JPH0212470B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel optically active compound that is a useful intermediate in producing optically active α-tocopherol, and a method for producing the same. In more detail, the general formula (In the formula, A is the formula

Group or formula represented by [Formula]

The present invention relates to an optically active compound represented by the formula (meaning a group represented by the formula) and a method for producing the same. d-α-Tocopherol is the most representative form of vitamin E that is widely distributed in nature. Among these, it is an extremely important substance. However, d-α-tocopherol must be isolated from natural products, primarily vegetable oils;
Not suitable for industrial mass production. That is,
Since the content of d-α-tocopherol in vegetable oil is extremely small, an extremely large amount of vegetable oil is required, and it is also difficult to isolate as it requires separation and purification from homologs such as β, γ, and δ. It has the disadvantage of being accompanied by Therefore, optically active α-tocopherol, especially d
Various attempts have been made to chemically synthesize −α-tocopherol (for example, H. Mayler,
O. Isler et al., Helv. Chim. Acta, 46, 650 (1963); J.
W. Scott, W. M. Cort, H. Harley, F.T.
Bizzarro, DRPanish, G. Saucy, JACS51,
200 (1974), 52, 174 (1975), Helv.Chim.
Acta.59, 290 (1976); KCChan, N.Cohen et al.
J.Org.Chem.41, 3497, 3512 (1976), 43, 3435
(1978), etc.), but there are no industrially useful methods. That is, all previously proposed methods require optical resolution of the dl form with an intermediate material at some point. The necessity of this optical resolution has the major disadvantage that the yield is significantly reduced by 30 to 40%, and it cannot be called an industrial method. As a result of many years of research into a method that does not require optical splitting of dl bodies, the present inventors have discovered that this is possible by the method described below, and have now completed the present invention. Ivy. The outline of the synthesis method according to the present invention is as follows. [In the above optical structural formula, R ₁ , R ₂ and
R ₃ represents the same or different hydroxyl group-protecting group.
X represents a halogen atom. The symbol 〓 indicates that the substituent attached to it is on the plane of the paper, and the symbol 〓
indicates that the substituent attached to it is below the plane of the paper. The symbol ~ indicates a mixture of both. ] According to the method illustrated above, natural d-α-tocopherol, i.e. (2R,4′R,8′R)-α
-Tocopherols are obtained. The present invention will be explained in more detail as follows. First, natural phytol () is used as a starting material and subjected to enantioselective oxidation to obtain a 2,3-epoxy compound. To give an example of a specific method, natural phytol (), tartrate diester, titanium tetraisopropoxide, and t-butyl hydroperoxide are mixed in a halogenated hydrocarbon such as dichloroethane or trichloroethane at a temperature of about -70 to 30%. Oxidation is carried out at a temperature of °C. As the tartrate, for example, diethyl tartrate, dimethyl tartrate, etc. can be used, but in the case of diethyl tartrate, if D-(-)-diethyl tartrate is used, a 2,3-epoxy compound () having the three-dimensional structure shown above can be obtained. However, only
If L-(+)-diethyl tartrate is used, only the 2,3-epoxy compound (') having the following three-dimensional structure can be obtained. By using this 2,3 epoxy body (') as a raw material and performing the same operation as the method illustrated above, optically active α-tocopherol (2S,
4′R, 8′R)-α-tocopherol is obtained. This patent specification includes both of these production methods, and in the present invention, optically active α-tocopherol refers to the two mentioned above, namely (2R, 4′R, 8′R).
―α-Tocopherol, (2S, 4′R, 8′R) ―α―
Contains all tocopherols. Using 2,3-epoxy body (′) as raw material (2S,
The method for producing 4'R, 8'R)-α-tocopherol is illustrated as follows. () or (′) to () or (′)
The step leading to is a step of reductively cleaving each 2,3-epoxy compound to obtain () or ('). For reductive cleavage, good results can be obtained 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 the reaction is usually carried out at about -10°C to 40°C. () or (′) to () or (′)
Furthermore, the step leading to () or (') is a step in which the hydroxyl group at position 3 is protected and only the hydroxyl group at position 1 is oxidized to form an aldehyde group. In this case, it is preferable to first protect the hydroxyl group at position 1 with a protecting group that reacts only with the primary hydroxyl group at position 1, then protect the tertiary hydroxyl group at position 3, and then protect the hydroxyl group at position 1. Only the group is removed to form () or ('). The hydroxyl group at position 1 of () or (') is then oxidized to an aldehyde group to obtain () or (').
This process is illustrated as follows. When producing (-a) or ('-a) from () or ('), only the primary hydroxyl group at position 1 is protected, but a protecting group that reacts only with primary alcohol is selected. do. Any protecting group can be selected as long as it reacts only with primary alcohols. Therefore, in the above structural formula, R ₄ means a protecting group that can react only with primary alcohols. A typical example is an ester form using an acylating agent. Specifically, carboxylic acid halides such as acetyl chloride, propionyl chloride, butyroyl chloride, and bivaloyl chloride, carboxylic acid anhydrides, and the like are used to form the corresponding esters. The method using carboxylic acid chloride is a typical method, but there are no particular limitations on the method, but amine solvents such as pyridine, trimethylamine, triethylamine, etc. are used, and the temperature is about 0.
