JPH0635467B2 - Novel glycosylation method - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel glycosylation method of a sugar anomer.

[Prior Art] The glycosylation method is a so-called Koenig- coupling of a halogenated sugar obtained by halogenating a hydroxyl group of a sugar anomer with another alcohol in the presence of a silver salt or a mercury salt.
The method utilizing the Knorr reaction has been the main method.

In addition, a glycosylation method using pyranosyl bromide of methanol in the presence of triethylamine is known.
Very low yields have been obtained in reactions involving more complex alcohols as acceptors [C. Schuerc
h et al. "Carbohydr. Res." Vol. 39, No. 33
Page (1975)].

[Problems to be Solved by the Invention] When a conventional glycosylation method represented by the Koenig-Knorr reaction is used, it is uneconomical to use an excessive heavy metal salt such as silver or mercury as an activator. There was a problem.

Further, the above-mentioned method of Scheurch et al. Is an excellent method in that heavy metal salts are not used, but it cannot be applied to substrates other than lower alcohols such as methanol.

[Means for Solving Problems] As a result of intensive studies on the glycosylation method of alcohols, the present inventors have found that receptors having various hydroxyl groups can be glycosylated under high pressure conditions. A new glycosylation reaction was found and the present invention was completed.

The halogenated sugar derivative of the present invention includes, for example, glucopyranosyl bromide, galactopyranosyl bromide, mannopyranosyl bromide, and other common hexose pyranosyl bromides, xylopyranosyl bromides, and arabinopyranos. Examples include usual pentose pyranosyl bromides such as silbromide, and deoxy or aminodeoxy derivatives of these sugars. The hydroxyl group or amino group of these halogenated sugars is protected with a protective group. The halogenated sugar is used in the range of 1.2 to 1.5 equivalents with respect to the alcohol.

Examples of alcohols which are the acceptor compounds of the present invention include methanol, ethanol, cyclohexanol, t
Examples thereof include alcohols such as ert-butyl alcohol, monosaccharides such as galactose, glucose, mannose, sterols such as cholesterol, and amino acids such as serine and threonine.

That is, various compounds having a hydroxyl group represented by the general formula R-0H can serve as acceptors. In addition, when these acceptor compounds have other functional groups, these are protected by a protecting group.

Examples of the tertiary amines used in the present invention include triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, 2,6-di-tert-butylpyridine, 2,4,6-collidine and tetramethylurea. can give. The tertiary amines are 1.2 to 3.0 equivalents, preferably 1.2 to 1.
Use in the range of 5 equivalents.

The glycosylations of the present invention include halogenated sugars, alcohols,
The above-mentioned tertiary amines and molecular sieve 4A are dissolved in a solvent, sealed in a Teflon capsule, set in a high-pressure reaction vessel, and pressure is applied to the capsule to react. Examples of the solvent include halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as toluene, acetonitriles and the like. To be

The reaction pressure can be set in the range of 4000 to 15000 atm, but is preferably in the range of 8000 to 15000 atm. The reaction temperature can be set in the range of room temperature to 100 ° C. according to the intended product, but room temperature to 40 ° C. is suitable. The reaction time is not constant depending on the reactivity of the receptor and the reaction temperature, but 20 to 40 hours is usually sufficient.

The compound obtained in the present invention can be purified by a usual means such as silica gel column chromatography and recrystallization.

[Effect of the Invention] According to the method of the present invention, the corresponding glycosyl compound can be obtained from the halogenated sugar derivative and the alcohol under high pressure conditions. The method of the present invention is a safe and economical method as compared with the conventional method in that the operation is simple and it is not necessary to use any heavy metal salt such as silver or mercury. Further, as shown in Examples described later, according to the method of the present invention, α-O
-Glycoside bonds can be obtained with high selectivity.

EXAMPLES Next, the present invention will be described in more detail based on examples.

Example 1 O- (2,3,4,6-tetra-O-benzyl-D-glucopyranosyl) cholesterol (1) 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl Bromide (181.3mg, 0.301mmo
l), cholesterol (96.7mg, 0.251mmo
l), 2,6-lutidine (35 μ, 0.300 mmol)
And molecular sieve 4A (about 100 mg),
Methylene chloride (2 m) was added to and dissolved therein, and the mixture was sealed in a Teflon capsule and set in a high-pressure reaction vessel. Apply a pressure of about 8000 atm to the capsules, and
The reaction was allowed for 0 hours. The pressure was returned to normal pressure, the insoluble material was filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (silica 10
g, 5 → 10% ethyl acetate-hexane), and α and β
To obtain a mixture (1) (151.7 mg, 67%).

HPLC (8% ethyl acetate-hexane, flow rate 1 m / mi
n) tr (tr indicates the retention time of liquid chromatography) α: 10.4 min, β: 7.9 min α / β = 93/7 Further, the α-form was separated by preparative thin-layer chromatography and re-extracted from ethanol. It crystallized.

mp 145-145.5 ° C (In the formula, Bn represents a benzyl group.) Example 2 Cyclohaxyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside (2) 2,3,4,6-tetra-O-benzyl- α-D-glucopyranosyl bromide (179.2 mg, 0.297 mmo
l), cyclohexanol (24.9mg, 0.246mmo
l), 2,6-lutidine (35 μ, 0.300 mmol)
And molecular sieve 4A (about 100 mg),
Methylene chloride (2 m) was added to and dissolved therein, and the mixture was sealed in a Teflon capsule and set in a high-pressure reaction vessel. Apply a pressure of about 8000 atm to the capsules, and
The reaction was allowed for 0 hours. The pressure was returned to normal pressure, the insoluble material was filtered through Celite, diluted with chloroform, and washed with a 0.5 M aqueous hydrochloric acid solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (silica 15 g, 1: 5 → 1: 4 ethyl acetate-hexane) to give a mixture of α and β. (2) (122.7 mg, 79%) was obtained.

