JP6558968B2 - Oligomer containing epicatechin and method for producing the same - Google Patents

Description

  The present invention relates to a simple method for producing an oligomer containing epicatechin. More specifically, the present invention relates to a simple method for producing an epicatechin-containing heterogas oligomer partially containing catechin.

Compounds in which two or more flavonoids such as catechin or epicatechin are polymerized are collectively called procyanidins, and have antioxidant, antiviral, antibacterial, antitumor, arteriosclerosis, gastric ulcer, carcinogenesis, It has physiological effects such as hair growth activity and whitening, and is widely used as a material for health foods and cosmetics.
As procyanidins, procyanidin B1 having the structure of epicatechin- (β4 → 8) -catechin, procyanidin B2 having the structure of epicatechin- (β4 → 8) -epicatechin, and the structure of catechin- (α4 → 8) -catechin Procyanidin B3 having a structure, procyanidin B4 having a structure of catechin- (α4 → 8) -epicatechin, procyanidin B5 having a structure of epicatechin- (β4 → 6) -epicatechin, and the like are known.
In addition, due to the recent increase in health-oriented and natural-oriented, various researches on naturally-derived physiologically active substances have been promoted. For example, peanut flavonoids and polyphenols include vitamin C and antioxidant BHA. It has been confirmed that it exhibits the same level of antioxidant effect.
The polyphenol contained in the red beans has been confirmed to be proanthocyanidins. Moreover, although there is little data regarding a specific structure, it has been confirmed that it is an oligomer mainly composed of epicatechin, of which a heterogas oligomer containing one molecule of catechin.

Procyanidins have physiological activity that is not found in catechin or epicatechin monomers, and it is expected that the higher the oligomer is, the stronger the physiological activity is. For this reason, several methods have been proposed so far for producing procyanidins from flavonoids such as catechins (for example, see Non-Patent Documents 1 and 2).
In Non-Patent Document 1, catechin is converted into two reactive derivatives of an electrophile and a nucleophile by a known method, and titanium tetrachloride is used as a catalyst under low temperature conditions (for example, −20 ° C.). A method for optically and selectively obtaining a procyanidin B3 derivative from a dimer mixture obtained by reacting 1 to 4.5 equivalents is disclosed.
Non-Patent Document 2 also discloses a method of optically selecting a dimer derivative by reacting two reactive derivatives similarly converted from catechins in a two-to-one manner using titanium tetrachloride as a catalyst. Is disclosed.

  However, the method for producing a catechin or epicatechin polymer disclosed in Non-Patent Documents 1 and 2 includes, for example, the problem of economic loss due to the large excess of one of the production raw materials, There is a problem that the efficiency is remarkably inferior due to, for example, a complicated purification operation due to the residue. Moreover, for example, the reaction under a low temperature condition (for example, −20 ° C.) is essential, and there is a defect that equipment for maintaining the low temperature is required, and that the optical purity of the obtained product is low. Because of these problems, these synthetic reactions are hardly used industrially.

JP 2007-84536 A

A. Saito et al., Tetrahedron, 2002, 58, 7829-7837 A. Saito et al., Tetrahedron, 2003, 44, 5449-5452

  As described above, procyanidin is a component that is abundant in plants, but its structure is complex and chemically unstable, and thus it has been difficult to obtain a highly pure compound. In particular, the more the polymer was, the more difficult it was to produce.

As a result of studies conducted by the present inventors to solve the above-mentioned problems, a step of preparing a reactive derivative of two types of catechin or epicatechin, electrophile and nucleophile, derived from catechin or epicatechin; As catalysts, ytterbium triflate (Yb (CF ₃ SO ₃ ) ₃ ), indium triflate (In (CF ₃ SO ₃ ) ₃ ), copper triflate (Cu (CF ₃ SO ₃ ) ₂ ), lanthanum triflate (La (CF ₃ SO ₃ )) ₃ ) ₃ ) or metal triflates such as scandium triflate (Sc (CF ₃ SO ₃ ) ₃ ), silver tetrafluoride silver (AgBF ₄ ) or tris (pentafluorophenyl) boron (B (C ₆ F ₅ ) ₃ ) A step of reacting with a boron compound of It was found that it is possible to synthesize catechin or epicatechin dimers such as bleeding B1 to B4 (see Patent Document 1).
The “metal triflate” is a salt of trifluoromethanesulfonic acid and a metal, and (CF ₃ SO ₃ ) in the above formula is sometimes referred to as “OTf”.

