JP2010024213A - Method for producing saccharide 1-phosphoric acid compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for selectively producing a stereoisomer of an anomer position of a saccharide 1-phosphoric acid compound. <P>SOLUTION: The method for producing a saccharide 1-phosphoric acid compound represented by formula (I): R-X-P(R<SP>1</SP>)(R<SP>2</SP>) (R is a residue after the removal of hydroxy group at the 1-position from a saccharide compound; R<SP>1</SP>and R<SP>2</SP>are each an alkyl group, an alkoxy group or the like; and X represents an oxygen atom or the like) comprises a process of reacting a saccharide compound represented by formula (II): R-Y (wherein Y is an iodine atom or the like and the bond of Y is an α bond) with a phosphorus compound represented by formula (III): X=PH(R<SP>1</SP>)(R<SP>2</SP>) in the presence of a base such as DMAN, etc. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a sugar 1-phosphate compound.

  A compound (sugar 1-phosphate compound) in which phosphoric acid is bonded to the anomeric position (C1 position) of a sugar compound is extremely important as a substrate for a sugar chain biosynthesis reaction. In addition, sugar-1 phosphate structures are found in cell walls and capsules of bacteria and yeasts, sugar chains of glycoproteins of animals, etc., and have been reported to function as antigenic determinants. For these reasons, phosphorous has the potential to serve as a probe for elucidating the function of glycosyltransferases, as a glycosyltransferase inhibitor, and as a vaccine against bacteria, etc. Sugar 1-phosphate analogs that have been chemically modified at the acid site have attracted attention. However, sugar 1-phosphate compounds have the problem that they are chemically unstable and difficult to synthesize. In particular, it is extremely difficult to stereoselectively synthesize two anomeric isomers (α-form and β-form) of glycoside.

  As a general method for synthesizing a stereoselective sugar 1-phosphate compound, an SN2-type glycosylation method of a glycosyl donor having a leaving group at the anomeric position is known (Tetrahedron Lett., 31, pp.327- 330, 1990; J. Am. Chem. Soc., 124, pp. 2263-2266, 2002; Carbohyd. Res., 223, pp. 169-185, 1992). In this method, β-form can be obtained from α-glycosyl donor, and α-form can be obtained from β-glycosyl donor, but it is necessary to obtain the raw glycosyl donor as a sterically pure compound, and the reaction time is prolonged. Therefore, there is a problem that the product is isomerized. The glycosylation method (Org. Lett., 9, pp.1227-1230, 2007) that utilizes the participation of adjacent groups by the acyl group introduced at the 2-position of the sugar is used to convert the substituent and trans of the 2-position of the sugar skeleton. A sugar 1-phosphate compound in a positional relationship is obtained. For example, β-form can be obtained from glucose, and α-form can be obtained from mannose. This method is extremely useful from the viewpoint of stereoselectivity and application range of the substrate, but has a problem that it cannot synthesize a sugar 1-phosphate compound in a cis positional relationship with a substituent at the 2-position.

  Also, a method for biasing the equilibrium toward thermodynamically stable isomers under protonic acid and Lewis acid conditions using the difference in thermodynamic stability between α and β isomers of sugar 1-phosphate compounds (J. Chem. Soc., Perkin Trans 1, pp. 1699-1704, 1998; Org. Lett., 2, pp. 2135-2138, 2000; Can. J. Chem., Pp. 743-747, 2006) It has been known. In this method, the α-form is preferentially produced in the case of a sugar skeleton due to the influence of the anomeric effect. However, if the difference in thermodynamic stability between anomeric isomers is not large, it is difficult to achieve complete stereoselectivity, and it is applicable to compounds having substituents that are unstable under acidic conditions. Even when applicable, there is a concern that the yield may decrease due to side reactions during the isomerization process. Furthermore, SN2 reaction via sugar 1,2-orthoester (Org. Lett., 8, pp.1815-1818, 2006) and SN2 reaction via sugar 1,2-epoxide (Org. Lett., 1, pp.211-214, 1999) has also been reported for the synthesis of sugar 1-phosphate compounds. However, in these methods, as in the glycosylation method utilizing the neighboring group participation by the acyl group, 1,2- A trans form is obtained.

