl, dimethylisopropylsilyl,
Trialkyl (having 1 to 4 carbon atoms), dialkyl (having 1 to 4 carbon atoms), phenyl or diphenylalkyl such as dimethyl-t-butylsilyl, dimethylphenylsilyl, diphenyl-t-butylsilyl Silyl group; aralkyl group such as benzyl, p-nitrobenzyl, p-bromobenzyl; 2-phenyl-2-propyl group; 2-phenyl-2-butyl group; diphenylmethyl group; trityl group or acetyl, propionyl, butyryl, Examples include acyl groups such as benzoyl and p-methylbenzoyl,
Preferably, an alkyl group having 1 to 4 carbon atoms having an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a trihalogenomethyl group, or an aralkyloxy group at the α-position as a substituent;
2-methoxyethoxymethyl group; tetrahydrofuran-2-yl group; tetrahydropyran-2-yl group; 4-methoxytetrahydrothiopyran-4
-yl group; trialkyl (having 1 to 4 carbon atoms) or dialkyl (having 1 to 4 carbon atoms); phenylsilyl group; acetyl group; propionyl group or benzoyl group; more preferably is a methoxymethyl group, a tetrahydropyran-2-yl group, a dimethyl-t-butylsilyl group, an acetyl group or a benzoyl group. Examples of the optionally substituted alkyl group for ^R3 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, n-hexyl, n-heptyl,
1,1-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 2-ethylpentyl,
n-octyl, 2-methyloctyl, n-nonyl, 2-methylnonyl, 2-ethyloctyl, n
Examples include alkyl groups having 1 to 12 carbon atoms, such as -decyl, 2-methyldecyl, or 2-ethyldecyl groups, and are preferred if they are unsubstituted or have a halogen atom or an alkoxy group as a substituent as described below. is an alkyl group having 4 to 10 carbon atoms, such as n-butyl, isobutyl, n-pentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, n-hexyl,
n-heptyl, 1,1-dimethylpentyl, 1-
Methylhexyl, 2-methylhexyl, 2-ethylpentyl, n-octyl, 2-methyloctyl or 2-ethyloctyl groups can be mentioned, and more preferably n-pentyl, 1-methylpentyl, n-hexyl, Examples include 1,1-dimethylpentyl, 1-methylhexyl or 2-methylhexyl groups, and optionally substituted cycloalkyl groups, aryl groups or -W-Ar groups (formula In the middle, W is an oxygen atom,
It represents a sulfur atom or -NH group, and Ar represents an aryl group. ) as a substituent, preferably an alkyl group having 1 to 3 carbon atoms, such as a methyl, ethyl, n-propyl or isopropyl group, more preferably a methyl group or an ethyl group. be. Substituents for these alkyl groups include fluorine,
Halogen atoms such as chlorine and bromine; methoxy, ethoxy, n-propoxy, isopropoxy, n-
Alkoxy groups having 1 to 4 carbon atoms such as butoxy; optionally substituted three- to seven-membered cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl groups, (preferably can be a cyclopentyl group or a cyclohexyl group, and substituents for these cycloalkyl groups include halogen atoms such as fluorine, chlorine, and bromine;
Methyl, ethyl, n-propyl, isopropyl,
Examples include an alkyl group having 1 to 4 carbon atoms such as n-butyl or a trifluoromethyl group, and preferably a methyl group or an ethyl group. ); an aryl group, such as a phenyl or naphthyl group (preferred is a phenyl group, and the substituents of these aryl groups are similar to the substituents of the cycloalkyl group described above); or a group of the formula - A W--Ar group (wherein W and Ar have the same meanings as described above, and W is preferably an oxygen atom or a sulfur atom) can be mentioned.
