JP2000143688A - Production of zeaxanthin mono-beta-glucoside - Google Patents

Abstract

PROBLEM TO BE SOLVED: To selectively obtain the subject compound by glycosylating a hydroxy-β-ionone having one hydroxyl group followed by extending the side chain of the resultant compound to form a carotenoid skeleton. SOLUTION: This compound, a zeaxanthin mono-β-glucoside, is selectively obtained by the following process: 3-hydroxy-β-ionone is reacted with a glucose derivative of formula I (X1 is a halogen; Y is an acyl) followed by reaction of the resulting compound with an imine salt of formula II to form a compound of formula III (Y1 to Y4 are each H or an acyl); subsequently e.g. a basic substance followed by a phosphonium salt I of formula IV (X2 is a halogen; Z is formyl or the like) in the presence of an alkali metal alkoxide is made to act on the compound of formula III to form a compound which, in turn, is reacted with a phosphonium salt II of formula V (X3 is a halogen) in the presence of an alkali metal alkoxide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the following formula (1), which is believed to contribute to the stabilization of living cell membranes.

[0002]

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A method for producing zeaxanthin mono-β-glucoside represented by

[0004]

2. Description of the Related Art As a method for producing zeaxanthin mono-β-glucoside, a method for producing zeaxanthin and glucose as raw materials is known [Helv. Chim.
a, 57 , 1641 (1974)].

[0005]

However, in the above-mentioned method, a compound in which both hydroxyl groups of zeaxanthin are glycosidized is by-produced, and it is difficult to selectively obtain a target monoglucoside. The present invention has been made in view of such problems of the related art, and has as its object to provide a method capable of selectively producing zeaxanthin mono-β-glucoside.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have glycosylated 3-hydroxy-β-ionone which is a compound having one hydroxyl group, The present inventors have found that a target compound can be selectively obtained by a method of forming a carotenoid skeleton by extending a side chain, and as a result of further study, the present invention has been completed.

That is, the present invention is a method for producing zeaxanthin mono-β-glucoside represented by the above formula (1), comprising the following steps 1 to 4.

Step 1: 3-hydroxy-β-ionone and the following formula (2)

[0009]

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(Wherein X ¹ represents a halogen atom and Y represents an acyl group) by reacting a glucose derivative represented by the following formula (3):

[0011]

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Wherein Y is as defined above,

Step 2: The compound of the formula (3) obtained in the step 1 is added to the compound of the following formula (4)

[0014]

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(However, when a deprotection reaction of a hydroxyl group protected with an acyl group occurs as a side reaction of the reaction, if necessary, the hydroxyl group generated by the deprotection reaction may be removed). May be protected), the following formula (5)

[0016]

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Wherein Y ¹ , Y ² , Y ³ and Y ⁴ each represent an acyl group or a hydrogen atom,

Step 3: i) When at least one of Y ¹ , Y ² , Y ³ and Y ^{4 in} the above formula (5) showing the compound obtained in step 2 is an acyl group, the formula (5) The hydroxyl group protected with an acyl group is deprotected by reacting a basic substance on the compound represented by the formula (1), and further in the presence of an alkali metal alkoxide, the following formula (6)

[0019]

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(Wherein X ² represents a halogen atom, Z represents a formyl group or a formyl group protected in an acetal form) by reacting a phosphonium salt I represented by the following formula: When Y ¹ , Y ² , Y ³ and Y ⁴ are all hydroxyl groups in the above formula (5) showing the obtained compound, the compound represented by the formula (5) is treated with the above compound in the presence of an alkali metal alkoxide. By reacting the phosphonium salt I represented by the formula (6), the following formula (7)

[0021]

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A process for producing a compound represented by the formula:

Step 4: The compound represented by the formula (7) obtained in the step 3 is added to the compound of the following formula (8) in the presence of an alkali metal alkoxide.

[0024]

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A step of producing a zeaxanthin mono-β-glucoside represented by the above formula (1) by reacting a phosphonium salt II represented by the formula (wherein X ³ represents a halogen atom).

[0026]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in the order of steps.

Step 1 In this step, 3-hydroxy-β-ionone is reacted with a glucose derivative represented by the above formula (2),
A compound represented by the above formula (3) is produced.

In the formula (2), examples of the halogen atom represented by X ¹ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In Formula (2), examples of the acyl group represented by Y include an acetyl group, a propionyl group, an isobutyryl group, an isovaleryl group, a pivaloyl group, a benzoyl group, and a 4-methylbenzoyl group. 8 or less are preferred.

