JPH08143542A - Unsaturated aldehyde derivative, intermediate, their production and use - Google Patents

Abstract

PURPOSE: To obtain a new unsaturated aldehyde derivative, useful as an intermediate for medicines, agrochemicals, perfumes, analytical reagents, etc., and capable of industrially, advantageously and readily producing prostaglandin derivatives. CONSTITUTION: The compound of formula I (A-B is C-C bond, C=C bond or C≡C bond; R<1> is an OH-protecting group; R<3> and R<4> are each H or an alkyl; R<6> is a lower alkyl), e.g. (2R,3R,4R)-4-(t-butyldimethylsilyl)oxy-3-(2-formyl) ethenyl-2-(6-methoxycarbonylhex-2-ynyl)cyclopentanone. The compound of formula I is obtained by reacting a compound of the formula R<3> -CH(SR<2> )-C(R<4> )=CH- OR<5> [R<2> is a (substituted) aryl; R<5> is an alkyl] with a lithiating agent such as t-butyl-lithium, then reacting the resultant compound with a compound of formula II, further reacting the compound of the formula X-CH2 -A-B-(CH2 )3 - COOR<6> (X is a halogen) therewith, providing a compound of formula III and then reacting the prepared compound with an oxidizing agent such as sodium periodate.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an unsaturated aldehyde derivative useful as an intermediate for medicines, agricultural chemicals, perfumes, etc., an intermediate, a method for producing the same, and a method for producing a prostaglandin derivative using the derivative.

[0002]

2. Description of the Related Art The reaction of adding an organolithium compound to a double bond is widely known. However, when it is attempted to apply this reaction to α, β-unsaturated ketones, it is known that the addition of the organolithium compound takes precedence over the 1,4-addition of the Grignard reaction type 1,2-addition. Therefore, it has been considered difficult to selectively introduce a substituent into the β-position. On the other hand, β of α, β-unsaturated ketone
As the addition reaction to the position, a method using lithium and copper in place of the lithium compound is known (Tetrahedron,
Vol.33, 1977, p.1105-1112). However, this method is an industrially sufficient method that conditions such as reaction temperature and reaction rate must be strictly controlled and that water in the reaction solvent must be strictly removed before use. It was hard to say.

[0003]

The object of the present invention is to provide α,
An object of the present invention is to provide an industrially advantageous method for producing an addition reaction of a β-unsaturated ketone to the β-position and a novel intermediate of a prostaglandin derivative.

[0004]

Means for Solving the Problems As a result of various investigations in order to solve the above problems, the present inventors have found that when an organolithium compound obtained by reacting a compound having a specific skeleton with a lithium-containing agent is used, It was found that 1,4-addition, that is, addition reaction of α, β-unsaturated ketone to β-position occurs selectively, and the following vinyl ether derivative [2] can be industrially advantageously obtained. Is
It was found that the compound is useful as an intermediate for medicines, agricultural chemicals, fragrances, analytical reagents, etc. by converting it to the corresponding aldehydes, and the present invention has been completed.

That is, the present invention has the general formula [1] (In the formula, AB is a carbon-carbon single bond, a carbon-carbon double bond,
Alternatively, it represents a carbon-carbon triple bond, R ¹ represents a hydroxyl-protecting group, R ³ and R ⁴ each represent a hydrogen atom or an alkyl group, and R ⁶ represents a lower alkyl group. ), An intermediate thereof, a method for producing the same, a mixture of prostaglandin derivatives using the unsaturated aldehyde derivative, or a method for producing an optically active substance of either one.

The present invention will be described in detail below. The unsaturated aldehyde derivative represented by the general formula [1] is represented by the general formula [3] (In the formula, R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above.) After reacting the alkenyl thioether represented by the formula (4) (In the formula, AB, R ¹ and R ⁶ have the same meanings as described above.) The cyclopentenones represented by the formula are reacted to give general formula [2]. (In the formula, AB, R ¹ , R ³ , R ⁴ and R ⁶ have the same meanings as described above, R ² represents an aryl group which may have a substituent, and R ⁵ represents an alkyl group. It is possible to obtain the vinyl ether derivative represented by the formula (1) and reacting it with an oxidizing agent.

R ² of the alkenyl thioethers [3], which is the starting material for the above reaction, is an aryl group which may have a substituent, such as a phenyl group, a tolyl group, an ethylphenyl group and a butylphenyl group. Alkylphenyl group;
Halophenyl groups such as chlorophenyl group, fluorophenyl group; alkoxyphenyl groups such as methoxyphenyl group, butoxyphenyl group, methylenedioxyphenyl group; alkylnaphthyl groups such as naphthyl group, methylnaphthyl group, butylnaphthyl group; chloronaphthyl group, Examples thereof include a halonaphthyl group such as a fluoronaphthyl group; and an alkoxynaphthyl group such as a methoxynaphthyl group, a butoxynaphthyl group and a methylenedioxynaphthyl group.

