JP2001025395A - Production of optically active 4-hydroxy-2,6,6-trimethyl-2- cyclohexen-1-one - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optically active 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-1- one useful as a synthetic intermediate for phytohormones, or the like, in high yield by treating (±)-4-oxo-trimethyl-cyclohexenyl chloroacetate with an esterase and solvolyzing the product. SOLUTION: The objective optically active 4-hydroxy-2,6,6-trimethyl-2- cyclohexen-1-one of formula III useful as a synthetic intermediate for optically active abscisic acid known as a phytohormone, zeaxanthin belonging to carotenoid, or the like, is produced in high yield and optical purity by treating (±)-4- oxo-3,5,5-trimethyl-2-cyclohexenyl chloroacetate of formula I with an enzyme having ester hydrolyzing activity such as a lipase produced by microorganism belonging to the genus Pseudomonas and solvolyzing the obtained optically active 4-oxo-3,5,5-trimethyl-2-cyclohexenyl chloroacetate of formula II (* shows an asymmetric carbon atom).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to optically active 4-hydroxy-2,6,6-trimethyl-2-cyclohexene-
The present invention relates to a method for producing 1-one. Optically active 4-hydroxy-2,6,6-trimethyl-2 obtained by the present invention
-Cyclohexen-1-one is useful as a synthetic intermediate, for example, an optically active abscisic acid, a plant hormone, or a carotenoid, zeaxanthin.

[0002]

2. Description of the Related Art Optically active 4-hydroxy-2,6,6-
The method for producing trimethyl-2-cyclohexen-1-one includes 1) cis- and trans-2,6,6-trimethyl derived from 2,6,6-trimethyl-2-cyclohexen-1,4-dione. -2-cyclohexene-
Asymmetric monoacetylation of 1,4-diol by an enzyme (lipase PS-30: manufactured by Amano Pharmaceutical Co., Ltd.) to give a 4-O-acylated product (40% yield, 81% ee) and a 1-O-acylated product ( An 18% yield, 92% ee) was obtained, and then optically active 4-hydroxy-2,2 was obtained through multiple steps such as recrystallization and oxidation.
A method for obtaining a silyl ether form of 6,6-trimethyl-2-cyclohexen-1-one [Tetrahedron Asymmetry]
y), Vol. 6, p. 1273 (1995)], 2)
2,6,6-trimethyl-2-cyclohexene-1,4
-Dione in yeast (Saccharomyces cer)
(R) -2,6,6-
Trimethyl-1,4-cyclohexanedione is obtained, and then the 4-position of this compound is reduced in the presence of Raney nickel catalyst to give (1R, 5R) -4-oxo-3,3,5-trimethylcyclohexan-1-ol. This was converted to an acetate ester, and then brominated at the 5-position, followed by dehydrobromination and deesterification to give (S) -4-
Method for obtaining hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one [Helv. Chimica Acta, Helv. Chim. Acta, Vol.
32 (1976); see Helvetica Kimika Acta, Vol. 61, p. 2609 (1978)].

[0003]

The above-mentioned method requires many steps, and in each step, it is not easy to separate a product from an isomer produced as a by-product, and optically active 4-hydroxy-2, 6,6-trimethyl-2-cyclohexene-
This is not an industrially advantageous method for producing 1-one. Thus, an object of the present invention is to provide an optically active 4-hydroxy-2,
It is an object of the present invention to provide a method capable of producing 6,6-trimethyl-2-cyclohexen-1-one 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 formula (1)

[0005]

Embedded image

(±) -4-oxo-3,5,
5-trimethyl-2-cyclohexenyl chloroacetate (hereinafter abbreviated as chloroacetate (1)) is reacted with an enzyme capable of hydrolyzing an ester to obtain a compound of the formula (2)

[0007]

Embedded image

(In the formula, * represents an asymmetric carbon atom.) Optically active 4-oxo-3,5,5-trimethyl-
Formula (3) characterized in that 2-cyclohexenyl chloroacetate (hereinafter abbreviated as optically active chloroacetate (2)) is obtained, and the obtained optically active chloroacetate (2) is subjected to solvolysis.

[0009]

Embedded image

(In the formula, * is as defined above.)
Which is achieved by providing a method for producing optically active 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one (hereinafter abbreviated as optically active hydroxycyclohexenone (3)) You.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION

First, a process for obtaining an optically active chloroacetate (2) by reacting an enzyme having an ester hydrolytic activity on chloroacetate (1) will be described.

