JPS60146840A - (2s,4r)-4-methyl-6-heptene-1,2,4-triol and preparation thereof - Google Patents

Abstract

NEW MATERIAL:(2S,4R)-4-Methyl-6-heptene-1,2,4-triol expressed by formula 1. USE:An intermediate for medicines and optically active mevalonolactone (an additive for microbial fermentation). PREPARATION:A (5S)-compound expressed by formula 2 (Tr is trityl) is asymmetrically oxidized with oxodiperoxymolybdenium.pyridine.hexamethyl phosphoric amide, and the resultant optically active (3R,5S)-compound expressed by formula 3 is then reacted with Li(AlH4) to open the ring and give a (2S,4R)-compound expressed by formula 4, which is then reacted with p-toluenesulfonyl chloride to afford a (2S,4R)-compound expressed by formula 5 (Ts is tosyl). The resultant (2S,4R)-compound expressed by formula 5 is further reduced in the presence of Li(AlH4) to give a (2S,4R)-compound expressed by formula 6, which is treated with a catalytic amount of hydrochloric acid in methanol to afford the compound expressed by formula 1.

Description

Detailed Description of the Invention The present invention relates to a novel optically active substance (28,4tL)-4-methyl-6-hebutene-1,2,4-triol (hereinafter abbreviated as triol) and a method for producing the same. It is.

The triol of the present invention is a compound useful as a synthetic intermediate for pharmaceuticals and for optically active meparolactone, 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 below.

(R)-mevalolactone Details will be explained in reference examples.

The conventional combination method for mevalolactone was published in Japanese Patent Publication No. 47-483.
No. 86 and JP-A-47-20116 Klj
Several documents can be found here and there, such as the method shown in Pl. However, the method for selectively synthesizing optically active mevalolactone is based on microbial fermentation (Ota et al., J.
Org, Chem, 47, 2400 (1982) and C, J. etal, Tetrahe
4 Jron Lett, -3415 (1978)), and no examples of pure synthetic success are known. As a result of intensive research into a method for asymmetrically synthesizing optically active rolactone using organic synthesis techniques, the present inventors found that
We have arrived at the present invention.

That is, the present invention provides a novel optically active (28,4R)-4-methyl-6-hebutene-1.2.4-) diol represented by the formula [1] and its production comprising the following reaction steps. It's a method.

+1) (58)-3-Allyl-5-trityloxymethyltetrahydrofuran-2-one (2) was asymmetrically oxidized with oxydiperoxymolybdenium pyridine hexamethylphosphoric amide (hereinafter abbreviated as Mo0P). , (31(,,5i9)-3-ori-ru-3-hydroxy-5-trityloxymethyltetrahydrofuran-
2-one[3]'ti, (2) further reacted with lithium aluminum hydride to open the ring to form (28,4)-4-hydroxymethyl-1-trityloxy-6-
Heptene-2゜4-diol [4] was obtained (3) and then treated with 4-toluenesulfonyl chloride to obtain (28,4R1-4-tosyloxymethyl-1-trityloxy-6-hebutene -2,4-diol [5] was obtained, (4) which was then purified in the presence of lithium aluminum hydride to (28,4R)-4-methyl-1-trityloxy-6-hebutene- As 2,4-diol [6], (5) it is further treated with a catalytic amount of hydrochloric acid in methanol to remove the trityl group, which is represented by the formula [1] (
28.4B)-4-Methyl-6-hebutene-1.2.4
- Method for producing triol.

This reaction can be illustrated as follows.

m (3) (4) (5) (6) (1) 3-allyl-5-trityloxymethyltetrahydrofuran-2-one, which is the starting material of the present invention, is disclosed in JP-A-56
It is synthesized from glutamic acid by the method disclosed in JP-147780.

MoQPH used in the first step of the present invention is a peroxide having a structure shown by the formula, and its manufacturing method is B, V
edejs, J, Org, Chem,, Dan, 188 (
1978) K. The same document also describes a reaction scheme in which a hydroxyl group is introduced into the α-position carbon of a carbonyl compound at this M00 pH.