These methods are methods for synthesizing glycosyl phosphate derivatives or glycosyl H-phosphonate derivatives, and are not applied to the synthesis of glycosyl phosphite derivatives, glycosyl phosphoramidite derivatives, and the like. As a method for stereoselectively synthesizing glycosyl phosphite derivatives and glycosyl phosphoramidite derivatives, a method utilizing the bias of α / β composition ratio of sugar anomeric hydroxyl group and its alcoholate due to steric factors has been reported. (J. Org. Chem., 66, pp. 6234-6243, 2001; Carbohyd. Res., 242, pp. 91-107, 1993; Tetrahedron Lett., 27, pp. 6271-6274, 1986; Angew Chem. Int. Ed., 43, pp.5674-5677, 2004, etc.). These methods have been successfully used for N-acetylglucosamine, galactose, and mannose derivatives, and particularly for N-acetylglucosamine derivatives, good α selectivity is often obtained. However, since the three-dimensional factors of the substituents on the sugar skeleton are important in these methods, the above method is not applicable to various sugar derivatives.
Tetrahedron Lett., 31, pp.327-330, 1990 J. Am. Chem. Soc., 124, pp.2263-2266, 2002 Carbohyd. Res., 223, pp.169-185, 1992 Org. Lett., 9, pp.1227-1230, 2007 J. Chem. Soc., Perkin Trans 1, pp.1699-1704, 1998 Org. Lett., 2, pp.2135-2138, 2000 Can. J. Chem., Pp.743-747, 2006 Org. Lett., 8, pp.1815-1818, 2006 Org. Lett., 1, pp.211-214, 1999 J. Org. Chem., 66, pp.6234-6243, 2001 Carbohyd. Res., 242, pp.91-107, 1993 Tetrahedron Lett., 27, pp. 6271-6274, 1986 Angew. Chem. Int. Ed., 43, pp.5674-5677, 2004

  An object of the present invention is to provide a method for selectively producing anomeric stereoisomers of sugar 1-phosphate compounds.

  As a result of diligent research to solve the above-mentioned problems, the present inventors have reacted glycosyl ester by reacting H-phosphonate diester compound and the like under basic conditions using a sugar compound such as iodinated sugar as a raw material compound. It was found that stereoisomers at the anomeric position of sugar 1-phosphate compounds such as phosphite compounds can be selectively produced. The present invention has been completed based on the above findings.

That is, according to the present invention, the following general formula (I):
R to XP (R ¹ ) (R ² ) (I)
[Wherein, R represents a saccharide compound residue (in the case where the saccharide compound is a monosaccharide compound, the saccharide compound residue represents a residue excluding the hydroxyl group at position 1; In the case of a compound, it is a residue obtained by removing the hydroxyl group at the 1-position in the reducing end sugar compound among the plurality of sugar compounds constituting the sugar compound, and the sugar compound residue has one or more protecting groups. And the wavy line in the formula indicates that the linkage of sugar compound residues R and X is an α bond, a β bond, or a mixture thereof, and R ¹ and R ² are each independently An alkyl group, an aryl group, an alkoxy group, an aryloxy group, a silyloxy group, or an alkylamino group (these groups may have a substituent), and X is an oxygen atom, a sulfur atom, or selenium A method for producing a sugar 1-phosphate compound represented by: The serial of the general formula (II):
RY (II)
(R is as defined above, Y represents an iodine atom, a bromine atom, a chlorine atom, or a sulfo group, and the Y bond at the 1-position is substantially an α bond); The following general formula (III):
X = PH (R ¹ ) (R ² ) (III)
(Wherein X, R ¹ , and R ² are as defined above), and a method comprising the step of reacting in the presence of a base.

According to a preferred embodiment of the present invention, the above method wherein Y is an iodine atom; the above method wherein X is an oxygen atom or a sulfur atom; and the base is an organic base having a high proton scavenging ability, preferably N, N, N, N There is provided the above process which is -bisdimethylaminonaphthalene.
According to a further preferred embodiment, the above process wherein X is an oxygen atom and R ¹ and R ² are the same or different alkoxy groups; X is an oxygen atom, R ¹ is an alkoxy group, preferably a cyanoethoxy group Wherein R ² is an alkylamino group, preferably a diisopropylamino group; any of the above methods is provided which is a selective production of the α isomer.
Also provided is the above method wherein X is an oxygen atom and R ¹ and R ² are the same or different silyloxy groups, preferably a trialkylsilyloxy group; and the above method is a selective production method of β isomers Is done.

From another viewpoint, the present invention provides a method for producing a glycosyl phosphoramidite compound in which X is an oxygen atom, R ¹ is an alkoxy group, and R ² is an alkylamino group in the above general formula (I). And the above general formula (II) (Y represents an iodine atom) and the above general formula (III) (X is an oxygen atom, R ¹ is an alkoxy group, and R ² is an alkylamino group) A method comprising the step of reacting a phosphorus compound represented by formula (I) with a base in the presence of a base is provided. A preferred embodiment of this method provides the above method wherein the anomeric position of the compound represented by the general formula (I) is an α bond. Further, in the above general formula (I), a glycosyl phosphoramidite compound in which X is an oxygen atom, R ¹ is an alkoxy group, R ² is an alkylamino group, and the anomeric position is an α bond is also according to the present invention. Provided.

