JP2001224396A - Method for producing optically active 1,2-epoxy-2,6,6- trimethylcyclohexane methanol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing optically active 1,2-epoxy-2,6,6-trimethylcyclohexane methanol in high yield and high optical purity. SOLUTION: This method for producing (-)-(1S,2S)-1,2-epoxy-2,6,6- trimethylcyclohexane methanol represented by formula (4) is characterized by acting (±)-1,2-epoxy-2,6,6-trimethylcyclohexane methyl acetate represented by formula (1) on an enzyme having hydrolysis function of an ester to obtain (+)-(1R,2R)-1,2-epoxy-2,6,6-trimethylcyclohexane methanol represented by formula (2) and (+)-(1S,2S)-1,2-epoxy-2,6,6-trimethylcyclohexane methyl acetate represented by formula (3) and carrying out solvolysis of the obtained (+)-(1S,2 S)-1,2-epoxy-2,6,6-trimethylcyclohexane methyl acetate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active 1,2-epoxy-2,6,6-trimethylcyclohexanemethanol. Optically active 1,2-epoxy-2,6,6-trimethylcyclohexanemethanol obtained according to the present invention, for example (+)-(1R, 2R)-
1,2-Epoxy-2,6,6-trimethylcyclohexanemethanol is useful, for example, as a synthetic intermediate of epoxy-β-ionylideneacetic acid having an activity equivalent to the optically active abscisic acid, which is a plant hormone.

[0002]

2. Description of the Related Art Optically active 1,2-epoxy-2,6,6
As a method for producing trimethylcyclohexanemethanol, 2,6,6-trimethyl-1-cyclohexenemethanol is subjected to an asymmetric epoxidation reaction developed by Sharpless et al. To give 95% e. e. [Phytochemistry]
Vol. 22, p. 1909 (1983)].

[0003]

The above-mentioned method is a method for preparing (+)-(1R, 2R) -1,2-epoxy-2, which is an intermediate for the synthesis of epoxy-β-ionylideneacetic acid having a high phytohormone-like activity. In order to synthesize 6,6-trimethylcyclohexanemethanol, there is a problem that an unnatural type tartaric acid ester, which is an expensive asymmetric ligand, must be used. Hard to say. Thus, an object of the present invention is to provide an optically active 1,2-
It is an object of the present invention to provide a method capable of producing epoxy-2,6,6-trimethylcyclohexanemethanol with high yield and high optical purity in an industrially advantageous manner.

[0004]

According to the present invention, the above object is achieved by the following equation (1).

[0005]

Embedded image

(±) -1,2-epoxy-
Formula (2) characterized in that an enzyme having ester hydrolytic ability is allowed to act on 2,6,6-trimethylcyclohexanemethyl acetate (hereinafter abbreviated as acetate (1)).

[0007]

Embedded image

(+)-(1R, 2R) -1,
A method for producing 2-epoxy-2,6,6-trimethylcyclohexanemethanol (hereinafter abbreviated as (+)-(1R, 2R) -alcohol (2)), and an ester (1) having ester hydrolytic ability (+)-(1R, 2R) -alcohol (2) and formula (3)

[0009]

Embedded image

(+)-(1S, 2S) -1,
2-epoxy-2,6,6-trimethylcyclohexanemethyl acetate (hereinafter abbreviated as (+)-(1S, 2S) -acetate (3)) was obtained, and the obtained (+)-
Formula (4) characterized in that (1S, 2S) -acetate (3) is solvolyzed.

[0011]

Embedded image

(-)-(1S, 2S) -1,
This is achieved by providing a method for producing 2-epoxy-2,6,6-trimethylcyclohexanemethanol (hereinafter abbreviated as (-)-(1S, 2S) -alcohol (4)).

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION First, an enzyme having an ester hydrolytic activity is allowed to act on acetate (1) to make (+)-(1
R, 2R) -alcohol (2) and (+)-(1S, 2
The step of obtaining S) -acetate (3) will be described.

