JPH07267976A - Method for producing oligosaccharide - Google Patents

Abstract

(57) [Summary] [Objective] To provide a method for efficiently producing an oligosaccharide. When a saccharide is reacted with a saccharide having an active group at the 1-position to produce an oligosaccharide, a combination of a trifluoroboron ether complex and N-iodosuccinimide is used as a glycosylation reaction activator.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the synthesis of oligosaccharides having pharmacological activity or used for elucidating the mechanism of action of those pharmacological activities. Examples of oligosaccharides of interest include factors involved in cell adhesion and related structures of lipid sugar chains that function as cancer-related antigens (Chemical Supplement 122, “Sugar-Exploring its diversity”,
p85, 1992, Kagaku Dojinsha).

[0002]

BACKGROUND ART Carbohydrates have been occupying a more important position than conventional constituent units and energy sources in the living body, but due to the rapid progress of separation and analysis technology in recent years, higher level of biology such as information transmission between cells has been achieved. It has become clear that they are deeply involved in intellectual phenomena. However, detailed elucidation at the molecular level between their functions and the structure of carbohydrates has just begun ("Protein and Nucleic Acid Enzymes" August 1992 special issue, vol.
37, No. 11, 1992, Kyoritsu Shuppan). Generally, the so-called “bioactive” sugars involved in the above-mentioned physiological phenomena have an extremely small amount of endocrine in vivo. One of the major challenges at present is to supply them in large quantities easily by means of organic synthesis. From this point of view, in recent years, many reports have been made on the synthesis reaction of sugars, focusing on the development of a new glycoside bond formation reaction.
There are still many problems (H. Paulsen, Angelwa
ndte Chemie International Edition in English, 2
1,155 (1982)).

[0003]

The object of the present invention is to obtain oligosaccharides in a high yield with easy operation.

[0004]

[Means for Solving the Problems] The inventors of the present invention have conducted diligent research focusing on various glycoside bond forming reactions. As a result, a trifluoroboron ether complex, which has not been known as an activator of glycoside bond forming reactions, has been obtained. The inventors have found that it is possible to obtain an oligosaccharide with a high yield by an easy operation by selecting a combination of N-iodosuccinimide as an activator. Therefore, the present invention provides a method for producing an oligosaccharide that forms a new glycosidic bond between sugar units. The production method of the present invention uses a combination of a trifluoroboron ether complex and N-iodosuccinimide as an activator of a glycosylation reaction when an oligosaccharide is produced by reacting a saccharide with a saccharide having an active group at the 1-position. It consists of a reaction step.

More specifically, the following reaction step can be given as an example. That is, the following formula (1)

[0006]

[Chemical 8]

(In the above formula, X ₁ is an active group which is activated by a combination of a trifluoroboron ether complex and N-iodosuccinimide to give a reaction intermediate,
R ₁ is a hydrogen atom or a hydroxyl-protecting group, Y ₁ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group, or a protected functional group thereof, provided that when there are a plurality of Y _1, these Y ₁ may be the same as or different from each other, Z ₁ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected these functional groups, with the proviso these Z ₁ if Z ₁ there are a plurality of may be the same or different from each other, W ₁ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected these functional groups, with the proviso these W ₁ if W ₁ there are a plurality of mutually identical Or they may be different, V
₁ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group, or a protected functional group thereof, h ₁ is an integer of 0 or 1 to 3, and i ₁ is 0 or 1 , J ₁ is an integer of 0 or 1, k ₁ is an integer of 0 or 1, m ₁ is an integer of 0 or 1, and n
₁ is an integer of 0 or 1; p ₁ is 0 or an integer of 1 to 6; q ₁ is 0 or 1;
6 is any integer, s ₁ is any integer of 0 or 1 to 3, t ₁ is any integer of 0 or 1 to 3, and u ₁ is 0 or 1 to 3 A sugar derivative represented by the following formula (2) in the presence of a trifluoroboron ether complex and N-iodosuccinimide.

[0008]

[Chemical 9]

