JPH0460119B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing glycoside compounds. Specifically, the present invention relates to a method for producing a glycoside compound by reacting a thiophosphinate at an anomeric position of a sugar with a silyl ether. Glycoside compounds are widely distributed in nature and are attracting attention as they are used as physiologically active substances such as antibiotics and anticancer agents in medicine, agriculture, etc. However, their production method requires unstable intermediates. The only known methods are methods that use oxidation or harsh reaction conditions, and no method that can be used industrially is known yet. In addition, there are many hydroxyl groups in sugars, and in conventional methods, all hydroxyl groups that do not participate in the reaction must be protected, so a protective reagent is required, and the weight loss during deprotection is significant, making it difficult to industrialize. It has become an obstacle. Among the conventionally known methods, the method of W. Koenig and E. Knorr [see Chem. Ber. vol. 34, p. 957 (1901, Germany)] is known as a commonly used method. In this method, halogenosaccharide and alcohol are reacted, but the stability of the raw material halogenosaccharide is poor.
It has many drawbacks, such as the need to carry out the reaction under highly dehydrated conditions and the necessity to protect hydroxyl groups that do not participate in the reaction, making industrialization difficult. As a result of intensive research in view of the above circumstances, the present inventor found that the purpose could be achieved by using a specific sugar derivative, and arrived at the present invention. That is, the gist of the present invention is a method for producing a glycoside compound, which is characterized by reacting a thiophosphinic acid ester at the anomeric position of a sugar with a silyl ether. The present invention will be explained in detail below. 1. Synthesis of a thiophosphinic acid ester derivative at the anomeric position of sugar As a raw material for the thiophosphinate derivative at the anomeric position of sugar, which is one of the raw materials of the present invention, well-known sugars can be used. It is necessary that the anomeric position of these sugars is hemiacetal bonded. The cyclic hemiacetal may be a 5-membered ring or a 6-membered ring. Usually aldoses are used, but ketoses can also be used. Specifically, these sugars include tetraoses such as erythrose and threoses, pentoses such as ribose, arabinose, and xylose, hexoses such as glucose, galactose, mannose, allose, and talose, and deoxyribose, in which some of these sugars are deoxygenated. In addition, oligosaccharides in which these sugars are ether-linked to each other can also be used. These sugars can be used in D-form, L-form, or mixtures thereof. It goes without saying that these sugars can be used with all hydroxyl groups other than the anomeric position protected, but they may also have free hydroxyl groups protected to the minimum extent necessary for solubility and the like. As the protecting group for the hydroxyl group, conventionally known ones can be used. Specifically, acetyl,
trifluoroacetyl, trichloroacetyl,
Examples include a method of protecting with an acyl group such as benzoyl or P-nitrobenzoyl, a method of acetalization with acetaldehyde, acetone, etc., and a method of etherification with a hydrocarbon group such as methyl, benzyl, or triphenylmethyl. The anomeric thiophosphinic acid ester of a sugar can be easily synthesized by reacting the above-mentioned sugar derivative with a strong base and then reacting it with a halogenated phosphinothioyl. As the halogenated phosphinothioyl used in this method, well-known ones can be used. That is, various halides such as dimethylphosphinothioyl, diethylphosphinothioyl, methylphenylphosphinothioyl, and diphenylphosphinothioyl can be used.
