JPH035470A - Production of optically active gamma-lactone derivative - Google Patents

Abstract

PURPOSE:To easily obtain the subject compound useful as a synthetic intermediate for prostaglandin, in high efficiency at a low cost, by carrying out intramolecular cyclization of a specific optically active compound in the presence of an acid catalyst. CONSTITUTION:An optically active compound of formula I [R<1> is (alkoxy)alkyl, cycloalkyl or 1-12C group of aralkyl having hetero atom on aromatic group or alkyl group; R<2> is H or easily eliminable protecting group of acyl, silyl, aralkyl or alkyloxyalkyl; R<4> is 1-5C lower alkyl; C labeled with * is asymmetric C] is hydrolyzed in a solvent consisting of water and methanol, etc., in the presence of an acid catalyst (e.g. CuSO4) at room temperature to 80 deg.C to effect the intramolecular lactonization and obtain the objective compound of formula V having an optical activity of (3S, 3'S, 4S), etc., and useful as a synthetic intermediate for PGF of formula II or PGE of formula III {in the case of natural prostaglandin, R<1> is n-C5H11; R<2> is [(CH2)6COOH or group of formula IV]}.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention is based on a prostaglandin synthesis method (G, 5tork, T, Ta
kahashi.

1. Kawamoto, T., 5uzuki: J.
Am, Chem, Soc,, 100.

8272 (1978)) is an important intermediate in the following general formula (P) (In the above general formula (P), R1 is an alkyl group that may have an alkoxy group, a cycloalkyl group, an aromatic ring, or an alkyl group. A group having 1 to 12 carbon atoms selected from aralkyl groups having a heteroatom in the group, R2 is a hydrogen atom or an easily separable protecting group selected from acyl groups, silyl groups, aralkyl groups, and alkyloxyalkyl groups. and the symbol * represents an asymmetric carbon atom).

(Prior art and problems to be solved) Regarding the production of prostaglandin, the above G, 5t
In addition to the synthetic method of Ork et al., a method starting from Corey lactone or 4-hydroxycyclobentenone has been put into practical use, but this method requires optical resolution or asymmetric hydrolysis by microorganisms to obtain an optically active form of tU4. It is necessary to go through the following steps, and there are also many problems in the stereoscopic control at the stage of introducing α and ω side chains based on these steps. From this point of view, the prostaglandin synthesis method using the optically active γ-lactone derivative of general formula (P) as a key intermediate, developed by G. 5tork et al., can be said to be an excellent method. However, the problem with this method lies in how economically the compound of general formula (P), which serves as a key intermediate, can be produced.

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

In the present invention, an optically active compound represented by the following general formula (B) (R4 represents a lower alkyl group having 1 to 5 carbon atoms, and the symbol * represents an asymmetric carbon atom) is synthesized within the molecule in the presence of an acid catalyst. This is a method for producing an optically active γ-lactone derivative represented by the following general formula (P), which is characterized by ring closure.

(In the above general formula (B), R1 is a group having 1 to 12 carbon atoms selected from an alkyl group that may have an alkoxy group, a cycloalkyl group, and an aralkyl group having a heteroatom in an aromatic ring or an alkyl group. , R2 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; In the above general formula (P), R1, R2, and the symbols * represent the general formula The symbols R1, R2 and * in (B) have the same meanings.

Specific examples of R1 in the above general formula (P) include methyl 2-ethyl, propyl, and isopropyl.

Butyl, isobutyl, pentyl, impentyl.

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-Ethylcyclopentyl, cyclohexyl.

Straight chain or branched alkyl groups or cycloalkyl groups which may have an alkoxy substituent such as 2-methylcyclohexyl, 4-lopropylcyclohexyl, phenyloxymethyl, 3-trifluoromethylphenyloxymethyl, 2- Examples include aralkyl groups having a petero atom in the aromatic ring or alkyl group, such as chlorothiophen-5-yloxymedyl and furan-2-yl-2-ethyl.

Specific examples of R2 other than hydrogen atoms in the above general formula (P) include acyl groups such as benzoyl, acetyl, and p-phenylbenzoyl, silyl groups such as t-butylmethylsilyl, trimethylsilyl, and t-butyldiphenylsilyl, and benzyl. , 4-nitrophenylmethyl, aralkyl groups, tetrahydropyranyl, 1-ethoxyethyl and other alkyloxyalkyl groups, and easily removable groups.