Carry out the reaction at ~70°C. The process from (-a) or ('-a) to (-b) or ('-b) is a process of protecting the tertiary hydroxyl group at position 3, but the protecting group protects the tertiary hydroxyl group. It is possible to select any protecting group as long as it is capable of protecting the protective group. Therefore, in the above structural formula, R ₁ means a protecting group capable of protecting a tertiary hydroxyl group. However, it is different from the protecting group for the hydroxyl group at position 1. Typical protecting groups include:
Alkyl group, allyl group, alkoxyalkyl group,
Examples include aralkyl groups. Of these, the one most commonly used and giving favorable results is the methoxymethylene group. When protecting with a methoxymethylene group, a methoxymethylene halide such as methoxymethylene chloride or methoxymethylene bromide is reacted in a solvent such as dichloroethane, dichloromethane, or diethyl ether. The obtained (-b) or ('-b) is
Only the protecting group at position 1 is removed to obtain () or ('). The method for removing only the protecting group at the 1-position may be any method as long as it can remove only the protecting group at the 1-position without removing the protecting group at the 3-position. caustic soda, caustic potash,
Although the ester may be hydrolyzed under basic conditions such as sodium carbonate, it is convenient and convenient to remove the protecting group using lithium aluminum hydride in an ether solvent such as diethyl ether or tetrahydrofuran. () or (′) to () or (′)
The step leading to is a step of oxidizing the hydroxyl group at position 1 to an aldehyde while protecting the hydroxyl group at position 3. In this case, a preferred method is to use pyridinium chlorochromate (PCC) in a halogenated hydrocarbon solvent such as dichloromethane, dichloroethane, trichloroethane, etc.
Oxidation is performed using a chromic acid-based oxidizing agent such as Collins reagent (chromic anhydride-pyridine). At this time, the reaction temperature is not particularly limited, but it is carried out at about 0 to 40°C. () or (′) to () or (′)
The process leading to () was obtained by the above method.
Alternatively, it is a step of reacting (') and () to obtain () or ('). In the structural formula (), X represents a halogen atom such as chlorine, bromine, or iodine. () is 2-Hello-
It means 3,5,6-trimethyl-1,4-benzohydroquinone in which the hydroxyl group at the 1,4 position is protected with a protecting group, and the definitions of R ₂ and R ₃ are (-b) or ( It is the same as that explained in '-b). In other words, typical protecting groups include alkyl groups, allyl groups, alkoxyalkyl groups, aralkyl groups, etc., but one that is simple and gives favorable results is protection with a methoxymethylene group. what you did,
That is, 2-halo-3,5,6-trimethyl-
1,4-benzohydroquinone dimethoxymethyl ether is often used. The reaction in this step is a Grignard reaction using metallic magnesium, but more specifically, () or ('), () and React with metallic magnesium to obtain () or (′). () used as a raw material can be produced, for example, by the following method. i.e. 3, 5, 6
-Using trimethylbenzoquinone (TMQ) as a starting material, it is treated with a halogen to introduce a halogen into the 2-position, which is then reduced to a hydroxyl group, and this hydroxyl group is protected to form (). A specific illustration of the case where X in () is a bromine atom and R ₂ and R ₃ are methoxymethylene groups is as follows. () or (′) to () or (′)
The step leading to () is the step of dehydrating () or (') to obtain () or ('). Among the various dehydration methods, one preferred example is ()
Or, after chlorinating (') with thionyl chloride etc., for example, DBN{1,5-diazabicyclo[4,3,0]nonene-5}, DBU{1,5-diazabicyclo[5,4,0]undecene- 5} or the like, it is possible to obtain () or (') in a good yield. As a solvent for chlorination, any inert solvent that does not participate in the reaction may be used, such as diethyl ether, benzene, toluene, tetrahydrofuran, etc., and the reaction temperature is not particularly limited, but the reaction temperature is about 0 to 50°C. . Further, as a solvent for dehydrochlorination, a solvent that does not participate in the reaction, such as DMSO (dimethyl sulfoxide), benzene, toluene, etc., is used. () or (′) to (XI) or (XI′)
The step leading to is a step of reducing the double bond in the side chain of () or (') to obtain (XI) or (XI'). Preferred methods include reduction using palladium-carbon, Raney nickel, platinum oxide, rhodium-alumina, and the like. At this time, the temperature is about 0 to 80 DEG C., and alcohols such as ethanol, methanol, and propanol, acetic acid, benzene, toluene, and ethers can be used as the solvent. () or (') to (X) or (')
The step leading to is a step of removing the protecting groups of the mother nucleus and side chains, and further oxidizing with an oxidizing agent to obtain α-tocopherylquinone () or (′). In this case, depending on the method, an intermediate (-a) or ('-a) having the following structural formula is used. (-a) or ('
-a) may be isolated and the reaction may proceed further, or the reaction may proceed without isolation to obtain () or ('). There are various ways to remove a protecting group depending on the type of protecting group, but examples include using acetic acid, hydrochloric acid-methanol, sulfuric acid-methanol, etc., or reductive removal using palladium-carbon. However, any method may be used as long as it can be removed. Examples of the oxidizing agent include lead dioxide, silver oxide, hydrogen peroxide, Flemy's salt, etc., but in short, any oxidizing agent that can convert hydroquinone to quinone can be used. α-Tocofuesolquinone [() or (′)]
The process from to the final substance optically active α-tocopherol [(XI) or (XI′)] is the process of cyclizing α-tocopherylquinone to optically active α-tocopherol, which can be carried out using a conventional method. , for example, in an alcoholic solvent such as methanol, ethanol, or propanol, or a polar solvent such as acetic acid or ethers at a temperature of about 0 to 90°C.