In the production method described in Patent Document 1, a metal triflate, preferably ytterbium triflate (Yb (OTf) ₃ ), indium triflate (In (OTf) ₃ ), copper triflate (Cu (OTf) ₂ ), lanthanum, is used as a reaction catalyst. Triflate (La (OTf) ₃ ) or scandium triflate (Sc (OTf) ₃ ) or a boron compound, preferably silver tetrafluoride silver boron (AgBF ₄ ) or tris (pentafluorophenyl) boron (B (C ₆ F ₅ ) _In the presence of ₃ ), an electrophile and a nucleophilic catechin or epicatechin monomer reactive derivative are reacted to produce a catechin or epicatechin dimer.

The present inventors use metal triflate, silver tetrafluoride silver (AgBF ₄ ) or tris (pentafluorophenyl) boron (B (C ₆ F ₅ ) ₃ ) according to the production method described in Patent Document 1. Attempts were made to produce catechins or epicatechin tetra-hexamers, but they could not be produced in the desired yield and purity.

On the other hand, various research results on naturally-derived physiologically active substances have been reported due to the recent increase in health and natural orientation. For example, it has been reported that red beans flavonoids and polyphenols exhibit the same level of antioxidant activity as vitamin C and antioxidant BHA.
In addition, it has been confirmed that one type of polyphenol contained in red beans is proanthocyanidins mainly composed of epicatechin, of which one molecule of catechin is contained.
However, the catechin or epicatechin polymer whose production has been reported so far has centered on homologous oligomers of only catechin or epicatechin. Therefore, the production method is not limited to homologous oligomers, and a production method capable of efficiently producing heterogas oligomers such as proanthocyanidins has been demanded.

As described above, red beans contain components that exhibit useful physiological activity, but red beans are only used as raw materials for processed products such as Japanese confectionery and boiled beans, and are mostly used for other processed products. Absent. For this reason, there has been a demand for expansion of new applications focusing on physiologically active substances contained in red beans.
However, it was difficult to produce a preparation for confirming physiological activity, and research on physiological activity could not be advanced.

  In view of the above, an object of the present invention is to provide a synthesis method capable of easily producing a heterogas oligomer as contained in red beans. Moreover, it aims at expanding the new use which paid its attention to the physiological activity of a red bean by elucidating the physiological activity of the oligomer obtained by this manufacturing method.

The present invention relates to the following contents.
(1) The following general formula (I)
(In general formula (I), R _{1 to} R ₈ each independently represents an arbitrary protecting group selected from groups used as protecting groups for phenolic hydroxyl groups, and X _{1 to} X ₂ are: Each independently represents any protecting group selected from the groups used as protecting groups for alcoholic hydroxyl groups, and Y represents a leaving group),
The following general formula (II)
(In the general formula (II), R _{9 to} R ₁₆ each independently represents an arbitrary protecting group selected from groups used as protecting groups for phenolic hydroxyl groups, and n is 0 or 1 or more. Each of the bonds represented by the wavy line represents an integer of 10 or less, and represents a wedge-shaped connection with a solid line or a broken line, provided that all of the bonds represented by the wavy line are broken-line wedge-shaped connections. Note that when n is 2 or more, the contents of R _{13 to} R ₁₆ and the bond represented by the wavy line, which are present in the repeated structure in parentheses, may be the same or different. A step of condensing the compound represented by
The following general formula (III)
(In General Formula (III), the bond represented by R _{1 to} R ₁₆ , X _{1 to} X ₂ , n, and the wavy line has the same meaning as described above.).
(2) The production method according to (1), wherein R _{1 to} R ₁₆ are each independently an aromatic hydrocarbon group or an aliphatic hydrocarbon group.
(3) X ₁ and X ₂ are each independently an acyl group, a substituted acyl group, a benzyl group, a substituted benzyl group, an alkyl group, an arylalkyl group or a substituted arylalkyl group, (1) or (2) The manufacturing method as described in.
(4) The production method according to any one of (1) to (3), wherein Y is an alkyloxy group, an alkyloxyalkyloxy group, or an arylalkyloxy group.
(5) The production method according to any one of (1) to (4), wherein the condensation is performed in the presence of a Lewis acid.
(6) The production method according to (5), wherein the condensation is performed at 0 ° C. or higher and 23 ° C. or lower.
(7) The following general formula (III) obtained by the production method according to any one of (1) to (6)
(In the general formula (III), R _{1 to} R ₁₆ , X _{1 to} X ₂ , n and the bond represented by the wavy line have the same meaning as described above.)
(8) R _{1 to} R ₁₆ and X _{1 to} X ₂ of the compound represented by the general formula (III) obtained by the production method according to any one of (1) to (6) A further reaction for deprotecting the protecting group is carried out. The following general formula (IV)
(In general formula (IV), the bond represented by n and a wavy line has the same meaning as the above.) The manufacturing method of the compound represented by this.
(9) Obtained by the production method described in (8), the following general formula (IV)
(In general formula (IV), the bond represented by n and a wavy line has the same meaning as the above.).