R ³ and R ⁴ are each a hydrogen atom or an alkyl group, and examples of the alkyl group include a methyl group, an ethyl group, a propyl group and a butyl group.
R ⁵ is an alkyl group, for example, a methyl group, an ethyl group,
Examples thereof include a propyl group and a butyl group.

Specific examples of the alkenyl thioethers [3] include, for example, 1-methoxy-3-phenylthio-
1-propene, 1-ethoxy-3-phenylthio-1-
Propene, 1-propoxy-3-phenylthio-1-propene, 1-methoxy-2-methyl-3-phenylthio-1-propene, 1-propoxy-2-methyl-3-phenylthio-1-propene, 1-methoxy- 3-methyl-3-phenylthio-1-propene, 1-propoxy-
3-methyl-3-p-tolylthio-1-propene, 1-
Methoxy-2,3-dimethyl-3-p-chlorophenylthio-1-propene, 1-propoxy-2,3-dimethyl-3-p-methoxyphenylthio-1-propene, 1
-Propoxy-2,3-dimethyl-3- (2-naphthylthio) -1-propene and the like can be mentioned.

The amount of the alkenyl thioethers [3] used is usually 0.5 to 5 mol times that of the cyclopentenones [4].

Examples of the lithiating agent used in the above reaction include n-butyllithium, s-butyllithium,
Alkyllithium such as t-butyllithium, and lithium dialkylamides prepared from these and secondary amines, for example, lithium diethylamide, lithium diisopropylamide, lithium dicyclohexylamide,
Lithium 2,2,6,6-tetramethylpiperidide and the like can be mentioned, and the amount thereof is usually 1.1 mol times or less with respect to the alkenyl thioether [3].

The reaction between the alkenyl thioether [3] and the lithiating agent is usually carried out in the presence of a solvent, and examples of such a solvent include ethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, hexamethylphosphoric triamide, hexane, Mention may be made of inert solvents such as heptane, which may be used alone or as a mixture. The reaction is usually carried out under an inert gas flow of helium, argon, nitrogen or the like, and the reaction method is usually a method of dropping a lithium agent solution on an alkenyl thioether [3] solution or an alkenyl thioether solution on a lithium agent solution. It is carried out by a method of dropping a solution of the class [3]. The reaction temperature is usually -100 to -10 ° C.

After the reaction of the alkenyl thioethers [3] with the lithiating agent, the resulting reaction solution is further reacted with cyclopentenones [4] without further isolation, and the vinyl ether derivative [2] is reacted. ] Is obtained. The reaction is usually performed under an inert gas stream such as helium, argon or nitrogen.

The protecting group for the hydroxyl group which is R ¹ of the cyclopentenones [4] used in the above reaction is represented by the general formula [13] R ¹⁰ -Si (-R ¹¹ ) -R ¹² [13] (wherein , R ¹⁰ , R ¹¹ and R ¹² each independently represent an alkyl group which may have a substituent or an aryl group which may have a substituent).
Alternatively, ethers such as tetrahydropyranyl group and ethoxyethyl group, and acyl groups such as acetyl group and propionyl group can be exemplified.

Specific compounds thereof include, for example, (4
R) -4- (t-butyldimethylsilyl) oxy-2-
(6-Carbomethoxy) hexyl-2-cyclopentenone, cis- (4R) -4- (t-butyldimethylsilyl) oxy-2- (6-carbomethoxyhex-2-enyl) -2-cyclopentenone , (4R) -4- (t-
Butyldiphenylsilyl) oxy-2- (6-carbomethoxyhex-2-ynyl) -2-cyclopentenone,
(4R) -4- (t-butyldimethylsilyl) oxy-
2- (6-Carboethoxy) hexyl-2-cyclopentenone, cis- (4R) -4- (t-butyldimethylsilyl) oxy-2- (6-carbethoxyhex-2-
(Enyl) -2-cyclopentenone, (4R) -4- (t
-Butyldiphenylsilyl) oxy-2- (6-carboethoxyhex-2-ynyl) -2-cyclopentenone, (4R) -4- (2-tetrahydropyranyl) oxy-2- (6-carbomethoxy) Hexyl-2-cyclopentenone, cis- (4R) -4- (2-tetrahydropyranyl) oxy-2- (6-carbomethoxyhexa-
2-enyl) -2-cyclopentenone, (4R) -4-
(2-Tetrahydropyranyl) oxy-2- (6-carbomethoxyhex-2-ynyl) -2-cyclopentenone, (4R) -4- (2-tetrahydropyranyl) oxy-2- (6-carbo Ethoxy) hexyl-2-cyclopentenone, cis- (4R) -4- (2-tetrahydropyranyl) oxy-2- (6-carbethoxyhexa-
2-enyl) -2-cyclopentenone, (4R) -4-
(2-Tetrahydropyranyl) oxy-2- (6-carboethoxyhex-2-ynyl) -2-cyclopentenone and the like can be mentioned.