Addition of camphorsulfonic acid or cyclization with sulfuric acid in methanol solvent yields the final optically active α-tocopherol, i.e. (2R, 4′R,
8′R)-α-tocopherol (XI), or (2S,
4′R, 8′R)-α-tocopherol (XI′) is obtained. Obtained by the method of the present invention (2R, 4′R, 8′R)
-α-Tocopherol is a naturally occurring d-α
-It was confirmed from the physicochemical properties that it is the same as tocopherol. To give an example, the acetate form of (2R, 4′R, 8′R)-α-tocopherol obtained by the method of the present invention, and the natural d-α-tocopherol obtained from K ₃ Fe(CN) ₆ oxide. Comparing the optical rotation with the corresponding substance, both of them are as follows.
Agreed. Among the intermediates in each step of the method of the present invention described above, (), ('), (), ('), (), (
′),
(), (′), (), (′), (), (′
), (),
('), (-a), ('-a), (-b), (
′−
b), (-a) and ('-a)) are all new compounds. The method of the present invention does not require dl resolution and can industrially produce optically active α-tocopherol in high yield, and therefore the value of the present invention is extremely high. Examples are listed below, but it goes without saying that the present invention is not limited thereto. Example 1 (2S, 3S) - Epoxy, (3S, 7R, 11R) -
3,7,11,15-tetramethylhexadecane-
Synthesis of 1-ol 400ml of dry dichloromethane was heated to −20 to −− in a nitrogen stream.
While cooling to 30°C, 11.4 g (0.04 mol) of titanium tetraisopropoxide and 8.24 g (0.04 mol) of L-(+)-diethyl tartrate were gradually added dropwise, and the mixture was stirred at the same temperature for 10 minutes. Next, 30 ml of a dry dichloromethane solution containing 12 g (0.04 mol) of natural phytol was added dropwise, and after 5 minutes, 14.5 ml (5.5 mM/ml) of a dichloroethane solution containing 0.08 mol of anhydrous t-butyl hydroperoxide was gradually added dropwise to complete the dropwise addition. After that, the mixture was stirred at the same temperature for 2 hours. The completion of the reaction is confirmed by TLC (chloroform, benzene development) to confirm the disappearance of the raw materials. Furthermore, while stirring at the same temperature, add 10% tartaric acid aqueous solution.
Add 100ml and gradually increase the reaction temperature to room temperature (20-25℃)
rise to. The organic layer is separated, washed with water, dried, and concentrated under reduced pressure to obtain 12.4 g of a colorless oil. Dissolve this in 300ml of diethyl ether and cool with ice water.
Add 120 ml of 1N aqueous sodium hydroxide solution, stir for 30 minutes, separate the diethyl ether layer, wash with water, dry, and evaporate the solvent to obtain 12.2 g of a colorless oil. 200g of silica gel with 60 to 80 meshes of this stuff,
Purification by chromatography using n-hexane and ethyl acetate yields 11.7 g of the title compound. (Yield 91.3%) [α] ²⁵ _D = -4.4° (C = 3.63, ethanol) Elemental analysis value: Molecular formula C ₂₀ H ₄₀ O ₂ , molecular weight 312.52, C (%) H (%) Theoretical value 76.86 12.90 Actual value 77.14 12.75 IR spectrum: Absorption by OH group at 3400 cm _-1 NMR spectrum (CDCl ₃ , δppm): 0.87 (d, 6H, J=6Hz) 1.30 (s, 3H) 2.20 (m, 1H, D ₂ O addition Disappearance) 2.97 (dd, 1H) 3.48-4.00 (m, 2H) MS spectrum: M ⁺ = 312, m/e = 294 (M-18) Example 2 (2R, 3R)-Epoxy, (3R, 7R, 11R)3,
7,11,15-tetramethylhexadecane-1-
Synthesis of all 200 ml of dry dichloromethane, 5.7 g (0.02 mol) of titanium tetraisopropoxide, D-(-)
- 7.3 ml of dichloroethane solution containing 4.2 g (0.02 mol) of diethyl tartrate, 6 g (0.02 mol) of natural phytol, 0.04 mol of anhydrous t-butyl hydroperoxide (5.5 mmol/ml), 50 ml of 10% tartaric acid, 1N
- Example 1 using 60 ml of sodium hydroxide aqueous solution
Proceed in the same manner to obtain the desired title compound as a colorless oil.
