JPH0432808B2 - - Google Patents

Description

Detailed Description of the Invention The present invention relates to a novel optically active substance (2S,4R)-4-methyl-6-heptene-1,2,4-triol (hereinafter abbreviated as triol) and a method for producing the same. be. The triol compound of the present invention is a compound useful as a synthetic intermediate for pharmaceuticals and for optically active mevalolactone, which is important as an additive in microbial fermentation. For example, (R)-mevalolactone and (S)-mevalolactone can be produced from the compound of the present invention according to the reaction formula shown in the following figure. Details will be explained in reference examples. The conventional method for synthesizing mevalolactone was
Several documents can be found here and there, such as methods disclosed in Japanese Patent Application Laid-open No. 48386 and Japanese Patent Application Laid-open No. 47-20116. However, the method for selectively synthesizing optically active mevalolactone is by microbial fermentation ( Ota etal, J.
Org.Chem. 47 , 2400 (1982) and CJSih etal,
Tetrahedron Lett.-3415 (1978) has been reported, and no examples of pure synthetic success are known. The present inventors have arrived at the present invention as a result of intensive research into a method for asymmetrically synthesizing optically active mevalolactone using organic synthesis techniques. That is, the present invention provides formula [1] This is a novel optically active substance (2S,4R)-4-methyl-6-heptene-1,2,4-triol represented by the following formula and a method for producing the same, which comprises the following reaction steps. (1) (5S)-3-allyl-5-trityloxymethyltetrahydrofuran-2-one [2] was converted into oxodiperoxymolybdenium pyridine.
Hexamethylphosphoric amide (hereinafter referred to as
asymmetric oxidation (abbreviated as MoOPH), (3R, 5S)
-3-aryl-3-hydroxy-5-trityloxymethyltetrahydrofuran-2-[3]
-, (2) This was further treated with lithium aluminum hydride to open the ring, giving (2S,4R)-hydroxymethyl-1-trityloxy-6-heptene-2,
4-diol [4] is obtained, (3) then treated with p-toluenesulnyl chloride to form (2S,4R)-4-tosyloxymethyl-1-trityloxy-6-heptene-
2,4-diol [5] was obtained, (4) which was then reduced in the presence of lithium aluminum hydride to form (2S,4R)-4-methyl-1-
Trityloxy-6-heptene-2,4-diol [6], (5) and further treating this with a catalytic amount of hydrochloric acid in methanol to remove the trityl group [1]
A method for producing (2S,4R)-4-methyl-6-heptene-1,2,4-triol shown by This reaction can be illustrated as follows. 3-allyl-5-trityloxymethyltetrahydrofuran-2-one, which is the starting material of the present invention, is synthesized from glutamic acid by the method disclosed in JP-A-56-147780. MoOPH used in the first step of the present invention has the formula It is a peroxide having the structure shown in the following, and its manufacturing method is described in E. Vedejs, J. Org., 43 , 188 (1978). The same document also describes reaction conditions for introducing a hydroxyl group into the α-position carbon of a carbonyl compound using MoOPH. The present inventors conducted this special oxidation reaction using 3-allyl-5-trityloxymethyltetrahydro-2-
When applied to ion, an asymmetric oxidation reaction takes place and optically active (3R,5S)-3-allyl-3-hydroxy-5-trityloxymethyltetrahydrofuran-2-one is obtained in good yield. This heading was used as the beginning of the present invention. The mechanism of this reaction is not fully understood, but due to the bulkiness of the trityloxymethyl group substituted at the 5-position,
This is thought to be because MoOPH is highly sterically regulated. The second to fifth steps of the present invention are commonly used organic synthesis reactions, and will be explained in detail in Examples. The industrially applicable advantages of the present invention are summarized as follows: (1) Optically active substances can be synthesized in good yields. (2) Raw materials are easily available. (3) Optically active pharmaceuticals including optically active mevalolactone can be synthesized from the compound of the present invention. The present invention will be explained in detail below using Examples and Reference Examples. Example 1 (3R,5S)-3-allyl-3-hydroxy-5
-trityloxymethyltetrahydrofuran-2
-Production of one [3] Diisopropylamine 6.36g (0.063mol), n
-Butyllithium (10w/v hexane solution) 38.4
11.9 g (0.030 mol) of 3-allyl-5-trityloxymethyltetrahydrofuran-2-one [2] was added to a tetrahydrofuran solution of lithium diisopropylamide prepared from 80 ml of tetrahydrofuran and 80 ml of tetrahydrofuran at -78°C under an argon atmosphere. 60 ml of the solution was added and stirred for 1.5 hours. This is a solution of MoOPH in tetrahydrofuran.