The present inventors have demonstrated that when this special oxidation reaction is applied to 3-allyl-5-trityloxymethyltetrahydro-2-one, an asymmetric oxidation reaction takes place and optically active (3R,,58
) The novel fact that -3-allyl-3-hydroxy-5-trityloxymethyltetrahydrofuran-2-one can be obtained in good yield was discovered, and this was the beginning of the present invention. Although the mechanism of this reaction is not fully elucidated, 5
Depending on the bulkiness of the position-substituted trityloxymethyl group, M
It is thought that this is because oOP H 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 advantageous point pressure for industrial use of the present invention will be briefly described. (1) Optically active substances can be synthesized in good yield.

(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 Diisopropylamine 6.36F (0,063 mol),
3 g of n-butyllithium (10 w/v hexane solution),
4a/ (0,060 mol), tetrahydrofuran 80
y4JJ from d! ! ! A solution of lithium diisopropylamide in tetrahydrofuran at -78C under an argon atmosphere.
Then, 60 g of a tetrahydrofuran solution containing 11.9 P (0,030 mol) of 3-allyl-5-trityloxymethyltetrahydrofuran-2-one (2') was added and stirred for 1.5 hours. This was added to 200 ml of a tetrahydrofuran solution of Mo Q P H at -78C under an argon stream, and the mixture was heated at -78C for 2.5 minutes.
Stir for hours. Add 50jL of saturated sodium sulfate solution to this.
After adding J and returning to room temperature, extract with ether. The organic layer was washed with 100 ml of saturated brine, dried over anhydrous sulfuric acid and magnesium, and the solvent was distilled off to obtain 14.9P of a crude product. This was purified by silica gel column chromatography (chloroform) to obtain the title compound 7.8Of.

The analytical values were as follows, and the yield was 63.

6NMRδ (ppm): 2.17 (m, 2H,
CHz -CH-0), 2.55(m, 2H0CH*
CH=), 3.30 (m, 2)1. C1-11-0)
, 4.50-5.40 (m, 3H8CH-0, CH
*=CH), 5.50-6.30 (m, I H6CH
=C)12), 7.10-7.60 (m.

15H1arom-H)1, IR(IM-Re:3400(0)1), 1765(
C=0) Example 2 Production of [4] Lithium aluminum hydride 3.80? (0.10 mol) ft Tetrahydrofuran 50ynl IC was suspended in 50 ynl IC and cooled with water under an argon stream to give 8.28 p (0.
, 020 mol) in tetrahydrofuran was added dropwise and stirred for 30 minutes. Add to this 30 thiammonia water 20+
117 was added and the precipitated gel-like substance was purified using Celite.
After drying the liquid f over anhydrous magnesium sulfate, the solvent was distilled off to obtain 8.0O5L of a crude product. This was purified by silica gel column chromatography (n-hexane + ether) to obtain the title compound 4.55? I got it. The yield was 54L4, and the analytical values were as follows.

ONMRδ (ppm, ): 1.55 (m, 2H,
CHz -CH-0), 2.33 (d, 2H1J=
8Hz, CH2-CH=), 3.03-3.60(
m, 7H, CH20X2.0HX3), 3.87-4.
50 (m.

1)1. CH-0), 4.87-5.27 (m, 2H
0 history h=CH) 5, 60~6.20 (m, IH0C
H=CHz)OIR(cIn-'): 3350
(OH)O[α),:+4.4°(C1,08,C)I
c Right) Example 3 Compound 3.76) (0,009 mol) of the above [4] was dissolved in 50 g of pyridine, and 12.9 fP (0,068 mol) of toluenesulfonyl chloride was added under water cooling. Stirred for 6 hours. Pyridine was distilled off using a vacuum pump under ice cooling, and the residue was extracted with 100 g of dichloromethane.