Obtain 5.6g. (Yield 89.7%) [α] ²⁵ _D = +4.3° (C = 2.8, ethanol) IR, NMR, and MS spectra were the same as those obtained in Example 1. Example 3 Synthesis of (3S, 7R, 11R)-3,7,11,15-tetramethylhexadecane 1,3-diol Lithium aluminum hydrite 0.76g
(0.02 mol) was suspended in 100 ml of tetrahydrofuran, and while stirring at 5°C, (2S, 3S)-epoxy,
(3R,7R,11R)-3,7,11,15-tetramethylhexadecane-1-ol 6.24g (0.02mol)
20 ml of a tetrahydrofuran solution containing the above was added dropwise over a period of 30 minutes, and after the addition was completed, the mixture was further stirred at the same temperature for 2 hours, and the disappearance of the raw material was confirmed by TLC. Then add 0.8 ml of water and 0.8 ml of 15% sodium hydroxide solution.
ml and 2.4 ml of water to decompose excess lithium aluminum hydrite, filter the reaction, and concentrate the liquid to obtain 6.1 g of the title compound as a colorless oil.
Yield is quantitative. Elemental analysis value: Molecular formula C ₂₀ H ₄₂ O ₂ , molecular weight 314.54 C (%) H (%) Theoretical value 76.37 13.46 Actual value 76.10 13.57 IR spectrum OH group absorption at 3400 cm _-1 NMR spectrum (CD Cl ₃ , δppm ): 0.86 (d, 6H, J=6Hz) 1.24 (s, 3H) 2.40 (bs, 1H, D ₂ O addition disappeared) 2.84 (bs, 1H, D ₂ O addition disappeared) 3.65 ~ 4.00 (m, 2H) MS spectrum: M ⁺ = 314, m/e = 296 (M-18) Example 4 Synthesis of (3R, 7R, 11R)-3,7,11,15-tetramethylhexadecane-1,3-diol Lithium aluminum Hydrite 1.52g
(0.04 mol), tetrahydrofuran 200ml, (2R,
3R) - Epoxy, (3S, 7R, 11R) - 3, 7,
11,15-tetramethylhexadecane-1-ol
Using 12.48 g (0.04 mol), the same procedure as in Example 3 is carried out to obtain 12.3 g of the title compound as a colorless oil.
Yield is quantitative. The IR, NMR, and MS spectra were the same as those obtained in Example 3. Example 5 Synthesis of (3S,7R,11R)-3,7,11,15-tetramethyl-3-methoxymethyleneoxyhexadecane-1-ol (i) (3S,7R,11R)-3,7,11 , 15-tetramethylhexadecane-1,3-diol 6.3g
(0.02 mol) was dissolved in 50 ml of pyridine, and while stirring at 0°C, 2.9 g (0.024 mol) of pivaloyl chloride was dissolved in 50 ml of pyridine.
mol) was added dropwise, and after the completion of the addition, the mixture was stirred at the same temperature for 1 hour to complete the reaction. The reaction solution was dispersed in 200 ml of a 5% aqueous hydrochloric acid solution, and the product was extracted with 100 ml of diethyl ether. The extract was washed with water, dried, and the solvent was distilled off to obtain 7.7 g of an ester form of TLC monospot (developed with benzene). (ii) Dissolve 7.7 g of the pivaloyl ester obtained above in 100 ml of dichloromethane, add 2.9 g (0.024 mol) of N,N-dimethylaniline at room temperature, and add 1.9 g (0.024 mol) of methoxymethyl chloride while stirring. Gradually drip. After the dropwise addition was completed, the reaction was carried out at the same temperature for 4 hours, and the disappearance of the raw materials was confirmed by TLC.
The reaction solution was dispersed in 100 ml of 5% aqueous hydrochloric acid solution, and the product was extracted with 200 ml of diethyl ether. The extract was washed with water, dried, and the solvent was distilled off to give 8.2 g of a colorless oil.
get. 150g of silica gel with 60 to 80 meshes of this stuff,
Purification by chromatography using n-hexane and ethyl acetate gave 8 g of a colorless oil. (Yield 95%) [α] ²⁵ _D = +2.13゜ (C = 6.34, ethanol) Elemental analysis value: Molecular formula C ₂₇ H ₅₄ O ₄ , molecular weight 442.70 C (%) H (%) Theoretical value 73.25 12.30 Actual value 73.86 12.45 IR spectrum: Absorption due to ester group at 1745 cm _-1 NMR spectrum (CD Cl ₃ , δppm): 0.86 (d, 6H, J = 6Hz) 1.20 (s, 9H) 1.24 (s, 3H) 1.85 ( t, 2H, J = 7Hz) 3.37 (s, 3H) 4.16 (t, 2H, J = 7Hz) 4.70 (s, 2H) MS spectrum M ⁺ = 442 (iii) 1g of lithium aluminum hydrite
(0.028 mol) was suspended in 50 ml of diethyl ether,
While stirring at room temperature, 30 ml of a diethyl ether solution containing 8 g of the compound obtained above was gradually added dropwise, and after the dropwise addition was completed, stirring was continued at room temperature for 1 hour. Then, while cooling the reaction solution with ice water, add 1 ml of water,
