JPH06128244A - Optically active epoxide derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new compound useful as a synthetic intermediate for various physiologically active substances, functional materials, etc. CONSTITUTION:The compound of formula I (R<1> to R<4> are 1-6C alkyl; *represents asymmetric C), e.g. (3R,4R)-3,4-epoxy-2,5-dihydroxy-2,5-dimethylhexane. The compound of formula I can be produced by the asymmetric oxidation reaction of a tertiary allyl alcohol of formula II in the presence of molecular sieve 4A in a solvent (e.g. methylene chloride) at -78 to 0 deg.C using an oxidizing agent, a tartaric acid ester and a titanium alkoxide at the same time. The oxidizing agent is e.g. a peroxide such as t-butyl hydroperoxide and the tartaric acid ester is e.g. L or D-diethyl tartrate. The amount of the titanium alkoxide is 0.0-1.5 equivalent based on the substrate.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention has the general formula,

[0002]

[Chemical 3]

(Wherein R ¹ , R ² , R ³ and R ⁴ represent an alkyl group having 1 to 6 carbon atoms, and * represents an asymmetric carbon), and the production thereof. Concerning the law.

[0004]

2. Description of the Related Art In recent years, there is an increasing need to synthesize physiologically active substances and functional materials as optically active substances. When a plurality of optical isomers are present in these compounds, a difference in activity and properties is usually observed between the isomers.
Therefore, in order to express sufficient physiological activity or functionality, it is essential to selectively synthesize only desired optical isomers.

The optically active epoxide derivative represented by the general formula (I) in the present invention is the first compound synthesized by the present inventors. This novel compound can be widely used as a synthetic intermediate for useful compounds such as various physiologically active substances such as chrysanthemic acid and functional materials.
However, in the past, only a method for synthesizing a racemate using peracetic acid has been known (VI Nikitin
Zh. Obshch. Khim., 32 , 413 (1962)), an industrially excellent and efficient synthetic method of an optically active substance has not been known.

On the other hand, as a method for synthesizing an optically active epoxide, Kazuki-Sharpress asymmetric epoxidation reaction (J. Am. C
hem. Soc., 102 , 5974 (1980)) is widely used as an asymmetric modification method for allyl alcohols. However, all reports so far have used primary and secondary alcohols as substrates, and there have been no examples of application to tertiary alcohols (Rossiter et al., Asymmetric Synthes
is, 1985, Vol.5, pp.193-246).

[0007]

Based on the above points, the inventors of the present invention have conducted extensive studies to achieve the purpose of efficiently obtaining an optically active epoxide derivative, and as a result, are represented by the general formula (I). The present invention has been completed by finding a production method for efficiently obtaining an optically active epoxide derivative.

[0008]

The present invention has the general formula

[0009]

[Chemical 4]

(In the formula, R ¹ , R ² , R ³ , and R ⁴ represent an alkyl group having 1 to 6 carbon atoms, and * represents an asymmetric carbon.), Which is an optically active epoxide derivative. Also, the general formula

[0011]

[Chemical 5]

By the asymmetric oxidation of the tertiary allyl alcohol represented by the formula (wherein R ¹ , R ² , R ³ and R ⁴ represent an alkyl group having 1 to 6 carbon atoms), the general formula A method for producing an optically active epoxide derivative, characterized in that the optically active epoxide derivative represented by (I) is obtained. Further, preferably, optically active L- or D-tartaric acid ester, titanium alkoxide, and molecular sieves 4A are used in the oxidation step.

