JPH0717629B2 - Process for producing optically active α-tocopherol - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for industrially useful production of optically active α-tocopherol.

[Conventional technology and problems]

d-α-tocopherol is the most representative of widely distributed vitamin E in nature. Not only itself but also various derivatives are widely used as medicines, foods, feeds, etc. It is an extremely important substance.

However, d-α-tocopherol must be isolated from natural products, mainly vegetable oils, and is not suitable for industrial mass production. That is, since the content of d-α-tocopherol in the vegetable oil is extremely small, an extremely large amount of vegetable oil is required, and further separation and purification from homologues such as β, γ and δ-forms are required, and isolation However, there is a drawback that it is difficult.

Therefore, various attempts have been made to chemically synthesize optically active α-tocopherol, particularly d-α-tocopherol (for example, H. Mayler, 0. Isler et al., Helv. Chim. Act).
a, 46 , 650 (1963); JWScott, WMCort, H.Harley, FTB
izzarro, DRPanish, G.Sauey, JACS 51 , 200 (197
4), 52 , 174 (1975); Helv.Chim.Acta. 59 , 290 (1976);
KK Chan, N. Cohen et al., J. Org. Chem. 41 , 3497,3512 (197
6), 43 , 3435 (1978)), but there is no industrially useful method.

That is, all previously proposed methods require optical resolution of the dl body at some point in the intermediate material. The necessity of this optical resolution means that the yield of 30 ~
There is a big drawback that it will be greatly reduced to 40%, so it is hard to say that it is an industrial method.

[Means for solving problems]

Therefore, the present inventors have conducted many years of research on a method that does not require optical resolution of the dl body, and as a result, found that this is possible by the method shown below, and completed the present invention here. It was

That is, the present invention has the structural formula: [In the formula, R ₁ is Represents The same applies hereinafter] The compound represented by is tosylated with p-toluenesulfonyl chloride to give a structural formula: [In the formula, Ts is a tosyl group Represents The same applies hereinafter] A compound represented by the following formula is obtained, and then the compound is reacted with isopropyl mercaptan in the presence of metallic sodium to give a structural formula: Or A compound represented by the following formula is obtained, and then the compound is reductively cleaved to obtain a structural formula: Or A compound represented by the following formula is obtained, and then the compound is acetylated to obtain the structural formula: [In the formula, Ac represents an acetyl group. The same applies hereinafter] A compound represented by the following formula is obtained, and then the compound is reacted with 4-acetoxy 2,3,5-trimethylphenol to give a structural formula: A compound represented by the following formula is obtained, and then the compound is reacted with Raney nickel and further deacetylated to obtain the structural formula: A compound represented by the formula (1) and then cyclizing the compound directly, or oxidizing the compound to obtain α-tocopherylquinone, and then cyclizing the compound. (2R, 4′R, 8′R) -α-tocopherol represented by or a structural formula: The present invention provides a method for producing (2S, 4'R, 8'R) -α-tocopherol represented by Furthermore, the present invention provides a compound represented by the structural formula (I) or (I ′) by reductively cleaving the compound of the structural formula: Or A compound represented by the following formula is obtained, and the compound is then tosylated with p-toluenesulfonyl chloride to give a structural formula: [In the formula, Ts is a tosyl group Represents The same applies hereinafter] A compound of formula (IV) or (IV ') is obtained by reacting the compound with isopropyl mercaptan in the presence of sodium metal. ) Or (V ′), (VI) or (VI ′), and (VII) or (VII ′) to obtain an optically active α-tocopherol (VIII) or (VIII ′). .

The synthetic routes for α-tocopherol by the method of the present invention are summarized below.

In the present invention, the optically active α-tocopherol is
(2R, 4'R, 8'R) -α-tocopherol, (2S, 4'R,
8'R) -α-tocopherol.

Hereinafter, the present invention will be described more specifically.

The phytols represented by the above structural formula (I) or (I ') used as a starting material in the present invention can be produced, for example, by the method disclosed in JP-A-57-136582.

For example, the case of natural phytol is specifically described below.