From another point of view, according to the present invention, the following general formula (IV):
R ~ O-PH (= O) OH (IV)
(Wherein R is as defined above, and the wavy line in the formula indicates that the linkage of sugar compound residues R and O is substantially a β bond). A method comprising the following steps:
(a) A compound represented by the above general formula (II) (Y represents an iodine atom) and the above general formula (III) (X is an oxygen atom, and R ¹ and R ² are the same or different silyloxy groups. In the general formula (I), X is an oxygen atom, and R ¹ and R ² are the same or different. Producing a compound which is a silyloxy group and in which the bond between sugar compound residues R and O is substantially a β bond; and
(b) A method comprising the step of hydrolyzing the compound represented by the general formula (I) obtained in the step (a) is provided.

According to the present invention, the following general formula (V):
R to OP (R ¹ ) (R ² ) → BH ₃ (V)
(Wherein, R is as defined above, the wavy line in the formula indicates that the binding of the sugar compound residues R and O is substantially α bond, the R ¹ and R ² are the same or different alkoxy groups And a boranophosphate compound represented by the following steps:
(a) A compound represented by the above general formula (II) (Y represents an iodine atom) and the above general formula (III) (X is an oxygen atom, and R ¹ and R ² are the same or different alkoxy groups. In the above general formula (I), X is an oxygen atom, R ¹ and R ² are the same or different alkoxy groups, and a sugar compound residue Producing a compound wherein the bond of R and O is substantially an α bond; and
(b) A method comprising a step of boranoating the compound obtained in the step (a) is provided.

  By the method of the present invention, various sugar 1-phosphate compounds can be produced efficiently and in high yield. In particular, the method of the present invention is characterized by the ability to selectively produce anomeric stereoisomers of sugar 1-phosphate compounds.

In the general formula (I), R ¹ and R ² each independently represents an alkyl group, an aryl group, an alkoxy group, an aryloxy group, a silyloxy group, or an alkylamino group. R ¹ and R ² may be the same or different. These groups may have one or two or more substituents, and when they have two or more substituents, they may be the same or different.

The alkyl group represented by R ¹ and R ² may be any of an alkyl group composed of linear, branched, cyclic, or a combination thereof. The number of carbon atoms of the alkyl group is not particularly limited, but is about 1 to 20 carbon atoms, preferably about 1 to 12 carbon atoms. Alkyl groups may contain one or more unsaturated bonds (double or triple bonds), and if they contain two or more unsaturated bonds, they may be conjugated or non-conjugated It may be. A double bond and a triple bond may be appropriately combined. One or more of the carbon atoms constituting the chain or cyclic alkyl group may be replaced with a heteroatom. Examples of the hetero atom include a nitrogen atom, an oxygen atom, or a sulfur atom.

The alkyl group may have one or more substituents at any position, and when it has two or more substituents, they may be the same or different. For example, it may have an aryl group such as a halogen atom, a hydroxyl group, an oxo group, a cyano group, a carboxyl group, an amino group, or a phenyl group, or a heteroaryl group such as a pyridyl group. You may have the substituent of. Examples of the alkyl group having a substituent include, but are not limited to, for example, a benzyl group and a cyanoethyl group. The same applies to the alkyl moiety of other substituents having an alkyl moiety (such as an alkoxy group or an alkylamino group). The alkyl group represented by R ¹ and R ² is preferably a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, or tert-butyl group. It is not limited to.

As the aryl group represented by R ¹ and R ² , a monocyclic or condensed polycyclic aromatic group can be used. The number of ring-constituting atoms of the aryl group is not particularly limited, but is, for example, about 5 to 20, preferably about 5 to 10. One or more heteroatoms out of the carbon atoms constituting the aryl ring may be substituted, and when two or more heteroatoms are included as ring constituent atoms, they may be the same or different. Good. Examples of the hetero atom include a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of the aryl group include, but are not limited to, a phenyl group, a naphthyl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyridyl group, and a pyrimidinyl group. The aryl group may have a substituent, an alkyl group, or the like described for the alkyl group as a substituent. The same applies to the aryl moiety of the aryloxy group represented by R ¹ and R ² .

Examples of the alkoxy group represented by R ¹ and R ² include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, an isobutoxy group, or a tert-butoxy group. However, it is not limited to these. The alkoxy group may have a substituent described for the alkyl group, and for example, it may be preferable to have a substituent such as a cyano group.

As the silyloxy group represented by R ¹ and R ² , a silyloxy group substituted with an aryl group and / or an alkyl group can be used. For example, a trimethylsilyloxy group, a triethylsilyloxy group, a tert-butyldimethylsilyloxy group, a dimethylphenylsilyloxy group, a triphenylsilyloxy group, and the like can be used, but are not limited thereto. As the alkylamino group represented by R ¹ and R ² , a monoalkylamino group or a dialkylamino group can be used, but a dialkylamino group is preferred. As the alkyl group of the alkylamino group, an alkyl group in R ¹ and R ² can be used. Two amino groups in the dialkylamino group may be the same or different.

