JP3533440B2 - Method for producing O-glycoside molecular assembly - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a novel O-glycoside molecular assembly, which has various morphological characteristics and can be used in the fields of fine chemicals, pharmaceuticals, cosmetics, foods, fibers and the like. Is.

[0002]

2. Description of the Related Art Certain lipids are self-assembled to form stable molecular aggregates, and are used as functional materials in various fields including fine chemicals. Such lipids, for example, spherical molecular aggregates composed of naturally-occurring phospholipids, so-called liposomes, are produced by a thin film method, a heat dispersion method, a solution injection method, a cholic acid method, a reverse phase evaporation method, etc. All of these methods have been difficult to put into practical use because they require complicated and skillful techniques. Moreover, the molecular aggregates obtained by these methods are single-membrane vesicles or spherical multi-membrane vesicles, and fibrous molecular aggregates and liquid crystalline molecular aggregates cannot be obtained. I was not free from restrictions on my field.

On the other hand, it is known that by dispersing a synthetic amphipathic compound in water, a spiral fibrous or rod-shaped molecular assembly is formed [Journal of the American Chemicals. Society (J. Am.
Chem. Soc. ) ", 107, 509-51
Page 0 (1985)]. However, the molecular assembly thus obtained is stable only in water, and when water is removed, its structure collapses and cannot retain a specific form. However, it has the drawback that it is almost unavailable.

[0004]

The present invention has been made for the purpose of providing a novel molecular assembly which can be produced from easily available raw materials by a simple method and which is reproducible and has a wide range of applications. It is a thing.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies on a method for easily producing a functional material having a wide range of use from an easily available raw material, and as a result, separated from cashew nut shell oil. It was found that fibrous or spherical molecular aggregates or liquid crystalline molecular aggregates can be obtained by molecular assembly of O-glycoside type glycolipids containing a long-chain alkylphenol or its derivative as an aglycone by various methods. The present invention has been completed based on this finding.

That is, in the present invention, the aldose residue is a glycosyl group, and

[Chemical 4] (R in the formula is an aliphatic saturated or unsaturated straight chain hydrocarbon group having 12 to 18 carbon atoms) O-glycoside having an aglycone as a group is dissolved in water at an elevated temperature to a saturated concentration. After that, the aqueous solution is gradually cooled to induce molecular assembly to produce a fibrous O-glycoside molecular assembly, and the fibrous molecular assembly is heated to be spheroidized to form a spherical O-glycoside. A method for producing a molecular assembly, and a aldose residue as a glycosyl group

[Chemical 5] (Wherein R is an aliphatic saturated or unsaturated linear hydrocarbon group having 12 to 18 carbon atoms) is an O-glycoside having an aglycone as a group, heated in the absence of a solvent to give a liquid crystal. The present invention provides a method for producing a liquid crystal type O-glycoside molecular assembly by causing a functional molecular assembly.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The molecular assembly of the present invention is an O-glycoside type glycolipid containing an aldose residue as a glycosyl group and a long chain alkylphenol residue represented by the above general formula (I) as an aglycone, That is, the general formula

[Chemical 6] (Wherein R has the same meaning as described above, and G is an aldofuranose or aldopyranose residue in which the carbon atom at the reducing end participates in the O-glycoside bond). It is used as a raw material and manufactured.

Examples of G in the above general formula (II), that is, a glycosyl group, include aldopyranoses such as glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, glopyranose, idopyranose and talopyranose, and Examples thereof include a residue obtained by removing a hydrogen atom from the hydroxyl group at the reducing end of the corresponding aldofuranose.

Next, R in the general formula (II) has 1 carbon atom.
2 to 18, preferably 15 aliphatic straight-chain hydrocarbon radicals, which may be saturated or unsaturated. When unsaturated, those containing 1 to 3 double bonds are preferred. As such an aliphatic saturated linear hydrocarbon group,
For example, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group and the like can be mentioned, but the pentadecyl group is preferable from the viewpoint of easy availability of raw materials. Further, examples of the aliphatic unsaturated linear hydrocarbon group include triene, diene or monoene residues corresponding to the above aliphatic saturated linear hydrocarbons, but the raw materials are easily available. 8-pentadecenyl group, 8,10-pentadecadienyl group, 8,10,12
-Pentadecatrienyl group is preferred.

