JP3194777B2 - Stereoselective D-ribofuranosylation method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to an α-D-protein which is extremely useful as an intermediate for synthesizing various carbohydrate-related physiologically active substances.
The present invention relates to a method for stereoselectively synthesizing ribofuranoside and β-D-ribofuranoside.

[0002]

2. Description of the Related Art Carbohydrates are widely distributed in nature and exist not only as energy storage sources such as starch and glycogen, but also as cell components of plants and bacteria as well as biological components such as blood group determining substances. I do. Recently,
As the relationship between life and carbohydrates becomes clearer, carbohydrate synthesis research has been actively conducted in the field of synthetic organic chemistry.

[0003] Most of such carbohydrates are occupied by glycosyl compounds. Here, the glycosyl compound is
It is a general term for compounds corresponding to a form in which a hemiacetal hydroxyl group (lactolic hydroxyl group) at position 1 generated by a saccharide having a cyclic structure is substituted with a protic nucleophile.

Glycosyl compounds are structurally composed of a sugar moiety (glycon) and a non-sugar moiety (aglycone; aglyco).
n), which are roughly classified into four types according to the types of atoms involved in the binding of the non-sugar moiety to the sugar moiety. That is,
O -glycosyl compounds (glycosides) if the atom is an oxygen atom, S -glycosyl compounds (such as pungent glycosides) if the atom is a sulfur atom, and N -glycosyl compounds (nucleosides or glycosylamines) if the atom is a nitrogen atom. ) And C -glycosyl compounds (anthraquinone glycosides, C-nucleosides, etc.) if they have carbon atoms. Furthermore, each glycosyl compound is classified into two types, α- and β-anomers, depending on the configuration of the anomeric carbon.

[0005] Here, an anomer refers to a diastereomer pair formed when a sugar has a pyranose or furanose ring structure and has one more asymmetric carbon atom than in a straight chain structure. At this time, if the hydroxyl group or glycosidic bond bonded to the anomeric carbon is below the ring surface of the sugar, it is called α-anomer (for example, α-D-glucopyranose), and if it is above, it is called β-anomer.

Generally, in chemical synthesis of glycosyl compounds, the desired product is almost always obtained as a mixture of such anomers. Therefore, in order to obtain a specific anomer with high selectivity and high yield, temperature
A delicate study was indispensable not only for the reaction conditions such as the solvent, but also for the protecting group and leaving group of the sugar donor, the nucleophilicity of the acceptor hydroxyl group, the reactants and the like, and combinations thereof.

Heretofore, in general, a protecting group (eg, D-glucopyranose, D-ribofuranose, etc.) in which the 2-position hydroxyl group is located below the ring surface of the saccharide is shown to be involved in the adjacent group. , An acyl group), and glycosylation utilizing the participation of the adjacent group as shown in the following formula (Formula 1) is considered to give a β-anomer preferentially ( LRSchroeder and JWGreeen, J. Che
m. Soc., 1966 , 530). However, when the protecting group for the hydroxyl group at the 2-position of the sugar donor is a protecting group that does not involve an adjacent group such as an alkyl group or acetal, the 1,2-cis isomer is presumed to be overwhelmingly generated.

[0008]

Embedded image

Similar tendency (protection involving adjacent group at position 2)
Β-anomer formation when a group is used)
When a glycosyl halide derivative is used as the isomer (Ko
enigs-Knorr method, W. Koenigs and E. Knorr, Chem. Ber.,Three
Four, 957 (1901)).

Regarding the method for synthesizing α-glycosides in hexoses such as glucose, a method of reacting glycosyl fluoride with tin (II) chloride-silver perchlorate in ether (T. Mukaiyama et al., Chem. Lett., 1981) 431), a method of reacting β-1-trichloroacetimidate with trimethylsilyl triflate (TMSOTf) (RRSchmidt
Et al., Tetrahedron Lett., 31 , 1849 (1990)), a method of reacting a thioglycoside sugar donor with copper (II) bromide-tetrabutylammonium bromide (catalytic amount) -silver triflate (S. Sato et al., Carbohydr. . Res., 155 , C6 (1986)). However, these methods have the disadvantage that the sugar donor is relatively unstable and its preparation cannot be said to be easy, and that it is essential to use a heavy metal salt such as silver as a reactant.

On the other hand, when a glycosylation reaction is carried out on D-ribofuranose, which is a pentose, it has been generally said that the β-anomer is generally predominantly formed due to the involvement of the adjacent group at the 2-position.

[0012]

Most of naturally occurring D-ribofuranosides, including ribonucleosides, which are N-glycosyl compounds, exist as β-anomers, but rarely exist as α-anomers. Things are also known.

For example, poly (ADP-ribose) is a substance widely found in eukaryotic cells, and is known to be covalently bound to histones and other nuclear proteins. It is a very important compound for studying cell differentiation, cell division, etc. (for example, Pyridine Nucleotide
Coenzymes; Chemical, Biochemical and Medical Aspe
cts, Vol. 2B , 147-195p, (1987) John W
iley & Sons).

In this poly (ADP-ribose), the C-1 position of D-ribofuranose and the 2 ′ position of adenosine form an α (1,2-cis) bond as shown in the following formula (Formula 2). In order to achieve the total synthesis, it is extremely important to efficiently perform the α-D-ribofuranosylation reaction. However, good results have not been obtained conventionally because of steric hindrance.

