JP2580538B2 - Method for selective acetalization of sugars - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for selectively acetalizing saccharides, and more particularly, to reacting a saccharide with a thiocarbonyl compound to selectively react 2,3- or 4,6-positions of the saccharide. And a method for acetalization in good yield.

[0002]

2. Description of the Related Art Conventionally, an acetalization reaction is generally carried out by heating a carbonyl compound such as an aldehyde or a ketone and an alcohol in the presence of an acid to cause dehydration condensation. However, in such a reaction, the types of carbonyl compounds that can be used are inevitably limited, and since an acid is required, side reactions such as isomerization are likely to occur, and therefore, the reaction is unstable to acids and heat. There is a problem that good results cannot be obtained with a simple compound.

[0003] To protect the hydroxyl groups of saccharides, a method of heating under acidic reaction conditions using benzaldehyde or acetone is usually used, but this method involves side reactions such as isomerization and is not necessarily accompanied by side reactions. Satisfactory results have not been obtained and the introduction of protecting groups by this acetalization is inevitably restricted by the position of the hydroxyl groups.

[0004]

DISCLOSURE OF THE INVENTION The present invention overcomes the drawbacks of the conventional methods for acetalizing saccharides, suppresses side reactions such as isomerization, and allows saccharides to be produced in good yield and regioselectively. The purpose of the present invention is to provide a novel method for acetalization.

[0005]

Means for Solving the Problems The present inventors have conducted various studies on a method for acetalizing a saccharide, and as a result, have developed a method using a thiocarbonyl compound which is completely different from the conventional method using a carbonyl compound. According to this method, it was found that the 2-, 3- or 4-position of the saccharide was selectively acetalized, and based on this finding, the present invention was completed.

That is, according to the present invention, when acetalizing a saccharide, the saccharide is added to a base in the presence of a silver salt or a copper salt.
An object of the present invention is to provide a method for selectively acetalizing the saccharide at the 2,3 or 4,6 position by reacting a thiocarbonyl compound having a bulky organic group.

The saccharides used in the method of the present invention include, for example, monosaccharides such as glucose, mannose, and galactose, and α- or β-methylated anomeric hydroxyl groups and those obtained by partially acylating or etherifying hydroxyl groups. And sugar alcohols such as mannitol and glucitol, disaccharides and oligosaccharides such as sucrose, maltose, trehalose and cyclodextrin, and derivatives thereof.

The bulky material used in the method of the present invention,
As the thiocarbonyl compound having an organic group, a general formula

Embedded image Can be mentioned.

In the above formula, R ¹ and R ² are each a bulky organic group bonded to a thiocarbonyl group, and specifically, an aryl group such as a phenyl group, a nitrophenyl group and a dimethylaminophenyl group. And heterocyclic groups such as isopropyl group, isopropyl group, t-butyl group, pyridyl group and thienyl group, and disubstituted amino groups such as morpholino group, dimethylamino group and piperidino group. R ¹ and R ² may be the same or different,
Further, they may combine with each other to form a ring structure.

As the thiocarbonyl compound, those in which an aromatic ring or a heterocyclic ring or both are directly bonded to a thiocarbonyl group are preferable. For example, bis (dialkylaminophenyl) thioketone, nitrophenylmorpholinothioketone, 2,6 -Dialkyl-γ-pyranthion, xanthenethione, thioxanthenthione and the like are preferred.

In the method of the present invention, the thiocarbonyl compound is reacted with the saccharide in the presence of a base and a silver salt or a copper salt. In this case, the reaction is preferably performed in an organic solvent. As the organic solvent, for example, acetonitrile,
Tetrahydrofuran, toluene, ethyl acetate, N, N-
Examples include dimethylformamide, pyridine, dichloromethane and the like. These solvents may be used alone,
Two or more kinds may be used as a mixture.

Examples of the base include organic tertiary amines such as triethylamine, 4-dimethylaminopyridine, pyridine and diisopropylethylamine, and potassium t-butoxide and potassium carbonate. Tertiary amines are preferred from the viewpoint of solubility in organic solvents. In addition, these bases may be used alone or in combination of two or more.

On the other hand, the silver salt or the copper salt may be any of an organic salt and an inorganic salt, for example, silver trifluoroacetate, silver acetate, silver perchlorate, silver nitrate, silver oxide, silver sulfate, tetrafluoride. Silver borate, silver trifluoromethanesulfonate, copper oxide, copper (I) chloride, copper (II) trifluoroacetate, copper (II) trifluoromethanesulfonate, and the like. On the other hand, trifluoroacetate and trifluoromethanesulfonate having high solubility are preferred. These silver salts and copper salts may be used alone or in combination of two or more.

