JPH0714890B2 - Optically active 2-methylenepentanal derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to an optically active 2-methylenepentanal derivative as a raw material for producing a prostaglandin.

(Prior Art and Problems to be Solved) Conventionally, with respect to the production of prostaglandins, a method starting from corey lactone or 4-hydroxycyclopentenone has been the mainstream, but in order to obtain an optically active substance of this raw material, Had to undergo steps such as optical resolution and asymmetric hydrolyzation by microorganisms, resulting in a problem such as a decrease in yield.

(Means for Solving the Problem) As a result of intensive studies on the method for producing a prostaglandin intermediate in place of 4-hydroxycyclopentenone, the present inventors have found that halogen or alkyl at the 1-position carbon will be described later. An optically active cyclopentene represented by the following general formula (XI) known as an intermediate of prostaglandins by a method using an optically active 2,3-epoxypropane (VII) substituted with a sulfonyloxy group or an arylsulfonyloxy group as a starting material. The present inventors have found a method for synthesizing a tenone derivative, and the present invention provides an optically active compound as an intermediate obtained by the series of synthetic reactions.

The present invention provides an optically active compound represented by the following general formula (IV):
It is a methylenepentanal derivative.

In the above general formula (IV), R ¹ is a hydrogen atom or an alkenyl group, an aralkyl group, an alkyloxymethyl group, a 1-alkyloxyethyl group, a cycloalkyl group having a hetero atom, and an easily removable group selected from a silyl group. Possible protecting groups, X is a halogen atom or an R ⁴ SO ₃ group, R ⁴ is an alkyl group or an aryl group, and the symbol * indicates an asymmetric carbon atom, respectively.

In the present invention, specific examples of R ¹ other than a hydrogen atom in the formula (IV) include allyl as an alkenyl group, benzyl as an aralkyl group, p-methoxybenzyl, diphenylmethyl, trityl, and methoxymethyl as an alkyloxymethyl group. Benzyloxymethyl, t-butoxymethyl,
2,2,2-Trichloroethoxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl as 1-alkyloxyethyl group, 1-methyl-1-methoxyethyl, 1-isopropoxyethyl, cyclic alkyl having a hetero atom Tetrahydropyranyl, tetrahydrofuranyl as a group, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methyldi-t-butylsilyl, triphenylsilyl, phenyldimethylsilyl, triphenylmethyldimethylsilyl as a silyl group. And so on. Specific examples of X include halogen atoms such as chlorine, bromine and iodine, alkylsulfonyloxy groups such as methanesulfonyloxy and trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, m-trifluoromethylbenzenesulfonyl. An arylsulfonyloxy group such as an oxy, m-chlorobenzenesulfonyloxy group and the like can be mentioned.

Among the compounds represented by the general formula (IV) of the present invention, compounds in which R ¹ is other than a hydrogen atom can be synthesized by the method shown in the following reaction route 1. Obtained (IV)
From the compound, an optically active 2-methylenecyclopentanone derivative (I) was synthesized from the compound, and subsequently the reaction route 2
To the optically active cyclopentenone derivative (XI), which is an intermediate of prostaglandins.

In the following formula, R ² is a 1-alkyloxyethyl group, a cycloalkyl group having a hetero atom and an easily removable protecting group selected from silyl groups, and R ³ may have a halogen substituent. An easily removable protecting group selected from an alkyl group and an aralkyl group, two R ^{3 s} may be different from each other, and these two R ^{3 s} are bonded to each other to form a cyclic acetal. May be. X ¹ is a halogen atom, *
The sign of each represents an asymmetric carbon atom.

