JPS63222193A - Use of phosphinothioyl group as protective group of saccharide hydroxyl group - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the use of phosphinothioyl groups as protecting groups for sugar hydroxyl groups.

Saccharides are generally a group of compounds having multiple hydroxyl groups,
In order to perform a glycosylation reaction or a functional group conversion reaction on only a specific hydroxyl group, other hydroxyl groups must be temporarily protected. Furthermore, after separating the plurality of hydroxyl groups kR, Vc requires many types of protecting groups with different properties. For example, alkyl groups such as benzyl group and trityl group, and 7-cetal groups such as impropylidene group and benzylidene group are known as those that can be removed under acidic conditions and are stable under basic conditions.

On the other hand, acyl-type protecting groups such as acetyl group and benzoyl group are commonly used as those which are stable under acidic conditions and can be deprotected under basic conditions. However, when these acyl groups have a free hydroxyl group in their molecules, they often cause intramolecular acyl rearrangements that are said to be unpredictable under various conditions, resulting in a significant decrease in the purity of the product. Moreover, separation of these rearrangement products is generally extremely difficult. Therefore, the development of an acyl-type S-retaining group that does not undergo acyl rearrangement is strongly desired.

The present inventor conducted extensive research from the above viewpoint.

After learning that the purpose could be achieved by using a specific phosphoric acid derivative, he completed the present invention.

That is, the gist of the present invention is a step of reacting m or a 1111 conductor having at least one free hydroxyl group with a halogenated phosphinothioyl in the presence of a base to obtain a phosphinothioyl sugar derivative; A high-fructose sugar derivative is reacted with hydroxide ions, the phosphinothioyl group is deprotected, and a sugar or sugar derivative is formed. This method uses a phosphinothioyl group as a protecting group for a sugar hydroxyl group.

The phosphinothioyl saccharide derivative obtained by the present invention 1'C can be used as a synthetic intermediate of branched oligosaccharides, 2 food additives, a synthetic intermediate of various antibiotics, or a synthetic intermediate of macrolide compounds. .

The present invention will be explained in detail below.

First, the step of obtaining a phosphinothioyl saccharide derivative in the method of the present invention will be explained.

As the sugar or sugar derivative used in this step, well-known sugars or sugar derivatives can be used. Specifically, these substances include tetraoses such as erythrose and threoses, pentoses such as ribose, ara-nose, and xylose, glucose, and galactose.

Hexoses such as mannose, allose, and talose.

t't is a partially deoxylated sugar such as deoxyribose or 7 such as N-acetylgelcosaone.
In addition to disaccharides, 9-oligo mt in which these s are mutually ether bonded can also be used. It was. Needless to say, it can also be used for glycerol, sialic acid, etc.

These five sugars can be used as D-units, L-units, and mixtures thereof.As the sugar derivatives, derivatives in which the hydroxyl groups of the well-known sugars mentioned above are protected by conventional methods, or specific derivatives obtained by functional group conversion are used. can.

Specific examples of protective groups include benzyl and methyl groups.

Alkyl groups such as trityl groups, isopropylidene groups.

Acetal groups such as benzylidene groups, acetyl groups.

Examples include acyl groups such as benzoyl group and silyl groups such as t-butyldimethylsilyl group. Examples of derivatives with nine functional groups include azide and uronic acids. Needless to say, the above sugar derivatives must have at least one free hydroxyl group.

As the halogenated phosphinothioyl used as another raw material in this step, well-known ones can be used. i.e. dimethylphosphinothioyl.

Diethylphosphinothioyl, methylphenylphosphinothioyl, dibutylphosphinothioyl.

Various halides such as diphenylphosphinothioyl can be used. Fluorine is a halogen atom.

It may be any of chlorine, bromine, and chlorine, but chloride and bromide are usually used. Particularly preferred is dimethylphosphinothioyl chloride due to its reactivity and ease of handling.

As the base used in this step, well-known bases can be used. Specifically, triethylamine, pyridine, l, 8-
Diazabicyclo[:5,4.0]undecene-7 (DB
Examples include tertiary amines such as U), n-butyllithium, sodium hydride, and sodium hydroxide. In particular, DBU+n-butyllithium is excellent.