This was washed successively with 50 g of water, 50 g of 10 molar sulfur steel solution, 50 g of water, and 50 g of saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product 14.2? I got it. Excess toluenesulfonyl chloride was removed by silica gel column chromatography (n-hexane+ethyl acetate) to obtain the title compound 4.69P. The analytical values were as shown below, and the yield was 91%.

oNMRδ (ppm): 1.55 (d, 2H0J=7
Hz, CHx-CI-1-0), 2.38(s, 3H0
CHs), 2.30-2.50(d, 2H,C)l
*C)l=), 3.05 (d, 2H1J=6H
z.

CH, -'-CM-0), 3.83 (s, 2H
, CHx O), 4.00-4.30 (m, 1M,
CH-0), 4.70-5.20 (m, 2H, CH
z=C)i>, 5.25~6.10 (m, IH,
CH=C)it), 7. lO ~ 7.90 (m, 19
H0arom-H)o IR(crII-” 1:3
500 (01 () Example 4 Lithium aluminum hydrogenation 2.40 ? (0,06
Compound 4.50P (o, o
osmol) of tetrahydrofuran solution was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. Add 30ml of ammonia water and 20ml of aqueous ammonia to this and precipitate a gel-like product W? Separate P using celite and j! ! Add 100 ml of ether to the solution and add 5 ml of water.
After washing with 56 m of saturated brine and drying with anhydrous magnesium sulfate, the solvent was distilled off to obtain the crude product 3.
I got 10P'jk. This was purified by silica gel column chromatography (4-(n-hexane+ether)) to obtain the title compound 2.50F. The analysis values are as follows,
The yield was 79%.

o NMRJ (ppm): 1.17 (s, 3H,
CHa), 1.46-1.80 (m, 3H, CHt
CH,OH), 2.34(d.

2H, J ~7 Hz, CHt-CH= ), 2.
97~a, z7 (m.

3) (, OH, CHz C1(-0), 3.90-4.
40 (m, IH.

CH-0), 4.80-5.30 (m, 2H1CHz=
CH), 5.40-6.20 (m, IH, CH=CHz
), 7.10-7.60 (m, 15H0arom-
kl) o IR(an-”): 3600(O)L), 164
0 (C=C) Example 5 Compound [6] above 1.00 F (0,0025 mol)
was dissolved in 20 rnl of methanol, 0.2 d of concentrated hydrochloric acid was added thereto under ice-cooling, and the mixture was stirred for 4 hours. Add 3 methanol to this
After neutralizing with sodium bicarbonate, the mixture was washed twice with 20 d of n-hexane. The mep/-l layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain the title compound 2401.
I got R9. The yield was 60%, and as a result of the analysis described below, it was confirmed that there was no difference between the compounds of the present invention.

, NMRδ(+)pm): 1.20(s, 3H,
CHs'), 1.50-1.80 (m, 2H, (j
(2-CI-10), 2.36 (d.

2H, J=7Hz%CH2CH=), 3.30-4.
60 (m.

6H1CH20,01-1x3), 4-83~5.
30 (m, 2H0CHz=C port), 5.43-6.1
0 (m,1l-1,Cdan=CH,)o IR(m-'
): 3350 (OH), 1640 (C=C)O
[α fan: +13.8° (C1,0, CHCpu3) o M
ass :C5H1tOs found 161.11
78 cald, 161.1178 Reference Example 1 Compound [1] above 160 Ill (1,0m mo
le) ff141)-Le 10JK was dissolved, and sodium metaperiodate 320a7 (1.5 mmole) was added under water cooling.
) Water of#! Late 5I! Ll was added dropwise and stirred for 30 minutes.

To this, sodium borohydride 75nQ (2,0mmo
After adding 20 minutes of methanol and stirring for 30 minutes,
1! Ll was added thereto and washed once with Celite, and the solution f was concentrated. After adding 41 ml of dichloromethane to the residue and drying over anhydrous magnesium sulfate, the solvent was completely distilled off to obtain 130 ml of a crude product.

This was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain the title compound 120m9
I got it. Yield: 92%, analyzed by FiNMR.

l　R,Mass to confirm.