The halogen may be any of fluorine, chlorine, bromine, and iodine, but chloride and bromide are usually used. As the strong base, well-known ones can be used. Namely, alkali metals such as sodium metal, lithium metal, and potassium metal, metal alcoholates such as sodium methoxide and thallium ethoxide, alkali metal hydrides such as sodium hydride, and alkyl metals such as n-butyllithium and phenyllithium. Or aryl metals or strongly basic amines such as 1,8-diazabicyclo-[5,4,0]-undecene-7. Although it is possible to use the halogenated phosphinothioyl and the strong base in large excess relative to the sugar, the amount is usually 1 to 2 molar equivalents. There are no particular restrictions on the solvent. That is, benzene, toluene, chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, acetonitrile, nitromethane and the like can be mentioned. The reaction temperature is not particularly limited from -60°C to the boiling point of the solvent. Anomeric thiophosphinates of sugars exist in α and β forms, which can be separated from a mixture, but they can also be produced with good selectivity by changing the solvent, base, reaction temperature, etc. It is. On the other hand, the raw material for the glycosylation reaction may be either the α-form, the β-form, or a mixture thereof. 2 Synthesis of Silyl Ether Silyl ether, which is a raw material for the method of the present invention, can be obtained by silylating a well-known alcohol. As well-known alcohols, compounds having hydroxyl groups such as aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, sugar derivatives, and amino acid derivatives can be used. Examples of aliphatic alcohols include methanol, ethanol, propanol, isopropanol, cetyl alcohol, butanol, ethylene glycol, propylene glycol, and the like. Of course, cycloaliphatic alcohols such as cyclohexanol, methylcyclohexanol, and menthol can also be used. Aromatic alcohols include phenol, P-
Chlorophenol, O-chlorophenol, phenetol, P-nitrophenol, O-nitrophenol, 2,4-dinitrophenol,
Examples include P-cresol, o-cresol, α-naphthol, β-naphthol, catechol, resorcinol, and hydroquinone. Examples of steroid alcohols include cholesterol, cholestanol, stigmasterol, campesterol, sitosterol, ergosterol, fucosterol, estrone, estradiol, testosterone, androsterone, and the like. Examples of glycerol derivatives include glycerin and its monoacyl and diacyl forms. Here, examples of the acyl group include acetyl, benzoyl, balmityl, stearyl, oleyl, etc. In the diacyl form, the same acyl group or different acyl groups may be used. Although some of these stereoisomers exist, it goes without saying that any of them can also be used as a mixture. As the sugar, well-known sugars can be used. That is, the sugars mentioned above can be used, but the anomeric position does not necessarily have to be hemiacetal bonded. It goes without saying that oligosaccharides can also be used. Sugars have many hydroxyl groups, all of which can be protected by the method described above, or they can be used with free hydroxyl groups. Amino acid derivatives include serine, threonine, hydroxyproline, hydroxylysine,
Examples include tyrosine. These amino acids exist in L-form and D-form, and either one or a mixture can be used. It goes without saying that amino alcohols obtained by reducing the carboxyl groups of amino acids and peptides in which amino acids are condensed can also be used. Furthermore, those having a protecting group introduced into the amino group or carboxyl group can also be used. A well-known method can be used for the silylation of the alcohol described above. In addition, as a silyl group, the general formula (In the formula, R ₁ , R ₂ , R ₃ are methyl groups, ethyl groups,
Propyl group, isopropyl group, butyl group, s-
It represents either a butyl group, t-butyl group, phenyl group, or p-methoxyphenyl group. ) can be used. Specifically, trimethylsilyl, triethylsilyl,
Well-known examples include t-butyldimethylsilyl, t-butyldiphenylsilyl, and triisopropylsilyl. (3) Reaction between a thiophosphinic acid ester derivative at an anomeric position of a sugar and a silyl ether The reaction between a thiophosphinic acid ester derivative at an anomeric position of a sugar and a silyl ether, which is the method of the present invention, will be explained. In this method, there is no particular restriction on the molar ratio of the two, and the silyl ether may be used in large excess, but it is usually 1 to 3 molar equivalents, preferably 1 to 1.2 molar equivalents. Alternatively, the thiophosphinic acid ester derivative at the anomeric sugar position can be used in excess. There are no particular restrictions on the solvent. For example, benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, methanol, butanol, or a mixed solvent thereof can be used, but solvents such as tetrahydrofuran and benzene are preferably used. The reaction temperature is not particularly limited from -40°C to the boiling point of the solvent, but is usually -20°C to 40°C, preferably -10°C to 25°C. The reaction time varies depending on the reaction temperature, the type of raw materials, etc., but is in the range of several hours to several tens of hours. The reaction is carried out in the presence of a known silver salt, copper salt or mercury salt in a substantially equimolar amount to the thiophosphinate derivative at the anomeric position of the sugar. Preferred salts that can be used here include silver perchlorate, silver acetate, silver trifluoromethanesulfonate, silver P-toluenesulfonate, silver nitrate, copper perchlorate, mercury perchlorate, and mercury acetate. Use silver perchlorate and copper perchlorate. It is sufficient to use these metal salts in the presence of a dehydrating agent such as a molecular sieve in the reaction system without making them particularly anhydrous. The reaction of the anomeric thiophosphinate of the sugar used in the present invention with alcohol is considerably poorer in reactivity than the reaction with silyl ether. Therefore, in compounds having many hydroxyl groups such as sugar derivatives, it is not necessarily necessary to protect other hydroxyl groups that do not participate in the reaction. As described above, the method of the present invention has the advantage that useful compounds can be produced in good yield under mild and neutral conditions, and that there are few by-products. In addition, it is an unprecedentedly advantageous production method that does not necessarily require protection of hydroxyl groups that do not participate in the reaction.
