JPH07316204A - Cyclomaltopentaose and derivative thereof - Google Patents

Abstract

PURPOSE:To obtain a new cyclomaltopentaose and derivatives thereof, which are useful in the field of pharmaceuticals, foodstuffs and cosmetics, by deriving them through chemical syntheses from ethyl-beta-D-glucopyranoside as.a starting material. CONSTITUTION:A compound of formula I (R is H) is prepared by a chemical synthesis from ethyl-beta-D-glucopyranoside as a starting material. The compound of formula I is condensed with a compound of formula II at room temperature in 1,2-dichloroethane in the presence of methyl triflate to obtain a pentasaccharide derivative of formula III. Then the pentasaccharide of formula III is thiolyzed into a pentasaccharide derivative of formula IV (R<1> is OH; R<2> is acetyl), which is carbamoyled and deacetylated to obtain a cyclization precursor compound. The resultant cyclization precursor compound is cyclized under dilute conditions and then decarbamoyled and debenzylated to obtain a cyclomaltopentaose of formula V (R<1> is H, benzyl or acetyl; R<2> is H, acetyl or phenylcarbamoyl).

Description

Detailed Description of the Invention

[0001]

The present invention relates to novel cyclodextrin pentasaccharide homologues and derivatives thereof.

[0002]

BACKGROUND OF THE INVENTION Cyclodextrins are used in starch or starch degradation products as Bacillus maceras.
ns), Bacillus circulans
Is a degradation product obtained by the action of a cyclodextrin-producing enzyme produced by a microorganism such as D-glucopyranose is an α- (1-4) -bonded cyclic oligosaccharide, which has a polymerization degree of 6 or more. Things are known. Due to their structure, these cyclodextrins have voids inside, and since the voids are lipophilic regions, various oily substances can be incorporated. Therefore, by utilizing such properties, the results of stabilization of unstable substances, retention of volatile substances, masking of unpleasant odors, water-solubilization of poorly soluble / insoluble substances in water, etc. Widely used in such fields.

However, it has been thought that cyclodextrins having a degree of polymerization of 5 or less cannot exist. This is a non-bond i of Sundararajan and Rao's "mechanism of degree of cyclodextrin of 5" by the molecular mechanics method.
The nteraction energy is 10.8 to 6.5 kcal / mol per D-glucose residue, which is larger than that of polymerization degree 6 (α-cyclodextrin) or polymerization degree 7 (β-cyclodextrin), and the stabilizing effect by intramolecular hydrogen bonding 14.0 if considered
It was pointed out that ~ 11.3kcal / mol was also large (Carbohydr.Res., 1
970,13,351-358).

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a cyclodextrin homologue having a degree of polymerization of 5 and a derivative thereof, which has heretofore been impossible to synthesize.

[0005]

Under such circumstances, the inventors of the present invention have conducted intensive studies on the synthesis of cyclodextrin having a degree of polymerization of 5, and as a result, found that a cyclodextrin having a degree of polymerization of 5 can be synthesized. The present invention has been completed.

That is, the present invention provides cyclomaltopentaose represented by the following general formula (I) and its derivatives.

[0007]

[Chemical 2] (Formula R ¹ represents a hydrogen atom, a benzyl group or an acetyl group, and R ² represents a hydrogen atom, an acetyl group or a phenylcarbamoyl group.).

The present invention is described in detail below.

The compound of the present invention can be synthesized, for example, by the reaction formula shown below.

[0010]

[Chemical 3] As shown in the above reaction scheme, the compound of the present invention is prepared by condensing the compound [5] and the compound [6] at room temperature in the presence of methyl triflate (MeOTf) in 1,2-dichloroethane to give a pentasaccharide derivative [7α , Β] is obtained. A pentasaccharide derivative obtained by carbamoylating a pentasaccharide derivative [8] obtained by thiolyzing a pentasaccharide derivative [7α]

[9] is obtained and further deacetylated to obtain a cyclized precursor compound [10]. The cyclized precursor compound [10] thus obtained is subjected to a cyclization reaction under diluting conditions in order to avoid intermolecular condensation as much as possible to obtain the desired cyclic pentasaccharide derivative [11]. At that time, other three kinds of products are also produced as by-products. Then, decarbamoylation and debenzylation are carried out by a conventional method to obtain cyclomaltopentaose [1].

The compound [5], which is the starting material of the above reaction formula [Chemical Formula 3], can be synthesized, for example, by the following reaction formula.

[0012]

[Chemical 4] As shown in the above reaction formula, the compound [5] is ethyl-β
Ethyl-4-O-acetyl-2,3-di-O-benzyl-6 prepared from -D-glucopyranoside by a conventional method
-O- (N-phenylcarbamoyl) -1-thio-β-
D-glucopyranoside [2] was added to 1,2-dichloroethane in the presence of methyl triflate (MeOTf) to give 1,6-
It is obtained by condensation with anhydro-2,3,2 ′, 3 ′, 6′-penta-O-benzyl-β-maltose [3], followed by deacetylation. (Total yield 70%) The compound [6], which is a raw material of the above reaction formula [Chemical Formula 3], can be synthesized, for example, by the reaction formula shown below.