(In the above formula, X ₂ is a functional group that is inactive in the combination of the trifluoroboron ether complex and N-iodosuccinimide, and R ₂ is the trifluoroboron ether complex and N-iodo which are reaction activators. A reaction point with a derivative moiety of the formula (1) activated by a combination of succinimide, which is a hydrogen atom or a trialkyl-substituted silyl group, Y ₂ is a hydroxyl group, an amino group,
Methyl group, a hydroxymethyl group or a protected these functional groups, with the proviso if the Y ₂ have multiple or different and these Y ₂ are identical to each other, Z ₂ represents a hydroxyl group, an amino group, a methyl group , hydroxymethyl group, or a protected a these functional groups, provided that these Z ₂ if Z ₂ there are a plurality may be the same as or different from each other, W ₂ represents a hydroxyl group, an amino group, a methyl group, hydroxy a methyl group or a protected these functional groups, with the proviso W _{2 If} there are multiple of these W ₂ may be the same as or different from each other, V ₂ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected these functional groups, h ₂ is any integer of 0 or 1 to 3, i ₂ is any integer of 0 or 1, j ₂ is 0 or 1 It is any integer, k
₂ is an integer of 0 or 1, m ₂ is an integer of 0 or 1, n ₂ is an integer of 0 or 1, p ₂ is 0 or 1 to 6 Q ₂ is any integer of 0 or 1 to 6, s ₂ is any integer of 0 or 1 to 3,
t ₂ is an integer of 0 or 1 to 3 and u ₂ is an integer of 0 or 1 to 3), and X _{1 of the} formula (1) is reacted. Is a step of forming a glycosidic bond between the bonding position of and the oxygen atom to which R _{2 of} formula (2) is bonded.

Thus, according to the present invention, an oligosaccharide represented by the following formula (3) having a new glycoside bond can be produced.

[0011]

[Chemical 10]

(In the above formula, X ₂ , R ₁ , Y ₁ , Y ₂ ,
Z ₁ , Z ₂ , W ₁ , W ₂ , V ₁ , V ₂ , h ₁ , h ₂ , i
₁ , i ₂ , j ₁ , j ₂ , k ₁ , k ₂ , m ₁ , m ₂ ,
n ₁ , n ₂ , p ₁ , p ₂ , q ₁ , q ₂ , s ₁ , s ₂ , t
₁ , t ₂ , u ₁ and u ₂ have the meanings defined above, *
Each follows a correspondingly numbered bond. ) In addition, the combination of the above active groups X ₁ and X ₂ is X ₁
Is active for the combination of trifluoroboron ether complex and N-iodosuccinimide, X ₂ is selected to be inactive for the combination of trifluoroboron ether complex and N-iodosuccinimide, and the same reaction mixture Any combination used in the technical field may be used as long as it does not adversely affect the reaction relating to the other combinations therein.

Further, the production method of the present invention may include at least the following two reaction steps. One of the steps is the following formula (4)

[0014]

[Chemical 11]

(In the above formula, X ₃ is an active group which is activated by a trifluoroboron ether complex to give a reaction intermediate, R ₃ is a hydrogen atom or a hydroxyl group-protecting group, and Y ₃ is a hydroxyl group or an amino group. group, methyl group, hydroxymethyl group, or a protected a these functional groups, provided that these Y ₃ if Y ₃ there are a plurality may be the same as or different from each other, Z ₃ represents a hydroxyl group, an amino group, methyl group, a hydroxymethyl group or a protected these functional groups, with the proviso if Z ₃ have multiple or different and these Z ₃ are the same as each other, W ₃ represents a hydroxyl group, an amino group, a methyl group , hydroxymethyl group, or a protected a these functional groups, provided that these W ₃ being if W ₃ there are a plurality may be the same as or different from each other, V ₃ represents a hydroxyl group, amino Group, a methyl group, a hydroxymethyl group or a protected these functional groups,, h ₃ is any integer of 0 or 1 to 3, i
₃ is an integer of 0 or 1; j ₃ is an integer of 0 or 1; k ₃ is an integer of 0 or 1; m ₃ is either 0 or 1 And n ₃ is an integer of 0 or 1 and p 3
₃ is 0 or an integer of 1 to 6, and q ₃ is 0.
Or an integer of 1 to 6, s ₃ is an integer of 0 or 1 to ₃ , and t ₃ is 0 or 1 to 3
In the presence of a trifluoroboron ether complex, a sugar derivative represented by the following formula (5), wherein u ₃ is 0 or an integer of 1 to 3).

[0016]

[Chemical 12]

(In the above formula, X ₄ is an active group which is inactive to the trifluoroboron ether complex but is activated by the combination of the trifluoroboron ether complex and N-iodosuccinimide to give a reaction intermediate. ,
R ₄ is a reaction point with the derivative of the formula (4) which is activated by a trifluoroboron ether complex which is a reaction activator, and is a hydrogen atom or a trialkyl-substituted silyl group, and Y ₄ is a hydroxyl group or an amino group. A group, a methyl group, a hydroxymethyl group, or a protected functional group thereof,
However, if Y ₄ have multiple or different and these Y ₄ are the same as each other, Z ₄ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected these functional groups, with the proviso Z _When there are a plurality of _4, these Z _{4 s} may be the same as or different from each other, W ₄ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group, or a protected functional group thereof, provided that W ₄ is When there are plural W _{4 s} , they may be the same as or different from each other, V ₄ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or these protected functional groups, and h ₄ is 0 or 1 Is an integer from 1 to 3, i
₄ is an integer of 0 or 1; j ₄ is an integer of 0 or 1; k ₄ is an integer of 0 or 1; m ₄ is either 0 or 1 And n ₄ is an integer of 0 or 1, p
₄ is 0 or an integer of 1 to 6, and q ₄ is 0
Or an integer of 1 to 6, s ₄ is an integer of 0 or 1 to 3, and t ₄ is 0 or 1 to 3
U ₄ is an integer of 0 or an integer of 1 to 3) and is reacted with a sugar derivative represented by the formula (4) to the bonding position of X ₃ and the formula (5). This is a step of forming a glycosidic bond with the oxygen atom to which R ₄ is bonded.

