JPH0631201B2 - Process for producing optically active γ-lactone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention relates to a prostaglandin synthesis method (G.Stork, T.Takahashi, I.Kawamoto, T.) developed by G.Stork et al.
Suzuki: J. Am. Chem. Soc., 100 , 8272 (1978)), the following general formula (P) (In the general formula (P), R ¹ has 1 to 12 carbon atoms selected from an alkyl group optionally having an alkoxy group, a cycloalkyl group and an aralkyl group having a hetero atom in an aromatic ring or an alkyl group. The group R ² represents a hydrogen atom or an easily removable protecting group selected from an acyl group, a silyl group, an aralkyl group and an alkyloxyalkyl group, and the symbol * represents an asymmetric carbon atom). It relates to a method for producing an optically active γ-lactone derivative.

(Prior Art and Problems to be Solved) Regarding the production of prostaglandins, in addition to the synthetic method of G. Stork et al., A method starting from corey lactone or 4-hydroxycyclopentenone has been put into practical use. , This method needs to undergo steps such as optical resolution and asymmetric hydrolysis by microorganisms in order to obtain the optically active substance of the raw material,
Furthermore, there are many problems in stereocontrol at the stage of introducing α and ω side chains based on these. From this point of view, it can be said that the prostaglandin synthesis method developed by G. Stork et al. Using the optically active γ-lactone derivative of the general formula (P) as a key intermediate is an excellent method. However, the problem in this method depends on how economically the compound of the general formula (P), which is a key intermediate, can be produced.

(Means for Solving the Problems) As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a compound represented by the above general formula (P) of the present invention, which is a key intermediate, can be more easily prepared than ever before. In addition, the present invention has found a method of efficiently manufacturing the same.

The present invention includes the following general formula (B) (In the general formula (B), R ¹ has 1 to 12 carbon atoms selected from an alkyl group which may have an alkoxy group, a cycloalkyl group and an aralkyl group having a hetero atom in an aromatic ring or an alkyl group. R ² is a hydrogen atom or an easily removable protecting group selected from an acyl group, a silyl group, an aralkyl group and an alkyloxyalkyl group, R ⁴
Represents a lower alkyl group having 1 to 5 carbon atoms, and the symbol * represents an asymmetric carbon atom), and an optically active compound represented by the formula (I) is subjected to intramolecular ring closure in the presence of an acid catalyst. P) is a method for producing an optically active γ-lactone derivative.

In formula (P), the same meanings as R ^1, R ² and * symbols R ^1, R ² and * symbols are the general formula (B).

Specific examples of R ¹ in the general formula (P) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpentyl, hexyl, 2-hexyl, heptyl, 2-heptyl, Octyl, 2-octyl, nonyl, 2-nonyl, decyl, 2-decyl, undecyl, 2-undecyl, dodecyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxy-1-methylpentyl, cyclopentyl, 3- A linear or branched alkyl group or cycloalkyl group which may have an alkoxy substituent such as ethylcyclopentyl, cyclohexyl, 2-methylcyclohexyl, 4-n-propylcyclohexyl, phenyloxymethyl, 3-trifluoromethyl Phenyloxymethyl, 2
-Chlorothiophen-5-yloxymethyl, furan-
Examples thereof include an aralkyl group having a hetero atom in an aromatic ring or an alkyl group such as 2-yl-2-ethyl.

Specific examples of R ² other than a hydrogen atom in the general formula (P) include acyl groups such as benzoyl, acetyl and p-phenylbenzoyl, silyl groups such as t-butylmethylsilyl, trimethylsilyl and t-butyldiphenylsilyl, Examples thereof include aralkyl groups such as benzyl and 4-nitrophenylmethyl, and easily removable groups such as alkyloxyalkyl groups such as tetrahydropyranyl and 1-ethoxyethyl.

Prostaglandins are compounds having extremely strong physiological activity, which are produced by the chemical conversion of higher unsaturated fatty acids such as arachidonic acid by prostaglandin synthase in vivo and have the following structures.

