JPH0570473A - Production of beta-glucoside - Google Patents

Abstract

PURPOSE:To synthesize the title compound in high stereoselectivity without utilizing participation of adjacent group located at second position by reacting phenylthioglycoside with alcohols in the presence of a specific compound in a nitrile based solvent. CONSTITUTION:Phenylthioglycoside is reacted with alcohols (e.g. methanol, galactose, cholesterol or serine in the presence of a N-halosuccinic acid imide (preferably N-bromosuccinic acid imide) and trifluoromethanesulfonic acid in a nitrile-based solvent (e.g. acetonitrile or propionitrile), preferably at -78 to -42 deg.C for 0.5-1hr to provide the objective compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing β-glycosides with high stereoselectivity.

[0002]

BACKGROUND OF THE INVENTION Many β-glycosides are useful as various medicines or synthetic intermediates thereof. β-
As a method for producing a glycoside, conventionally, an acyl-protected sugar is used as a sugar donor, and the participation of the adjacent acyl group at the 2-position acyl group is utilized [(i) Hanessian and Banoub, Carbohydr.
s. 53, C13 (1977); (ii) Kunz and Harreus, Liebigs A
nn. Chem., 41 (1982)] is widely used.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The above-mentioned conventional method utilizing the adjacent group participation of the 2-position acyl group is a by-product of 1,2-orthoester and deprotection of the acyl group under basic conditions. There is a problem that it is necessary. That is, an object of the present invention is to provide a method capable of synthesizing β-glycoside in a highly stereoselective manner without utilizing the involvement of the adjacent group at the 2-position.

[0004]

The method for producing β-glycoside of the present invention comprises reacting phenylthioglycoside with alcohols in the presence of N-halosuccinimide and trifluoromethanesulfonic acid in a nitrile solvent. It is characterized by. Examples of the phenylthioglycoside used in the present invention include phenyl 1-thio-β-D-glucopyranoside, phenyl 6-O- (α-D-glucopyranosyl) -1-thio-β-D-glucopyranoside, and phenyl 1-thio-β. Common hexoses such as -D-galactopyranoside, phenyl 1-thio-β-D-mannopyranoside, phenyl 1-thiopyranoside, phenyl 1-thio-β-D-xylopyranoside, phenyl 1-thio-β
Examples of the pentose include phenyl 1-thiopyranoside such as -D-arabinopyranoside and deoxy or aminodeoxy derivatives thereof. The hydroxyl group or amino group of these phenylthioglycosides is protected with a protective group.

Examples of the hydroxyl-protecting group include an alkyl group, a benzyl group, a trimethylsilyl group and an alkylidene group. Further, as the amino group-protecting group, for example, acetyl, acyl groups such as benzoyl, tert
-Alkoxycarbonyl groups such as butoxycarbonyl and allyloxycarbonyl, and sulfonyl groups such as tosyl or mesyl. Phenylthioglycoside is preferably used in the range of 1.1 to 1.5 equivalents with respect to alcohols.

Examples of alcohols used in the present invention include methanol, ethanol, cyclohexanol and te.
Examples thereof include alcohols such as rt-butyl alcohol, monosaccharides such as galactose, glucose and 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-OH can be used. In addition, when these alcohols have other functional groups, these are protected by a protecting group. Examples of the N-halosuccinimide used in the present invention include N-bromosuccinimide and N-iodosuccinimide, with N-bromosuccinimide being particularly preferred.

The N-halosuccinimide is preferably used in the range of 2.0 to 2.5 equivalents with respect to the alcohols. Further, trifluoromethanesulfonic acid is preferably used in the range of 0.1 to 1.0 equivalent with respect to alcohols. Examples of the nitrile solvent used in the present invention include acetonitrile and propionitrile.

The reaction temperature is -78 ° C to -42 ° C.
C. is preferred, but the stereoselectivity of the reaction is better when the temperature is as low as possible. The reaction time is not constant depending on the reactivity of alcohols and the reaction time, but usually 0.5 to 1 hour is sufficient. The β-glycoside obtained in the present invention can be purified by usual means such as silica gel column chromatography and recrystallization.

[0009]

The present invention will be described in more detail below with reference to examples, but these examples do not limit the scope of the present invention in any way.

Example 1 Methyl 2,3,4-tri-O-benzyl-6-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -α-D-glucopyranoside Phenyl 2,3,4,6-tetra-under an argon atmosphere
O-benzyl-1-thio-β-D-glucopyranoside (174.0 mg, 0.275 mmol) and methyl 2,3,4
-Tri-O-benzyl-α-D-glucopyranoside (1
15.8 mg, 0.250 mmol) was dissolved in dry propionitrile (3 mL) and cooled to -78 ° C. N-bromosuccinimide (89.5 mg, 0.503 mmol) and trifluoromethanesulfonic acid (2.2 μL, 0.0
25 mmol) was added, and the mixture was stirred at -78 ° C for 30 minutes. The reaction was quenched by adding triethylamine (0.1 mL) and diluted with ethyl acetate (30 mL). The extract was washed with 10% aqueous sodium thiosulfate solution and then with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (silica 10
g, 10% ether-benzene) to obtain a mixture of α and β (220.6 mg, 90%). As a result of HPLC analysis, it was determined that α: β = 1: 27.