The optically active epoxide derivative of the present invention is represented by the above general formula (I). Specific examples of the compound name are (3R, 4R) -3,4-epoxy-2,5-dihydroxy-2. , 5-dimethylhexane, (4R, 5R)
-4,5-Epoxy-3,6-dihydroxy-3,6-
Dimethylheptane, (4R, 5R) -4,5-epoxy-3,6-dihydroxy-3-ethyl-6-methylheptane, (4R, 5R) -4,5-epoxy-3,6-dihydroxy-3- Ethyl-6-methyloctane, (4
R, 5R) -4,5-Epoxy-3,6-dihydroxy-3,6-diethyloctane, (3S, 4S) -3,4
-Epoxy-2,5-dihydroxy-2,5-dimethylhexane, (4S, 5S) -4,5-epoxy-3,6
-Dihydroxy-3,6-dimethylheptane, (4S,
5S) -4,5-Epoxy-3,6-dihydroxy-3
-Ethyl-6-methylheptane, (4S, 5S) -4,
5-epoxy-3,6-dihydroxy-3-ethyl-6
-Methyloctane, (4S, 5S) -4,5-epoxy-3,6-dihydroxy-3,6-diethyloctane and the like.

The asymmetric oxidation reaction of the present invention is preferably accomplished by using an oxidizing agent, a tartaric acid ester, and a titanium alkoxide simultaneously in the presence of molecular sieves 4A. Examples of the oxidizing agent used in the reaction include:
Peroxides such as t-butyl hydroperoxide may be mentioned. As the tartrate ester, L- or D-form diethyl tartrate, dipropyl tartrate, diisopropyl tartrate or the like can be used. Examples of titanium alkoxides include titanium isopropoxide and titanium t-butoxide. The titanium alkoxide can be used in an amount of 0.05 to 1.5 equivalents, preferably 1 equivalent or more, relative to the substrate. There is no particular effect even if it is used in excess of 1.5 equivalents.

As the reaction solvent, halogenated hydrocarbon solvents such as methylene chloride, chloroform and 1,2-dichloroethane can be used. Reaction temperature is -78 ℃ ~ 0
C. is suitable, particularly preferably -20.degree. By the above operation, an optically active epoxide derivative can be obtained. Depending on the tartaric acid used, the optically active epoxide derivative may be either (+)-form or (-)-form.

The configuration of the optically active epoxide derivative of the present invention was determined as follows. That is, natural (S) -malic acid having a known configuration is methyl esterified with diazomethane and further reacted with methyllithium to form (S) -2,3 represented by the formula (III) in two steps. ，
5-Trihydroxy-2,5-dimethylhexane was synthesized ([α] _D ²⁹ : -19.6 ° (c 1.00, CHCl ₃ )).

[0017]

[Chemical 6]

On the other hand, the compound of the present invention (3R, 4
R) -3,4-epoxy-2,5-dihydroxy-2,
Reduction of 5-dimethylhexane with lithium aluminum hydride to give (R) -2,3,5-trihydroxy-2,5
-The steric configuration of the compound of the present invention was determined by converting to dimethylhexane and comparing with the specific optical rotation described above.

[0019]

EFFECTS OF THE INVENTION By using the production method of the present invention, an asymmetric epoxidation reaction of a tertiary allyl alcohol, which has hitherto been impossible, can be easily achieved. In addition, the general formula (I) of the present invention
The compound represented by is a novel compound synthesized for the first time by the present inventors, and can be used as a synthetic intermediate for useful compounds such as various physiologically active substances and functional materials.

For example, according to the following reaction route, the formula (IV)
It is possible to lead to a chrysanthemic acid derivative such as

[0021]

[Chemical 7]

[0022]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples. Reference Example 1 (E) -2,5-dihydroxy-2,5-dimethyl-3
-Synthesis of hexene 11.4 g (0.3 mol) of lithium aluminum hydride was suspended in 300 ml of tetrahydrofuran and under ice cooling, 2,5-dihydroxy-2,5-dimethyl-3-hexyne 14.2 g (0.1 mol).
50 ml of a tetrahydrofuran solution of was added dropwise and stirred at the same temperature for 1 hour. Concentrated aqueous ammonia was added dropwise, the mixture was stirred at room temperature for 1 hr, and then filtered through Celite. The residue on Celite was extracted again with tetrahydrofuran and filtered. The combined filtrate was concentrated under reduced pressure to obtain 14.7 g of a crude product. Recrystallization from ether-hexane gave colorless needle crystals of (E) -2,5-dihydroxy-2,5-dimethyl-3-hexene.