[0014] Pseudomona is an enzyme capable of acting on ester (1) having the ability to hydrolyze esters.
Burkhold, an enzyme produced by microorganisms belonging to the genus s
lipase P (manufactured by Nagase Sangyo), lipase P (manufactured by Amano Pharmaceutical), lipase PS (manufactured by Amano Pharmaceutical), which is an enzyme produced by a microorganism belonging to the genus Eria cepacia Burkholderia cepacia
Kirazyme L-, an enzyme produced by a microorganism belonging to the genus
1, c. -F. (Roche Diagnostics). Among these, when lipase P (manufactured by Nagase & Co., Ltd.), lipase P (manufactured by Amano Pharmaceutical), and lipase PS (manufactured by Amano Pharmaceutical) are used, the acetate (1) (-)-(1)
The (R, 2R) form is preferentially hydrolyzed, so that (+)-
(1R, 2R) -alcohols (2) and (+)-(1
(S, 2S) -acetate (3) can be obtained with high optical purity and high yield. The amount of the enzyme having the ability to hydrolyze the ester is usually 0.01 to 0.01 to the acetate (1).
Preferably in the range of 200% by weight, 0.1 to 100% by weight
Is more preferable.

[0015] The reaction is preferably carried out in the presence of a solvent. Examples of the solvent include ethers such as diethyl ether, diisopropyl ether and t-butyl methyl ether; nitriles such as acetonitrile; ketones such as acetone; and hydrocarbons such as toluene and hexane. Among these, diisopropyl ether is particularly preferred. The amount of the solvent to be used is generally preferably 5 to 100 times by weight relative to the acetate (1), and is preferably 10 to 40 times by weight.
The range of the weight ratio is more preferable.

At the time of the reaction, the pH of the reaction solution is adjusted to 4 to 4 from the viewpoint of maximizing the ability of the enzyme to hydrolyze the ester.
The pH is preferably maintained at 8, and the pH is particularly preferably adjusted by coexisting a buffer such as a phosphate buffer or an acetate buffer in the reaction system. The amount of the buffer used is not particularly limited, but is usually 1 to 10 with respect to acetate (1).
A range of 0 times by weight is preferable, and a range of 10 to 40 times by weight is more preferable.

The reaction temperature is preferably in the range of 0 to 40 ° C, more preferably in the range of 10 to 30 ° C. The reaction time is
Although it varies depending on the ratio of the amount of the acetate (1) to the enzyme having the ability to hydrolyze the ester, the type of the solvent and the type of the buffer used, the range is usually from 1 hour to 1 week.

The reaction is preferably carried out by mixing the acetate (1) with an enzyme capable of hydrolyzing an ester, a solvent and, if necessary, a buffer solution and stirring the mixture at a predetermined temperature. The reaction may be carried out in a batch mode or may be carried out in a continuous mode using an enzyme having an immobilized ester hydrolytic ability.

The (+)-(1R,
2R) -alcohols (2) and (+)-(1S, 2
Isolation of S) -acetate (3) from the reaction mixture can be performed in the same manner as in a method generally used for isolating and purifying an organic compound. For example, an enzyme having ester hydrolysis ability is filtered from the reaction mixture, the filtrate is extracted with diethyl ether, diisopropyl ether, ethyl acetate, etc., and the extract is washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride and dried. After drying over magnesium sulfate or the like, the product obtained by concentration is purified by column chromatography or the like.

Next, the (+)-(1) obtained in the above step is obtained.
(S, 2S) -acetate (3) is solvolyzed to give (-)
The step of obtaining-(1S, 2S) -alcohol (4) will be described.

