JPH0733390B2 - Method for isolating optically active 4-substituted-2-cyclopentenones - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing optically active 4-substituted-2-cyclopentenones. More specifically, the present invention is
By protecting each hydroxyl group of a mixture of hydroxy-2-cyclopentenone and 3-hydroxycyclopentanone with a silyl group and treating it with a basic compound, optically active 4-substituted-2-cyclopentenones can be obtained. It relates to a method of isolation.

According to such a production method, an optically active 4-important as an intermediate for the production of various drugs such as prostaglandins having various pharmacological actions or maytansine having an anticancer action is used.
Substituted-2-cyclopentenones can be obtained in high yield without reducing optical purity.

<Object of the Invention> An object of the present invention is to produce optically active 4-substituted-2-cyclopentenones. A method for producing optically active 4-hydroxy-2-cyclopentenone was previously published by Noyori et al. (55th Autumn Meeting of the Chemical Society of Japan, 4WO3, 1987; allyl alcohols based on catalytic asymmetric hydrogenation reaction). Optical resolution and the 52nd Symposium on Organic Synthesis 1-4; Kinetic optical resolution of allyl alcohols catalyzed by BINAP transition metal complexes, 1987) Optically active 2,2'-bis (diphenylphosphino) An excellent method for producing 4-hydroxy-2-cyclopentenone by kinetic optical resolution based on asymmetric hydrogenation reaction catalyzed by -1,1, '-binaphthyl ((BINAP) transition metal complex) is known. According to the method, it is necessary to separate the 3-hydroxycyclopentanone by-produced in the hydrogenation reaction, but it is possible to isolate it while maintaining the optical purity of the optically active 4-hydroxy-2-cyclopentenone. It was a strange difficult.

Therefore, the present inventors have investigated the optically active 4-
As a result of intensive studies on a method for isolating optically active 4-substituted-2-cyclopentenones in a high yield without decreasing the optical purity of hydroxy-2-cyclopentenone, the above-mentioned asymmetric hydrogenation reaction was conducted. Optically Active 4-Substitution-
A mixture of 2-cyclopentenone and 3-substituted-cyclopentanone is introduced into a silyl ether derivative, and the mixture is treated with a basic compound to maintain the optical purity, and the optically active 4-substituted 4-substitution is achieved. The present invention has been accomplished by finding a method for isolating 2-cyclopentenone.

<Structure of Invention> That is, the present invention provides the following formula [III]: And an optically active 4-hydroxy-2-cyclopentenone represented by the following formula [IV] Each of the hydroxyl groups in the mixture of 3-hydroxycyclopentanone represented by And an optically active 4-substituted-2-cyclopentenone represented by the following formula [II] [In the formula, R ¹ , R ² and R ³ are the same as defined above. ] The optically active 4-substituted-2 represented by the above-mentioned formula [I] is obtained by deriving a mixture of 3-substituted cyclopentanone represented by the above formula, obtaining this mixture and treating with a basic compound.
-A method for isolating and producing cyclopentenones. In this reaction, the following reaction formula As shown in FIG. 3, when the mixture of the formulas [I] and [II] comes into contact with the basic compound, only the 3-substituted cyclopentanone represented by the formula [II] selectively undergoes a desyloxy reaction to give a formula [V ] To give 2-cyclopentenone. 2-Cyclopentenone represented by the formula [V] is a low boiling point compound and can be easily distilled off when the solvent is concentrated. In this reaction, the 4-substituted-2-cyclopentenone represented by the formula [I] does not undergo an isomerization reaction on the asymmetric carbon, so that the 4-substituted-substituted-cyclopentenone represented by the formula [I] is desired. 2-
Only cyclopentenone can be produced quantitatively while maintaining optical purity.

In the optically active 4-substituted-2-cyclopentenone of the formula [I] and the 3-substituted-cyclopentanone of the formula [II] used in the present invention, —SiR ¹ R ² R ³ is a hydroxyl-protecting group. —SiR ¹ R ² R ³ includes, for example, trimethylsilyl,
Triethylsilyl, triisopropylsilyl, isopropyldimethylsilyl, diisopropylmethylsilyl, t-
Butyldimethylsilyl, methyldi-t-butylsilyl, t-
Butyldiphenylsilyl, triphenylsilyl, tri-
Examples thereof include p-xylylsilyl, ciphenylvinylsilyl, dimethylphenylsilyl, diethylphenylsilyl, methylphenylvinylylyl, benzyldimethylsilyl, dibenzylmethylsilyl, tribenzylsilyl and the like.

