JPH035475A - Optically active compound and its production - Google Patents

Abstract

NEW MATERIAL:The optically active compound of formula I [R<1> is 1-12C group selected from (alkoxy)alkyl, cycloalkyl and aralkyl having hetero atom on aromatic ring or alkyl; R<2> is H or easily eliminable protecting group selected from acyl, silyl, aralkyl and alkyloxyalkyl; R<4> is 1-5C lower alkyl; * represents asymmetric carbon atom]. EXAMPLE:The compound of formula II. USE:Useful as a production raw material for optically active gamma-lactone derivative which is a key intermediate for the synthesis of prostaglandin. PREPARATION:The objective compound of formula I can be produced by reacting a compound of formula III with a trialkyl orthoacetate of formula IV (R<4> is 1-5C lower alkyl) in the presence of an acid catalyst under heating. The starting compound of formula III can be synthesized from a compound of formula V via several steps.

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, Kavvamoto, T, 5uzuki: J
, Am, Chem, Soc,, 100.

8272 (1978)), the following general formula (P) R2 (In the above general formula (P), R1 is an alkyl group, a cycloalkyl group, an aromatic ring, or A group having 1 to 12 carbon atoms selected from aralkyl groups having a heteroatom in the alkyl group, R2 is a hydrogen atom or an easily removable protected group selected from acyl groups, silyl groups, aralkyl groups, and alkyloxyalkyl groups. The present invention relates to an optically active compound which is an intermediate for producing an optically active γ-lactone derivative represented by a group (wherein the symbol * represents an asymmetric carbon atom), and a method for producing the same.

(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 optically active raw materials. 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 discovered that the compound represented by the above general formula (P), which is a key intermediate, can be produced more easily and efficiently than before. The present invention provides an intermediate obtained in the process of this production and a method for producing the same.

The present invention is based on the following general formula (△) (in the above general formula (A>), R1 is an aralkyl group having a hetero atom in an aromatic ring or alkyl group, an alkyl group that may have an alkoxy group, a cycloalkyl group, and an aromatic ring or an aralkyl group having a heteroatom in the alkyl group. A selected group having 1 to 12 carbon atoms, 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, R
4 represents a lower alkyl group having 1 to 5 carbon atoms, and the symbol * represents an asymmetric carbon atom) and a method for producing the same.

Specific examples of R1 in the above general formula (A) include methyl, ethyl 210 biru, and isopropyl.

Butyl, inbutyl, pentyl, isopentyl 22.2
-dimethylpentyl, hexyl, 2-hexyl, hepdyl, 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 group or cycloalkyl group optionally having an alkoxy substituent such as 2-methylcyclohexyl, 4-n-propylcyclohexyl, phenyloxymethyl, 3-trifluoromethylphenyloxymethyl, 2 -Chlorothiophen-5-yloxymethyl, furan-2-yl-2-ethyl, and other aralkyl groups having a heteroatom in an aromatic ring or an alkyl group can be mentioned.

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

Specific examples of R4 in the above general formula (A>) include groups such as methyl, ethyl, propyl, butyl, and pentyl.

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 -05H1
1-1R is (CH2) 6COOH or CH2CH=C
It is known that it is important for the expression of physiological activity that the substituent group R1 has lipid solubility. 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, Alkyl groups such as hexyl, 2-hexyl, heptyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxy-1-methylpentyl, cyclopentyl, 3-
Cycloalkyl groups such as ethylcyclopentyl, 4-propylcyclohexyl, phenyloxymethyl, 3-trifluoromethylphenyloxymethyl, 2-chlorothiophen-5-yloxymethyl, furan-2-yl-
It has been revealed that aralkyl groups such as 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-unsaturated carboxylic acid derivative represented by the general formula (A>) of the present invention will be explained below according to the synthetic route. In the following, X represents a halogen atom and M represents an alkali metal.

(1) (2') (4) Ku2) (5) (6) (B) (A> In the above reaction, n-butyllithium, t-butyllithium, methyllithium, lithium diisopropyl is added to the halogen compound (1). Acetylene compound (2) is produced by reacting with a strong base such as amide, and then alkali metal acetylide (2') is produced by using these strong bases. Compound (4) is produced by reacting optically active aldehyde (3) with this. can get.

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°C to 0°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 a mixture of erythro form (6-1) and threo form (6-2) as shown by the following chemical formula.