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

OH OH GF OH GE In natural prostaglandins, R1 is n-C3H11
-1R is (CH2)a C0OH or CH2CH=CH
(CH2)3 Coot-! It is known that it is important for the R1 substituent to have fat solubility for the expression of physiological activity. As R1 is being developed and researched as a pharmaceutical, an alkyl group, cycloalkyl group, or aralkyl group with 4 to 10 carbon atoms is generally effective, such as pentyl, isopentyl, 2,2-dimethylpentyl, Hexyl, 2-hexyl, heptyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxy-1-
Alkyl groups such as methylpentyl, cyclopentyl, 3
-Cycloalkyl groups such as ethylcyclopentyl and 4-propylcyclohexyl, phenyloxymethyl, 3-
It has been revealed that aralkyl groups such as trifluoromethylphenyloxymethyl, 2-chlorothiophen-5-yloxymethyl, and furan-2-yl-2-ethyl exhibit particularly strong physiological activity. The compounds of the present invention are useful as raw materials into which substituents including these organic groups can be introduced.

The method for synthesizing the γ-lactone derivative represented by the above general formula (P) of the present invention will be explained below according to synthetic route (2). In the following, X represents a halogen atom and M represents an alkali metal.

(1) (2) (2') (6) (4) (7) (P) In the above reaction, n-butyllithium, t-butyllithium, methyllithium, lithium diisopropylamide, etc. are added to the halogen compound (1). Acetylene compound (2) is obtained by the action of a strong base, and alkali metal acetylide (2') is obtained by adding a strong ml of these. Compound (4) is obtained by reacting optically active aldehyde (3) with this.

The alkali metal acetylide (2') may be prepared by isolating the acetylene compound (2) as described above and reacting it again with a strong base, but more simply, the halogen compound (1) is Alkali metal acetylides obtained by reacting with twice or more of a strong base can be used as they are.

This alkali metal acetylide and optically active aldehyde (3
) is preferably carried out at a low temperature of -78 to O'C.

The reaction to obtain compound (4) is tetrahydrofuran.

It can be carried out in an inert solvent such as diisopropyl ether or toluene at a temperature range of -78°C to room temperature. Compound (4) obtained by this reaction is an erythro form (6-1>) and a threo form (6-2>) as shown in the following chemical formula.
Filter with a mixture of

OH From this mixture, erythro form (6-1> or threo form (6-1)
-2> can be separated by column separation or the like, but each optical isomer can be easily and more selectively produced by a chemical method as described below. An oxidizing agent such as Cr03-pyridine, dimethyl sulfoxide (DM
The ethynyl ketone derivative of compound (5) can be obtained by oxidation using SO)-acid halide or the like.

In the reaction of synthesizing the optically active ethynyl alcohol derivative (6) from this compound (5), the ethynyl alcohol derivative (6) to be obtained is an erythro form (
The reaction conditions differ depending on whether it is the threo form (6-1> or the threo form (6-2>). That is, the erythro form (6, -
1>, the compound (5) is a borohydride zinc button body (Zn (8H4)2) or a threo body <6
-2> If the purpose is alkali metal selectride,
For example, by reduction with potassium selectride, the ethynyl alcohol derivative 6) having the desired configuration can be obtained with good selectivity.