Furthermore, when using tertiary ammonium chloride, the reaction time can be shortened and the yield can be improved by coexisting a catalytic amount (~20 mol fk>LD4-dimethylaminopyridine gold).

With the halogenated phosphinothioyl mentioned above! The amount of each group to be used is in the range of 1 to 5 times the mole of II or the number of aqueous groups of the sugar derivative. Usually, L2 to λO times the molar amount is used.

As the solvent, well-known organic solvents other than alcohols can be used. Specific examples include chloroform, dichloromethane, ether, tetrahydrofuran, pyridine, N,N-dimethylformand, and benzene.

Particularly preferred is dichloromethane.

There is no particular restriction on the reaction temperature. However, usually -30℃~8
It is in the range of 0°C, preferably in the range of 0°C to room temperature.

Reaction times range from several hours to several days depending on the type of base used. For example, when using DBU and 4-dimethylaminopyridine, the time range is from 1 to 20 hours.

Through the above steps, the phosphinothioyl saccharide derivative can be obtained in good yield, but it is also possible to identify the primary hydroxyl group, especially when a primary hydroxyl group and a secondary hydroxyl group are present.

Next, phosphinothiomolization 11! The process of deprotecting a phosphinothioyl group from a conductor will be explained.

The phosphinothioyl saccharide derivative that is used as the raw material in this step is further subjected to various reactions such as glycosylation reaction, introduction of other protecting groups, deprotection, etc. Needless to say, it is a phosphinothioyl saccharide derivative obtained after conversion of functional groups, etc. Unlike Yuko Yuko, who was mentioned above,
The presence or absence of free hydroxyl groups does not matter.

As the hydroxide used in the reaction with the hydroxide ion, any of the well-known hydroxides can be used. Specific examples include sodium hydroxide, potassium hydroxide, ammonium hydroxide, and trimethylbenzylammonium hydroxide. Particularly preferred is trimethylbenzylammonium hydroxide.

The amount of hydroxide ion to be used may be in large excess, but is in the range of 1 to 10 times the number of phosphinothioyl groups in the phosphinothiomolated sugar derivative. It is usually used in a range of 2 to 5 times the mole.

There are no particular restrictions on the solvent used. However, the selection depends on the solubility of the phosphinothioyl saccharide derivative, and specific examples include the well-known organic solvents mentioned above, water, and alcoholic solvents such as methanol and ethanol.

The reaction temperature is not particularly limited and is usually in the range of -30°C to 80°C. Preferably, the temperature is in the range of 0°C to room temperature.

The reaction time varies depending on the amount of hydroxide ion used and its concentration, but ranges from several minutes to several tens of hours.

Through the above steps, the phosphinothioyl group can be removed from the phosphinothioyl saccharide derivative. At this time, the phosphinothioyl group becomes the corresponding thiophosphinic acid, which becomes a water-soluble ionic substance similar to the hydroxide used as a deprotecting agent.

The sugar or sugar derivative that becomes the product can be easily removed by extraction, washing with water, ion exchange chromatography, etc.

Note that the phosphinothioyl group can also be removed using a basic nucleophile such as sodium methoxide;
In this case, the reaction is extremely slow and it is difficult to find a practical method.

Through the above two steps, it can be used as a protecting group for the hydroxyl group of the phosphinothioyl base sugar. In addition, this phosphinothioyl group is extremely sensitive to various conditions such as introduction and deprotection, dispersion conditions such as detritylation and deacetalization, and various conditions such as tertiary azun and catalytic amounts of sodium methoxide. This is an unprecedented acyl-deaf protecting group that is stable and does not give a ζ-position product. Therefore, unlike conventional acyl groups, there is no risk of reducing the purity of the product during the manufacturing process, and its industrial value is great.

The present invention will be described in more detail below with reference to Examples and Reference Examples; however, the present invention is not limited in any way by the Examples and Reference Examples unless the gist thereof is exceeded.