  R- represents a sugar compound residue. When the sugar compound is a monosaccharide compound, the sugar compound residue is a residue obtained by removing the hydroxyl group at the anomeric position (position 1). When the saccharide compound is a saccharide compound other than a monosaccharide compound, a residue obtained by removing the anomeric hydroxyl group (position 1) of the saccharide compound at the reducing end from a plurality of saccharide compounds constituting the saccharide compound is shown. The sugar compound constituting the sugar compound residue may have a functional group such as an amino group (which may have a substituent such as an alkyl group or an acetyl group) in addition to the hydroxyl group. The functional group such as a hydroxyl group or an amino group of the sugar compound constituting the sugar compound residue may have an appropriate protecting group. The type of protecting group is not particularly limited, but generally one or two appropriate protecting groups such as acetyl group, benzyl group, benzoyl group, pivaloyl group, trimethylsilyl group, Tert-butyldimethylsilyl group, ether protecting group are used. It can be used in combination of more than one species. For the protecting group of the sugar compound, reference can be made to Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. In the general formula (I), the wavy line in the formula indicates that the bond of R and X in the sugar compound residue is an α bond, a β bond, or a mixture thereof. The anomer is preferably an α-bonded or β-linked pure form of anomer, more preferably an α-linked sugar compound, but may be a β-linked sugar compound.

  The type of sugar compound constituting the sugar compound residue is not particularly limited, and may be any of a monosaccharide compound, an oligosaccharide or a disaccharide or more, and a polysaccharide. For example, allose, talose, growth, glucose, altrose, mannose, galactose, idose, fructose, ribose, lyxose, xylose, arabinose, apiose, erythrose, threose, glyceraldehyde, sedoheptulose, coliose, psicose, fructose, sorbose, tagatose , Ribulose, xylulose, erythrulose, dihydroxyacetone, cordobiose, nigerose, maltose, isomaltose, sophorose, laminaribiose, cellobiose, melibiose, gentiobiose, lactose, sucrose, deoxyribose, fucose, rhamnose, glucuronic acid, galacturonic acid, glucosamine, Galactosamine, N-acetylgalactosamine, N-acetylmannosamine , N-acetyllactosamine, ascorbic acid, glucuronolactone, gluconolactone, starch, amylose, amylopectin, glycogen, cellulose, pectin, glucomannan, or iduronic acid, or stereoisomers thereof. It is not limited to.

X is preferably an oxygen atom. The sulfo group represented by Y may be substituted with an alkyl group, an aryl group, or the like, and as the alkyl group or aryl group, those described for R ¹ and R ² above can be preferably used. Y is preferably an iodine atom.

  In producing the compound represented by the above general formula (I), the method of the present invention is a compound represented by the general formula (II): RY (the bond of the iodine atom at the anomeric position is substantially an α bond). A sugar compound represented by the formula (III) and a phosphorus compound represented by the general formula (III). A reaction scheme is shown below for the case where an iodosaccharide compound is used as the compound represented by the general formula (II), but this reaction is an example, and the scope of the present invention is limited to the reaction described in the following scheme. Never happen. In the scheme, for the sugar compounds represented by the general formulas (I) and (II), only the anomeric part and its periphery are schematically shown.

  The iodinated sugar compound used as the raw material compound can be easily produced by iodination of the corresponding sugar compound. In the iodination reaction, since only the α isomer used as a raw material in the present invention is generated due to the anomeric effect of the sugar compound, it is generally easy to obtain the raw material compound. For example, the method described in Carbohyd. Res., 320, pp. 61-69, 1999 can be used. The same applies to the case where another halogen atom or sulfo group is used as Y. In the method of the present invention, it is preferable to use a substantially pure form of the α isomer, but the reaction may generally be carried out using a raw material containing a small amount of the β isomer.

  As the base, either an organic base or an inorganic base may be used, but it is generally preferable to use an organic base such as an organic amine. Two or more bases may be used in combination. Examples of the organic base include triethylamine, trimethylamine, diisopropylethylamine (DIPEA), n-butylamine, N, N, N, N-bisdimethylaminonaphthalene (DMAN), 1,8-diazabicyclo [5.4.0] undeca-7. Organic bases such as -ene (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO) can be used. As the inorganic base, for example, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like can be used. Of these bases, an organic base is preferably used, and an organic amine compound is more preferably used. A particularly preferred base is an organic amine compound having a high proton capturing ability, and most preferred is DMAN. When a strong base such as DBU is used, the amount of the base used can be adjusted as appropriate.

  The amount of the base relative to the saccharide compound represented by the general formula (II) is not particularly limited, but is, for example, about 1 to 20 equivalents, preferably about 2 to 10 equivalents, relative to the saccharide compound. The amount of the sugar compound represented by the general formula (II) with respect to the phosphorus compound represented by the general formula (III) is not particularly limited, but for example, about 1 to 20 equivalents, preferably several equivalents to the phosphorus compound. About 10 equivalents. As the reaction solvent, for example, an aprotic solvent can be preferably used. For example, nitrile solvents such as acetonitrile, amide solvents such as dimethylformamide (DMF), halogenated carbon solvents such as dichloromethane, ether solvents such as diethyl ether and 1,4-dioxane, aromatic hydrocarbons such as toluene Although a solvent etc. can be used, it is not limited to these. In general, the reaction can be performed under ice cooling to about 50 ° C., preferably under ice cooling to about room temperature. The reaction time is about several minutes to several days.