The furyl alcohol derivative (7) can be synthesized from the ethynyl alcohol derivative (6) by reducing the triple bond to a trans double bond in the ethynyl alcohol derivative (6) 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 an acid together with trialkyl orthoacetate represented by the following general formula () % formula % () (In the above general formula (D), R4 represents a lower alkyl group having 1 to 5 carbon atoms) A heating reaction is carried out in the presence of a catalyst, and a Johnson-Claisen rearrangement reaction is carried out to convert the γ-unsaturated carboxylic acid derivative (B). Examples of the trialkyl orthoacetate represented by the general formula (D>) include trimethyl orthoacetate, triethyl orthoacetate, tripropyl orthoacetate, tributyl orthoacetate, triheptyl orthoacetate, etc. 130 to 10 times equivalent in a solvent such as toluene, xylene, mesitylene, etc.
The reaction is carried out at a temperature of 180°C. As acid catalysts, Lewis acids, Lewis acids 8M bodies, such as 8F3.(C2Hs >
20> and heptanoic acid are used. γ-unsaturated carboxylic acid derivative (B) thus obtained
When the acetonide is ring-opened with an acid catalyst and intramolecularly lactonized, an optically active γ-lactone derivative represented by the general formula (P) of the present invention, which is a key intermediate in prostaglandin synthesis, is obtained. Hydrolysis of acetonide in this reaction is carried out using water-containing organic acids, alcohols such as methanol and ethanol, mineral acids in solvents such as acetone or dioxane, and B.
It can be carried out at a temperature of room temperature to 80° C. using a Lewis acid or a Lewis acid complex such as F3.ether complex and CLJSO4°ZnS″o4.

The compound of the general formula (P) thus obtained can be converted into prostaglandins (the above-mentioned PGE, PGF) according to the prostaglandin synthesis method of G. 5torh et al. Therefore, in the optically active compound of the general formula (P) in the present invention, the 3-, 3-, and 4-positions in the general formula (P) are all required to be S as the raw material.

The halogen compound (1
) can be easily synthesized by reacting optically active 2,3-0-isopropylidene glyceraldehyde obtained from D-mannitol or optically active glycidol by a known method with triphenylphosphine and tetrahalomethane.

Further, the above-mentioned optically active aldehyde (3) can be synthesized according to the following synthetic route (2). In the following, R1
, R2 and * are the general formula (A> R1, R2 and *
, and X and Y each independently represent a hydroxyl group or an acyl group.

Represents a group or atom selected from a sulfoxy group and a halogen atom.

<C> (a) (d) (f) (3) The above optically active mannitol is reacted with acetone in the presence of an acid catalyst to form triacetonide (a), which is partially hydrolyzed with hydrous acetic acid to form tetraol ( b), and its -class hydroxyl group and secondary hydroxyl group are selectively treated with triphenylphosphine-CCIla, acid halide-pyridine, pyridine-methanesulfonyl chloride, etc., partially or with an acyl group, sulfoxy group, or halogen atom. All are converted to acetonide <C>. Then this acetonide (
After converting C) to dieboxide (d>) with a base, R3MgB
r, R3MClBr-Cu2 (CN)2゜R3Lj
(However, R3 represents a group with one less carbon number than R1) or lithium aluminum hydride, etc., and the hydroxyl group is further reacted with R2X'(X' is a halogen atom or a sulfoxy group) to form acetonide. (e), and after hydrolyzing this to obtain diol (f), Pb (O
The desired optically active aldehyde (3) can be obtained by oxidation with Ac)a, Nal0a, etc.

The present invention will be explained below with reference to Examples.

(Example) Synthesis of Example Compound (a)> 45 g of D-mannitol was mixed with 1 part of acetone and 1 part of concentrated hydrochloric acid.
After stirring vigorously for 3 days at maximum temperature in d, potassium carbonate 5
0 () 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 resulting residue, and the precipitated crystals were collected by suction filtration. Crude product 4
1 q of 5 (J) was dissolved by heating in 20 ml of ethanol and then filtered. The filtrate was cooled to a very low temperature and the precipitated crystals were collected by filtration.
R,5R) triacetonide (a) 37.3g (
A yield of 50% was obtained.

The optical activity (
2R, 3R, 4R, 5R) tetraol (b)a,
aC) (yield 80%) was obtained.

'HNMR (CC1a) δ: 1.40 < 6H,S, CH3X2 > 1
．． 43 (12H,S, CH3X4)3.7
~4.4 (8H, m, CH2, Cf-1) <Synthesis of compound (b)> Triacetonide obtained above (a> 15 g (0,0
D-mannitol (0,7
2g> was separated by filtration, and acetone was distilled off from the filtrate under reduced pressure to obtain a syrup-like product. This was analyzed by Penze'HNMR (D2
0) δ:1.3B (6H,S,CH3X2)3.
3-4.2 (8H, m, CH2, CH)〈Compound (
Synthesis of C) and (d)> Tetrol (b) obtained above 15.3(](0
,089 mol), anhydrous pyridine 55d (0,68
-70 mol), in a solution of 1250 ml of CH2CJ
Hensoil chloride 16m (0,138mol >
A mixed solution of 25 ml of anhydrous CH2Cl was added dropwise over a period of 15 minutes, and after the dropwise addition, the mixture was further stirred at -30'C for 1 hour and then at the bottom for 10 hours. After confirming the completion of the reaction with an N-layer romatograph, the solvent was distilled off under reduced pressure. did.