Excess lithium aluminum hydrite is decomposed by adding 1 ml of 15% sodium hydroxide solution and 3 ml of water, and the reaction mixture is filtered and concentrated to obtain 6.5 g of the title compound as a colorless oil. (Yield 95%) [α] ²⁵ _D = +1.8゜ (C = 7.50, ethanol) Elemental analysis value: Molecular formula C ₂₂ H ₄₆ O ₃ , molecular weight 358.6 C (%) H (%) Theoretical value 73.74 12.93 Actual value 73.36 13.28 IR spectrum: Absorption due to OH group at 3450cm _-1 NMR spectrum (CD Cl ₃ , δppm): 0.86 (d, 6H, J = 6Hz) 1.28 (s, 3H) 2.80 (t, 1H, J = 5Hz, D ₂ O addition disappeared) 3.28 (s, 3H) 3.78 (q, 2H, J = 5Hz, D ₂ O addition, t, J
= 5Hz) 4.72 (s, 2H) MS spectrum: M ⁺ = 358, m/e = 340 (M-18) m/e = 327 (M-31) Example 6 (3R, 7R, 11R) - Synthesis of 3,7,11,15-tetramethyl-3-methoxymethyleneoxyhexadecane-1-ol (3R,7R,11R)-3,7,11,15-tetramethylhexadecane-1,3-diol 6.3g
(0.02 mol) was operated in the same manner as in (i), (ii), and (iii) of Example 5 to obtain 6.4 g of the title compound as a colorless oil. (Total yield 89.3%) [α] ²⁵ _D = -1.8° (C = 3.59, ethanol) IR, NMR, and MS spectra were the same as those obtained in Example 5. Example 7 Synthesis of (3S,7R,11R)-3,7,11,15-tetramethyl-3-methoxymethyleneoxyhexadecane-1-al (3S,7R,11R)-3,7,11,15- 3.6 g (0.01 mol) of tetramethyl-3-methoxymethyleneoxyhexadecane-1-ol was dissolved in 50 ml of dichloromethane, and 6.4 g (0.03 mol) of pyridinium chlorochromate (PCC) was divided into 4 portions while stirring at room temperature. Add. The reaction solution immediately turns dark brown, and after confirming the disappearance of the raw materials by TLC (chloroform), diethyl ether is added dropwise until the reaction solution becomes cloudy. The reaction solution was then filtered through 50 g of Florisil, and the solution was concentrated to obtain 3.7 g of a pale yellow oil. 70g of silica gel with 60 to 80 meshes of this stuff,
Purification by chromatography using n-hexane and diethyl ether gave 3.1 g of the title compound as a colorless oil. (Yield 87.1%) [α] ²⁵ _D = +6.66゜ (C = 2.1, ethanol) Elemental analysis value: Molecular formula C ₂₂ H ₄₄ O ₃ , molecular weight 356.6 C (%) H (%) Theoretical value 74.10 12.44 Actual value 73.89 12.73 IR spectrum: Absorption by carbonyl group at 1730 cm _-1 NMR spectrum (CD Cl ₃ , δppm): 0.86 (d, 6H, J = 6Hz) 1.32 (s, 3H) 2.52 (t, 2H, J = 3Hz ) 3.36 (s, 3H) 4.72 (s, 2H) 9.80-9.97 (m, 1H) MS spectrum: M ⁺ = 356 Example 8 (3R, 7R, 11R) - 3,7, 11, 15-tetramethyl - Synthesis of 3-methoxymethyleneoxyhexadecane-1-al (3R,7R,11R)-3,7,11,15-tetramethyl-3-methoxymethyleneoxyhexadecane-1-ol 5.4g (0.015 mol), dichloromethane 80ml , pyridinium chlorochromate 9.6 g (0.045 mol)
The procedure was repeated in the same manner as in Example 7 to obtain 4.8 g of the title compound as a colorless oil. (Yield 89.7%) [α] ²⁵ _D = -6.45° (C = 2.17, ethanol) IR, NMR, and MS spectra were the same as those obtained in Example 7. Example 9 2-[(3'S, 7'R, 11'R)-3', 7', 11', 15'
―
Tetramethyl-3'-methoxymethyleneoxy-
1'-Hydroxyhexadecanyl]-3,5,6
-Synthesis of trimethyl-1,4-benzohydroquinone dimethoxymethyl ether 20 ml of dry tetrahydrofuran was added to 0.24 g (0.01 mol) of magnesium metal, and after activating the magnesium metal by adding 1 to 2 drops of ethylene dibromide at room temperature, 10 ml of dry tetrahydrofuran solution containing 3.19 g (0.01 mol) of 2-promo-3,5,6-trimethyl-1,4-benzohydroquinone dimethoxymethyl ether was gradually added dropwise, and after the dropwise addition was completed, the metal was stirred and refluxed for 2 hours. Dissolve magnesium and prepare Grignard reagent. In this Grignard reagent (3S, 7R, 11R) -
3,7,11,15-tetramethyl-3-methoxymethyleneoxyhexadecane-1-al 2.85g
(0.008 mol) in dry tetrahydrofuran solution
15 ml of the solution was added dropwise, and after the addition was completed, the reaction was completed by stirring and refluxing for 1 hour. The reaction solution was dispersed in 100 ml of saturated ammonium chloride solution, and the product was extracted twice with 100 ml of diethyl ether, washed with water, dried, and the solvent was distilled off to form a pale yellow oil.