The O-glycoside type glycolipids represented by the general formula (II) are novel compounds which have not been published in any literature. Such O-glucoside type glycolipids are represented by the general formula

[Chemical 7] The reducing terminal hydroxyl group of aldopyranose or aldofuranose (hereinafter simply referred to as protected aldose) in which all the hydroxyl groups other than the reducing terminal hydroxyl group are protected in the long-chain alkylphenol represented by (wherein R has the same meaning as described above) It can be produced by reacting the reactive functional derivative of (1) to form an O-glucoside bond, and then removing the protecting group. As this protecting group, for example, an acetyl group, a 1,2-methylene group, a 1,2-isopropylidene group or the like is used. Further, as the reactive functional derivative of the reducing terminal hydroxyl group, for example, trichloroacetimidate of corresponding aldose, bromide (brom sugar), fluoride (fluor sugar), thioglycoside, O-
Examples thereof include acylate. Among these, fluorinated compounds and trichloroacetimidate are preferable because they react in a high yield.

Among the long-chain alkylphenols represented by the general formula (III), those having a saturated or unsaturated alkyl group having 15 carbon atoms can be easily obtained by using cashew nut as a raw material. That is, cashew nut shell oil, which is generally used as a raw material for cashew varnishes, brake pads for machines and automobiles, and linings, is vacuum distilled to collect a fraction having a boiling point of 220 to 235 ° C. At this time, the degree of vacuum is appropriately in the range of 250 to 700 Pa. This cashew nut shell liquid is also called cashew nut oil, and the cashew nut tree (Anacardium occidentale) of the sumac family
It is an oily liquid obtained by solvent extraction or heat-fractionation of the fruit shells. Then, when extracted with a solvent, it is obtained as a mixture containing anacardic acid and cardol as main components, and when heated and fractionated, it is obtained as a mixture containing cardanol and cardol as main components.

To use as a raw material for the method of the present invention, this cashew nut shell liquid is subjected to an extraction operation using a solvent such as n-hexane, and the obtained cardanol, cardol and anacardic acid are dissolved in the solvent to obtain the desired product. According to a conventional method, a long-chain alkylphenol having an aliphatic saturated hydrocarbon group is hydrogenated. Usually, as the reaction solvent in this hydrogenation reaction, methyl alcohol,
Alcohols such as ethyl alcohol are used, and as the hydrogenation catalyst, platinum / carbon-based catalyst, palladium / carbon-based catalyst and the like are used.

On the other hand, the reactive functional derivative of protected aldose which is reacted with this long chain alkylphenol is
For example, it can be manufactured as follows. That is, a halide such as a bromide or a fluoride of a reducing terminal hydroxyl group of aldose, a so-called bromine sugar or a fluorine sugar, is obtained by acetylating aldose in pyridine and then reacting hydrogen bromide or hydrogen fluoride in acetic acid. Obtained by

In addition, the corresponding trichloroacetimidate is obtained by acetylating aldose in the same manner as described above, and then reacting hydrazine acetate in dimethylformamide to selectively deacetylate the sugar chain component only at the reducing end. It is obtained by forming and then reacting trichloroacetonitrile in the presence of a base catalyst. At this time, the reaction solvent is preferably a halogen compound such as methylene chloride or chloroform, and the base catalyst is preferably sodium hydride or cesium carbonate.

In the reaction for obtaining the halide of aldose, the α-form is selectively obtained, and in the reaction for obtaining trichloroacetimidate, the α-form is selectively obtained by reacting at room temperature for 2 hours or more. . This means that the ¹ H-NMR spectra of these compounds (in deuterated chloroform, 25 ° C.) showed a doublet signal (spin-spin coupling constant 3.4 at δ value of 6.4 to 6.6 ppm).
It can be confirmed by showing ~ 4.0 Hz).