In natural prostaglandins, R ¹ is n-C ₅ H _11- ,
R is (CH ₂ ) ₆ COOH or CH ₂ CH = CH (CH ₂ )
It is known that it is ₃ COOH and that the substituent of R ¹ has lipophilicity in order to exert physiological activity. In the course of development and research as pharmaceuticals, R ¹ is more preferably an alkyl group, a cycloalkyl group or an aralkyl group having 4 to 10 carbon atoms, such as pentyl,
Isopentyl, 2,2-dimethylpentyl, hexyl, 2
-Alkyl groups such as hexyl, heptyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxy-1-methylpentyl, cyclopentyl, 3-ethylcyclopentyl,
A cycloalkyl group such as 4-propylcyclohexyl,
It has been clarified that aralkyl groups such as phenyloxymethyl, 3-trifluoromethylphenyloxymethyl, 2-chlorothiophen-5-yloxymethyl and furan-2-yl-2-ethyl have particularly strong physiological activity. Came. The compound of the present invention is useful as a raw material into which a substituent including these organic groups can be introduced.

The synthetic method of the γ-lactone derivative represented by the above general formula (P) of the present invention will be described below according to the synthetic route I. In the following, X represents a halogen atom and M represents an alkali metal.

In the above reaction, the halogen compound (1) is reacted with a strong base such as n-butyllithium, t-butyllithium, methyllithium, lithium diisopropylamide to give an acetylene compound (2), and the alkali metal acetylide is further added with these strong bases. (2 '). The compound (4) is obtained by reacting this with an optically active aldehyde (3).

The above-mentioned alkali metal acetylide (2 ′) may be prepared by isolating the acetylene compound (2) once and reacting it with a strong base again as described above. The alkali metal acetylide obtained by reacting with an amount of a strong base or more can be used as it is.
The reaction between the alkali metal acetylide and the optically active aldehyde (3) is preferably carried out at a low temperature of -78 to 0 ° C. The reaction for obtaining the compound (4) is carried out in an inert solvent such as tetrahydrofuran, diisopropyl ether or toluene.
It can be performed in the temperature range of 78 ° C to room temperature. The compound (4) obtained by this reaction is a mixture of the erythro body (6-1) and the threo body (6-2) as shown by the following chemical formula.

From this mixture, the erythro body (6-1) or the threo body (6)
In order to selectively obtain -2), it can be separated by column separation or the like, but each optical isomer can be produced easily and more selectively by a chemical method as described later. An oxidant such as CrO ₃ -pyridine or dimethyl sulfoxide (DM) is added to the compound (4).
The ethynyl ketone derivative of the compound (5) can be obtained by oxidation with (SO) -acid halide or the like.

In the reaction for synthesizing the optically active ethynyl alcohol derivative (6) from the compound (5), the ethynyl alcohol derivative (6) to be obtained is the erythro body (6-1) represented by the above chemical formula, or a threo body. The reaction conditions differ depending on whether it is (6-2). That is, the erythro body (6-
For the purpose of 1), the compound (5) is a zinc borohydride complex (Zn (BH ₄ ) ₂ ) and the threo compound (6-2).
In the case of aiming at, the ethynyl alcohol derivative (6) having the desired configuration can be obtained with good selectivity by reducing with an alkali metal selectlide, for example, potassium selectride.

To synthesize the allyl alcohol derivative (7) from the ethynyl alcohol derivative (6), the ethynyl alcohol derivative (6) can be obtained by reducing the triple bond to a trans double bond with lithium aluminum hydride or the like. This reaction can be carried out in an inert solvent such as tetrahydrofuran or dioxane at a temperature of 40 to 80 ° C.

The allyl alcohol derivative (7) is represented by the following general formula (D) CH ₃ C (OR ⁴ ) ₃ (D) (in the general formula (D), R ⁴ represents a lower alkyl group having 1 to 5 carbon atoms). It is converted into a γ-unsaturated carboxylic acid derivative (B) by heating and reacting with the represented trialkyl orthoacetate in the presence of an acid catalyst to carry out a Johnson-Claisen rearrangement reaction. Examples of the trialkyl orthoacetate represented by the general formula (D) to be used include trimethyl orthoacetate, triethyl orthoacetate, tripropyl orthoacetate, tributyl orthoacetate, triheptyl orthoacetate, etc. 2-10 times equivalent,
130-180 ℃ in solvents such as toluene, xylene, mesitylene
The reaction is carried out at the temperature of. As the acid catalyst, a Lewis acid, a Lewis acid complex (for example, BF _3. (C ₂ H ₅ ) ₂ O), or an organic acid such as heptanoic acid is used. When the acetonide of the thus obtained γ-unsaturated carboxylic acid derivative (B) is ring-opened with an acid catalyst and subjected to intramolecular lactonization, the general formula (P of the present invention, which is a key intermediate in prostaglandin synthesis, is used. An optically active γ-lactone derivative represented by Hydrolysis containing organic acid acetonide in this reaction, using methanol, ethanol and the like alcohol, solvent mineral acid and BF ₃ · ether complex, such as acetone or dioxane, CuSO _4, ZnSO ₄ Lewis acid or a Lewis acid complex such as Can be performed at room temperature to 80 ° C.