In another step, the sugar derivative represented by the above formula (5) or a sugar moiety derived therefrom is treated with the following formula (6) in the presence of a trifluoroboron ether complex and N-iodosuccinimide.

[0019]

[Chemical 13]

(In the above formula, X ₅ is a functional group inert to the combination of the trifluoroboron ether complex and N-iodosuccinimide, and R ₅ is the trifluoroboron ether complex and N-iodo which are reaction activators. A reaction point with the derivative moiety of the formula (5), which is activated by the combination of succinimide, is a hydrogen atom or a trialkyl-substituted silyl group, Y ₅ is a hydroxyl group, an amino group,
Methyl group, a hydroxymethyl group or a protected these functional groups, with the proviso Y _{if 5} there are a plurality or different and these Y ₅ are the same as each other, Z ₅ represents a hydroxyl group, an amino group, a methyl group a hydroxymethyl group or a protected these functional groups, with the proviso if Z ₅ have multiple or different and these Z ₅ are the same as each other, W ₅ represents a hydroxyl group, an amino group, a methyl group, hydroxy a methyl group or a protected these functional groups, with the proviso W _{5 If} there is more than one or different and these W ₅ are identical to each other, V ₅ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected these functional groups, h ₅ is any integer of 0 or 1 to 3, i ₅ is any integer of 0 or 1, j ₅ 0 or 1 It is any integer, k
₅ is an integer of 0 or 1, m ₅ is an integer of 0 or 1, n ₅ is an integer of 0 or 1, p ₅ is 0 or 1 to 6 Q ₅ is any integer of 0 or 1 to 6, s ₅ is any integer of 0 or 1 to 3,
t ₅ is the integer of 0 or 1 to 3, u ₅ is the X ₄ of is reacted with a sugar derivative represented by 0 or 1 to 3 is any integer) and Equation (5) It is a step of forming a glycosidic bond between the bonding position and the oxygen atom to which R _{5 of} formula (6) is bonded. These steps can be carried out sequentially in the same reaction mixture.

Thus, according to the present invention, an oligosaccharide represented by the following formula (7) having at least two new glycoside bonds can be produced.

[0022]

[Chemical 14]

(In the above formula, X ₅ , R ₃ , Y ₃ , Y ₄ ,
Y ₅ , Z ₃ , Z ₄ , Z ₅ , W ₃ , W ₄ , W ₅ , V ₃ , V
₄ , V ₅ , h ₃ , h ₄ , h ₅ , i ₃ , i ₄ , i ₅ ,
_{j 3, j 4, j 5} , k 3, k 4, k 5, m 3, m 4, m
₅ , n ₃ , n ₄ , n ₅ , p ₃ , p ₄ , p ₅ , q ₃ ,
q ₄ , q ₅ , s ₃ , s ₄ , s ₅ , t ₃ , t ₄ , t ₅ , u
₃ , u ₄ and u ₅ have the meanings defined above, and the * 's each follow a correspondingly numbered bond. ) In the combination of the above active groups X ₃ , X ₄ and X ₅ , X ₃ is active with respect to the trifluoroboron ether complex and X ₄ is with respect to the combination of the trifluoroboron ether complex and N-iodosuccinimide. Is active but inactive towards the trifluoroboron ether complex, X ₃ is selected to be inactive towards the combination of the trifluoroboron ether complex and N-iodosuccinimide, and in the same reaction mixture If it does not adversely affect the reaction of other combinations of,
It may be any combination used in the art.

The sugar derivatives used in the present invention may be monosaccharides or oligosaccharides having a pyranose skeleton or a furanose skeleton, respectively.
It can be prepared by selectively protecting the hydroxyl group, amino group and hydroxymethyl group of a saccharide known per se by a conventional protection method. As a monosaccharide having a pyranose skeleton or a furanose skeleton or an oligosaccharide to be subjected to the above reaction,
Prepared from monosaccharides such as glucose and galactose, and oligosaccharides composed of two or more of these sugars, for example, disaccharides such as maltose, lactose and cellobiose, and other hydrolysates such as starch, dextrin or cellulose. Other oligosaccharides can be mentioned. Therefore, the configuration of these anomeric positions may be either α-type or β-type, and the linkage mode between the sugar units of the oligosaccharide is 1 → 3, 1 → 4, 1 → 6.
Alternatively, it may rarely be 1 → 2, and may include multiple binding modes.