The solvolysis reaction can be carried out in the presence of a basic substance, an acidic substance or a neutral substance. Examples of such a basic substance include amines such as triethylamine, hydrazine and pyridine; alkali metal alkoxides such as sodium methoxide and potassium t-butoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium carbonate, carbonate And alkali metal carbonates such as potassium. Examples of the acidic substance include protic acids such as hydrochloric acid and sulfuric acid; and Lewis acids such as titanium tetrachloride and boron trifluoride. Examples of the neutral substance include cyanide such as potassium cyanide. The amount of the basic substance, acidic substance or neutral substance used is not particularly limited, but is usually (+)-
(1S, 2S) -0.2 to 2 for acetate (3)
The molar ratio is preferably in the range of 0.5 to 1 and more preferably 0.5 to 1.

The reaction is carried out in the presence of water; an alcohol such as methanol, ethanol, propanol or butanol; or a mixture of water and an alcohol. The amount of water, alcohol or a mixture of water and alcohol is not particularly limited, but is preferably 5 to 300 times the weight of (+)-(1S, 2S) -acetate (3).

At the time of the reaction, a solvent which does not adversely affect the reaction may be further coexisted.
Examples thereof include aliphatic or aromatic hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane. These solvents may be used alone or as a mixture of two or more. When the above-mentioned solvent is allowed to coexist, the use amount thereof is not particularly limited, but is preferably 1 to 200 times the weight of (+)-(1S, 2S) -acetate (3).

The reaction temperature is preferably in the range of 0 to 100 ° C, more preferably in the range of 20 to 50 ° C. The reaction time is
Although it depends on the reaction conditions, it is usually within 8 hours.

The thus obtained (-)-(1S,
2S) -Alcohol (4) can be isolated and purified by a method generally used for isolating and purifying organic compounds. For example, an organic solvent such as ethyl acetate, diethyl ether, or methylene chloride is added to the reaction solution for extraction, and the extract is washed with diluted hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride, and the like, and dried over anhydrous magnesium sulfate. After drying, the crude product obtained by concentration is purified by column chromatography, recrystallization, distillation or the like.

The acetate (1), which is a starting material of the present invention, is obtained by treating β-ionone with ozone and then with sodium borohydride, 2,6,6-trimethyl-1-cyclohexenemethanol [Journal of
Organic Chemistry (J. Org. Che)
m. ), Vol. 61, p. 5916 (1996)], the epoxidation using an oxidizing agent such as metachloroperbenzoic acid, and the hydroxyl group of the obtained compound is acetylated using acetic anhydride or the like. Thus, it can be easily manufactured (see Reference Examples 1 and 2).

[0027]

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

Reference Example 1 2,6,6-Trimethyl-1-cyclohexenemethanol (7.2 g, 47 mmol) and sodium hydrogencarbonate (1.0 g, 29 mmol) were suspended in dry chloroform and cooled to 0 ° C. Metachloroperbenzoic acid (9.5
g, 55 mmol) was added while maintaining the internal temperature at 0 ° C. or lower. After the addition was completed, the mixture was stirred at 20 ° C. for 5 hours. The reaction solution was diluted with diethyl ether, and washed sequentially with a saturated aqueous solution of sodium thiosulfate, water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 5/1 (volume ratio)] to give a colorless oil. The same IR and ¹ H-NMR spectrum as that of the corresponding optically active substance reported in the past [Journal of Organic Chemistry (J. Org.
m. ), Vol. 61, p. 5916 (1996)], which shows (±) -1,2-epoxy-2,6,6-trimethylcyclohexanemethanol (6.5 g, 38 mmol).
1) was obtained (82% yield).

IR νmax (cm ⁻¹ , film): 3
450 (s), 2935 (s), 2873 (m), 14
56 (m), 1382 (m), 1035 (m) ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) δ: 1.03 (3H, s, 6-H), 1.05
(3H, s, 6-Me), 1.05 (1H, m), 1.
37 (3H, s, 2-Me), 1.38 (3H, m),
1.72 (1H, m), 1.89 (1H, m), 1.9
4 (1H, t, J = 4.9 Hz, OH), 3.67 (1
H, dd, J = 11.3, 4.9 Hz, CH ₂ O),
3.84 (1H, d, J = 11.3, 4.9 Hz, CH
₂ O)