In the reaction of the present invention, the α isomer of the anomeric isomers is generally selectively obtained as the main product. Therefore, the method of the present invention can be preferably used to selectively produce the α isomer. . Also, after a trialkylsilyl group as R ¹ and R ^2, for example, in the general formula (I) in the case of using the trimethylsilyloxy groups I R ¹ and R ² are a trialkylsilyl group unstable intermediate, hydrolytically Although the H-phosphonate monoester can be obtained as a decomposed product, this product is obtained β-selectively. Therefore, any of the anomeric isomers can be selectively produced by appropriately selecting reaction conditions, starting materials and the like.

More specifically, as a preferable combination of substituents,
When X is an oxygen atom and R ¹ and R ² are the same or different alkoxy groups, preferably an alkoxy group such as a methoxy group, an ethoxy group, or a cyanoethoxy group;
X is an oxygen atom, R ¹ is an alkoxy group, preferably an alkoxy group such as a methoxy group, an ethoxy group, or a cyanoethoxy group, and R ² is an alkylamino group, preferably a dialkylamino group such as a dimethylamino group, Examples include a diethylamino group or an isopropylamino group. These combinations are useful for the selective production of the α isomer.

As another preferred combination,
A case where X is an oxygen atom and R ¹ and R ² are the same or different silyloxy groups, preferably a trialkylsilyloxy group, for example, a trimethylsilyloxy group can be mentioned. This combination is useful for the selective production of the β isomer.

Using this reaction, the above general formula (IV): R to O-PH (= O) OH (wherein R is as defined above, and the wavy lines in the formula indicate the sugar compound residues R and O). The glycosyl H-phosphonate monoester represented by (wherein the bond is substantially a β bond) can be efficiently produced. More specifically, the compound represented by the above general formula (II) (Y represents an iodine atom) and the above general formula (III) (X is an oxygen atom, and R ¹ and R ² are the same or A compound represented by a different silyloxy group, preferably a trialkylsilyloxy group) in the presence of a base, and in the general formula (I), X is an oxygen atom, and R ¹ and R ² are Manufacture a compound which is the same or different silyloxy group and in which the bond of sugar compound residues R and O is substantially a β bond, and hydrolyze the resulting compound to produce a target compound selectively Can do. Hydrolysis proceeds rapidly in the presence of water and TEAB (triethylammonium hydrogen carbonate) under ice cooling or at room temperature.

Also, using the method of the present invention, a glycosyl phosphoramidite compound in which X is an oxygen atom, R ¹ is an alkoxy group, and R ² is an alkylamino group in the above general formula (I) is produced. Can do. In this method, the above general formula (II) (Y represents an iodine atom) and the above general formula (III) (X is an oxygen atom, R ¹ is an alkoxy group, R ² is an alkylamino group, And the phosphorus compound represented by (A) can be reacted in the presence of a base, and the target product in which the anomeric position is an α bond can be obtained in high yield.

Further, by using the method of the present invention, a sugar boranophosphate compound useful for the efficient production of a sugar 1-phosphate compound can be efficiently produced, and in particular, a sugar boranophosphate compound which is an α isomer Can be selectively produced in high yield. For example, the above general formula (V): R to OP (R ¹ ) (R ² ) → BH ₃ (wherein R is as defined above, and the wavy line in the formula indicates the binding of sugar compound residues R and O) Is substantially an α bond, and R ¹ and R ² are the same or different alkoxy groups), and the sugar boranophosphate compound represented by the general formula (II) (Y is an iodine atom) And a compound represented by the above general formula (III) (X is an oxygen atom, and R ¹ and R ² are the same or different alkoxy groups) in the presence of a base. A compound in which X is an oxygen atom in the general formula (I), R ¹ and R ² are the same or different alkoxy groups, and the bond between sugar compound residues R and O is substantially an α bond by the reaction. After production, the obtained compound can be produced by boranoing. The boranoization reaction can be performed, for example, according to a method of boranoating from H-phosphonate diester (Tetrahedron, 56, pp. 4811-4815, 2000).