Next, a preferred embodiment of the present invention will be described. First, a thiocarbonyl compound represented by the general formula (I) and a saccharide are mixed in a suitable organic solvent, preferably in a molar ratio of 1: 0.5. To 1: 2, more preferably 1:
After dissolving at a ratio of 0.8 to 1: 1.2, a base is usually added in an amount of 1 equivalent or more, preferably 2 to 5 equivalents, per 1 mol of the thiocarbonyl compound, and the mixture is stirred at room temperature. To this solution, usually 2 to 3 moles, preferably 2 to 2.5 moles of a silver salt or a copper salt is added directly or dissolved in a solvent to 1 mole of the thiocarbonyl compound, and the mixture is added dropwise with stirring at room temperature. I do. At this time, the reaction may be promoted if necessary by heating. After completion of the reaction, insoluble silver sulfide or copper sulfide is removed by a method such as filtration or dissolution, and volatile components such as a solvent are distilled off under reduced pressure. The acetal compound thus produced can be purified by recrystallization or column chromatography if necessary.

Confirmation that the obtained compound is an acetal compound and determination of its structure are performed by melting point, elemental analysis, ¹ H
-NMR and ¹³ C-NMR.

Thus, the general formula

Embedded image Is obtained. In the general formula (II), R ¹ and R ² have the same meanings as described above, and A is two hydroxyl groups at the 2,3-position of the saccharide or 4,6
It is a residue excluding the two hydroxyl groups at the position. Substituents such as an aliphatic group, an aromatic group, and a heterocyclic group may be introduced into the sugar residue, and these substituents may be a hydroxyl group, an amino group, an alkoxy group, a thioalkoxy group. , An ester group, an acyl group, or the like. further,
The substituents may be bonded to each other to form a cyclic structure.

Next, regarding the reaction mechanism in the present invention, bis (4-dimethylaminophenyl) thioketone (thiomihlazketone) is used as the thiocarbonyl compound.
Using methyl α-D-glucoside as a saccharide, triethylamine as a base and silver trifluoroacetate as a silver salt, and reacting methyl α-D-glucoside with thiomihlaz ketone in the presence of triethylamine and silver trifluoroacetate. Taking the case where this is done as an example, it is estimated as follows.

[0018]

Embedded image

Table 1 shows that methyl α-D-glucoside is used as a saccharide, and bis (4-dimethylaminophenyl) thioketone (thiomichler's ketone), 4-nitrophenylmorpholinothioketone, xanthenethione and thioxanthene are used as thiocarbonyl compounds. An example of an acetal compound synthesized by thione using the method of the present invention is shown by a structural formula. Further, Table 2 shows that methyl α-D-mannoside is synthesized as a saccharide and bis (4-dimethylaminophenyl) thioketone (thiomichler's ketone), xanthenethione and thioxanthenethione are synthesized as thiocarbonyl compounds according to the method of the present invention. An example of the acetal compound thus obtained is shown by a structural formula.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

According to the method of the present invention, a completely new type of acetal compound of a saccharide can be produced simply and in high yield under a mildly basic condition near room temperature in a novel reaction mode which has not been known. can do. If this reaction is applied to a reaction for protecting a hydroxyl group of a saccharide, the above-mentioned general formula (I)
By appropriately selecting the types of R ¹ and R ^{2 in} the above, the protection of hydroxyl groups at different positions can be performed selectively and efficiently. That is, taking methyl α-D-glucoside as an example, when using a thiocarbonyl compound as a thiocarbonyl compound (R ¹ and R ² are each a 4-dimethylaminophenyl group), an acetal compound at the 4,6-position is used. Compound (1) "is obtained. On the other hand, when reacted using xanthenethione as a thiocarbonyl compound,
The 2,3-position acetal compound "compound (3)" is obtained.

According to the method of the present invention, the hydroxyl group of the saccharide is acetalized as described above, and further combined with the protection and deprotection reactions of the conventional method, so that the saccharide can be liberated at the 2,3-position which is extremely difficult to produce by the conventional method. Thus, a sugar derivative having a hydroxyl group can also be easily produced.