To this residue was added 11.2 d of methanesulfonyl chloride (0,
144 mol) was added over 20 minutes at 0°C, and the suspension was further stirred at the bottom for 3 days. After confirming the completion of the reaction by thin layer chromatography, 100 parts of a mixed solvent of ethyl ether:hexane = 7:3 (by volume) was added to the reaction mixture, and the yellow suspension was filtered through Celite-545 to remove the solvent. was distilled off under reduced pressure. 1q of the brown residue was dissolved in CH2Cl.
The mixture was diluted with 2 and acidified with concentrated hydrochloric acid, and then extracted with CH2Cb three times. The extract was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain optically active compounds (2R, 3R,
4R.

Acetonide (C) 42(), a brown semi-solid substance of 5R) body, was obtained (where MS is a methyl sulfoxy group and pH is an engineering group). After stirring for 15 hours, the reaction solution was filtered through Celite-545, the filtrate was concentrated under reduced pressure at 40'C, 30 ml of a mixed solvent of ethyl ether:hexane = 7:3 (volume) was added, and the mixture was filtered through Celite-545 again. The solvent was distilled off under reduced pressure at 40°C, and a crude product was obtained by steaming under reduced pressure. This is roughly recrystallized from benzene to obtain a pure optically active product (23,3R,4R
, 5S) dieboxide (d) 2.7(] (yield 21%) was obtained.

(C) 'HNMR (CD(llff13) δ:t39 (6H,S,CH3X2)2.6
~2.9 (4H, m, CH2X2)2.95~
3.12 (2H, m, CH) 3.7-3.95
(2H, m, CH) <Synthesis of compounds (e) and (f)> A separately prepared concentration 1.
A solution of 47nof of n-butylmagnesium bromide in ether 64d (94 mmol) was added over 5 minutes at 0°C. After roughly stirring for 5 minutes, a solution of diepoxide (d) 6.48 () obtained above in 50r111 of anhydrous tetrahydrofuran was added dropwise over 10 minutes with stirring at 0°C, and the mixture was roughly stirred for 1 hour.Completion of the reaction. After confirming by thin-layer chromatography, it was decomposed with NH4α and saturated saline, stirred for 30 minutes, extracted three times with ethyl ether,
The ether layer was sequentially washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent of the filtrate was distilled off to obtain the optically active (6
3,7R,8R,98) crude diol (e-1>) was obtained.

The crude diol (e-1) obtained above was dissolved in 30 ml of anhydrous tetrahydrofuran, and 0.0 mL of sodium hydride was added to the solution.
48 g (1.07 mmol) of 100 parts of anhydrous tetrahydrofuran was added dropwise over 15 minutes under reflux, and the mixture was roughly stirred and refluxed for 1 hour, and then cooled to 0'C. To this suspension were added 6132 mg of DC-18-crown ether and 9.1 mg of benzyl bromide. , W (78 mmol) were added at 0°C, and the mixture was stirred and refluxed for 4 hours. The reaction solution was concentrated under reduced pressure, decomposed with 1N hydrochloric acid, extracted three times with hexane, the extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Acetonide (e-2) of the optically active (63,7R,8R,9S) form shown by the chemical formula
> obtained.

OH0Bn (However, Bn represents a benzyl group) The above acetonide (e-2> was dissolved in 100 ml of 80% acetic acid.
After heating and stirring at 00°C for 10 hours, the solvent was distilled off under reduced pressure.
Next, it was extracted with ethyl ether, the extract was washed with an aqueous solution of caustic soda, and the aqueous layer was roughly extracted with ethyl ether.
These ether layers were combined, washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine, and dried over anhydrous magnesium sulfate.