[0015]

Embedded image

The main object of the present invention is to solve the above-mentioned problems, to use a relatively stable sugar donor which is easy to prepare, under mild reaction conditions, and to participate in adjacent groups or react with silver, mercury or the like. Highly stereoselective α- and β- that do not require the use of heavy metal salts
It is to provide a method for synthesizing D-ribofuranoside.

[0017]

Means for Solving the Problems As a result of diligent studies, the present inventors have found that D-ribonucleic acid is conventionally only available under heating and melting conditions because it is relatively stable as a sugar donor. That the furanose 1-carbonate derivative exhibits excellent reactivity with the hydroxy compound in solution (rather than in its molten state), and furthermore that the D-ribofuranose 1-carbonate derivative in solution and the hydroxy compound The novel combination provides a simple control means to produce α- and β-D-ribofuranosides under mild reaction conditions (without the necessity of involving adjacent groups or using heavy metal salts as in the conventional method) in high yield. It was found that high stereoselectivity was given.

The D-ribofuranosylation method of the present invention is based on such findings, and more specifically, is characterized in that a D-ribofuranose 1-carbonate derivative is reacted with a hydroxy compound in a solution state. It is assumed that.

Since the above-mentioned D-ribofuranose 1-carbonate is a sugar donor which is much more stable than the above-mentioned halogenated sugar derivatives and the like, conventionally, thermal decomposition reaction under heating and melting conditions, and The synthesis of phenylglycosides and disaccharide derivatives by autocatalytic glycosylation has been studied in detail (Y. Ishido
J. Chem. Soc., Perkin Trans. I, 521 (1977))
The reaction of D-ribofuranose 1-carbonate in a solution state has not yet been studied.

Hereinafter, the present invention will be described in detail. (D-ribofuranose 1-carbonate derivative) The D-ribofuranose 1-carbonate derivative used in the present invention is a sugar carbonate ester derivative (glycosyl) having a structure in which a carbonate group is introduced at the C-1 position of sugar. Carbonate). This 1-carbonate derivative preferably has a structure represented by the following general formula (1).

[0021]

Embedded image

In the general formula (1), R ¹ represents an organic group constituting a 1-carbonate group, and is preferably an alkyl group (more preferably a lower alkyl group having 1 to 4 carbon atoms) or an aryl group (for example, a phenyl group). ) Is preferable. These alkyl groups or aryl groups may have a substituent (for example, chlorine atom Cl) that is inert to the reaction of the present invention.

In the present invention, R ¹ is a phenyl group or a trichloroethyl group (—CH ₂ CCl ₃ )
It is particularly preferably used in view of the balance between reactivity and stability as a 1-carbonate derivative.

On the other hand, in the general formula (1), R ² represents the same or different hydroxyl-protecting groups. As this protecting group, any (inactive) protecting group that is not substantially removed under the reaction conditions in the present invention can be used without particular limitation. More specifically, for example, an acyl group (for example, an aromatic acyl group such as a benzoyl group), an aralkyl group (for example, a benzyl group C ₆ H ₅ CH)
_2- ) is preferably used because deprotection under mild conditions is possible.

The method for obtaining the D-ribofuranose 1-carbonate derivative (hereinafter also referred to as “sugar donor”) used in the present invention is not particularly limited. For example, a carbonate ester derivative represented by the above general formula (1) (for example, , R ¹ = phenyl group P
h, R ² = benzyl group Bn) can be suitably prepared by a method represented by the following formula (Formula 4).

[0026]

Embedded image

In the reaction shown in the above chemical formula (4), the D-ribofuranose 1-carbonate derivative ( 59 ) is usually obtained as a mixture of α- and β-anomers. Pure α
-And β-anomers can be easily obtained respectively. From the viewpoint of ensuring the reproducibility of the reaction, it is preferable to perform the glycosylation reaction using the α- or β-anomer separated by column chromatography or the like.

(Hydroxy compound) In the present invention, D-
As the hydroxy compound to be ribofuranosylated (alcohol compound, phenol compound, etc.), a hydroxy compound having a primary (or primary) or secondary (or secondary) hydroxyl group can be used without particular limitation. Usually, a cyclic hydroxy compound is preferably used. As used herein, the term “cyclic hydroxy compound” refers to at least one primary or secondary (or primary or secondary) hydroxyl group in the structural formula.
And an organic compound having at least one cyclic atomic arrangement.

The cyclic structure may have an unsaturated bond (for example, an aromatic ring such as a benzene ring), or has one or more heteroatoms (for example, O, N, S and / or Si). It may be. The hydroxyl group to be involved in the D-ribofuranosylation reaction of the present invention does not necessarily have to be directly bonded to the cyclic structure. When the cyclic structure has a hydroxyl group (secondary hydroxyl group) directly bonded thereto, the ring having the second hydroxyl group is preferably about 3 to 8 membered ring (more preferably about 5 to 6 membered ring).

In the present invention, the fact that the steric structure (for example, steric configuration) between the carbon atom to which the hydroxyl group to be D-ribofuranosylated is bonded and the carbon atom constituting the cyclic alcohol is determined, From the viewpoint of usefulness as an intermediate for product synthesis, it is preferable to use a sugar, a carbohydrate, or a derivative thereof as the hydroxy compound.