Reference Example 2 (±) -1,2-epoxy-2, obtained in Reference Example 1
6,6-trimethylcyclohexanemethanol (6.5
g, 38 mmol) with pyridine (30 g, 380 mmol)
1) and cooled to 0 ° C., and acetic anhydride (5.0 g, 49 mmol) was added dropwise to the solution while maintaining the internal temperature at 0 ° C. or lower. After completion of the dropwise addition, the mixture was stirred at 20 ° C. for 5 hours. The reaction solution was diluted with 30 ml of diethyl ether, and water (5 m
1) The mixture was washed twice with 2N hydrochloric acid (10 ml) and sequentially with a saturated aqueous solution of sodium hydrogen carbonate (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 5/1 (volume ratio)] to give a colorless oil. Has the following physical properties (±)
-1,2-Epoxy-2,6,6-trimethylcyclohexanemethyl acetate (5.8 g, 27 mmol) was obtained (yield 71%).

IR νmax (cm ⁻¹ , film): 2
935 (s), 1741 (s), 1380 (m), 13
65 (m), 1241 (s), 1228 (s), 103
5 (m) ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) [delta]: 1.05 (6H, s, 6-Me) 1.08
(1H, m), 1.34 (3H, s, 2-Me), 1.
40 (3H, m), 1.70 (1H, m), 1.90
(1H, m), 2.08 ( 3H, s, CH 3 C = O),
4.01 (1H, d, J = 12Hz, CH 2 O), 4.
45 (1H, d, J = 12 Hz, CH ₂ O) HREIMS m / z (M ⁺ ) = Calcd for
_{C 12 H 20 O 3: 212.1412} , found:
212.1409.

Example 1 (±) -1,2-epoxy- obtained by the method of Reference Example 2
2,6,6-trimethylcyclohexanemethyl acetate (48 mg, 0.23 mmol), diisopropyl ether (2.0 ml) and phosphate buffer (0.1 M,
pH = 7.0, 2.0 ml), and lipase P (manufactured by Amano Pharmaceutical, 45 mg) was added as an enzyme.
Stir for 8 hours. The reaction solution was filtered through celite, and the filtrate was separated into an organic layer and an aqueous layer.
Extracted. The extract and the organic layer were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate (3 ml) and a saturated aqueous solution of sodium chloride (3 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by column chromatography [developing solvent: hexane / ethyl acetate = 5/1 (volume ratio)] was carried out as (+)-(1S, 2S) -1,2-epoxy-2, as a colorless oil.
6,6-trimethylcyclohexanemethyl acetate (22 mg, 0.10 mmol, 44% yield) and (+)-(1R, 2R) -1,2-epoxy-2,6,
6-trimethylcyclohexanemethanol (17 g,
0.10 mmol, yield 44%).

The IR and ¹ H-NMR spectra of (+)-(1S, 2S) -1,2-epoxy-2,6,6-trimethylcyclohexanemethyl acetate were in agreement with the corresponding (±) -form. . The obtained (+)-
The enantiomeric purity of (1S, 2S) -1,2-epoxy-2,6,6-trimethylcyclohexanemethyl acetate was determined by reacting the compound with potassium carbonate and methanol to convert the acetate moiety to an alcohol and then obtaining The resulting alcohol was allowed to react with p-nitrobenzoic acid chloride in the presence of pyridine to derive the corresponding p-nitrobenzoic ester, followed by high performance liquid chromatography [column: Chiralcel OD, φ4.
6 mm × 250 mm [manufactured by Daicel Chemical Industries, Ltd.], eluent: hexane / 2-propanol = 20: 1 (volume ratio), flow rate 0.5 ml / min, detector: UV 254 nm]
Was determined by analysis. (+)-(1S, 2S) -1,2-epoxy-2,6,
6-trimethylcyclohexanemethyl acetate; specific rotation: [α] _D = + 19 ° (c = 1.1, CHC
l ₃ ), enantiomeric purity: 98.2% e. e.