Next, the reaction for forming an O-glycoside bond from the long-chain alkylphenol represented by the general formula (III) and the reactive functional derivative of the protected aldose is carried out as follows. You can For example, when the protected functional derivative of protected aldose is a bromide, it is reacted in the presence of a basic substance using tin trifluoromethanesulfonate as a catalyst. Chloroform, toluene and the like are used as the reaction solvent in this case, but a chloroform / toluene mixed solvent system is preferable from the viewpoint of solubility. As the basic substance,
2,4,6-Trimethylpyridine and 1,1,3,3-tetramethylurea are used. The reaction temperature at this time is suitably room temperature to 40 ° C. for 10 to 20 hours. This reaction gives better results when molecular sieve 4A coexists.

Then, when the reactive functional derivative of the protected aldose is trichloroacetimidate,
It is carried out in the presence of a Lewis acid catalyst. As the reaction solvent at this time, a halogen-based solvent such as chloroform, methylene chloride, 1,2-dichloroethane, acetonitrile, nitromethane, etc. are used, and methylene chloride is particularly preferable. As the Lewis acid catalyst for this reaction, trimethylsilyl trifluoromethanesulfonate and boron trifluoride / ether complex are used. The amount of the Lewis acid catalyst used is preferably 2 to 3 equivalents based on trichloroacetimidate. The reaction temperature in this case is preferably -5 to 0 ° C. The reaction time depends on the type of Lewis acid catalyst and the reaction temperature, but is usually 2 to 3 hours. This reaction is preferably carried out in the presence of molecular sieves while stirring. Using glucose as aldose,
With the boron trifluoride-ether complex, without converting glucose into trichloroacetimidate in advance,
O-glycosides can also be obtained in good yield by directly reacting all hydroxyl groups including reducing terminal hydroxyl groups with acetylated aldose. In particular, when glucose is used, this method is convenient because it reacts in a high yield. When bromide or trichloroacetimidate is used, β-form O-glycoside is selectively obtained. This means that the ¹ H-NMR spectrum of these compounds (in deuterated dimethyl sulfoxide at 25 ° C.) has a δ value of 4.4 to
This can be confirmed by showing a doublet signal (spin-spin coupling constant of 7.8 to 8.0 Hz) at 4.9 ppm.

O having a sugar chain protected in this way
-Glycosides are obtained, but finally it is necessary to remove the protecting groups. Then, the elimination reaction of this protecting group, for example, an acetyl group, is carried out by treating an O-glycoside having a protected sugar chain with an alkali metal alcoholate such as sodium methoxide or potassium methoxide, and then using a strongly acidic cation exchange resin. It can be performed by neutralization. Further, it can be more easily carried out by mixing an aqueous solution of trialkylamine such as trimethylamine with several times the volume of the reaction solvent and reacting it with the O-glycoside having the protected sugar chain. At this time, the concentration of the trialkylamine aqueous solution is preferably 30 to 50% by weight. As the reaction solvent at this time, an alcohol solvent such as methyl alcohol or ethyl alcohol, or a mixed solvent of an ether solvent such as diethyl ether or tetrahydrofuran and an alcohol solvent is suitable. At this time, it is desirable to keep the pH of the reaction solution at 8.0 to 8.5 in order to avoid side reactions such as ester hydrolysis reaction. The reaction time depends on the reaction conditions, but is usually 12 to 2
4 hours is appropriate. After the reaction is completed, the solvent is distilled off to obtain an O-glycoside type glycolipid having a long-chain alkylphenol residue represented by the general formula (I) as an aglycone as a white powder. The crude product thus obtained can be highly purified by a separation and purification operation using a silica gel column.