That is, the structural formula The natural phytol represented by is subjected to enantioselective oxidation to obtain a 2,3-epoxy compound. To give an example of a specific method, natural phytol, tartaric acid diester, titanium tetraisopropoxide, and t in halogen-based hydrocarbons such as dichloroethane and trichloroethane.
-Butyl hydroperoxide is oxidized at a temperature of -70 to 30 ° C. As the tartrate ester, for example, diethyl tartrate, dimethyl tartrate or the like can be used. In the case of diethyl tartrate, if L-(+)-diethyl tartrate is used, 2S, 3 having a stereostructure represented by the above structural formula (I) can be used.
Only the S-epoxy compound can be obtained, but if D-(-)-diethyl tartrate is used, only the 2S, 3S-epoxy compound having the steric structure represented by the above structural formula (I ') can be obtained.

The step from (I) or (I ') to (IX) or (IX') is a step of reductively cleaving the respective 2,3-epoxy compound to obtain (IX) or (IX '). For reductive cleavage, good results can be obtained by using, for example, lithium aluminum hydride. At this time, as the solvent, for example, an ether solvent such as diethyl ether or tetrahydrofuran is used, and the temperature is not particularly limited, but usually about -10
The reaction is carried out at -40 ° C.

Steps from (I) or (I ') to (II) or (II'), or (IX) or (IX ') or (X) or (X')
The process leading to is a tosylation process. That is, p-toluenesulfonyl chloride is added to (I) or (I ') or (IX) or (IX') in the presence of pyridine or the like to react.

(II) or (II ') to (III) or (III'), or (X) or (X ') to (IV) or (IV')
The process up to is a process of adding isopropyl mercaptan in the presence of metallic sodium to obtain a sulfide.

The steps from (III) or (III ') to (IV) or (IV') are the steps (I) or (I ') to (IX) or (I
It is carried out by reductive cleavage as in the step of obtaining X ').

The step of obtaining (V) or (V ') from (IV) or (IV') is an acetyl step and is acetylated with an acetylating agent such as acetic anhydride.

The step of obtaining (VI) or (VI ') from (V) or (V') is performed by adding and reacting 4-acetoxy-2,3,5-trimethylphenol.

The (V), (V '), and (VI), (VI') are novel compounds.

The step of obtaining (VII) or (VII ') from (VI) or (VI') is a step of reacting with Raney nickel to perform deacetylation. Deacetylation is performed by a method of reductively removing an acetyl group using lithium aluminum hydride or the like.

In the step of obtaining the optically active α-tocopherol (VIII) or (VIII ′) which is the final target substance from (VII) or (VII ′), (VII) or (VII ′) is converted into p-toluenesulfonic acid,
It can be directly cyclized with anhydrous zinc chloride, etc., or oxidized to give the structural formula: Or After obtaining α-tocopheryl quinone represented by the formula (1), it is cyclized with, for example, a palladium / carbon catalyst and p-toluenesulfonic acid or anhydrous zinc chloride.

Examples of the oxidizing agent used in the oxidizing step include lead dioxide, silver oxide, hydrogen peroxide, and Flemmy's salt. In short, any oxidizing agent capable of converting a hydroquinone form to a quinone form can be used. Is.

(2R, 4'R, 8'R) -α-obtained by the method of the present invention
It was confirmed from the physicochemical properties that tocopherol was the same as naturally occurring d-α-tocopherol.
As an example, (2R, 4'R,
8'R) -α-tocopherol acetate, and K ₃ F
Comparing the optical rotations of e (CN) ₆ oxide with the corresponding substances of natural d-α-tocopherol, they were in agreement.

〔The invention's effect〕

The method of the present invention is a method capable of industrially producing an optically active α-tocopherol in a high yield without requiring dl resolution,
Therefore, the value of the present invention is extremely high.

〔Example〕

Examples will be given below, but it goes without saying that the present invention is not limited thereto.