Its industrial value is great. The present invention will be described in more detail below with reference to Examples, but the present invention is not limited in any way by the following Examples unless it goes beyond its gist. Example 1 2,3,4,6-tetrabenzyl-D-glucopyranose dimethylthiophosphinic acid ester
126.5 mg (0.2 mmol) of tetrahydrofuran (2
28.9 mg (0.2 mmol) of cyclohexyltrimethylsilyl ether and 41.5 mg (0.2 mmol) of silver perchlorate dissolved in
mg (0.2 mmol) was added and stirred at room temperature overnight. A 5% aqueous sodium sulfide solution was added to the reaction solution, filtered, and extracted with ether. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain an oily substance. When this was purified using silica gel thin layer chromatography (developing agent: n-hexane:ether = 4:1), the Rf value on silica gel thin layer chromatography was found to be cyclohexyl 2,3,4,6-tetrabenzyl, which matched the literature value. −
61.6 mg (50 mol%) of D-glucopyranoside was obtained as an oil. Example 2 2,3,4,6-tetrabenzyl-α-D-glucopyranose, dimethylthiophosphinic acid ester 126.5 mg (0.2 mmol) molecular sieves
100 mg of 4A and 86.5 mg (0.2 mmol) of β-cholestanyl trimethylsilyl ether were placed in a reaction vessel, and a solution of 41.5 mg (0.2 mmol) of silver perchlorate in tetrahydrofuran (2 ml) was added thereto, followed by stirring at room temperature overnight. Thereafter, when treated in the same manner as in Example 1, β-cholestanyl 2,3,4,6-tetrabenzyl-β
-D-glucopyranoside as white crystals 35.8mg
(20 mol%) was obtained. Melting point: 93.5°C, [α] ²⁵ _D +20.2° (C1.04, CHCl ₃ ) Also, 109.3 mg (60 mol) of β-cholestanil 2,3,4,6-tetrabenzyl-α-D-glucopyranoside as white crystals. %) obtained. Melting point 117.5−
119°C, [α] ²⁵ _D +65.0° (C1.06, CHCl ₃ ) Example 3 2,3,4,6-tetrabenzyl-α-D-glucopyranose dimethylthiophosphinic acid ester 126.5 mg (0.2 mmol), molecular sieves
100 mg of 4A and 41.5 mg (0.2 mmol) of perchloric acid were placed in a reaction vessel, and a solution of 86.5 mg (0.2 mmol) of β-cholestanyl trimethylsilyl ether in tetrahydrofuran (2 ml) was added thereto, followed by stirring at room temperature.
Thereafter, when treated in the same manner as in Example 2, β-cholestanyl 2,3,4,6-tetrabenzyl-α-D-
Glucopyranoside as white crystals 100.5 mg (55
mol%) and β-cholestanil 2,3,4,6-
27.7 mg (15 mol %) of tetrabenzyl-β-D-glucopyranoside was obtained as white crystals. The physical property values were consistent with those of Example 2. Example 4 The same operation as in Example 2 was carried out at 0°C, and the treatment yielded 99.0 mg (55 mol%) of β-cholestanyl 2,3,4,6-tetrabenzyl-α-D-glucopyranoside as white crystals. , 35.0 mg (19 mol %) of β-cholestanyl 2,3,4,6-tetrabenzyl-α-D-glucopyranoside was obtained.
The physical property values were consistent with those of Example 2. Example 5 The same procedure as in Example 2 was carried out using a mixed solvent (3 ml) of dichloromethane-tetrahydrofuran (21) instead of tetrahydrofuran.