Mp: 96-97 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.30 (s, 12H), 1.82 (brs, 2H),
5.80 (s, 2H), IR (nujol): νmax 3450cm ^-1 MS (m / e): 129 (M ⁺ -CH ₃ ), 59 (100%). Example 1 Synthesis of (3R, 4R) -3,4-epoxy-2,5-dihydroxy-2,5-dimethylhexane Step 1 4 g of crushed and dried molecular sieves 4A was suspended in 200 ml of methylene chloride, and -20 A solution of titanium isopropoxide (6.3 ml, 21 mmol) and L-(+)-diisopropyl tartrate (5.62 g, 24 mmol) in methylene chloride was added at 30 ° C.
Stir for minutes. (E) -2,5-dihydroxy-2,5
-Methyl chloride solution of 2.88g (20mmol) of dimethyl-3-hexene was added and stirred for 1 hour, then 16.7ml (30mmol) of 1.8M methylene chloride solution of t-butyl hydroperoxide was added dropwise, and stirred at -20 ° C for 80 hours. did. 36 ml of water and 180 ml of tetrahydrofuran were added to the reaction mixture, and the mixture was stirred at room temperature and then filtered through Celite. The residue on Celite was washed with tetrahydrofuran (500 ml) and then filtered, and the combined filtrate was concentrated under reduced pressure to give a crude product. Purification by column chromatography (silica gel, ether-hexane 2: 1) gave (3R, 4R) -3,4-epoxy-2,5-dihydroxy-2,5-dimethylhexane (3.15 g). Yield 96%.

Mp: 29 to 31 ° C. (α) _D ²³ : -18.4 ° (c 2.0, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ): δ 1.24 (s, 6H), 1.33 (s, 6H), 1.8
8 (brs, 2H, D ₂ O substitution), 3.02 (s, 2H) IR (neat): νmax 3400cm ^-1 MS (m / e): 145 (M ⁺ -CH ₃ ), 59 (100%).

The optical purity of this compound is (R) -2,3,5-trihydroxy-2,5-obtained in step 2.
The optical purity of the monobenzoyl derivative of dimethylhexane was determined to be 70% ee by measuring it using an optical resolution column (CHIRALCEL OD manufactured by Daicel). Step 2 (3R, 4R) -3,4-epoxy-2 obtained in Step 1,
250 mg of 5-dihydroxy-2,5-dimethylhexane (1.
56 mmol) in 10 ml of tetrahydrofuran, and under ice cooling,
210 mg (5.47 mmol) of lithium aluminum hydride was added, and the mixture was stirred at the same temperature for 3 hours. A saturated aqueous ammonium chloride solution was added, the mixture was stirred at room temperature, and filtered through Celite. The residue on Celite was further washed with tetrahydrofuran, filtered, and the filtrates were combined and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol-ether 5:95) to obtain (R) -2,3,5-trihydroxy-2,5-dimethylhexane (229 mg). Yield 92
%.

[Α] _D ²⁹ : + 15.6 ° (c 1.01, MeOH). The spectral data were completely in agreement with those of the standard sample prepared from (S) -malic acid in the comparative example shown below. Comparative Example Synthesis of (S) -2,3,5-trihydroxy-2,5-dimethylhexane Step 1 1.34 g (10 mmol) of (S) -malic acid was dissolved in 15 ml of ether and saturated with diazomethane under ice cooling. The ether solution was added dropwise until the reaction liquid remained yellow. A nitrogen stream was introduced into the reaction solution, excess diazomethane was removed, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration and evaporation under reduced pressure, the residue was purified by column chromatography (silica gel, hexane-ether 1: 2), and (S) -dimethyl malate 1.56
g was obtained. Yield 95%.