The reaction method is usually carried out by adding cyclopentenones [4] to the reaction liquid obtained by the reaction of the alkenyl thioether [3] and the lithiating agent. Examples of the solvent for the reaction include the solvent used for the reaction between the alkenyl thioether [3] and the lithiating agent. The reaction temperature is usually -100 to -10.
° C. After completion of the reaction, the vinyl ether derivative represented by the general formula [2] is usually obtained by charging the reaction solution in ice water and performing operations such as extraction and concentration. If necessary, it can be purified by column chromatography or the like, but the crude product as it is can be reacted with an oxidizing agent to obtain an unsaturated aldehyde derivative [1].

Examples of the oxidizing agent used in the reaction include hydrogen peroxide, t-butyl hydroperoxide, m-
Examples thereof include those capable of oxidizing sulfides to sulfoxides such as chloroperbenzoic acid and sodium periodate, and sodium periodate is preferable. The amount of the oxidizing agent used is usually 1 with respect to the vinyl ether derivative [2].
˜4 molar times, and preferably 1.5 to 3 molar times. Examples of the reaction solvent include acetone, water, tetrahydrofuran, dioxane, dimethoxyethane and the like, and these solvents can be used alone or in a mixture. The reaction temperature is usually -20 to 60 ° C,
It is preferably 10 to 35 ° C. The reaction time is usually
The objective can be sufficiently achieved in 3 to 15 hours. After completion of the reaction, the unsaturated aldehyde derivative [1] can be obtained by subjecting it to usual post-treatment operations such as extraction, washing, drying, and concentration, and can be purified by column chromatography or the like if necessary.

The unsaturated aldehyde derivative [1] thus obtained is, for example, (2R, 3R, 4R) -4-
(T-Butyldimethylsilyl) oxy-3- (2-formyl) ethenyl-2- (6-methoxycarbonylhex-2-ynyl) cyclopentanone, (2R, 3R, 4
R) -4- (2-Tetrahydropyranyl) oxy-3-
(2-formyl) ethenyl-2- (6-methoxycarbonylhex-2-ynyl) cyclopentanone, (2R,
3R, 4R) -4- (t-butyldimethylsilyl) oxy-3- (2-formyl) ethenyl-2- (6-ethoxycarbonylhex-2-ynyl) cyclopentanone,
Cis- (2R, 3R, 4R) -4- (t-butyldimethylsilyl) oxy-3- (2-formyl) ethenyl-2
-(6-methoxycarbonylhex-2-enyl) cyclopentanone, cis- (2R, 3R, 4R) -4- (2
-Tetrahydropyranyl) oxy-3- (2-formyl) ethenyl-2- (6-methoxycarbonylhexa-
2-enyl) cyclopentanone, cis- (2R, 3R,
4R) -4- (t-butyldimethylsilyl) oxy-3
-(2-formyl) ethenyl-2- (6-ethoxycarbonylhex-2-enyl) cyclopentanone, (2
R, 3R, 4R) -4- (t-butyldimethylsilyl)
Oxy-3- (2-formyl) ethenyl-2- (6-methoxycarbonyl) hexylcyclopentanone, (2
R, 3R, 4R) -4- (2-Tetrahydropyranyl)
Oxy-3- (2-formyl) ethenyl-2- (6-methoxycarbonyl) hexylcyclopentanone, (2
R, 3R, 4R) -4- (t-butyldimethylsilyl)
Examples thereof include oxy-3- (2-formyl) ethenyl-2- (6-ethoxycarbonyl) hexylcyclopentanone.

The vinyl ether derivative [2] is obtained by reacting an alkenyl thioether represented by the general formula [3] with a lithiating agent, and then reacting with the general formula [5]. (In the formula, R ¹ has the same meaning as described above.) A cyclopentenone represented by (In the formula, AB and R ⁶ have the same meanings as described above, and X represents a halogen atom), and can also be obtained by reacting ω-halocarboxylic acids.

Examples of the protective group for the hydroxyl group which is R ¹ of the cyclopentenones [5] used in the above reaction include a silyl group represented by the general formula [13], a tetrahydropyranyl group, an ethoxyethyl group and the like. Examples thereof include ethers and acyl groups such as acetyl group and propionyl group. As the specific compound, for example,
(4R) -t-butyldimethylsilyloxy-2-cyclopentenone, (4R) -t-butyldiphenylsilyloxy-2-cyclopentenone, (4R) -triethylsilyloxy-2-cyclopentenone, (4R) ) -Triphenylsilyloxy-2-cyclopentenone, (4
R) -tetrahydropyranyloxy-2-cyclopentenone, (4R)-(methoxymethyl) oxy-2-cyclopentenone, (4R)-(1-ethoxyethyl) oxy-2-cyclopentenone, (4R )-(2-Methoxyethoxymethyl) oxy-2-cyclopentenone, (4
R) -acetoxy-2-cyclopentenone, (4R)-
Examples thereof include n-butoxy-2-cyclopentenone.