[0013] Pseudom is an enzyme capable of acting on chloroacetate (1) having the ability to hydrolyze esters.
Kle, a lipase produced by microorganisms belonging to the genus onas
There are enzymes produced by microorganisms belonging to the genus bsiella oxytoca, for example, Pseudomonas
Lipase 2G (manufactured by Nagase Sangyo) produced by a microorganism belonging to the genus, SNSM-87 (manufactured by Nagase Sangyo) produced by a microorganism belonging to the genus Klebsiella oxytoca, P
Lipase P (manufactured by Amano Pharmaceutical) and Lipase PS30 (manufactured by Amano Pharmaceutical) produced by microorganisms belonging to the genus pseudomonas. Among them, when lipase 2G or SNSM-87 is used, chloroacetate (1)
Since the (R) form is preferentially hydrolyzed, the (S) form of optically active chloroacetate (2) can be obtained.
When lipase P or lipase PS30 is used,
Since the (S) form of chloroacetate (1) is preferentially hydrolyzed, the (R) form of optically active chloroacetate (2) can be obtained. The amount of the enzyme used is usually preferably in the range of 0.01 to 100% by weight, more preferably 0.1 to 10% by weight, based on chloroacetate (1).

The reaction is preferably performed in the presence of a solvent. Examples of the solvent include ethers such as diethyl ether and diisopropyl ether; nitriles such as acetonitrile; ketones such as acetone; and hydrocarbons such as toluene, hexane and heptane. Among these, diisopropyl ether is particularly preferred. The amount of solvent used is usually 5 to chloroacetate (1).
The range is preferably from 40 to 40 times by weight, more preferably from 10 to 20 times by weight.

During 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 in the range of 8, and such pH adjustment is particularly preferably performed 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 preferably 1 to 50 times by weight, more preferably 10 to 30 times by weight, relative to chloroacetate (1).

[0016] The reaction temperature is preferably in the range of 0 to 40 ° C, more preferably 10 to 30 ° C. The reaction time is
Although it varies depending on the ratio of chloroacetate (1) to the enzyme used, the type of solvent and the type of buffer used, it is usually in the range of 1 hour to 1 week.

The reaction is carried out by reacting chloroacetate (1) with an enzyme,
If necessary, a solvent and a buffer are mixed, and the mixture is stirred at a predetermined temperature. The reaction may be carried out in a batch mode or in a continuous mode using immobilized enzymes.

Isolation of the optically active chloroacetate (2) thus obtained from the reaction mixture can be carried out in the same manner as in a method generally used for isolating and purifying an organic compound. For example, the enzyme is filtered from the reaction mixture,
The filtrate was extracted with diethyl ether, diisopropyl ether, ethyl acetate, etc., and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, etc., and concentrated. Purify by chromatography or the like.

Next, the step of obtaining the optically active hydroxycyclohexenone (3) by solvolysis of the optically active chloroacetate (2) will be described.

The solvolysis reaction can be carried out in the presence of a basic substance or an acidic substance. Examples of such basic substances 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;
And alkali metal carbonates such as sodium carbonate and potassium carbonate. 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. The amount of the basic substance or acidic substance used is not particularly limited, but is usually preferably in the range of 0.2 to 2 mol times, more preferably 0.5 to 1 mol times, relative to the optically active chloroacetate (2). The range is more preferred.

The solvolysis reaction can be carried out under neutral conditions, for example, potassium cyanide or Cand.
Lipase MY (manufactured by Meito Sangyo Co., Ltd.) produced by genus ida cylindraceae can be used as a catalyst. The use amount of such a catalyst is not particularly limited, but is usually preferably in the range of 0.2 to 2 times the molar amount of the optically active chloroacetate (2).

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 or alcohol used is not particularly limited, but is usually preferably in the range of 5 to 200 times by weight based on the optically active chloroacetate (2).

The reaction may further be carried out in the presence of a solvent which does not adversely influence the reaction, such as an aliphatic or aromatic hydrocarbon such as hexane, heptane, cyclohexane, benzene, toluene and xylene;
Examples thereof include 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. The amount of the solvent to be used is not particularly limited, but is usually preferably 1 to 200 times by weight based on the optically active chloroacetate (2).

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 optically active hydroxycyclohexenone (3) thus obtained 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, and diluted hydrochloric acid, water,
After washing with a saline solution or the like, the organic layer is dried over anhydrous sodium sulfate or the like, and then concentrated to obtain a crude product.
Purify by column chromatography or the like.