More preferred substituents for the above alkyl groups include a fluorine atom, a methoxy group, an ethoxy group, a cyclopentyl group, a 3-methylcyclopentyl group, a 3-ethylcyclopentyl group, a cyclohexyl group, a 3-methylcyclohexyl group, and a 3-ethylcyclohexyl group. , phenyl group, m-chlorophenyl group, phenoxy group, phenylthio group or p-trifluoromethylphenoxy group. Examples of the alkenyl group for R ³ include vinyl, allyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4- Pentenyl, 4-hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 5
-heptenyl, 6-methyl-5-heptenyl,
2,6-dimethyl-5-heptenyl, 1,1,6
-trimethyl-5-heptenyl, 6-methyl-5
-octenyl, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, 2-methyl-
2 to 12 carbon atoms, such as 6-ethyl-5-octenyl or 2,6-diethyl-5-octenyl group
Examples include alkenyl groups having 4 to 12 carbon atoms, preferably alkenyl groups having 4 to 12 carbon atoms,
For example, 2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 4-hexenyl, 5-hexenyl, 1 ,4-dimethyl-3-pentenyl, 5
-heptenyl, 6-methyl-5-heptenyl,
2,6-dimethyl-5-heptenyl, 1,1,6
-trimethyl-5-heptenyl, 6-methyl-5
-octenyl, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, 2-methyl-
Examples include 6-ethyl-5-octenyl or 2,6-diethyl-5-octenyl, more preferably 2-pentenyl, 4-pentenyl,
Mention may be made of 4-hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 6-methyl-5-heptenyl or 2,6-dimethyl-5-heptenyl groups. Examples of the alkynyl group for R ³ include ethynyl,
propargyl, 2-butynyl, 2-pentynyl,
3-pentynyl, 1-methyl-2-butynyl, 2
-hextynyl, 1-methyl-2-pentynyl, 1
- an alkynyl group having 2 to 6 carbon atoms, such as a methyl-3-pentynyl group, preferably an alkynyl group having 4 to 6 carbon atoms, such as a methyl-3-pentynyl group;
-butynyl, 2-pentynyl, 3-pentynyl,
Examples include 1-methyl-2-pentynyl group and 1-methyl-3-pentynyl group, and more preferably 1-methyl-3-pentynyl group. The optionally substituted cycloalkyl group for R ³ is the same as the substituent for the alkyl group having 1 to 12 carbon atoms, but suitable groups for the cycloalkyl group for R ³ include Cyclohexyl, cyclopentyl or 1-n-butyl-1
-cyclopropyl group. The protecting group for the carbonyl group of Z is not particularly limited as long as it does not affect other parts of the compound due to the removal reaction when the protecting group is removed later, and preferred examples include dimethoxy and diethoxy. Dialkoxy groups; alkylene dioxy groups such as methylene dioxy and ethylene dioxy; alkylene dithio groups such as ethylene dithio and trimethylene dithio; more preferably dimethoxy groups or ethylene dioxy groups. can be given. Further, in the general formula (), particularly preferred compounds are those in which R ¹ is a hydrogen atom, a tetrahydropyran-2-yl group, a dimethyl-tert-butylsilyl group, an acetyl group, or a benzoyl group, and R ²
is formyl group or formula

[Formula] Group (wherein R ³ is n-pentyl group, 1-methylhexyl group, 1,1-dimethylpentyl group, 5-methoxypentyl group, phenoxymethyl group, 2-pentenyl group, 4-pentenyl group, 1 ,4-dimethyl-3
-pentenyl group, 1,1,4-trimethyl-3-
Pentenyl group, 4-hexenyl group, 5-hexenyl group, 6-methyl-5-heptenyl group, 2,6-
dimethyl-5-heptenyl group, 1-methyl-3-
Indicates a pentynyl group or a cyclopentyl group. )
Examples include compounds in which Ar is a phenyl group, Y is a sulfur atom, and Z is an oxygen atom, dimethoxy group, or ethylenedioxy group. Moreover, as specific compounds of the compound having the general formula (), the following may be mentioned.