In the O-glycoside type glycolipid thus obtained, the measured elemental analysis value agrees with the calculated value within the error range. Further compounds which the sugar chains are protected with an acetyl group, (in deuterated chloroform, 25 ℃) ¹ H-NMR in the characteristic of δ values can be assigned to the hydrogens of the methyl group of acetyl groups 2.03~2.08ppm Since there are various signals, it can be easily identified. On the other hand, in the ¹ H-NMR (in heavy dimethyl sulfoxide, 25 ° C.), the δ value of the compound from which the acetyl group was removed was 0.88 ppm (hydrogen of methyl group of long-chain alkyl group), 1.26 ppm (long-chain). Hydrogen of methylene group of alkyl group), 1.58 ppm (hydrogen of methylene group second from the aromatic part in the long-chain alkyl group), 2.56 ppm (hydrogen of methylene group directly linked to aromatic group) ) 3.13 to 3.69 ppm
(Hydrogen linked to C2, C3, C4, C5, C6 carbon of sugar chain), 4.82 ppm (anomeric hydrogen linked to C1 carbon of sugar chain), 5.34 to 5.42 ppm (hydrogen linked to vinyl group) ), 6.79, 6.80-6.89 pp
The product can be identified and confirmed from m, 7.19 to 7.20 ppm (hydrogen linked to the aromatic ring) and the like.

In the method of the present invention, first, water is added to O-glycoside as a raw material and heated to prepare a saturated aqueous solution. At this time, if the amount of water is too small, the insoluble portion remains, and if the amount of water is too large, the saturated concentration cannot be reached.
It is selected within the range of 100 times by weight. The heating temperature at this time is preferably raised to the boiling temperature in order to increase the amount of dissolved O-glycoside as much as possible, but a lower temperature can be used if desired.

Then, the aqueous solution of O-glycoside thus prepared is gradually cooled to form a molecular assembly.
If the cooling rate at this time is high, long fibers are less likely to be formed and aggregates of short fibers are formed. Therefore, it is preferable to select the cooling rate in the range of 0.5 ° C./min or less, particularly 0.2 ° C./min or less. . Water is usually used alone as a solvent for preparing the aqueous solution, but a mixed solvent of water and alcohol can be used if desired. As the alcohol in this case, for example, water-miscible alcohol such as methyl alcohol, ethyl alcohol, propyl alcohol, etc. is used. In this way, fibrous substances are precipitated from the aqueous solution, and by collecting them and air-drying or vacuum-drying, several μm having a partially twisted structure that is stable in air
Length on the order of m to several mm and several tens of nm to several μ
Fibrous O-glycoside molecular assemblies with fiber widths on the order of m are obtained. The structure of the obtained molecular assembly can be easily confirmed by observing with a polarization optical microscope or a phase contrast optical microscope.

According to another embodiment of the method of the present invention, the fibrous O-glycoside molecular assembly obtained as described above is redissolved into an aqueous solution, which is slowly warmed to be spheroidized, Vesicles can be formed. At this time, the heating rate is 1 to 20 ° C. /
Min, particularly preferably 10 ° C./min or less. Further, the temperature to be heated needs to be equal to or higher than the gel-liquid crystal phase transition temperature of the long chain hydrocarbon group present in the O-glycoside. This temperature can be accurately known by differential scanning calorimetry. Then, when observing the structure of the molecular assembly during temperature increase with an optical microscope, when the temperature reaches a predetermined temperature, the fibrous molecular assembly suddenly shrinks and changes into a spherical vesicle, and the spherical vesicle Is recognized. Further, even when observed with the naked eye, it can be confirmed by changing the aqueous solution containing the cotton-like fibrous substance from a non-uniform state to a dilute opaque solution in a uniform state. This temperature is usually in the range of 70-80 ° C. The spherical O-glycoside molecular assembly thus produced cannot be isolated in air, but is stable above the gel-liquid crystal phase transition temperature in an aqueous solution.

According to still another embodiment of the method of the present invention, the O-glycoside as a raw material is heated in the absence of a solvent, for example, as a solid powder to cause a liquid crystalline molecular assembly, whereby a liquid crystalline O -Glycoside molecular assemblies can be produced. The heating rate at this time is 0.5 to 10
The range of ° C / min is suitable. Also, the heating temperature is 120-
It is in the range of 140 ° C. The generation of liquid crystal at this time can be easily confirmed using an optical microscope.