The compound of the general formula (P) thus obtained is
Prostaglandins (PGE, PGF) can be derived according to the prostaglandin synthesis method of G. Stork et al. Therefore, the optically active compound of the general formula (P) in the present invention is required to have S as the three-dimensional configuration of the 3-position, 3′-position and 4-position in the general formula (P) as the above-mentioned raw material.

Halogen compound (1) as a starting material in the above reaction
Can be easily synthesized by reacting optically active 2,3-0-isopropylideneglyceraldehyde obtained from D-mannitol or optically active glycidol by a known method with triphenylphosphine and tetrahalomethane.

In addition, the above-mentioned optically active aldehyde (3) is obtained by the following synthetic route.
It can be synthesized according to II. In the following,
R ¹ of R ^1, R ² and * symbols are the general formula (A), R ² and *
And X and Y each independently represent a group or atom selected from a hydroxyl group, an acyl group, a sulfoxy group and a halogen atom.

The optically active mannitol is reacted with acetone in the presence of an acid catalyst to give triacetonide (a), which is partially hydrolyzed with hydrous acetic acid to give tetraol (b), which has primary and secondary hydroxyl groups separately. Triphenylphosphine-CCl ₄ , acid halide-pyridine, pyridine-
Acetonide (c) is obtained by partially or completely converting with an acyl group, a sulfoxy group or a halogen atom with methanesulfonyl chloride or the like. Then this acetonide (c)
To a diepoxide (d) with a base, then R ³ MgBr,
_{^{R 3 MgBr-Cu 2 (CN}} ) 2, R 3 Li ( where, R ³ represents one less group with a carbon number of from R ¹⁾ introducing a group R ¹ and the like or lithium aluminum hydride, a further hydroxyl group After reacting with R ² X '(X' is a halogen atom or a sulfoxy group) to give an acetonide (e), which is hydrolyzed to give a diol (f), Pb (OAc) ₄ or NaIO ₄
For example, the desired optically active aldehyde (3) can be obtained by oxidization.

The present invention will be described below with reference to examples.

(Example) Example <Synthesis of Compound (a)> 45 g of D-mannitol was added to acetone 1 and concentrated hydrochloric acid 1 m.
After stirring vigorously at room temperature for 3 days, potassium carbonate 50
g was added, and the mixture was further stirred for 1 day. The solid matter was removed by suction filtration, the solvent in the filtrate was distilled off under reduced pressure, water was added to the obtained residue, and the precipitated crystals were collected by suction filtration to obtain 45 g of a crude product. This was dissolved in 20 m of ethanol by heating and then filtered, the filtrate was cooled to room temperature, and the precipitated crystals were collected by filtration, and the optically active (2R, 3R, 4R, 5R) triacetonide (a) 37.3 represented by the following chemical formula was obtained. g (yield 50%) was obtained.

¹ HNMR (CCl ₄ ) δ: 1.40 (6H, s, CH ₃ × 2) 1.43 (12H, s, CH ₃ × 4) 3.7 to 4.4 (8H, m, CH ₂ , CH) <Compound ( Synthesis of b)> Triacetonide (a) 15 g (0.05 mol) obtained above 70%
After stirring at 40 ° C for 3.5 hours in 50m of acetic acid, the mixture was quickly concentrated at 40 ° C under reduced pressure, and acetone was added to the residue to crystallize D-mannitol (0.72g), and acetone was distilled off under reduced pressure from the filtrate. A syrupy product was obtained. This was recrystallized with 50 m of benzene and 8.8 g (yield 80%) of an optically active (2R, 3R, 4R, 5R) tetraol (b) represented by the following chemical formula.
%) Was obtained.