Explaining the above reaction, the acetal derivative (VI) of 2-halogenoacrylaldehyde known per se is used as a solvent with ethers such as tetrahydrofuran, diethyl ether and ethylene glycol diethyl ether, or hydrocarbons such as hexane, and methyllithium, A vinyl anion produced by reacting an equivalent or more of a strong base such as n-butyllithium, sec-butyllithium, t-butyllithium or the like is used to form an optically active epoxy compound represented by the formula (VII) and a Lewis acid such as trifluoroboron. When the reaction is performed in the presence of etherate, a 4-hydroxy-2-methylenepentane derivative represented by the formula (V-2) is obtained. It is desirable to carry out this reaction at a low temperature of -30 to -100 ° C. This reaction proceeds even without a catalyst, but the addition of the 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 by the above reaction to obtain the compound of formula (V-
1) Convert to a compound. 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, R ¹ Y (Y represents a halogen atom such as chlorine, bromine, iodine, etc.) equivalent to the corresponding molar amount and a base such as triethylamine or ethyl. The reaction can be carried out by reacting in the presence of an organic base such as diisopropylamine, pyridine, 4-dimethylaminopyridine, imidazole, etc., and an inorganic base such as sodium hydride, sodium amide, etc. in an equimolar amount or more. In the case where R ¹ is a 1-alkyloxyethyl group or a cyclic alkyl group having a hetero atom, the introduction is carried out by using a vinyl ether equivalent or more and an acid catalyst such as hydrogen chloride, p-toluenesulfonic acid, pyridine-p-toluene. The reaction may be performed using a sulfonate or an acidic ion exchange resin (Amberlyst-H15, etc.).

When the compound of formula (V-1) obtained above is hydrolyzed in the presence of a weak Lewis acid, the compound of formula (V-1) can be obtained as the compound 2 of the present invention.
A methylenepentanal derivative (IV) 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 water-ethanol mixed solvent.

The compound of formula (IV) of the present invention obtained above can be converted into a compound of formula (III-2) by cyanohydrinating the carbonyl group thereof. Cyanohydrinization can be accomplished using hydrogen cyanide as is conventional. As a simple method for cyanohydrination, a trimethylsilylated cyanohydrin formula (III-3) is obtained by reacting with trimethylsilyl cyanide in the presence of an 18-crown ether-6 catalyst to hydrolyze the formula (III-3). III-2) It is also possible to lead to a compound. In addition, the trimethylsilylated compound of formula (III-3) is used as it is in formula (I-3
You can also lead to I).

The optically active 1-cyano-1-pentanol (III-2) obtained above is converted into a compound of formula (III-1) by introducing a protecting group R ² into the hydroxyl group of this compound. The protecting group can be appropriately selected from the above-mentioned ¹ -alkyloxyethyl group of R ¹ , a cyclic alkyl group having a hetero atom, and a silyl group. At this time, R ² may be the same as or different from R ¹ . Introduction of the protecting group R ² can be carried out using the same conditions as when converting the compound of formula (V-2) to the compound of formula (V-1).

The compound of formula (III-1) is converted into a cyclized compound of formula (II) by reacting it with a strong base. As the strong base, lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, sodium hexamethyldisilazane, lithium hexamethyldisilazane, potassium hexamethyldisilazane, etc. are used. The reaction temperature and solvent are appropriately selected depending on the type of strong base. For example, in the case of lithium diisopropylamide, it is preferably carried out in diethyl ether or tetrahydrofuran at +60 to -100 ° C, and when sodium hexamethyldisilazane is used, the reaction is carried out in tetrahydrofuran, dioxane, benzene or toluene at room temperature to 110 ° C. Can be made. The amount of strong base is 1 to 10 relative to the compound of formula (III-1).
It is used in the range of double equivalent, preferably 1 to 5 equivalent.

The above formula (II) compound can be obtained by hydrolyzing its —OR ² group and then decyanohydrogenating with a base to obtain a formula (I) compound. A known method can be used for the hydrolysis of —OR ² . For example, acids such as hydrochloric acid, p-toluene sulfonic acid, acetic acid, acidic ion exchange resins, Lewis acids such as trifluoroboron etherate, zinc bromide, aluminum chloride, etc., or weak acid such as pyridine, p-toluene sulfonate. The substance can be used in a water-containing solvent in a temperature range of 0 to 100 ° C. When R ² is a silyl group, it can be deprotected with a quaternary ammonium fluoride salt such as tetra-n-butylammonium fluoride. When using an aralkyl group, hydrogenolysis using palladium is also an effective means.

Decyanohydration is carried out with sodium hydroxide, potassium hydroxide,
Inorganic bases such as sodium bicarbonate and potassium carbonate,
It can be achieved by reacting with an organic base equivalent or more such as ammonia, triethylamine, pyridine and 4-dimethylaminopyridine.

Specific examples of R ² , R ³ and X ^{1 in} the above reaction formula are as follows.

