JPH06166696A - Fucosyl-glucosamine derivative - Google Patents

Abstract

PURPOSE:To provide the title derivative which is composed of fucosyl- glucosamine derivative and serves as a synthetic intermediate for synthesis of saccharides having fucose participating intercellular recognition and carcinic alteration in the saccharide chains such as sialyl-Lewis X. CONSTITUTION:beta-D-glucosamine penta-acetate of formula I (Ac is acetyl) is treated with trimethylsilyl-trifluoromethanesulfonate in a solvent to form a compound of formula II, which is allowed to react with benzyl alcohol to effect benzylation. The product is treated with a sodium methoxide solution in methanol, then with benzaldehyde dimethyl acetal to give a compound of formula III (Ph is phenyl, Bz is benzyl), which is allowed to react with a fucose derivative of formula IV (Me is methyl) to form a compound of formula V. The product is treated with sodium cyanoborohydride to give the objective fucosyl- glucosamine derivative of formula VI (Z<1>-Z<5> are protection groups for hydroxyls; Y is acyl).

Description

Detailed Description of the Invention

[Background of the Invention]

TECHNICAL FIELD The present invention relates to a fucosyl-glucosamine derivative as an intermediate useful in the chemical synthesis of a sugar chain having fucose as a branched chain, and a method for producing the same.

[0002]

2. Description of the Related Art Sugar chains having fucose as a branched chain are
It is said to be involved in cell-cell recognition, cancerous changes, etc., and is thought to play an important role when considering a drug delivery system that aims to deliver a therapeutic drug to a specific tissue. ing.

For example, a sugar chain having Lewis X or sialyl Lewis X having sialic acid bound thereto is P-selectin or E-selectin (ELAM-) which is one of lectins having an action as a cell adhesion molecule.
It is known as a ligand of 1) and is also considered to have a function as a recognition element for cells that specifically express these lectins. This ELAM-1 is expressed in vascular endothelial cells by inflammatory stimulation, and therefore, when sialyl Lewis X is used as a recognition element, an anti-inflammatory agent is specifically delivered to an inflammatory site including vascular endothelial cells exhibiting inflammation. Can be expected.

Therefore, it can be said that it is of great significance to obtain a synthetic intermediate which facilitates the chemical synthesis of a sugar chain having such a fucose as a branched chain.

[Outline of the Invention]

An object of the present invention is to provide a fucosyl-glucosamine derivative which is an intermediate useful for chemically synthesizing a sugar chain having fucose as a branched chain.

Further, the present invention aims to provide a method for producing the fucosyl-glucosamine derivative.

[0007]

The fucosyl-according to the present invention
The glucosamine derivative is a compound represented by the following general formula (I).

[0008]

[Chemical 2] (In the above formula, Z ^{1 to} Z ⁵ each independently represent a hydroxyl-protecting group, and Y represents an acyl group.) The compound represented by the general formula (I) is different from the 4-position of the glucosamine moiety. All the hydroxyl groups are protected by a protecting group, and an arbitrary compound such as monosaccharide or oligosaccharide can be introduced into this portion. Therefore, it is a useful intermediate in the chemical synthesis of sugar chains having fucose as a branched chain.

[Detailed Description of the Invention] Fucosyl-glucosamine derivative The fucosyl-glucosamine derivative constituting the present invention is
The fucose having a protective group introduced at the hydroxyl groups at the 2, 3 and 4 positions, the α (1 → 3) bond to the glucosamine obtained by introducing a protective group at the hydroxyl groups at the 1 and 6 positions and acylating the amino group at the 2 position. It has a structure in which it is bound via.

Z ^{1 to} Z ⁵ in the general formula (I) each independently represent a hydroxyl-protecting group. As these protecting groups, those commonly used for protecting hydroxyl groups are preferably used, and examples thereof include ester protecting groups, ether protecting groups, silyl protecting groups and divalent protecting groups used for diols. And so on.

Preferred examples of the ester protecting group are acetyl group, benzoyl group and pivaloyl group, and preferred examples of the ether protecting group are benzyl group, paramethoxybenzyl group, methoxymethyl group and 1-ethoxyethyl group. A 2- (trimethylsilyl) ethoxymethyl group and the like are preferable examples of the silyl-based protecting group, and a tert-butyldimethylsilyl group, a triisopropylsilyl group, and the like are included.
Preferred examples of the divalent protecting group used for the diol include a benzylidene group and an isopropylidene group. A benzyl group and a paramethoxybenzyl group are particularly preferable.