On the other hand, 3-hydroxy-β-ionone, which is reacted with the glucose derivative represented by the formula (2), is a known substance, and is described, for example, in the literature [Helv. Chim. Acta., 63 , 1].
377 (1980)]. The literature [J. Chem. Soc., Perkin Trans
1, 2569 (1998)], in which the hydroxyl group is protected with a trialkylsilyl group.
It is also possible to produce β-ionone by deprotecting a trialkylsilyl group in the compound according to a conventional method (such as a method of treating with hydrogen fluoride). In addition, as 3-hydroxy-β-ionone,
(3R) -3-hydroxy-β-ionone and (3S)-
An optically active substance such as 3-hydroxy-β-ionone may be used. Hereinafter, in the present specification, the name "3-hydroxy-β-ionone" is used to include such an optically active substance.

In this step, the amount of the glucose derivative represented by the formula (2) is usually in the range of 1 to 3 mol per 1 mol of 3-hydroxy-β-ionone.

The glucose derivative represented by the formula (2) and 3
The reaction of -hydroxy-β-ionone is usually carried out in the presence of a solvent. Examples of usable solvents include, for example,
Halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform are exemplified. The amount of the solvent used is not particularly limited, but is generally 0.5 to 1000 times the weight of 3-hydroxy-β-ionone.

The glucose derivative represented by the formula (2) and 3
The reaction of -hydroxy-β-ionone is usually -30 to
The reaction is performed at a temperature of 50 ° C, preferably -20 to 20 ° C. Further, the glucose derivative represented by the formula (2) and 3-
The reaction of hydroxy-β-ionone is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

The glucose derivative represented by the formula (2) and 3
In the reaction of -hydroxy-β-ionone, by using a silver compound or a mercury compound together, the yield of the target compound can be improved and the reaction time can be shortened. Examples of the silver compound include silver chloride, silver bromide,
Silver trifluoroacetate, silver trifluoromethanesulfonate (silver triflate), and the like, and examples of mercury compounds include mercury chloride (I) and mercury chloride (I
I), mercury bromide (I), mercury iodide (I) and the like, and all of them are preferably compounds containing a halogen atom. The amount of the silver compound or the mercury compound is calculated by the formula (2)
Is preferably 1 to 4 gram equivalent to 1 mol of the glucose derivative represented by

The reaction between the glucose derivative represented by the formula (2) and 3-hydroxy-β-ionone may be carried out in the presence of various molecular sieves.

After completion of the reaction, the product represented by the formula (3) can be separated and obtained by treating the reaction mixture according to a conventional method. Examples of a method for treating the reaction mixture include a method in which water is added to the reaction mixture to obtain a liberated organic layer. At this time, for example, extraction may be carried out using a halogenated hydrocarbon solvent such as dichloromethane, dichloroethane, and chloroform; an ester solvent such as ethyl acetate. When the separation of the organic layer becomes difficult due to the insoluble matter, the insoluble matter may be separated by filtration using celite or the like. The compound represented by the formula (3) can be obtained from the thus obtained organic layer by subjecting the organic layer to a washing operation with a sodium bicarbonate solution, a saline solution or the like, if necessary, and then distilling off the solvent. it can.

The thus-obtained compound represented by the formula (3) can be used as it is as a starting material in the next step 2, but if desired, its purity can be increased by means such as silica gel column chromatography. After that, it may be used as a raw material in the next step 2.

Step 2 In this step, the compound of the formula (3) obtained in the step 1 is reacted with the imine salt of the above formula (4) to give the compound of the above formula (5) Produce compound. Here, in the formula (5) representing the product, the acyl group represented by Y ¹ , Y ² , Y ³ and Y ⁴ is, similarly to Y, an acetyl group, a propionyl group, an isobutyryl group, an isovaleryl group, a pivaloyl group Benzoyl group, 4-methylbenzoyl group and the like, and those having 8 or less carbon atoms are preferable.

The imine salt represented by the formula (4) used in this step is, for example, α-triethylsilyl-t-butylimine of acetaldehyde [ie, 2-methyl-N-
[2- (triethylsilyl) ethynylidene] -2-propanamine] was converted into n-butyllithium, s-butyllithium, and t in an ether solvent such as tetrahydrofuran.
It can be prepared by reacting with an organic lithium such as -butyllithium. At this time, the amount of the organolithium used was the same as that of α-triethylsilyl-
It is usually 1 to 1.2 mol, preferably 1 to 1.05 mol, per 1 mol of t-butylimine. The amount of the solvent used is usually 1 to 100 times the weight of α-triethylsilyl-t-butylimine of acetaldehyde. The preparation of the imine salt represented by the formula (4) generally comprises-
It is carried out at a temperature between 80 and 0 ° C. The preparation of the imine salt represented by the formula (4) is preferably performed in an atmosphere of an inert gas such as nitrogen or argon.

The amount of the imine salt represented by the formula (4) is
Usually, 0.9 to 1 mol of the compound represented by the formula (3) is used.
It is in the range of 10 moles.