Obtain 5.5g. 100g of silica gel with 60 to 80 meshes of this stuff,
Chromatographic purification using n-hexane and diethyl ether yielded the title compound as a colorless oil 3.8
(yield 79.7%) [α] ²⁵ _D = -4.58゜ (C = 2.4, ethanol) Elemental analysis value: Molecular formula C ₃₅ H ₆₄ O ₇ , molecular weight 596.9 C (%) H (%) Theoretical value 70.43 10.81 Actual value 70.30 11.01 IR spectrum: Absorption due to OH group at 3500 cm _-1 NMR spectrum (CD Cl ₃ , δppm): 0.86 (d, 6H, J = 7Hz) 2.18 (s, 3H) 2.20 (s, 3H) 2.42 (d, 3H, J = 2Hz) 3.40 (s, 3H) 3.63 (s, 6H) 3.76-3.96 (m, 1H, D ₂ O addition disappeared) 4.75 (d, 2H, J = 2Hz) 4.88 (s, 2H) 4.96 (s, 2H) 5.28-5.57 (m, 1H) MS spectrum: M ⁺ = 596 Example 10 2-[(3'R, 7'R, 11'R) - 3', 7', 11 ′，15′
―
Tetramethyl-3'-methoxymethyleneoxy-
1'-Hydroxyhexadecanyl]-3,5,6
-Synthesis of trimethyl-1,4-benzohydroquinone dimethoxymethyl ether Metallic magnesium 0.12 g (0.005 mol), dry tetrahydrofuran 15 ml, ethylene dipromide 1
drops, 2-bromo-3,5,6-trimethyl-1,
4-benzohydroquinone dimethoxymethyl ether 1.6 g (0.005 mol), (3R, 7R, 11R) -3,
7,11,15-tetramethyl-3-methoxymethyleneoxyhexadecane-1-al 1.4g (0.004
mol) in the same manner as in Example 9 to obtain 1.8 g of the title compound as a colorless oil. (Yield 75.6%) [α] ²⁵ _D = +5.87° (C = 5.14, ethanol) The IR, NMR, and MS spectra were the same as those obtained in Example 9. Example 11 2-[(3′S, 7′R, 11′R)-3′, 7′, 11′, 15′
−
Tetramethyl-3'-methoxymethyleneoxy-
Synthesis of 1'-hexadecenyl]-3.5,6-trimethyl-1,4-benzohydroquinone dimethoxymethyl ether 2-[(3'S, 7'R, 11'R)-3', 7', 11', 15
′-
Tetramethyl-3'-methoxymethyleneoxy-
1'-Hydroxyhexadecanyl]-3,5,6-
Dissolve 1.8 g (0.003 mol) of trimethyl-1,4 benzohydroquinone dimethoxymethyl ether in 50 ml of diethyl ether, and while stirring while cooling with ice water to 5°C, add 3 ml of pyridine and 1 g of thionyl chloride.
(0.0084 mol) was gradually added dropwise and stirred for 30 minutes to complete the reaction. The reaction solution was dispersed in 50 ml of a 5% aqueous hydrochloric acid solution, and the product was extracted with 50 ml of diethyl ether, washed with water, dried, and the solvent was distilled off to obtain 1.9 g of a crude product. (The absorption of the OH group has disappeared in the IR spectrum of this product.) 1.9 g of the chlorinated product obtained here was dissolved in 30 ml of dimethyl sulfoxide, and 1,5-diazabicyclo[4,3,0]nonene- Add 2g of 5 (DBN) and stir at 100℃ for 30 minutes, then add 100ml of ice water.
The product was extracted with 100 ml of diethyl ether, washed with water, dried, and the solvent was distilled off to obtain 1.8 g of a pale yellowish white oil. 50g of silica gel with 60 to 80 meshes of this stuff,
Chromatography purification using n-hexane and diethyl ether yielded the title compound as a colorless oil.
get g. (Yield 86.4%) [α] ²⁵ _D = -10.08゜ (C = 7.8, ethanol) Elemental analysis value: Molecular formula C ₃₅ H ₆₂ O ₆ , molecular weight 578.85 C (%) H (%) Theoretical value 72.62 10.80 Actual measurement Value 72.98 11.07 NMR spectrum (CD Cl ₃ , δppm): 0.87 (d, 6H, J=7Hz) 1.44 (s, 3H) 2.23 (s, 6H) 2.27 (s, 3H) 3.40 (s, 3H) 3.57 (s , 3H) 3.63 (s, 3H) 4.75 (q, 2H, J = 6Hz) 4.85 (s, 2H) 4.90 (s, 2H) 5.90 (d, 1H, J = 17Hz) 6.52 (d, 1H, J = 17Hz ) MS spectrum: M ⁺ =578 Example 12 2—[(3′R, 7′R, 11′R)—3′, 7′, 11′, 15′
―
Tetramethyl-3'-methoxymethyleneoxy-
Synthesis of 1'-hexadecenyl]-3,5,6-trimethyl-1,4-benzohydroquinone dimethoxymethyl ether 2-[(3'R, 7'R, 11'R)-3', 7', 11' ,15
′-
Tetramethyl-3'-methoxymethyleneoxy-
1'-Hydroxyhexadecanyl]-3,5,6-
Trimethyl-1,4-benzohydroquinone dimethoxymethyl ether 1.2 g (0.002 mol), diethyl ether 30 ml, pyridine 2 ml, thionyl chloride
Example using 0.67 (0.0056 mol), DBN1.3g
Proceed as in step 11 to obtain 0.9 g of the title compound as a colorless oil.