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. In the examples, Me represents a methyl group, Et represents an ethyl group, Bn represents a benzyl group, and TMS represents a tetramethylsilyl group.
Example 1

To a solution of Compound 1 (10 μL, 0.11 mmol) and DMAN (53.6 mg, 0.25 mmol) in acetonitrile (1.0 mL) dried with Molecular Sieves 3A, Compound 2 (Chem. Ber., 113, pp. 3075) -3085, 1980 or Carbohyd. Res., 320, pp. 61-69, 1999) 0.1 M acetonitrile solution (1.0 mL) was added. This was stirred at 25 ° C. for 48 hours, diluted with dichloromethane (3 mL), and a saturated aqueous sodium hydrogen carbonate solution (3 mL) was added to the organic layer. The solution was further diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (20 mL). The aqueous layer was extracted again with dichloromethane (15 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The solution from which the solid matter was removed by filtration was concentrated under reduced pressure to obtain Compound 3. The stereoisomer ratio of the crude product was determined by ³¹ P NMR. BH ₃ · THF (0.99 M THF solution; 0.5 mL) was added to the crude product and stirred vigorously at room temperature for 15 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction. The reaction solution was diluted with dichloromethane (25 mL) and washed 3 times with saturated aqueous sodium hydrogen carbonate solution (15 mL). The organic layer was dried over anhydrous sodium sulfate, the solid matter was removed by filtration, and the solution was concentrated under reduced pressure. Purification by silica gel column chromatography [hexane-ethyl acetate (5: 1, v / v)] gave compound 4 as a colorless oily compound (26.8 mg, 41%).
Compound 4
_{^{1 H NMR (CDCl 3) δ}} 7.40-7.10 (m, 20H), 5.84 (dd, 1H, J = 3.3 Hz, 7.7 Hz), 4.96-4.43 (m, 8H), 4.00-3.94 (m, 2H), 3.81-3.60, 1.2 to -0.2 (br).
³¹ P NMR (CDCl ₃ ) δ 121.4-116.5 (br).
Similarly, the reaction conditions were changed and the results shown in Table 1 were obtained.

モレキュラーシーブス3Aにて乾燥させた化合物1 (92μl, 1.0 mmol)とジイソプロピルエチルアミン (42μL, 0.25 mmol)のアセトニトリル (1.0 mL)溶液に化合物5(Synlett, pp.499-501, 1996; J. Org. Lett., 3, pp.2081-2084, 2001に準じて合成)の0.1 M アセトニトリル溶液 (1.0 mL)を加えた。この混合物を25 ℃にて30分撹拌した後ジクロロメタン (20 mL)で希釈し、飽和炭酸水素ナトリウム水溶液 (20 mL)にて洗浄した。水層をジクロロメタン (15 mL)にて再度抽出し、有機層を合わせて無水硫酸ナトリウムにて乾燥した。固形物をろ過にて除去した溶液を減圧濃縮して粗生成物を得た。この粗生成物の立体異性体比を³¹P NMRにて決定した。粗生成物にBH₃・THF(0.99MTHF溶液; 0.5 mL)を加えて室温にて15分間激しく撹拌した後、飽和炭酸水素ナトリウム水溶液を加えて反応を終結させた。反応溶液をヘキサン(25 mL)で希釈し、飽和炭酸水素ナトリウム水溶液 (25 mL)にて3回洗浄した。有機層を無水硫酸ナトリウムにて乾燥し、固形物をろ過にて除去して溶液を減圧濃縮して無色油状化合物 を得た(24.9 mg, ¹H NMRより主成分は化合物8)。
化合物8 (αアノマー)
¹H NMR (CDCl₃) δ 5.52 (dd, J = 3.0 Hz, 7.4 Hz), 3.75-3.30 (m), 1.2 to -0.2 (br). 0.2 to -0.2 (m).
³¹P NMR (CDCl₃) δ 120.0-116.0 (br).
同様にして原料化合物として化合物6及び7（Chem. Ber., 113, pp.3075-3085, 1980又はCarbohyd. Res., 320, pp.61-69, 1999に準じて合成）を用いて、それぞれ化合物9及び10を得た。 Example 2

Compound 5 (Synlett, pp. 499-501, 1996; J. Org.) Was added to a solution of Compound 1 (92 μl, 1.0 mmol) and diisopropylethylamine (42 μL, 0.25 mmol) in acetonitrile (1.0 mL) dried with Molecular Sieves 3A. A 0.1 M acetonitrile solution (1.0 mL) of Lett., 3, pp. 2081-2084, 2001) was added. The mixture was stirred at 25 ° C. for 30 minutes, diluted with dichloromethane (20 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (20 mL). The aqueous layer was extracted again with dichloromethane (15 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The solution from which the solid matter was removed by filtration was concentrated under reduced pressure to obtain a crude product. The stereoisomer ratio of this crude product was determined by ³¹ P NMR. BH ₃ · THF (0.99 MTHF solution; 0.5 mL) was added to the crude product, and the mixture was vigorously stirred at room temperature for 15 minutes, and then saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction. The reaction solution was diluted with hexane (25 mL) and washed 3 times with saturated aqueous sodium hydrogen carbonate solution (25 mL). The organic layer was dried over anhydrous sodium sulfate, the solid matter was removed by filtration, and the solution was concentrated under reduced pressure to give a colorless oily compound (24.9 mg, the main component was compound 8 from ¹ H NMR).
Compound 8 (α anomer)
¹ H NMR (CDCl ₃ ) δ 5.52 (dd, J = 3.0 Hz, 7.4 Hz), 3.75-3.30 (m), 1.2 to -0.2 (br) .0.2 to -0.2 (m).
³¹ P NMR (CDCl ₃ ) δ 120.0-116.0 (br).
Similarly, using compounds 6 and 7 (synthesized according to Chem. Ber., 113, pp. 3075-3085, 1980 or Carbohyd. Res., 320, pp. 61-69, 1999) as starting compounds, respectively Compounds 9 and 10 were obtained.