The reaction between the imine salt represented by the formula (4) and the compound represented by the formula (3) is usually carried out in the presence of an ether solvent such as tetrahydrofuran. The amount of the solvent to be used is not particularly limited, but generally, the formula (3)
Is 0.5 to 1000 times the weight of the compound represented by The reaction between the imine salt represented by the formula (4) and the compound represented by the formula (3) is performed by adding the solution represented by the formula (3) to a solution of the imine salt represented by the formula (4) prepared by the above method or the like. It is preferable to carry out the method by adding a compound to be added.

The reaction between the imine salt represented by the formula (4) and the compound represented by the formula (3) is usually performed in a temperature range of -80 to 0 ° C. The reaction time is usually about 5 minutes to 5 hours. The reaction between the imine salt represented by the formula (4) and the compound represented by the formula (3) is preferably performed in an atmosphere of an inert gas such as nitrogen or argon.

After completion of the reaction, the product represented by the formula (5) can be separated and obtained by treating the reaction mixture according to a conventional method. As a method of treating the reaction mixture, for example, an aqueous solution of an organic acid such as acetic acid, oxalic acid, or citric acid is added to the reaction mixture to stop the reaction, and then an ester solvent such as ethyl acetate; an ether such as diethyl ether A method of extracting a compound represented by the formula (5) into an organic layer using an organic solvent such as an aromatic hydrocarbon solvent such as benzene and toluene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform. Can be From the organic layer thus obtained, if necessary, after performing a washing operation with a sodium bicarbonate solution, a saline solution, or the like,
By distilling off the organic solvent, the compound represented by the formula (5) can be obtained.

The thus-obtained compound represented by the formula (5) can be used as it is as a starting material in the next step 3, but if desired, its purity can be increased by means such as silica gel column chromatography. After that, it may be used as a raw material in the next step 3.

In this step, at least a part of the protected hydroxyl group contained in the glucoside moiety may be hydrolyzed to form a hydroxyl group. In this case,
If necessary, the hydroxyl group can be re-esterified according to a conventional method. Examples of the esterification method include a method in which an acid halide such as benzoyl chloride, acetyl chloride, or acetyl bromide is reacted in the presence of a basic substance such as pyridine or triethylamine.

Step 3 In this step, i) when at least one of Y ¹ , Y ² , Y ³ and Y ^{4 in} the above formula (5) representing the compound obtained in step 2 is an acyl group, A hydroxyl group protected by an acyl group is deprotected by reacting a compound represented by (5) with a basic substance, and a phosphonium salt I represented by the above formula (6) is further reacted in the presence of an alkali metal alkoxide. And ii) when Y ¹ , Y ² , Y ³ and Y ^{4 in the} above formula (5) showing the compound obtained in step 2 are all hydroxyl groups, they are represented by the formula (5) In the presence of an alkali metal alkoxide in the compound, the phosphonium salt I represented by the above formula (6)
To produce the compound represented by the above formula (7).

In this step, an alkali metal alkoxide can be used as a basic substance for deprotection of the hydroxyl group. In this case, the deprotection of the hydroxyl group and the reaction with the phosphonium salt I can be carried out simultaneously. It is possible.

Hereinafter, a method of performing a reaction with phosphonium salt I after deprotection of a hydroxyl group will be described. In the deprotection of the hydroxyl group of the compound represented by the formula (5) (hereinafter abbreviated as “deprotection reaction”), examples of the basic substance to be used include sodium methoxide, sodium ethoxide, sodium t-butoxide, Alkali metal alkoxides such as potassium methoxide, potassium ethoxide and potassium t-butoxide; hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; and alkali metal carbonates such as sodium carbonate and potassium carbonate. . The amount of the basic substance to be used is generally 0.01 to 20 mol, preferably 0.1 to 15 mol, per 1 mol of the compound represented by the formula (5).

The deprotection reaction is usually performed in the presence of a solvent. Examples of usable solvents include, for example, methanol,
Alcohols such as ethanol, 1-propanol, 2-propanol, butanol, 2-butanol and t-butanol; and ethers such as tetrahydrofuran and diethyl ether. The amount of the solvent to be used is not particularly limited, but is generally 0.5 to 1000 times the weight of the compound represented by the formula (5).

The deprotection reaction is usually carried out at a temperature of 0 to 100 ° C., preferably 10 to 30 ° C. The reaction time is usually about 10 minutes to 5 hours. The deprotection reaction is preferably performed in an atmosphere of an inert gas such as nitrogen or argon.

The compound obtained by the deprotection reaction (hereinafter abbreviated as "deprotected compound") can be separated and obtained by treating the reaction mixture according to a conventional method. As a method for treating the reaction mixture, for example, 1 to 10 times the weight of the acidic ion exchange resin with respect to the compound represented by the formula (5) used in the reaction is added to the reaction mixture,
After stirring at 50 ° C. for about 5 minutes to 2 hours, a solid substance is separated by a method such as filtration, and the obtained filtrate is concentrated to obtain a deprotected product. The thus-obtained deprotected product can be used for the reaction with the phosphonium salt I as it is. If desired, the purity of the deprotected product is increased by means such as silica gel column chromatography, and then the reaction with the phosphonium salt I is carried out. May be used.