After removing the solvent, it was purified by silica gel column chromatography and eluted with ethyl ether:hexane = 1:4 (volume)), and the optical activity represented by the following chemical formula (6S, 7R,
8f? , 9S) diol (f) 8.66 g (
A compound (yield 55% from d>) was obtained.

(However, Bn represents a benzyl group) 'HNMR (CDC13) δ: 0.88 (6H, br, CH: l X2
)1.0~1.8 (t6H,m, CH2X8)
3.4-3.7 (4H, m, CH) 4.46
(2H, d, J=10.8Hz, CH)4.62
(2H, d, J=10.81(z, CH)
7.30 (10H,S,C6H5)〈Compound (
Synthesis of 3)> 200 mg of the diol (f) obtained above, K2C
0360m (J) and 260mg of lead tetraacetate were added to 4.5d of anhydrous benzene at 4°C and stirred for 3 minutes. After the reaction, 100Ir11 of hexane was added, filtered using Celite-545, and the filtrate was diluted with saturated sodium bicarbonate solution. The aqueous layer was extracted twice with hexane, and the hexane layers were combined and washed with saturated brine, then dried over anhydrous magnesium sulfate. After distilling off the solvent, silica gel column chromatography (ethyl ether:hexane=1: 2 (volume)) and purified with (S)
-2-benzyloxyheptanal (3) 160 mg (
A yield of 80% was obtained.

(However, Bn represents a benzyl group) 'HNMR (CDCex) δ: 0.87 (3H, t, J = 5.8Hz
.

CH3) 1.0-1.8 (8H, m, CH2) 3.73
(IH, dt, J = 2.2Hz.

6.2H2,CH) 4.51 (IH,d, J=11.6
H2, CH) 4.65 (IH, d, J=11
．． 6H7,CH)7.34 (5H,S,C
6Hs >9.64 (IH, d, J= 2
．． 2H2) <Synthesis of compound (4)> (S)-dibromide 4.8C1 (16,
13 mmol 1) of anhydrous tetrahydrofuran 100I11
N was cooled to -78℃ and the concentration was 1.62m under nitrogen atmosphere.
Butyllidium hexane solution of ol 16.4m! (2
6.6 mmol) was added dropwise over 10 minutes, and -78
The mixture was stirred for roughly 1 hour at ℃ and 1 hour at room temperature to convert it into optically active lithium acetylide (2'), which was then cooled to -78℃ to convert the above-obtained (S)-2-benzyloxyheptanal ( 3) 2.41(1(4,4111m01>
20 ml of anhydrous tetrahydrofuran was added dropwise, and after further stirring for 30 minutes, the mixture was decomposed with an aqueous ammonium chloride solution, extracted three times with ethyl ether, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (ethyl ether nihexane = 1:3 (volume)) to obtain the following chemical formula (4
) Represented by (28.63> compound 3. slg
yield of 64%). This product was a mixture of erythro-nidoreo-64 and 36 (weight).

(However, Bn represents a benzyl group) <Synthesis of compound (5)> 680 mg of anhydrous dimethyl sulfoxide (8.7 mm
ol > anhydrous methylene chloride 157! Add 0.38 d (4.4 mmol) of oxalyl dichloride to the solution at -7
The mixture was added dropwise at 0° C. over 5 minutes and roughly stirred at the same temperature for 10 minutes. In addition to this, the erythro body Nidoreo body-6 obtained above
4: 38 compound (4) 1.0012.9mmo
4 ml of anhydrous methylene chloride was added dropwise at -70°C for 9 minutes.
It was stirred with Add to this 2.0rdl of anhydrous triethylamine
(14 mmol) was added dropwise and the temperature was gradually returned to room temperature, then hexane was added and the mixture was filtered through Celite-545, and the filtrate was washed with 1N hydrochloric acid. The aqueous layer was extracted three times with methylene chloride, and the extract was washed with saturated brine and dried over anhydrous magnesium JR acid. The solvent was distilled off under reduced pressure and subjected to silica gel column chromatography (ethyl ether:hexane=
1:10 (volume)) and purified with the following chemical formula (
23.63>-modinyl ketone derivative (5) 550
m(] was obtained (yield 55%).