Examples of the sugar compound or carbohydrate preferably used in the present invention include monosaccharides such as hexose and pentose (for example, aldohexose or aldpentose capable of forming a pyranose ring or a furanose ring) and derivatives thereof. And oligosaccharides which are oligomers of these monosaccharides. From the viewpoint of usefulness in the synthesis of a nucleoside or nucleotide-related compound, it is preferable to use a pentose such as D-ribose (particularly, D-ribofuranose) as the hydroxy compound used in the present invention.

When the above-mentioned hydroxy compound to be D-ribofuranosylated has other functional groups (for example, hydroxyl groups) which may be affected by this reaction, in addition to the hydroxyl group to be D-ribofuranosylated, Is preferably such that the functional group is protected by a suitable protecting group (preferably a protecting group which is inert to the reaction of the present invention).

(Solution State) In the present invention, the “D-ribofuranose 1-carbonate derivative in a solution state” means that the D-ribofuranose 1-carbonate derivative together with at least one other substance is A state in which a uniform mixture is in a liquid state at a reaction temperature.
In the present invention, the “other substance” may be the “hydroxy compound” itself described above, or may be a “solvent” different from the hydroxy compound.

As the above-mentioned "solvent", those generally used in organic reactions can be used without particular limitation as long as they are liquid at the reaction temperature (normally 30 ° C. or lower, more preferably 20 ° C. or lower) in the present invention. can do. As specific examples, for example, dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, ether and the like are preferably used. When ethyl ether is used as the solvent, α-D-ribofuranoside is preferentially obtained in the present invention as described later.

In the D-ribofuranosylation reaction of the present invention, as long as the progress of the reaction is not substantially inhibited, the above-mentioned “hydroxy compound” and / or “solvent” is used.
The amount of D-ribofuranose 1 is not particularly limited, but D-ribofuranose 1
-Carbonic acid ester derivative is on a scale of 200 mmol (mmol), and the amount of (hydroxy compound + solvent) used is about 2 mL (milliliter) or more, and further 2 to 15 m
It is preferable to use about L (particularly about 2 to 6 mL).

(Reaction Temperature) In the present invention, the above-mentioned "reaction temperature" means a so-called bath temperature. In the present invention, the reaction is usually performed at a temperature at which the D-ribofuranose 1-carbonate derivative is not substantially heated and melted. More specifically, the reaction is preferably performed at a bath temperature of 30 ° C. or lower (more preferably, 20 ° C. or lower).

As will be described later, when the reaction temperature is lowered (especially when the D-ribofuranose 1-carbonate derivative is dissolved in a substance other than ethyl ether), the α in the product is reduced.
-The production ratio of anomer tends to increase. More specifically, when the α-anomer is preferentially produced, for example, ethyl ether is used as a solvent, or a solvent other than ether (dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, etc.) or hydroxy is used. It is preferable to lower the reaction temperature by using a compound.
When the α-anomer is preferentially obtained by lowering the reaction temperature,
The reaction temperature is preferably lower than 0 ° C, more preferably -20.
It is preferable that it is about -40 degreeC (more preferably about -30 degreeC--40 degreeC).

On the other hand, when the β-anomer is preferentially obtained, it is preferable to make the D-ribofuranose 1-carbonate derivative into a solution with a substance (solvent or hydroxy compound) other than ethyl ether, and the temperature is set at 0. C. or more (more preferably about 15 ° C. to 30 ° C.). Further, as described later, when preferentially obtaining a β-anomer, a longer reaction time is preferable, and more specifically,
The reaction time is preferably at least 5 minutes, more preferably at least 10 minutes (particularly at least 20 minutes).

(Acid Catalyst) In the present invention, the "acid catalyst" has an effect of increasing the reaction rate when added to the reaction system of the present invention (if necessary). Per se refers to Bronsted acids and / or Lewis acids that are not substantially subject to D-ribofuranosylation.

In the present invention, it is preferable to use a Lewis acid as the acid catalyst. More specifically, for example, trimethylsilyl triflate (TMSOTf, (C
_{H 3) 3 SiOSO 2 CF 3} ), boron trifluoride diethyl etherate _(BF 3 · _OEt 2), silicon tetrafluoride, titanium tetrafluoride, zinc fluoride, tin chloride (II) -
Silver triflate (I), dimethylchlorogallium, zirconocene dichloride (Cp ₂ ZrCl ₂ ) -silver perchlorate,
Hafnocene dichloride (Cp ₂ HfCl ₂ ) -silver perchlorate,
Although it is possible to use TMSOTf (trimethylsilyl triflate), it is particularly preferable from the viewpoint that the α / β ratio can be easily controlled.
When TMSOTf is used, the amount of TMSOTf used is 1.0 equivalent or less, more preferably 0.8 equivalent or less, based on the D-ribofuranose 1-carbonate derivative from the viewpoint of suppressing side reactions and improving selectivity. And particularly preferably 0.5 equivalent or less.

(Reaction Product) In the present invention, when α-anomer is to be preferentially obtained, α / anomer in the product
The β generation ratio (hereinafter referred to as “α / β”) is preferably α / β ≧ 1.2, and more preferably α ≧ 1.5 (particularly α / β ≧
2) is preferable. On the other hand, in the present invention, β-
When preferentially obtaining an anomer, α / β ≦ 5/6
And more preferably α / β ≦ 2/3 (particularly α / β
/ Β ≦ １ ／).