¹ HNMR (D ₂ O) δ: 1.38 (6H, s, CH ₃ × 2) 3.3 to 4.2 (8H, m, CH ₂ , CH) <Synthesis of Compounds (c) and (d)> The tetra obtained above. All (b) 15.3 g (0.069 mol), anhydrous pyridine 55 m (0.68 mol), CH ₂ C
l ₂ 50m solution in benzoyl chloride 16m at -70 ° C
A mixture of (0.138 mol) and anhydrous CH ₂ Cl ₂ 5m was added dropwise over 15 minutes, and after the addition, the mixture was stirred at −30 ° C. for 1 hour and at room temperature for 10 hours, and the completion of the reaction was confirmed by thin layer chromatography. The post-solvent was distilled off under reduced pressure. To this residue was added methanesulfonyl chloride 11.2m (0.144mol) at 0 ° C over 20 minutes, and the suspension was further stirred at room temperature for 3 days. After confirming the completion of the reaction by thin layer chromatography, the reaction mixture was mixed with 100 m of a mixed solvent of ethyl ether: hexane = 7: 3 (volume).
Was added and the yellow suspension was filtered through Celite-545,
The solvent was distilled off under reduced pressure. The obtained brown residue was diluted with CH ₂ Cl ₂ , acidified by adding concentrated hydrochloric acid, and then extracted with CH ₂ Cl ₂ three times. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give an optically active (2R, 3R, 4R, 5R) body of a brown semisolid. 42 g of the product acetonide (c) was obtained.

(However, Ms represents a methylsulfoxy group and ph represents a phenyl group.) 42 g of the above acetonide (c) and 20 g of K ₂ CO ₃ were added to 13 parts of methanol.
After stirring for 15 hours in 0 m, the reaction solution was filtered through Celite-545, the filtrate was concentrated under reduced pressure at 40 ° C., 30 m of a mixed solvent of ethyl ether: hexane = 7: 3 (volume) was added, and Celite-545 was added again. After filtration, the solvent was distilled off under reduced pressure at 40 ° C., and the crude product was obtained by distillation under reduced pressure. This was recrystallized from benzene to obtain 2.7 g (21% yield) of pure optically active (2S, 3R, 4R, 5S) -form diepoxide (d) represented by the following chemical formula.

¹ HNMR (CDCl ₃ ) δ: 1.39 (6H, s, CH ₃ × 2) 2.6 to 2.9 (4H, m, CH ₂ × 2) 2.95 to 3.12 (2H, m, CH) 3.7 to 3.95 (2H, m, CH) <Synthesis of compounds (e) and (f)> Cu ₂ (CN) ₂ 320 mg, anhydrous tetrahydrofuran 100 m
64 m (94 mmol) of a separately prepared ether solution of n-butylmagnesium bromide having a concentration of 1.47 mol was added to the above mixture at 0 ° C. over 5 minutes. After stirring for another 5 minutes,
A solution of 6.48 g of the diepoxide (d) obtained above in 50 m of anhydrous tetrahydrofuran was added dropwise at 0 ° C. over 10 minutes with stirring, and the mixture was further stirred for 1 hour. After confirming the completion of the reaction by thin layer chromatography, it was decomposed with NH ₄ Cl and saturated saline,
After stirring for 30 minutes, the mixture was extracted 3 times with ethyl ether, the ether layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent of the filtrate was evaporated. Optical activity represented by the following chemical formula (6S, 7R, 8R,
9S) form crude diol (e-1) was obtained.

The crude diol (e-1) obtained above was dissolved in 30 m of anhydrous tetrahydrofuran, and 0.48 g of sodium hydride was added.
(1.07 mmol) of anhydrous tetrahydrofuran 100 m was added dropwise under reflux for 15 minutes, and the mixture was further stirred and refluxed for 1 hour, and then 0
Cooled to ° C. To this suspension, 132 mg of DC-18-crown ether-6 and 9.3 m (78 mmol) of benzyl bromide were added at 0 ° C.
Was added and the mixture was stirred and refluxed for 4 hours. Concentrate the reaction mixture under reduced pressure to 1
After decomposing it with normal hydrochloric acid and extracting 3 times with hexane, the extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the optical activity (6S , 7R, 8R, 9S) acetonide (e-2) was obtained.