The starting material of the present invention, chloroacetate (1), is (±) -4-hydroxy-2,6,6
-Trimethyl-2-cyclohexen-1-one and chloroacetic acid chloride can be easily produced by condensation in the presence of a base. Examples of the base used in this reaction include amines such as triethylamine and pyridine; alkali metal alkoxides such as sodium methoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The reaction can be performed in the presence or absence of a solvent. Examples of the solvent include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as diethyl ether and diisopropyl ether; hydrocarbons such as hexane and toluene. [Tetrahedron L (Tetrahedron L)
ett. ), Vol. 20, p. 251 (1979)]. (±) -4-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one is 2,6,6
It can be easily produced by reducing 6-trimethyl-2-cyclohexene-1,4-dione with sodium borohydride in the presence of cerium chloride [Journal of Organic Chemistry (J. Org.
Chem. ), Vol. 51, p. 491 (1986)].

[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 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one (1.50 g, 9.73 mmol)
And pyridine (1.24 g, 14.8 mmol) were dissolved in dry diethyl ether (30 ml) and cooled to 0 ° C., and chloroacetic chloride (1.32 g, 1
(1.7 mmol) was added dropwise 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 washed sequentially with water (5 ml), 2N hydrochloric acid (10 ml), and a saturated aqueous sodium hydrogen carbonate solution (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 7/1 (volume ratio)] to give a colorless oil. (±) -4-oxo- having the following physical properties
3,5,5-Trimethyl-2-cyclohexenyl chloroacetate (2.13 g, 9.23 mmol) was obtained (yield 94.9%).

UV (c = 8.7 × 10 ⁻⁵ mol / l)
in EtOH): ε = 9900 (λmax 228)
nm) IR νmax (cm ⁻¹ , film): 2960
(S), 2930 (s), 2860 (s), 1755
(S, C = O), 1740 (s, C = O), 1680
(S, C = C), 1470 (m), 1450 (m), 1
410 (m), 1380 (m), 1350 (m), 13
15 (s), 1280 (s), 1160 (br.s, C
-O), 1105 (m), 1045 (m), 1000
(S), 980 (s), 960 (s), 860 (m),
790 (m), 700 (w) ¹ H-NMR (300 MHz, CDCl ₃ , TMS, p
pm) δ: 1.182 (s, 3H, 5-Me), 1.
187 (s, 3H, 5-Me), 1.82 (t, 3H,
3-Me, J = 1.7 Hz), 2.00 (dd, 1H,
J = 12.9, 9.3 Hz, 6-H), 2.21 (dd
d, 1H, J = 12.9, 5.5, 1.9 Hz, 6-
H), 4.11 (s, 2H , Cl-CH 2), 5.71
(1H, m, 1-H), 6.53 (dq, 1H, J =
4.1, 1.4 Hz, 2-H) EIMS m / z: 43, 61, 98, 174, 230
(M ⁺ ) HREIMS m / z (M ⁺ ) = Calcd. fo
_{r C 11 H 15 O 3 Cl} : 230.0709, fo
und: 230.0711

Example 1 (±) -4-oxo-3, obtained by the method of Reference Example 1,
5,5-trimethyl-2-cyclohexenyl chloroacetate (60.0 mg, 260 μmol), diisopropyl ether (1.5 ml) and acetate buffer (0.1
M, pH = 5.0, 1.5 ml), and added SNSM-87 (manufactured by Nagase Sangyo, 60 mg) as an enzyme.
Stirred at 0 ° C. for 2 days. The reaction solution was filtered through celite, and the filtrate was separated into an organic layer and an aqueous layer.
Extracted with 0 ml. 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 = 7/1 (volume ratio)] gives the following physical properties of (S) -4-oxo-3,5,
5-Trimethyl-2-cyclohexenyl chloroacetate (12.2 mg, 52.9 μmol) was obtained (yield 2).
0.3%).

[Α] _D ²⁴ : −73.7 ° (c = 0.4
55, EtOH) IR and ¹ H-NMR spectra were consistent with (±) -4-oxo-3,5,5-trimethyl-2-cyclohexenylchloroacetate. The obtained compound was subjected to high performance liquid chromatography [column: Chiralce].
1 OB-H, φ4.6 mm x 250 mm [manufactured by Daicel Chemical Industries, Ltd.], eluent: hexane / isopropanol = 7: 1 (volume ratio), flow rate: 1.0 ml / min, detector: UV 233 nm] As a result, the optical purity was 9
8.8% e. e. Met.