Example 1 Synthesis of (2S, 3S, 7R, 11R) -2,3-epoxy-3,7,11,15-tetramethylhexadecyltosylate (2S, 3S, 7R, 11R) -2,3-Epoxy-3,7,11,15-tetramethylhexadecan-1-ol (synthesized according to Example 1 of JP-A-57-136582) 5.00 g (16 mmol) was dissolved in 40 ml of pyridine, 6.10 g (32 mmol) of p-toluenesulfonyl chloride was added as crystals at 0 ° C., stirred for 90 minutes, and then stored in a refrigerator overnight. The reaction solution was poured into 50 ml of ice water, extracted with ether, and the extract was washed and dried,
The solvent was distilled off to obtain 5.84 g of the title compound (yield 93%).

The refractive index, IR spectrum and NMR spectrum of the obtained compound are as follows.

n _D ²⁰ 1.4886 IR spectrum: 2930,1600,1500,1370,1190,1180 cm ^-1 NMR spectrum (CCl ₄ ): δ0.82 (12H, d, J = 6Hz), 1.13
(24H, bs), 2.36 (3H, s), 2.74 (1H, t, J = 6Hz), 3.94
(2H, d, J = 6Hz), 7.23 (2H), 7.64 (2H) (ABq, J = 8H
z) Example 2 Synthesis of (2R, 3R, 7R, 11R) -2,3-epoxy-3,7,11,15-tetramethylhexadecyltosylate (2R, 3R, 7R, 11R) -2,3-epoxy-3,7,11,15-tetramethylhexadecane-1-ol (synthesized according to Example 2 of JP-A-57-136582) 25.4 g Using (81.3 mmol), pyridine (150 ml), methylene chloride (40 ml) and p-toluenesulfonyl chloride (31.0 g, 163 mmol), the same procedure as in Example 1 was carried out to obtain 35.8 g of the title compound (yield: 95
%).

IR and NMR spectra were obtained in Example 1 (2S, 3S, 7R, 11
R) identical to that of the body.

Example 3 Synthesis of (2S, 3S, 7R, 11R) -2,3-epoxy-3,7,11,15-tetramethylhexadecylisopropyl sulfide After adding 370 mg of small pieces of sodium metal to 30 ml of methanol and reacting and dissolving, 1.48 ml of isopropyl mercaptan (16
mmol) was added at room temperature and stirred for 30 minutes. (2S, 3S, 7R, 1
A solution of 5.75 g (12 mmol) of 1R) -2,3-epoxy-3,7,11,15-tetramethylhexadecyltosylate in 15 ml of methanol was added dropwise at room temperature over 20 minutes, and the mixture was stirred at 50 ° C. for 2 hours.
After cooling to room temperature, it is poured into 50 ml of cold water, extracted with ether, the extract is washed with water, dried and the solvent is distilled off to give 4.62 g of the title compound.
Was obtained (yield quantitative).

The refractive index IR spectrum and NMR spectrum of the obtained compound are as follows.

n _D ²⁰ 1.4689 IR spectrum: 2930,1460,1380,1250 cm ^-1 NMR spectrum (CCl ₄ ): δ0.85 (12H, d, J = 6Hz), 1.21
(24H, m), 1.27 (6H, d, J = 6Hz), 2.30 ~ 2.77 (3H, m),
2.83 (1H, hept, J = 6Hz) Example 4 Synthesis of (2R, 3R, 7R, 11R) -2,3-epoxy-3,7,11,15-tetramethylhexadecylisopropyl sulfide (2R, 3R, 7R, 11R) -2,3-epoxy-3,7,11,15-tetramethylhexadecyltosylate 34.2 g (73.3 mmol) and isopropyl mercaptan 7.4 ml (6.1 g: 80.1 mmol), metal Sodium 1.9g (82.6mg atom), methanol as solvent
The same operation as in Example 3 was carried out using 150 ml to obtain 27.2 g of the title compound (quantitative yield).

IR and NMR spectra were obtained in Example 3 (2S, 3S, 7R, 11
R) identical to that of the body.