On the other hand, the (+)-(1R, 2
The IR and ¹ H-NMR spectra of R) -1,2-epoxy-2,6,6-trimethylcyclohexanemethanol were consistent with the corresponding (±) -form. Also, (+)-
The enantiomeric purity of (1R, 2R) -1,2-epoxy-2,6,6-trimethylcyclohexanemethanol is determined by reacting this compound with p-nitrobenzoic acid chloride in the presence of pyridine to give the corresponding p-nitrobenzene. After derivation to benzoate, high performance liquid chromatography [column: C
hiralcel OD, φ4.6mm X 250m
m [manufactured by Daicel Chemical Industries, Ltd.], eluent: hexane / 2-
Propanol = 20: 1 (volume ratio), flow rate 0.5 ml /
Min, detector: UV 254 nm]. (+)-(1R, 2R) -1,2-epoxy-2,6,
Physical properties of 6-trimethylcyclohexanemethanol:
Specific rotation: [α] _D = + 40 ° (c = 0.80, CHC
l ₃ ), enantiomeric purity: 97.1% e. e.

Example 2 (+)-(1S, 2S)-obtained by the method of Example 1.
1,2-Epoxy-2,6,6-trimethylcyclohexanemethyl acetate (22 mg, 0.10 mmol
l), potassium carbonate (5.0 mg, 0.036 mmol)
l) and methanol (5.0 ml),
For 4 hours. The reaction solution was concentrated under reduced pressure, and methanol was distilled off. Water (10 ml) was added to the residue and extracted with diethyl ether (20 ml). Extract the water with water (10
ml) and a saturated aqueous sodium chloride solution (10 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [developing solvent: hexane / ethyl acetate = 7/1 ( (Volume ratio)] to give (-)-(1S, 2S) -1,2-epoxy-2,6, having the following physical properties.
6-trimethylcyclohexanemethanol (17 mg,
0.10 mmol) was obtained (yield ~ 100%). In addition,
The obtained (-)-(1S, 2S) -1,2-epoxy-
The enantiomeric purity of 2,6,6-trimethylcyclohexanemethanol was determined in the same manner as in the method for analyzing the enantiomeric purity of (+)-(1R, 2R) -1,2-epoxy-2,6,6-trimethylcyclohexanemethanol. Decided.

Specific rotation: [α] _D = −39 ° (c = 0.
80, CHCl ₃ ), enantiomeric purity: 98.2% e. e.

[0037]

According to the present invention, optically active 1,2-epoxy-2,6,6-trimethylcyclohexanemethanol can be industrially advantageously produced with high yield and high optical purity.

Claims (3)

[Claims] (1) Formula (1) Wherein an enzyme having an ester hydrolytic activity is allowed to act on (±) -1,2-epoxy-2,6,6-trimethylcyclohexanemethyl acetate represented by the formula (2): A method for producing (+)-(1R, 2R) -1,2-epoxy-2,6,6-trimethylcyclohexanemethanol represented by the formula: 2. Formula (1) (±) -1,2-epoxy-2,6,6-trimethylcyclohexanemethyl acetate represented by the formula (2) (+)-(1R, 2R) -1,2-epoxy-2,6,6-trimethylcyclohexanemethanol represented by the formula: ## STR5 ## (+)-(1S, 2S) -1,2-epoxy-2,6,6-trimethylcyclohexanemethyl acetate represented by the following formula (+)-(1S, 2S) -1,2-
Formula (4) characterized by solvolysis of epoxy-2,6,6-trimethylcyclohexanemethyl acetate. A method for producing (-)-(1S, 2S) -1,2-epoxy-2,6,6-trimethylcyclohexanemethanol represented by the formula: 3. An enzyme having an ester hydrolytic ability,
The production method according to claim 1 or 2, wherein the production method is an enzyme produced by a microorganism belonging to the genus pseudomonas or an enzyme produced by a microorganism belonging to the genus Burkholderia cepacia.