According to the production method of the present invention, an oligomer containing epicatechin can be produced easily. Furthermore, epicatechin-containing heterogas oligomers containing catechin in part can also be easily produced.
The catechin-containing heterogas oligomer partially obtained by the production method of the present invention, like conventional procyanidins, has an antioxidant action, an antiviral action, an antibacterial action, an antitumor action, and an arteriosclerosis inhibiting action. It is expected to exhibit physiological actions such as gastric ulcer inhibitory action, carcinogenesis inhibitory action, hair growth active action, and whitening action, and is useful as a material for health foods and cosmetics.

FIG. 1 is a diagram showing the mechanism of the condensation reaction. FIG. 2 is a structural formula of Arecatannin A2 and Arecatannin A3. FIG. 3 is a reaction formula of epicatechin dimer according to Preparation Example 1. FIG. 4 is a reaction formula of a catechin trimer according to Preparation Example 2. FIG. 5 is a reaction formula of arecatannin A2 according to Example 1. FIG. 6 is a reaction formula of arecatannin A3 according to Example 2. FIG. 7 is a reaction formula of arecatannin A2 according to Comparative Example 1. FIG. 8 shows the results of HPLC observation of the water extract of red beans at room temperature.

Hereinafter, the present invention will be described with reference to embodiments, but the present invention is not limited to the following embodiments.
[Production method]
Embodiments of the present invention include, for example, general formula (III)
(In General Formula (III), R _{1 to} R ₁₆ each independently represents an arbitrary protecting group selected from groups used as protecting groups for phenolic hydroxyl groups, and X _{1 to} X ₂ are: Each independently represents any protecting group selected from the groups used as protecting groups for alcoholic hydroxyl groups, and n is an integer of 0 or 1 or more and 10 or less, which is the number of repetitions of the structure in parentheses. Each of the couplings represented by a wavy line independently represents a wedge-shaped coupling with a solid line or a broken line, except that all the couplings represented by a wavy line are a wedge-shaped coupling with a broken line. When n is 2 or more, a plurality of R _{13 to} R ₁₆ present in the repeated structure in parentheses and the content of the bond represented by the wavy line may be the same or different, respectively. It relates to the manufacturing method. The production method according to the embodiment is not limited to a homologous oligomer containing epicatechin, and an epicatechin-containing heterogas oligomer partially containing catechin can also be produced efficiently.

The manufacturing method according to the embodiment includes, for example, the general formula (I)

(In general formula (I), R _{1 to} R ₈ and X _{1 to} X ₂ have the same meaning as described above), and a compound as an electrophile represented by:
Formula (II)
(In General Formula (II), the bond represented by R _{9 to} R ₁₆ , n and the wavy line has the same meaning as described above) and a step of condensing the compound (hereinafter, “first condensation step”). ")".

  In this production method, by using an epicatechin dimer represented by the general formula (I) as an electrophile, the target product can be produced in a short time and at a high yield at room temperature or lower. . Specifically, when an epicatechin dimer is used as an electrophile, a process for synthesizing a trimer or higher oligomer as compared with a case where an epicatechin monomer is used as an electrophile, which is a conventional method. The number is halved, and the efficiency of synthesis is greatly improved. This was first discovered by the present inventors.

  In this production method, the compound represented by the general formula (III) can be produced by the above-mentioned first condensation step. However, the compound obtained in the first condensation step can be represented by the general formula (I) or ( You may have the 2nd condensation process which further condenses the compound represented by II). Further, the compounds obtained in the first condensation step may be condensed. Therefore, the design of the compound represented by the general formula (III) is facilitated, and the production efficiency is improved.