The selective protection of the hydroxyl group, amino group and hydroxymethyl group is carried out by any known protection which can individually protect the hydroxyl group at the anomeric position (1 position) or the reactive site and the other hydroxyl group, amino group and hydroxymethyl group. Can be carried out by a method (or may include a desorption step).
Examples of the other hydroxyl group, amino group and hydroxymethyl group protecting group include acetyl group, benzoyl group, substituted benzoyl group, benzyl group, substituted benzyl group, pivaloyl group, allyloxycarbonyl group and substituted methylenedioxy group. Then, the protecting group can be introduced by reacting by a conventional method.

Regarding the selection of these protecting groups, the hydroxyl group at the anomeric position (1-position) or the hydroxyl group at the reaction site or the protected ones of these hydroxyl groups and other hydroxyl groups, amino groups, methyl groups, hydroxymethyl groups or these Any combination used in the art can be used as long as it is a combination selected in consideration of the difference in reactivity with the protected one.

Examples of the functional groups X ₁ , X ₃ and X ₄ in the sugar derivative as the raw material in the present invention include a halogen atom, a phenylthio group, an imidoyl group and an allyloxy group, and the functional groups X ₂ and X ₅ are Include an alkyloxy group, a ceramide group, and the like, and as R ₁ and R ₃ , a hydrogen atom, a trialkyl-substituted silyl group, an acetyl group, a benzoyl group, a substituted benzoyl group, a benzyl group, a substituted benzyl group, a pivaloyl group, and allyl. Examples thereof include an oxycarbonyl group and a substituted methylenedioxy group, and examples of R ₂ , R ₄ and R ₅ include a hydrogen atom and a trialkyl-substituted silyl group.

More specifically, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom,
Examples of the imidoyl group include an acetimidoyl group and
Examples of the trichloroacetimidoyl group and the alkyloxy group include a methoxy group, an ethoxy group, a dodecyloxy group, and a trialkyl-substituted silyl group such as a trimethylsilyl group, a tertiary butyldimethylsilyl group, and a substituted benzoyl group. For example, the paramethylbenzoyl group and the substituted benzyl group include, for example, the paramethylbenzyl group, and the substituted methylenedioxy group includes, for example, an acetonide group, etc., but the present invention is not limited to these examples. In consideration of the reactivity with respect to a trifluoroboron ether complex or a combination of a trifluoroboron ether complex and N-iodosuccinimide, a suitable X ₁ , X ₂ , X ₃ , X ₄ , X
_{A combination of 5} , R ₁ , R ₂ , R ₃ , R ₄ and R ₅ can be selected.

Representative X ₁ , X ₂ , and
Examples of the combination of X ₃ , X ₄ , X ₅ , R ₁ , R ₂ , R ₃ , R ₄ and R ₅ include (i) X ₁ phenylthio group, X ₂ ; methoxy group, R ₁ ; acetyl. Group, R
₂ ; hydrogen atom, (ii) X _3, trichloroacetimidoyl group, X _4, phenylthio group, X ₅ ; methoxy group,
R ₃ ; acetyl group, R ₄ ; hydrogen atom, R ₅ ; hydrogen atom,
(Iii) X ₃ ; fluorine, X ₄ ; phenylthio group, X ₅ ;
Methoxy group, R ₃ ; acetyl group, R ₄ ; hydrogen atom,
R ₅ ; a hydrogen atom and the like can be mentioned.

The solvent used in the reaction is nitromethane, toluene, dichloromethane or tetrahydrofuran (THF), which is used in usual glycosylation.
Etc., or a mixed solvent obtained by combining these solvents can also be used.

In the reaction of the present invention, for example, the sugar derivative represented by the formula (1) and the sugar derivative represented by the formula (2) are used in usual glycosylation, such as nitromethane, toluene, dichloromethane and tetrahydrofuran. (TH
F) or the like, and a trifluoroboron ether complex, which is a glycosylation reaction activator that activates only X ₁ in the formula (1), and N-iodosuccinimide are sequentially added thereto. it can. 0 to the above reaction steps
It is usually performed at 80 ° C. for 2 to 60 minutes, but it may be appropriately extended.

The reaction of the present invention can also be carried out by sequentially performing the following at least two reaction steps. For example, the sugar derivative represented by the formula (4) and the sugar derivative represented by the formula (5) are dissolved in a solvent such as nitromethane, toluene, dichloromethane or tetrahydrofuran (THF) used in ordinary glycosylation. Then, a trifluoroboron ether complex, which is a glycosylation reaction activator that activates only X ₃ in formula (4), is added thereto and reacted. The reaction step is usually 2 to 6 at -45 ° C to room temperature.
It is performed for 0 minutes, but it may be appropriately extended.