Cholestanil 2,3,4,6-tetrabenzyl-
α-D-glucopyranoside 92.1 mg (50 mol%),
52.3 mg (29 mol %) of β-cholestanil 2,3,4,6-tetrabenzyl-β-D-glucopyranoside was obtained. The physical property values were consistent with those of Example 2. Example 6 The same procedure as in Example 2 was carried out using 74.1 mg (0.2 mmol) of copper perchlorate hexahydrate in place of silver perchlorate, and β-cholestanyl 2,3,4,6-tetrabenzyl was obtained. -α-D-glucopyranoside 42.6mg
(23 mol%), β-cholestanil 2,3,4,6-
Tetrabenzyl-β-D-glucopyranoside
19.7 mg (11 mol%) was obtained. Physical property values are as in Example 2
matched. Example 7 In the same manner as in Example 2, 2,3,4,6-tetrabenzyl-β-D-glucopyranose dimethylthiophosphinic acid ester was used, and β-
Cholestanil 2,3,4,6-tetrabenzyl-
85.2 mg (47 mol%) of D-glucopyranoside was obtained. Example 8 When 100.6 mg (0.2 mmol) of β-cholestanyl t-butyldimethylsilyl ether was used in the same manner as in Example 2, β-cholestanil 2,3,
85.6 mg (47 mol%) of 4,6-tetrabenzyl-D-glucopyranoside was obtained. Example 9 When 2,3,4,6-tetrabenzyl-α-D-glucopyranose diphenylthiophosphinate was used in the same manner as in Example 2, β
-148.5 mg (82 mol%) of cholestanil 2,3,4,6-tetrabenzyl-D-glucopyranoside
Obtained. Example 10 Same as Example 2, 86.5 mg of methyl 6-t-butyldiphenylsilyl-α-D-glycopyranoside
(0.2 mmol). After extraction using methylene chloride instead of ether, the extract was washed with water and dried. 5 ml of a tetrahydrofuran solution containing 0.2 mmol of tetrabutylammonium fluoride was added to the oily substance obtained by concentrating the solvent under reduced pressure, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and purified by silica gel thin layer chromatography (20 x 20 cm), resulting in methyl 6-
25.8 mg (18 mol %) of (2,3,4,6-tetrabenzyl-D-glucopyranosyl)-α-D-glucopyranoside was obtained as an oily substance. NMR (CDCl ₃ , ppm) 3.41 (S, 3H, OCH ₃ ) 7.29 (S, 7.34 (S, 20H, Ph) Comparative example 1 2,3,4,6-tetrabenzyl-α-D-glucopyranose dimethylthio Phosphinic acid ester 126.5mg (0.2mmol), molecular sieves
100 mg of 3A and 16 μm (0.4 mmol) of methanol were placed in a reaction vessel, and a solution of 41.5 mg (0.2 mmol) of silver perchlorate in tetrahydrofuran (2 ml) was added, followed by stirring overnight. No other spots other than the raw material spot on silica gel thin layer chromatography could be detected. Reference Example 1 2.70 mg (5 mmol) of 2,3,4,6-tetrabenzyl-D-glucopyranose is dissolved in tetrahydrofuran (20 ml) and cooled to -30°C under a nitrogen atmosphere. To this, 1.6Mn-butyllithium/n-
Add 3.4ml (5.4mmol) of hexane solution and after 10 minutes 0.69g of dimethylphosphinothioyl chloride
(5.4 mmol). The reaction solution was stirred at -30°C for 3 hours and then returned to room temperature. Ether and water are added to this to separate the layers, and the ether layer is washed with water, dried, and concentrated under reduced pressure to obtain 3.71 g of an oily substance. When this was purified by silica gel column chromatography (2.5 x 42 cm) using dichloromethane as the eluent, 2, 3, 4, 6
-Tetrabenzyl-D-glucopyranose dimethylthiophosphinate as white crystals
The ratio of the α-form and β-form obtained was 2.41g (76 mol%).
It was 98:2. Decantation with n-hexane gives 2,3,4,6-tetrabenzyl-α
-D-glucopyranose dimethylthiophosphinate was obtained. Melting point 62-64℃ NMRδ (CDCl ₃ ppm) 1.86 (d, 6H, P-CH ₃ ,
J = 13Hz) 6.18 (d, d, 1H, H-
1, J = 13Hz, 3Hz) 7.23 (S, 7.30 (S, 20H, Ph) Reference example 2 2.38 g (4.4 mmol) of 2,3,4,6-tetrabenzyl-D-glucopyranose was dissolved in 20 ml of tetrahydrofuran. , at 0°C, 2.75 ml (4.8 mmol) of 1.6M n-butyllithium/n-hexane solution and 0.62 g of dimethylphosphinothioyl chloride.
(4.8 mmol) was used. The same procedure as in Reference Example 1 was carried out.
When purified by silica gel column chromatography (2.5 x 30 cm) using dichloromethane as eluent, 2, 3, 4,
6-tetrabenzyl-D-glucopyranose dimethylthiophosphinic acid ester as an oily substance
2.78 g (99 mol%) was obtained. The ratio of α-form and β-form determined by NMR was 50:50. Reference Example 3 1.08 g (2 mmol) of 2,3,4,6-tetrabenzyl-D-glucopyranose was dissolved in a mixed solution of 10 ml of benzene and 10 ml of tetrahydrofuran.