In the formula, Y represents an acyl group, and a preferable example thereof is a C _1-6 alkanoyl group (eg, acetyl group).

In the fucosyl-glucosamine derivative according to the present invention, all hydroxyl groups are protected except for the 4-position hydroxyl group of the glucosamine moiety. Therefore, any compound can be introduced at the 4-position of this glucosamine moiety.

For example, when the compound to be introduced is galactose, the compound (Lewis X) represented by the following formula can be obtained by binding the galactose to the derivative by β (1 → 4).

[0015]

[Chemical 3] (In the above formula, Ac represents an acetyl group.) Further, sialic acid is further α (2 → 3) -bonded to the 3-position of the galactose portion of Lewis X, or sialyl is added to the compound of the general formula (I). A compound represented by the following formula by introducing galactose (sialyl Lewis X)
Is obtained.

[0016]

[Chemical 4] (In the above formula, Ac represents an acetyl group.) Production of Fucosyl-Glucosamine Derivative The fucosyl-glucosamine derivative according to the present invention can be synthesized by various purposeful methods. According to a preferred synthetic method, the derivative according to the invention is a compound of formula (II):

[0017]

[Chemical 5] (In the above formula, Y and Z ¹ have the same meanings as defined in formula (I), Q represents a substituted or unsubstituted phenyl group, preferably a phenyl group or a paramethoxyphenyl group). A compound represented by the following formula (III):

[0018]

[Chemical 6] (In the above formula, Z ³ , Z ⁴ and Z ⁵ have the same meanings as defined in formula (I), R represents a leaving group, preferably a lower (C _1-6 ) alkyl group) It can be synthesized by reacting with and then subjecting to a reduction operation.

The reaction of the compound of formula (II) with the compound of formula (III) is carried out in a solvent that does not participate in the reaction (for example, methylene chloride, acetonitrile, or a mixed solvent thereof).
It can be completed in a few days in the presence of a suitable catalyst (N-iodosuccinimide / trifluoromethanesulfonic acid, dimethyl (methylthio) sulfonium triflate, etc.) at a temperature of -40 to -25 ° C.

As a result of this reaction, the compound represented by the following formula:

[0021]

[Chemical 7] Is obtained.

Next, the compound represented by the general formula (I) according to the present invention can be obtained by reducing the cyclic acetal moiety of glucosamine of this compound. The reduction is
Using a suitable reducing agent (eg sodium cyanoborohydride) in a solvent not participating in the reaction (eg tetrahydrofuran, dioxane, diethyl ether),
The reaction can be completed within 1 hour at a temperature of 0 to 25 ° C.

The compound of formula (II) can be preferably synthesized from β-D-glucosamine according to a method similar to the method described in Carbohydrate Research, 200 , 269-285 (1990).

Further, the compound of the formula (III) is J. Carbohydra
can be synthesized from L-fucopyranose tetraacetate according to the method described in te Chemistry, 10 (4), 549-560 (1991).

[0025]

EXAMPLES The present invention will be explained in more detail by the following examples, but the present invention is not limited thereto.

The synthetic process of the examples is shown below as a scheme. The compound numbers in the examples are the numbers shown in the scheme.

[0027]

[Chemical 8]

Example 1 Compound 1 was synthesized as described in J. Carbohydrate Chemistry, 10 (4), 549-560 (1991).

Example 2 β-D-Glucosamine pentaacetate (14.0 g)
Was dissolved in 1,2-ethylene chloride (180 ml), trimethylsilyltrifluoromethanesulfonate (6.96 ml) was added, and the mixture was stirred at 55 ° C for 4 hr.
After adding triethylamine (10.1 ml) at room temperature,
The solvent was evaporated, the residue was purified by column chromatography using silica gel (200 g) (ethylene chloride-methanol-triethylamine 200: 1: 1), and compound 2 was obtained as a crude product (11.8 g).

Example 3 Compound 2 (7.90 g) and benzyl alcohol (4.97 ml) were added to Molecular Sieves 4A (8).
g) was dissolved in a 1,2-ethylene chloride solution (80 ml) containing trimethylsilyltrifluoromethanesulfonate (4.64 ml), and the mixture was stirred at 55 ° C. for 2 hours. After adding triethylamine (7.70 ml) at room temperature and filtering the reaction solution, the filtrate was diluted with methylene chloride, washed with water and dried, and then the solvent was distilled off. Subsequently, the obtained residue was washed with diisofluropyl ether to obtain compound 3 (7.50 g).