In the formula (6) representing the phosphonium salt I to be reacted with the deprotected product, examples of the halogen atom represented by X ² include a chlorine atom, a bromine atom and an iodine atom. In the formula, when Z represents a formyl group protected in an acetal form, Z is represented by the formula —CH (O
R) _{2 wherein} R represents an alkyl group. Here, examples of the hydrocarbon group represented by R include a methyl group, an ethyl group, and an isopropyl group, and those having 6 or less carbon atoms are preferable.

Among the phosphonium salts I, the compounds corresponding to the case where Z in the formula (6) is a formyl group are prepared according to the method described in the literature [see Helv. CHim. Acta., 63 , 1473 (1980)]. be able to. Further, among the phosphonium salts I, the compound corresponding to the case where Z is a formyl group protected in an acetal form in the formula (6) is a compound corresponding to the case where Z is a formyl group in the above formula (6). Can be prepared by acetalizing the formyl group of the formula (1) according to a conventional method. As a method of acetalization, in an alcohol such as methanol or ethanol, in the presence of p-toluenesulfonic acid and phosphoric acid,
A method of reacting trimethyl orthoformate, triethyl orthoformate, or the like can be used. As the phosphonium salt I, a compound corresponding to the case where Z is a formyl group protected in an acetal form in the formula (6) may be used from the viewpoint of the yield of the compound represented by the formula (7). preferable.

The amount of the phosphonium salt I to be used is, when converted to the compound of the formula (5), which is a precursor of the deprotected product, usually 0.1 mol per mol of the compound of the formula (5).
The range is 8 to 10 mol, preferably 1 to 10 mol.

As the alkali metal alkoxide used in the reaction with the phosphonium salt I, the same ones as those exemplified in the above deprotection reaction can be exemplified. The amount of the alkali metal alkoxide used is expressed by the formula (6)
With respect to 1 mol of the phosphonium salt I represented by
The range is 1 to 3 mol, preferably 1 to 1.5 mol.

The reaction between the deprotected product and the phosphonium salt I represented by the formula (6) is usually carried out in the presence of a solvent. Examples of usable solvents include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, 2-butanol and t-butanol;
Examples thereof include ethers such as tetrahydrofuran and diethyl ether. The amount of the solvent used is not particularly limited, but is generally 0.5 to 1000 times the weight of the phosphonium salt I represented by the formula (6).

The reaction between the deprotected compound and the phosphonium salt I represented by the formula (6) is preferably carried out by adding the deprotected compound and an alkali metal alkoxide to the phosphonium salt I solution. When a compound in which Z in the formula (6) is a formyl group protected in an acetal form is used as the phosphonium salt I represented by the formula (6), the acid used to protect the formyl group in the acetal form is used. Before the addition of the deprotected product and the alkali metal alkoxide, it is desirable to add the alkali metal alkoxide to such an extent that the remaining acid can be neutralized.

The reaction between the deprotected product and the phosphonium salt I represented by the formula (6) is usually carried out at a temperature in the range of -10 to 20 ° C for about 10 minutes to 1 hour. Thereafter, in order to complete the reaction, it is preferable to raise the temperature of the reaction mixture to 20 to 50 ° C. and stir for about 10 minutes to 5 hours. The reaction between the deprotected product and the phosphonium salt I is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

After completion of the reaction, the product represented by the formula (7) can be separated and obtained by treating the reaction mixture according to a conventional method. As a method for treating the reaction mixture, for example, an acidic ion exchange resin 1 to 100 times the weight of the alkali metal alkoxide used for the reaction is added to the reaction mixture, and the mixture is stirred at 10 to 50 ° C. for about 5 minutes to 2 hours, A method of obtaining a compound represented by the formula (7) by separating a solid substance by a method such as filtration and concentrating the obtained filtrate.

The thus-obtained compound represented by the formula (7) can be used as it is as a starting material in the following step 4, but if desired, its purity can be increased by means such as silica gel column chromatography. After that, it may be used as a raw material in step 4.

In the present step, when Y ¹ , Y ² , Y ³ and Y ⁴ are all hydroxyl groups in the above formula (5) showing the compound obtained in the step 2, it is represented by the formula (5) The compound represented by the above formula (7) is produced by reacting the phosphonium salt I represented by the above formula (6) on the compound to be produced in the presence of an alkali metal alkoxide.
In this case, the "deprotected body" in the above description is replaced with the formula (5)
And the reaction conditions, separation and acquisition of products, and the like are the same as those described above.

Step 4 In this step, the compound represented by the formula (7) obtained in the step 3 is reacted with the phosphonium salt II represented by the above formula (8) in the presence of an alkali metal alkoxide to give the compound The zeaxanthin mono-β-glucoside represented by the formula (1) is produced.