(However, 3n represents a pencil group) 'HNMR (CDCb) δ: 0.86 (3H, br
t, J=7.2NZ.

CH3) 1.0-1.9 (8H, m, CH2) 1.38
(3H, s, CH3) 1.47 (3H,
S, CH3) 4.02 (1H, dd, J=
5.6Hz.

8.241+2. CH) 4.18 (II-(, dd, J= 6.4H
2゜8.24Hz, CH) 4.42 (IH, d, J=11.5H2,C
H) 4.70, (1H, d, J=11.5H
2, CH) 4.86 (1H, dd, J= 5
．． 6Hz.

6.4H7,CH) 7.31 (5H,S, Cc+Hs)IR
l/maX (neat> 695, 735. 835.1060.1220.1
320°1370, 1380.1450.1675.2
200.2860゜2920,3020cnrl <Synthesis of compound (6)> Ethynyl ketone derivative (5) of the (23.6S) form obtained above was added to 550 mg (1.6 mmol) of anhydrous ether 16 ml at -30'C. 0.26...01 zinc borohydride-ethyl ether solution 9.6d (2,5
mmol) was added dropwise over 5 minutes under a nitrogen atmosphere, and the mixture was roughly stirred for 30 minutes. After the reaction was completed, water and 20 ml of 0.5N Shioshun were added, and the mixture was stirred at 0°C for 30 minutes. The aqueous layer was extracted three times with ethyl ether, and the extract was washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. Remove the solvent under reduced pressure and perform silica gel column chromatography (ethyl ether:hexane = 1:3 (volume)).
) and purified by the following chemical formula (2S, 5R, 6
349 mg of the ethynyl alcohol derivative (6) (erythro form and nidoleo form = 90:10 (weight)) was obtained (yield: 63%).

(However, Bn represents a benzyl group) 'HNMR (CDCb) δ: 0.87 (3H, br t, J = 7
．． 2Hz.

CH3) 1.0-1.8 (8H, m, CH2) 1.36
(3H,S,CH3)1.45 (3H,
S, CH3) 3.49 (IH, dt, J=
3.8H2゜6.4H2, CH) 3.88 (IH, dd, J = 6.4H2゜7.7H2, CH) 4.12 (IH, dd, J = 6.4Hz.

7.7H7,CH) 4.4~4.7 (11-1,m, J= 1.5H
z.

3.8+12. CH) 4.59 (2H, s, CH2) 4.69
(11-1, ddd, J= 1.5Hz.

6.4H2,6,4H2,CH) 7.30 (5H,S, Cs Hs)”C
NMR (CDCI13) δ: 13.98. 22.54. 25.27.
25°96. 26.22゜30.0&, 31.8
5. 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)> Ethynyl alcohol derivative (6) of the (2S, 5R,68) form obtained above 10bmc+ (0,30m
24.1 mg (0.63 m mol) of lithium aluminum hydride was added to anhydrous tetrahydro 7 run 2d solution
> into 5 ml of anhydrous tetrahydrofuran at O'C,
Stir and reflux for 18 minutes. After the reaction was completed, ethyl acetate, ethanol, water, and 0.1N 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 purified by silica gel column chromatography (ethyl ether:hexane = 1:3 (volume)) to obtain a product represented by the chemical formula below. (23.5R,63) allyl alcohol derivative <7) 80.1 mg was obtained (yield 7).
6%).

(However, 3n represents a benzyl group) 'HNMR (, CDCb) δ 20.86 (3H, t, J=
5.4Hz.

CH3) 1.38 (3H, S, CH3) 1.40
(3H,s, CH3) 1.04-4.8
(8H, m, CH2) 3.2~3.5 (IH
, m, Ct-()3.52 (IH, dd,
J = 7.7tlz.

7.7Hz, CH) 4.08 (1.dd, J= 6.4H2
゜8, OH2, C)-1>"CNMR (CDCb) 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 Synthesis of compound (B)〉 Allyl alcohol derivative (7) of the (23.5R,63) form obtained above 80.1m(] (00,23mmo
l ), triethyl orthoacetate 0.15 ml (
0.82 mmol) and a catalytic amount of heptanoic acid were heated and reacted in xylene 3d at 160°C for 20 minutes, the xylene and the produced ethanol were deposited under reduced pressure, and after the reaction was completed, they were decomposed with saturated sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl ether, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the product was purified by silica gel column chromatography (ethyl ether: hexin = 1:10 (volume)) to obtain the (1°S, 38.63) form of γ-unsaturated carboxylic acid represented by the chemical formula below. 65.6 mg of ethyl (B) was obtained (yield 68%).
).