R ² : a group similar to the 1-alkyloxyethyl group, the heteroalkyl-containing cyclic alkyl group and the silyl group mentioned in R ¹ R ³ : an alkyl group such as methyl, ethyl, 2,2,2-trichloroethyl, benzyl And an aralkyl group such as R ³ —O—C—OR ³ is an example in which two R ³ are bonded. Cyclic acetal X ^{1 represented by} : chlorine, bromine, iodine Among the compounds represented by the general formula (IV) of the present invention, compounds in which R ¹ is a hydrogen atom have the formula (1) in which R ¹ is a t-butyldiphenylsilyl group. IV) The compound is obtained by treating the compound with tetra-n-butylammonium fluoride, tetra-n-butylammonium chloride, trityl fluoroborate, lithium fluoroborate and the like.

The optically active 2-methylenecyclopentanone derivative represented by the general formula (I) obtained above is represented by the general formula (XI) known as an intermediate of prostaglandin by the method shown in the following reaction route 2. It can lead to active cyclopentenone derivatives. In the following formula, R ⁵ represents a linear or branched alkyl group which may contain oxygen, sulfur or silicon, an alkenyl group, an alkynyl group or an alkyl-substituted phenyl group, in which alkoxy, alkyloxyalkoxy, cyclic Alternatively, it means a group having 5 to 22 carbon atoms, which may contain an acyclic acetal group, a silyl group, or an alkylthio group. M is an organic zinc compound such as (CH ₃ ) ₂ ZnLi or an organic copper compound such as Cu (CN) Li,
Cu (CN) MgBr, Cu (CN) MgCl, Cu (CN) MgI, (CuL
i) _1/2 , (2-thienyl) Cu (CN) Li ₂ , Cu (PBu ₃ ) _n (n
= 2-3, Bu means a butyl group) and the like. R ⁶ ZY ¹ R ⁶
Is methyl, phenyl, p-tolyl, p-chlorophenyl, 2-
Represents a pyridyl group, Z represents selenium or sulfur, and Y ¹
Represents a halogen atom such as chlorine, bromine, iodine or ZR ⁶ .

The 2-methylenecyclopentano derivative represented by the formula (I) is reacted with a separately prepared organometallic compound represented by the formula (VIII) to introduce an α chain, and the resulting enolate is represented by the general formula (IX). Substitution with an organic selenium compound or an organic sulfur compound to give a compound of formula (X), which is oxidized with an oxidizing agent such as hydrogen peroxide or organic peracid, and then 0 to
The cyclopentenone derivative (XI) can be obtained by performing an elimination reaction at a temperature of 150 ° C.

Organometallic compound represented by the formula (VIII) used above
R ¹ M is prepared as follows. The organic copper compound is R ⁵ X ¹ (X ¹
Is a halogen atom such as chlorine, bromine, or iodine) that is lithiated with an organolithium compound such as methyllithium, sec-butyllithium, or t-butyllithium, or metallic lithium, or is converted to a Grignard reagent with metallic magnesium, and then cyanated. Cuprous, cuprous iodide or prepared separately (2
-Thienyl) Cu (CN) Li.
Alternatively, the organozinc compound can be obtained by separately reacting a tetramethylethylenediamine complex of zinc chloride with 2 equivalents of methyllithium to give dimethylzinc, and adding a reaction solution obtained by lithiating the above R ⁵ X ¹ thereto. R ⁵ M can be prepared in an inert solvent, for example, a hydrocarbon such as n-hexane or toluene, an ether such as diethyl ether, tetrahydrofuran or dioxane, or a mixed solvent thereof, at a temperature of 0 to −100 ° C.

Specific examples of R ⁵ are: —CH = CH (CH ₂ ) ₃ CH (OC ₂ H ₅ ) ₂ , _{-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 , - (CH ₂₎ such as _{2 SCH 2 CH (OC 2 H} 5) 2 and the like.

The optically active cyclopentenone derivative represented by the general formula (XI) obtained above can be converted to an aldehyde or alcohol by deprotecting the acetal, silyl or alkyloxyalkyl group of R ^{5 in} the above-mentioned known direction. Expression (X
The prostaglandin derivative can be synthesized from the compound of I) by a known method.

(Example) Example 1 <Synthesis of compound of formula (V-2)> To a solution of 9.35 g (44.9 mmol) of 2-bromo-3,3-diethoxypropene cooled at -78 ° C in 80 ml of anhydrous tetrahydrofuran, n-butyllithium was added dropwise over 20 minutes while stirring under an argon atmosphere. Further, the mixture was stirred at -78 ° C for 40 minutes to prepare a vinyllithium solution.