【table】

【table】

【table】

【table】

【table】

[Table] Compounds (a) and (b) according to the present invention are
It can be manufactured by the method shown below. In the above formula, R ¹ , R ² , R ³ , Ar, Y and Z have the same meanings as described above, and R ⁴ is phenyl, p
- represents an aryl group such as tolyl, R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-
It represents a lower alkyl group such as butyl or isobutyl, and X represents a halogen atom such as chlorine, bromine, or iodine. The first step is to produce a compound having the general formula (), in which an aldehyde compound having the general formula () is mixed with the general formula (R ⁴ ) ₃₊ P CH ₂ OR ⁵ ]X ^- (a) in an inert solvent. (In ^the formula, R ⁴ _, ^{R 5} _and (wherein R ⁴ and R ⁵ have the same meanings as defined above). The starting material compound () for this step can be produced by a known method, for example, the method described in JP-A No. 54-95552, and especially the substituent
It is preferable that R ¹ represents a hydroxyl group-protecting group such as a tetrahydropyran-2-yl group, and the substituent Z represents a carbonyl group-protecting group such as an ethylenedioxy group, and optically active forms thereof are used. You can also. Further, as the phosphonium halide compound (a), triphenyl methoxymethylphosphonium halide such as triphenyl methoxymethylphosphonium chloride is particularly suitable. This reaction is carried out under the usual Wittig reaction conditions, and the inert solvents used are ethyl ether, tetrahydrofuran,
Ethers such as dimethoxyethane, diglyme, hydrocarbons such as hexane, benzene, toluene, amides such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or hexamethylphosphoramide (HMPA)
or a mixed solvent thereof. Bases used include organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide, alkali metal alkoxides such as sodium ethoxide, potassium tert-butoxide, or sodium hydride-dimethylsulfoxide (dimethyl anion). ) etc. can be given. The reaction temperature is usually -78°C to 50°C, preferably -
The temperature is about 70°C to room temperature, and the time required for the reaction varies depending on the reaction temperature, etc., but is usually 30 minutes to 5 hours. The second step is a step of producing a compound having the general formula (a), which is the target compound of the present invention, in which a compound having the general formula () is mixed with the general formula Ar-Y-X in the presence of a base in an inert solvent. () (wherein Ar, Y and X have the same meanings as defined above). Examples of the raw material compound () in this step include benzenesulfenyl chloride, benzenesulfenyl bromide, p-toluenesulfenyl chloride, and the like, with benzenesulfenyl chloride being particularly preferred. Inert solvents used include ethers such as ethyl ether, tetrahydrofuran and dioxane, hydrocarbons such as hexane, benzene and toluene, and halogenated hydrocarbons such as methylene chloride and chloroform. can. Examples of the base used include alkali metal carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate. Moreover, in this reaction, in order to suppress side reactions, it can be carried out under a stream of an inert gas such as nitrogen, helium, or argon, if necessary. The reaction temperature is usually a low temperature of -78°C to 0°C, preferably around -70°C, and the time required for the reaction varies depending on the reaction temperature, but is usually 30 minutes to 10 hours. The third step is a step for producing a compound having the general formula (b), which is the target compound of the present invention, in which an aldehyde compound having the general formula (a) is mixed with the general formula [(R ⁴ ) ₃₊ P General formula (R ⁴ ) 3 produced by treating a compound