Compound 9 (α anomer)
¹ H NMR (CDCl ₃ ) δ 7.38-7.23 (m), 5.83 (dd, J = 3.3 Hz, 7.7 Hz), 4.97-4.42 (m), 4.13-4.09 (m), 4.02 (m), 3.92-3.87 (m), 3.71-3.54 (m), 1.2 to -0.2 (br).
³¹ P NMR (CDCl ₃ ) δ 122.0-117.0 (br).

Example 3
Compound 11 (215 mg, 1.0 mmol) dried with molecular sieves 4A and N, N, N ', N'-tetramethyl-1,8-naphthalenediamine (DMAN, 53.3 mg, 0.25 mmol) in toluene (1.0 To the solution, a 0.1 M toluene solution of compound 2 (1.0 mL) was added. The mixture was stirred at room temperature for 48 hours, diluted with dichloromethane (15 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (20 mL). The aqueous layer was extracted again with dichloromethane (15 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The solution from which the solid matter was removed by filtration was concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography [hexane-ethyl acetate-triethylamine (84: 16: 1, v / v / v)] gave compound 13. Colorless oily compound (53.8 mg, 73%).
Compound 13
¹ H NMR (CDCl ₃ ) δ 7.37-7.14 (m), 5.49-5.41 (m), 4.98-4.42 (m), 4.00-3.55 (m), 2.54-2.40 (m), 1.32-1.15 (m).
³¹ P NMR (CDCl ₃ ) δ 153.6 (s), 152.8 (s), 151.4 (s), 150.4 (s).
Similarly, compounds 14 and 15 were obtained from compounds 6 and 12.

Compound 14
¹ H NMR (CDCl ₃ ) δ 7.43-7.23 (m), 5.50-5.44 (m), 5.01-4.59 (m), 4.48-4.38 (m), 4.15-3.44 (m), 2.41-2.23 (m), 1.28-1.12 (m).
³¹ P NMR (CDCl ₃ ) δ 152.7 (s), 152.5 (s), 151.5 (s), 150.2 (s).
Compound 15
¹ H NMR (CDCl ₃ ) δ 7.44-7.24 (m), 5.48-5.40 (m), 5.03-4.66 (m), 4.12-3.54 (m), 2.61-2.56 (m), 2.48-2.40 (m), 2.31-2.24 (m) 1.34-1.05 (m).
³¹ P NMR (CDCl ₃ ) δ 151.9 (s), 151.8 (s), 151.7 (s), 150.0 (s).

Example 4

A 0.1 M toluene solution (1.0 mL) of compound 2 was added to a toluene (1.0 mL) solution of compound 16 (235 L, 1.0 mmol) and DMAN (53.4 mg, 0.25 mmol) dried with molecular sieves 4A. The mixture was stirred at room temperature for 2 hours, and 1 M TEAB aqueous solution (3 mL) was added. After bubbling of the reaction system had subsided, the reaction mixture was diluted with dichloromethane (20 mL), and the organic layer was washed with 1 M TEAB aqueous solution. The aqueous layer was extracted again with dichloromethane (15 mL), and the organic layer was concentrated under reduced pressure to obtain a crude product. The stereoisomer ratio of the crude product was determined by ³¹ P NMR. Purification by silica gel column chromatography [dichloromethane-methanol-triethylamine (100: 3: 1, v / v / v)] gave compound 18 as a colorless oily compound (44.8 mg, 64%).
Compound 18
¹ H NMR (CDCl ₃ ) d 12.16 (br), 8.16 (s), 8.11 (s), 6.00 (s), 5.96 (s), 5.87 (dd, J = 3.2 Hz, 8.7 Hz), 5.15 (t, J = 8.4 Hz).
Similarly, Compound 19 was obtained from Compound 17.

Compound 19
¹ H NMR (CDCl ₃ ) δ 8.01-7.77 (m), 7.53-7.20 (m), 5.88-5.83 (m), 5.73-5.64 (m), 5.52 (t, J = 8.8 Hz), 4.63 (dd, J = 2.8 Hz, 12.1 Hz), 4.40 (dd, J = 4.4 Hz, 12.1 Hz), 4.26-4.21 (m), 2.65 (q), 1.07 (t).
³¹ P NMR (CDCl ₃ ) δ 1.78 (s).

