JP3116420B2 - Optically active epoxide derivative and production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the general formula:

[0002]

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(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 atom). About the law.

[0004]

2. Description of the Related Art In recent years, there has been 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, isomers usually show differences in their activities and properties in many cases.
Therefore, it is indispensable to selectively synthesize only desired optical isomers in order to express sufficient physiological activity or functionality.

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 used very widely as an intermediate for synthesizing useful compounds such as various physiologically active substances such as chrysanthemic acid and functional materials.
However, in the past, only a method of synthesizing a racemate using peracetic acid is known, and (VI Nikitin
Zh. Obshch. Khim., 32 , 413 (1962)), and an industrially efficient and efficient method for synthesizing an optically active substance has not been known.

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

[0007]

In view of the above, the present inventors have conducted intensive studies to achieve the object of efficiently obtaining an optically active epoxide derivative. As a result, the present invention is represented by the general formula (I). The present inventors have found a production method for efficiently obtaining an optically active epoxide derivative, and have accomplished the present invention.

[0008]

According to the present invention, there is provided a compound represented by the general formula:

[0009]

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(Wherein, R ¹ , R ² , R ³ , and R ⁴ each represent an alkyl group having 1 to 6 carbon atoms, and * represents an asymmetric carbon atom). Also, the general formula

[0011]

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(Wherein R ¹ , R ² , R ³ , and R ⁴ represent an alkyl group having 1 to 6 carbon atoms). A method for producing an optically active epoxide derivative, characterized by obtaining the optically active epoxide derivative represented by (I). More preferably, in the oxidation step, an optically active L- or D-tartaric acid ester, a titanium alkoxide, and a molecular sieve (4 mm in diameter) are used.

The optically active epoxide derivative of the present invention is represented by the above-mentioned general formula (I). Specific examples of the compound name include (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.

[0014] asymmetric oxidation reaction of the present invention, molecular sieves (diameter 4 Å) the presence, oxidizing agent, tartaric acid esters,
And titanium alkoxide. Examples of the oxidizing agent used for the reaction include peroxides such as t-butyl hydroperoxide. As the tartaric acid ester, L- or D-
Diethyl tartrate, dipropyl tartrate, diisopropyl tartrate and the like can be used. Examples of the titanium alkoxide include titanium isopropoxide and titanium t-butoxide. The titanium alkoxide can be used in an amount of 0.05 to 1.5 equivalents to the substrate, but is particularly preferably 1 equivalent or more. Use in excess of 1.5 equivalents has no significant effect.

As the reaction solvent, halogenated hydrocarbon solvents such as methylene chloride, chloroform, 1,2-dichloroethane and the like can be used. Reaction temperature is -78 ° C to 0
C is suitable, particularly preferably -20C. By the above operation, an optically active epoxide derivative can be obtained. Depending on the tartaric acid used, the optically active epoxide derivative can be in both (+)-and (-)-forms.

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 methylesterified with diazomethane, and further reacted with methyllithium, whereby (S) -2,3 represented by the formula (III) is obtained in two steps. ,
5-Trihydroxy-2,5-dimethylhexane was synthesized ([α] _D ²⁹ : -19.6 ° (c 1.00, CHCl ₃ )).

[0017]

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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 gives (R) -2,3,5-trihydroxy-2,5
-The configuration of the compound of the present invention was determined by conversion to dimethylhexane and comparison with the specific rotation described above.

[0019]

According to the production method of the present invention, an asymmetric epoxidation reaction of tertiary allyl alcohol, which was impossible in the past, can be easily achieved. Further, the formula (I) of the present invention
Are novel compounds synthesized for the first time by the present inventors, and can be used as intermediates for synthesizing useful compounds such as various physiologically active substances and functional materials.

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

[0021]

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[0022]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention. 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 14.2 g (0.1 mol) of 2,5-dihydroxy-2,5-dimethyl-3-hexyne was suspended under ice-cooling.
Was added dropwise and stirred at the same temperature for 1 hour. Concentrated aqueous ammonia was added dropwise, and the mixture was stirred at room temperature for 1 hour and 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 (E) -2,5-dihydroxy-2,5-dimethyl-3-hexene as colorless needles.