Example 1゜Methyl 2.3-0-dibenzyl-6-0-)lythyl-α-D-glucopyranoside (1) 123.3q (0,2
mmol) was dissolved in dichloromethane α5-.

DBU 61 td- (0.4 mmol) and 4-dimethylaminopyridine Z 4 W (0.02 mmol
) 2 added. Dissolve this in dichloromethane 1.5-m dimethylphosphinothioyl chloride 51.4181 (
0.4 mmol) k Soaked under ice cooling. After 10 minutes, the reaction solution was returned to room temperature and stirred overnight. Remove the solvent under reduced pressure,
Ether and water were added to separate the layers. The organic layer was washed with water, dried, concentrated, and purified by silica gel thin layer chromatography.
．． 130.719 (92 pieces) of 3-0-dibenzyl-4-0-dimethylphosphinothioyl-6-0-) lythyl-α-ri-glucobyranoside (2) were obtained as white crystals. 'HNMR(CDCl,) δ=1.20 (
3H, d, J = 13Hz, P-CH,).

1.45 (3H, d, J = 13Hz, P-
CH,).

a56 (3H, a, OCH,), 6.62-
7.55 (25H, m, Ph) ppm.

Example 2 DBU 33 td-(0,22 mmol), chloride')l fk*Sufinothioil 2&3 q(0,2
Using 2 mmol) 1, compound (1) was reacted in the same manner as in Example 1. Then, compound (s) cuff 7.3
q (s s q4) obtained Lareta.

Example λ A reaction was carried out for 3 days in the same manner as in Example 2 without the coexistence of 4-dimethylaminopyridine, and compound (2) was found to be 73.
1v (s, zLs) obtained Lareta.

In the example, triethyl ane 31μ (0.22m) was used instead of DBUO.
mol) and compound (1)'f in the same manner as in Example 2.
When the compound (2) was reacted with 57.419 (4
1 h) Obtained 9.

Methyl 2. a-0-dibenzyl-α-D-/rucobyranoside (3) 149.8 q (0.4 mmol)
, DBU67 tsL (Q, 44 mmol)
, 4-dimethylaminopyridine 49 Q (0,04
mmol), dimethylphosphinothioyl chloride 5
a6 q (0.44 mmol)'! Proceed as in Example 1 in dichloromethane (2-) using r and t.

When purified by silica gel thin layer chromatography, the compound (3
) was recovered, 22,411FC15%) was recovered, and methyl 2.3
119.711f (65%) of -o-dibenzyl-6-0-dimethylphosphinothioyl-α-D-glucopyranoside (4) was obtained as an oil.

'HNMR(CDCl, )δ=1.99 (3H, d
, Jx137, p-c), ZOI (3H, d, J
=13 Examples & Methyl 3-0-benzyl-4,6-0-benzylidene-
α-D-glucopyranoside (5) 0.58t (L56
mmol) kjikoo)1/n20 m
K: DBU O, 49ml to this.
C&2 mmol), 4-')j 9.8 q (0.08 mmol) k of thylaminopyridine were added. Furthermore, dimethylphosphinothioyl chloride α23f (L
8 mmol) yz was added at room temperature and stirred overnight.

After treatment in the same manner as in Example 1, purification by silica gel column chromatography revealed that methyl 2-0-dimethylphosphinothioyl-3-0-benzyl-4,6-0-benzylidene-α-D-gelcopi-2-noside (6) is o, 5ar
(78%) A good friend.

'HNMR(CDC1,)J=1.66 (3H,d
, J=13Hz, P-CH,), 1.77 (3
H, d, J=13H1,P-CHa), 136
(3H,a,0CHI).

7.00-7.59 (15H, In, $) P
p.m.

Example 7゜(7) (sha) Compound (2) synthesized in Example 1 was detritylated by a conventional method to give 9-methyl 2.3-0-dibenzyl-4-〇-dimethylphosphinothioyl-α-D- Glucopyranoside (7) 16.7 wq (0,036 mmol) + i
Next, dissolve 0.4 mK of 0.1N trimethylbenzylammonium hydroxide/dichloromethane-methanol solution. Analysis by high-performance liquid chromatography showed that after 8 hours, the dimethylphosphinothioyl group was removed and compound (3) was formed. At this time, no rearrangement product (4) of dimethylphosphinothioyl group could be detected.