M. p. 161.5-162 ° C. (colorless needle crystal, recrystallized from a mixed solvent of n-hexane and methylene chloride) [α] _D ²⁴ -50.7 ° (cl.21, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) Δ: 7.38-7.28
(5H, m), 5.37 (1H, br.d, J = 8.5)
Hz), 5.20 (1H, dd, J = 10.5, 9.3)
Hz), 5.10 (1H, dd, J = 9.8, 9.3H)
z), 4.90, 4.60 (both 1H, d, J =
12.0 Hz), 4.63 (1H, d, J = 8.3H
z), 4.28 (1H, dd, J = 12.3, 4.6H)
z), 4.17 (1H, dd, J = 12.3, 2.4H
z), 3.98 (1H, ddd, J = 10.5, 8.
5, 8.3 Hz), 3.67 (1H, ddd, J = 9.
8, 4.6, 2.4 Hz), 2.11, 2.02, 1.
91 (each 3H, s).

Example 4 A methanol solution (8) in which the compound 3 (7.50 g) was dissolved
To 5 ml), 28% sodium methoxide-methanol solution (1 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution is a cation exchange resin (Dowex 50W-X8H ⁺
form) was added for neutralization, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure (5.38 g).

Subsequently, 437 mg of the obtained residue was dissolved in N, N'-dimethylformamide (5.0 ml), and benzaldehyde dimethyl acetal (0.6 m) was added.
l) and d-camphorsulfonic acid (16 mg) were added, and 5
The mixture was stirred at 5 ° C. for 3 hours under reduced pressure (45 mmHg). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of n-hexane and methylene chloride to give compound 4 (360 mg).
Column chromatography (methylene chloride-methanol 3) using silica gel (15 g) as the mother liquor.
Purification by 0: 1) gave an additional 56 mg.

M. p. 237-238 ° C (colorless needle crystals,
Recrystallized from a mixed solvent of n-hexane and methylene chloride) [α] _D ²⁴ -74.8 ° (c0.53, CHCl ₃ : M
_{eOH: H 2 O = 10:} 10: 3) IR (KBr): 3288,1657cm -1 1 H-NMR (CDCl 3) δ: 7.64-7.68
(2H, m), 7.52-7.58 (2H, m), 7.
28-7.40 (6H, m), 5.78 (1H, s),
5.18 (1H, d, J = 8.3 Hz), 5.11,
4.83 (each 1H, d, J = 12.5 Hz),
4.63 (1H, dd, J = 8.3, 9.8Hz),
4.56 (1H, dd, J = 9.8, 9.0Hz),
4.49 (1H, dd, J = 10.0, 4.9Hz),
3.98 (1H, dd, J = 9.3, 9.0 Hz),
3.95 (1H, dd, J = 10.0, 9.3Hz),
3.72 (1H, ddd, J = 9.3, 9.3, 4.9
Hz), 2.11 (3H, s).

Example 5 Compound 1 (2.91 g) and compound 4 (1.00) in a mixed solvent of methylene chloride (112 ml) and acetonitrile (48 ml) containing molecular sieves 3A (10 g).
g) was added, and the mixture was stirred at room temperature for 3 hours, then N- at -40 ° C.
Iodosuccinimide (2.81 g) and trifluoromethanesulfonic acid (110 μl) were added, and the mixture was stirred at the same temperature for 63 hours. After the reaction solution was filtered, the filtrate was washed with an aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, and then dried to remove the solvent. The residue was purified by column chromatography using silica gel (150 g) (toluene-ethyl acetate-methanol 210: 40: 1) to give compound 5 (916 mg).