Then, in the presence of the trifluoroboron ether complex, the sugar derivative represented by the formula (6) and the formula (5)
N, which is a glycosylation reaction activator that activates X ₄ of
-Iodosuccinimide is added and usually 2 at 0-80 ° C.
The reaction is carried out for about 60 minutes, but it may be appropriately extended.

Hereinafter, the reaction conditions, reagents and the like of the reaction step of the present invention will be further described based on two examples of the combination of the above reagents. The halogenated sugars, trichloroacetimidoyl sugars, thioglycosylated sugars, methyl glycosylated sugars, etc., which are the starting materials for the reaction of the present invention, can be obtained from the corresponding monosaccharides or oligosaccharides by a known method by a conventional preparation method. it can.

As an example, a thioglycosylated sugar of the formula (1) (X ₁ = phenylthio group) and a methyl glycosylated sugar of the formula (2) (X ₂ = methoxy group) are added to dichloromethane in the presence of 4A molecular sieves. , A trifluoroboron ether complex, which is an activator capable of activating only the phenylthio group, and N-iodosuccinimide are sequentially added to activate the phenylthio group. 2-60 at 0-80 ° C
After the reaction for a minute, the reaction is stopped with an organic base such as triethylamine, the liberated salts and the like are removed by filtration, and the solvent is distilled off under reduced pressure to obtain a crude product.

The reaction of the present invention can also be carried out by sequentially carrying out the following at least two reaction steps. For example, a trichloroacetimidoylated sugar of formula (4) (X ₃
= Trichloroacetimidoyl group) and a thioglycosylated sugar of formula (5) (X ₄ = phenylthio group) in an activator capable of activating only the trichloroacetimidoyl group in the presence of 4A molecular sieves in dichloromethane. After performing a glycosylation reaction with a certain trifluoroboron ether complex at −45 ° C. to room temperature for 2 to 60 minutes, in the presence of the trifluoroboron ether complex, a methyl glycosylated sugar of formula (6) (X ₅ = methoxy group) and N-iodosuccinimide is added to activate the phenylthio group.

After reacting at 0 to 80 ° C. for 2 to 60 minutes, the reaction is stopped with an organic base such as triethylamine, the released salts are removed by filtration, and the solvent is distilled off under reduced pressure to obtain a crude product. be able to. The obtained crude product is recrystallized or purified by silica gel column chromatography or the like, if necessary.

[0038]

EXAMPLES The present invention will be described in more detail with reference to examples. Example 1 Methyl 2,3,4-tri-O-acetyl-6-O-
[2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl] -α-D-glucopyranoside (4a)
Synthesis of

[0039]

[Chemical 15]

Phenylthio 2,3,4,6-tetra-O
-Acetyl-β-D-glucopyranoside (2a, 192
mg (0.43 mmol), in the formula (1), X ₁ = β-substituted phenylthio group, R ₁ = acetyl group, Y ₁ = hydroxyl group protected by acetyl group, h ₁ = 0, i ₁ = 1, k ₁ = 1, p ₁ =
0, s ₁ = 3), methyl 2,3,4-tri-O-acetyl-α-D-glucopyranoside (3a, 140 mg (0.4
3 mmol), in the formula (2), X ₂ = α-substituted methoxy group, R ₂
= Hydrogen atom, Y ₂ = hydroxyl group protected by an acetyl group, h
₂ = 0, i ₂ = 1, k ₂ = 1, p ₂ = 0, s ₂ = 3) was dissolved in dichloromethane (5 ml) in the presence of activated molecular sieves MS4A and stirred at room temperature for 15 minutes, Fluoroboron ether complex (BF ₃ · OEt
An ether solution of ( ₂ ) (0.21 ml (1.75 mmol)) was added dropwise. Next, N-iodosuccinimide (NIS, 39
3 mg (1.75 mmol)) was added to the reaction solution. 5 at room temperature
After reacting with stirring for a minute and confirming the disappearance of the raw materials by thin layer chromatography, triethylamine (1 ml) was added to terminate the reaction, the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain a crude product. It was The obtained crude product was separated and purified by silica gel column chromatography using hexane-ethyl acetate as an eluent to obtain oily substance 4a (201 mg (0.31 mmol), yield 72%).