get. (Yield 77.8%) [α] ²⁵ _D = +11.81° (C = 2.07, ethanol) The IR, NMR, and MS spectra were the same as those obtained in Example 11. Example 13 2-[(3′S, 7′R, 11′R)-3′, 7′, 11′, 15′
―
Tetramethyl-3'-methoxymethyleneoxyhexadecanyl]-3,5,6-trimethyl-
Synthesis of 1,4-benzohydroquinone dimethoxymethyl ether 2-[(3'S, 7'R, 11'R)-3', 7', 11', 15
′-
Tetramethyl-3'-methoxymethyleneoxy-
Dissolve 1.5 g (0.0026 mol) of 1'-hexadecenyl]-3,5,6-trimethyl-1,4-benzohydroquinone dimethoxymethyl ether in 50 ml of an ethanol solution containing 0.5 g of 5% palladium-carbon that has been replaced with hydrogen gas. , Hydrogen gas absorption is completed by stirring at room temperature for 2 hours. Filter the reaction solution and concentrate to obtain 1.45 g of the title compound as a colorless oil. Yield is quantitative. [α] ²⁵ _D = -4.58゜ (C = 3.5, ethanol) Elemental analysis value: Molecular formula C ₃₅ H ₆₀ O ₆ , molecular weight 576.83 C (%) H (%) Theoretical value 72.87 10.48 Actual value 73.15 10.65 NMR spectrum ( CD Cl ₃ , δppm): 0.87 (d, 6H, J = 6Hz) 2.20 (s, 6H) 2.25 (s, 3H) 2.52 - 2.84 (m, 2H) 3.40 (s, 3H) 3.62 (s, 6H) 4.76 (s, 2H) 4.88 (s, 2H) 4.89 (s, 2H) MS spectrum: M ⁺ = 576 Example 14 2-[(3'R, 7'R, 11'R) - 3', 7', 11′, 15′
―
Tetramethyl-3'-methoxymethyleneoxyhexadecanyl]-3,5,6-trimethyl-1,
Synthesis of 4-benzohydroquinone dimethoxymethyl ether 2-[(3'R, 7'R, 11'R)-3', 7', 11', 15
′-
Tetramethyl-3'-methoxymethyleneoxy-
1'-hexadecenyl]-3,5,6-trimethyl-1,4-benzohydroquinone dimethoxymethyl ether 1.06 g (0.002 mol), 5% palladium
The same procedure as in Example 13 is carried out using 0.3 g of carbon and 40 ml of ethanol to obtain 1.04 g of the title compound as a colorless oil. [α] ²⁵ _D = +5.02° (C = 4.8, ethanol) IR, NMR, and MS spectra were the same as those obtained in Example 13. Example 15 2-[(3′S, 7′R, 11′R)-3′, 7′, 11′, 15′
―
Tetramethyl-3'-hydroxyhexadecanyl]-3,5,6-trimethyl-1,4-benzoquinone (α-(3'S)-tocopherylquinone)
Synthesis (i) 2-[(3'S, 7'R, 11'R)-3', 7', 11', 15
′-
Tetramethyl-3'-methoxymethyleneoxyhexadecanyl]-3,5,6-trimethyl-1,4
-Benzohydroquinone dimethoxymethyl ether
1.45g (0.0025mol) in 20ml of tetrahydrofuran
10% aqueous hydrochloric acid solution with stirring at room temperature.
ml of the solution was added dropwise, and after the completion of the addition, the reaction was completed by stirring at the same temperature for 1 hour. The reaction solution was dispersed in 50 ml of water, and the product was extracted twice with 50 ml of diethyl ether. Next, 2 g of lead dioxide was added to the extract, and after stirring at room temperature for 1 hour, the reaction solution was filtered, dried, and the solvent was distilled off to form a yellow oil.
Obtain 1.4g. This product is purified by chromatography using 3.0 g of 60-80 mesh silica gel, n-hexane, and diethyl ether to obtain 1.1 g of α-(3'S)-methoxymethyltocopherylquinone as a yellow oil. (Yield 89.6%) [α] ²⁰ _D = -3.27° (C = 1.69, ethanol) Elemental analysis value: Molecular formula C ₃₁ H ₅₄ O ₄ , molecular weight 490.7 C (%) H (%) Theoretical value 75.87 11.09 Actual measurement Value 76.18 11.36 IR spectrum: Absorption of p-benzoquinone at 1640 cm _-1 NMR spectrum (CD Cl ₃ , δppm): 0.87 (d, 6H, J = 6Hz) 2.02 (s, 6H) 2.04 (s, 3H) 2.36 ~ 2.62 (m, 2H) 3.40 (s, 3H) 4.75 (s, 2H) MS spectrum: M ⁺ = 490, m/e = 429 (M-61) (ii) α-(3′S) obtained above -Dissolve 1.1 g (0.0022 mol) of methoxymethyl tocopherylquinone in 30 ml of methanol, dropwise add 20 ml of 10% aqueous hydrochloric acid solution while stirring at room temperature, and react for an additional 5 hours.