On the other hand, optically active (S) -epichlorohydrin cooled to -78 ° C (chemical purity 98.5% or more, optical purity 99% or more) 3.46
g (37.4m mol) in anhydrous tetrahydrofuran 70ml solution,
5.31 g (37.4 mmol) of trifluoroboron etherate was added dropwise with stirring under an argon atmosphere, 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, and the mixture was further stirred for 20 minutes. The reaction mixture was poured into pre-cooled saturated ammonium chloride aqueous solution with vigorous stirring, the aqueous layer was extracted 6 times with ether, and the ether extract was washed twice with saturated aqueous ammonium chloride solution and twice with saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 6.97 g (yield 84%) of an optically active 4-hydroxy-2-methylenepentane derivative (V-2-a) represented by the following chemical formula.

NMR (CDCl ₃ ) δ: 1.23 (6H, t, J = 7.0Hz, CH ₃ ) 2.34 to 2.52 (2H, m, CH ₂ ) 3.25 to 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 synthesis, optically active (S) - instead optically active epichlorohydrin (S) - Epiburomohido Optically active 4-hydroxy-2-methylenepentane derivative (V-2 represented by the above chemical formula is obtained in the same manner as above except that phosphorus is used.
-B) was obtained.

NMR (CDCl ₃ ) δ: 1.23 (6H, t, J = 7.0Hz, CH ₃ ) 2.34 to 2.52 (2H, m, CH ₂ ) 3.29 to 3.80 (8H, m, CH ₂ O, CH ₂ Br, CH) 3.80~4.14 (1H, m, OH) 4.71 (1H, s, OCH-O) 5.14~5.32 (2H, m, = CH 2) < formula (V-1) synthesis of compound> the obtained optically active 4 -Hydroxy-2-methylenepentane derivative (V-2-a) (6.96 g) in N, N-dimethylformamide (10 ml) solution was stirred at 0 ° C to give imidazole (6.43 g).
(94.5m mol) was added dropwise, then 14.07g (51.3m mol) of t-butyldiphenylsilyl chloride was added dropwise, and the mixture was stirred overnight in a water bath, neutralized with 3N hydrochloric acid, and the aqueous layer was extracted 3 times with ether. The extract was washed twice with saturated aqueous sodium hydrogen carbonate and then three times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 19.96 g of a hydroxyl group-protected optically active 2-methylenepentane derivative (V-1-a) represented by the following chemical formula.

IR (neat) 3400,1640,1050 cm ^{-1 In the} above synthesis, the optically active 4-hydroxy-2-methylenepentane derivative (V-2-a) was replaced by an optically active compound (V-2-b) in which X = Br. ) An optically active (V-1-b) compound represented by the above chemical formula was obtained in the same manner except that the compound was used.

<Synthesis of Formula (IV) Compound> The optically active 2-methylenepentane derivative (V-1-
a) 19.87 g was dissolved in 120 ml of 80% aqueous methanol solution, 10.09 g of copper sulfate was added, and the mixture was heated and stirred for 1 hour. The reaction mixture was filtered 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 hydrogen carbonate. The aqueous layer was extracted 6 times with ether, the extract was washed with brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the optically active 2-methylenepentanal of the present invention represented by the following chemical formula was used. 18.66 g of the derivative (IV-a) was obtained.

NMR (CDCl ₃ ) δ: 1.07 (9H, s, CH ₃ ) 2.49 to 2.71 (2H, m, CH ₂ ) 3.34 (2H, d, J = 5.0OHz, CH ₂ ) 3.94 to 4.26 (1H, m, CH ) 5.99 (1H, s, CH) 6.24 (1H, s, = CH) 7.29 to 7.91 (1OH, m, C ₆ H ₅ ) 9.94 (1H, s, CHO) IR (neat) 1685,1480,1100,700cm ^{-1 In the} above synthesis, in place of the optically active 2-methylenepentane derivative (V-1-a), an optically active (V-
An optically active (IV-b) compound represented by the above chemical formula was obtained in the same manner except that the 1-b) compound was used.