The conformation of the product serving as D- ribofuranoside is, D- also vary according hydroxy compound or other protecting group to be ribofuranosyl, but the the in the C-1 position to the ¹ H-NMR Proton and C The coupling of the proton at the -2 position is such that the dihedral angle of the α-anomer is C-2endo.
Type, since it becomes 30 degrees back and forth in both C-3endo type, and J _{1, 2} 4 Hz and forth.

In the case of the β-anomer, the C-3endo type is close to 90 °, so that it is close to J _1,2 OHz,
A signal of 1 gives a singlet. Also C-2en
In the case of the do type, since it is around 160 degrees, J _{1,2 is} around 10 Hz. From this, the C-1 configuration of both anomers can be determined. Further, the α: β formation ratio is ¹ H-N
In the MR spectrum, it can be calculated from the area intensity of the proton signal at the C-1 position of each of the α-anomer and β-anomer.

[0044]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Synthesis Examples (preparation of "D-ribofuranose 1-carbonate derivative" as a sugar donor) and Examples.

Synthesis Example 1 Methyl 2,3,5-tri-O-benzyl-D-ribofuranoside ( 57 ) D-ribose ( 55 ) (5.0 g, 37.3 mmol) was dissolved in anhydrous methanol (100 mL), Under cooling, concentrated sulfuric acid (0.5 mL) was added, and the mixture was stirred and left at 0 ° C. for 15 hours. After the disappearance of the raw materials (TLC (thin layer chromatography), ethyl acetate: 1-propanol: water = 5: 3: 1), the mixture was neutralized by adding an anion exchange resin Amberlite IRA-410. After removing the ion exchange resin, the mixture was concentrated to obtain 5.3 g of syrupy methyl-D-ribofuranoside ( 56 ).
(97% yield).

The resulting methyl D-ribofuranoside (5
6) With N, N-dimethylformamide (DMF) (300
Dissolve in ice-cold solution and add sodium hydride (55%) under ice-cooling.
(5.7 g, 0.13 mol) and stirred for 5 minutes.
Thereafter, benzyl bromide (16.0 ml, 0.13 mol)
l) is added dropwise, and tetra-n-butylammonium iodide is further added.
(0.12 g, 0.32 mmol) at room temperature
Stir for 1 hour. Raw material disappearance (TLC, toluene: acetic acid
(Chill = 10: 1), methanol was added to stop the reaction.
And neutralized with acetic acid. After concentrating the product, the chloroform
Extracted with water, washed with water and dried over anhydrous magnesium sulfate
After that, the syrup obtained by concentration was
Separation was performed. Mixture of toluene: ethyl acetate = 100: 1
When eluted with a mixed solvent, methyl syrup 2,
3,5-tri-O-benzyl-D-ribofuranoside is 12.5
g (89% yield).

Synthesis Example 2 2,3,5-Tri-O-benzyl-D-ribofuranoose ( 58 ) methyl 2,3,5-tri- O -benzyl-D-ribofuranoside ( 57 ) (10.5 g, 24.4 mmol) was dissolved in 80% acetic acid (200 mL), 1N hydrochloric acid (60 mL) was added, and the mixture was heated under reflux at 90 ° C. for 150 minutes. After the reaction is completed (TL
C, toluene: ethyl acetate = 5: 1), the temperature was returned to room temperature, and most of the solvent was distilled off.
And neutralized with sodium bicarbonate. The aqueous solution was extracted with chloroform (300 mL), and the aqueous layer was extracted once more with chloroform (150 mL) and combined with the previous chloroform layer. After drying over anhydrous magnesium sulfate,
It concentrated and separated using silica gel. Elution with a mixed solvent of toluene: ethyl acetate = 10: 1 yielded 8.8 g (87% yield) of 2,3,5-tri- O -benzyl-D-ribofuranose ( 58 ) in syrup form. Was done.

¹ H-NMR (CDCl ₃ ); δ 3.25
(D, 1H, J6.9 Hz) 3.43-3.50 (m)
3.66 (dd) 3.86 (d) 3.95-4.00
(M) 4.17 (d, J11.2 Hz) 4.23-4.
70 (m) 5.30-5.34 (m) 7.24-7.3
6 (m) Note that the multiplet of δ5.30-5.34 gives two signals by heavy water exchange, and δ3.25, 4.17
Signal disappeared.

Synthesis Example 3 2,3,5-Tri-O-benzyl-1-O-phenoxycarboni
Le -D- Ribofurano - scan ^{(59, R 1 = Ph)} 2,3,5- tri - O - benzyl -D- ribofuranose (58)
(6.3 g, 15.0 mmol) and pyridine (3 mL)
Was dissolved in dichloromethane (60 mL), phenyl chlorocarbonate (2.4 mL, 19.5 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. After the disappearance of the raw materials (TLC, n-hexane: ethyl acetate = 4: 1), the mixture was diluted with chloroform, washed successively with a 1N aqueous sodium hydroxide solution, 1N hydrochloric acid, and water, and then concentrated to obtain a syrup, which was then turned into a silica gel Separation was performed using. After elution with a mixed solvent of n-hexane: ethyl acetate = 10: 1, first, a syrup-like 2,3,5-tri- O -benzyl-1- O -phenoxycarbonyl-D-ribofuranose β-form ( 59 beta) is 5.0 g (62% yield) obtained, then syrupy α-
Body (59 alpha) was obtained 2.8 g (34% yield) of (total yield 96%, α: β = 35 : 65).