[0013]

[Chemical 5] As shown in the above reaction formula, the compound [6] is obtained by acetylating the free hydroxyl group of the compound [3], and then performing the Hannesian method (TMS).
Obtained by thiolysis with SMe / ZnI ₂ ) followed by condensation with phenyl isocyanate (PhNCO) in pyridine. (Total yield 75%) Cyclomaltopentaose having a degree of polymerization of 5 is an unknown compound whose existence has been considered impossible until now. The cyclodextrin having a degree of polymerization of 6 to 8 (α-, β-, γ-cyclodextrin) has an inner diameter of 5.7 to 9.5 A, which is a size suitable for including a benzene skeleton. On the other hand, that of cyclomaltopentaose with a degree of polymerization of 5 is 4A.
Since it is as follows, the aromatic compound cannot be a guest molecule because it is too large, and it is expected to selectively include linear molecules or ions such as acetylenes and cyano compounds. In other words, it is a useful compound that can be expected to be used as a selective separation medium for linear molecules or ions suitable for the inner diameter of cyclomaltopentaose having a degree of polymerization of 5 from these mixtures.

[0014]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

[0015]

Example 1 1,6-anhydro-2,3,2 ′, 3 ′, 6 ′, 2 ″, 3 ″
Synthesis of -hepta-O-benzyl-6 "-O- (N-phenylcarbamoyl) -β-maltotriose [5] Methyl triflate in 1,2-dichloroethane (4 ml)
(63 mg) and molecular sieves (4A, 300 mg),
Ethyl-4-O-acetyl-2,3-di-O-benzyl-6-O- (N-phenylcarbamoyl) -1-thio-
β-D-glucopyranoside [2] (87.5 mg) and 1,6-
Anhydro-2,3,2 ′, 3 ′, 6′-tetra-O-benzyl-β-maltose [3] (100 mg) was stirred at room temperature for 1 hour under an argon atmosphere. After neutralization with triethylamine and filtration, the filtrate was washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (C30
0, PhMe: AcOEt = 5: 1), 4 ″ -O-acetyl-1,6-anhydro-2,3,2 ′, 3 ′, 6 ′, 2 ″,
3 ″ -hepta-O-benzyl-6 ″ -O- (N-phenylcarbamoyl) -β-maltotriose [4] (128 m
g, 76%) and its β-bond isomer (30 mg, 18%) were obtained.
Compound [4] (415 mg) was dissolved in anhydrous methyl alcohol-anhydrous tetrahydrofuran (5: 1, 24 ml), 2M-sodium methylate (0.2 ml) was added, and the mixture was stirred overnight at room temperature, and the mixture was washed with a cation exchange resin. After neutralization, the reaction solution was concentrated under reduced pressure to obtain compound [5] (369 mg, 92%).

[0016]

Example 2 4 ″ ″-O-acetyl-1,6-anhydro-2,3
2 ', 3', 6 ', 2'',3'',2''', 3 ''',2'''',
3 "", 6 ""-dodeca-O-benzyl-6 ", 6 '"
Synthesis of -di-O- (N-phenylcarbamoyl) -β-maltopentaose [7α] Presence of methyl triflate (0.66 g) and molecular sieves (4A, 1 g) in 1,2-dichloroethane (40 ml) Below, methyl-4'-O-acetyl-2,3,2 ', 3', 6'-penta-O-benzyl-6-O- (N-phenylcarbamoyl) -1-thio-α, β-maltoside. [6] (1.71 g)
And compound [5] (1.66 g) were stirred at room temperature for 1 hour under an argon atmosphere. After neutralization with triethylamine and filtration,
The filtrate was washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (C300, PhMe: AcOEt
= 15: 1) to obtain the compound [7α] (2.09 g, 72%) and its β-bond isomer [7β] (466 mg, 16%).

[0017]

Example 3 Methyl-2,3,2 ′, 3 ′, 6 ′, 2 ″, 3 ″, 2 ′ ″,
3 ″ ′, 2 ″ ″, 3 ″ ″, 6 ″ ″-dodeca-O-benzyl-6,6 ″, 6 ′ ″-tri-O- (N-phenylcarbamoyl) -1-Thio-α, β-maltopentaoside [1
0] in 1,2-dichloroethane (10 ml), (methylthio) trimethylsilane (Me ₃ SiSMe) (0.16 ml) and zinc iodide (ZnI ₂ ) (1.71
In the presence of g), the compound [7α] (396 mg) was stirred at room temperature for 2 hours under an argon atmosphere. The reaction mixture was neutralized with saturated sodium bicarbonate water, the insoluble material was filtered off, and chloroform (10 m
l), the filtrate and the washing solution are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue of 1,2.
-Dissolved in dichloroethane (10 ml). Methanesulfonic acid (5 μl) was added to this solution, stirred for 1 minute, neutralized with triethylamine, the reaction mixture was concentrated under reduced pressure, and silica gel column chromatography (C300, PhMe: AcOEt = 10: 1).
And methyl-4 ″ ″-O-acetyl-2,3,
2 ', 3', 6 ', 2'',3'',2''', 3 ''',2'''',
3 "", 6 ""-dodeca-O-benzyl-6 ", 6 '"
-Di-O- (N-phenylcarbamoyl) -1-thio-
α, β-maltopentaoside [8] (347 mg, 86%) was obtained. Then, phenyl isocyanate (24 μl) was added to pyridine solution (10 ml) of thiopentaside [8] (342 mg) and stirred at room temperature for 2 hours and a half, and methyl alcohol was added to decompose excess phenyl isocyanate. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (C300, PhMe: AcOEt = 10: 1) to give methyl-
4 ""-O-acetyl-2,3,2 ', 3', 6 ', 2 ",
3 ", 2 '", 3'",2"",3"",6""-dodeca-
O-benzyl-6,6 ″, 6 ′ ″-tri-O- (N-phenylcarbamoyl) -1-thio-α, β-maltopentaoside