HPLC (10% ethyl acetate-hexane, flow rate 1 m /
min) tr α: 10.6 min, β: 9.0 min α / β = 92/8 (In the formula, Bn represents a benzyl group.) Example 3 tert-butyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside (3) 2,3,4,6-tetra-O- Benzyl-α-D-glucopyranosyl bromide (203.1 mg, 0.337 mmo
l), tert-butyl alcohol (20.6 mg, 0.
278 mmol), 2,6-lutidine (39 μ, 0.33
(5 mmol) and molecular sieve 4A (about 100 mg) were dissolved in methylene chloride (2 m), the mixture was sealed in a Teflon capsule, and a pressure of 8000 atm was applied, and the reaction was carried out at room temperature for 20 hours. The same post-treatment as in Example 2 was performed, and the obtained crude product was subjected to silica gel column chromatography (silica 15 g, 1: 5 → 1: 4 ethyl acetate-hexane) to give a mixture of α and β (3) ( 98.5 mg, 59%) was obtained.

HPLC (10% ethyl acetate-hexane, flow rate 1 m /
min) tr α: 10.9 min, β: 9.9 min α / β = 93/7 (In the formula, Bn represents a benzyl group.) Example 4 Methyl 2,3,4, -tri-O-benzyl-6-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -α-D-glucopyranoside (4) 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl Bromide (232.2mg, 0.385mmo
l), methyl 2,3,4-tri-O-benzyl-α-
D-glucopyranoside (117.6 mg, 0.253 mmol), diisopropylethylamine (70 μ, 0.402 mmol) and molecular sieve 4A (about 100 mg) were added to methylene chloride (2 m).
Dissolve in, seal in a Teflon capsule, 40 ℃, 80
The reaction was carried out at 00 atm for 20 hours. The same post-treatment as in Example 2 was performed, and the resulting crude product was subjected to silica gel column chromatography (silica 10 g, 10 → 20% ethyl acetate-hexane) to give a mixture of α and β (4) (171.8 mg). , 69%).

HPLC (hexane / THF = 5/1, flow rate 1 m / mi
n) tr α: 15.7 min, β: 13.9 min α / β = 85/15 (In the formula, Bn represents a benzyl group.) Example 5 1,2,3,4-di-O-isopropylidene-6-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -α-D-galactopyranoside (5) 2,3,4,6-tetra-O-benzyl-α-D-gluco Pyranosyl bromide (185.0 mg, 0.307 mmo
l), 1,2,3,4-di-O-isopropylidene-α
-D-galactopyranose (65.7 mg, 0.252 mm)
ol), diisopropylethylamine (53μ, 0.3
(04 mmol) and molecular sieves 4A (about 100 mg) were dissolved in methylene chloride (2 m), encapsulated in a Teflon capsule, and reacted at 25 ° C. and about 8000 atm for 44 hours. The same post-treatment as in Example 2 was carried out, and the resulting crude product was subjected to silica gel column chromatography (silica 10 g,
10 → 20% ethyl acetate-hexane) to obtain α and β
To give a mixture (5) of (156.0 mg, 79%).

HPLC (20% ethyl acetate-hexane, flow rate 1 m /
min) tr α: 10.2 min, β: 11.6 min α / β = 88/12 (In the formula, Bn represents a benzyl group.) Example 6 1,2,3,4-tetra-O-acetyl-6-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -β-D-glucopyranose (6) 2,3,4,6-tetra-O-benzyl-α-D-glucopyrano Silbromide (182.5mg, 0.303mmo
l), 1,2,3,4-tetra-O-acetyl-β-D
-Glucopyranose (87.0 mg, 0.250 mmol),
2,6-lutidine (35 μ, 0.300 mmol) and molecular sieve 4A (about 100 mg) were added to methylene chloride (2
m), seal in Teflon capsules, 25
The reaction was carried out at a temperature of about 8000 atm for 20 hours. The same post-treatment as in Example 2 was carried out, and the resulting crude product was subjected to silica gel column chromatography (silica 20 g, 30 → 35%.
Ethyl acetate-hexane), and a mixture of α and β (6)
(104.8 mg, 48%) was obtained.

HPLC (3% ethanol-hexane, flow rate 1 m / mi
n) tr α: 10.7 min, β: 9.8 min α / β = 94/6 (In the formula, Bn represents a benzyl group and Ac represents an acetyl group.) Example 7 N-benzyloxycarbonyl-O- (2,3,4,6)
-Tetra-O-benzyl-α-D-glucopyranosyl)
-L-serine methyl ester (7) 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl bromide (189.3 mg, 0.314 mmo
l), N-benzyloxycarbonyl-L-serine methyl ester (65.3 mg, 0.258 mmol), 2,6
-Lutidine (36μ, 0.309mmol) and molecular sieve 4A (about 100mg) in methylene chloride (2m).
Dissolve in, seal in a Teflon capsule, 25 ℃,
The reaction was carried out at about 8000 atm for 20 hours. The same post-treatment as in Example 2 was performed, and the obtained crude product was subjected to silica gel column chromatography (silica 15 g, 5 → 10% ether-benzene) to give a mixture of α and β (7) (1).
19.2 mg, 60%) was obtained.

HPLC (acetonitrile / water = 5/1, flow rate 1 m /
min) tr α: 10.1 min, β: 11.5 min α / β = 95/5 (In the formula, Bn represents a benzyl group.)

Claims (1)

[Claims] 1. A glycosylation method, which comprises reacting a halogenated sugar derivative with an alcohol in the presence of a tertiary amine under high pressure conditions (at least 4000 atm).