  FIG. 1 shows the mechanism of the condensation reaction in the embodiment of the present invention. As shown in FIG. 1, Lewis acid first coordinates to an oxygen atom of an acetyl group and an alkoxyl group which is an electrophilic site, and activates and leaves the alkoxy group. Next, the electrophilic site is stereoselectively activated due to the participation of the adjacent group of the acetyl group, and the 8th position of the nucleophile having a high electron density attacks the 4 ′ position of the electrophile to generate an oligomer. The

In the production method according to the embodiment, as an optional step, the protecting group for the phenolic hydroxyl group and the protecting group for the alcoholic hydroxyl group of the compound represented by the general formula (III) obtained in the first condensation step are deprotected. (Hereinafter also referred to as “deprotection step”), the compound represented by the general formula (IV)
(In general formula (IV), n, which is the number of repetitions of the structure in parentheses, represents 0 or an integer of 1 to 10, and the bond represented by the wavy line is independently a wedge of a solid line or a broken line. Represents a bond, except when all of the bonds represented by the wavy lines are broken wedge-shaped bonds, and when n is 2 or more, the bonds represented by a plurality of wavy lines in the repeated structure in parentheses , Which may be the same or different from each other).

R _{1 to} R ₁₆ are arbitrary protecting groups selected from groups used as protecting groups for phenolic hydroxyl groups, which may be the same as or different from each other, and preferably an aromatic hydrocarbon group Or it is an aliphatic hydrocarbon group.

R _{1 to} R ₁₆ are preferably alkyl, benzyl, substituted benzyl, arylalkyl, substituted arylalkyl and the like, more preferably alkyl or benzyl, and even more preferably benzyl.
“Substituted benzyl” includes, for example, each independently, for example, benzyl substituted with alkyl, and “substituted arylalkyl”, for example, each independently includes, for example, arylalkyl substituted with alkyl. It is done. These alkyl substituents preferably have 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.

The protecting groups for the phenolic hydroxyl groups R _{1 to} R ₁₆ may be the same as or different from each other. However, if they are the same, there is an advantage that the preparation becomes easy.

X ₁ and X ₂ are a hydrogen atom or an arbitrary protecting group selected from groups used as a protecting group for an alcoholic hydroxyl group, which may be the same as or different from each other. X ₁ and X ₂ are preferably each independently an acyl group, a substituted acyl group, a benzyl group, a substituted benzyl group, an alkyl group, an arylalkyl group or a substituted arylalkyl group.

  Y is an arbitrary protecting group selected from groups used as protecting groups for alcoholic hydroxyl groups.

Preferred examples of the protecting group for the alcoholic hydroxyl group include acyl, substituted acyl, benzyl, substituted benzyl, alkyl, arylalkyl, and substituted arylalkyl. “Acyl” includes, independently, acyl of an aliphatic carboxylic acid or an aromatic carboxylic acid.
“Substituted acyl” includes acyl in which the aryl of the acyl of the aromatic carboxylic acid is substituted. Specifically, aryl (more specifically, for example, phenyl) is substituted with a substituent, for example, alkyl. Acyl.

  In the substituted benzyl and substituted arylalkyl, as in the protecting group for the phenolic hydroxyl group, examples of the “substituted benzyl” include, independently, benzyl substituted with alkyl, and “substituted arylalkyl” Each independently includes, for example, arylalkyl substituted with alkyl. These alkyl substituents preferably have 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.

  Y is a group which is eliminated during the reaction between the compound represented by the general formula (I) and the compound represented by the general formula (II), preferably an alkyloxy group or an alkyloxyalkyloxy group. Or an arylalkyloxy group.

  The size of the alkyl group of the alkyloxy group is preferably 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms. More preferably, it is a C1-C5 alkyl. More preferred are methyl, ethyl, isopropyl, allyl and the like. Most preferred is methyl.

  The size of the alkyloxy group of the alkyloxyalkyloxy group is preferably 1 to 10 carbon atoms, and more preferably 1 to 5 carbon atoms. Preferred is a methoxymethoxy group and the like, and most preferred is an ethoxyethoxy group.