The phosphonium salt I used in this step
In the formula (8) representing I, examples of the halogen atom represented by X ³ include a chlorine atom, a bromine atom, and an iodine atom.

The phosphonium salt II is described, for example, in the literature [He
lv. Chim. Acta., 63 , 1377 (1980)] and the like. Phosphonium salt I
The amount of I to be used is generally 0.8-5 mol, preferably 2-5 mol, per 1 mol of the compound represented by the formula (7).

As the alkali metal alkoxide used in the reaction between the compound represented by the formula (7) and the phosphonium salt II represented by the formula (8), those similar to those exemplified in the description of the step 3 are exemplified. Can be. The amount of the alkali metal alkoxide to be used is generally 1 to 4 mol, preferably 1 to 2 mol, per 1 mol of the phosphonium salt II represented by the formula (8).

The reaction between the compound represented by the formula (7) and the phosphonium salt II represented by the formula (8) is usually carried out in the presence of a solvent. Usable solvents include, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, 2-butanol and t-butanol; ethers such as tetrahydrofuran and diethyl ether; halogenation such as dichloromethane and chloroform. Hydrocarbons and the like. The amount of the solvent to be used is not particularly limited, but generally, the formula (8)
With respect to the phosphonium salt II represented by
It is 0 times the weight.

The reaction between the compound represented by the formula (7) and the phosphonium salt II represented by the formula (8) is performed by adding the compound represented by the formula (7) and an alkali metal alkoxide to a solution of the phosphonium salt II. It is preferable to carry out this method.

The reaction between the compound represented by the formula (7) and the phosphonium salt II represented by the formula (8) is usually carried out in the range of -10 to
It is carried out at a temperature in the range of 5 ° C. for about 10 minutes to 1 hour. Thereafter, the temperature of the reaction mixture was raised to 1 to complete the reaction.
It is preferable to raise the temperature to 0 to 50 ° C and stir for about 10 minutes to 7 hours. The reaction between the compound represented by the formula (7) and the phosphonium salt II represented by the formula (8) is preferably performed in an atmosphere of an inert gas such as nitrogen or argon.

After completion of the reaction, the product, zeaxanthin mono-β-glucoside, can be separated and obtained by treating the reaction mixture according to a conventional method. As a method for treating the reaction mixture, for example, an acidic ion exchange resin 1 to 100 times the weight of the alkali metal alkoxide used for the reaction is added to the reaction mixture, and the mixture is stirred at 10 to 50 ° C. for about 5 minutes to 2 hours, A method of obtaining a zeaxanthin mono-β-glucoside by separating a solid substance by a method such as filtration and concentrating the obtained filtrate.

The zeaxanthin mono-β-glucoside thus obtained can be further purified, if desired, by means such as silica gel column chromatography.

[0070]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 Step 1 2,3,4,6-
8.08 g (12.26 mmol) of tetra-O-benzoyl-α-D-glucopyranosyl bromide and (3
R) -3-hydroxy-β-ionone 1.50 g (7.
21 mmol) in 75 ml of sufficiently dried 1,2-dichloroethane, 25 g of Molecular Sieves 4A was added under a nitrogen atmosphere, and silver triflate was added to the obtained mixture under ice-cooling. 70g (1
(4.4 mmol), and the mixture was stirred under ice cooling for 2 hours. The resulting reaction mixture was diluted with ethyl acetate and filtered using celite. The obtained filtrate was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and then the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography [developing solvent: a mixed solvent of methylene chloride, n-hexane and diethyl ether (volume ratio; methylene chloride: n-hexane: diethyl ether = 5: 4: 0.
7)] to give (3R) -3- (2,3,4,6-
3.74 g (yield: 66%) of tetra-O-benzoyl-β-D-glucopyranosyloxy) -β-ionone was obtained as a colorless foam.

The physical properties of the obtained compound are shown below. IR ν _max (cm ⁻¹ ): 1732, 1668, 1603 ¹ H-NMR δ (ppm, CDCl ₃ , 300 MHz): 0.99
(3H, s; 1-gem-Me), 1.00 (3H,
s; 1-gem-Me), 1.56 (1H, t, J = 1)
2 Hz; 2ax-H), 1.58 (3H, s; 5-M)
e) 1.88 (1H, ddd, J = 12 Hz, 3.5)
Hz, 2 Hz; 2 eq-H), 2.00 (1 H, br)
dd, J = 17.5 Hz, 9 Hz; 4ax-H);
25 (3H, s; COMe), 2.29 (1H; 4 eq)
-H), 4.03 (1H, m; 3-H), 4.21 (1
H, m; 5'-H), 4.53 (1H, dd, J = 12)
Hz, 6 Hz; 6'-H), 4.64 (1H, dd, J)
= 12 Hz, 3 Hz; 6'-H), 4.99 (1H,
d, J = 8 Hz; 1′-H), 5.52 (1H, dd,
J = 10 Hz, 8 Hz; 2′-H), 5.64 (1H,
t, J = 10 Hz; 4′-H), 5.93 (1H, t,
J = 10 Hz; 3′-H), 6.00 (1H, d, J =
16.5 Hz; 8-H), 7.11 (1H, br d,
J = 16.5 Hz; 7-H), 7.2-8.1 (20
H, m; Ar-H) high-resolution mass spectrum measurement value: [M + Na] ⁺ 809.295 calculated value: (C ₄₇ H ₄₆ O ₁₁ Na) m / z: 809.29
4