(However, Bn represents a benzyl group.) The above-mentioned acetonide (e-2) was added to 100 m of 80% acetic acid at 100 ° C.
After heating and stirring for 10 hours, the solvent was evaporated under reduced pressure, followed by extraction with ethyl ether, the extract was washed with a caustic soda aqueous solution, and the aqueous layer was further extracted with ethyl ether. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with ethyl ether: hexane = 1: 4 (volume)), and the optically active (6S, 7R, 8R, 9S) diol (f) represented by the following chemical formula was obtained. 8.66 g (55% yield from compound (d)) was obtained.

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.88 (6H, br, CH ₃ × 2) 1.0 to 1.8 (16H, m, CH ₂ × 8) 3.4 to 3.7 (4H, m, CH) 4.46 (2H, d, J = 10.8Hz, CH) 4.62 (2H, d, J = 10.8Hz, CH) 7.30 (10H, s, C 6 H 5) < synthesis of compound (3)> obtained above Diol (f) 200mg, K ₂ CO ₃ 60mg and lead tetraacetate 260m in anhydrous benzene 4.5m.
mg was added at 4 ° C. and stirred for 3 minutes. Hexane after reaction
100 m was added, and the mixture was filtered through Celite-545, the filtrate was washed with saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted twice with hexane, the hexane layers were combined, washed with saturated brine, and then dried over anhydrous magnesium sulfate. . After distilling off the solvent, silica gel column chromatography (ethyl ether: hexane = 1: 1)
(S) -2-benzyloxyheptanal (3) (160 mg, yield 80%).

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 5.8Hz, CH ₃ ) 1.0 to 1.8 (8H, m, CH ₂ ) 3.73 (1H, dt, J = 2.2Hz, 6.2Hz, CH) 4.51 (1H, d, J = 11.6Hz, CH) 4.65 (1H, d, J = 11.6HZ, CH) 7.34 (5H, s, C 6 H 5) 9.64 (1H, d, J = 2.2 Hz) <Synthesis of compound (4)> The following chemical formula (1) 100m of anhydrous tetrahydrofuran of 4.8g (16.8mmol) of (S) -dibromide represented by is cooled to -78 ° C, and 16.4m (26.6mmol) of butyllithium-hexane solution having a concentration of 1.62mol is applied for 10 minutes under a nitrogen atmosphere. Drop it, -78
The mixture was further stirred at 1 ° C. for 1 hour and at room temperature for 1 hour to be converted into optically active lithium acetylide (2 ′), which was cooled to −78 ° C. to obtain (S) -2-benzyloxyheptanal (3) obtained above. ) 2.41 g (4.4 mmol) of anhydrous tetrahydrofuran 20
m was added dropwise, the mixture was further stirred for 30 minutes, decomposed with an aqueous solution of ammonium chloride, extracted three times with ethyl ether, washed with saturated saline, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 3 (volume)) to obtain 3.81 g of a (2S, 6S) compound represented by the following chemical formula (4) ( Yield 64%). This was a mixture of erythro body: threo body = 64: 36 (weight).

(However, Bn represents a benzyl group.) <Synthesis of Compound (5)> Oxalyl dichloride 0.38 m (4.4) in anhydrous methylene chloride 15 m solution of anhydrous dimethyl sulfoxide 680 mg (8.7 mmol).
4 mmol) was added dropwise at −70 ° C. over 5 minutes, and the mixture was further stirred for 10 minutes at the same temperature. 4 m of anhydrous methylene chloride of 1.00 g (2.9 mmol) of the compound (4) having the erythro body: threo body = 64: 36 obtained above was added dropwise thereto, and the mixture was stirred for 9 minutes at -70 ° C. Anhydrous triethylamine (2.0 m, 14 mmol) was added dropwise to this, and the temperature was gradually returned to room temperature. Then, hexane was added, and Celite-54
The mixture was filtered through 5, and the filtrate was washed with 1N hydrochloric acid. The aqueous layer was extracted 3 times with methylene chloride, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 10 (volume)), and the (2S, 6S) ethynyl ketone derivative (5) 5 represented by the following chemical formula was obtained.
50 mg was obtained (yield 55%).