Α-form (59α)¹H-NMR (CDCl
_Three); Δ 3.44 (dd, 1H, J_{Four , 5a}3.5Hz, J
_{5a, 5b}10.7 Hz, H-5a) 3.49 (dd, 1
H, J_{Four , 5b}3.9 Hz, H-5b) 3.99 (dd, 1
H, J_3,42.3 Hz, H-3) 4.08 (dd, 1
H, J_2,36.3 Hz, H-2) 4.42-4.80
(M, 7H, H-4, -CH_Two-Ph x 3) 6.28
(D, 1H, J_1,24.3, H-1) 7.20-7.3
7 (m, 20H, -Ph × 4) β-form (59β)¹H-NMR (CDCl_Three); Δ 3.6
3 (dd, 1H, J_{Four, 5a}4.6Hz, J_{5a, 5b}11.1
Hz, H-5a) 3.73 (dd, 1H, J_{Four, 5b}3.3
Hz, H-5b) 4.08 (d, 1H, J_2.34.4H
z, H-2) 4.23 (dd, 1H, J_3,47.6H
z, H-3) 4.42-4.47 (m, 1H, H-4)
4.50-4.77 (m, 6H, -CH_Two-Ph × 3)
6.17 (s, 1H, H-1) 7.11-7.38
(M, 20H, -Ph x 4) Elemental analysis C₃₅H₃₂O₇ Calculated value C 73.31; H 5.97 Measured value C 73.13; H 6.02

[0051] Example 1 (1,2,3,5-tetra - O - benzyl-.alpha.-D-ribofuranoside (alpha-body, 62 alpha) and β- synthetic body (62 beta)) following (Formula 5 According to the scheme shown in), at room temperature, trimethylsilyl triflate (TMSOTf) was used as an acid catalyst in an amount of 1.0 equivalent to the sugar derivative obtained in Synthesis Example 3 and reacted with benzyl alcohol as a hydroxy compound at room temperature. . Specifically, the procedure was performed as follows.

1) 2,3,5-Tri- O -benzyl-1- O -phenoxycarbonyl-D-ribofuranose (100.0 mg, 0.19 mmol) was placed in a two-necked flask, and benzyl alcohol (0.038 mL) was added. , 0.38 mmol) was added. 2) Add molecular sieve 4A (200mg) to the flask
And a stirrer, and the inside of the system was dried under reduced pressure using a vacuum pump, followed by purging with argon. 3) Solvent (6.0) through septum rubber using syringe
mL), and the system was heated or cooled to the temperature of each reaction condition (the solvent used for the reaction was boiling over lithium aluminum hydride or calcium hydride followed by distillation). 4) When the temperature of the system became constant, trimethylsilyl triflate (0.017 ml, 0.01 mmol) was injected to start the reaction. 5) When the raw materials disappeared, a saturated aqueous sodium hydrogen carbonate solution was immediately added to the reaction system to stop the reaction. 6) The mixture was diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. 7) Column chromatography was performed on the syrup obtained by concentration, and 1,2,3,5-tetra- O -benzyl-D-
Ribofuranoside was obtained.

[0053]

Embedded image

In the above reaction, relatively large amounts of by-products were produced. According to the study of the present inventors, it was considered that this result was due to the fact that the reactivity of D-ribofuranose was higher than that of pyranoses such as glucose. Therefore, in the following examples, the number of equivalents of TMSOTf was reduced to 0.5 equivalents relative to the saccharide to carry out the reaction.

Example 2 A D-ribofuranosyl reaction was carried out in the same manner as in Example 1 except that the following formula (Formula 6) and Tables 1 and 2 were followed. The obtained results are shown in (Table 1) and (Table 2).

[0056]

Embedded image

[0057]

[Table 1]

[0058]

[Table 2]

The above column chromatography was eluted with a mixed solvent of toluene: ethyl acetate = 100: 1. (Hereinafter, the same applies to Example 4.) The α: β formation ratio was calculated from the isolation yield of each of the α-anomer and β-anomer. 1,2,3,5-tetra-O-benzyl-α-D-ribofuranoside
(Α-isomer, 62α) ¹ H-NMR (CDCl ₃ ); δ 4.40 (dd, 1
H, J _{4,5a 4.2} Hz, J _{5a, 5b} 10.5 Hz, H-5
a) 3.46 (dd, 1H, J _4,5b 3.9 Hz, H-5
b) 3.80 (dd, 1H, J _2,3 6.7 Hz, H-
2) 3.88 (dd, 1H, J _3,4 3.5Hz, H-
3) 4.31 (m, 1H, H-4) 4.42-4.91
_{(M, 8H, -CH 2 -Ph} × 4) 5.08 (d, 1
H, J _1,2 4.2 Hz, H-1) 7.22-7.48
_{(M, 20H, -C 6 H} 5 × 4) Elemental analysis C ₃₃ H ₃₄ O ₅ Calculated C77.62; H6.71 measurements C77.41; H6.74