Among these protecting groups, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dimethylphenylsilyl, diphenylmethylsilyl and t-butyldiphenyl are preferable, and t-butyldimethylsilyl, trimethylsilyl and dimethylphenylsilyl are particularly preferable. .

Optically active 4-hydroxy-2- represented by the formula [III]
A mixed composition of cyclopentenone and 3-hydroxycyclopentanone represented by the formula [IV] is prepared by asymmetric hydrogenation reaction using the BINAP transition metal complex catalyst described above to mix racemate or R isomer and S isomer at any ratio. Ratio of 4-hydroxy-2
-Easily obtained from cyclopentenone. A specific example of subjecting this mixed composition to a silylation reaction to produce an optically active 4-substituted-2-cyclopentenone represented by the formula [I] and a 3-substituted cyclopentanone represented by the formula [II] Means and methods are not limited at all, and any known means and methods may be adopted. For example, a mixture of optically active 4-hydroxy-2-cyclopentenone represented by the formula [III] and 3-hydroxycyclopentanone represented by the formula [IV] is dissolved in dichloromethane, and the mixture is added in the presence of triethylamine and 4-dimethylaminopyridine. After reacting with t-butyldimethylsilyl chloride, the compound is represented by the formula [I] by the usual washing and post-treatment.
Substituted-2-cyclopentanone and represented by the formula [II] 3
A mixture of substituted cyclopentanones is obtained.

The method of isolating the formula [I] from the obtained mixture of the formula [I] and the formula [II] is as follows: when these mixtures are dissolved in a solvent and then reacted with a basic compound, as shown in the following reaction formula, Only the formula [II] selectively causes the siloxy reaction and the formula [V]
Cyclopentenone represented by The reaction solution is washed with water, saturated potassium hydrogensulfate, saturated sodium hydrogencarbonate, saturated saline, etc. by a conventional method, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give cyclopentenone represented by the formula [V] together with the solvent. It is completely distilled off, and the desired 4-substituted-2-cyclopentenone represented by the formula [I] is easily isolated while maintaining its quantitative and optical purity.

The basic compound used in the reaction of the present invention includes triethylamine, pyridine, 4-dimethylaminopyridine,
1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene and mixtures thereof are used.

Among these basic compounds, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.
4.0] Undeca-7-ene is preferred. The amount of the basic compound is about 0.01 to 10 times mol, preferably 0.1 to 1 times mol, of the mixture of 4-substituted-2-cyclopentenone and 3-substituted cyclopentanone. When the basic compound also serves as a solvent, it may be used in an amount about 100 times mol. It is also possible to carry out the siloxylation reaction by adding the above-mentioned basic compound after the silylation reaction.

As the solvent, halogen solvents such as carbon tetrachloride, chloroform and methylene chloride, ether solvents such as diethyl ether and etrahydrofuran, hydrocarbon solvents such as benzene, toluene, xylene and hexane, or a mixture thereof is preferably used. However, the present invention is not limited to this. The basic compound itself can also be used as a solvent.

The reaction temperature is -50 ° C to 150 ° C, preferably 0 ° C to 100 ° C. The reaction time varies depending on the reaction temperature and the basic compound used, but is usually about 1 hour to 4 days.

<Operation and Effect of the Invention> The feature of the present invention is that the formula prepared by kinetic optical resolution of 4-hydroxy-2-cyclopentenone based on the asymmetric hydrogenation reaction by the BINAP transition metal complex catalyst of Noyori et al. [III] and a mixture of optically active 4-hydroxy-2-cyclopentenone and 3-cyclopentanone represented by the formula [IV]. Production of useful compounds such as prostaglandins. Optically active formula [III]
It is a method of isolating optically active 4-hydroxy-2-cyclopentenone represented by the formula (1) in a high yield while maintaining its optical purity. In this method, the hydroxyl group of the mixture of formulas [III] and [IV] is once protected with a silyl group to obtain a mixture of formulas [I] and [II], and then the mixture is treated in the presence of a basic compound. Only the formula [II] is simply removed and the optically active 4-substituted-2-cyclopentenone represented by the formula [I] is isolated.