The mixture was added to 200 ml at -78°C under an argon stream and stirred for 2.5 hours. Add 50 ml of saturated sodium sulfate solution to this, return to room temperature, and extract with ether. The organic layer was washed with 100 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 14.9 g of a crude product. This was purified by silica gel column chromatography (chloroform) to yield 7.80 g of the title compound.
I got it. The analytical values were as follows, and the yield was 63%. NMRδ (ppm): 2.17 (m.2H. CH ₂ -CH-O),
2.55 (m.2H. CH ₂ −CH=), 3.30 (m.2H. CH ₂ −
O), 4.50-5.40 (m.3H. CH −O, CH ₂ = CH),
5.50~6.30 ( m.1H.CH = _CH2 ), 7.10~7.60
(m.15H.arom-H), ΓIR (cm ^-1 ): 3400 (OH), 1765 (C=O) Γ [α] _D : +34.7° (CO60, CHCl ₃ ) Example 2 2S, 4R )-4-Hydroxymethyl-1-trityloxy-6-heptene-2,4-diol [4] 3.80 g (0.10 mol) of lithium aluminum hydride was suspended in 50 ml of tetrahydrofuran and cooled with ice under an argon stream. 8.28g of the compound [3] above
(0.002 mol) of tetrahydrofuran solution was added dropwise and stirred for 30 minutes. Add this to 30% ammonia water 20%
The precipitated gelatinous substance was separated using Celite, the liquid was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 8.00 g of a crude product. This was purified by silica gel column chromatography (n-hexane + ether) to obtain the title compound 4.55
I got g. The yield was 54%, and the analytical values were as follows. ΓNMRδ (ppm): 1.55 (m.2H. CH ₂ −CH−O),
2.33 (d.2H.J=8Hz, _CH2 −CH=), 3.03~3.60
(m.7H, _CH2 -O×2, OH×3), 3.87~4.50
(m.1H. CH −O), 4.87~5.27 (m.2H. CH ₂ = CH)
5.60 to 6.20 (m.1H. CH = CH ₂ ) ΓIR (cm ^-1 ): 3350 (OH) Γ [α] _D : +4.4° (C1.08, CHCl ₃ ) Example 3 (2S, 4R) -4-Tosyloxymethyl-1-trityloquine-6-heptene-2,4-diol [5] Production of 3.76 g (0.009 mol) of the compound [4] above was dissolved in 50 ml of pyridine, and p-toluene was added under ice cooling. Add 12.9 g (0.068 mol) of sulfonyl chloride to 6
Stir for hours. Pyridine was distilled off using a vacuum pump under ice cooling, and the residue was extracted with 100 ml of dichloromethane. Add this to 50ml of water, 50ml of 10% copper sulfate solution, and 50ml of water.
ml and 50 ml of saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the crude product.