Therefore, the method of the present invention can provide an important new material for constructing a sugar chain, and greatly contributes to the development of sugar chain engineering.

[0025]

Next, the present invention will be described in more detail with reference to examples.

Example 1 As sugars, methyl-α-D-glucoside and methyl α-
D-Mannoside was subjected to acetalization of saccharides using bis (4-dimethylaminophenyl) thioketone (thiomihlaz ketone), 4-nitrophenylmorpholinothioketone, xanthenethione and thioxanthenethione as thiocarbonyl compounds.

The thiocarbonyl compound (1.0 mmol) and the saccharide (1.2 mmol) were treated with anhydrous dimethylformamide (DM).
F) The reaction solution dissolved in 15 ml and further added with 0.5 ml of triethylamine was added with 2.5 m of silver trifluoroacetate.
5 ml of a DMF solution was added dropwise over 5 to 10 minutes. After stirring at room temperature for 1 to 4 hours, ethyl acetate and brine were added to separate the ethyl acetate layer, washed with water and dried over anhydrous MgSO ₄ . The crude product obtained by evaporating the ethyl acetate under reduced pressure was purified by recrystallization (ethyl acetate / hexane) or silica gel column chromatography. The melting points (mp) of the compounds (1) to (8) thus obtained, the optical rotation ([α] _D ²⁰ ) of a 1% (w / v) chloroform solution at 20 ° C., the thiocarbonyl compound , ¹ H-NMR, ¹³ C-NMR, and the results of elemental analysis are as follows.

Compound (1) mp: 190-191 ° C., [α] _D ²⁰ = + 106.7 °,
Yield: 77% ¹ H-NMR: 2.31 (1H, d.J = 9.1H)
z), 2.82 (1H, br), 2.87 (6H,
s), 2.98 (6H, s), 3.43 (3H, s),
3.4 to 3.6 (2H, m), 3.7 to 4.1 (4H,
m), 4.68 (1H, d, J = 4.0 Hz), 6.5
６6.6 (2H, m), 6.7〜6.8 (2H, m),
7.2 to 7.3 (2H, m), 7.3 to 7.4 ppm
(2H, m). ¹³ C-NMR: 40.2, 40.4, 55.2, 63.
2,63.6,72.0,72.5,74.6,99.
5, 103.1, 111.7, 112.3, 125.
2,126.7,128.7,132.0,149.
9, 150.3 ppm. Elemental analysis: measured value (%); C, 65.01; H, 7.1
N; 6.20 Calculated (%); C, 64.85; H, 7.26; N,
6.30

Compound (2) mp: 198.5-199.5 ° C., yield: 20% ¹ H-NMR: 2.3-2.5 (4H, m), 2.51
(1H, d, J = 9.7 Hz), 3.05 (1H, b
r), 3.42 (1H, s), 3.6-4.3 (11
H, m), 4.80 (1H, d, J = 3.8 Hz),
7.5 to 7.6 (2H, m), 8.2 to 8.3 ppm
(2H, m). ¹³ C-NMR: 45.3, 55.5, 61.7, 62.
5,66.6,71.7,72.3,73.2,99.
8, 104.7, 122.7, 126.6, 141.
2,147.6 ppm. Elemental analysis: measured value (%); C, 52.50; H, 5.8
N; 6.74 Calculated (%); C, 52.42; H, 5.87;
6.79

Compound (3) mp: 204-205 ° C., [α] _D ²⁰ = + 87.70
°, yield: 78% ¹ H-NMR: 2.10 (1H, br, s, 6-O
H), 2.76 (1H, d, J = 3.0 Hz, 4-O
_{H), 3.56 (3H, s} , -OCH 3), 3.5~
3.7 (1H, m, H-5), 3.8-3.9 (2H,
m, H-6), 3.96 (1H, dd, J = 9.6H)
z, J = 3.0 Hz, H-2), 4.05 (1H, m,
H-4), 4.48 (1H, t, J = 9.6 Hz, H-
3), 5.21 (1H, d, J = 3.0 Hz), 7.1
-7.3 (4H, m), 7.3-7.5 (2H, m),
7.61 (1H, dd, J = 7.8 Hz, J = 1.6H
z), 7.93 ppm (1H, dd, J = 7.6 Hz,
J = 1.4 Hz). ¹³ C-NMR: 55.7, 61.3, 69.8, 73.
1,76.7,77.3,98.1,102.2,11
6.6,116.8,122.2,122.3,12
3.2, 123.3, 125.7, 126.4, 13
0.0, 130.1, 151.6, 151.7 pp
m. Elemental analysis: measured value (%); C, 64.77; H, 5.4
1 Calculated value (%); C, 64.51; H, 5.41