Step 2 In a 200 ml three-necked flask, 2-methyl-N-
A solution obtained by dissolving [2- (triethylsilyl) ethynylidene] -2-propanamine (21.5 mmol) in 30 ml of sufficiently dried tetrahydrofuran was charged,
Under a nitrogen atmosphere, at −78 ° C., 22.4 ml of a solution (concentration: 0.97 M) of s-butyllithium dissolved in a mixed solvent of cyclohexane and hexane (21.7 mmol as s-butyllithium) was added dropwise. . After stirring the obtained mixture at -78 ° C for 20 minutes, the mixture was stirred at the same temperature for step 1
(3R) -3- (2,3,4,6-tetra-
O-benzoyl-β-D-glucopyranosyloxy)-
A solution of 2.11 g (2.68 mmol) of β-ionone dissolved in 20 ml of sufficiently dried tetrahydrofuran was added dropwise, and the resulting mixture was stirred at the same temperature for 20 minutes. A saturated oxalic acid aqueous solution was added to the obtained reaction mixture to make it acidic, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained residue is pyridine 25
and benzoyl chloride (6 ml) was added thereto.
Stirred for hours. The obtained reaction mixture was diluted with ethyl acetate, washed successively with 5% hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue is purified by silica gel column chromatography [developing solvent: a mixed solvent of methylene chloride, n-hexane and diethyl ether (volume ratio; methylene chloride: n-hexane: diethyl ether = 5: 4: 1)]. 1.65 g (yield: 76%) of (3R) -3- (2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyloxy) -β-ionylideneacetaldehyde was pale yellow. Obtained as a foam. As a result of ¹ H-NMR analysis, the obtained compound was a mixture of compounds in which the configuration of the double bond at the α-position of the aldehyde was cis-form and trans-form (ratio: cis-form / trans-form = 55/1). I found it.

The physical properties of the obtained compound are shown below. UV λ _max (nm, solvent: ethanol): 230, 273,
317 IR ν _max (cm ⁻¹ ): 1735, 1657, 1603 ¹ H-NMR (trans form) δ (ppm, CDCl ₃ , 300 MHz): 0.98
(6H, s; 1-gem-Me), 1.57 (3H,
s; 5-Me), 4.03 (1H, m; 3-H);
20 (1H, m; 5'-H), 4.52 (1H, dd,
J = 12 Hz, 6 Hz; 6′-H), 4.64 (1H,
dd, J = 12 Hz, 3.5 Hz; 6'-H), 4.9
9 (1H, d, J = 8 Hz; 1′-H), 5.51 (1
H, dd, J = 10 Hz, 8 Hz; 2'-H), 5.6
3 (1H, t, J = 10 Hz; 4'-H), 5.90
(1H, brd, J = 8 Hz; 10-H), 5.92
(1H, t, J = 10 Hz; 3'-H), 6.09 (1
H, d, J = 16.5 Hz; 8-H), 6.58 (1
H, br d, J = 16 Hz; 7-H), 7.25-
8.04 (20H, m; Ar-H), 10.12 (1
H, d, J = 8 Hz; CHO) ¹ H-NMR (cis form) δ (ppm, CDCl ₃ , 300 MHz): 2.09
(S, 9-Me), 5.87 (br d, J = 8 Hz);
10-H), 6.48 (br d, J = 16 Hz; 7-
H), 6.98 (d, J = 16 Hz; 8-H), 10.
10 (d, J = 8 Hz; CHO)

Step 3 (a) Deprotection Reaction The (3R) -3- (2,3,4,6-tetra-O-benzoyl-β-D-glucose obtained in Step 2 was placed in a 200 ml three-necked flask. A solution obtained by dissolving 923 mg (1.14 mmol) of pyranosyloxy) -β-ionylideneacetaldehyde in 50 ml of methanol was charged, and 1.5 ml of a methanol solution of sodium methoxide (concentration: 1 N) (nitrogen atmosphere) was added under a nitrogen atmosphere. (1.5 mmol as methoxide) and stirred at room temperature for 2 hours. A cation exchange resin [Dowe] is added to the obtained reaction mixture.
x (registered trademark) 50W (H type)], and the mixture was stirred at room temperature for 30 minutes. The obtained filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography [developing solvent: a mixed solvent of methylene chloride and methanol (volume ratio; methylene chloride: methanol =
9: 1)] to give (3R) -3- (β-D-glucopyranosyloxy) -β-ionylideneacetaldehyde (420 mg, yield 93%) as a pale yellow foam. .