Example 2 Methyl 2,3,4-tri-O-acetyl-6-O-
[2,3,4-tri-O-acetyl-6-O- (2,
Synthesis of 3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -β-D-glucopyranosyl] -α-D-glucopyranoside (4b) (I)

[0042]

[Chemical 16]

2,3,4,6-tetra-O-acetyl-
D-glucopyranosyl trichloroimidate (1a, 5
8 mg (0.11 mmol), in formula (4), X ₃ = trichloroacetimidoyl group, R ₃ = acetyl group, Y ₃ = hydroxyl group protected by acetyl group, h ₃ = 0, i ₃ = 1, k ₃ =
1, p ₃ = 0, s ₃ = 3) and phenylthio 2,3,4-
Tri-O-acetyl-β-D-glucopyranoside (2
b, 41 mg (0.10 mmol), in the formula (5), X ₄ = β-substituted phenylthio group, R ₄ = hydrogen atom, Y ₄ = hydroxyl group protected by acetyl group, h ₄ = 0, i ₄ = 1, k ₄ = 1, p
₄ = 0, s ₄ = 3) was dissolved in dichloromethane (5 ml) in the presence of activated molecular sieves MS4A,
Trifluoroboron ether complex (BF) as activator
₃・ OEt ₂ ) ether solution (0.05 ml (0.40 mmo
l)) was added dropwise at -45 ° C.

After removing the cooling bath and reacting for about 2 minutes and confirming the disappearance of the raw materials by thin layer chromatography, methyl 2,3,4-tri-O-acetyl-α-D-glucopyranoside (3a) dissolved in dichloromethane was confirmed. , 36 mg (0.11 mm
ol), in the formula (6), X ₅ = α-substituted methoxy group, R ₅ = hydrogen atom, Y ₅ = hydroxyl group protected by acetyl group, h ₅ =
_{0, i 5 = 1, k} 5 = 1, p 5 = 0, s 5 = 3) and the activator N- iodosuccinimide (NIS, 100 mg
(0.44 mmol)) was added to the reaction solution. After stirring and reacting at room temperature for 5 minutes, triethylamine (1 ml) was added to terminate the reaction, the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography using hexane-ethyl acetate as an eluent to obtain oily substance 4b (60 mg (0.064 mmol), yield 62%).

[Α] D ²⁵ + 44.2 ° (c = 0.688, CHCl ₃ ) Rf 0.22 (AcOEt-Hex = 2: 1) ¹ H-NMR (270 MHz, CDCl ₃ ) 1.96 s (9H, acetyl: Me) 1.98 s (3H, acetyl: Me) 1.9 s (3H, acetyl: Me) 2.00 s (3H, acetyl: Me) 2.02 s (6H, acetyl: Me) ) 2.03 s (3H, acetyl: Me) 2.06 s (3H, acetyl: Me) 3.36 s (3H, OMe) 3.47-3.70 m (4H) 3.83-3.97 m (3H) 4.07-4.12 m (1H) 4.23 dd (1H, J = 4.5, 12.1 Hz) 4.49 d (1H, J = 7.8 Hz, anomeric position) 4. 56 d (1H, J = 8.1Hz, anomeric position 4.79-4.98 m (6H) 5.03 t (1H, J = 9.5 Hz) 5.160 t (1H, J = 9.4 Hz) 5.167 t (1H, J = 9.3 Hz) 5.42 d (1H, J = 9.4Hz)

¹³ C-NMR (67.8 MHz, CDCl ₃ ) 55.3, 64.8, 67.9, 68.0, 6
8.1, 68.2, 68.8, 69.0, 70.
1, 70.8, 71.0, 71.9, 72.7,
73.2, 77.2, (96.5, 100.7
(2c): anomeric position), (169. 3, 1
69.4, 169.6, 170.21, 170.
28, 170.3, 170.7, 178.4:
Acetyl). IR (neat) 3234, 2948, 1751, 1713, 1
430, 1370, 1291, 1222, 117
5, 1039 cm ^-1 .

Example 3 Methyl 2,3,4-tri-O-acetyl-6-O-
[2,3,4-tri-O-acetyl-6-O- (2,
Synthesis of (3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -β-D-glucopyranosyl] -α-D-glucopyranoside (4b) (II)

[0048]

[Chemical 17]

The above oligosaccharide was synthesized in the same manner as in Example 2 except that the compound of the formula (4) was changed as follows. That is, 2b 78 mg (0.20 mmo of the formula (5)
l), 62 mg (0.20 mmol) of 3a of formula (6), trifluoroboron ether complex (BF) as the first activator
0.05 ml (0.40 mmo) of ether solution of ₃・ OEt ₂ )
l), 88 mg (0.39 mmol) of N-iodosuccinimide (NIS) as the second activator, and 2,3,4,6-instead of 1a of Example 2 as the compound of formula (4).
Tetra-O-acetyl-1-fluoro-β-D-glucopyranoside (1b, 103 mg (0.29 mmol), formula (4)
In the formula, X ₃ = fluorine, R ₃ = acetyl group, Y ₃ = hydroxyl group protected by acetyl group, h ₃ = 0, i ₃ = 1 and k ₃ =
1, p ₃ = 0, s ₃ = 3) and oily substance 4b (140
mg (0.15 mmol), yield 76%) was obtained.