(B) (However, Bn represents a benzyl group) 'HNMR (CDCI13) δ: 0.86 (3H, br t, J = 7
．． 2Hz.

CH3) 1.0 to 1.8 (8H, m, CH2)1.
33 (3H,S,CH3)1.41 (
3H, S, CH3) 2.40 (IH, dd,
J = 9.0Hz.

14.7Hz, CH) 2.50 (IH, dd, J = 5.1Hz.

14.7H2, CH) 2.6-3.0 (IH, m, CH) 3.5-3.8
<2t-1,m, CH2) 3.9~4.3
(2H, m, CHx2 >4.09 (2H,
Q, J= 7°2tlz.

Cf-ho) 4.31 (IH, d, J=11.7NZ.

CH208H5) 4.55 (IH, d, J=11.7112°CH2C8H5) 5.2~5.7 (2H, m, = Chl-) 7.27
(5th, S, 06 H5)”
CNMR (CDCfh) δ: 14.00. 14.25. 22.
59. 25.03. 26.30°31.77,
35.72. 3B, 50. 41.77, 60.
32°6 &, 81. 69.79. 77.30. 7
9.74.109.08゜127.28.127.72
．． 128.20.130.84.134.45゜139
．． 00.171.79 Synthesis of compound (P)>
Unsaturated ethyl carboxylate (B) 65m(J (0,
16m not), methanol 5Uil, water 1.2
5d and CuSO4・5H20186mg (0,75m
mof> was stirred and refluxed for 13 hours. After the reaction was completed, ethyl ether was added and the mixture was filtered through Celite-545. The filtrate was washed with saturated brine and dried over anhydrous magnesium balate. After distilling off the solvent under reduced pressure, silica gel column chromatography (ethyl acetate:hexane = 1:5 (container)
) is purified by the following chemical formula (33. 3'S,
35.5 mg of γ-lactone derivative (P) of 43> form was obtained (yield 69%).

(However, 3n represents a benzyl group) 'HNMR (CD(1'3 > δ: 0.86 (3H, br t, J = 7
．． 2! lz.

Ct-h) 1.0 ~ 1.8 (81-1, m, CH2)
3.72-3.9 (5H, m, CH2, CH)4.
4-4.7 (IH, m, CH) 4.36
(1H, d, J=11.7Hz.

CH2) 4.51 (IH, d, J = 41.7Hz.

CH2) 5.55 (IH, dd, J = 6.7Hz.

15.4Hz, =CH) 5.68 (1H, dd, J= 1 in 7.7t
5.4NZ, =CH) 7.29 (5H,S, Cs Hs)13
CNMR (CDC13) 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 (Effects of the Invention) The present invention is a method for producing an optically active γ-lactone derivative, which is a key intermediate for prostaglandin synthesis. Moreover, it can be manufactured efficiently.

Claims (1)

[Claims] (1) The following general formula (B) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(B) (In the above general formula (B), R^1 may have an alkoxy group A group having 1 to 12 carbon atoms selected from an alkyl group, a cycloalkyl group, and an aralkyl group having a heteroatom in an aromatic ring or an alkyl group, R^2 is a hydrogen atom or 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 *
A method for producing an optically active γ-lactone derivative represented by the following general formula (P), which comprises intramolecularly closing an optically active compound represented by (the symbol represents an asymmetric carbon atom) in the presence of an acid catalyst. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the above general formula (P), the signs R^1, R^2, and * have the same meaning as the signs R^1, R^2, and * in general formula (B). represents. (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 any one of claims 1 to 3, wherein R^2 in general formula (P) is an aralkyl group. (5) The method according to claim 4, wherein the aralkyl group is a benzyl group. (6) The compound of general formula (P) has optical activity (3S, 3'S
, 4S) is the production method according to any one of claims 1 to 5.