¹ H-NMR (CDCl ₃ ): δ 2.60-3.00 (m, 2H),
3.24 (d, 1H, D ₂ O substitution), 3.72 (s, 3H), 3.82 (s, 3H), 4.5
0 (dd, 1H, J = 5.1, 5.1Hz) IR (neat): νmax 3490, 1732cm ^-1 . Step 2 200 mg (1.23 mmo) of (S) -dimethyl malate obtained in Step 1
l) was dissolved in 3 ml of tetrahydrofuran, 8.8 ml (12.3 mmol) of 1.4M ether solution of methyllithium was added dropwise at -20 ° C, and the mixture was stirred at the same temperature for 8 hours. After adding a saturated aqueous ammonium chloride solution and stirring at room temperature, the mixture was diluted with ether, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine.
After drying over anhydrous magnesium sulfate, filtration and evaporation under reduced pressure, the residue was purified by column chromatography (silica gel, methanol-ether 5:95) (S) -2,3,3.
5-trihydroxy-2,5-dimethylhexane 129mg
Got Yield 65%.

[Α] _D ²⁹ : −19.6 ° (c 1.00, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ): δ 1.16 (s, 3H), 1.20 (s, 3H), 1.2
9 (s, 3H), 1.32 (s, 3H), 1.45-1.85 (m, 2H), 2.65 (brs, 1
H, D ₂ O substitution), 3.45 (brs, 1H, D ₂ O substitution), 3.70-3.85 (m, 1
H), 4.20 (brd, 1H, J = 1.5Hz, D ₂ O substitution) IR (neat): νmax 3360cm ^-1 MS (m / e): 163 (M ⁺ +1), 129, 71 (100%).

Example 2 Synthesis of (3S, 4S) -3,4-epoxy-2,5-dihydroxy-2,5-dimethylhexane Grinded and dried molecular sieves 4A (1 g) was suspended in methylene chloride (50 ml) to give -20 A solution of 1.6 ml (5.3 mmol) of titanium isopropoxide and 1.41 g (6.0 mmol) of diisopropyl D-(-)-tartrate in methylene chloride was added at 30 DEG C.
Stir for minutes. (E) -2,5-dihydroxy-2,5
A solution of 0.72 g (5.0 mmol) of dimethyl-3-hexene in methylene chloride was added and stirred for 1 hour, and then 4.2 ml (7.6 mmol) of a 1.8 M solution of t-butyl hydroperoxide in methylene chloride was added dropwise, and the mixture was heated at -20 ° C at 80 ° C. Stir for hours. 9 ml of water and 45 ml of tetrahydrofuran were added to the reaction mixture, and the mixture was stirred at room temperature and then filtered through Celite. The residue on Celite was washed with 125 ml of tetrahydrofuran and then filtered, and the combined filtrates were concentrated under reduced pressure to give a crude product. Purification by column chromatography (silica gel, ether-hexane 2: 1) gave (3S, 4S) -3,4-epoxy-2,5-dihydroxy-2,5-dimethylhexane 0.78 g. Yield 95%.

Mp: 29-31 ° C. [α] _D ²³ : + 18.2 ° (c 2.0, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ): δ 1.24 (s, 6H), 1.33 (s, 6H), 1.8
8 (brs, 2H, D ₂ O substitution), 3.02 (s, 2H) IR (neat): νmax 3400cm ^-1 MS (m / e): 145 (M ⁺ -CH ₃ ), 59 (100%).

The optical purity of this compound was determined to be 70% ee by the same method as that shown in Example 1.

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Claims (3)

[Claims] 1. A general formula: (In the formula, R ¹ , R ² , R ³ and R ⁴ represent an alkyl group having 1 to 6 carbon atoms, and * represents an asymmetric carbon.) An optically active epoxide derivative. 2. A general formula: The tertiary allyl alcohol represented by the formula (wherein R ¹ , R ² , R ³ and R ⁴ represent an alkyl group having 1 to 6 carbon atoms) is asymmetrically oxidized to obtain a tertiary allyl alcohol according to claim 1. A process for producing an optically active epoxide derivative, which comprises obtaining the optically active epoxide derivative represented by the general formula (I). 3. Optically active L- or D in the oxidation step
-The production method according to claim 2, wherein a tartaric acid ester, a titanium alkoxide, and a molecular sieve 4A are used.