Example 5 Synthesis of (3S, 7R, 11R) -1-isopropylthio-3,7,11,15-tetramethylhexadecane-3-ol 700 mg (18 mmol) of lithium aluminum hydride was suspended in 40 ml of anhydrous tetrahydrofuran, and (2S, 3S, 7R, 11R) -2,3
-Epoxy-3,7,11,15-tetramethylhexadecylisopropyl sulfide 4.62 g (12 mmol) in 15 ml of tetrahydrofuran was added dropwise at room temperature over 15 minutes, and 2.5
The reaction was carried out under reflux for an hour. After cooling, add a 1: 1 mixture of tetrahydrofuran and water gradually while suppressing heat generation, and add I
50 ml of N hydrochloric acid was added. Extract with ether, wash the organic layer with water,
After drying, the crude product was subjected to silica gel color chromatography and eluted with n-hexane-ethyl acetate mixture to obtain 3.25 g of the title compound (yield 71%).

The refractive index, IR spectrum and NMR spectrum of the obtained compound are as follows.

n _D ²⁰ 1.4718 IR spectrum: 3400,2925,1375,1360,1150 cm ^-1 NMR spectrum (CCl ₄ ): δ0.89 (12H, d, J = 6Hz), 1.15
(3H, s), 1.21 (24H, bs), 1.26 (6H, d, J = 6Hz), 2.40 ~
2.67 (2H, m), 2.88 (1H, hept, J = 6Hz) Example 5 '(3S, 7R, 11R) -1-isopropylthio-3,7,11,15-tetramethylhexadecane-3-ol Synthesis Lithium aluminum hydride (285 mg, 7.5 mmol) was suspended in anhydrous tetrahydrofuran (20 ml), and (2S, 3S, 7R, 11R) -2,
3-epoxy-3,7,11,15-tetramethylhexadecane-
A solution of 1-ol 1.56 g (5 mmol) in 5 ml of tetrahydrofuran was added dropwise, and the mixture was reacted under reflux for 2.5 hours. After cooling to 0 ° C., 3 ml of water was added little by little, 25 ml of 1N hydrochloric acid was further added to extract ether oil, and the extract was dried and concentrated to obtain a crude diol.

IR spectrum: 3500, 2920, 1460, 1370 cm ^-1 Then, this crude oily substance was dissolved in 3 ml of pyridine, cooled to 0 ° C, 1.33 g (7 mmol) of p-toluenesulfonyl chloride was added, and after stirring for 30 minutes, I left it in the refrigerator overnight. Add 12 ml of ice water, extract with methylene chloride, wash the extract and dry it.
Concentration gave a crude monotosylate.

IR spectrum: 3500, 2920, 1360, 1180 cm ^{-1 To} 10 ml of methanol was added 115 mg of Na for reaction and dissolution, and 0.46 ml (5 mmol) of isopropyl mercaptan was added. A solution of the monotosylate derivative obtained above in 5 ml of methanol was added to this solution, and the mixture was stirred at 50 ° C. for 3 hours. After cooling, open in water,
It was extracted with ether and purified by column chromatography to obtain 1.43 g of the desired product (yield 75%).

IR and NMR spectra were identical to those obtained in Example 5.

Example 6 Synthesis of (3R, 7R, 11R) -1-isopropylthio-3,7,11,15-tetramethylhexadecane-3-ol 4.0g of lithium aluminum hydride (0.105mo
l) was suspended (under nitrogen) and the sulfide obtained in Example 4 26.
A solution of 2 g (70.7 mmol) in 50 ml of THF was added dropwise at room temperature over 20 minutes. The title compound was prepared in the same manner as in Example 5 to give 19.9.
g was obtained (75% yield).

IR and NMR spectra were obtained in Example 5 (3S, 7R, 11R)
It was identical to that of the body.

Example 6 ′ Synthesis of (3R, 7R, 11R) -1-isopropylthio-3,7,11,15-tetramethylhexadecane-3-ol (2R, 3R, 7R, 11R) -2,3-epoxy- The same procedure as in Example 5'was carried out using 1.56 g (5 mmol) of 3,7,11,15-tetramethylhexadecane-1-ol to obtain 1.4 g of the title compound (yield 74%).

IR and NMR spectra were identical to those obtained in Example 6.