  The size of the arylalkyloxy group is preferably 7 to 20 carbon atoms, and more preferably 7 to 10 carbon atoms. More preferred is phenylalkyl having 7 to 10 carbon atoms, and most preferred is benzyl.

  The catechin or epicatechin monomer reactive derivative used in the production method of the present invention is derived from any catechin or epicatechin as long as it falls within the above chemical formula, regardless of whether it is naturally derived or synthetically derived. Even a thing can be used. Moreover, what was synthesize | combined by the well-known organic synthetic chemistry method can also be used. It is preferable to use a catechin monomer derived from red beans.

The condensation is preferably performed in the presence of a Lewis acid. As the Lewis acid used as a reaction catalyst in the method of the present invention, zinc triflate (Zn (OTf) ₂ ) and ytterbium triflate (Yb (OTf) ₃ ) are preferable. When producing a dimer from a monomer, a dimer to a tetramer, a dimer and a trimer from a trimer, zinc triflate (Zn (OTf) ₂ ) is preferred. When producing a trimer from a monomer and a dimer, ytterbium triflate (Yb (OTf) ₃ ) is preferable.

  These reaction catalysts can be obtained as commercially available reagents. The form of the reaction catalyst to be used is not particularly limited, and may be in a powder state or crystallized, but is preferably in a powder state.

The addition amount of the Lewis acid used as the reaction catalyst is not particularly limited, but a suitable use amount varies depending on the type and the catechin or epicatechin. For example, in the production of catechin or epicatechin dimer, the addition amount of zinc triflate (Zn (OTf) ₂ ) is preferably about 0.7 equivalent, and in the production of catechin or epicatechin trimer, ytterbium The addition amount of triflate (Yb (OTf) ₃ ) is preferably about 2.0 equivalents. In the production of catechin or epicatechin tetramer, the addition amount of zinc triflate (Zn (OTf) ₂ ) is about 2 About 0.5 equivalent is preferable, and in the production of catechin or epicatechin pentamer, the amount of zinc triflate (Zn (OTf) ₂ ) added is preferably about 3.0 equivalent.

In the production method according to the embodiment of the present invention, it is preferable that the use ratio of the two catechins or epicatechin reactive derivatives of the electrophile and the nucleophile in the production raw material is approximately 1: 1. The conventional production methods, for example, the methods described in Non-Patent Documents 1 to 3, use one production raw material in a large excess, for example, 1: 2 to 1: 4.5 equivalents, and are very inefficient. This is a method that requires labor for the subsequent purification treatment.
The production method according to the embodiment of the present invention is an extremely efficient method in which the use ratio of the electrophilic compound and the reactive derivative of the nucleophilic compound is 1: 0.8 to 1.2. Processing operations after the reaction such as removal and removal of residual raw materials are also very simple methods.

The compound represented by the general formula (I) used as a production raw material for the first condensation step can be obtained by introducing a substituent into an epicatechin dimer. That is, (i) protective groups R _{1 to} R ₈ are introduced into the phenolic hydroxyl group of the dicate of epicatechin, and if necessary,
(B) Introducing protective groups X ₁ and X ₂ into the alcoholic hydroxyl group of epicatechin dimer,
(C) It can be produced by introducing an ethoxyethoxy group (hereinafter also referred to as “OEE”) as Y of the epicatechin reactive derivative.

Specifically, an aliphatic or aromatic hydrocarbon group as R _{1 to} R ₈ and a benzyl group as a more preferred specific example to the phenolic hydroxyl group of the dicate of epicatechin in the procedure (i). Introduce.
The procedure for introducing a benzyl group can be carried out, for example, by adding benzyl bromide to a dimer of epicatechin and causing the reaction. The reaction with benzyl bromide can be suitably performed, for example, by using dimethylformamide (hereinafter also referred to as “DMF”) as a solvent.
As a procedure for introducing an acetyl group as the protecting group X ₁ or X ₂ into the alcoholic hydroxyl group in the procedure (b), for example, acetic anhydride can be added and reacted. The addition of acetic anhydride can be performed, for example, in pyridine as a solvent.
The introduction of the methoxy group in the procedure (c) can be performed, for example, by adding 2,3-dichloro-5,6-dicyano-para-benzoquinone (hereinafter also referred to as “DDQ”) and reacting with methanol. it can. The introduction of the methoxy group can be performed, for example, in dichloromethane as a solvent.
In addition, ethoxyethoxy group (OEE) can be introduced, for example, by adding 2,3-dichloro-5,6-dicyano-para-benzoquinone (DDQ) and reacting with ethoxyethanol in the same manner as the methoxy group described above. Can be done.