Further, X of the ω-halocarboxylic acid [6] used in the above reaction may be a chlorine atom, a bromine atom or an iodine atom, and R ⁶ may be methyl, ethyl, n-propyl or isopropyl. , N-butyl, n-pentyl, cyclopentyl and the like. Specific examples of the compound include 7-
Methyl chloro-5-heptate, 7-bromo-5-ethyl heptate, isopropyl 7-iodo-5-heptate, (cis) -7-bromo-5-methyl heptenoate,
(Cis) -7-iodo-5-n-butyl heptenoate,
Examples thereof include (cis) -7-iodo-5-heptenate cyclopentyl, methyl 7-iodoheptanoate, ethyl 7-iodoheptanoate and the like.

The reaction method is usually to add cyclopentenones [5] to the reaction solution obtained by the reaction of alkenyl thioethers [3] and a lithiating agent, and then add ω-carboxylic acid to this reaction solution. It is done by doing. ω
The amount of the carboxylic acid [6] used is usually 0.5 to 5 mol times that of the cyclopentenones [5]. Examples of the solvent for the reaction include the solvent used for the reaction between the alkenyl thioether [3] and the lithiating agent. The reaction temperature is usually -100 to -10 ° C. After completion of the reaction, the reaction solution is usually charged in ice water, and operations such as extraction and concentration are performed to obtain the vinyl ether derivative [2], which can be purified by column chromatography or the like, if necessary.

Examples of the lithiating agent include alkyllithium such as n-butyllithium, s-butyllithium and t-butyllithium, and the amount thereof is usually 1.1 with respect to alkenylthioethers [3]. It is a molar ratio or less. The reaction between the alkenyl thioethers [3] and the lithiating agent is usually carried out in the presence of a solvent, and examples of such a solvent include ethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, hexamethylphosphoric triamide, hexane and heptane. Mention may be made of inert solvents, which may be used alone or as a mixture. The reaction is usually carried out in an inert gas stream such as helium, argon or nitrogen. The reaction method is usually to add a lithium agent solution to the alkenyl thioether solution [3] solution or to add the alkenyl thioether compound to the lithium agent solution. [3] It is performed by dropping the solution. The reaction temperature is usually -100 to -10 ° C.

After the reaction of the alkenyl thioethers [3] with the lithiating agent, the resulting reaction solution is further reacted with cyclopentenones [5] without the usual isolation operation, and then the ω-halocarboxylic acid is further reacted. The vinyl ether derivative [2] is obtained by reacting with an acid [6]. The reaction is usually performed under an inert gas stream such as helium, argon or nitrogen.

The unsaturated aldehyde derivative [1] thus obtained has the general formula [7] R ⁷ Mg X [7] (in the formula, X has the same meaning as described above, and R ⁷ has a substituent. Represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group) or a general formula [8] (R ⁷ ) ₂ Zn [8] (in the formula, R ⁷ has the same meaning as described above), by reacting an organozinc compound represented by the general formula

[9] (In the formula, AB, R ¹ , R ³ , R ⁴ , R ⁶ and R ⁷ have the same meanings as described above) and the general formula [10]. (In the formula, AB, R ¹ , R ³ , R ⁴ , R ⁶ and R ⁷ have the same meanings as described above.) A mixture of prostaglandin derivatives can be obtained.

Examples of the organomagnesium compound [7] include methylmagnesium bromide, ethylmagnesium bromide, n-propylmagnesium chloride, isopropylmagnesium bromide, n-butylmagnesium chloride, s-butylmagnesium chloride and n-pentylmagnesium bromide. , 4-methylpentylmagnesium chloride, n-hexylmagnesium chloride, cyclopentylmagnesium bromide, cyclohexylmagnesium bromide, phenylmagnesium bromide and the like, and examples of the organozinc compound [8] include dimethylzinc and diethylzinc. it can.

The amount of the organomagnesium compound [7] or the organozinc compound [8] used is usually 1 to 10 mol times the unsaturated aldehydes [1], and preferably,
It is 1.5 to 7.5 mol times.

The solvent used in the reaction is
Examples thereof include inert solvents such as ethyl ether, tetrahydrofuran, hexane, heptane, and toluene, which are used alone or as a mixture.
The reaction temperature is generally -100 ° C to 70 ° C, preferably -3.
It is 0 ° C to 25 ° C. A reaction time of about 1 to 10 hours is usually sufficient. After completion of the reaction, by applying ordinary post-treatment operations such as extraction, washing, drying and concentration, the general formula

The prostaglandin derivatives represented by [9] and [10] can be obtained and, if necessary, can be purified by column chromatography or the like.