Example 7 Synthesis of (3S, 7R, 11R) -3-acetoxy-3,7,11,15-tetramethylhexadecylisopropyl sulfide (3S, 7R, 11R) -1-Isopropylthio-3,7,11,15-tetramethylhexadecane-3-ol 3.04 g (8.1 mmo
l), acetic anhydride 7.6 ml (81 mmol), pyridine 6.5 ml (81 mmo
l) and N, N-dimethyl-4-aminopyridine 0.21 g (1.7
(mmol) and mixed at room temperature for 24 hours. After slowly adding methanol, the mixture was poured into 50 ml of cold water and extracted with ether. After washing the organic layer with water and drying, the solvent was distilled off, and 4.01 g of the crude product was subjected to silica gel column chromatography and eluted with an n-hexane-isopropyl ether mixed system to obtain 2.37 g of the title compound (yield 94%).

Refractive index of the obtained compound, specific optical rotation, IR spectrum and
The NMR spectrum is as follows.

n _D ²⁰ 1.4647 [α] _D ²⁰ −0.2 ° (C = 9.0, ethanol) IR spectrum: 2960,1740,1380,1360 cm ⁻¹ NMR spectrum (CCl ₄ ): δ0.85 (12H, d, J = 6Hz) , 1.17
(29H, m), 1.39 (3H, s), 1.91 (3H, s), 1.83 to 2.53 (4
H, m), 2.86 (1H, hept, J = 6Hz) Example 8 Synthesis of (3R, 7R, 11R) -3-acetoxy-3,7,11,15-tetramethylhexadecylisopropyl sulfide 1.12 g (3 mmol) of the hydroxy sulfide obtained in Example 4,
Mix 10 ml of acetic anhydride and 15 mg of p-toluenesulfonic acid,
After stirring at room temperature for 2 hours, the same operation as in Example 7 was carried out to obtain 1.17 g of the title compound (yield 94%).

IR and NMR spectra were obtained in Example 7 (3S, 7R, 11R)
It was identical to that of the body.

The specific optical rotation [α] _D ²⁰ was + 0.94 ° (C = 0.96, ethanol).

Example 9 (3'S, 7'R, 11'R) -4-acetoxy-2- (3 '
-Acetoxy-1'-isopropylthio-3 ', 7', 1
Synthesis of 1 ', 15'-tetramethylhexadecyl) -3,5,6-trimethylphenol (3S, 7R, 11R) -3-acetoxy-3,7,11,15-tetramethylhexadecyl isopropyl sulfide 1.24 g (3.0 mm
ol) and 10 ml of methylene chloride were cooled to -40 ° C, 0.29 ml (3.6 mmol) of sulfuryl chloride was added dropwise over 1 minute, and the mixture was stirred at the same temperature for 5 minutes. A solution of 1.75 g (9 mmol) of 4-acetoxy-2,3,5-trimethylphenol dissolved in 5 ml of methylene chloride was added dropwise at -40 ° C over 5 minutes, and the mixture was stirred at the same temperature for 15 minutes. Next, triethylamine 2.5 ml (18 mmol)
And 3 ml of methylene chloride were added dropwise at -40 ° C for 3 minutes,
The temperature was gradually raised to room temperature. Reaction liquid was ice-cooled 1N hydrochloric acid 40
The mixture was poured into ml, the organic layer was separated, and the aqueous layer was extracted with hexane. The organic layers are combined, washed with water, dried, and the solvent is distilled off.
3.08 g of crude product was obtained. This was subjected to silica gel chromatography and eluted with a n-hexane-ethyl acetate mixed system to obtain 1.22 g of the title compound, 4-acetoxy-2,3,5-
1.19 g of trimethylphenol was recovered (yield 67%).