The physical properties of the obtained compound are shown below. UV λ _max (nm, solvent: ethanol): 231, 275,
316 IR ν _max (cm ⁻¹ ): 3407, 1660, 1609 ¹ H-NMR δ (ppm, CDCl ₃ , 300 MHz): 1.07
(6H, s; 1-gem-Me), 1.71 (s ,; E
-5-Me), 1.74 (s; Z-5-Me), 2.1
1 (s, Z-9-Me), 2.30 (s; E-9-M
e) 3.37 (1H, m; 5'-H), 3.46 (1
H, br t-like, J = 7.5 hz; 2′-
H), 3.61 (1H, brt, J = 9 Hz; 4'-
H), 3.71 (1H, t, J = 9 Hz; 3'-H),
3.82-3.95 (2H, m; 6'-H2), 4.0
5 (1H, m; 3-H), 4.51 (1H, br d,
J = 7.5 Hz; 1′-H), 5.89 (brd, J
= 8 Hz; Z-10-H), 5.91 (br d, J =
8 Hz; E-10-H), 6.16 (d, J = 16H)
z; E-8-H), 6.53 (br d, J = 16H)
z; Z-7-H), 6.63 (br d, J = 16H)
z; E-7-H), 7.07 (d, J = 16 Hz; Z-
8-H), 10.10 (d, J = 8 Hz; Z-CH)
O) 10.12 (d, J = 8 Hz; E-CHO)

(B) Reaction with phosphonium salt I In a 200 ml three-necked flask, (2,7-dimethyl-8-oxo-2,4,6-octatrienyl) triphenylphosphonium chloride (790 mg, 1.77 mmol) ) And 0.8 ml of trimethyl orthoformate
Is dissolved in 5 ml of a methanol solution.
Under a nitrogen atmosphere, 0.8 ml of a solution prepared by dissolving 500 mg of p-toluenesulfonic acid and 725 mg of phosphoric acid in 37.5 ml of methanol was added, and the mixture was stirred at room temperature for 2 hours (8,8-dimethoxy-2,7-). Dimethyl-2,4,6
A solution of (octatrienyl) triphenylphosphonium chloride in methanol was prepared. The resulting solution was added to a methanol solution of sodium methoxide (concentration: 1) under ice-cooling.
N) was added until just before the reaction mixture turned red due to the formation of the ylide, and to the resulting mixture the (3R) -3- (β-D-glucopyranosyloxy) obtained in (a) above.
140 mg of β-ionylideneacetaldehyde (0.
35 mmol) in 4 ml of methylene chloride and 2.0 ml of sodium methoxide in methanol (concentration: 1N) (2.0 mmol as sodium methoxide) were added. The resulting mixture was stirred for 30 minutes under ice-cooling, and further heated to room temperature and stirred for 30 minutes. To the obtained reaction mixture, 4 g of a cation exchange resin [Dowex (registered trademark) 50W (H type)] was added, and the mixture was stirred at room temperature for 15 minutes. The obtained filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography [developing solvent: a mixed solvent of methylene chloride, diethyl ether and methanol (volume ratio; methylene chloride: diethyl ether: methanol = 5: 4: 1)] and purified by (3R) -3- (β-D-glucopyranosyloxy) -12′-apo-β-carotene-12′-all 1
28 mg (yield: 69%) were obtained as an orange foam.

The physical properties of the obtained compound are shown below. UV λ _max (nm, solvent: ethanol): 423 IR ν _max (cm ⁻¹ ): 3408, 1660, 1610, ¹
548 high-resolution mass spectrum measurement value: [M] ⁺ 528.308 calculated value: (C ₃₁ H ₄₄ O ₇ ) m / z: 528.309

Step 4 In a three-necked flask having an inner volume of 200 ml, (3-hydroxy-
383 mg (0.68 mmol) of (β-ionylideneethyl) triphenylphosphonium chloride and (3R) -3- (β-D-glucopyranosyloxy) -12′-apo-β-carotene obtained in Step 3 120 mg (0.23 mmol) of -12'-all was added to 5 ml of methylene chloride.
And a solution of sodium methoxide in methanol (concentration: 1N) 1.0 m under a nitrogen atmosphere.
1 (1.0 mmol as sodium methoxide) was added, and the resulting mixture was stirred under ice-cooling for 30 minutes and further at room temperature for 3 hours. The obtained mixture is mixed with 10 m of methanol.
l and a cation exchange resin [Dowex (registered trademark)
50W (H type)], and the mixture was stirred at room temperature for 30 minutes. The obtained filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography [developing solvent: a mixed solvent of methylene chloride, diethyl ether and methanol (volume ratio; methylene chloride: diethyl ether: methanol = 4: 5: 1)], followed by high performance liquid chromatography [stationary phase: CHEMCOSO
RB 7-ODS-H (trade name), column diameter: 1.0
mobile column: mixed solvent of methanol and water (volume ratio; methanol: water = 96: 4); detection wavelength: 400 nm] to separate zeaxanthin mono-β-glucoside 71 mg. (Yield: 43%) was obtained as a red solid.