Further, in the reaction, tetraalkoxy titanium and the general formula [11] are added to the organic zinc compound [8] together with the organic zinc compound [8]. (In the formula, Y represents a halogen atom or a lower alkoxy group, R ⁸ lower alkyl group, an aryl group which may have a substituent, an aralkyl group which may have a substituent, an alkylidene group, a substituent Represents an optionally active phenylidene group, R ⁹ represents a lower alkyl group, or a phenyl group which may have a substituent). (In the formula, R ⁸ and R ⁹ have the same meanings as described above.) By using an optically active titanium compound represented by the general formula

The prostaglandin derivative represented by [9] can be selectively obtained. Examples of such tetraalkoxy titanium include tetraethoxy titanium and tetra n-.
Propoxy titanium, tetraisopropoxy titanium, tetra n-butoxy titanium, etc. can be mentioned, Preferably, tetraisopropoxy titanium can be mentioned. Examples of the optically active titanium compound include bis [(2R, 3R)-(2,3-isopropylidenedioxy-1,1,4,4-tetraphenyl) butyl-1,
4-dioxy] titanate, bis [(2R, 3R)-
(2,3-benzylidenedioxy-1,1,4,4-tetraphenyl) butyl-1,4-dioxy] titanate, dichloro [(2R, 3R)-(2,3-isopropylidenedioxy-1, 1,4,4-Tetraphenyl) butyl-1,4-dioxy] titanate, dimethoxy [(2R, 3R)-(2,3-isopropylidenedioxy-1,1,4,4-tetraphenyl) butyl- 1,4
-Dioxy] titanate and the like.

The amount of the tetraalkoxy titanium and the optically active titanium compound used is usually 0.1 to 100 mol%, preferably 10 to 70 mol% based on the organozinc compound [8].

[0031]

The unsaturated aldehyde derivative of the present invention [1]
Is useful as an intermediate for medicines, agricultural chemicals, fragrances, analytical reagents and the like. According to the method of the present invention, by using a specific compound called alkenyl thioethers [3],
The prostaglandin derivative can be produced industrially advantageously. Especially prostaglandin derivatives

[9] can easily produce prostaglandins D, E, F, and
It is a very useful compound because it can be induced to class I.

[0032]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 1-methoxy-3-phenylthio was placed in a reactor under a nitrogen stream.
-1-propene 70 mg (0.39 mmol) and te
2 ml of trahydrofuran and hexamethylphosphorict
Charge Liamide (0.2 ml, 1.17 mmol),
Cool to −78 ° C. and, under stirring, 1.
7M pentane solution (0.23 ml, 0.39 mmol)
Is dripped. After stirring at the same temperature for 10 minutes, 4- (t-
Butyldimethylsilyloxy) -2-cyclopentenone
(64 mg, 0.3 mmol) in tetrahydrofuran
Drop the solution in 0.5 ml over 3 minutes at -78 ° C.
And further stirred for 15 minutes at the same temperature. Then Triff
Phenyltin chloride (166mg, 0.43mmol)
Tetrahydrofuran solution (1 ml) was added, and the temperature was -78 ° C.
Stir for 10 minutes. Further 7-iodo-5-heptic acid
The methyl ester (120 mg, 0.45 mmol)
Add a solution of trahydrofuran (0.5 ml) over 2 minutes,
78 ° C for 2 hours, -50 ° C for 2 hours, -25 ° C for 12:00
Stir for a while. Saturated aqueous ammonium chloride was added to the obtained reaction solution.
Add 1 ml and extract with 30 ml of ethyl acetate. Anhydrous sulfuric acid
After drying over sodium, it is concentrated under reduced pressure. The obtained residue
And sodium metaperiodate (400mg, 1.87m
mol) is a mixed solvent of 1,4-dioxane and water (volume ratio
(4: 1.7 ml) at room temperature for 8 hours. Siri this
Kagel column chromatography [Developing solvent: Hexane
-Purified with ethyl acetate (90:10 to 80:20)]
And (2R, 3R, 4R) -4- (t-butyldimethyl)
Silyl) oxy-3- (2-formyl) ethenyl-2-
(6-methoxycarbonylhex-2-ynyl) cyclo
79 mg (64% yield) of pentanone are obtained.¹ HNMR (CDCl₃) δ 0.050 (s, 3H), 0.055 (s, 3H), 0.87
(s, 9H), 1.71-1.82 (m, 2H), 2.13-2.46 (m, 7H), 2.56-
2.67 (m, 1H), 2.69-2.79 (m, 1H), 1.95-3.95 (m, 1H), 3.
67 (s, 3H), 4.21 (q-like, J = 7.26 Hz, 1H), 6.29 (dd, J
= 7.69, 15.5 Hz, 1H), 6.80 (dd, J = 8.30, 15.5 Hz, 1
H), 9.59 (d, J = 7.69 Hz, 1H).¹³CNMR (CDCl ₃) δ-
4.8, -4.6, 17.2, 17.8, 18.0, 23.9, 25.5, 32.6, 47.
2, 51.4, 52.4,53.0, 72.0, 81.7, 134.7, 155.7, 173.
4, 193.0, 211.4. MS (m / z) 410 (M +).