The refractive index, IR spectrum and NMR spectrum of the obtained compound are as follows.

n _D ²⁰ 1.4956 IR spectrum: 3260,2940,1760,1735,1210 cm ^-1 NMR spectrum (CCl ₄ ): δ0.87 (12H, d, J = 6Hz), 1.18
(30H, bs), 1.83 (3H, s), 2.01 (3H, s), 2.09 (3H, s),
2.17 (3H, s), 2.25 (3H, s), 1.8 to 2.9 (3H, m), 4.57 (1
H, t, J = 5 Hz), 7.56 (1H, s) Example 10 (3'R, 7'R, 11'R) -4-acetoxy-2- (3 '
-Acetoxy-1'-isopropylthio-3 ', 7', 1
Synthesis of 1 ', 15'-tetramethylhexadecyl) -3,5,6-trimethylphenol (3R, 7R, 11R) -3-acetoxy-3,7,11,15-tetramethylhexadecyl isopropyl sulfide 1.24 g (3.0 mm
was used in the same manner as in the synthesis of the (3'S, 7'R, 11'R) form of Example 9 to give 1.25 g of the title compound (yield 69%).

IR and NMR spectra were obtained above (3'S, 7'R, 11 '
It was identical to that of the R) form.

Example 11 (3'S, 7'R, 11'R) -4-acetoxy-2- (3 '
-Acetoxy-3 ', 7', 11 ', 15'-tetramethylhexadecyl) -3,5,6-trimethylphenol synthesis (3'S, 7'R, 11'R) -4-acetoxy-2- (3 '
-Acetoxy-1'-isopropylthio-3 ', 7', 1
390 mg (0.64 mmol) of 1 ', 15'-tetramethylhexadecyl) -3,5,6-trimethylphenol was dissolved in a small amount of ethanol, about 5 g of Raney nickel (W4) was added, and the mixture was heated under reflux for 75 minutes and cooled. Nickel was filtered off, the solvent was distilled off, and the residue was subjected to silica gel chromatography to give 306 mg of the title compound.
Was obtained (yield 90%).

The IR spectrum and NMR spectrum of the obtained compound are as follows.

IR spectrum: 3300,2940,1760,1735cm ^-1 NMR spectrum (CCl ₄ ): δ0.86 (12H, d, J = 6Hz), 1.17
(30H, bs), 1.85 (3H, s), 1.95 (3H, s), 2.02 (3H, s),
2.09 (3H, s), 2.19 (3H, s), 1.8 to 2.9 (4H, m), 7.41 (1
H, s) Example 12 (3'R, 7'R, 11'R) -4-acetoxy-2- (3 '
-Acetoxy-3 ', 7', 11 ', 15'-tetramethylhexadecyl) -3,5,6-trimethylphenol synthesis (3'R, 7'R, 11'R) -4-acetoxy-2- (3 '
-Acetoxy-1'-isopropylthio-3 ', 7', 1
Using 1 ', 15'-tetramethylhexadecyl) -3,5,6-trimethylphenol 503 mg (0.83 mmol), Example 11
The same procedure was followed to obtain 397 mg of the title compound (yield: 90
%).

IR and NMR spectra were identical to those obtained above.

Example 13 (3'S, 7'R, 11'R) -2- (3'-hydroxy-
3 ', 7', 11 ', 15'-tetramethylhexadecyl) -3,
5,6-Trimethyl-1,4-benzoquinone (3'S) -α-
Tocopherylquinone) synthesis 150 mg (3.9 mmol) of lithium aluminum hydride was suspended in 10 ml of ether, and (3'S, 7'R, 11'R) -4-
Acetoxy-2- (3'-acetoxy-3 ', 7', 11 ',
A solution of 303 mg (0.57 mmol) of 15'-tetramethylhexadecyl) -3,5,6-trimethylphenol dissolved in 10 ml of ether was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 1.5 hours. After that, ether saturated with water was added under cooling and further IN
Hydrochloric acid (10 ml) was added to separate the organic layer, and the aqueous layer was extracted with ether. After washing the organic layers together with water and drying, the solution is about 10 ml.
The mixture was concentrated to 1, 600 mg of lead dioxide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, the solvent was evaporated, and the crude product was subjected to silica gel column chromatography to obtain 229 mg of the title compound (yield 90%).

The specific optical rotation, IR spectrum and NMR spectrum of the obtained compound are as follows.