Example 2 (±) -4-oxo-3, obtained by the method of Reference Example 1,
5,5-trimethyl-2-cyclohexenyl chloroacetate (60.0 mg, 260 μmol), diisopropyl ether (1.5 ml) and phosphate buffer (0.
1M, pH = 7.0, 1.5 ml), lipase P (manufactured by Amano Pharmaceutical Co., 60 mg) was added as an enzyme, and the mixture was added to 40 ml.
Stirred at C for 2 days. The reaction solution was filtered through Celite, and the filtrate was separated into an organic layer and an aqueous layer.
Extracted in ml. 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. Column chromatography [Developing solvent: hexane /
Ethyl acetate = 7/1 (volume ratio)] to give (R) -4-oxo-3,5,5 having the following physical properties.
5-Trimethyl-2-cyclohexenyl chloroacetate (16.0 mg, 52.9 μmol) was obtained (yield 2).
6.7%).

[Α] _D ²² : + 70.0 ° (c = 0.8
(00, EtOH) IR and ¹ H-NMR spectra were consistent with (±) -4-oxo-3,5,5-trimethyl-2-cyclohexenylchloroacetate. When the obtained compound was analyzed by high performance liquid chromatography in the same manner as in Example 1, the optical purity was 98.5% e.g. e. Met.

Example 3 (S) -4-oxo-3, obtained by the method of Example 1,
5,5-Trimethyl-2-cyclohexenyl chloroacetate (300 mg, 1.30 mmol), potassium carbonate (100 mg) and methanol (50 ml) were mixed and stirred at 20 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and methanol was distilled off. 5 ml of water was added to the residue,
Extracted with 50 ml of diethyl ether. Extract the water with water (5
ml) and saturated aqueous sodium chloride solution (5 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 (S) -4-hydroxy-2,6,6-trimethyl-2 having the following physical properties.
-Cyclohexen-1-one (209 mg, 1.19 m
mol) was obtained (yield 92.3%, optical purity 98.8%).
e. e. ).

[Α] _D ²⁴ : -50.0 ° (c = 0.1
00, EtOH) ¹ H-NMR (300 MHz, CDCl ₃ , TMS, p
pm) δ: 1.12 (s, 3H, 6-Me), 1.1
6 (s, 3H, 6-Me), 1.60 (br, s, 1
H, OH), 1.79 (dd, 3H, J = 3 Hz, 2H
z, 2-Me), 1.82 (dd, 1H, J = 13H)
z, 10 Hz, 5-H), 2.16 (ddd, 1H, J
= 13, Hz, 6 Hz, 2 Hz, 5-H), 4.60
(M, 1H, 4-H), 6.61 (m, 1H, 3-H) IR νmax (cm ⁻¹ , film): 3430
(S), 3015 (w), 2960 (s), 2920
(S), 2860 (m), 1675 (s), 1660
(S), 1450 (m), 1380 (m), 1350
(M), 1100 (m), 1040 (s), 1020
(S), 950 (w), 955 (w), 935 (m),
900 (w), 860 (w)

Example 4 (R) -4-oxo-3, obtained by the method of Example 2,
5,5-Trimethyl-2-cyclohexenyl chloroacetate (300 mg, 1.30 mmol), potassium carbonate (100 mg) and methanol (50 ml) were mixed and stirred at 20 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and methanol was distilled off. 5 ml of water was added to the residue,
Extracted with 50 ml of diethyl ether. Extract the water with water (5
ml) and saturated aqueous sodium chloride solution (5 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 (R) -4-hydroxy-2,6,6-trimethyl-2 having the following physical properties.
-Cyclohexen-1-one (203 mg, 1.16 m
mol) was obtained (yield: 89.7%, optical purity: 98.5%).
e. e. ).

[Α] _D ²⁴ : + 52.7 ° (c = 0.4
45, EtOH) IR and ¹ H-NMR spectra were consistent with (S) -4-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one.

[0038]

According to the present invention, optically active 4-hydroxy-2,6,6-trimethyl-2-cyclohexene-1 is provided.
-One can be industrially advantageously produced with high yield and high optical purity.

Claims (2)

[Claims] (1) Formula (1) (±) -4-oxo-3,5,5-trimethyl-2-cyclohexenyl chloroacetate represented by the formula (2) (In the formula, * represents an asymmetric carbon atom.) An optically active 4-oxo-3,5,5-trimethyl-2-cyclohexenyl chloroacetate was obtained, and the obtained optically active 4-oxo-3,5,5-trimethyl-2-cyclohexenylchloroacetate was obtained.
Formula (3) wherein oxo-3,5,5-trimethyl-2-cyclohexenyl chloroacetate is solvolyzed. (In the formula, * is as defined above.) Optically active 4-hydroxy-2,6,6-trimethyl-2-
A method for producing cyclohexen-1-one. 2. An enzyme having the ability to degrade an ester is P
2. The production of an optically active 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one according to claim 1, which is a lipase produced by a microorganism belonging to the genus pseudomonas or an enzyme produced by a microorganism belonging to the genus Klebsiella oxytoca. Method.