50 ml of water was added, and the product was extracted twice with 50 ml of diethyl ether, washed with water, dried, and the solvent was distilled off to obtain 1.1 g of a reddish-yellow oil. 25g of silica gel with 60 to 80 meshes of this stuff,
Chromatographic purification using n-hexane and diethyl ether gives 0.9 g of the title compound as a reddish-yellow oil. (Yield 89%) [α] ²⁰ _D = +1.08゜ (C = 10.6, ethanol) Elemental analysis value: Molecular formula C ₂₉ H ₅₀ O ₃ , molecular weight 446.69 C (%) H (%) Theoretical value 77.97 11.28 Actual value 78.15 11.41 IR spectrum: Absorption of OH group at 3450cm _-1 Absorption of p-benzoquinone at 1640cm _-1 NMR spectrum (CD Cl ₃ , δppm): 0.87 (d, 6H, J = 7Hz) 1.24 (s, 3H ) 2.00 (s, 6H) 2.03 (s, 3H) 2.44-2.70 (m, 2H) MS spectrum: M ⁺ = 446, m/e = 428 (M-18) Example 16 2-[(3'R, 7′R, 11′R) - 3′, 7′, 11′, 15′
―
Synthesis of tetramethyl-3'-hydroxyhexadecanyl]-3,5,6-trimethyl-1,4-benzoquinone (α-(3'R)-tocopherylquinone) (i) 2-[(3'R , 7′R, 11′R) - 3′, 7′, 11′, 15
′-
Tetramethyl-3'-methoxymethyleneoxyhexadecanyl]-3,5,6-trimethyl-1,4
- 1 g (0.0017 mol) of benzohydroquinone dimethoxymethyl ether, 15 ml of tetrahydrofuran,
A yellow oily α-
(3′R)-Methoxymethyltocopherylquinone 0.75
get g. (Yield 89.9%) [α] ²⁰ _D = +3.8° (C = 4.39, ethanol) The IR, NMR, and MS spectra were the same as those obtained in Example 15 (i). (ii) 0.75 g (0.0015 mol) of α-(3′R)methoxymethyltocopherylquinone obtained above, methanol
(ii) of Example 15 using 20 ml and 15 ml of 10% aqueous hydrochloric acid solution.
Proceed in the same manner as above to obtain 0.6 g of the title compound as a red-yellow oil.
get. (Yield 89.5%) [α] ²⁰ _D = -1.01° (C = 18.8, ethanol) IR, NMR, and MS spectra are the same as those obtained in Example 15 (ii). Example 17 Synthesis of (2S, 4′R, 8′R)-α-tocopherol 2-[(3′S, 7′R, 11′R)-3′, 7′, 11′, 15
′-
Tetramethyl-3′-hydroxyhexadecanyl]
-Dissolve 0.9 g (0.002 mol) of 3,5,6-trimethyl-1,4-benzoquinone in 20 ml of methanol, and add 1 g of d-camphorsulfonic acid to this.
(0.004 mol) and stirred at room temperature for 15 hours. Then, the reaction solution was dispersed in 50 ml of ice water, and the product was extracted twice with 50 ml of diethyl ether. The extract was thoroughly washed with water, dried, and the solvent was distilled off to obtain 0.85 g of a pale yellow oil. This stuff is 30g of silica gel with 60 to 80 meshes,
Chromatographic purification using n-hexane and diethyl ether yielded the title compound as a colorless oil.
Obtain 0.8g. (Yield 93%) [α] ²⁰ _D = +0.85° (C = 1.15, benzene) K ₃ Fe (CN) ₆ oxidation product: [α] ²⁰ _D = -29.6° (C = 1.70, isooctane) The obtained (2S, 4′R, 8′R)-α-tocopherol was acetylated using dry pyridine and acetic anhydride to obtain (2S, 4′R, 8′R)-α-tocopheryl acetate. obtained in quantitative yield. [α] ²⁰ _D = −2.25° (C = 1.1, ethanol) Example 18 Synthesis of (2R, 4′R, 8′R)-α-tocopherol 2-[(3′R, 7′R, 11′ R) ―3′, 7′, 11′, 15
′-
Tetramethyl-3′-hydroxyhexadecanyl]
The same procedure as in Example 17 was carried out using 0.6 g (0.0013 mol) of -3,5,6-trimethyl-1,4-benzoquinone, 20 ml of methanol, and 0.65 g (0.0026 mol) of d-camphorsulfonic acid. 0.52 g of the title compound is obtained. (Yield 90.3%) UV spectrum (ethanol) λmax = 292 mμ; E ¹ %cm = 69.7 [α] ²⁰ _D = -2.76° (C = 1.07, benzene) K ₃ Fe (CN) ₆ oxidation product; [α ] ²⁰ _D = +29.8° (C = 1.05, isooctane) Acetyl form: [α] ²⁰ _D = +3.49° (C = 1.1, ethanol)

Claims (1)

[Claims] 1. General formula (A in the stock means a group represented by the formula [formula] or a group represented by the formula [formula]). 2 The following general formula characterized by enantioselective oxidation of natural phytol (wherein A means a group represented by the formula [formula] or a group represented by the formula [formula]) A method for producing an optically active compound represented by the following.