having the following formula with a base: CH ₂ R ₃ ]X ^- (a) (wherein, R ³ , R ^{4 and} X have the same meanings as described above) ₊ P _- C HR ³ () (wherein R ³ and R ⁴ have the same meanings as described above). This reaction is a Witteig reaction similar to the reaction in the first step, and the solvent and base used are almost the same as in the first step, but the inert solvent used is tetrahydrofuran-dimethyl sulfoxide or tetrahydrofuran-hexane. Mixed organic solvents such as methylphosphoramide are particularly preferred. The reaction temperature is usually -78°C to 30°C,
Particularly preferably, the reaction can be carried out by adding compound (a) to a solution of compound (a) at around -70°C, and then gradually raising the reaction temperature to around room temperature. The time required for the reaction varies depending on the reaction temperature, etc., but is usually 1 to 7 hours. Furthermore, the compound (b) obtained by this step
, the substituent R ¹ is a hydroxyl group protecting group,
For compounds where Z is a carbonyl protecting group, each protecting group is removed according to a conventional method to obtain the general formula (wherein R ³ , Ar and Y have the same meanings as defined above). This reaction is carried out, for example, by adding a compound (b) in which R ¹ is a tetrahydropyran-2-yl group and Z is an ethylenedioxy group to a mineral acid such as hydrochloric acid, sulfuric acid, acetic acid, p - toluenesulfonic acid, preferably acetic acid in the presence of aqueous tetrahydrofuran. After the completion of the reaction, the target compound in each of the above steps is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into water, adjusting the pH as necessary, and then extracting with a water-immiscible organic solvent, washing and drying the extract, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. The compound having the general formula (b) according to the present invention can be converted into a carbacycline derivative () useful as a pharmaceutical by the reaction shown below. That is, the general formula A compound having the general formula A compound having the general formula This can lead to carbacycline derivatives having a 15α-hydroxy group. In the above formula, R ¹ , R ³ , Ar, Y and Z have the same meanings as described above. The reaction to produce the compound having the general formula () is carried out in the presence of a solvent, and the solvents used include alcohols such as methanol and ethanol, ethers such as ethyl ether, tetrahydrofuran, and dioxane, and benzene. ,
Examples include aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as methylene chloride and chloroform, organic solvents such as acetonitrile, and mixed solvents of these organic solvents and water. The oxidizing agent used is a compound (
There is no particular limitation as long as it is a reagent that converts a thio group or seleno group into a sulfinyl group or selenooxy group without affecting other moieties in b). peracid,
Mention may be made of alkali metal perhydrogen salts such as hydrogen peroxide, sodium periodate, and sodium perchlorate. Examples of the phosphorous acid trialkyl ester used include trimethyl phosphite and triethyl phosphite. This reaction can be carried out by adding an oxidizing agent to compound (b) and reacting it, and then treating it with a phosphorous acid trialkyl ester, but the reaction temperature is -70°C to 60°C, preferably -30°C. ℃ to 0℃, and the time required for the reaction varies depending on the type of oxidizing agent and the reaction temperature, but is usually 30 minutes to 14 hours. After the reaction is completed, the target compound of this reaction is collected according to a conventional method. For example, it can be obtained by adding a water-immiscible organic solvent to the reaction mixture, washing and drying the organic solvent layer, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. In addition, in this reaction, instead of compound (b), the stereoisomer of the general formula (In the formula, R ¹ , R ³ , Ar, Y and Z have the same meanings as described above.) The target compound () can also be obtained by using a compound having the following as a raw material. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Example 1 2β-(2′-methoxyvinyl)-3α-(2′-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,3,0]octane 1.308 g of 55% oily sodium hydrogen and 7.5 g of triphenyl-methoxymethylphosphonium chloride is added to a solution of dimyl anion (sodiomethylsulfinyl carbanide) prepared in a conventional manner from 100 ml of dimethyl sulfoxide at room temperature. To the obtained ylide solution was added 20 ml of a solution of 3.0 g of 2β-formyl-2α-(2'-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,3,0]octane in dimethyl sulfoxide at room temperature. Stir for an hour. After the reaction is complete, add ice water and extract with ethyl acetate. The extract was washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. The obtained residue is purified by column chromatography using 100 g of silica gel. From the outflow of hexane containing 9 to 10% ethyl acetate, 1.771 g of the desired oily compound was obtained. IR spectrum (Liq), ν _nax cm ^-1 : 1665 NMR spectrum δ _ppn (CDCl ₃ ): 3.50, 3.55 (3H,
s×2) 3.80 (4H, s) 4.7 (1H, br, s) Example 2 2β-(1′-formyl-1′-phenylthiomethyl)
-3α-(2'-tetrahydropyranyloxy)-
7,7-ethylenedioxybicyclo[3,3,
0] Octane 1.606g of 2β-(2'-methoxyvinyl)-3α-
3.3 g of powdered potassium carbonate in 100 ml of a toluene solution of (2'-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,3,0]octane
Add. The resulting suspension was cooled to -70°C, and 4.0 ml of benzenesulfenyl chloride was added dropwise under vigorous stirring under a nitrogen atmosphere. 10% after 1 hour reaction
Add 100ml of sodium bicarbonate water and sift vigorously with a separating funnel. Thereafter, the reaction mixture is extracted with ethyl acetate. The extract is washed with water and then dried over anhydrous sodium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel chromatography. From the outflow of hexane containing 10 to 20% ethyl acetate, 1.882 g of the target product was obtained in the form of an oil. IR spectrum (Liq) cm ^-1 : 1710, 2720 NMR spectrum (CDCl ₃ ) δ _ppn : 3.91 (4H, s)
4.71 (1H, br.s) 7.32 (5H, brs) 9.27 (1H, d
-d) Then from the hexane outlet containing 20% ethyl acetate.
2β-(1′-formyl-1′-phenylthiomethyl)-
3α-(2'-tetrahydropyranyloxy)-7-oxobicyclo[3,3,0]octane (IR spectrum (Liq) cm ^-1 : 1740, 1720) was obtained. Example 3 2β-(1′-phenylthio-2′(Z),5′(Z)-octadienyl)-3α-(2′-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,3 ,0] 7.52 g of triphenyl-(3Z-hexenyl)phosphonium iodide at room temperature to a dimethyl sulfoxide solution of the dimyl anion prepared from 650 mg of 55% oily sodium hydrogen and 25 ml of dimethyl sulfoxide.
Add. The obtained ylide solution was added to 200 ml of tetrahydrofuran at room temperature and cooled to -70°C. Then 1.711 g of 2β-(1′-formyl-1′-phenylthiomethyl)-3α-(2′-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,
10 ml of 3,0] octane solution in tetrahydrofuran
was added under stirring, the cooling bath was removed, the temperature was gradually raised to 0°C, and the temperature was left at the same temperature for 1 hour. After the reaction is complete, acetic acid and saturated brine are added, followed by extraction with ethyl acetate.
The extract is washed with saturated brine and then dried with anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using 90 g of silica gel to obtain 1.460 g of the target compound as an oil. IR spectrum (Liq) cm ^-1 : 1025, 1585 NMR spectrum (CDCl ₃ ) δ _ppn : 0.90 (3H, t)