Example 2 O- (2,3,4,6-tetra-O-benzyl-α-D
-Glucopyranosyl)-(1 → 6) -O- (2,3,4)
-Tri-O-benzyl-D-glucopyranosyl)-(1
→ 6) -2,3,4-tri-O-benzyl-N- (O-
Benzyl-N-benzyloxycarbonyl-L-β-aspartyl) -α-D-glucopyranosylamine Phenyl 2,3,4-tri-O-benzyl-6-O- (2,3,4) under an argon atmosphere. , 6-Tetra-O-benzyl-α-D-glucopyranosyl) -1-thio-β-D
-Glucopyranoside (412.4 mg, 0.387 mmo
l) 2,3,4-tri-O-benzyl-N- (O-benzyl-N-benzyloxycarbonyl-L-β-aspartyl) -α-D-glucopyranosylamine (20
2.8 mg, 0.257 mmol) and molecular sieve 4A
(300 mg) was dissolved in dry propionitrile (10 mL) and cooled to -78 ° C. This was mixed with N-bromosuccinimide (101.1 mg, 0.568 mmol) and a solution of trifluoromethanesulfonic acid in propionitrile (about 0.1
1M, 2 mL) was added, and the mixture was stirred at -78 ° C for 1 hr. The reaction was quenched by adding triethylamine (0.1 mL) and diluted with ethyl acetate (80 mL). The extract was washed with a 10% aqueous sodium hydrogen sulfite solution, a saturated aqueous sodium hydrogen carbonate solution, and then with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (silica 50 g, 30% ethyl acetate-hexane) to obtain a mixture of α and β (332.6 m).
g, 74%). As a result of HPLC analysis, α: β =
It was decided to be 4:96.

Example 3 1,2,3,4-di-O-isopropylidene-6-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -α-D-galactopyranose 1,2,3,4-di-O-isopropylidene-α-D-galactopyranose as alcohols A mixture of α and β (94%) was prepared in the same manner as in Example 1 except that
Got As a result of HPLC analysis, it was determined that α: β = 1: 23.

Example 4 1,2,3,4-di-O-isopropylidene-6-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -α-D-galactopyranose N-iodosuccinimide was used as the N-halosuccinimide, the reaction temperature was -42 ° C, and the reaction time was To 0.2
A mixture of α and β (quantitative) was obtained in the same manner as in Example 3 except that the time was used. As a result of HPLC analysis, α: β =
It was decided to be 1:13.

Example 5 Methyl 2,3,6-tri-O-benzyl-4-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -α-D-glucopyranoside Other than using methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside as alcohols In the same manner as in Example 1, a mixture of α and β (86%) was obtained.
As a result of HPLC analysis, it was determined that α: β = 1: 3.6.

Example 6 Methyl 2,3,4-tri-O-benzyl-6-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -α-D-glucopyranoside N-iodosuccinimide was used as the N-halosuccinimide, the reaction temperature was -42 ° C, and the reaction time was 0.2
A mixture of α and β (92%) was obtained in the same manner as in Example 1 except that the time was used. As a result of HPLC analysis, α: β =
It was decided to be 1:14.

Example 7 N-benzyloxycarbonyl-O- (2,3,4,6)
-Tetra-O-benzyl-D-glucopyranosyl) -L
-Serine benzyl ester N-benzyloxycarbonyl-L as alcohols
Example 1 except that serine benzyl ester was used
Similarly to the above, a mixture of α and β (88%) was obtained. ¹³ C
As a result of NMR analysis, it was determined that α: β = 1: 5.

Comparative Example 1 Methyl 2,3,4-tri-O-benzyl-6-O-
(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl) -α-D-glucopyranoside The solvent was dry acetonitrile, trifluoromethanesulfonic acid was not used, the reaction temperature was room temperature, and the reaction time was 2
A mixture of α and β (93%) was obtained in the same manner as in Example 6 except that the time was set to 0 hour. As a result of HPLC analysis, α: β
= 1: 3.6 was determined.

[0018]

INDUSTRIAL APPLICABILITY According to the present invention, β-glycoside can be synthesized in a highly stereoselective manner without utilizing the participation of the adjacent group at the 2-position.

Front page continuation (72) Inventor Hiroshi Nakanishi, 1-1 Higashi 1-1-chome, Tsukuba, Ibaraki Prefectural Institute of Chemical Technology

Claims (2)

[Claims] 1. A process for producing β-glycoside, which comprises reacting phenylthioglycoside with alcohols in the presence of N-halosuccinimide and trifluoromethanesulfonic acid in a nitrile solvent. 2. The method according to claim 1, wherein the N-halosuccinimide is N-bromosuccinimide.