[Α] _D ²⁰ + 1.0 ° (C = 10.0, ethanol) IR spectrum: 3450,1640cm ^-1 NMR spectrum (CCl ₄ ): δ0.87 (12H, d, J = 6Hz), 1.17
(23H, bs), 2.00 (6H, s), 2.03 (3H, s), 1.8 ~ 2.8 (5H,
m) Example 14 (3'R, 7'R, 11'R) -2- (3'-hydroxy-
3 ', 7', 11 ', 15'-tetramethylhexadecyl) -3,
5,6-Trimethyl-1,4-benzoquinone ((3'R) -α
-Tocopherylquinone) (3'R, 7'R, 11'R) -4-acetoxy-2- (3 '
-Acetoxy-3 ', 7', 11 ', 15'-tetramethylhexadecyl) -3,5,6-trimethylphenol 319 mg (0.60
mmol) in the same manner as in Example 13 to give the title compound 23
8 mg was obtained. (Yield 89%).

[Α] _D ²⁰ −1.0 ° (C = 10.0, ethanol) IR and NMR spectra were identical to those obtained above.

Example 15 Synthesis of (2R, 4'R, 8'R) -α-tocopherol (1) (3'R, 7'R, 11'R) -2- (3'-hydroxy-
3 ', 7', 11 ', 15'-tetramethylhexadecyl) -3,
5,6-Trimethyl-1,4-benzoquinone 223 mg (0.50 mmo
l) was dissolved in 20 ml of ethyl acetate, 100 mg of 5% palladium / carbon catalyst was added, and the mixture was shaken at room temperature in a hydrogen stream. When the absorption of hydrogen stopped, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained oily substance was dissolved in 10 ml of benzene, 9 mg of p-toluenesulfonic acid was added, and the mixture was refluxed for 1 hour. After cooling, 5 ml of saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with ether. . The organic layers were combined and dried, the solution was evaporated, and the crude product was subjected to silica gel column chromatography to obtain 194 mg of the title compound (yield 90
-%).

The specific optical rotation [α] _D ²⁰ of the obtained compound was −2.7 ° (C = 5,
0, benzene). Also, the IR and NMR spectra were in perfect agreement with those of the standard sample.

Specific rotation of alkaline K ₃ Fe (CN) ₆ oxide dimer [α] _D ¹⁷
Is + 32 ° (C = 0.17, isooctane) {reference value [α] _D ²⁵ + 31.5 ° (C = 5, isooctane)}, and it was confirmed that the substance was optically pure d-α-tocopherol.

Example 16 Synthesis of (2R, 4'R, 8'R) -α-tocopherol (2) 390 mg (0.8 mmol) of the desulfurized product obtained in Example 12 was treated with ether 20
150 ml (3.9 mm) of lithium aluminum hydride
ol) was added dropwise to a suspension of 10 ml of ether at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. Then, ether saturated with water was added under ice cooling, 10 ml of 1N hydrochloric acid was further added to separate the organic layer, and the aqueous layer was extracted with ether. The organic layers were combined, washed with water and dried, and then the solvent was distilled off. The obtained oily substance was dissolved in 10 ml of benzene, and 15 mg of p-toluenesulfonic acid was dissolved.
(0.08 mmol) was added and the mixture was refluxed for 1 hour. After cooling, 5 ml of saturated aqueous sodium hydrogen carbonate solution was added to separate the organic layer, and the aqueous layer was extracted with ether. The organic layers were combined and dried, the solvent was evaporated, and the crude product was subjected to silica gel column chromatography to obtain 280 mg of the title compound (yield 90%).

The specific optical rotation [α] _D ²⁰ of the obtained compound was −2.7 ° (C = 5,
0, benzene). The IR and NMR spectra were the same as those obtained in Example 15.