Example 2 7-Iodo-5-heptic acid methyl ester (120 m
(2R, 3R, 4R) -4- (t-butyldimethylsilyl) oxy-3 was prepared in the same manner as in Example 1 except that 7-iodo-5-heptanoic acid methyl ester (122 mg) was used instead of g). -(2-formyl) ethenyl-2-
(6-Methoxycarbonylhexyl) cyclopentanone is obtained.

Example 3 Aldehyde obtained in Example 1 (433 mg, 1.06
-7 in tetrahydrofuran (5 ml) solution of (mmol)
At 8 ° C, n-pentylmagnesium bromide (2
M ether solution, 1 ml, 2 mmol) was added dropwise. same
After stirring for 1 hour at temperature, phosphate buffer (PH7, 1 ml)
Was added to stop the reaction. After extraction with ethyl acetate, saturated sodium chloride
It was washed with water. Dry over anhydrous sodium sulfate and concentrate under reduced pressure
The crude product (517 mg) obtained by
Chromatography (elution solvent hexane: ethyl acetate
= 80: 20) and allyl alcohol (15R,
344 mg (68%) of 15S was obtained. Generation ratio
Was determined by HPLC analysis, and 15S: 15R = 69: 3
It was 1. Pure 15S form (25
2 mg) and 15R form (97 mg) are obtained. 15
S body;¹HNMR (CDCl ₃) δ 0.05 (s, 3H), 0.07 (s, 3H),
0.88 (br s, 12H), 1.2-1.4 (m, 8H), 1.5-2.8 (m, 13H),
3.67 (s, 3H), 4.02-4.18 (m, 2H), 5.58 (dd, J = 7.76, 1
5.3 Hz, 1H), 5.70 (dd, J = 5.80, 15.2 Hz, 1H).¹³ CNMR (CDCl3) δ -4.7, -4.6, 13.9, 16.7, 17.9, 1
8.0, 22.5, 24.0, 25.1, 25.6, 31.6, 32.6, 37.3, 47.
4, 51.4, 52.2, 52.6, 72.3, 72.7, 77.2, 80.8, 129.
4, 136.4, 173.6, 213.5. [Α]_D ²⁰-4.6 ° (C 1.0,
(MeOH) Rf = 0.45 (hexane: ethyl acetate = 80: 20, quadruple development)
Rt = 24min (Develosil Si 100, 98.5: 1.5 = Hexane: 2-Prop
Nol, 1.5ml / min, 215nm). 15R body; 1HNMR (CDCl3)
δ 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 0.89 (t,
J = 6.72 Hz, 3H), 1.2-1.5 (m, 8H), 1.7-2.8 (m, 13H), 3.
67 (s, 3H), 4.02-4.17 (m, 2H), 5.56 (dd, J = 8.24, 15.3
 Hz, 1H), 5.71 (dd, J = 6.23, 15.3 Hz, 1H).¹³CNMR
(CDCl₃) δ -4.7, -4.6, 14.0, 16.8, 17.9, 18.0, 2
2.5, 24.0, 25.0, 25.6, 31.7, 32.7, 37.3, 47.4, 51.
5, 52.4, 52.8, 72.5, 72.7, 77.3, 80.8, 129.9, 136.
7, 173.6, 213.5. [Α]_D ²⁰-6.8 ° (C 1.1, MeOH) R
f = 0.40 (hexane: ethyl acetate = 80: 20, quadruple development) Rt = 36min
(Develosil Si 100, 98.5: 1.5 = Hexane: 2-Propanol, 1.5m
l / min, 215 nm).