NMR (CDCl ₃ ) δ: 1.07 (9H, s, CH ₃ ) 2.43 to 2.83 (2H, m, CH ₂ ) 3.21 (2H, d, J = 5.0Hz, CH ₂ ) 3.86 to 4.23 (1H, m, CH ) 5.99 (1H, brs, = CH) 6.26 (1H, brs, = CH) 7.29 to 7.91 (1OH, m, C ₆ H ₅ ) 9.94 (1H, s, CHO) IR (neat) 1685,1580,1100, 700 cm ^-1 Using the compound (IV) of the present invention obtained above, via the optically active 1-cyano-2-methylenepentane derivative (III) and the optically active 2-methylenecyclopentane cyanohydrin derivative (II) below, An optically active 2-methylenecyclopentanone derivative (I) was synthesized, and from this, an optically active cyclopentanone derivative (XI) known as an intermediate of prostaglandin was synthesized.

<Synthesis of Formula (III-2) Compound> The optically active 2-methylenepentanal derivative (IV-
a) A catalytic amount of potassium cyanide complex of 18-crown ether was added to 18.66 g under an argon atmosphere, and 3.65 g (36.8 mmol) of trimethylsilyl cyanide was added dropwise with stirring. The reaction mixture was further stirred on the water bath for 1 hour, diluted with 100 ml of tetrahydrofuran, added with 30 ml of 1N hydrochloric acid and stirred for 20 minutes. The aqueous layer was extracted 6 times with ether, the extract was washed with brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the optically active 1-cyano-2-methylene represented by the following chemical formula was used. A crude product of the pentane derivative (III-2-a) was obtained. This was treated with n-hexane: ether = 8: 1 using silica gel column chromatography to obtain 6.14 g of a purified product. The yield from the formula (V-2-a) is 47.4%.
Met. At this time, the starting (IV-a) compound 2.80 was recovered.

NMR (CDCl ₃ ) δ: 1.0 to 1.17 (9H, d, CH ₃ ) 2.51 to 2.86 (2H, m, CH ₂ ) 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 2-methylenepentanal derivative (IV-a ) Instead of X), the optical activity (IV-
An optically active (III-2-b) compound represented by the above chemical formula was obtained in the same manner except that the compound b) was used.

NMR (CDCl ₃ ) δ: 1.0 to 1.32 (9H, m, CH ₃ ) 2.55 to 3.67 (5H, m, CH ₂ , CH) 3.90 to 4.21 (1H, m, CH) 4.84 (1H, s, OH) 5.18 ~5.67 (2H, m, = CH 2) 7.28~7.85 (1OH, m, C 6 H 5) < formula (III-1) synthesis of compound> the optically active 1-cyano-2-methylene-pentane derivative (III- 2-a) 6.14g (14.8m mol) anhydrous benzene 90m
A catalytic amount of p-toluenesulfonic acid was added to the solution under an argon atmosphere, and the mixture was stirred on a water bath with ethyl vinyl ether 1.
18 g (16.3 mmol) was added dropwise. After stirring for another 40 minutes,
Neutralize with pre-cooled saturated aqueous sodium hydrogen carbonate, and add water to the aqueous layer with ether.
The extract was washed twice with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an optically active 1-cyano-2-methylenepentane derivative (III-1) represented by the following chemical formula. -A) 6.68 g were obtained.

_{NMR (CDCl 3) δ: 0.93~1.43} (15H, m, CH 3) 2.35~2.74 (2H, m, CH 2) 3.23~3.77 (4H, m, CH 2) 3.89~4.11 (1H, m, CH) 4.34 to 5.03 (2H, m, CH) 5.19 (1H, brs, = CH) 5.43 to 5.63 (1H, m, = CH) 7.29 to 7.91 (1OH, m, C ₆ H ₅ ) Optical activity 1 in the above synthesis -Cyano-2-methylenepentane derivative (III-2-a) was replaced by an optical activity (III-2-b) in which X = Br, and the same optical activity (III- 1-b) compound was obtained.