Compound (4) mp: 198-200 ° C., [α] _D ²⁰ = + 77.7 °,
Yield 54% ¹ H-NMR: 2.08 ( ¹ H, t, J = 7.2 Hz,
6-OH), 2.85 (1H, d, J = 3.6 Hz, 4
-OH), 3.52 (3H, s), 3.4 to 3.6 (1
H, m, H-5), 3.72 (1H, dd, J = 9.6).
Hz, J = 3.0 Hz, H-2), 3.8-3.9 (1
H, m, H-4), 3.99 (1H, dt, J = 9.4).
Hz, J = 3.6 Hz, H-4), 4.19 (1H, d
d, J = 9.6 Hz, J = 9.4 Hz, H-3), 5.
20 (1H, d, J = 3.0 Hz, H-1), 7.3 to
7.4 (4H, m), 7.4 to 7.6 (2H, m),
7.7 to 7.8 (1H, m), 8.0 to 8.1 ppm
(1H, m). ¹³ C-NMR: 55.5, 66.2, 69.6, 73.
8, 76.7, 77.2, 97.9, 104.9, 12
5.2, 126.1, 126.2, 126.2, 12
6.6, 126.6, 128.1, 128.2, 13
2.7, 132.9, 133.9, 133.9 pp
m. Elemental analysis: measured value (%); C, 61.96; H, 5.2
9; S, 8.17 Calculated (%); C, 61.84; H, 5.19;
8.26,

Compound (5) mp: 192 ° -194 ° C., [α] _D ²⁰ = + 72.5 °,
Yield 26% ¹ H-NMR: 2.48 (1H, br), 2.74 (1
H, br), 2.88 (6H, s), 2.98 (6H,
s), 3.38 (3H, s), 3.8-3.9 (2H,
m), 3.9-4.1 (4H, m), 4.66 (1H,
d, J = 1.1 Hz), 6.5 to 6.6 (2H, m),
6.7 to 6.8 (2H, m), 7.2 to 7.3 (2H,
m), 7.3-7.4 ppm (2H, m). ¹³ C-NMR: 40.6, 55.0, 63.7, 63.
9, 69.1, 70.9, 72.7, 101.2, 10
3.9, 111.7, 112.7, 125.6, 12
7.0, 128.8, 150.2 ppm. Elemental analysis: measured value (%); C, 65.11; H, 7.0
8; N, 6.31 Calculated (%); C, 64.85; H, 7.26;
6.30

Compound (6) mp: 182-184 ° C., [α] _D ²⁰ = + 72.7 °,
Yield 34% ¹ H-NMR: 2.17 (1H, br), 2.75 (1
H, br), 2.91 (6H, s), 2.94 (6H,
s), 3.39 (3H, s), 3.6-3.7 (1H,
m), 3.7-3.8 (3H, m), 4.06 (1H,
d, J = 6.3 Hz, H-2), 4.28 (1H, t,
J = 6.3 Hz, H-3), 5.04 (1H, s, H-)
1), 6.6 to 6.7 (4H, m), 7.2 to 7.4
ppm (4H, m). ¹³ C-NMR: 40.5, 40.6, 55.2, 63.
0, 69.4, 70.2, 75.1, 78.2, 98.
6, 110.7, 111.8, 127.3, 127.
4, 130.4, 150.2, 150.3. Elemental analysis: measured value (%); C, 64.85; H, 7.0
6; N, 6.26 Calculated (%); C, 64.85; H, 7.26;
6.30

Compound (7) mp: 199.5-201 ° C., [α] _D ²⁰ = −9.9
°, yield 65% ¹ H-NMR: 2.51 (1H, br, 6-OH),
3.33 (3H, s), 3.59 (1H, d, J = 5.
0 Hz, 4-OH), 3.69 (1H, m, H-5),
3.8-3.9 (2H, m, H-6), 4.0-4.2
(1H, m, H-4), 4.39 (1H, d, J = 6.
6Hz, H-2), 4.66 (1H, t, J = 6.6H)
z, H-3), 4.89 (1H, s, H-1), 7.1
-7.3 (4H, m), 7.3-7.5 (2H, m),
7.51 (1H, dd, J = 7.8 Hz, J = 1.6H
z), 7.84 ppm (1H, dd, J = 7.8 Hz,
J = 1.6 Hz). ¹³ C-NMR: 55.1, 62.2, 66.8, 69.
7, 75.1, 79.5, 98.2, 101.8, 11
6.7, 116.9, 121.7, 122.9, 12
3.3, 123.5, 125.0, 125.7, 12
9.8, 130.2, 151.7, 152.8 pp
m. Elemental analysis: measured value (%); C, 64.37; H, 5.4
1 Calculated value (%); C, 64.51; H, 5.41