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.86 (3H, br, t, J = 7.2Hz, CH ₃ ) 1.0 to 1.9 (8H, m, CH ₂ ) 1.38 (3H, s , CH ₃ ) 1.47 (3H, s, CH ₃ ) 4.02 (1H, dd, J = 5.6Hz, 8.24Hz, CH) 4.18 (1H, dd, J = 6.4Hz, 8.24Hz, CH) 4.42 (1H, d , J = 11.5Hz, CH) 4.70 (1H, d, J = 11.5Hz, CH) 4.86 (1H, dd, J = 5.6Hz, 6.4Hz, CH) 7.31 (5H, s, C 6 H 5) IR νmax (Neat) 695, 735, 835, 1060, 1220, 1320, 1370, 1380, 1450, 1675, 2200, 2860, 2920, 3020cm ^-1 <Synthesis of compound (6)> The above obtained (2S, 6S) body Ethynyl ketone derivative of (5) 5
Concentration into 50 mg (1.6 mmol) 16m anhydrous ether at -30 ° C
0.26mol zinc borohydride-ethyl ether solution 9.6m
(2.5 mmol) was added dropwise under a nitrogen atmosphere over 5 minutes, and the mixture was further stirred for 30 minutes. After the reaction, water and 0.5N hydrochloric acid 2
0 m was added, and the mixture was stirred at 0 ° C for 30 minutes. The aqueous layer was extracted 3 times with ethyl ether, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 3 (volume)) and the (2S, 5R, 6S) ethynyl alcohol derivative (6) represented by the following chemical formula (erythro). Body: threo = 90:10
(Weight)) 349 mg was obtained (63% yield).

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.87 (3H, br t, J = 7.2 Hz, CH ₃ ) 1.0 to 1.8 (8H, m, CH ₂ ) 1.36 (3H, s, _{CH 3) 1.45 (3H, s} , CH 3) 3.49 (1H, dt, J = 3.8Hz, 6.4Hz, CH) 3.88 (1H, dd, J = 6.4Hz, 7.7Hz, CH) 4.12 (1H, dd, J = 6.4Hz, 7.7Hz, CH) 4.4~4.7 (1H, m, J = 1.5Hz, 3.8Hz, CH) 4.59 (2H, s, CH 2) 4.69 (1H, ddd, J = 1.5Hz, 6.4Hz 6.4H
z, CH) 7.30 (5H, s, C 6 H 5) 13 CNMR (CDCl 3) δ: 13.98,22.54,25.27,25.96,26.22, 30.06,31.85,64.16,65.57,69.94, 72.49,81.50,83.70,84.00 , 100.31, 127.83, 128.40, 138.21 <Synthesis of Compound (7)> 105 mg (0.30 mmol) of anhydrous tetrahydrofuran 2 of (2S, 5R, 6S) ethynyl alcohol derivative (6) obtained above.
24.1 mg (0.63 mm) of lithium aluminum hydride
ol) in anhydrous tetrahydrofuran 5 m at 0 ° C.,
The mixture was stirred and refluxed for 18 minutes. After completion of the reaction, ethyl acetate, ethanol, water, and 0.1 N hydrochloric acid were sequentially added for decomposition, and the aqueous layer was extracted twice with ethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 3 (volume)) to be represented by the following chemical formula. 80.1 mg of allyl alcohol derivative (7) of (2S, 5R, 6S) form was obtained (yield 76%).

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 5.4Hz, CH ₃ ) 1.38 (3H, s, CH ₃ ) 1.40 (3H, s, CH ₃ ) _{1.04~1.8 (8H, m, CH 2} ) 3.2~3.5 (1H, m, CH) 3.52 (1H, dd, J = 7.7Hz, 7.7Hz, CH) 4.08 (1H, dd, J = 6.4Hz, 8.0Hz , CH) ¹³ CNMR (CDCl ₃ ) δ: 14.02, 22.61, 25.46, 25.92, 26.72, 29.42, 31.93, 69.44, 72.22, 72.56, 82.18, 127.72, 127.79, 128.40, 129.89, 132.47, 140.60 <of compound (B). Synthesis> The obtained (2S, 5R, 6S) allyl alcohol derivative (7) 80.1 mg (0.23 mmol), triethyl orthoacetate 0.15 m (0.82 mmol) and a catalytic amount of heptanoic acid in xylene 3 m. React with heating at ℃ for 20 minutes, distill off xylene and generated ethanol under reduced pressure, and decompose with saturated aqueous sodium hydrogen carbonate after the reaction. . The aqueous layer was extracted twice with ethyl ether, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 10 (volume)) and the (1 ′S, 3S, 6S) -form γ-unsaturated carboxylic acid represented by the following chemical formula was obtained. 65.6 mg of ethyl (B) was obtained (68% of yield).