Reference example 2, 11! ! Compound 110WIg (0.85 mmole) of [7]
) was dissolved in 20 ml of methanol, and ozone was introduced at -78C for 30 minutes. A trowel into which nitrogen was introduced for 30 minutes, 10 g of methyl sulfide were added, the temperature was returned to room temperature, and the solvent was distilled off to obtain 160 g of a crude product. This was made into f# using silica gel column chromatography (n-hexane + ethyl acetate),
The title compound Q'lJ 110 m was obtained. Yield is 98
The analysis was confirmed by NMRI, I[%, Mass.

Reference Example 3 Fl Preparation Compound 160R9 (1.0 mmole) of the above [1] was dissolved in 20 ml of methanol, and ozone L40 was added at -78C.
It was introduced for a minute. After introducing nitrogen for 45 minutes, 570 Da (15 mmole) of sodium borohydride was added and the mixture was returned to room temperature. 2 hours later Sodium metaperiodate 1.28
71111 of an aqueous solution of P (6.0 mmole) was added dropwise and stirred for 3 hours. After drying with Celite and concentrating the r liquid, 10 Inl of gold dichloromethane was added to the residue, and after drying over anhydrous magnesium sulfate, the solution was distilled off to obtain 100 η of a crude product. This was subjected to silica gel column chromatography (n-
Hexane + ethyl acetate) to produce the title compound 60m
I got a 9. Yield: 45%, analysis: N M RlI R,
Confirmed with Mass.

Reference Example 4 (8) - Production of mevalolactone [9a] Compound 80rr4 (0.61 mmole) of the above [8a] was dissolved in 15 ml of dichloromethane, and pyridinium chloride was 9ite65.
0 Da (3.0 mmole) was added and stirred at room temperature for 14 hours. After distilling off the solvent, the residue was purified by silica gel chromatography (n-hexane + 1,000 liters of acetic acid) to obtain the title compound 6311+! I got a 7. The yield was 80%, and the results of the analysis below confirmed that the product was the same as the target product.

ONMRδ (ppm): 1.37 (s, 3H,
CHs), 1, 90 (m, 2H1CHz), 2.
57 (m, 2H-6-CH2), 4.10-4.8
0 (m, 2H1CH20)' I R(Crn-'
): 340(1(OH), 1720 (C=C)O[
αID: +23.3° (C0,98, Eta) () Reference Example 5 (1 too) - Production of mevalolactone (9b) [8b]
Compound 50* (8 mmole of o, a) was dissolved in 12 tlcfi of dichloromethane, 410 da (1.9 mmole) of pyridinium chlorochromate was added, and the mixture was stirred at room temperature for 14 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography (n-hexane + 1,000 liters of acetic acid) to obtain the title compound 44. The yield was 89%, and as a result of the following analysis, it was confirmed that the product was different from the target product.

Claims (1)

[Claims] 1. (28,4R,)-4-methyl-6 represented by formula [1]
-hebutene-1,2,4-) diol 2, represented by the formula [2] (wherein 'vr represents a trityl group) (58
)-3-allyl-5-trityloxymethyltetrahydrofuran-2-one is reacted with oxodiperoxymolybdenium pyridine hexamethylphosphoric amide to perform an asymmetric oxidation reaction, resulting in formula [3] (in the formula Tr is the same as above)
,,58)-3-allyl-3-hydroxy-5-trityloxymethyltetrahydrofuran-2-one was obtained, which was further ring-opened by the action of lithium aluminum hydride to give the formula [4] (in the formula Tr Fim (2S. 4l-)-4-hydroxymethyl-1-trityloxy-6-hebutene-2,4-diol (same as above) was obtained, and then treated with VcG-)luenesulfonyl chloride. , Formula [5] 0-chor (In the formula, Tr is the same as above. Ts represents a tosyl group.)
(28', 411.) -4-)Syloxymethyl-1-trityloxy-6-hebutene-2,4-
A diol is obtained, which is then converted into lithium aluminum hydride to form (2S. 4)-4-methyl-1-trityloxy-6- (where Tr is the same as above). Hebutene-2,4-diol is obtained, which is further treated with a catalytic amount of hydrochloric acid in methanol to remove the protection fund.(2S,4R,)-4-methyl-6
-Production method of heptene-1, 2゜4-triol.