3.88 (4H, s) ~ 5.3 (4H, m) ~ 7.3 (5H, m) Example 4 2β-(1'-phenylthio-2(Z), 5(Z)-octadienyl)-3α-hydroxy-7- Oxobicyclo[3,3,0]octane 2β-(1'-phenylthio-2'(Z),5'(Z)-
octadienyl)-3α-(2′-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,
A mixture of 1.27 g of 3,0] octane, 10 ml of acetic acid, 20 ml of water and 10 ml of tetrahydrofuran is stirred at 45° C. for 6 hours. After the reaction was completed, saturated brine was added and the mixture was extracted with ether. The extract was washed successively with 10% aqueous sodium bicarbonate and saturated brine, and dried with anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 782 mg of the target compound as an oil. IR spectrum (Liq) cm ^-1 : 1740, 3430 NMR spectrum (CDCl ₃ ) δ _ppn : 0.92 (3H, t)
~4.1 (2H, m) ~5.3 (4H, m) ~7.4 (5H, m) This compound was converted to the corresponding oily tetrahydropyranyl compound with dihydropyran-paratoluenesulfonic acid. IR spectrum (Liq)cm
^-1 : 1740, 1020 Example 5 2β-(1'-phenylthio-2(Z)-octenyl)
-3α-(2'-tetrahydropyranyloxy)-
7,7-ethylenedioxybicyclo[3,3,
0] Octane 815 mg of 2β-(1'-formyl-1'- When 5 ml of a tetrahydrofuran solution of phenylthiomethyl)-3α-(2'-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,3,0]octane was added and treated in the same manner as in Example 3, an oily 480 mg of the target compound was obtained. IR spectrum (Liq) cm ^-1 : 1020, 1130 NMR spectrum (CDCl ₃ ) δ _ppn : 0.83 (3H, t)
3.86 (4H, s) ~ 5.3 (2H, m) ~ 7.2 (5H, m) Example 6 1 (S), 2 (S), 3 (R), 5 (R) -2-
(1'(R)-phenylthio-5(R),9-dimethyl-2(Z),8-decadienyl)-3-(2'-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3 ,3,0]Octane 1(S),2(R),3(R),5(R)-2-(1
′−
Formyl-1(R'-phenylthiomethyl)-3-
(2'-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,3,0]octane
850 mg and triphenyl-[3(S),7-dimethyl-oct-6-enyl]phosphonium iodide
When 3.85g was used and treated in the same manner as in Example 3, 725mg
The desired oily compound was obtained. IR spectrum (Liq) cm ^-1 : 1024, 1585 NMR spectrum (CDCl ₃ ) δ _ppn : 1.60 (3H, s)
1.78 (3H, s) 3.89 (4H, s) 7.3 (5H, m) Reference example 1 2β-(3′α-hydroxy-1′(E),5′(Z)-octadienyl)-3α-(2′ -tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,3,0]octane 168 mg of 2β-(1'-phenylthio-2(E),5(Z)-) obtained in Example 3 octadienyl)-3α-
Dissolve (2'-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3,3,0]octane in 16 ml of methanol and heat to 77 mg at -25°C to -30°C.
of methachloroperbenzoic acid (powder). After reacting at the same temperature for 45 minutes, 2 ml of trimethyl phosphite was added, the temperature was raised to 0°C, and the mixture was left for 13 hours and 30 minutes.
After the reaction is completed, ethyl acetate is added to the reaction solution, and the mixture is washed with saturated brine, 10% sodium bicarbonate water, and then saturated brine. After drying with anhydrous sodium sulfate, the solution is distilled off. The obtained residue is purified by column chromatography using 5 g of silica gel. Ten~
132mg from the hexane outflow containing 15% ethyl acetate
The desired oily compound was obtained. IR spectrum (Liq) cm ^-1 : 3450, 1030 NMR spectrum (CDCl ₃ ) δ _ppn : 0.95 (3H, t)
3.86 (4H, S) 4.64 (1H, brs) ~ 5.5 (4H, m) Reference example 2 2β-(3′α-hydroxy-1(E),5(Z)-octadienyl)-3α-hydroxy-7- Oxobicyclo[3,3,0]octane 353 mg of 2β-(1′-phenylthio-2(Z),5(Z)-octadienyl-3α-) obtained in Example 4
Hydroxy-7-oxobicyclo[3,3,0]
Octane was dissolved in 30 ml of methanol and subjected to reaction treatment in the same manner as in Reference Example 1. The resulting residue was purified by silica gel column chromatography to obtain 253 mg of the target compound in the form of an oil. IR spectrum (Liq) cm ^-1 : 3400, 1740, 970 NMR spectrum (CDCl ₃ ) δ _ppn : 0.96 (3H, t)