(6-1-H) From this mixture, erythro form (6-1> or threo form (6-1)
-2> can be separated by column separation etc., but each optical isomer can be easily and more selectively produced by the chemical method described in 1. . This compound (4) has an oxidizing agent,
For example, Cr03-pyridine, dimethyl sulfoxide (D
The ethynyl ketone derivative of compound 5) can be obtained by oxidation using MSO)-acid halide or the like.

The reaction for synthesizing the optically active ethynyl alcohol derivative (6) from the compound (5) is carried out in such a way that the ethynyl alcohol derivative (6) to be iq is either the erythro form (6-1>) shown in the above chemical formula or the threo form. The reaction conditions differ depending on whether (6-2>).In other words, the erythro form (6-2>
1>, the compound 5) is a borohydride zinc complex (Zn (BHa) 2), and when the purpose is the threo form (6-2>, an alkali metal selectride, such as potassium selectride) is used. By reducing with , the ethynyl alcohol derivative 6) having the desired configuration can be obtained with good selectivity.

The above ethynyl alcohol derivative (6) is then led to the allyl alcohol derivative (B) 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 (B) is an acid catalyst 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). The γ-unsaturated carboxylic acid derivative (A>) which is the object of the present invention can be obtained by carrying out a heating reaction in the presence of and carrying out a Johnson-Claisen rearrangement reaction.The above general formula (
Examples of the trialkyl orthoacetate in D) include trimethyl orthoacetate, triethyl orthoacetate, tripropyl orthoacetate, tributyl orthoacetate, triheptyl orthoacetate, etc., in an amount of 2 to 10 times equivalent to the allyl alcohol derivative (B). used, toluene, xylene.

The reaction is carried out in a solvent such as mesitylene at a temperature of 130-180'C. Lewis acids and Lewis acid complexes (
For example, organic acids such as BF3.(C2R5) 20) and heptanoic acid are used.

Halogen compound (1) as a starting material in the above reaction
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 (R1, R2 and * of A>
, and X and Y each independently represent a hydroxyl group or an acyl group.

A group selected from a sulfoxy group and a halogen atom or (C) Ca") (d> (f) (3) The above optically active mannitol is reacted with acetone in the presence of an acid catalyst to form triacetonide (a), and this is Tetraol (b) is partially hydrolyzed with aqueous acetic acid, and its -class and secondary hydroxyl groups are selectively converted into acyl with triphenylphosphine-CCJla, acid halide-pyridine, pyridine-methanesulfonyl chloride, etc. group, sulfoxy group or halogen atom to give acetonide (C).Then, this acetonide (C) is converted into acetonide (C).
After converting C) to diepoxide (d) with a base, R3MgB
r, R3MgBr-CCl2 (CN)2゜R3Li
(However, R3 represents a group with one less carbon number than R1) or lithium aluminum hydride to introduce the R1 group, and roughly react the hydroxyl group with R2X'(X' is a halogen atom or a sulfoxy group). After acetonide (e) is hydrolyzed to give rSchiff J −/l, (f), it can be oxidized with Pb(OAc)a, Na104, etc. to obtain the desired optically active aldehyde (3). .

The optically active T-unsaturated carboxylic acid derivative represented by the general formula <A), which is the object of the present invention obtained above, is a compound (P ) can be converted into T-lactone derivatives.

(A) 0 R2 (P) In the above reaction, γ-unsaturated carboxylic acid derivative (A)
When the acetonide of this product is ring-opened with an acid catalyst and intramolecularly lactonized, it becomes an optically active r-lactone derivative (P).
is obtained. Hydrolysis of acetonide in this reaction can be carried out using hydrous organic acids, alcohols such as methanol and ethanol,
Mineral acid or BF3 in a solvent such as acetone or dioxane.
It can be carried out using an ether complex, a Lewis acid such as CLISO4, Zn5Oa, or a Lewis acid complex at a temperature of air temperature to 80°C.

The compound of general formula (P) thus obtained can be converted into prostaglandin (the above-mentioned PGE, PGF) according to the above-mentioned prostaglandin synthesis method of G. 5tork et al. Therefore, in the present invention, the optically active compound of general formula (A>
The steric configurations at the 3rd, 3rd and 6th positions are all required to be S.

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

(Example) Example <Synthesis of compound (a)> After 45 (l) of D-mannitol was stirred vigorously in 1 g of acetone and 1 d of concentrated hydrochloric acid under air temperature for 3 days, 50 (l) of potassium carbonate was added and 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 to obtain 45 g of a crude product. This was heated and dissolved in 20rn1 of ethanol and then filtered, the filtrate was cooled to air temperature, the precipitated crystals were collected by filtration, and the optical activity (2R, 3R, 4
R,5R) triacetonide (a) 37.3q(
A yield of 50% was obtained.