The feature of this method is that the 3-substituted cyclopentanone represented by the formula [II] is skillfully utilized in its property of being easily decomposed under basic conditions, and the optically active hydroxyl group is protected by a silyl group. The objective is to isolate the desired product while simultaneously solving the two problems of preventing the decrease. That is, this isolation method is excellent in the following points. It can be isolated while maintaining the optical purity. It can be isolated almost quantitatively in high yield. Isolated optically active 4-substituted-2-
Cyclopentenone can itself be an intermediate in the synthesis of various prostaglandins.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Reference example 1 Dry 500ml flask catalyst under a stream of N ₂ [Ru ((S)
- (-) - binap) ( O 2 CCH 3) 2] was taken 1740Mg, dehydrated and degassed methanol 200 ml, was dissolved with acetic acid 28 mg.
There (±) -4-hydroxy-2-cyclopentenone
22.0g was added, the solution of N ₂ under a stream of air was transferred to a 1 glass autoclave, and stirred by substituting H ₂ H ₂ pressure of 3 kg / cm ² G, at room temperature.

The reaction solution was sampled, the conversion rate of the raw material was measured by ¹ H NMR, and the reaction was terminated at a conversion rate of 76%. The reaction solution was concentrated under reduced pressure to obtain 22 g of a mixture of optically active (R) -4-hydroxy-2-cyclopentenone, 3-hydroxy-cyclopentanone and 1,3-cyclopentanediol as a crude product.

When 10 mg of this was used as (+)-MTPA ester and the optical purity of the optically active (R) -4-hydroxy-2-cyclopentenone was measured by HPLC, it was 99.3% ee. ¹ HNMR (CDCl ₃ , ppm) 270MHz 1 δ2.29 (1H, dd, J5,5 '= 18.5Hz, J4.5 = 2.0Hz, H-5), 2.65 (1H, br S, OH) 2.79 (1H , dd, J5,5 '= 18.5Hz, J4.5 = 6.1Hz, H-5'), 5.07 (H-1, m, H-4) 6.24 (1H, dd, J2,3 = 5.6Hz, J2 .4 = 1.32Hz, H-2) 7.58 (1H, dd, J2,3 = 5.6Hz, J3.4 = 2.3Hz, H-3) 2 δ1.8 to 2.5 (7H, m, −CH ₂ − × 3, OH), 4.64 (1H, m, H-3) 3 δ1.8 to 2.5 (8H, m, −CH ₂ − × 3, OH × 2), 4.51 (2H, m, H−1, H− 3), IR (neat, cm ^-1 ) 1 , 2 3400,2950,1740,1400,1345 Then, the crude product was purified by column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain an optical spectrum. Activity (R)-
4-hydroxy-2-cyclopentenone (24.7%, 99.3
% Ee) and 3-hydroxycyclopentanone (75.3%)
21.4 g of a mixture of

Reference example 2 Optically active (R) -4-hydroxy-2-obtained in Reference Example 1
21.4 g of a mixture of cyclopentenone and 3-hydroxycyclopentanone was dissolved in 150 ml of dichloromethane, 37.0 ml of triethylamine and 7.5 g of 4-dimethylaminopyridine were added and stirred. After cooling with an ice bath and adding 40.0 g of t-butyldimethylsilyl chloride, the mixture was stirred overnight at room temperature, the precipitated salt was separately removed, 100 ml of water was added, and the mixture was extracted twice with n-hexane. The organic layer was washed with a saturated aqueous solution of potassium hydrogensulfate, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in this order, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain optically active (R) -4-t-butyldimethylsilyl. 46.3 g of a mixture of oxy-2-cyclopentenone and 3-t-butyldimethyloxycyclopentanone was obtained.