Claims (3)

[Claims] 1. When a saccharide is reacted with a saccharide having an active group at the 1-position to produce an oligosaccharide, a combination of a trifluoroboron ether complex and N-iodosuccinimide is used as an activator of a glycosylation reaction. A method for producing a characteristic oligosaccharide. 2. A method for producing an oligosaccharide which forms a glycosidic bond between sugar units, which comprises the following formula (1): (In the above formula, X ₁ is an active group activated by a combination of a trifluoroboron ether complex and N-iodosuccinimide, R ₁ is a hydrogen atom or a hydroxyl-protecting group, and Y ₁ is a hydroxyl group or an amino group. , methyl group, hydroxymethyl group or a protected these functional groups, with the proviso these Y ₁ if Y ₁ is more may be the same as or different from each other, Z ₁ is hydroxyl group, amino group, methyl group, hydroxymethyl group, or a protected a these functional groups, provided that these Z ₁ if Z ₁ there are a plurality may be the same or different,
W ₁ is hydroxyl group, amino group, methyl group, hydroxymethyl group or a protected these functional groups, with the proviso these W ₁ if W ₁ there are a plurality may be the same as or different from each other, V ₁ Is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group, or a protected functional group thereof, h ₁ is an integer of 0 or 1 to 3, and i ₁ is 0 or 1 An integer, j
₁ is an integer of 0 or 1; k ₁ is an integer of 0 or 1; m ₁ is an integer of 0 or 1; n ₁ is either 0 or 1 Is an integer of 0, p ₁ is an integer of 0 or 1 to 6, q ₁ is an integer of 0 or 1 to 6, and s
₁ is an integer of 0 or 1 to 3, and t ₁ is 0
Or an integer of 1 to 3 and u ₁ is an integer of 0 or 1 to 3) in the presence of a trifluoroboron ether complex and N-iodosuccinimide. , The following formula (2) (In the above formula, X ₂ is a functional group inert to the combination of the trifluoroboron ether complex and N-iodosuccinimide, R ₂ is a hydrogen atom or a trialkyl-substituted silyl group, and Y ₂ is a hydroxyl group or an amino group. , Methyl group,
Hydroxymethyl group, or a protected a these functional groups, provided that these Y ₂ if Y ₂ there are a plurality may be the same as or different from each other, Z ₂ represents a hydroxyl group, an amino group, methyl group, hydroxymethyl group or a protected these functional groups, provided that Z _{2 If} there are multiple of these Z ₂ may be the same as or different from each other, W ₂ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group, or a protected these functional groups, provided that W _{2 If} there are multiple or different and these W ₂ is the same as each other, V ₂ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or protected, In these functional groups, h ₂ is an integer of 0 or 1 to 3, i ₂ is an integer of 0 or 1,
j ₂ is an integer of 0 or 1, k ₂ is an integer of 0 or 1, m ₂ is an integer of 0 or 1, n ₂ is 0 or 1 , P ₂ is an integer of 0 or 1 to 6, q ₂ is an integer of 0 or 1 to 6, and s
₂ is an integer of 0 or 1 to 3, and t ₂ is 0
Or an integer of 1 to 3 and u ₂ is an integer of 0 or 1 to 3) to react with a sugar derivative represented by the formula (1) to form a bond with X _1. R in formula (2)
By forming a glycosidic bond with the oxygen atom to which ₂ is bonded, the following formula (3): (In the above formula, X ₂ , R ₁ , Y ₁ , Y ₂ , Z ₁ , Z ₂ ,
W ₁ , W ₂ , V ₁ , V ₂ , h ₁ , h ₂ , i ₁ , i ₂ , j
₁ , j ₂ , k ₁ , k ₂ , m ₁ , m ₂ , n ₁ , n ₂ ,
p ₁ , p ₂ , q ₁ , q ₂ , s ₁ , s ₂ , t ₁ , t ₂ , u
₁ and u ₂ have the meanings defined above, and * represents an oligosaccharide represented by a bond having a corresponding number). 3. A method for producing an oligosaccharide in which at least two glycosidic bonds are formed between sugar units, which comprises (a) the following formula (4): (In the above formula, X ₃ is an active group activated by a trifluoroboron ether complex, R ₃ is a hydrogen atom or a protective group for a hydroxyl group, and Y ₃ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group. , Or these protected functional groups, provided that when there are plural Y _3, these Y ₃ may be the same or different, and Z ₃ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group, or a these functional groups protected, with the proviso Z ₃ these Z ₃ If there are a plurality may be the same as or different from each other, W ₃ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected, and a these functional groups, provided that W ₃ these W ₃ being if there are plural may be the same as or different from each other, V ₃ represents a hydroxyl group, an amino group, methyl group, hydroxymethyl A group or a protected these functional groups,, h ₃ is any integer of 0 or 1 to 3, i ₃ is any integer of 0 or 1, j ₃ is 0 or 1 Any integer, k