NMR (CDCl ₃ ) δ: 0.93 to 1.43 (15H, m, CH ₃ ) 2.37 to 2.74 (2H, m, CH ₂ ) 3.09 to 3.77 (4H, m, CH ₂ , CH) 3.89 to 4.23 (1H, m, CH) 4.60 to 5.14 (2H, m, CH) 5.14 to 5.71 (2H, m, = CH ₂ ) 7.31 to 7.91 (1OH, m, C ₆ H ₅ ) IR (neat) 1700 (C = C), 1110, 1050,940,830,740,700 cm ^-1 <Synthesis of compound of formula (II)> 10.3 ml of benzene solution of sodium hexanemethyldisilazane (concentration 0.66N) is added to 50 ml of anhydrous tetrahydrofuran under argon atmosphere and the above-mentioned optical activity 1 is obtained with stirring.
-Cyano-2-methylenepentane derivative (III-1-
a) 1.23 g of anhydrous tetrahydrofuran in 20 ml of solution at 50 ° C
It was added dropwise over 0 minutes. The reaction solution was poured into a pre-cooled saturated ammonium chloride aqueous solution with vigorous stirring,
Then, the mixture was extracted 5 times with ether, and the extract was washed with 1N hydrochloric acid and brine in this order. This was purified by silica gel column chromatography (n-hexane: ether = 20: 1), and 756 mg of the optically active 2-methylenecyclopentane cyanohydrin derivative (II) represented by the following chemical formula (formula (III-2-
a) The yield from the compound was 61.6%).

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 (1OH, m, C 6 H 5) in the above synthesis, optically active 1- When an optically active (III-1-b) compound in which X = Br is used instead of the cyano-2-methylene derivative (III-1-a), the optically active (II) compound is obtained in the same yield as above. Was obtained.

<Synthesis of Compound of Formula (I)> A solution of 756 mg (1.68 mmol) of the optically active 2-methylenecyclopentane cyanohydrin derivative (II) obtained above in 30 ml of anhydrous methanol was catalyzed by pyridine p-toluenesulfonate under an argon atmosphere. The amount was added and refluxed for 1.2 hours.
After the solvent was distilled off under reduced pressure, 25 ml of anhydrous tetrahydrofuran was added to the residue.
And 10 ml of saturated aqueous sodium hydrogen carbonate were added 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. The aqueous layer was further extracted 5 times with ether, and the extracts were combined, washed successively with 1N hydrochloric acid and brine and dried, and the solvent was distilled off under reduced pressure, followed by silica gel column chromatography (n-hexane: ether = 40). 1) to obtain 307.5 mg (yield 52.2%) of optically active 2-methylenecyclopentanone derivative (I) represented by the following chemical formula.

^{IR (neat) 1730,1645,1100,730cm -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 (1OH, m, C 6 H 5) 13CNMR (CDCl 3) δ: 19.06,26.79,40.02,48.26,68.51,118.03,127.70,12
7.76,129.82,129.86,133.50,133.73,135.64,143.22,20
4.40 <Synthesis of Formula (X) Compound> Vinyl iodide derivative represented by the following formula (XII) under an argon stream. A solution of 247.8 mg (0.831 mmol) in n-hexane (7 ml) was added at -78 ° C.
The mixture was cooled to 1, and t-butyllithium was added dropwise thereto with stirring using a syringe for 5 minutes, and subsequently stirred at the same temperature for 90 minutes to obtain a vinyllithium compound represented by the following chemical formula.

On the other hand, in a three-necked flask, 230.8 mg (0.914 mmol) of tetramethylethylenediamine complex of zinc chloride under argon flow
Then, 7 ml of anhydrous tetrahydrofuran was added, and the mixture was cooled to −20 ° C. and stirred, and 1.07 ml (1.828 mmol) of 1.7Nn-hexane solution of methyllithium was added dropwise to this using a syringe for 3 minutes, and further stirred for 10 minutes. After that, it was cooled to -80 ° C. A solution of the above vinyllithium compound was added dropwise to this solution at -78 ° C over 5 minutes with stirring using a bridge, and further at -78 ° C.
Stirred at ~ -60 ° C for 1 hour. 223.5 mg of the optically active 2-methylenecyclopentanone derivative (I) obtained above
7 ml of anhydrous tetrahydrofuran solution (0.6376 mmol)-
The mixture was added dropwise at 78 ° C over 40 minutes with thorough stirring. Further, this container was washed with 2 ml of anhydrous tetrahydrofuran, added to the reaction solution over 10 minutes with stirring, and further stirred at -78 ° C for 30 minutes.