The compound represented by the chemical formula (II) in the first condensation step can be obtained, for example, by introducing a substituent into a 1-11 mer of catechin or epicatechin. That is, the protective groups R _{9 to} R ₁₆ are introduced into a catechin or epicatechin monomer or a phenolic hydroxyl group of a 2-11 mer.

As the order of the procedure (a) to the procedure (c), (a) introduction of R _{9 to} R ₁₆ of the protecting group of phenolic hydroxyl group → (b) introduction of X ₁ and X ₂ of protecting group of alcoholic hydroxyl group → (C) Order of introduction of leaving group Y, or (b) introduction of R _{9 to} R ₁₆ of protecting group of phenolic hydroxyl group → (c) introduction of leaving group Y → (b) protecting group of alcoholic hydroxyl group X ₁ and X ₂ are preferably introduced in this order.

  The solvent used for the coupling reaction may be any solvent that does not affect the reaction. For example, a solvent such as hexane, benzene, toluene, xylene, carbon tetrachloride, methylene chloride, chloroform, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, dimethylformamide, acetonitrile, ethyl acetate, dimethyl sulfoxide, alone or Can be used as a mixture. Of these solvents, benzene, hexane, toluene, xylene, carbon tetrachloride and methylene chloride are preferred, and methylene chloride is most preferred.

The reaction time of the present invention is not particularly limited, and can be appropriately adjusted according to the type of production raw material and the type of target product. If the reaction time is too short, the reaction may be inadequate and unreacted raw materials may remain, reducing the yield of the product. In addition, when the reaction time is too long, not only the work efficiency deteriorates, but also the products or unreacted raw materials react with each other irregularly to produce impurities other than the intended purpose. There is.
Specifically, in the case of production of a tetramer, about 24 hours is preferable for both catechin and epicatechin tetramers. In the case of catechin pentamer, about 72 hours are preferable, and in the case of epicatechin pentamer, about 47 hours are preferable.

A feature of the production method of the present invention is that the reaction temperature is not particularly limited. The conventional manufacturing method, for example, the method described in Non-Patent Document 1, requires low temperature conditions (for example, −20 ° C.), whereas the method of the present invention does not require such low temperature conditions.
In addition, the reaction temperature in the method of the present invention is not particularly limited, and can be appropriately adjusted according to the type of production raw material and the type of target product.
Specifically, it is preferably room temperature or lower (0 ° C. or higher and 23 ° C. or lower). The lower limit is more preferably 10 ° C. or higher, and particularly preferably 20 ° C. or higher.

The use ratio of the compound represented by the chemical formula (I) and the compound represented by the chemical formula (II) used in the first condensation step is preferably close to a molar ratio of 1: 1. It is preferable to make it react by 8-1.2 equivalent.
Thus, by making the addition ratios substantially the same, waste of excessive use of raw materials can be prevented, and further purification operations including removal of residual raw materials can be simplified.

  As the deprotection method in the deprotection step of the compound represented by the chemical formula (III) in the deprotection step, a known method can be used.

Specifically, for example, when an acetyl group is present as the protective group X ₁ , X ₂ , or Y for the alcoholic hydroxyl group, the acetyl group can be eliminated by a method of adding sodium methoxide or the like. As the solvent in this case, for example, methanol can be used.

Further, for example, when a benzyl group is present as the protecting group R _{1 to} R ₁₆ for the phenolic hydroxyl group, the benzyl group is removed by a method of adding palladium hydroxide (Pd (OH) ₂ ) under a hydrogen atmosphere. Can be separated. As the solvent at this time, for example, a mixed solvent of tetrahydrofuran (THF), methanol, and water can be used.