Example 4 Bis [(2R, 3R)-was added to the reactor under an argon stream.
(2,3-isopropylidenedioxy-1,1,4,4
-Tetraphenyl) butyl-1,4-dioxy] titanate (97.7 mg, 0.1 mmol) and toluene (2
ml), and titanium tetraisopropoxide (0.18 ml, 0.6 mmol) and diethyl zinc (1.0 M hexane solution, 0.9 ml, 0.9 m) were added at 15 ° C.
mol) was added to bring the temperature to -25 ° C. A solution of the aldehyde (50 mg, 0.12 mmol) obtained in Example 2 in toluene (0.5 ml) was added dropwise thereto, and the mixture was stirred at -25 ° C for 1 hour. After quenching the reaction with saturated aqueous ammonium chloride solution (1 ml) and extracting with ethyl acetate (70 ml),
The mixture was washed successively with saturated aqueous ammonium chloride solution (10 ml) and saturated brine (10 ml), and dried over anhydrous sodium sulfate. Crude product obtained by concentration under reduced pressure (102 mg)
Was subjected to silica gel column chromatography (eluting solvent benzene: ethyl acetate = 97: 3) to give an allyl alcohol compound (mixture of 15R and 15S) (31 mg, 59%).
Get. The production ratio was 15S: 15R = 98: 2 as determined by HPLC analysis after converting the hydroxyl group to benzoyl.
15S body; [α] _D ¹⁷ -39.7 ° (c 2.8, CHCl ₃ ) IR (CCl4)
3628, 3552, 1744cm-1 Rf = 0.53 (hexane: ether = 50: 50)
¹ HNMR (CDCl ₃ ) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.83
(s, 9H), 0.88 (t, J = 7.39 Hz, 3H), 1.30-1.75 (m, 13H),
1.87-1.97 (m, 1H), 2.14 (dd, J = 8.67, 18.3 Hz, 1H),
2.24 (t, J = 7.50 Hz, 2H), 2.40 (dt, J = 7.88, 11.3 Hz,
1H), 2.58 (dd, J = 7.14, 18.3 Hz, 1H), 3.61 (s, 3H),
3.94-4.05 (m, 2H), 5.51 (dd, J = 7.51, 15.4 Hz, 1H),
5.60 (dd, J = 5.50, 15.4 Hz, 1H). ¹³ CNMR (CDCl ₃ ) δ -4.69, -4.60, 9.8, 18.0, 24.7, 25.6, 26.4, 27.
7, 28.7,29.2, 30.1, 33.9, 47.4, 51.4, 53.7, 53.8,
72.9, 73.9, 130.9, 135.8, 174.2, 215.7. 15R body; [α] _D ¹⁶ -49.6 (c 1.6, CHCl ₃ ) IR (CC
l ₄ ) 3632, 3552, 1744cm-1 Rf = 0.43 (hexane: ether = 50: 5
0) ¹ HNMR (CDCl ₃ ) δ 0.02 (s, 3H), 0.86 (s, 9H), 0.9
3 (t, J = 7.57 Hz, 3H), 1.20-1.70 (m, 12H), 1.72 (br, 1
H), 1.90-2.01 (m, 1H), 2.16 (dd, J = 8.79, 18.6 Hz, 1H),
2.27 (t, J = 6.59 Hz, 2H), 2.38-2.49 (m, 1H), 2.62 (dd,
J = 7.08, 18.6 Hz, 1H), 3.64 (s, 3H), 3.96-4.10 (m, 2
H), 5.53 (dd, J = 8.24, 15.3 Hz, 1H), 5.64 (dd, J = 5.0
7, 15.3 Hz, 1H). ¹³ CNMR (CDCl ₃ ) δ -4.7, -4.6, 9.
6, 17.9, 24.6, 25.6, 26.3, 27.6, 28.6, 29.1, 30.1,
33.9, 47.4, 51.4, 53.81, 53.88, 72.8, 73.7, 136.0,
174.3, 215.7.

Example 5 The aldehyde obtained in Example 1 (30 mg, 0.073
-7 in tetrahydrofuran (1 ml) solution of (mmol)
Ethyl magnesium bromide (3M ether solution, 0.035 ml, 0.105 mmol) was added dropwise at 8 ° C. After stirring at the same temperature for 0.5 hours, saturated ammonium chloride aqueous solution was added to stop the reaction. After extraction with ethyl acetate, the extract was washed successively with saturated aqueous ammonium chloride solution and saturated brine. The crude product (45 mg) obtained by drying over anhydrous sodium sulfate and concentrating under reduced pressure was subjected to silica gel column chromatography (elution solvent hexane: ethyl acetate = 70:
It was subjected to 30) to obtain 13 mg (40%) of an allyl alcohol compound (mixture of 15R and 15S). The production ratio was determined by HPLC analysis after converting the hydroxyl group to benzoyl, and 15S: 1
5R = 69.7: 30.3.