[0024]

Industrial Applicability The O-glycoside molecular assembly obtained by the method of the present invention can be obtained, for example, in the field of fine chemical industry,
Materials for forming liposome membranes in the fields of medicine and cosmetics,
As ultra-thin films and microstructures, as well as microelectronic parts in the electronic and information fields, food industry, agriculture and forestry,
It is useful as an emulsifier, stabilizer, dispersant, wetting agent, etc. in the textile industry and has a high industrial utility value.

[0025]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. In addition, R of thin layer chromatography
f value is hexane / ethyl acetate (volume ratio 6/4)
The value when the mixed solvent was used as the developing solvent was defined as Rf ₁ .

Reference Example 1 Cashew nut oil was vacuum distilled twice at about 400 Pa, and components having a boiling point of 220 ° C to 235 ° C were collected to obtain cardanol. 1.52 g (5 mmol) of the cardanol was dissolved in anhydrous methylene chloride (10 ml),
In the presence of 2 g of molecular sieve 4A, 3.9 g (5 mmol) of β-D-glucose pentaacetate and 0.62 ml (5 mmol) of boron trifluoride diethyl ether were added. The reaction mixture was stirred at room temperature for 24 hours and then poured into a 5% -aqueous sodium hydrogen carbonate solution.
The organic phase was separated, washed with an aqueous sodium hydrogen carbonate solution and then with water, and then dried over anhydrous sodium sulfate.
The organic solvent was completely distilled off under reduced pressure, and the obtained crude product was recrystallized from ethanol. The obtained product solid was subjected to column chromatography using a mixed solvent of hexane / ethyl acetate (volume ratio 7/3) as an eluent to give 1-white solid.
2.36 g (yield 75%) of (O-β-D-glucopyranoside tetraacetate) cardanol was obtained. The physical properties of this product are as follows. Rf value of thin layer chromatography: Rf ₁ = 0.47 Melting point: 60 ° C.

Next, a 45% by weight aqueous solution of trimethylamine was mixed with 4 volumes of methanol to obtain 1-
The reaction was performed with (O-β-D-glucopyranoside tetraacetate) cardanol (1.26 g, 2 mmol) for 24 hours. After distilling off the solvent under reduced pressure, the resulting syrupy residue was methanol / acetonitrile (volume ratio 1 /
2) Crystallization from a mixed solvent and recrystallization from the same solvent gave the desired deacetylated 1-
(O-β-D-glucopyranoside) cardanol was obtained almost quantitatively as a white solid 0.88 g (yield 95%). The physical properties of this product are as follows. Melting point: 135.2 ° C

Reference Example 2 Instead of cardanol in Reference Example 1, 3'-n-
Reference Example 1 except that pentadecylphenol was used
By the same operation as above, the following compound was obtained. 3'-n-pentadecylphenyl-2,3,4,6-O
-Acetyl-β-D-glucopyranoside (white solid) Rf value of thin layer chromatography: Rf ₁ = 0.55 Melting point: 101 ° C 3'-n-pentadecylphenyl-β-D-glucopyranoside (white solid) Melting point: 143.5 ° C

Example 1 100 mg of 1- (O-β-D-glucopyranoside) cardanol obtained in Reference Example 1 was weighed into a flask, and 5 ml of water was added to this, which was heated with a mantle heater and boiled. Dissolved. The heating temperature of the mantle heater was slowly adjusted, and the temperature was lowered at a cooling rate of 0.2 ° C./min, and the heating was allowed to stand for 2 days. When the generated fibrous substance is observed as an aqueous solution with an optical microscope, the pitch is about 100.
nm, width is about 200 nm, length is several tens of μm to several hundreds.
It was found to be a molecular assembly composed of coiled fibers of μm. Figure 1 shows a copy of an optical micrograph of this molecular assembly.
Shown in.