[9] (273 mg, 76%) was obtained. Then, it was dissolved in anhydrous methyl alcohol-anhydrous tetrahydrofuran (3: 1, 8 ml), 2M-sodium methylate (100 μl) was added, and the mixture was stirred at room temperature overnight and neutralized with a cation exchange resin.
The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (C300, PhMe: AcOEt = 10: 1) to obtain compound [10] (235 mg, 87%).

[0018]

Example 4 Synthesis of Cyclomaltopentaose [1] A 1,2-dichloroethane solution (5 m) containing methyl triflate (35.4 mg) in the presence of molecular sieves (4A, 800 mg).
To l), a solution of pentasaccharide [10] (165 mg) in 1,2-dichloroethane (7 ml) was added dropwise to the mixture under stirring in an argon atmosphere at room temperature for 2 and a half hours. After stirring overnight, the reaction mixture was neutralized with triethylamine and filtered. The filtrate was washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (C300, Hexane: AcOEt = 7: 2), and 2,3,6,2 ', 3', 2 ", 3", 2 "', 3"'. ,
6 "', 2"",3""-dodeca-O-benzyl-6',
6 '', 6 ''''-tri-O- (N-phenylcarbamoyl) -cyclomaltopentaose [11] (43 mg, 27
%) And its β-bond isomer (16 mg, 10%) were isolated. Compound [11] (24 mg) in isopropanol-tetrahydrofuran (5: 1) (3 ml) was added with 2M-sodium methylate.
(100 μl), heated under reflux for 1 hour and a half, neutralized with cation exchange resin, concentrated under reduced pressure, purified by silica gel column chromatography (C300, PhMe: AcOEt = 4: 1), 2, 3,
6, 2 ', 3', 2 '', 3 '', 2 ''',3''', 6 ''',2'''',
3 ″ ″-dodeca-O-benzyl-cyclomaltopentaose [12] (21 mg, quantitative) was obtained. After stirring compound [12] (6.4 mg) with 20% palladium hydroxide-carbon (44 mg) in a mixed solution of methyl alcohol (1.5 ml) -ethyl acetate (0.3 ml) under a hydrogen atmosphere at room temperature for 5 days, Filtration and the filtrate were concentrated under reduced pressure to obtain cyclomaltopentaose [1] (2.7 mg, quantitative).

FAB-MS: m / z 832 [M-H + N in positive ion mode
^{a] +, 833 [M +} Na] + in the negative ion mode ^{m / z 809 [MH] -} , 810 [M] - H-NMR (D 2 O): δ 5.048 (1H, d, J = 2.97Hz, H-1), 4.
008 (1H, dd, J = 9.89,8.26Hz, H-3), 3.927-3.800 (3H,
br.m, H-5, H-6,6 '), 3.618-3.569 (2H, m, H-2, H-4) Cyclomaltopentaose [1] pentadeca-O-acetate (cyclomaltopentaose) [1] was obtained by reacting with pyridine-acetic anhydride and then concentrated under reduced pressure.) H-NMR (CDCl ₃ ): δ 5.482 (1H, dd, J = 9.57, 7.59Hz,
H-3), 5.018 (1H, d, J = 3.30Hz, H-1), 4.855 (1H, dd,
J = 9.57, 3.30Hz, H-2), 4.396 (2H, br.d, J = 2.97Hz,
H-6,6 '), 4.210 (1H, br.dt, J = 8.25, 2.97Hz, H-5),
3.833 (1H, dd, J = 8.25, 7.59Hz, H-4), 2.135 (3H,
s, Ac), 2.076 (3H, s, Ac), 2.069 (3H, s, Ac).

[0020]

INDUSTRIAL APPLICABILITY The cyclodextrin having a degree of polymerization of 5 and its derivative of the present invention are novel compounds,
It can be expected to be widely used in the fields of food and cosmetics.

Claims (1)

[Claims] 1. Cyclomaltopentaose represented by the following general formula (I) and derivatives thereof: (Formula R ¹ represents a hydrogen atom, a benzyl group or an acetyl group, and R ² represents a hydrogen atom, an acetyl group or a phenylcarbamoyl group.)