Diphenyl diselenide 996.0mg (3.197m mo
7 ml of a solution of l) in anhydrous tetrahydrofuran was added with a syringe at -78 ° C with vigorous stirring. Continue to -50 ℃
After 30 minutes of stirring, the reaction solution was poured into a saturated aqueous solution of ammonium chloride that was cooled with vigorous stirring. After decomposition, the aqueous layer was extracted 6 times with ether, and the ether solutions were combined and washed twice with saturated brine. After that, it was dried over anhydrous magnesium sulfate. This is filtered, the solvent of the filtrate is evaporated, the crude product is purified by silica gel column chromatography (n-hexane: ether = 5: 1), and the optically active 2-phenylselenocyclopentanone represented by the following chemical formula is shown. 220.1 mg of the derivative (X) (yield 50.9%) was obtained.

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 Formula (XI) Compound> 115.7 mg (0.170 mmol) of the optically active 2-phenylselenocyclopentanone derivative (X) obtained above was dissolved in 15 ml of tetrahydrofuran and cooled to 0 ° C. With stirring, 30% hydrogen peroxide, 0.14 ml (156.1 mg, 1.80 mmol) was added at once. The reaction solution was gradually returned to room temperature and further stirred at room temperature for 3 hours. The reaction solution was diluted with ether, the ether layer was separated and washed with saturated brine. The aqueous layer was further extracted 5 times with ether, the ether layers were combined, washed again with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual oily substance was purified by silica gel chromatography (n-hexane: ether = 5: 1) and further purified by high performance liquid chromatography (silica gel “Si-160”, 7.6).
Optically active cyclopentenone derivative (XI-1) 40.6 mg (yield 45.9%) represented by the following chemical formula after purification with φ × 30 cm, n-hexane: ethyl acetate = 1: 4) and by-product of undetermined structure 25.8 mg was obtained.

_{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 (1OH, m, C 6 H 5) IR (neat) 1715,1105,700cm -1 the obtained optically active cyclopentenone derivative (XI−
1) To a solution of 31.9 mg (0.06 mmol) of anhydrous methanol in 2 ml of anhydrous methanol was added a catalytic amount of p-toluenesulfonic acid in an argon stream under ice cooling, and the mixture was stirred for 1 hour and 20 minutes under ice cooling, and further stirred for 1 hour at room temperature. did. The reaction solution was neutralized with a previously cooled saturated aqueous sodium hydrogen carbonate solution, the aqueous layer was extracted 5 times with dichloromethane, the extracts were combined, washed twice with saturated saline and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residual oily substance was subjected to silica gel column chromatography (n-hexane:
24.8 mg of an optically active cyclopentenone derivative (XI-2) represented by the following chemical formula after purification with ether = 1: 1 (yield 9
0.2%) was obtained.

▲ [α] ²⁵ _D ▼ ＝ ＋ 31.85 ° (C = 0.496, Methanol) ¹ HNMR (CDCl ₃ ) δ: 1.07 (9H, s, CH ₃ ) 1.15 to 1.79 (5H, m, CH ₂ , OH) 1.87 ~ 2.27 (2H, m, CH ₂ ) 2.06 (2H, brq, J = 6.4Hz, CH ₂ ) 2.87 (2H, brd, 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 to 7.75 (1OH, m, C ₆ H ₅ ) ¹³ CNMR ( CDCl ₃ ) δ: 19.72,23.24,26.22,27.47,32.89,43.94,46.00,63.3
4,70.54,125.38,128.41,130.58,132.64,134.26,136.26,
146.51,157.23,177.87 IR (neat) 3400,1710,1110,1070,780,700 cm ^-1 (Effect of the invention) The compound of the present invention is useful as a raw material for producing prostaglandins, Compared with the method using corey lactone or 4-hydroxycyclopentenone, which is the body, complicated steps can be largely omitted, and there is an advantage that it can be obtained in an extremely short step.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area C07C 309/73 C07F 7/18 A // C07D 309/12 317/26

Claims (1)

[Claims] 1. An optical activity 2 represented by the following general formula (IV):
-Methylenepentanal derivative. In the above general formula (IV), R ¹ is a hydrogen atom or an alkenyl group, an aralkyl group, an alkyloxymethyl group, a 1-alkyloxyethyl group, a cycloalkyl group having a hetero atom, and an easily removable group selected from a silyl group. Possible protecting groups, X is a halogen atom or an R ⁴ SO ₃ group, R ⁴ is an alkyl group or an aryl group, and the symbol * indicates an asymmetric carbon atom, respectively.