Example 5 (comparative example)
Compound 20 (3.1 μL, 50 μmol) was added to a solution of Compound 1 (92 μL, 1.0 mmol) and DMAN (53.0 mg, 0.25 mmol) in acetonitrile-d ₃ (0.50 mL) dried with Molecular Sieves 3A and shaken. A uniform solution was obtained. The reaction in this solution was observed at room temperature using ¹ H NMR and ³¹ P NMR. Observation of the reaction system after about 3 hours confirmed that compound 1 and compound 20 were not consumed. Similarly, Compound 1 and Compound 21 were reacted, and it was confirmed that Compound 1 and Compound 21 were not consumed in the observation of the reaction system after about 24 hours. Therefore, the reaction of the present invention is considered to be a unique reaction in the case of an anomeric glycoside that is questioned by the nucleophilic species.

Claims (10)

The following general formula (I):
R to XP (R ¹ ) (R ² ) (I)
[Wherein, R represents a saccharide compound residue (in the case where the saccharide compound is a monosaccharide compound, the saccharide compound residue represents a residue excluding the hydroxyl group at position 1; In the case of a compound, it is a residue obtained by removing the hydroxyl group at the 1-position in the reducing end sugar compound among the plurality of sugar compounds constituting the sugar compound, and the sugar compound residue has one or more protecting groups. And the wavy line in the formula indicates that the linkage of sugar compound residues R and X is an α bond, a β bond, or a mixture thereof, and R ¹ and R ² are each independently An alkyl group, an aryl group, an alkoxy group, an aryloxy group, a silyloxy group, or an alkylamino group (these groups may have a substituent), and X is an oxygen atom, a sulfur atom, or selenium A method for producing a sugar 1-phosphate compound represented by: The serial of the general formula (II):
RY (II)
(R is as defined above, Y represents an iodine atom, a bromine atom, a chlorine atom, or a sulfo group, and the Y bond at the 1-position is substantially an α bond); The following general formula (III):
X = PH (R ¹ ) (R ² ) (III)
(Wherein, X, R ¹ and R ² have the same meanings as described above), and a method comprising a step of reacting in the presence of a base. The method according to claim 1, wherein Y is an iodine atom. The method according to claim 1 or 2, wherein X is an oxygen atom or a sulfur atom. The method according to claim 1 or 2, wherein X is an oxygen atom, R ¹ and R ² are the same or different alkoxy groups, or R ¹ is an alkoxy group, and R ² is an alkylamino group. The method according to claim 5, which is a method for selectively producing an α isomer. The method according to claim 1 or 2, wherein X is an oxygen atom, and R ¹ and R ² are the same or different silyloxy groups. The method according to claim 6, which is a method for selectively producing a β isomer. A method for producing a glycosyl phosphoramidite compound, wherein X is an oxygen atom, R ¹ is an alkoxy group, and R ² is an alkylamino group in the general formula (I) according to claim 1, (the Y indicates a iodine atom) the general formula (II) is formula (III) (X is an oxygen atom of claim 1 and according to, R ¹ is an alkoxy group, R ² is an alkylamino group And a phosphorus compound represented by formula (1) in the presence of a base. The following general formula (IV):
R ~ O-PH (= O) OH (IV)
(Wherein R is as defined above, and the wavy line in the formula indicates that the linkage of sugar compound residues R and O is substantially a β bond). A method comprising the following steps:
(a) the compound represented by the general formula (II) according to claim 1 (Y represents an iodine atom) and the general formula (III) according to claim 1, wherein X is an oxygen atom, R ¹ and R ² is the same or different silyloxy group) in the presence of a base and X is an oxygen atom in the general formula (I) according to claim 1, and R ¹ and R ² A compound in which is a silyloxy group that is the same or different, and the bond of sugar compound residues R and O is substantially a β bond, and
(b) A method comprising a step of hydrolyzing the compound represented by the general formula (I) obtained in the step (a). The following general formula (V):
R to OP (R ¹ ) (R ² ) → BH ₃ (V)
(Wherein, R is as defined above, the wavy line in the formula indicates that the binding of the sugar compound residues R and O is substantially α bond, the R ¹ and R ² are the same or different alkoxy groups And a boranophosphate compound represented by the following steps:
(a) the compound represented by the general formula (II) according to claim 1 (Y represents an iodine atom) and the general formula (III) according to claim 1, wherein X is an oxygen atom, R ¹ and R ² is X is oxygen atom in formula (I) according to claim 1 and a compound are reacted in the presence of a base represented by the same or different alkoxy group), R ¹ and R ² Producing a compound wherein are the same or different alkoxy groups, and the bond of sugar compound residues R and O is substantially an α bond; and
(b) A method comprising a step of boranoating the compound obtained in the step (a).