Mp: 96-97 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.30 (s, 12H), 1.82 (brs, 2H),
5.80 (s, 2H), IR (nujol): ν _max 3450 cm ⁻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 Pulverized and dried molecular sieves (4 mm diameter) 4 g
Was suspended in 200 ml of methylene chloride, and a solution of 6.3 ml (21 mmol) of titanium isopropoxide and 5.62 g (24 mmol) of diisopropyl L-(+)-tartrate in methylene chloride was added at −20 ° C., followed by stirring for 30 minutes. (E) A solution of 2.88 g (20 mmol) of 2,5-dihydroxy-2,5-dimethyl-3-hexene in methylene chloride was added and stirred for 1 hour, and then 16.7 ml of a 1.8 M solution of t-butylhydroperoxide in methylene chloride ( 30m
mol) was added dropwise, and the mixture was stirred at -20 ° C for 80 hours. 36 ml of water and 180 ml of tetrahydrofuran were added to the reaction mixture, stirred at room temperature, and filtered through celite. The residue on celite was washed with 500 ml of tetrahydrofuran and filtered, and the combined filtrate was concentrated under reduced pressure to obtain a crude product. Column chromatography (silica gel, ether-hexane 2: 1)
And purified by (3R, 4R) -3,4-epoxy-2,5
3.15 g of dihydroxy-2,5-dimethylhexane were obtained. 96% yield.

Mp: 29-31 ° 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 3400 cm ⁻¹ MS (m / e): 145 (M ⁺ −CH ₃ ), 59 (100%).

The optical purity of the present compound is determined based on the (R) -2,3,5-trihydroxy-2,5-
The optical purity of the monobenzoyl form of dimethylhexane was determined to be 70% ee by using an optical resolution column (CHIRALCEL OD, manufactured by Daicel Corporation). 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 cooled with ice.
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 and 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 spectrum data completely coincided with that of a sample prepared from (S) -malic acid in Comparative Examples 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 solution continued to exhibit a yellow color. A nitrogen stream was introduced into the reaction solution to remove excess diazomethane, followed by extraction with ethyl acetate. The extract was washed with brine 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) to give (S) -dimethyl malate 1.56.
g was obtained. 95% yield.

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 mmol) of (S) -dimethyl malate obtained in Step 1
l) was dissolved in 3 ml of tetrahydrofuran, 8.8 ml (12.3 mmol) of a 1.4 M 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 a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution.
After drying over anhydrous magnesium sulfate, the mixture was filtered and evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, methanol-ether 5:95) to give (S) -2,3,3.
129 mg of 5-trihydroxy-2,5-dimethylhexane
I got 65% yield.

[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 = 1.5 Hz, D ₂ O substitution) IR (neat): νmax 3360 cm ⁻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 1 g of pulverized and dried molecular sieves (diameter 4 mm)
Was suspended in 50 ml of methylene chloride, and 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 −20 ° C., followed by stirring for 30 minutes. (E) A solution of 0.72 g (5.0 mmol) of 2,2,5-dihydroxy-2,5-dimethyl-3-hexene in methylene chloride was added and stirred for 1 hour. Then, 4.2 ml of a 1.8 M solution of t-butyl hydroperoxide in methylene chloride was added. (7.6m
mol) was added dropwise, and the mixture was stirred at -20 ° C for 80 hours. 9 ml of water and 45 ml of tetrahydrofuran were added to the reaction mixture, stirred at room temperature, and filtered through celite. The residue on celite was washed with 125 ml of tetrahydrofuran, filtered, and the combined filtrate was concentrated under reduced pressure to obtain a crude product. Column chromatography (silica gel, ether-hexane 2: 1)
And purified by (3S, 4S) -3,4-epoxy-2,5
0.78 g of dihydroxy-2,5-dimethylhexane was obtained. 95% yield.

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 3400 cm ⁻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 described in Example 1.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI // C07B 61/00 300 C07B 61/00 300

Claims (3)

(57) [Claims] 1. A compound of the general formula (In the formula, R ¹ , R ² , R ³ , and R ⁴ each represent an alkyl group having 1 to 6 carbon atoms, and * represents an asymmetric carbon atom.) 2. A compound of the general formula (Wherein, R ¹ , R ² , R ³ , and R ⁴ each represent an alkyl group having 1 to 6 carbon atoms). A method for producing an optically active epoxide derivative, comprising obtaining an optically active epoxide derivative represented by the general formula (I). 3. An optically active L- or D-oxide in the oxidation step.
3. The method according to claim 2, wherein a tartaric acid ester, a titanium alkoxide, and molecular sieves (4 mm in diameter) are used.