1,2,3,5-tetra-O-benzyl-β-D-li
Bofuranoside (β-form, 62β) ¹ H-NMR (CDCl ₃ ); δ 3.57 (dd, 1H,
J _{4,5a 5.7} Hz, J _{5 a, 5b} 10.6 Hz, H-5a)
3.68 (dd, 1H, J _{4,5b 3.7 Hz} , H-5b)
_{3.95 (d, 1H, J 2,3} 4.6Hz, H-2) 4.
12 (dd, 1H, J _3,4 7.2Hz, H-3) 4.3
9 (m, 1H, H-4) 4.41-4.75 (m, 8
_{H, -CH 2 -Ph × 4)} 5.12 (s, 1H, H-
1) 7.24-7.35 (m, 20H, -C 6 H 5 ×
4) Elemental analysis C ₃₃ H ₃₄ O ₅ Calculated C77.62; H6.71 measurements C77.37; H6.72

Example 3 A D-ribofuranosyl reaction was carried out in the same manner as in Example 1 except that the following (Chemical formula 7) and Table 3 were followed. The results obtained are shown in Table 3.

[0062]

Embedded image

[0063]

[Table 3]

As shown in Table 3, when a solvent other than ether was used, a result was obtained that when the reaction time was prolonged, the α: β formation ratio approached 1: 9. According to the study of the present inventors, such a result was obtained because the progress of the reaction itself was slower in the ether solvent than in the other solvents, so that a slight difference in the reaction time caused the α-β This is probably because the isomerization did not proceed very much.

Further, using galactose as a hydroxy compound, the reaction was completed at -20 ° C.
When stirring was continued for 4 hours, a production ratio of α: β = 68: 32 was obtained. According to the findings of the present inventors, it is considered that the same result as described above was obtained when pyranose was used as the hydroxy compound because the reaction rate was lower than that of furanose. From the above results, it was found that when ether was used, isomerization hardly occurred as a solvent, and no by-product of phenylriboside occurred.

Cyclohexyl 2,3,5-tri-O-ben
Jill-α-D-ribofuranoside (α-form, 63α) ¹ H-NMR (CDCl ₃ ); δ 1.11-1.98
_{(M, 10H, -CH 2 -} × 5) 3.39 (dd, 1
H, J _{4,5a 4.2} Hz, J _{5a, 5b} 10.6 Hz, H-5
a) 3.48 (dd, 1H, J _{4,5b 3.7 Hz} , H-5
b) 3.60 (m, 1H, H-1 ') 3.77 (dd,
1H, J _2,3 6.8 Hz, H-2) 3.85 (dd, 1
H, J _5,4 4.2 Hz, H-3) 4.24 (m, 1H,
H-4) 4.42-4.74 (m, 6H, -CH 2 -P
h × 3) 5.18 (d, 1H, J _1,2 4.2 Hz, H−
1) 7.21-7.36 (m, 15H, -C 6 H 5 ×
3) Elemental analysis calculated value of C ₃₂ H ₃₈ O ₅ C76.46; H7.63 measured value C76.19; H7.62

Cyclohexyl 2,3,5-tri-O-ben
Jill-β-D-ribofuranoside (β-form, 63β) ¹ H-NMR (CDCl ₃ ); δ 1.17-1.85
_{(M, 10H, -CH 2 -} × 5) 3.51-3.62
(M, 3H, H-5a, H-5b, H-1 ') 3.84
_{(Dd, 1H, J 2,3 4.8Hz} , H-2) 4.01
(Dd, 1H, J _3,4 6.7 Hz, H-3) 4.32
(M, 1H, H-4) 4.47-4.66 (m, 6H,
_{-CH 2 -Ph × 3) 5.17 (} s, 1H, H-1)
_{7.25-7.38 (m, 15H, -C 6} H 5 × 3)

Example 4 A D-ribofuranosyl reaction was carried out in the same manner as in Example 1 except that the following (Chemical formula 8) and Table 4 were followed. That is, when ether was used as a solvent and the hydroxy compound as the sugar acceptor was a secondary alcohol or a sugar derivative, how the anomeric formation ratio of α: β = 3: 1 obtained in Example 2 changed was examined. In the present embodiment, in consideration of reaction operability,
The reaction was carried out at -20 ° C for the α-anomer of the sugar donor and at 0 ° C for the β-anomer. The results obtained are shown in (Table 4).

[0069]

Embedded image

[0070]

[Table 4]

The physical properties of each product obtained in this example are shown below. [2,3,5-tri-O-benzyl-α-D-ribofuranosyl]-
(1 → 6) -1,2,3,4-di-O-isopropylidene-α-D
-Galactopyranose (64α) ¹ H-NMR (CDCl ₃ ); δ 1.26, 1.29,
1.43, 1.52 (s × 4.3H × 4, —CH ₃ )
3.40 (dd, 1H, J _4,5a 4.1 Hz, J _{5a, 5b} 1
0.6 Hz, H-5a) 3.46 (dd, 1H, J _4,5b)
3.9 Hz, H-5b) 3.76-3.82 (m, 2
H, H-2, H-6'a) 3.86-3.91 (m, 2
H, H-3, H-6'b) 4.13 (m, 1H, H-
5 ′) 4.25 (dd, 1H, J _3,4 3.9 Hz, H−
4) 42.9 (dd, 1H, J2 _{', 3'} 2.3 Hz, H-
2 ') 4.39 (dd, 1H, J _{3', 4 '} 8.0, J
_{4 ', 5'} 1.7Hz, H-4 ') 4.41-4.75
(M, 7H, H-3 ', - CH 2 -Ph × 3) 5.14
_{(D, 1H, J 1,2 4.2Hz} , H-1) 5.51
(D, 1H, J1,, _{2 '} 5.1Hz, H-1') 7.18
_{-7.39 (m, 15H, -C 6} H 5 × 3) elemental analysis C ₃₈ H ₄₆ O ₁₈ Calculated C68.86; H7.00 measurements C68.77; H7.03