Example 1 Optically active (R) -4-t-butyldimethylsilyloxy-2-cyclopentenone (24.7%, 99.3%) obtained in Reference Example 2
% Ee) and 3-t-butyldimethylsilyloxycyclopentanone (75.3%) 46.3 g of dichloromethane 4
Dissolve in 50 ml, add 6.6 g (43.7 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and stir overnight at room temperature, then distill off dichloromethane and n-hexane.
500 ml was added and washed with water. Then, it was washed with a saturated aqueous solution of potassium hydrogensulfate, saturated sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent and cyclopentenone were distilled off under reduced pressure to obtain 15 g of an optically active (R) -4-t as a crude product. -Butyldimethylsilyloxy-2
-Given cyclopentenone. This was purified by column chromatography (n-hexane / ethyl acetate = 19/1) to obtain 11.5 g of optically active (R) -4-t-butyldimethylsilyloxy-2-cyclopentanone (chemical purity 99.2).
% ByGC) was obtained.

An optical purity of a portion of this product measured by high performance liquid chromatography equipped with an optically active column was 99.5% e.
It was e. ¹ HNMR (CDCl ₃ , 90MHz), δ 0.1 (s, 6, Si (CH ₃ ) ₂ ), 0.9 (s, 9, C (CH ₃ ) ₃ ), 2.2 (dd, 1, J = 3and18Hz, C ( 5) H), 2.7 (dd, 1, J = 6and18Hz, C (5) H), 5.0 (m, 1, C (4) H), 6.2 (dd, 1, J = 1.5and6Hz, C (2) H), 7.5 (dd, 1, J = 2.5and6Hz, C (3) H), Example 2 Optically active (R) -4-t-butyldimethylsilyloxy-2-cyclopentenone (24.7%, 99.3%) ee) and 3-
t-Butyldimethylsilyloxycyclopentanone (7
5.37% (16.8 mmol) of a mixture of dichloromethane 40%
Soluble in 1,8-diazabicyclo [5.4.0] undeca
After adding 511 mg (3.4 mmol) of 4-ene and stirring the mixture at room temperature overnight, the same post-treatment as in Example 1 was performed to obtain optically active (R) -4-t.
-Butyldimethylsilyloxy-2-cyclopentenone
I got 857mg.

When the optical purity was measured by the same method as in Example 1, it was 99.6% e.
It was e.

Further, 1HNMR (CDCl ₃ , ppm) 90 MHz was measured to obtain the same spectrum as in Example 1.

Example 3 10 mg of optically active (R) -4-t-butyldimethylsilyloxy-2-cyclopentenone (28%) and 10 mg of 3-t-butyldimethyloxycyclopentanone (72%) were dissolved in 1 ml of dichloromethane to prepare trimethylamine. After 25 μm was added and the mixture was stirred at room temperature for 48 hours, the same post-treatment as in Example 1 was carried out to obtain optically active 4- (R) -t-butyldimethylsilyloxy-2-cyclopentenone. ¹ HNMR (CDCl ₃ , ppm) 90 MHz was measured and the same spectra as in Examples 1 and 2 were obtained.

Claims (4)

[Claims] 1. The following formula [I]: And an optically active 4-substituted-2-cyclopentenone represented by the following formula [II] [In the formula, R ¹ , R ² and R ³ are the same as defined above. ] A mixture of 3-substituted cyclopentanones represented by the following formula was added to triethylamine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8
-Diazabicyclo [5.4.0] undec-7-ene and mixtures thereof with a basic compound, characterized in that it is optically active 4-substituted-2-cyclopentenone of the above formula [I] For isolation of genus. 2. The above mixture has the following formula [III]: [* Represents an asymmetric carbon atom. ] An optically active 4-hydroxy-2-cyclopentenone represented by the following formula [IV] A compound obtained by protecting each hydroxyl group of a mixture of 3-hydroxycyclopentanone represented by by a silyl group (-SiR ¹ R ² R ³ ; R ¹ , R ² and R ³ are the same as defined above) The method for isolating the optically active 4-substituted-2-cyclopentenones according to claim 1, which is 3. In -SiR ¹ R ² R ³ in formulas [I] and [II], R ¹ , R ² and R ³ are selected from methyl, ethyl, t-butyl and phenyl groups. Item 1 or 2
Item 6. A method for isolating an optically active 4-substituted-2-cyclopentenone compound according to the item 1. 4. The optically active 4-substituted-2-cyclo according to any one of claims 1 to 3, wherein the configuration of the asymmetric carbon of formula [I] or [III] is R configuration. A method for isolating pentenones.