M. p. 171-172 ° C (colorless needle crystals, recrystallized from a mixed solvent of n-hexane and methylene chloride) Anal. Calcd for C ₄₉ H ₅₃ NO ₁₀ · 0.
_{5H 2 O: C, 71.34;} H, 6.60; N, 1.7
0. Found: C, 71.50; H, 6.44; N,
1.71. ^{_{[Α] D 26 -98.8 ° (}} c = 1.09, CHCl 3) IR (CHCl 3): 1678cm -1 1 H-NMR (CDCl 3) δ: 7.42-7.46
(2H, m), 7.35-7.23 (23H, m),
5.50 (1H, br.d, J = 6.1Hz), 5.5
0 (1H, s), 5.01 (1H, d, J = 3.4H
z), 4.89, 4.85, 4.61, 4.56 (ea
ch 1H, d, J = 11.5Hz) 4.84,4.5
3 (each 1H, d, J = 12.2 Hz), 4.3
4 (1H, dd, J = 10.3, 4.9Hz), 4.2
1 (1H, dd, J = 9.5, 9.3 Hz), 4.04
(1H, q, J = 6.3 Hz), 4.03 (1H, d
d, J = 10.2, 3.4 Hz), 3.91 (1H, d
d, J = 10.2, 2.4 Hz), 3.76 (1H, d
d, J = 10.3, 10.3 Hz), 3.59 (1H,
dd, J = 9.3, 9.3), 3.57 (1H, br.
s), 3.52-3.45 (2H, m), 1.57 (3
H, s), 0.82 (3H, d, J = 6.3 Hz). ¹³ C-NMR (CDCl ₃ ) δc: 170.6, 13
8.8, 138.8, 138.7 (x2), 137.4
(X2), 129.1, 128.8, 128.6, 12
8.4, 128.3, 128.0, 127.7, 12
7.5, 126.3, 101.7, 100.3, 98.
4, 81.0, 79.9, 77.7, 77.2, 75.
1, 75.1, 74.2, 72.8, 71.3, 69.
0, 67.1, 66.4, 58.1, 233.3, 16.
5.

Example 6 Compound 5 (750 mg) was dissolved in a tetrahydrofuran solution (11 ml) containing molecular sieves 3A (4 g), and the mixture was stirred at room temperature for 3 hours, and sodium cyanoborohydride (1.15 g) was slowly added. It was After sodium cyanoborohydride was completely dissolved, hydrogen chloride-ether solution was added dropwise until gas generation stopped.
Stir for 5 minutes. The reaction solution was filtered, the filtrate was diluted with methylene chloride, washed with 1% hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, and dried, and then the solvent was distilled off. The residue was purified by column chromatography using silica gel (45 g) (n-hexane-ethyl acetate-methanol 100: 50: 1) to give compound 6 (457).
mg) was obtained.

M. p. 184.5-186 ° C (colorless needle crystals, recrystallized from a mixed solvent of n-hexane and methylene chloride) Anal. Calcd for C ₄₉ H ₅₅ NO ₁₀ : C,
71.95; H, 6.78; N, 1.71. Foun
d: C, 72.03; H, 6.71; N, 1.81. ^{_{[Α] D 26 -56.1 ° (}} c1.01, CHCl 3) IR (CHCl 3): 3458,1678cm -1 1 H-NMR (CDCl 3) δ: 7.40-7.25
(25H, m), 5.42 (1H, br.d, J = 7.
1 Hz), 4.95, 4.81 (each 1H, d,
J = 11.5 Hz) 4.89, 4.74, 4.63,
4.62, 4.59 (each 1H, d, J = 12.
0Hz), 4.64, 4.61 (each1H, d, J = 1
2.2Hz, 4.96 (1H, d, J = 3.7H
z), 4.83 (1H, d, J = 8.1 Hz), 4.1
4 (1H, br.s, disappeared with D ₂ O), 4.10 (1
H, q, J = 6.3 Hz), 4.07 (1H, dd, J
= 10.2, 3.7 Hz), 3.93 (1H, dd, J
= 10.2, 2.0 Hz), 3.85 (1H, br.
d, J = 10.7 Hz), 3.79 (1H, dd, J =
9.2, 8.3 Hz), 3.73 (1H, dd, J = 1)
0.7, 4.6 Hz), 3.68 (1H, br.s),
3.53-3.44 (3H, m), 1.57 (3H, m
s), 1.15 (3H, J = 6.3Hz).

Front Page Continuation (72) Inventor Akira Hasegawa 1-1 Yanagido, Gifu City, Gifu Prefecture Gifu University Faculty of Agriculture

Claims (3)

[Claims] 1. A fucosyl-glucosamine derivative represented by the following general formula (I). [Chemical 1] (In the above formula, Z ^{1 to} Z ⁵ each independently represent a hydroxyl-protecting group, and Y represents an acyl group). 2. The fucosyl-glucosamine derivative according to claim 1, wherein the protecting group is an ester protecting group, an ether protecting group, a silyl protecting group or a divalent protecting group used for a diol. 3. The fucosyl-glucosamine derivative according to claim 1, wherein the protecting group is a benzyl group and Y is an acetyl group.