6-O- [2,3,5-tri-O-benzyl-β-D
-Ribofuranosyl] -1,2,3,4-di-O-isopropylide
-Α-D-galactopyranoose (64β) ¹ H-NMR (CDCl ₃ ); δ 1.30, 1.34,
1.43, 1.51 (s × 4.3H × 4, —CH ₃ )
3.56 (dd, 1H, J _4,5a 5.6 Hz, J _{5a, 5b} 1
0.7 Hz, H-5a) 3.60-3.66 (m, 2
H, H-5b, H-6'a) 3.82-3.89 (m,
2H, H-6'b, H-5 ') 3.96 (d, 1H, J
_2,3 4.6 Hz, H-2) 4.04 (m, 2H, H-)
3, H-4 ') 4.29 (dd, J2 _{', 3 '} 2.4 Hz,
H-2 ') 4.34 (m, 1H, H-4) 4.43-
_{4.47 (m, 6H, -CH 2} -Ph × 3) 4.54
(Dd, 1H, J3 _{', 4 '} 8.0 Hz, H-3 ') 5.1
5 (s, 1H, H-1) 5.53 (d, 1H, J1 _{', 2'}
5.0 Hz, H-1 ') 7.25-7.40 (m, 15
H, -C ₆ H ₅ × 3) Elemental analysis C ₃₈ H ₄₆ O ₁₈ Calculated value C 68.86; H 7.00 Measured value C 68.58; H 7.01 (column chromatography: toluene: ethyl acetate =
Elution was performed using a 60: 1 mixed solvent. )

Methyl 2,3,4-tri-O-benzoyl-6
-O- [2,3,5-tri-O-benzyl-α-D-ribofuranosi
] -Β-D-galactopyranoside (65α) ¹ H-NMR (CDCl ₃ ); δ 3.39 (dd, 1H,
_{J 4,5a 4.1Hz, J 5 a,} 5b 10.6Hz, H-5a)
3.47 (dd, 1H, J _4,5b 3.8 Hz, H-5b)
3.56 (s, 3H, -OMe) 3.75 (dd, 1
H, J5 _{', 6'a} 7.4 Hz, J6'a, _6'b 10.5 Hz, H
−6′a) 3.8a (dd, 1H, J _2,3 6.8 Hz,
H-2) 3.85 (dd, 1H, J _3,4 3.6 Hz, H
-3) 4.02 (dd, 1H, J5 _{', 6'b} 5.5 Hz, H
-6'b) 4.27-4.32 (m, 2H, H-4, H
-5 ') 4.41-4.78 (m, 6H , -CH 2 -P
h × 3) 4.70 (d, 1H, J _{1 ′, 2 ′} 7.9 Hz, H
-1 ') 4.97 (d, 1H , J 1,2 4.0Hz, H-
1) 5.58 (dd, 1H, J2 _{', 4'} 3.4 Hz, H-
3 ') 5.78 (dd, 1H, J2 _{', 3} '10.4 Hz,
H-2 ') 6.03 (d, 1H, H-4') 7.22-
_{8.11 (m, 30H, -C 6} H 5 × 6) Elemental analysis C ₅₄ H ₅₂ O ₁₃ Calculated C71.35; H5.77 measurements C71.17; H5.75

Methyl 2,3,4-tri-O-benzoyl-6
-O- [2,3,5-tri-O-benzyl-β-D-ribofuranosi
]-(1 → 6) -β-D-galactopyranoside (65β) ¹ H-NMR (CDCl ₃ ); δ 3.32 (dd, 1H,
_{J 4,5a 5.8Hz, J 5 a,} 5b 10.5Hz, H-5a)
3.51 (dd, 1H, J _{4,5b 3.7 Hz} , H-5b)
3.55 (s, 3H, -OMe) 3.65 (dd, 1
H, J5 _{', 6'a} 6.8 Hz, J6'a, _6'b 10.4 Hz, H
-6'a) 3.83-3.86 (m, 2H, H-2, H
-6'b) 3.95 (m, 1H, H-5 ') 4.01
(Dd, 1H, J _2,3 4.6 Hz, J _3,4 7.2 Hz,
H-3) 4.29 (m, 1H, H-4) 4.34, 4.
45-4.58 (s, m, 2H, 4H, -CH 2 -Ph
× 3) 4.57 (d, 1H, J _{1 ′, 2 ′} 7.9 Hz, H−
1 ') 5.05 (s, 1H, H-1) 5.49 (dd,
1H, J _{3 ', 4'} 3.5 Hz, H-3 ') 5.72 (d
d, 1H, J2 _{', 3 '} 10.4Hz, H-2 ') 5.80
(D, 1H, H-4 ') 7.23-8.06 (m, 30
_{H, -C 6 H 5 × 6} ) ( column chromatography toluene: ethyl acetate =
Elution was performed using a 60: 1 mixed solvent. )