14.2g was obtained. Excess -toluenesulfonyl chloride was removed by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 4.69 g of the title compound. The analytical values were as shown below, and the yield was 91%. ΓNMRδ (ppm): 1.55 (d.2H.J=7Hz, CH ₂ −CH
−O), 2.38 (s.3H.CH ₃ ), 2.30 to 2.50 (d.2H. CH ₂ −
CH=), 3.05 (d.2H.J=6Hz, CH ₂ ^-0 −CH−O),
3.83 (s.2H. CH ₂ −O), 4.00~4.30 (m.1H. CH −
O), 4.70-5.20 (m.2H. CH ₂ = CH), 5.25-6.10
(m.1H. CH = CH ₂ ), 7.10~7.90 (m.19H, arom−
H) ΓIR (cm ^-1 ): 3500 (OH) Example 4 Production of (2S,4R)-4-methyl-1-trityloxy-6-heptene-2,4-diol [6] Lithium aluminum hydride 2.40 To 60 ml of a tetrahydrofuran solution containing 4.50 g (0.063 mol) of compound [5] was added dropwise under ice cooling under an argon stream, and the mixture was stirred at room temperature for 1 hour. Add this to 30% ammonia water 20%
ml, separate the precipitated gel substance using Celite, add 100 ml of ether, 50 ml of water,
After sequentially washing with 50 ml of saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 3.10 g of crude product.
I got it. This was purified by silica gel column chromatography (n-hexane + ether) to obtain 2.50 g of the title compound. The analytical values were as follows, and the yield was 79%. ΓNMRδ (ppm): 1.17 ( _s.3H.CH3 ), 1.46~1.80
(m.3H. CH ₂ −CH, OH), 2.34 (d.2H, J=7Hz,
CH ₂ −CH=), 2.97 to 3.27 (m.3H.OH. CH ₂ −CH
-O), 3.90~4.40 (m.1H. CH -O), 4.80~5.30
(m.2H. CH ₂ = CH), 5.40~6.20 (m.1H. CH =
CH ₂ ), 7.10-7.60 (m.15H, arom-H) ΓIR (cm ^-1 ): 3600 (OH), 1640 (C=C) Example 5 (2S.4R)-4-methyl-6-heptene -1,
Production of 2,4-triol [1] 1.00 g (0.0025 mol) of the compound [6] above was dissolved in 20 ml of methanol, and 0.2 g of concentrated hydrochloric acid was added to it under ice cooling.
ml and stirred for 4 hours. Add 30 methanol to this
After neutralizing with sodium bicarbonate, the mixture was washed twice with 20 ml of n-hexane. After drying the methanol layer over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate),
240 ml of the title compound was obtained. The yield is 60%,
As a result of the analysis described below, it was confirmed that the compounds of the present invention are different from each other. ΓNMRδ (ppm): 1.20 ( _s.3H.CH3 ), 1.50~1.80
(m.2H. CH ₂ −CH−O), 2.36 (d.2H, J=7Hz,
CH ₂ −CH=), 3.30 to 4.60 (m.6H. CH ₂ −O, OH
×3), 4.83 to 5.30 (m.2H. CH ₂ = CH), 5.43 to 6.10
(m.1H. CH = CH ₂ ) ΓIR (cm ^-1 ): 3350 (OH), 1640 (C = C) Γ [α] _D : +13.8° (C 1.0, CHCl ₃ ) ΓMass: C ₃ H ₁₇ O ₃ found 161.1178 cald. 161.1178 Reference example 1 (R)-3-methyl-5-hexene-1,3-
Production of diol [7] 160 ml (1.0 mmole) of the compound [1] above was dissolved in 10 ml of methanol, and 5 ml of an aqueous solution of 320 mg (1.5 mmole) of sodium metaperiodate was added dropwise under ice cooling, followed by stirring for 30 minutes. After adding 75 mg (2.0 mmole) of sodium borohydride and stirring for 30 minutes, 20 ml of methanol was added and filtered through Celite.