Compound (8) mp: 100 ° C. (decomposition), [α] _D ²⁰ = + 2.7 °, yield: 47% ¹ H-NMR: 2.45 (1H, br), 3.32 (3
H, s), 3.3-3.4 (1H, m), 3.5-3.3.
7 (2H, m), 3.8 to 3.9 (1H, br), 3.
9 to 4.0 (1H, m), 4.09 (1H, d, J =
6.0 Hz), 4.58 (1H, dd, J = 7.2H)
z, J = 6.0 Hz), 4.94 (1H, s), 7.3
To 7.4 (4H, m), 7.5 to 7.6 (2H, m),
7.7 to 7.8 (1H, m), 7.9 to 8.0 ppm
(1H, m). ¹³ C-NMR: 55.1, 62.3, 69.1, 69.
3,75.3,79.8,97.8,105.0,12
5.0, 125.3, 125.9, 126.5, 12
7.0, 127.2, 128.1, 128.4, 13
3.0, 133.7, 134.2, 134.3 pp
m. Elemental analysis: measured value (%); C, 61.55; H, 5.5
9; S, 8.11 Calculated value (%); C, 61.84; H, 5.19; S,
8.26

Example 2 1 mmol of thiomihlaz ketone, 1.2 mmol of methyl α-D-glucoside and 0.5 ml of triethylamine
Was dissolved in 5 ml of anhydrous pyridine. After adding 2.5 mmol of copper (I) chloride to the reaction solution over 5 minutes, the mixture was stirred at room temperature for about 1 hour. Pyridine and triethylamine were distilled off from the reaction solution under reduced pressure, and diluted hydrochloric acid and ethyl acetate were added to the residue. After the precipitate was filtered off, the organic layer obtained was separated, washed with water and dried, and then ethyl acetate was distilled off under reduced pressure. The obtained crude product was developed on silica gel column chromatography and eluted with ethyl acetate / hexane to give compound (I) at a yield of 15%.

Comparative Example 1 1 mmol of thiomihlaz ketone and 1.2 mmol of methyl α-D-glucoside were dissolved in 15 ml of anhydrous DMF.
The reaction mixture to which 0.5 ml of triethylamine was further added was continuously stirred at room temperature for 5 hours. A very small amount of the reaction solution was taken out and developed on TLC (silica gel, thin layer chromatography), but the formation of compound (I) was not observed. Therefore, the reaction solution was further heated at 80 ° C. overnight, but the reaction proceeded. I didn't.

Comparative Example 2 3 ml of a solution of 2.5 mmol of silver trifluoroacetate in acetonitrile was added to a reaction solution in which 1 mmol of thiomihlaz ketone and 1.2 mmol of methyl α-D-glucoside were dissolved.
After dropwise addition over a period of minutes, the mixture was stirred at room temperature for about 2 hours.
A very small amount of the reaction solution was taken out and developed on TLC. Since the formation of compound (I) could not be confirmed, the reaction solution was further heated at 80 ° C. for 5 hours, but was not reacted.

Claims (5)

(57) [Claims] 1. A method for acetalizing a saccharide, comprising reacting the saccharide with a thiocarbonyl compound having a bulky organic group in the presence of a base and a silver salt or a copper salt. Alternatively, a method of selectively acetalizing the 4- and 6-positions. 2. A thiocarbonyl compound having a bulky organic group is a bis (dialkylaminophenyl) thioketone,
The method according to claim 1, which is nitrophenylmorpholinothioketone, 2,6-dialkyl-γ-pyranthion, xanthenethione or thioxanthenthione. 3. The method according to claim 1, wherein the reaction is carried out in an organic solvent. 4. The method according to claim 3, wherein an organic tertiary amine is used as the base. 5. The method according to claim 3, wherein trifluoroacetate or trifluoromethanesulfonate is used as the silver salt or the copper salt.
The described method.