Example 2 The same as Example 1 except that instead of using boiling water in Example 1, a water / ethanol mixed solvent (10: 1, volume ratio) was used and the solution was dissolved by heating at about 70 ° C. A fibrous molecular assembly was obtained by operating under the conditions. As a result of observing this molecular assembly as an aqueous solution with an optical microscope, the pitch is about 100 nm, the width is about 200 nm, and the length is several tens μm
It was a molecular assembly composed of coiled fibers of several 100 μm.

Example 3 The same as Example 1 except that instead of using boiling water in Example 1, a water / acetone mixed solvent (10: 1, volume ratio) was used and the solution was dissolved by heating at about 70 ° C. A fibrous molecular assembly was obtained by operating under the conditions. As a result of observing this molecular assembly as it was in an aqueous solution, it was found to be a molecular assembly composed of coiled fibers having a pitch of about 100 nm, a width of about 200 nm, and a length of several tens to several hundreds of μm.

Example 4 Instead of using 1- (O-β-D-glucopyranoside) cardanol in Example 1, the 3'-n-pentadecylphenyl-β-D-glucopyranoside obtained in Reference Example 2 was used. A fibrous molecular assembly was obtained by operating under the same conditions as in Example 1. As a result of observing this molecular assembly as an aqueous solution under an optical microscope, the pitch was about 1
00 nm, width about 200 nm, length several tens of μm to several 1
It was found to be a twisted fibrous molecular assembly of 00 μm.

Example 5 By heating the aqueous solution containing the fibrous molecular assembly obtained in Example 1 to about 78 ° C. at a temperature rising rate of 8 ° C./minute, the fibrous molecular assembly has a spherical molecular assembly. Morphological changes occurred in the body, and vesicles having a diameter of about 1 to 3 μm were obtained. The spherical morphology was easily confirmed by optical microscopy. A copy of an optical micrograph of this product is shown in FIG.

Example 6 1- (O-β-D-glucopyranoside) cardanol obtained in Reference Example 1 was heated as a solid powder at a heating rate of 2 ° C.
A smectic type thermotropic liquid crystal was obtained by heating at 125 ° C./min. The identification of the liquid crystal was confirmed by confirming it as a characteristic optical structure with a polarization optical microscope.

Example 7 By heating 3′-n-pentadecylphenyl-β-D-glucopyranoside obtained in Reference Example 2 as a solid powder at a heating rate of 5 ° C./min to 129 to 130 ° C. A smectic type thermotropic liquid crystal was obtained. The identification of the liquid crystal was confirmed by observation using a polarization optical microscope.

[Brief description of drawings]

FIG. 1 is an optical micrograph of a fibrous molecular assembly obtained in Example 1.

FIG. 2 is an optical micrograph of a spherical molecular assembly obtained in Example 5.

Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07H 15/203 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. An aldose residue is used as a glycosyl group and is represented by the general formula: (R in the formula is an aliphatic saturated or unsaturated straight chain hydrocarbon group having 12 to 18 carbon atoms) O-glycoside having an aglycone as a group is dissolved in water at an elevated temperature to a saturated concentration. After that, the aqueous solution is gradually cooled to induce molecular assembly, which is a method for producing a fibrous O-glycoside molecular assembly. 2. An aldose residue is used as a glycosyl group and is represented by the general formula: (R in the formula is an aliphatic saturated or unsaturated straight chain hydrocarbon group having 12 to 18 carbon atoms) O-glycoside having an aglycone as a group is dissolved in water at an elevated temperature to a saturated concentration. After that, the aqueous solution is gradually cooled to form a fibrous molecular assembly, and then the fibrous molecular assembly is heated to be spheroidized, thereby producing a spherical O-glycoside molecular assembly. 3. An aldose residue is used as a glycosyl group and is represented by the general formula: (Wherein R is an aliphatic saturated or unsaturated linear hydrocarbon group having 12 to 18 carbon atoms) is an O-glycoside having an aglycone as a group, heated in the absence of a solvent to give a liquid crystal. 1. A method for producing a liquid crystal type O-glycoside molecular assembly, which comprises causing a functional molecular assembly.