Example & When the same procedure as in Example 7 was carried out using 0.4 mg of 0.2N trimethylbenzylammonium hydroxide/dichloromethane-methanol solution, 97% of the subsequent compound (3) was produced in 4 hours. Moreover, compound (4) could not be detected at all.

Reference Example 1゜Compound (2) synthesized in Example 1 208.5 q(0
, 29 ml) was suspended in acetic acid 5-, and 11 ml of 25 hydrogen eubromide/acetic acid solution was added thereto. Stir for 2 minutes, neutralize with sodium hydrogen carbonate, and extract with ether.

This was purified by silica gel thin layer chromatography to obtain 67.2 capes (491) of the target compound (7). At the same time, this compound (7) is acetylated in the reaction system to give 35 .5q (241) were obtained. on the other hand,
The dimethylphosphinothioyl group is rearranged to form the next compound (4)
was not obtained at all.

Reference example 2 Methyl 2.3-0-dibenzyl-4-0-acetyl-6
-0-trityl-α-D-/rucobilanoside (9) 0.
64f (α97 mmol) k% vinegar a! 10mg.

When treated in the same manner as in Reference Example 1 using 25% hydrogen bromide/acetic acid solution 3d, the target methyl 2.3-0-dibenzyl-4-〇-acetyl-α-D-glucopyranoside (10) was obtained with 64" Only 15% of F (15%) was obtained, and the acetyl group was rearranged, resulting in 9methyl 2.3-0-dibenzyl-6-〇-acetyl-α-D-glucopyranoside (11) with 0.
20f (49S) was obtained. In this case, as in Reference Example 1, methyl 2.3-0-dibenzyl-4,6-0-diacetyl-α-D-glucopyranoside (12), which is an acetylated compound (lO) or (11), is 70q (1
51) Obtained.

Reference Example U Under the following conditions, compound (7) was analyzed using high performance liquid chromatography or silica gel thin layer chromatography in the same manner as in Example 7. (4) was also not accepted.

1) DBU (1 eq.) and 5 mol of 4-dimethylaminopyridine in dichloromethane for 6 hours 2) 15% trifluoroacetic acid/dichloromethane solution 2
4 hours 3) 4Nu acid-tetrahydrofuran (1:3) solution 2
2 hours 4) 57% sodium methoxide in methanol 1
8 hours 5) Tetrabutylammonium 7 fluoride (1 eq.) in dichloromethane 23 hours 6) 0.5N DBU/methanol solution 23 hours Reference Example Table Same as Example 7 Compound (7) 15.111F (0, 0
32 mmol) was added to 0.451114 of a 0.08N sodium methoxide/methanol solution and analyzed by high-performance liquid chromatography in the same manner as in Example 7. Even after 24 hours, a compound with the dimethylphosphinothioyl group removed (
3) produces only 17% and 9. In this case as well, no rearrangement product (4) was detected.

Claims (1)

[Claims] 1. Sugar or a sugar derivative having at least one free hydroxyl group in the presence of a base according to the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X is a halogen atom, R is the same or ) to obtain a phosphinothioyl saccharide derivative, and a step of reacting the phosphinothioyl saccharide derivative with a hydroxide ion to obtain a phosphinothioyl saccharide derivative. A method for using a phosphinothioyl group as a protecting group for a sugar hydroxyl group, which comprises the step of deprotecting an oil group to obtain a sugar or a sugar derivative. 2. In the presence of 4-dimethylaminopyridine as a base, 3
Claim 1 characterized in that a class amine is used.
The method described in section. 3. 1,8-diazabicyclo[5,4,0] as base
The method according to claim 1, characterized in that undecene-7 is used. 4. The method according to claim 1, characterized in that dimethylphosphinothioyl chloride is used as the halogenated phosphinothioyl. 5. The method according to claim 1, characterized in that trimethylbenzylammonium hydroxide is used in the reaction with hydroxide ions.