Example 17 Synthesis of (2R, 4'R, 8'R) -α-tocopherol (3) (3'S, 7'R, 11'R) -2- (3'-hydroxy-
3 ', 7', 11 ', 15'-tetramethylhexadecyl) -3,
5,6-Trimethyl-1,4-benzoquinone 223 mg (0.50 mmo
l) was dissolved in 20 ml of ethyl acetate, 100 mg of 5% palladium / carbon catalyst was added, and the mixture was shaken at room temperature in a hydrogen stream. When the absorption of hydrogen stopped, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained oily substance was dissolved in 20 ml of n-hexane, 1.0 g of anhydrous zinc chloride was added, the solvent was distilled off under reduced pressure, and the residue was heated to 50 ° C.
Heated to 1.5 hours. After cooling, water was added to decompose and the mixture was extracted with ether. The extract was washed with 3N hydrochloric acid and water successively and dried. The solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain 150 mg of the title compound (yield 70%).

The specific optical rotation [α] _D ²⁰ of the obtained compound was −1.8 ° (C = 5,
0, benzene). The IR and NMR spectra were the same as those obtained in Example 15.

Example 18 Synthesis of (2S, 4′R, 8′R) -α-tocopherol (1) Using 300 mg (0.56 mmol) of the desulfurized product obtained in Example 11, the same procedure as in Example 16 was carried out. 235 mg of the compound was obtained (yield 9
0%).

IR and NMR spectra were identical to (2R, 4'R, 8'R) -α-tocopherol. Specific rotation [α] _D ²⁰ is + 0.9 °
(C = 0.5, benzene).

Example 19 Synthesis of (2S, 4′R, 8′R) -α-tocopherol (2) (3 ′S) -α-tocopherylquinone 20 obtained in Example 13
Using 0 mg (0.45 mmol) and operating as in Example 15,
170 mg of the title compound was obtained (yield 88%).

The IR and NMR spectra of the resulting compound were identical to those obtained above.

Claims (2)

[Claims] 1. A structural formula: [In the formula, R ₁ is Represents The same applies hereinafter] The compound represented by is tosylated with p-toluenesulfonyl chloride to give a structural formula: [In the formula, Ts is a tosyl group Represents The same applies hereinafter] A compound represented by the following formula is obtained, and then the compound is reacted with isopropyl mercaptan in the presence of metallic sodium to give a structural formula: Or A compound represented by the following formula is obtained, and then the compound is reductively cleaved to obtain a structural formula: Or A compound represented by the following formula is obtained, and then the compound is acetylated to obtain the structural formula: [In the formula, Ac represents an acetyl group. The same applies hereinafter] A compound represented by the following formula is obtained, and then the compound is reacted with 4-acetoxy-2,3,5-trimethylphenol to give a structural formula: A compound represented by the following formula is obtained, and then the compound is reacted with Raney nickel and further deacetylated to obtain the structural formula: A compound of formula (1) is obtained, and the compound is then directly cyclized or is oxidized to obtain α-tocopheryl quinone and then cyclized. (2R, 4′R, 8′R) -α-tocopherol represented by or a structural formula: A method for producing (2S, 4'R, 8'R) -α-tocopherol represented by 2. Structural formula: [In the formula, R ₁ is Represents The same applies hereinafter] By reductively cleaving the compound represented by Or A compound represented by the following formula is obtained, and the compound is then tosylated with p-toluenesulfonyl chloride to give a structural formula: [In the formula, Ts is a tosyl group Represents The same applies hereinafter] A compound represented by the following formula is obtained, and then the compound is reacted with isopropyl mercaptan in the presence of metallic sodium to give a structural formula: Or A compound represented by the following formula is obtained, and then the compound is acetylated to obtain the structural formula: [In the formula, Ac represents an acetyl group. The same applies hereinafter] A compound represented by the following formula is obtained, and then the compound is reacted with 4-acetoxy-2,3,5-trimethylphenol to give a structural formula: A compound represented by the following formula is obtained, and then the compound is reacted with Raney nickel and further deacetylated to obtain the structural formula: A compound represented by the formula (1) and then cyclizing the compound directly, or oxidizing the compound to obtain α-tocopherylquinone, and then cyclizing the compound. (2R, 4′R, 8′R) -α-tocopherol represented by or a structural formula: A method for producing (2S, 4'R, 8'R) -α-tocopherol represented by