(0,72(II>) was filtered off, and acetone was distilled off from the filtrate under reduced pressure to obtain a syrup-like product.
After recrystallization at 0d, the optical activity (2R
, 3R, 4R, 5R) tetraol (b) 8.8 g
(yield 80%).

'HNMR (CCIla) δ: 1.40 (6H,S,CH3X2)1.
43 (12H,S, CH3X4) 3.7~
4.4 (8H,m,CH2,CH) compound (b)
Synthesis of triacetonide (a) 15(J(0,
05mol) to 70% vinegar! 3.5 at 40'C in 50m1
After stirring for an hour, it was quickly concentrated under reduced pressure at 40°C.
D-mannitol'H crystallized by adding acetone to the residue
NMR (D20) δ: 1.38 (6H,S, CH
3X2) 3.3~4.2 (8H, m, CH2,
CH) <Synthesis of compounds (C) and (d>> Tetraol (b) obtained above 15.3 g (0,
069 mol), anhydrous pyridine 55d (0,68
mol >, -7 in a solution of 1250 ml of CH2CJ
Benzoyl chloride 16d (0,138 mol
), a mixed solution of 25 m of anhydrous CH2Ce was added dropwise over 15 minutes, and after the dropwise addition, the mixture was further stirred at -30'C for 1 hour and at air temperature for 10 hours. After confirming the completion of the reaction with thin layer chromatography, the solvent was distilled off under reduced pressure. I left.

To this residue was added 11.2 d of methanesulfonyl chloride (0,
144 mol> was added over 20 minutes at O'C and the suspension was further stirred at room temperature for 3 days. After confirming the completion of the reaction by thin layer chromatography, 100 mZ of a mixed solvent of ethyl ether:hexane = 7:3 (volume) was added to the reaction mixture.
was added, and the yellow suspension was filtered through Celite-545, and the solvent was distilled off under reduced pressure. The resulting brown residue was dissolved in CH2C.
After diluting with l2 and making it acidic by adding concentrated hydrochloric acid, CH2Cf
12 and extracted three times. The extract was washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the optically active compound (2R,
3R, 4R.

42 g of acetonide (c), a brown semi-solid substance of the 5R) form, was obtained.

(C) (However, MS represents a methylsulfoxy group, and pH represents an engineering group) The above acetonide (C) 42L K2 CO320C
After stirring 15 h in 130 d of methanol, the reaction solution was filtered through Celite-545, and the filtrate was heated at 40'C.
Concentrate under reduced pressure with
The solvent was distilled off under reduced pressure at 40°C, and a crude product was obtained by distillation under reduced pressure. This is roughly recrystallized from benzene to obtain a pure optical activity (23,3
2.7 g (yield 21%) of diepoxide (d) of R, 4R, 53) form was obtained.

'HNMR(CDCb) δ:1.39 6H,S,CH:IX2)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)> Cu2 (CN)2 320 mg, anhydrous tetrahydrofuran 100rd! A separately prepared concentration 1.
A solution of 47 mol of butylmagnesium bromide in ether (94 m not ) was added over 5 minutes at o'c. After roughly stirring for 5 minutes, a solution of the diepoxide (d>6.48a) obtained above in 50 d of anhydrous tetrahydrofuran was added dropwise over 10 minutes with stirring at O'C, and the mixture was stirred roughly for 1 hour. After confirming with layer chromatography, it was decomposed with NHa Cfl and saturated brine, stirred for 30 minutes, extracted three times with ethyl ether, and the ether layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. It was dried over anhydrous magnesium sulfate and filtered, and the solvent of the filtrate was distilled off to obtain the optical activity (68
, 7R, 8R, 9S) crude diol (e-1) was obtained.

The crude diol (e-1> obtained above was dissolved in 30 rrdl of anhydrous tetrahydrofuran, and 10 hj! of anhydrous tetrahydrofuran containing 0.48a (1,07 mmol) of sodium hydride was added dropwise thereto over 15 minutes under reflux.
After roughly stirring and refluxing for 1 hour, the mixture was cooled to 0°C. To this suspension, 2 m (l) of DC-18-crown ether and 9.3 m (78 m mol) of benzyl bromide were added at O'C, and the mixture was stirred and refluxed for 4 hours. 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 to obtain the optically active compound (63, 7R, 8R, 93) acetonide (
e-2> was obtained.

(eluted with ether:hexane=1:4 (volume)), optical activity represented by the following chemical formula (63,7R,8R,9S)
8.86 g of diol (f) (yield 55% from compound (d)) was obtained.

(However, 3n represents a benzyl group) The above acetonide (e-2>) in 80% vinegar 11007
After heating and stirring at 0'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 further 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 evaporating the solvent, it was purified by silica gel column chromatography (however, Bn represents a benzyl group) 1HNMR (CDC13) δ: 0.88 (8H, br, CH3X2 >1
．． 0 to 1.8 (16H, m, CH2X8 >3.
4-3.7 (4H, m, CH) 4.46 (
2H, d, J=10.8112. CH) 4.62
(2H, d, J=10.8H2,CH)7.3
0 (10H,S, Cs Hs)〈Compound (
Synthesis of 3)> 200 mg of the diol (f) obtained above, K2C
0360 mg and 4.5 d of anhydrous benzene
60 mg was added at 4°C and stirred for 3 minutes. After the reaction, 100r111 of hexane was added, filtered through Celite-545, the filtrate was washed with saturated aqueous sodium bicarbonate, the aqueous layer was extracted twice with hexane, the hexane layers were combined and washed with saturated brine, and then anhydrous sulfuric acid was added. Dry with magnesium. After distilling off the solvent,
Purified by silica gel column chromatography (ethyl ether:hexane = 1:2 (volume)) to obtain (S)-2
-Benzyloxyheptanal (3) 160n+g
(yield 80%).

3.73 (1H, dt, J= 2.2t(z
.

6.2H2, CH) 4.51 (IH, d, J=11.6H2,
Cl-1>4.65 (IH, d, J=11.
6Hz, CH)7.34 (5H,S, Ce
Hs ) 9.64 (IH, d, J
= 2.2Hz><Synthesis of compound (4)> Chemical formula (1) below (however, Bn represents a benzyl group) 'HNMR (CDC13) δ: 0.87 (3H, t, J = 5.8Hz
.

4.8 g (16.8 mmol) of (S)-dibromide represented by CH3) 1.0 to 1.8 (8H, m, CH2)
10 M of anhydrous tetrahydrofuran was cooled to -78°C, and 16.4 d (26.6 mmol) of a butyllithium-hexane solution with a concentration of 1.62 mol was added under a nitrogen atmosphere.
was added dropwise over 10 minutes, and then heated at -78°C for approximately 1 hour.
Stir at air temperature for 1 hour to obtain optically active lithium acetylide (2
') and cooled to -78°C to obtain the above-obtained (S) = 2-penzyloxyheptanal (3) 2
．． 41 g (4.4 mmol) of anhydrous tetrahydrofuran (20 d) 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 subjected to silica gel column chromatography (ethyl ether:hexane=1:3 (volume)).
It is purified by the following chemical formula (4) (28.6S
) compound (3.81 g) was obtained (yield 64%). This product was a mixture of erythro and nidoleo forms = 64:36 (by weight).

(However, Bn represents a benzyl group) <Synthesis of compound (5)> 680 mg of anhydrous dimethyl sulfoxide (8.7 m mo
0.38 d (4.4 mmol) of oxalyl dichloride was added to 15 ml of anhydrous methylene chloride solution of -70
The mixture was added dropwise over 5 minutes at ℃, and further stirred at the same temperature for 10 minutes. In addition to this, the erythro body obtained above and the Nido leo body = 64
:36 compound (4) 1.00(1(2.9m mol
) of anhydrous methylene chloride was added dropwise at -70°C for 9 minutes.
It was stirred with This was added with 2.0 parts of anhydrous triethylamine (1
4m mo! ) 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 sulfate. The solvent was distilled off under reduced pressure and subjected to silica gel column chromatography (ethyl ether:hexane = 1:10).
(volume)) and is purified by the following chemical formula (23.6
3) ethynyl ketone derivative (5) ssomg was obtained (yield 55%).

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

CH3) 1.0-1.9 (8H, m, CH2) 1.38
(3H,S,CH3)t,47 (3H,
S, CH3) a, o2 (IH, dd, J=
5.6Hz.

8.24tlZ, 0H) 4.18 (IH, dd, J = 6.4Hz.

8.24H2, CH) 4.42 (11=l, d, J=11.5H
7, CH) 4.70 (IH, d, J=11.
5Hz, CH) 4.86 (1H, dd, J
= 5.6H2゜8.4NZ, CH) 7.31 (5H,S, Cs Hs)IR
νmax (neat) 695, 735. 835.1060.1220.1
320°137C), 13B0.1450.1675
．． 2200.2B60゜2920, 3020Cm-1 <Synthesis of compound (6)> The above-obtained (23.63>-ethynyl ketone derivative (5)) was added to 550 mg (1.6 mmol) of anhydrous ether 16d at -30°C. 9.6 m of zinc borohydride-ethyl ether solution with a concentration of 0.26 mol (2.5 m
mol> 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 0.5 N hydrochloric acid 2 (7) were added and stirred at 0°C for 30 molecules. The aqueous layer was extracted three times with ethyl ether, and the extract was sequentially extracted with saturated water and saturated brine. It was washed and 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 the (23.5R, 63) ethynyl alcohol derivative (6) (erythro 349 mg (yield: 6
3%).

(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, CI-(3)1.45 (
3H,s,CH3)3.49 (,IH,dt,
J = 3.8H2゜6.4H2, CH) 3.88 (IH, dd, J = 6゜4H2゜7
．． 7Hz, CH) 4.12 (IH, dd, J= 6.4H2゜7.7Hz, CH) 4.4~4.7 (IH, m, J= 1.5Hz.

3.8H2,Cl-1>4.59 (2H,S,CH2)4.69
(1H, ddd, J= 1.5Hz.

8.4H2,6,4H2,CH) 1゜30 (5H,S,C6H5)13CNMR
(CDα3) δ: 13°98. 22.54. 25.27. 25
．． 9 &, 26.22°30.06. 31.85.
64.16. 65.57. 69.94°72.4
9. 81.50. 83.70. 84.00.10
0.31゜127.83.128.40.138.21
<Synthesis of compound (B)> Ethynyl alcohol derivative (6) of the (2S, 5R, 63) form obtained above 105m(] (00,30m
mol> of anhydrous tetrahydrofuran to 24.1 mg of lithium aluminum hydride (0.63 m mof
) in 5 rni of anhydrous tetrahydrofuran at 0°C, and the mixture was stirred and refluxed 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. A (23.5R,63) allyl alcohol derivative (B) 8o, img was obtained (yield 76%).

(However, Bn represents a benzyl group) 'HNMR (CDCf'3) δ: 0.86 (3H, t, J = 5.4tl
z.

CH3) 1.38 (3H,S, CH3) 1.4
0 (3H,S,CH3)1.04~1.8
(8H, m, CH2) 3.2~3.5 (IH, m
, CH) 3.52 (IH, dd, J= 7.
7Hz.

7.7H2, CH) 4.08 (IH, dd, J = 6.4H2゜8, OH7, CH) r3CNMR (CD (ff13) δ: 14.02. 22.61. 25.46.
25.92. 26.72°29.42. 31.93
．． 69.44. 72.22. 72.56°82.
18.127.72.127.79.128.40.1
29.89゜132.47.140.60 Synthesis of compound (A>) 80.1 mg (0,23 m mo
l ), triethyl orthoacetate 0.15 ml (
Heptanoic acid in an amount of 0.82 mmol> and a ts amount was heated and reacted in xylene 3d at 160'C for 20 minutes, and the xylene and the generated ethanol were distilled off under reduced pressure.
After the reaction was completed, it was decomposed with saturated aqueous 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, it was purified by silica gel column chromatography (ethyl ethyl:hexane = 1':10 (volume M)) to obtain the (1'S, 33.63) form of T-union represented by the chemical formula below. Obtained 65.6 mg of saturated ethyl carboxylate (A>68
%).

○ (A> (3n represents a benzyl group) 'HNMR (CDCb) δ: 0.8B (3H, br t, J= 7
．． 2H2°CH3) t, o ~ta (8H, m, CH2)1.
33 (3H,S,CH3)1.41 (
3H,S,CH3)2.40 (it(,dd,
J=9.0l-IZ.

14.7H2, CH) 2.50 < IH, dd, J= 5.1Hz
.

14.7H2, CH) 2.6-3.0 (IH, m, CH) 3.5-3.8
(2H, m, CH2) 3.9~4.3 (2H
, m, CHx2 >4.09 (2H,Q, J
= 7.21′lZ.

CH20) 4.31 (IH, d, J = 11.7Hz.

CH2Cs Hs) 4.55 (IH, d, J = 11.711Z.

CH2C8Hs) 5.2-5.7 (2H, m, =CH-)7.27
(5H,S,C6H5)13ONMR(CDC
13) δ: 14.00. 14.25. 22.59. 2
5.03. 26.30°31.77, 35.72.
36.50. 41.77, 60.32゜6B, 8
1. 69.79. 77.30. 79.74.10
9.08°127.28.121.72.128.20
．． 130.84.134.45゜139.00.171
．． 79 Using the T-unsaturated carboxylic acid derivative obtained above, which is the target compound of the present invention, according to the following example, the compound represented by the general formula (P), which is a key intermediate for prostaglandin synthesis, is synthesized. An optically active γ-lactone derivative was synthesized.

<Synthesis of compound (P)> 65 mq (0,16 m
mol), methanol 5ml, water 1.25m and Cu5Oa ・5H207861g (0,751n
moi) was stirred and centrifuged 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 sulfate. After evaporating the solvent under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:hexane = 1:5 (volume)) to obtain a product represented by the following chemical formula (33.3"S, 4
35.5 mg of a γ-lactone derivative (P) in the S) form was obtained (yield 69%).

8n (However, Bn represents a benzyl group) 'HNMR (CDC13'') δ: 0.86 (3H, br t,
J = 7.2Hz.

CH3) 1.0~1.8 (8H, m, CH2) 3.72~
3.9 (5H, m, CI-(2, CH) 4.4~
4. '7 (,IH,m,CH)4.36 (I
H, d, J = 11.7Hz.

CH2) 4.51 (IH, d, J=11.7H2゜C
H2) 5.55 (IH, dd, J=
,,6.7Hz.

15.4H2,=CH) 5.68 (IH, dd, J = 7.7t (z.

15.4H7,=CH) 7.29 (5H,S, CB H5)13CN
MR (CDCU3) 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 optically active compound of the present invention is an important compound as a raw material for the production of optically active γ-lactone derivatives, which are key intermediates in prostaglandin synthesis. By using this compound, the key intermediate can be produced relatively easily and efficiently.

Claims (1)

[Scope of Claims] (1) An optically active compound represented by the following general formula (A). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (A) In the above general formula (A), R^1 is an alkyl group that may have an alkoxy group, a cycloalkyl group, an aromatic ring, or a hetero atom in the alkyl group. a group having 1 to 12 carbon atoms selected from aralkyl groups, R^2 is a hydrogen atom or an easily removable protecting group selected from acyl groups, silyl groups, aralkyl groups, and alkyloxyalkyl groups;
R^4 represents a lower alkyl group having 1 to 5 carbon atoms, and the symbol * represents an asymmetric carbon atom. (2) The optically active compound according to claim 1, wherein R^1 in general formula (A) is an alkyl group having 4 to 10 carbon atoms. (3) The optically active compound according to claim 2, wherein the alkyl group is a pentyl group. (4) The optically active compound according to any one of claims 1 to 3, wherein R^2 in general formula (A) is an aralkyl group. (5) The optically active compound according to claim 4, wherein the aralkyl group is a benzyl group. (6) The compound of general formula (A) has optical activity (1'S, 3S
, 6S) compound according to any one of claims 1 to 5. (7) The following general formula (A) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (A) (In the above general formula (A), R^1 is an alkyl group that may have an alkoxy group, a cycloalkyl group and a group having 1 to 12 carbon atoms selected from aralkyl groups having a heteroatom in an aromatic ring or an alkyl group, R^2 is a hydrogen atom or a 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, *
The symbol represents an asymmetric carbon atom) In order to produce an optically active compound represented by the following general formula (B) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (B) (In the above general formula (B), R The symbols ^1, R^2, and * have the same meanings as the symbols R^1, R^2, and * in general formula (A).) The optically active compound represented by the following general formula (D) CH
Heating in the presence of trialkyl orthoacetate represented by _3C(OR^4)_3(D) (in the above general formula (D), R^4 represents a lower alkyl group having 1 to 5 carbon atoms) and an acid catalyst. A method for producing an optically active compound, which is characterized by a reaction. (8) The method according to claim 7, wherein R^1 in general formula (A) is an alkyl group having 4 to 10 carbon atoms. (9) The method according to claim 8, wherein the alkyl group is a pentyl group. (10) The method according to any one of claims 7 to 9, wherein R^2 in general formula (A) is an aralkyl group. (11) The method according to claim 10, wherein the aralkyl group is a benzyl group. (12) The compound of general formula (A) has optical activity (1'S, 3
The manufacturing method according to any one of claims 7 to 11, which is S, 6S) form.