As mentioned above, although this invention was described by embodiment, it should not be understood that the description and drawing which form a part of this indication limit this invention. From this disclosure, various alternative embodiments, examples, and operational techniques will be apparent to those skilled in the art.
In the embodiment, the method for producing a heterogas oligomer has been mainly described. However, according to the present invention, a homologous oligomer containing epicatechin can also be produced. For example, in general formula (III), a compound other than the case where all of the bonds represented by wavy lines are broken wedge-shaped bonds can be produced. In addition, in the general formula (III), when n is 1 or 2, it is possible to produce a compound excluding the case where all of the bonds represented by the wavy line are broken-line wedge bonds. In addition, the interpretation of the substituent of the homologous oligomer represented by general formula (III) is the same as that of the above-mentioned heterogas oligomer.
Although it demonstrated centering on the manufacturing method, according to this invention, the compound represented by general formula (III) and (IV) is provided. Such compounds are useful, for example, for the identification of the proanthocyanidin fraction in red beans. As with conventional procyanidins, it exhibits physiological effects such as antioxidant, antiviral, antibacterial, antitumor, arteriosclerosis, gastric ulcer, carcinogenesis, hair growth, and whitening effects. Expected and useful as a material for health foods and cosmetics.

  Hereinafter, embodiments of the present invention will be described with reference to examples. However, the present invention is not limited to the following examples. The structural formulas of the resulting arecatannins A2 and A3 (heterogas oligomers) are shown together in FIG.

[Preparation Example 1]
Synthesis of Dimer Condensate (Epicatechin-Epicatechin) As shown in FIG. 3, epicatechin (monomer) represented by the general formula (V) was prepared.
Next, this epicatechin was used as a production raw material, and 0.7 equivalent of Zn (OTf) ₂ was used as a reaction catalyst, and the reaction was carried out in methylene chloride at room temperature (20 ° C.) for 1.5 hours. A dimer condensate represented by (II-1) was obtained (yield: about 58%).

[Preparation Example 2]
Synthesis of Trimer Condensate (Epicatechin-Epicatechin-Catechin / Alecatannin A1) As shown in FIG. 4, the catechin (monomer) represented by the general formula (V) was obtained in Preparation Example 1. An epicatechin dimer represented by the general formula (II-1) was prepared. Next, by using these as production raw materials and using 2.0 equivalents of Yb (OTf) ₃ as a reaction catalyst, the reaction is carried out in methylene chloride at room temperature (20 ° C.) for 4 hours to obtain a compound represented by the general formula (III-1). ) Was obtained (yield about 79%). Using this condensate, debenzylation was carried out to produce Arecatannin A1.

[Comparative Preparation Example]
Synthesis of catechin trimer An epicatechin trimer was prepared in the same manner as in Preparation Example 2, except that the reaction catalyst and reaction time were changed to the following conditions, respectively. The conditions and results obtained are summarized in the following table.
From the above results, it became clear that the reaction time was shortened and the yield was increased by using Yb (OTf) ₃ as a reaction catalyst.

[Example 1]
Synthesis of Tetramer Condensate (Epicatechin-Epicatechin-Epicatechin-Catechin / Arecatannin A2) As shown in the reaction formula of FIG. 5, the epicatechin dimer represented by the general formula (II-1) A catechin dimer represented by the general formula (II-2) prepared in Preparation Example 1 was prepared. Next, by using these as production raw materials and using 2.5 equivalents of Zn (OTf) ₂ as a reaction catalyst, the reaction is carried out in methylene chloride at room temperature (20 ° C.) for 24 hours. ) Was obtained (yield about 64%). Using this condensate, debenzylation was carried out to produce arecatannin A2.

[Example 2]
Synthesis of pentamer condensate (epicatechin-epicatechin-epicatechin-epicatechin-catechin / arecatannin A3) As shown in the reaction formula of FIG. 6, the dimers obtained in Preparation Examples 1 and 2, respectively. And trimer were prepared. Next, using the prepared dimer and trimer as production raw materials, using 3.0 equivalents of Zn (OTf) ₂ as a reaction catalyst, the reaction is carried out in methylene chloride at room temperature (20 ° C.) for 47 hours. As a result, a pentamer condensate having one end of catechin was obtained (yield: about 59%).
This condensate was used for debenzylation to produce arecatannin A3. (Yield about 90%)

[Reference Example 1]
Preparation (extraction) of ingredients derived from red beans
Sample 1 was a filtrate obtained by immersing red beans in water at room temperature for 12 to 18 hours and then filtering with cotton.