~5.3 (4H, m) Reference example 3 2β-(3′α-hydroxy-1(E)-octenyl)
-3α-(2'-tetrahydropyranyloxy)-
7,7-ethylenedioxybicyclo[3,3,
0] Octane 447 mg of 2β-(1'-phenylthio-2(Z)-octanyl)-3α-(2'-tetrahydropyranyloxy)-7,7-ethylenedioxybicyclo[3 ,3,0]octane to methanol
When dissolved in 40ml and treated in the same manner as in Reference Example 1, 331
mg of oily target compound was obtained. IR spectrum (Liq) cm ^-1 : 3450 NMR spectrum (CDCl ₃ ) δ _ppn : 0.90 (3H, t)
3.90 (4H, s) 4.67 (H, m) 5.58 (2H, m) Reference example 4 1 (S), 2 (S) 3 (R) 5 (R) -2- (3' (S
)
-Hydroxy-5(R),9-dimethyl-1
(E),8-decadienyl)-3-(2'-tetrahydropyranyloxy-7,7-ethylenedioxybicyclo[3,3,0]octane 1(S),2( obtained in Example 6) S), 3(R),
5(R)-2-(1'(R)-phenylthio-5(R)
，
9-dimethyl-2(Z),8-decadienyl)-3
-(2'-tetrahydropyranyloxy)-7,7-
When treated in the same manner as in Reference Example 1 using 680 mg of ethylenedioxybicyclo[3,3,0]octane, 573
mg of oily target compound was obtained. IR spectrum (Liq) cm ^-1 : 3480 NMR spectrum (CDCl ₃ ) δ _ppn : 0.90 (3H, d)
1.60 (3H, s) 1.67 (3H, s) 3.88 (4H, s)
4.65 (1H, m) 5.08 (1H, m) 5.52 (2H, m)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group protecting group, and R ² represents a formyl group or a group of the formula [Formula] [In the formula, R ³ is an optionally substituted alkyl group (the substituent is a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or a 3- to 7-membered cycloalkyl group optionally substituted with halogen, alkyl having 1 to 4 carbon atoms, or trifluoromethyl), Alkenyl group, alkynyl group or optionally substituted cycloalkyl group (the substituent is
It represents a halogen atom, an alkyl group having 1 to 4 carbon atoms, or a trifluoromethyl group. ) is shown. ], Ar represents an aryl group, Y represents a sulfur atom or a selenium atom, and Z represents an oxygen atom or a protecting group for a carbonyl group. ] A bicyclo[3.3.0]octane derivative having 2 General formula (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group-protecting group, and Z represents an oxygen atom or a carbonyl group-protecting group.) A compound having the general formula (R ⁴ ) ₃₊ P − _- C HOR ⁵ ( (In the formula, R ⁴ represents an aryl group and R ⁵ represents a lower alkyl group.) By reacting with a ylide compound having the general formula (In the formula, R ¹ , R ⁵ and Z have the same meanings as described above.) A compound having the general formula Ar-Y-X (wherein, Ar represents an aryl group, X represents a halogen atom, and Y represents a sulfur atom or a selenium atom. general formula (In the formula, R ¹ , Ar, Y and Z have the same meanings as described above.) A method for producing a bicyclo[3.3.0]octane derivative having the following formula: 3 General formula (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group-protecting group, Ar represents an aryl group, Y represents a sulfur atom or selenium atom, and Z represents an oxygen atom or a carbonyl group-protecting group.) The compound has the general formula (R ⁴ ) ₃₊ P − _- C HR ³ [wherein R ³ is an optionally substituted alkyl group (the substituent is a halogen atom, a carbon number of 1 to 4
represents a three- to seven-membered cycloalkyl group which may be substituted with halogen, alkyl having 1 to 4 carbon atoms, or trifluoromethyl. ), an alkenyl group, an alkynyl group, or an optionally substituted cycloalkyl group (the substituent represents a halogen atom, an alkyl group having 1 to 4 carbon atoms, or a trifluoromethyl group), and R ⁴ represents an aryl group. ] General formula characterized by reacting with a ylide compound having (In the formula, R ¹ , R ³ , Ar, Y and Z have the same meanings as described above.) A method for producing a bicyclo[3.3.0]octane derivative having the following formula: