JPH0585541B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to an optically active 1-cyano-2-methylenepentane derivative that is a raw material for producing prostaglandins. (Prior art and problems to be solved) Conventionally, the mainstream method for producing prostaglandins has been to start from Corey lactone or 4-hydroxycyclopentenone, but in order to obtain optically active forms of these raw materials, It is necessary to undergo steps such as optical resolution and asymmetric hydrolysis using microorganisms, which causes problems such as a decrease in yield. (Means for Solving the Problems) The present inventors have conducted intensive studies on a method for producing a prostaglandin intermediate in place of 4-hydroxycyclopentenone, and as a result, as described below, the present inventors have found that halogen or alkyl at the 1-position carbon An optically active cyclopentenone derivative represented by the general formula () below, known as a prostaglandin intermediate, produced by a method using optically active 2,3-epoxypropane () substituted with a sulfonyloxy group or an arylsulfonyloxy group () as a raw material. The present invention provides an optically active compound as an intermediate obtained by a series of these synthetic reactions. The present invention is an optically active 1-cyano-2-methylenepentane derivative represented by the following general formula ().

[Formula] In the above general formula (), R ¹ is easily selected from a hydrogen atom or an alkenyl group, an aralkyl group, an alkyloxymethyl group, a 1-alkyloxyethyl group, a cyclic alkyl group having a hetero atom, and a silyl group. A removable protecting group, R ² is a hydrogen atom or an easily removable protecting group selected from a 1-alkyloxyethyl group, a cyclic alkyl group having a heteroatom, and a silyl group, and X is a halogen atom or
R ⁴ SO ₃ groups, R ⁴ is an alkyl group or an aryl group, *
Each symbol represents an asymmetric carbon atom. In the present invention, specific examples of R ¹ other than a hydrogen atom in formula () include allyl, as an alkenyl group,
Aralkyl groups include benzyl, p-methoxybenzyl, diphenylmethyl, trityl; alkyloxymethyl groups include methoxymethyl, benzyloxymethyl, t-butoxymethyl, 2,2,
2-trichloroethoxymethyl, 2-methoxyethoxymethyl, 1-alkyloxyethyl groups include 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-isopropoxyethyl, and cyclic alkyl groups having a hetero atom include tetrahydro. Pyranyl, tetrahydrofuranyl, silyl groups include trimethylsilyl, triethylsilyl, t
-butyldimethylsilyl, t-butyldiphenylsilyl, methyldi-t-butylsilyl, triphenylsilyl, phenyldimethylsilyl, triphenylmethyldimethylsilyl, and the like. Examples of R ² other than the hydrogen atom in formula () include the same groups as the 1-alkyloxyethyl group, the cyclic alkyl group having a hetero atom, and the silyl group among the above R ¹ . Further, specific examples of Examples include arylsulfonyloxy groups such as oxy and m-chlorobenzenesulfonyloxy groups. Among the compounds represented by the general formula () of the present invention, compounds in which R ¹ is other than a hydrogen atom can be synthesized by the method shown in Reaction Route 1 below. From the obtained compound of formula (), an optically active 2-methylenecyclopentanone derivative () is synthesized, and subsequently, an optically active cyclopentenone derivative (2), which is an intermediate of prostaglandin, is synthesized according to reaction route 2 described below. X). In the following formula, R ³ is an easily removable protecting group selected from an alkyl group and an aralkyl group that may have a halogen substituent, and two
R ³ may be different from each other, and these two
R ³ may be bonded to form a cyclic acetal. X ¹ represents a halogen atom, and the symbol * represents an asymmetric carbon atom. Reaction route 1

[ka]

[Chemical formula] To explain the above reaction, the per se known acetal derivative of 2-halogenoacrylaldehyde () is mixed with tetrahydrofuran, diethyl ether,
Using ethers such as ethylene glycol diethyl ether or hydrocarbons such as hexane, methyllithium, n-butyllithium, sec
- A vinyl anion produced by reacting with an equivalent or more of a strong base such as butyllithium or t-butyllithium is reacted with an optically active epoxy compound represented by formula () in the presence of a Lewis acid such as trifluoroboron etherate. and formula (V-2)
A 4-hydroxy-2-methylenepentane derivative represented by is obtained. This reaction takes place at -30 to -100℃
It is desirable to carry out the test at a low temperature of . Although this reaction proceeds without a catalyst, the addition of a Lewis acid as described above accelerates the reaction. Next, a protecting group is introduced into the hydroxyl group of the compound of formula (V-2) obtained in the above reaction to convert it into a compound of formula (V-1). The introduction of the protecting group R ¹ is carried out by a known method. For example, in the case of an alkenyl group, an aralkyl group, an alkyloxymethyl group, and a silyl group, the corresponding R ¹ Y (Y represents a halogen atom such as chlorine, bromine, or iodine) or more and a base such as triethylamine, ethyl Diisopropylamine, pyridine, 4
- The reaction can be carried out in the presence of an equimolar or more amount of an organic base such as dimethylaminopyridine or imidazole or an inorganic base such as sodium hydride or sodium amide. When R ¹ is a 1-alkyloxyethyl group or a cyclic alkyl group having a hetero atom, introduction is performed using at least an equivalent amount of the corresponding vinyl ether and an acid catalyst, such as hydrogen chloride, p-
The reaction may be carried out using toluenesulfonic acid, pyridine-p-toluenesulfonate, or an acidic ion exchange resin (such as Amberlyst-H15). When the acetal moiety is hydrolyzed in the presence of a weak Lewis acid, the compound of formula (V-1) obtained above is converted to 2
-methylenepentanal derivative () is obtained. This reaction can be achieved by reacting with a weak Lewis acid catalyst such as copper sulfate, zinc bromide, or silica gel in a water-containing solvent, such as a mixed solvent of water and ethanol. Next, the carbonyl group of the compound of formula () is converted into a compound of formula (-2) of the present invention by cyanohydrination. Cyanohydrination can be accomplished using hydrogen cyanide in a conventional manner. A simple method for cyanohydrination is to react with trimethylsilyl cyanide in the presence of a 18-crown ether-6 catalyst to obtain trimethylsilylated cyanohydrin formula (-3), which is then hydrolyzed to form formula (- 2) It can also lead to compounds. This trimethylsilylated formula (-
3) The compound can also be directly derived into the formula (). The optically active 1-cyano-1-pentanol (-2) obtained above has a protective group on its hydroxyl group.
The compound of the present invention can be converted to the compound of formula (-1) by introducing R ² . The protecting group can be appropriately selected from the above-mentioned 1-alkyloxyethyl group, cyclic alkyl group having a hetero atom, and silyl group. In this case, R ² may be the same as or different from R ¹ . The introduction of the protecting group R ² is carried out using the formula (V-
2) It can be carried out using the same conditions as when converting a compound into a compound of formula (V-1). The compound of formula (-1) of the present invention can be converted into a cyclized compound of formula () by reacting it with a strong base. Strong bases include lithium hydride,
Sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, sodium hexamethyldisilazane, lithium hexamethyldisilazane, potassium hexamethyldisilazane, etc. are used, and the reaction temperature varies depending on the type of strong base. , the solvent is selected appropriately. For example, in the case of lithium diisopropylamide, it is preferable to carry out the reaction in diethyl ether or tetrahydrofuran at +60 to -100°C, and when using sodium hexamethyldisilazane, the reaction is carried out in the temperature range of room temperature to 110°C in tetrahydrofuran, dioxane, benzene or toluene. can be done. The amount of strong base used is 1 to 10 times equivalent, preferably 1 to 5 times equivalent, relative to the compound of formula (-1). The above formula () compound is obtained by hydrolyzing its -OR ² groups and then decyanohydrogenating with a base to obtain the formula ()
compound can be obtained. -OR ² can be hydrolyzed using a known method. For example, hydrochloric acid,
Using acids such as p-toluenesulfonic acid and acetic acid, acidic ion exchange resins, Lewis acids such as trifluoroboron etherate, zinc bromide, and aluminum chloride, or weak acids such as pyridine p-toluenesulfonate. 0~ in aqueous solvent
It can be carried out in a temperature range of 100°C. When R ² is a silyl group, it is also possible to deprotect with a quaternary fluorinated ammonium salt such as tetra n-butylammonium fluoride. In the case of an aralkyl group, hydrogenolysis using palladium is also an effective means. Decyanohydrogenation can be performed using inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, ammonia, triethylamine,
This can be achieved by reacting with an equivalent or more of an organic base such as pyridine or 4-dimethylaminopyridine. Specific examples of R ³ and X ¹ in the above reaction formula are as follows. R ³ : Alkyl group such as methyl, ethyl, 2,2,2-trichloroethyl, aralkyl group such as benzyl, R ³ -O-C-OR ³ is an example of two R ^3s bonded together.

【formula】

【formula】

Cyclic acetal X ¹ represented by the formula: chlorine, bromine, iodine Among the compounds represented by the general formula () of the present invention, compounds in which R ¹ is a hydrogen atom can be obtained as follows. First, the formula (V-2) obtained in the reaction route 1
The compound is converted into a compound of formula (V-1) in which R ¹ is an acetyl group using pyridine and acetyl chloride, and this acetal portion is hydrolyzed in the presence of a weak Lewis acid.
A compound of formula () where R ¹ is an acetyl group. Next, this is reacted with trimethylsilyl cyanide to form a compound of formula (-3) in which R ¹ is an acetyl group, and then hydrolyzed under acidic conditions or by treatment with quaternary ammonium fluoride to form a compound of formula (-3) in which R ¹ is an acetyl group.
-2) Use it as a compound. Furthermore, this is reacted with an alkyl vinyl ether, dihydropyran, dihydrofuran, etc. in the presence of an acid catalyst to introduce the necessary protecting group to R ² , and finally the acetyl of R ¹ is removed by a method such as potassium carbonate treatment in methanol. Obtained by eliminating the group. Also, the formula () where R ¹ and R ² are both hydrogen atoms
The compound can be obtained by hydrolyzing a compound of formula () in which R ¹ is a hydrogen atom and R ² is a 1-alkyloxyethyl group or a cyclic alkyl group having a hetero atom under acidic conditions. The Lewis acids used in the above hydrolysis include copper sulfate, zinc bromide, silica gel, boron trifluoride, and the like. The optically active 2-methylenecyclopentanone derivative represented by the general formula () obtained above can be obtained by the method shown in the following reaction route 2, and the optically active 2-methylenecyclopentanone derivative represented by the general formula (X), which is known as a prostaglandin intermediate. This can lead to optically active cyclopentenone derivatives. In the following formula, R ⁵ is a linear or branched alkyl group, an alkenyl group, an alkynyl group that may contain oxygen, sulfur, or silicon;
It represents an alkyl-substituted phenyl group, which may include alkoxy, alkyloxyalkoxy, a cyclic or non-cyclic acetal group, a silyl group, or an alkylthio group, and has 5 to 22 carbon atoms. M is an organozinc compound such as (CH ₃ ) ₂ ZnLi or an organocopper compound such as Cu
(CN)Li, Cu(CN)MgBr, Cu(CN)MgCl,
Cu(CN)Mg, (CuLi) _1/2 , (2-thienyl)Cu
(CN)Li ₂ , Cu(PBu ₃ ) _o (n=2 to 3, Bu is a butyl group), etc. R ⁶ of R ⁶ ZY ¹ is methyl,
phenyl, p-tolyl, p-chlorophenyl, 2
-pyridyl group, Z represents selenium or sulfur, and Y ¹ represents a halogen atom such as chlorine, bromine or iodine, or ZR ⁶ . Reaction route 2

[Chemical formula] A 2-methylenecyclopentanone derivative represented by the formula () is reacted with a separately prepared organometallic compound represented by the formula () to introduce an α chain, and the resulting enolate is reacted with a separately prepared organometallic compound represented by the formula (). The compound is substituted with an organic selenium compound or an organic sulfur compound to obtain a compound of formula (X), which is oxidized using an oxidizing agent such as hydrogen peroxide or an organic peracid, and then heated at 0 to 150°C.
The cyclopentenone derivative (X) can be obtained by carrying out the elimination reaction at a temperature of The organometallic compound R ⁵ M represented by the formula () used above is prepared as follows. Organocopper compounds can ^be prepared by lithiation ^of R ⁵ It can be produced by making a Grignard reagent with metallic magnesium and then treating it with cuprous cyanide, cuprous iodide, or separately prepared (2-thienyl)Cu(CN)Li. Further, the organozinc compound can be obtained by separately reacting a tetramethylethylenediamine complex of zinc chloride with 2 equivalents of methyllithium to obtain dimethylzinc, and adding the reaction solution obtained by lithiation of R ⁵ X ¹ to this. The preparation of R ⁵ M can be carried out in an inert solvent, for example a hydrocarbon such as n-hexane, toluene, an ether such as diethyl ether, tetrahydrofuran, dioxane, or a mixture thereof at a temperature of 0 to -100°C. Specific examples of R ⁵ above are −CH=CH(CH ₂ ) ₃ CH(OC ₂ H ₅ ) ₂ ,

【formula】

【formula】

【formula】

[Chemical] −CH=CH(CH ₂ ) ₄ OSi(C ₆ H ₅ ) ₂ t−C ₄ H ₉ , −(CH ₂ ) ₆ OSi(CH ₃ ) ₃ , −(CH ₂ ) ₃ CH=CHCH( OCH ₃ ) ₂ ,

【formula】

[Formula] etc. The optically active cyclopentenone derivative represented by the general formula (X) obtained above is an acetal of R ⁵ ,
A silyl or alkyloxyalkyl group can be deprotected in the known direction described above to convert it into an aldehyde or alcohol. Synthesis of prostaglandin derivatives from the compound of formula (X) can be performed by known means. (Example) Example 1 <Synthesis of compound of formula (V-2)>

[ka]

[Chemical] Add n-butyllithium to a solution of 9.35 g (44.9 mmol) of 2-bromo-3,3-diethoxypropene in 80 ml of anhydrous tetrahydrofuran cooled to -78°C while stirring under an argon atmosphere for 20 minutes. The solution was added dropwise and further stirred at -78°C for 40 minutes to prepare a vinyllithium solution. On the other hand, optically active (S)-epichlorohydrin (chemical purity of 98.5% or more, optical purity of 99%) cooled to -78°C
% or more) 3.46 g (37.4 mmol) in 70 ml of anhydrous tetrahydrofuran, add 5.31 g of trifluoroboron etherate while stirring under an argon atmosphere.
(37.4 mmol) was added dropwise, and the mixture was further stirred for 10 minutes. The previously obtained vinyllithium solution was added dropwise to the above epichlorohydrin solution at -78°C over 35 minutes.
Stirred for an additional 20 minutes. The reaction mixture was poured into a pre-cooled saturated ammonium chloride aqueous solution with vigorous stirring, the aqueous layer was extracted six times with ether, and the ether extract was washed twice with a saturated ammonium chloride aqueous solution and twice with saturated brine. , dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain optically active 4-hydroxy-2 represented by the following chemical formula.
-Methylenepentane derivative (V-2-a) 6.97g
(yield 84%).

[Formula] X=Cl(V-2-a) X=Br(V-2-b) NMR( _CDCl3 ) δ:1.23 (6H, t, J=7.0Hz,
CH ₃ ) 2.34-2.52 (2H, m, CH ₂ ) 3.25-4.17 (9H, m, CH ₂ O, CH ₂ Cl,
CH, OH) 4.70 (1H, s, OCH-O) 5.14-5.50 (2H, m, = CH ₂ ) In the above synthesis, optically active (S)-epichlorohydrin was replaced with optically active (S)-epichlorohydrin. An optically active 4-hydroxy-2-methylenepentane derivative (V-2-b) represented by the above chemical formula was obtained in the same manner as above except that bromohydrin was used. NMR ( _CDCl3 ) δ: 1.23 (6H, t, J=7.0Hz, _CH3 ) 2.34-2.55 (2H, m, _CH2 ) 3.29-3.80 (8H, m, _CH2O , _CH2Br ,
CH) 3.80-4.14 (1H, m, OH) 4.71 (1H, s, OCH-O) 5.14-5.32 (2H, m, = _CH2 ) <Synthesis of formula (V-1) compound> Optical properties obtained above To a solution of 6.96 g of active 4-hydroxy-2-methylenepentane derivative (V-2-a) in 10 ml of N,N-dimethylformamide, 6.43 g (94.5 mmol) of imidazole was added dropwise at 0°C with stirring, and then t- 14.07 g (51.3 mmol) of butyldiphenylsilyl chloride was added dropwise and stirred on a water bath for a day and night, then neutralized with 3N hydrochloric acid, the aqueous layer was extracted three times with ether, and the extract was extracted twice with saturated aqueous sodium bicarbonate solution. ,
The mixture was then washed three times with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an optically active 2-methylenepentane derivative (V-1) with a protected hydroxyl group represented by the chemical formula below.
-a) 19.96 g was obtained.

[Formula] X=Cl(V-1 ^- a)
The optically active (V-1- b) The compound was obtained. <Synthesis of compound of formula ()> The optically active 2-methylenepentane derivative (V
-1-a) 19.87g in 120ml of 80% methanol aqueous solution
10.09 g of copper sulfate was added thereto, and the mixture was heated and stirred for 1 hour. Filter the reaction mixture through Celite,
300 ml of benzene was added to the filtrate, methanol and water were distilled off azeotropically, the residual liquid was extracted with ether, and the ether extract was washed with saturated aqueous sodium bicarbonate. After the aqueous layer was extracted six times with ether, the extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an optically active 2-methylenepentanal derivative (- a) Obtained 18.66 g.

_[ Formula _] X=Cl( _-a ) J = 5.0Hz, CH ₂ ) 3.94 ~ 4.26 (1H, m, CH) 5.99 (1H, s, = CH) 6.24 (1H, s, = CH) 7.29 ~ 7.91 (10H, m, C ₆ H ₅ ) 9.94 (1H, s, CHO) IR (neat) 1685, 1480, 1100, 700 cm ^-1 In the above synthesis, optically active (V -1-b) Optical activity (-
b) The compound was obtained. NMR (CDCl ₃ ) δ: 1.07 (9H, s, CH ₃ ) 2.43-2.83 (2H, m, CH ₂ ) 3.21 (2H, d, J=5.0Hz, CH ₂ ) 3.86-4.23 (1H, m, CH ) 5.99 (1H, br s, = CH) 6.26 (1H, br s, = CH) 7.29~7.91 (10H, m, C ₆ H ₅ ) 9.94 (1H, s, CHO) IR (neat) 1685, 1580, 1100,700cm ^-1 <Synthesis of compound of formula (-2)> A catalytic amount of potassium cyanide complex of 18-crown ether was added to 18.66 g of the above optically active 2-methylenepentanal derivative (-a) under an argon atmosphere, and the mixture was stirred. 3.65g of trimethylsilyl cyanide
(36.8m mol) was added dropwise. Add 1 more of the reaction mixture
After stirring on a water bath for an hour, tetrahydrofuran
The mixture was diluted with 100 ml, 30 ml of 1N hydrochloric acid was added, and the mixture was stirred for 20 minutes. The aqueous layer was extracted six times with ether, and the extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A crude product of pentane derivative (-2-a) was obtained. Using silica gel column chromatography, this was
Purified product treated with hexane:ether = 8:1 6.14
I got g. Yield from formula (V-2-a) is 47.4%
It was hot. In addition, at this time, the raw material (-a) compound
2.80g was recovered.

[Formula _] X=Cl( _-2 -a ₎ 3.00 to 3.57 (3H, m, CH ₂ , CH) 3.91 to 4.23 (1H, m, CH) 4.71 to 4.96 (1H, m OH) 5.21 to 5.63 (2H, m, = CH ₂ ) 7.25 to 7.91 (1H, m, CH) In the above synthesis, the optically active compound represented by the above chemical formula was produced in the same manner except that an optically active (-b) compound in which X = Br was used instead of the optically active 2-methylenepentanal derivative (-a). (-2-
b) The compound was obtained. NMR (CDCl ₃ ) δ: 1.0 ~ 1.32 (9H, m, CH ₃ ) 2.55 ~ 3.67 (5H, m, CH ₂ , CH) 3.90 ~ 4.21 (1H, m, CH) 4.84 (1H, s, OH) 5.18 ~5.67 (2H, m = CH ₂ ) 7.28 ~ 7.85 (10H, m, C ₆ H ₅ ) <Synthesis of compound of formula (-1)> The optically active 1-cyano-2-methylenepentane derivative (-2-a ) A catalytic amount of p-toluenesulfonic acid was added to a solution of 6.14 g (14.8 mmol) in 90 ml of anhydrous benzene under an argon atmosphere, and 1.18 g (16.3 mmol) of ethyl vinyl ether was added under stirring on a water bath.
was dripped. After stirring for an additional 40 minutes, the aqueous layer was neutralized with pre-cooled saturated sodium bicarbonate solution, extracted four times with ether, the extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was distilled off to obtain 6.68 g of an optically active 1-cyano-2-methylenepentane derivative (-1-a) represented by the following chemical formula.

[ _Formula ] X=XCl( _{-1 -} a) 3.23 to 3.77 (4H, m, CH ₂ ) 3.89 to 4.11 (1H, m, CH) 4.34 to 5.03 (2H, m CH) 5.19 (1H, br s, = CH) 5.43 to 5.63 (1H, m, = CH ) 7.29 to 7.91 (10H, m, C ₆ H ₅ ) In the above synthesis, optically active 1-cyano-2-
An optically active (-1-b) compound represented by the above chemical formula was obtained in the same manner except that the methylenepentane derivative (-2-a) was replaced by an optically active (-2-b) in which X = Br. . NMR ( _CDCl3 ) δ: 0.93-1.43 (15H, m, _CH3 ) 2.37-2.74 (2H, m, _CH2 ) 3.09-3.77 (4H, m, _CH2 , CH) 3.89-4.23 (1H, m, CH) 4.60~5.14 (2H, m, CH ₎ 5.14~5.71 (2H, m, = _CH2 ) 7.31~7.91 (10H, m, _C6H5 ) IR (neat) 1700 (C=C), 1110, 1050, 940, 830, 740, 700 cm ^-1 Using the compound (-1) of the present invention obtained above, optical An active cyclopentenone derivative (formula (X)) was synthesized. <Synthesis of compound of formula ()> 10.3 ml of a benzene solution of sodium hexamethyldisilazane (concentration 0.66N) was added to 50 ml of anhydrous tetrahydrofuran under an argon atmosphere, and the above optically active 1-cyano-2-methylenepentane derivative ( -1-a) A solution of 1.23 g in 20 ml of anhydrous tetrahydrofuran was added dropwise at 50°C over 70 minutes. The above reaction solution was poured into a pre-cooled saturated aqueous ammonium chloride solution with vigorous stirring, and then extracted with ether five times, and the extract was washed successively with 1N hydrochloric acid and brine. This was subjected to silica gel column chromatography (n-hexane:ether = 20:
Optical activity 2 purified by 1) and shown by the following chemical formula
-Methylene cyclopentane cyanohydrin derivative () 756 mg (yield 61.6% from the compound of formula (-2-a)) was obtained.

[Formula] NMR (CDCl ₃ ) δ: 0.93 to 1.57 (15H, m, CH ₃ ) 2.06 to 2.71 (4H, m, CH ₂ ) 3.23 to 3.86 (1H, m, CH) 4.14 to 4.60 (1H, m, CH) 4.69-5.11 (1H, m, CH) 5.11-5.37 (1H, m, CH) 5.37-5.66 (1H, m, CH) 7.31-7.90 (10H, m, C ₆ H ₅ ) In the above synthesis, optical active 1-cyano-2-
X=Br instead of methylene derivative (-1-a)
When the optically active (-1-b) compound was used, the optically active (-1-b) compound was also obtained in the same yield as above. <Synthesis of compound of formula ()> 756 mg of the optically active 2-methylenecyclopentane cyanohydrin derivative () obtained above
A catalytic amount of pyridine p-toluenesulfonate was added to a solution of (1.68 mmol) in 30 ml of anhydrous methanol under an argon atmosphere, and the mixture was refluxed for 1.2 hours. After distilling off the solvent under reduced pressure, 25 ml of anhydrous tetrahydrofuran and 10 ml of saturated aqueous sodium bicarbonate were added to the residue at room temperature, and the mixture was stirred for 1.5 hours. Ether was added to the reaction mixture for extraction, and the extract was washed with brine. Add 5 more ether to the aqueous layer.
The extracts were combined, washed successively with 1N hydrochloric acid and brine, dried, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (n-hexane:ether = 40:1). 307.5 mg (yield: 52.2
%) was obtained.

[Formula] IR (neat) 1730, 1645, 1100, 730 cm ^{-1 1} HNMR (CDCl ₃ ) δ: 1.04 (9H, s, CH ₃ ) 2.42 (2H, d, J=5.0Hz, CH ₂ ) 2.72 (2H , quint, 2.4Hz, CH ₂ ) 4.47 (1H, quint, 5.0Hz, CH) 5.29 (1H, dt, J=2.4Hz, 1.5Hz,
=CH) 6.03 (1H, dt, J=2.4Hz, 1.5Hz,
=CH) 7.31~7.91 (10H, m, _C6H5 ) ¹³ CNMR ( _CDCl3 ) δ: 19.06, 26.79, 40.02, 48.26, 68.51 118.03, 127.70, 127.76, _129.82 , 129.86, 133.50, 133.73 , 135.64, 143.22 , 204.40 <Synthesis of compound of formula (X)> Vinyl iodide derivative represented by the following formula (X) under an argon stream

[Chemical formula] A solution of 247.8 mg (0.831 mmol) in 7 ml of n-hexane was cooled to -78°C, and t-butyllithium was added dropwise to it using a syringe over 5 minutes while stirring, followed by stirring at the same temperature for 90 minutes. By stirring, a vinyllithium compound represented by the following chemical formula was obtained.

[Formula] Meanwhile, 230.8 m of tetramethylethylenediamine complex of zinc chloride was placed in a three-necked flask under an argon atmosphere.
g (0.914 mmol), added 7 ml of anhydrous tetrahydrofuran, cooled to -20°C and stirred, and added 1.07 ml of a 1.7N n-hexane solution of methyllithium.
(1.828 mmol) was added dropwise using a syringe over 3 minutes, and after stirring for an additional 10 minutes, the mixture was cooled to -80°C.
The vinyllithium compound solution was added dropwise to this solution using a bridge at -78°C for 5 minutes with stirring, and the mixture was further stirred at -78°C to -60°C for 1 hour. To this was added 223.5 mg (0.6376 mmol) of the optically active 2-methylenecyclopentanone derivative () obtained above.
7 ml of anhydrous tetrahydrofuran solution was added dropwise at -78°C over 40 minutes with thorough stirring. The container was further washed with 2 ml of anhydrous tetrahydrofuran, which was added to the reaction mixture over 10 minutes with stirring, and then incubated at -78°C for 30 minutes.
Stir for a minute. Add 996.0 mg of diphenyl diselenide to this reaction solution.
(3.197m mol) in anhydrous tetrahydrofuran solution 7
ml was added using a syringe at −78° C. with vigorous stirring. After continuing to stir at −50°C for 30 minutes,
The above reaction solution was poured into a cooled saturated ammonium chloride aqueous solution with vigorous stirring, and after decomposition, the aqueous layer was extracted six times with ether.The ether solutions were combined and washed twice with saturated brine, followed by anhydrous magnesium sulfate. Dry. This was filtered, the solvent of the filtrate was distilled off, and the crude product was purified by silica gel column chromatography (n-hexane:ether = 5:1). Pentanone derivative (X) 220.1m
g (yield 50.9%) was obtained.

[Chemical] NMR (CDCl ₃ ) δ: 1.04 (9H, s, CH ₃ ) 1.04 to 1.74 (12H, m, CH ₃ , CH ₂ ) 1.82 to 2.86 (6H, m, CH ₂ CO, CH ₂ C=
C) 3.30 to 3.82 (4H, m, CH ₂ O) 4.34 to 4.78 (2H, m, OCH) 5.15 to 5.50 (2H, m, = CH) 7.10 to 7.70 (15H, m, C ₆ H ₅ ) IR ( neat) 1730, 1105, 740, 700 cm ^-1 <Synthesis of compound of formula (X)> 115.7 mg (0.170 m
mol) in 15 ml of tetrahydrofuran and cooled to 0°C.
30% hydrogen peroxide, 0.14 ml under stirring and cooled to
(156.1 mg, 1.80 mmol) was added in one portion. The reaction solution was gradually warmed to room temperature and further stirred at room temperature for 3 hours. The reaction solution was diluted with ether, and the ether layer was separated and washed with saturated brine. The aqueous layer was further extracted five times with ether, and the ether layers were combined and washed again with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual oil was subjected to silica gel chromatography (n-hexane:
Purify with ether = 5:1) and further perform high performance liquid chromatography (silica gel "Si-160", 7.6φ
30 cm, n-hexane:ethyl acetate = 1:4) to obtain 40.6 mg (yield 45.9%) of an optically active cyclopentenone derivative (X-1) represented by the chemical formula below.
25.8 mg of a by-product of undetermined structure was obtained.

[Chemical] NMR (CDCl ₃ ) δ: 1.07 (9H, s, CH ₃ ) 1.07-1.79 (12H, m, CH ₂ , CH ₃ ) 1.87-2.26 (2H, m, CH ₂ ) 2.34-2.54 (2H, m, CH ₂ ) 2.70 to 2.94 (2H, m, CH ₂ ) 3.18 to 3.82 (4H, m, CH ₂ ) 4.66 (1H, q, J = 5.5Hz, CH) 4.75 to 4.98 (1H, m, CH) 5.44 (1H, m, = CH) 6.88-7.02 (1H, m, = CH) 7.26-7.78 (10H, m, C ₆ H ₅ ) IR (neat) 1715, 1105, 700 cm ^-1 Optical activity obtained above A catalytic amount of p-toluenesulfonic acid was added to a solution of 31.0 mg (0.06 mmol) of cyclopentenone derivative (X-1) in 2 ml of anhydrous methanol under ice cooling in an argon stream, and the mixture was stirred for 1 hour and 20 minutes under ice cooling. The mixture was further stirred at room temperature for 1 hour. This reaction solution was neutralized with pre-cooled saturated aqueous sodium bicarbonate solution, the aqueous layer was extracted five times with dichloromethane, the extracts were combined, washed twice with saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residual oil was purified by silica gel column chromatography (n-hexane:ether = 1:1) to obtain an optically active cyclopentenone derivative (X-2) represented by the following chemical formula. 24.8 mg (yield 90.2%) was obtained.

[C] [α] ²⁵ _D = +31.85° (C = 0.496, methanol) ¹ HNMR (CDCl ₃ ) δ: 1.07 (9H, s, CH ₃ ) 1.15-1.79 (5H, m, CH ₂ , OH) 1.87～2.27 (2H, m, CH ₂ ) 2.06 (2H, br q, J=6.4Hz,
CH ₂ ) 2.87 (2H, br d, J = 6.0Hz,
CH ₂ ) 3.62 (2H, t, J = 6.4Hz, CH ₂ ) 4.75 to 4.96 (1H, m, CH) 5.30 to 5.55 (2H, m, = CH) 6.93 to 6.98 (1H, m, = CH) 7.27 ~7.75 (10H, m, C ₆ H ₅ ) ¹³ CNMR (CDCl ₃ ) δ: 19.72, 23.24, 26.22, 27.47, 32.89, 43.94, 46.00, 63.34, 70.54, 125.38, 128.41, 130.58, 132.64, 134 .26，136.26， 146.51, 157.23, 177.87 IR (neat) 3400, 1710, 1110, 1070, 780, 700 cm ^-1 (Effects of the invention) The compound of the present invention is useful as a raw material for producing prostaglandins, and can be used in conventional synthesis. Compared to methods using intermediates such as Corey lactone or 4-hydroxycyclopentenone, this method has the advantage of significantly omitting complicated steps and obtaining results in extremely short steps.

Claims (1)

[Claims] 1. Optical activity 1- represented by the following general formula ()
Cyano-2-methylenepentane derivative. [Formula] In the above general formula (), R ¹ is easily selected from a hydrogen atom or an alkenyl group, an aralkyl group, an alkyloxymethyl group, a 1-alkyloxyethyl group, a cyclic alkyl group having a hetero atom, and a silyl group. A removable protecting group, R ² is a hydrogen atom or an easily removable protecting group selected from a 1-alkyloxyethyl group, a cyclic alkyl group having a heteroatom, and a silyl group, and X is a halogen atom or
R ⁴ SO ₃ groups, R ⁴ is an alkyl group or an aryl group, *
Each symbol represents an asymmetric carbon atom.