[Reference Example 2]
Samples synthesized with proanthocyanidins contained in the water extract of the red beans at room temperature (Sample 1) were compared using HPLC (High Performance Liquid Chromatography). The analysis conditions of HPLC are shown below. The obtained results are shown in FIG.
Equipment: GL-7400, manufactured by GL Science
Column: InertSustain C18 5μm φ4.6 × 250mm
Column temperature: 35 ° C
Eluent conditions: shown in Table 2 below Flow rate: 0.8 ml / min
Injection: 5μl

As a result, procyanidin B1 (dimer), epicatechin-epicatechin-catechin (trimer) (Arecatannin A1), epicatechin-epicatechin-epicatechin-catechin (tetramer) ( It was found that Arecatannin A2) was included. In addition, epicatechin-epicatechin-epicatechin-epicatechin-catechin (pentamer) (Arecatannin A3) was not included.
Further, the anti-tumor activity test was performed on the human prostate cancer cell PC-3 for the synthesized product. As a result, it was found that the heterogas catechin and epicatechin oligomer have antitumor activity. Moreover, it became clear that activity increased as the degree of polymerization increased.
That is, the sample synthesized according to the examples is useful for identifying the proanthocyanidin fraction in red beans. Samples synthesized according to the examples are expected to have various physiological activities in addition to the antitumor activity described above.

[Comparative Example 1]
Synthesis of tetramer condensate (epicatechin-epicatechin-epicatechin-catechin / arecatannin A2)
According to the method described in A. Saito et al., Tetrahedron, 2009, 65, 7422-7428, it was produced according to the reaction formula shown in FIG. By using 1.0 equivalent of TMSOTf as a reaction catalyst in methylene chloride at a reaction temperature of about −40 ° C., a tetramer condensate was obtained with a yield of about 89%.
From this condensate, debenzylation was carried out in the same manner as in Example 1 to produce a tetramer condensate (arecatannin A2) (yield about 58%).

  ADVANTAGE OF THE INVENTION According to this invention, the epicatechin containing hetero gas oligomer which contains a catechin more than a tetramer with a high yield can be manufactured easily. Such oligomers are useful for the identification of the proanthocyanidin fraction in red beans. The oligomer produced according to the present invention makes accurate identification of the proanthocyanidin fraction in red beans, making it easier to grasp the physiological activity of each fraction, and as a result, derived from red beans focusing on the physiological activity of each fraction Of proanthocyanidins is expected to expand. Furthermore, clarification of the activity and related molecules will provide clues for elucidating the mechanism of action, and the development of more effective bioactive molecules can also be expected from this mechanism.

Claims (6)

The following general formula (I)
(In general formula (I), R _{1 to} R ₈ each independently represents an arbitrary protecting group selected from groups used as protecting groups for phenolic hydroxyl groups, and X _{1 to} X ₂ are: Each independently represents any protecting group selected from the groups used as protecting groups for alcoholic hydroxyl groups, and Y represents a leaving group),
The following general formula (II)
(In the general formula (II), R _{9 to} R ₁₆ each independently represents an arbitrary protecting group selected from groups used as protecting groups for phenolic hydroxyl groups, and n is 0 or 1 or more. Each of the bonds represented by the wavy line represents an integer of 10 or less, and represents a wedge-shaped connection with a solid line or a broken line, provided that all of the bonds represented by the wavy line are broken-line wedge-shaped connections. Note that when n is 2 or more, the contents of R _{13 to} R ₁₆ and the bond represented by the wavy line, which are present in the repeated structure in parentheses, may be the same or different. A step of condensing the compound represented by
The following general formula (III)
(In General Formula (III), the bond represented by R _{1 to} R ₁₆ , X _{1 to} X ₂ , n, and the wavy line has the same meaning as described above.). The production method according to claim 1, wherein R _{1 to} R ₁₆ are each independently an aromatic hydrocarbon group or an aliphatic hydrocarbon group. The production according to claim 1 or 2, wherein X ₁ and X ₂ are each independently an acyl group, a substituted acyl group, a benzyl group, a substituted benzyl group, an alkyl group, an arylalkyl group, or a substituted arylalkyl group. Method.   The manufacturing method as described in any one of Claims 1-3 whose said Y is an alkyloxy group, an alkyloxyalkyloxy group, or an arylalkyloxy group.   The production method according to claim 1, wherein the condensation is performed in the presence of a Lewis acid.   The production method according to claim 5, wherein the condensation is performed at 0 ° C. or more and 23 ° C. or less.