The liquid was concentrated. After adding 10 ml of dichloromethane to the residue and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 130 mg of a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 120 mg of the title compound. The yield was 92%, and analysis was confirmed by NMR, IR, and Mass. Reference Example 2 Production of (2RS, 4S)-2,4-dihydroxy-4-methyl-2,3,4,5-tetrahydropyran [8a] 110 mg (0.85 mmole) of the compound [7] above was added to 20 ml of methanol. It was dissolved and ozone was introduced for 30 minutes at -78°C. After introducing nitrogen for 30 minutes, methyl sulfide
10 ml was added, the temperature was returned to room temperature, and the solvent was distilled off to obtain 160 mg of a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 110 mg of the title compound. Yield is 98%,
The analysis was confirmed by NMR, IR, and Mass. Reference Example 3 Production of (2RS, 4R)-2,4-dihydroxy-4-methyl-2,3,4,5-tetrahydropyran [8a] 160 mg (1.0 mmole) of the compound [1] above was added to 20 ml of methanol. It was dissolved and ozone was introduced for 40 minutes at -78°C. After introducing nitrogen for 45 minutes, add 570 mg (15 mmole) of sodium borohydride and return to room temperature. 2 hours later Sodium metaperiodate 1.28
7 ml of an aqueous solution of g (6.0 mmole) was added dropwise thereto, and the mixture was stirred for 3 hours. After filtering through Celite and concentrating the liquid, 10 ml of dichloromethane was added to the residue, and after drying over anhydrous magnesium sulfate, the solution was distilled off to obtain 100 mg of a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 60 mg of the title compound. Yield is 45%, analysis is
Confirmed by NMR, IR, and Mass. Reference Example 4 Production of (S)-mevalolactone [9a] 80 mg (0.61 m mole) of the compound [8a] above was dissolved in 15 ml of dichloromethane, 650 mg (3.0 m mole) of pyridium chlorochromate was added, and the mixture was heated at room temperature for 14 min.
Stir for hours. After evaporating the solvent, the residue was purified by silica gel chromatography (n-hexane+ethyl acetate) to obtain 63 mg of the title compound. The yield was 80%, and the analysis below confirmed that it was the desired product. ΓNMRδ (ppm): 1.37 ( _s.3H.CH3 ), 1.90 (m.2H.
CH ₂ ), 2.57 (m.2H. [formula]), 4.10 to 4.80 (m.2H. CH ₂ −O) ΓIR (cm ^-1 ): 3400 (OH), 1720 (C=O) Γ [α] _D : +23.3° (C0.98, EtOH) Reference Example 5 Production of (R)-mevalolactone [9b] Dissolve 50 mg (0.38 mmole) of the compound [8b] above in 12 ml of dichloromethane, and prepare 410 mg of pyridinium chlorochromate. (1.9m mole) and at room temperature.
Stirred for 14 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 44 mg of the title compound. The yield was 89%, and the analysis below confirmed that it was the desired product. ΓNMRδ (ppm): 1.37 ( _s.3H.CH3 ), 1.90 (m.2H.
CH ₂ ), 2.57 (m.2H. [formula]), 4.10 to 4.80 (m.2H. CH ₂ -O-) ΓIR (cm ^-1 9:3400 (OH), 1720 (C=O) Γ [α ] _D : −23.4° (C0.32, EtOH)

Claims (1)

[Claims] 1 Formula [1] (2S,4R)-4-methyl-6-heptene-1,2,4-triol 2 represented by formula [2] (5S)-3-allyl-5-trityloxymethyltetrahydrofuran-2-one represented by (Tr represents a trityl group) is reacted with oxodiperoxymolybdenium pyridine hexamethylphosphoric amide, Perform an asymmetric oxidation reaction and form the formula [3] Optically active (3R,5S)-3-allyl-3-hydroxy-5- represented by (where Tr is the same as above)
Trityloxymethyltetrahydrofuran-2-
This is further treated with lithium aluminum hydride to open the ring, giving the formula [4] (2S, 4R) (where Tr is the same as above)
-4-hydroxymethyl-1-trityloxy-
6-heptene-2,4-diol was obtained and then treated with p-toluenesulfonyl chloride to form the formula [5] (2S,4R)-4-tosyloxymethyl-1-trityloxy-6-heptene- (in the formula, Tr is the same as above. Ts represents a tosyl group)
2,4-diol was obtained, which was then reduced in the presence of lithium aluminum hydride to form the formula [6] (2S, 4R) (where Tr is the same as above)
-4-Methyl-1-trityloxy-6-heptene-2,4-diol is obtained, which is further treated with a catalytic amount of hydrochloric acid in methanol to remove the protecting group, as shown by formula [1]. (2S, 4R) −4−
A method for producing methyl-6-heptene-1,2,4-triol.