The physical properties of the obtained compound are shown below. UV λ _max (nm, solvent: ethanol): 277, 427 (s
_{houlder), 450,476 λ max (nm} , solvent: acetone): 427 (shoulde
r), 453, 479 ¹ H-NMR δ (ppm, mixed solvent of CDCl ₃ and CD ₃ OD, 300
MHz): 1.08 (12H, s; 1,1'-gem-)
Me), 1.46 (1H, t, J = 12 Hz; 2'ax
-H), 1.57 (1H, t, J = 11.5 Hz; 2a)
xH), 1.74 (6H, s; 5,5'-Me), about 1.76 (2'eq-H), about 1.85 (2eq-H).
H), 1.97 and 1.98 (6H, s each; 9,
9 ', 13, 13'-Me), 2.04 (1H, br
dd, J = 17 Hz, 8 Hz; 4'ax-H), 2.1
1 (1H, br dd, J = 17 Hz, 9.5 Hz; 4
ax-H), 2.36 (1H, br dd, J = 17H
z, 4.5 Hz; 4'eq-H), 2.46 (1H, b
r dd, J = 17 Hz, 5 Hz; 4 eq-H);
26 (1H, dd, J = 9 Hz, 8 Hz; 2 ″ -H),
3.32 (1H, m; 5 "-H), 3.43-3.50
(2H, m; 3 ", 4" -H), 3.79 (1H, d
d, J = 12 Hz, 4.5 Hz; 6 ″ -H), 3.87
(1H, dd, J = 12 Hz, 3 Hz; 6 ″ -H),
3.96 (1H, m; 3′-H), 4.08 (1H,
m; 3-H), 4.47 (1H, d, J = 8 Hz; 1 "
-H), 6.05-6.16 (4H, m; 7, 7 ',
8,8'-H), 6.16 (2H, br d, J = 1)
1.5 Hz; 10, 10'-H) 6.26 (2H, d, J = 9.5 Hz; 14, 14'-H)
H), 6.37 (2H, d, J = 15 Hz; 12,1)
2′-H), 6.59-6.70 (4H, m; 11, 1)
1 ′, 15,15′-H) High-resolution mass spectrum measurement value: [M] ⁺ 730.480 Calculated value: (C ₄₆ H ₆₆ O ₇ ) m / z: 730.480

[0081]

According to the production method of the present invention, zeaxanthin mono-β-glucoside can be selectively obtained.

Claims (1)

[Claims] 1. The following formula (1) comprising the following steps 1 to 4: A method for producing zeaxanthin mono-β-glucoside represented by the formula: Step 1: 3-hydroxy-β-ionone and the following formula (2) (Wherein X ¹ represents a halogen atom and Y represents an acyl group) by reacting with a glucose derivative represented by the following formula (3): Wherein Y is as defined above; Step 2: adding the compound represented by the formula (3) obtained in the step 1 to the compound represented by the following formula (4) ] (However, when a deprotection reaction of a hydroxyl group protected by an acyl group occurs as a side reaction of the reaction, if necessary, the hydroxyl group generated by the deprotection reaction is protected. By the following formula (5): (Wherein Y ¹ , Y ² , Y ³ and Y ⁴ each represent an acyl group or a hydrogen atom). Step 3: i) The above showing the compound obtained in Step 2 In the formula (5), at least one of Y ¹ , Y ² , Y ³ and Y ⁴
When one is an acyl group, a hydroxyl group protected with an acyl group is deprotected by reacting a compound represented by the formula (5) with a basic substance, and further, in the presence of an alkali metal alkoxide, a compound represented by the following formula (6) ) (Wherein X ² represents a halogen atom, Z represents a formyl group or a formyl group protected in an acetal form), and ii) obtained in step 2 When Y ¹ , Y ² , Y ³ and Y ⁴ are all hydroxyl groups in the above formula (5) representing a compound, the compound represented by the above formula (6) is added to the compound represented by the formula (5) in the presence of an alkali metal alkoxide. )) To give the following formula (7): Step 4: producing a compound represented by the formula: Step 4: adding the compound represented by the formula (7) obtained in the step 3 to the compound represented by the following formula (8) in the presence of an alkali metal alkoxide: (Wherein X ³ represents a halogen atom) to produce a zeaxanthin mono-β-glucoside represented by the above formula (1) by acting a phosphonium salt II represented by the following formula (1).