₃ is an integer of 0 or 1, m ₃ is an integer of 0 or 1, n ₃ is an integer of 0 or 1, p ₃ is 0 or 1 to 6 Any integer, q ₃ is any integer of 0 or 1 to 6, s ₃ is any integer of 0 or 1 to 3,
t ₃ is an integer of 0 or 1 to ₃ and u ₃ is an integer of 0 or 1 to 3) in the presence of a trifluoroboron ether complex, The following formula (5) (In the above formula, X ₄ is an inert group that is inactive to the trifluoroboron ether complex, but is activated by the combination of the trifluoroboron ether complex and N-iodosuccinimide, and R ₄ is a hydrogen atom or triatomic group. an alkyl-substituted silyl group, Y ₄ is a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected these functional groups, with the proviso if Y ₄ have multiple different these Y ₄ are the same as each other Z ₄ may be a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group, or a protected functional group thereof, provided that when there are a plurality of Z _4, these Z ₄ groups may be the same or different. may, W ₄ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected these functional groups, with the proviso W ₄ multiple Oh If or different these W ₄ are identical to each other, V ₄ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or a protected these functional groups,, h ₄ is 0 or 1-3 of is any integer, i ₄ is any integer of 0 or 1, j ₄ is any integer of 0 or 1, k
₄ is an integer of 0 or 1, m ₄ is an integer of 0 or 1, n ₄ is an integer of 0 or 1, p ₄ is 0 or 1 to 6 Q ₄ is any integer of 0 or 1 to 6, s ₄ is any integer of 0 or 1 to 3,
t ₄ is an integer of 0 or 1 to 3, u ₄ is reacted with a sugar derivative represented by 0 or 1 to 3 is any integer) of formula X ₃ (4) In the presence of a trifluoroboron ether complex and N-iodosuccinimide after the step of forming a glycosidic bond between the bonding position and the oxygen atom to which R _{4 of} formula (5) is bonded, and (b) step (a) so,
The following formula (6) (In the above formula, X ₅ is a functional group that is inactive in the combination of the trifluoroboron ether complex and N-iodosuccinimide, R ₅ is a hydrogen atom or a trialkyl-substituted silyl group, and Y ₅ is a hydroxyl group or an amino group. , Methyl group,
A hydroxymethyl group or a protected these functional groups, with the proviso Y _{if 5} there are a plurality or different and these Y ₅ are the same as each other, Z ₅ represents a hydroxyl group, an amino group, methyl group, hydroxymethyl group or a protected these functional groups, provided that Z _{5 If} there is more than one or different and these Z ₅ are the same as each other, W ₅ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group, or a protected these functional groups, provided that if W ₅ have multiple or different and these W ₅ are identical to each other, V ₅ represents a hydroxyl group, an amino group, a methyl group, a hydroxymethyl group or protected, In these functional groups, h ₅ is an integer of 0 or 1 to 3, i ₅ is an integer of 0 or 1,
j ₅ is an integer of 0 or 1, k ₅ is an integer of 0 or 1, m ₅ is an integer of 0 or 1, n ₅ is 0 or 1 Is an integer of 0, p ₅ is an integer of 0 or 1 to 6, q ₅ is an integer of 0 or 1 to 6, and s
₅ is an integer of 0 or 1 to 3, and t ₅ is 0.
Or an integer of 1 to 3 and u ₅ is an integer of 0 or 1 to 3) to react with a sugar derivative, and the bonding position of X ₄ of the formula (5) and the formula R _{5 in} (6)
Forming a glycosidic bond with the attached oxygen atom, wherein steps (a) and (b) are each carried out in a common reaction mixture without isolation of the product,
The following formula (7): (In the above formula, X ₅ , R ₃ , Y ₃ , Y ₄ , Y ₅ , Z ₃ ,
Z ₄ , Z ₅ , W ₃ , W ₄ , W ₅ , V ₃ , V ₄ , V ₅ , h
_{3, h 4, h 5,} i 3, i 4, i 5, j 3, j 4,
j ₅ , k ₃ , k ₄ , k ₅ , m ₃ , m ₄ , m ₅ , n ₃ , n
₄ , n ₅ , p ₃ , p ₄ , p ₅ , q ₃ , q ₄ , q ₅ ,
s ₃ , s ₄ , s ₅ , t ₃ , t ₄ , t ₅ , u ₃ , u ₄ , u
₅ has the meaning defined above, and * represents an oligosaccharide represented by a continuous bond having a corresponding number).