Methyl 2,4,6-tri-O-benzoyl-6
-O- [2,3,5-tri-O-benzyl-α-D-ribofuranosi
]-(1 → 3) -β-D-galactopyranoside (66α) ¹ H-NMR (CDCl ₃ ); δ 3.21 (dd, 1H,
_{J 4,5a 4.6Hz, J 4, 5b} 10.7Hz, H-5a)
3.33 (dd, 1H, J _4,5b 3.1 Hz, H-5b)
3.57 (m, 4H, H-3, -OMe) 3.72 (d
d, 1H, J _2,3 6.2 Hz, H-2) 3.99 (m,
1H, H-4) 4.08-4.18, 4.36-4.5
2 (m, m, H- 5 ', H-6'a, -CH 2 -Ph ×
3) 4.50 (dd, 1H, J _{3 ′, 4 ′} 3.4 Hz, H−
3 ') 4.65 (dd, 1H, J5 _{', 6'b} 6.5 Hz, J
_{6'a, 6'b} 11.3 Hz, H-6b) 4.68 (d, 1
H, J1 _{', 2'} 8.0 Hz, H-1 ') 5.44 (d, 1
H, J _1,2 3.9 Hz, H-1) 5.63 (gg, 1
H, J2 _{', 3'} 10.2 Hz, H-2 ') 5.94 (d,
1H, H-4 ') 6.81-8.16 (m, 30H,-
C ₆ H ₅ × 6) Elemental analysis C ₅₄ H ₅₂ O ₁₃ Calculated value C 71.35; H 5.77 Measured value C 71.29; H 5.66

Methyl 2,4,6-tri-O-benzoyl-3
-O- [2,3,5-O- benzyl-beta-D-Li Bofuranoshiru -
(1 → 3) -β-D-galactopyranoside (66β) ¹ H-NMR (CDCl ₃ ); δ 3.52 (d, 1H, J
_2,3 4.5 Hz, H-2) 3.55 (s, 3H, -OM)
e) 3.63 (dd, 1H, J _4,5a 3.3 Hz, J
_{5a, 5b} 10.5 Hz, H-5a) 3.71 (dd, 1
H, J _{4,5b 7.3} Hz, H-5b) 3.75 (dd, 1
H, J _3,4 7.9 Hz, H-3) 6.65, 4.01
_{(ABtype, J12.0Hz, -CH 2 -Ph} )
4.13 (m, 1H, H-5 ') 4.23-4.49
(M, 7H, H-4 , H-3 ', H-6'a, -CH 2
−Ph × 2) 4.55 (m, 2H, J _{1 ′, 2 ′} 7.9H
z, H-1 ', H-6'b) 5.19 (s, 1H, H-
1) 5.59 (dd, 1H, J _{2 ′, 3 ′} 10.1 Hz, H
-2 ') 5.72 (d, 1H, J3 _{', 4 '} 3.3 Hz, H
-4 ') 6.86-8.13 (m, 30H , -C 6 H 5
X6) (Toluene: ethyl acetate = column chromatography
Elution was performed using a 60: 1 mixed solvent. )

[0077]

As described above, according to the present invention, by reacting a D-ribofuranose 1-carbonate derivative with a hydroxy compound in the solution state, α-stereoselectivity can be achieved in a highly stereoselective manner under mild reaction conditions. -Or β-D-ribofuranoside can be obtained.

──────────────────────────────────────────────────続 き Continuation of front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07H 1/00 C07B 53/00 C07H 15/18 C07H 15/20 C07H 11/00 CA (STN)

Claims (7)

(57) [Claims] 1. A method for D-ribofuranosylation of a hydroxy compound, comprising reacting a D-ribofuranose 1-carbonate derivative with a hydroxy compound in a solution state. 2. The D-ribofuranosylation method according to claim 1, wherein the D-ribofuranose 1-carbonate derivative is reacted with a hydroxy compound in the presence of an acid catalyst. 3. The D-ribofuranosylation method according to claim 1, wherein α-D-ribofuranoside is obtained by reacting the D-ribofuranose 1-carbonate derivative dissolved in ethyl ether with a hydroxy compound. 4. The reaction of the D-ribofuranose 1-carbonate derivative dissolved in a solvent other than ethyl ether with a hydroxy compound at a temperature lower than 0 ° C. to obtain a corresponding α-D-ribofuranoside. Item 6. The D-ribofuranosylation method according to Item 1. 5. The reaction of the D-ribofuranose 1-carbonate derivative dissolved in a solvent other than ethyl ether with a hydroxy compound at a temperature of 0 ° C. or higher to obtain β
The method according to claim 1, wherein -D-ribofuranoside is obtained. 6. The D-ribofuranosylation method according to claim 1, wherein the hydroxy compound is a sugar derivative. 7. The D-ribofuranosylation method according to claim 6, wherein the D-ribofuranose 1-carbonate derivative is reacted with a hydroxy compound in the presence of an acid catalyst.