Add 0.15 thallium ethoxide while passing nitrogen through this.
ml (2.1 mmol) was added and stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and after drying, it was dissolved again in 10 ml of benzene, followed by 0.28 g of dimethylphosphinothioyl chloride.
(2.2 mmol) was added and reacted for 4 hours. Thereafter, when purified in the same manner as in Reference Example 1, 0.38 g of 2,3,4,6-tetrabenzyl-D-glucopyranose dimethylthiophosphinic acid ester was obtained as white crystals.
(30 mol%) was obtained. The ratio of α and β forms determined by NMR was 9:91, and by decanting with n-hexane, 2,3,4,6-tetrabenzyl-β-D-glucopyranose dimethylthiophosphinic acid was obtained. An ester was obtained. Melting point 76-77℃ NMR (CDCl ₃ , ppm) 1.85 (d, d, 6H, p-
CH ₃ , J = 13Hz, 8Hz) 5.37 (dd, 1H, H-1, J = 13Hz,
7Hz) 7.26(S, 7.28(S, 7.30(S,〓 ｜ 〓 ｜〓20H, Ph) Reference example 4 2,3,4,6-tetrabenzyl-D-glucopyranose 108.1 mg (0.2 mmol), 20% n-Butyllithium/n-hexane solution 103.1μ
(0.22mmol), diphenylphosphinothioyl chloride 55.6mg (0.22mmol), tetrahydrofuran 1ml
The same procedure as in Reference Example 1 was carried out using . When purified using silica gel thin layer chromatography (20 x 20 cm), 2,3,4,6-tetrabenzyl-α-D-
81.3 mg (55 mol%) of glucopyranose diphenylthiophosphinic acid ester was obtained as an oily substance. NMR (CDCl ₃ , ppm) 6.38 (dd, 1H, H-1, J
= 13Hz, 3Hz) 6.98-8.26 (m, 30H, Ph) Reference example 5 1.00g (10mmol) of cyclohexanol was
Hexane was dissolved in a two-phase system of 30 ml and formamide 10 ml, and 0.16 ml (0.2 mmol) of pyridine and 1.4 ml (11 mmol) of trimethylsilyl chloride were added at 0°C and stirred. After 30 minutes, the reaction solution was heated to 40-50°C, and after stirring for 3 hours, the n-hexane layer was taken out and concentrated under reduced pressure to obtain 0.78 g (54 mol %) of cyclohexyltrimethylsilyl ether as a colorless oily substance. NMR; δ (ppm) 0.11 (S, 9H, Si-CH ₃ ) 1.00-1.98 (m, 11H,

[Formula]) Reference example 6 β-cholestanol 4.64g (11.9mmol)
- When dissolved in 20 ml of hexane and 8 ml of formamide and treated in the same manner as in Reference Example 5 using 0.096 ml (1.19 mmol) of pyridine and 1.66 ml (13.1 mmol) of trimethylsilyl chloride, 33.1 g (75 mole%)
Obtained. NMR; δ (ppm) 0.11 (S, 9H, Si-CH ₃ ) 0.30-2.33 (m, 47H, β-cholestanyl)

Claims (1)

[Scope of Claims] 1 The hydrogen of the hydroxyl group at the anomeric position of a sugar whose anomeric position is hemiacetal bonded has the general formula [] (In the formula, R ¹ and R ² represent either a methyl group, ethyl group, propyl group, isopropyl group, butyl group, s-butyl group, t-butyl group, phenyl group, or p-methoxyphenyl group.) The hydrogen of the hydroxyl group of the anomeric thiophosphinic acid ester derivative of a sugar represented by the formula and the alcohol selected from aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, sugar derivatives, and amino acid derivatives is represented by the general formula [] (In the formula, R ¹ , R ² , R ³ are methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, phenyl, p-methoxyphenyl) 1. A method for producing a glycoside compound, which comprises coexisting a silyl ether substituted with a silyl group represented by the following formula with a silver salt, a copper salt, or a mercury salt. 2. The production method according to claim 1, wherein the thiophosphinate derivative at the anomeric position of a sugar is a dimethylthiophosphinate derivative at the anomeric position of a sugar. 3. The production method according to claim 1, wherein the thiophosphinate derivative at the anomeric position of a sugar is a diphenylthiophosphinate derivative at the anomeric position of a sugar. 4. The manufacturing method according to claim 1, characterized in that silver perchlorate is used as the silver salt.