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.86 (3H, br t, J = 7.2Hz, CH ₃ ) 1.0 to 1.8 (8H, m, CH ₂ ) 1.33 (3H, s, _{CH 3) 1.41 (3H, s} , CH 3) 2.40 (1H, dd, J = 9.0Hz, 14.7Hz, CH) 2.50 (1H, dd, J = 5.1Hz, 14.7Hz, CH) 2.6~3.0 (1H, m, CH) 3.5~3.8 (2H, m, CH 2) 3.9~4.3 (2H, m, CH × 2) 4.09 (2H, q, J = 7.2Hz, CH 2 O) 4.31 (1H, d, J = _{11.7Hz, CH 2 C 6 H 5} ) 4.55 (1H, d, J = 11.7Hz, CH 2 C 6 H 5) 5.2~5.7 (2H, m, = CH-) 7.27 (5H, s, C 6 H 5 ) ¹³ CNMR (CDCl ₃ ) δ: 14.00, 14.25, 22.59, 25.03, 26.30, 31.77, 35.72, 36.50, 41.77, 60.32, 66.81, 69.79, 77.30, 79.74, 109.08, 127.28, 127.7.
2,128.20,130.84,134.45,139.00,171.79 <Synthesis of compound (P)> 65 mg (0.16 mmol) methanol of ethyl (B) γ-unsaturated carboxylate of (1 ′S, 3S, 6S) body obtained above 5m, water 1.25
m and CuSO ₄ .5H ₂ O (186 mg, 0.75 mmol) were stirred and refluxed for 13 hours. After completion of the reaction, ethyl ether was added and the mixture was filtered through Celite-545. The filtrate was washed with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5 (volume)) and the (3S, 3 ′S, 4S) -form γ-lactone derivative represented by the following chemical formula (P )
35.5 mg was obtained. (Yield 69%).

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.86 (3H, br t, J = 7.2Hz, CH ₃ ) 1.0 to 1.8 (1H, m, CH ₂ ) 3.72 to 3.9 (5H, m, CH ₂ , CH) 4.4 to 4.7 (1H, m, CH) 4.36 (1H, d, J = 11.7Hz, CH ₂ ) 4.51 (1H, d, J = 11.7Hz, CH ₂ ) 5.55 (1H, dd , J = 6.7Hz, 15.4Hz, = C
H) 5.68 (1H, dd, J = 7.7Hz, 15.4Hz, = C
H) 7.29 (5H, s, C 6 H 5) 13 CNMR (CDCl 3) δ: 14.00,22.57,24.98,31.69,34.94, 41.02,62.27,70.42,79.50,82.60, 127.52,127.62,128.23,135.62,138.63 176.48 (Effect of the invention) The present invention is a method for producing an optically active γ-lactone derivative which is a key intermediate for the synthesis of prostaglandins, and by using this method, the derivative can be relatively easily and efficiently produced. Can be manufactured well.

Claims (6)

[Claims] 1. The following general formula (B): (In the general formula (B), R ¹ has 1 to 12 carbon atoms selected from an alkyl group which may have an alkoxy group, a cycloalkyl group and an aralkyl group having a hetero atom in an aromatic ring or an alkyl group. R ² is a hydrogen atom or an easily removable protecting group selected from an acyl group, a silyl group, an aralkyl group and an alkyloxyalkyl group, R ⁴
Represents a lower alkyl group having 1 to 5 carbon atoms, and the symbol * represents an asymmetric carbon atom), and an optically active compound represented by the formula (I) is subjected to intramolecular ring closure in the presence of an acid catalyst. A process for producing an optically active γ-lactone derivative represented by P). In formula (P), the same meanings as R ^1, R ² and * symbols R ^1, R ² and * symbols are the general formula (B). 2. The method according to claim 1, wherein R ^{1 in the} general formula (P) is an alkyl group having 4 to 10 carbon atoms. 3. The method according to claim 2, wherein the alkyl group is a pentyl group. 4. The method according to claim 1, wherein R ^{2 in the} general formula (P) is an aralkyl group. 5. The aralkyl group is a benzyl group.
The manufacturing method described. 6. A compound represented by the general formula (P) is optically active (3S,
The method according to any one of claims 1 to 5, which is a 3'S, 4S) body.