Example 6 Under a nitrogen stream, the reactor was charged with diisopropylamine (1.16).
ml, 8.27 mmol) and tetrahydrofuran (20
ml), n-butyllithium (1.7 M hexane solution, 4.86 ml, 8.27 mmol) was added to 0.
The reaction was carried out at 10 ° C for 10 minutes. This was cooled to −78 ° C. and 1-methoxy-3-phenylthio-1-propene (1.49
g, 8.27 mmol) of tetrahydrofuran (1.5
ml) solution was added dropwise. Mixture at -40 ° C over 50 minutes
The temperature was raised to 40 ° C. and the mixture was stirred at −40 ° C. for 30 minutes. Again -78 ° C
After cooling to hexamethylphosphoric triamide (5.
72 ml, 33 mmol) and (3R) -3- (t-butyldimethylsilyl) oxy-2- (6-carbomethoxy) hexyl-2-cyclopentenone (1.96 g,
5.51 mmol) of tetrahydrofuran (1.5 m
1) The solution was sequentially charged, and after stirring at -78 ° C for 20 minutes, saturated ammonium chloride aqueous solution (4 ml) was added to stop the reaction. It was extracted with ethyl acetate (150 ml), twice with saturated aqueous ammonium chloride solution (20 ml), and saturated saline (2 ml).
(0 ml) and then dried over anhydrous sodium sulfate,
Concentration under reduced pressure gave a crude product (3.48 g). This crude product was dissolved in a mixed solvent of 1,4-dioxane and water (volume ratio 4: 1, 34 ml) without purification, sodium metaperiodate (3.53 g, 16.5 mmol) was added, and the mixture was stirred at room temperature. It was stirred for 22 hours. Ethyl acetate (200m
l) extracted with saturated aqueous sodium hydrogen carbonate solution (50 m
It was washed with 1) and saturated saline (20 ml). This was dried over anhydrous sodium sulfate and concentrated to give a crude product (2.64).
g) was obtained. This was purified by silica gel column chromatography [developing solvent: benzene-ethyl acetate (92: 8)], and (2R, 3R, 4R) -4- (t-butyldimethylsilyl) oxy-3- (2-formyl). ) Ethenyl-2- (6-methoxycarbonyl) hexylcyclopentanone (328 mg, yield 15%) was obtained. ¹ H NMR (C
DCl ₃ ) δ 0.000 (s, 3H), 0.009 (s, 3H), 0.83 (s, 9H),
1.18-1.66 (m, 10H), 2.09-2.18 (m, 1H), 2.22-2.33 (m,
1H), 2.25 (t, J = 7.73 Hz, 2H), 2.64-2.83 (m, 2H), 3.63
(s, 3H), 4.15 (q-like, J = 8.79 Hz, 1H), 6.22 (ddd, J =
0.64, 7.80, 15.6 Hz, 1H), 6.71 (dd, J = 8.57, 15.6 H
z, 1H), 9.55 (d, J = 7.80 Hz, 1H).

Claims (7)

[Claims] 1. The general formula [1] (In the formula, AB is a carbon-carbon single bond, a carbon-carbon double bond,
Alternatively, it represents a carbon-carbon triple bond, R ¹ represents a hydroxyl-protecting group, R ³ and R ⁴ each represent a hydrogen atom or an alkyl group, and R ⁶ represents a lower alkyl group. ) An unsaturated aldehyde derivative represented by 2. The general formula [2] (In the formula, AB, R ¹ , R ³ , R ⁴ and R ⁶ have the same meanings as described above, R ² represents an aryl group which may have a substituent, and R ⁵ represents an alkyl group. A vinyl ether derivative represented by. 3. A process for producing an unsaturated aldehyde derivative [1], which comprises reacting a vinyl ether derivative [2] with an oxidizing agent. 4. A general formula [3] (In the formula, R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above.) The alkenyl thioethers are reacted with a lithiating agent, and then the compound represented by the general formula [4] (Wherein AB, R ¹ and R ⁶ have the same meanings as described above), the cyclopentenones are reacted to obtain a vinyl ether derivative [2], and then an oxidant is reacted. The method for producing an unsaturated aldehyde derivative represented by the general formula [1] 5. An alkenyl thioether represented by the general formula [3] is reacted with a lithiating agent, and the alkenyl thioether is further reacted with the general formula [5]. (In the formula, R ¹ has the same meaning as described above.) A cyclopentenone represented by the formula is reacted, and this is further reacted with the general formula [6]. (In the formula, X represents a halogen atom, and AB and R ⁶ have the same meanings as described above.) A method for producing a vinyl ether derivative [2], which comprises reacting a ω-halocarboxylic acid. 6. An unsaturated aldehyde represented by the general formula [1] is added to the general formula [7] R ⁷ Mg X [7] (wherein, X represents the same meaning as described above, and R ⁷ represents a substituent. Represents an alkyl group which may have, an aryl group which may have a substituent or an aralkyl group which may have a substituent) or a general formula [8] (R ⁷ ) ₂ Zn [8] (wherein R ⁷ has the same meaning as described above) is reacted with a general formula [9] (In the formula, AB, R ¹ , R ³ , R ⁴ , R ⁶ and R ⁷ have the same meanings as described above) and the general formula [10]. (In the formula, AB, R ¹ , R ³ , R ⁴ , R ⁶ and R ⁷ have the same meanings as described above.) A method for producing a mixture of prostaglandin derivatives. 7. An unsaturated aldehyde represented by the general formula [1], an organozinc compound represented by the general formula [8], tetraalkoxytitanium and a general formula [11]. (In the formula, Y represents a halogen atom or a lower alkoxy group, R ⁸ lower alkyl group, an aryl group which may have a substituent, an aralkyl group which may have a substituent, an alkylidene group, a substituent And R ⁹ represents a lower alkyl group, a phenyl group which may have a substituent) or the general formula [12]. (In the formula, R ⁸ and R ⁹ have the same meanings as described above.) An optically active prostaglandin derivative represented by the general formula [9] is produced by reacting the optically active titanium compound. Law.