JPH07238080A - 4-(1,2-dihydroxy-3-butenyl)-1,3-dioxane derivative - Google Patents

Abstract

PURPOSE:To obtain the subject derivative obtainable from inexpensive D- mannose and being a key intermediate for efficiently producing L-gulose. CONSTITUTION:This derivative is expressed by formula I (R<1> and R<2> forms a group protecting two OH groups which are mutually in relation of 1,3-positions together with a carbon to which R<1> and R<2> are bound; R<3>, R<4> and R<7> each is H or a protecting group of OH group; R<5> and R<6> each is H, a lower alkyl, etc.), e.g. (1'R, 2R, 2'R, 4R, 5R)-4-(1,2-dibenzyloxy-3-butenyl)-2-phenyl-1,3-dioxane-5- ol. The derivative is obtained by reacting a compound of formula II with aldehydes, etc., in the presence of an acid catalyst to afford a derivative of formula III to which OH groups at 4-position and 6-position are protected, further introducing protecting groups to OH groups at 2-position and 3-position to form a derivative of formula 1V having wholly protected OH groups, hydrolyzing the derivative to afford a derivative of formula V and passing through a process, etc., carrying out Wittig type reaction at 1-position of the derivative of formula V.

Description

Detailed Description of the Invention

[0001]

The present invention relates to cell membrane permeability and selective toxicity of bleomycin, which is used as an anticancer agent, and has the following formula

[0002]

[Chemical 3]

A constitutional unit of a disaccharide represented by the following formula [I]

[0004]

[Chemical 4]

The present invention relates to a synthetic intermediate in the method for producing L-gulose represented by:

[0006]

Bleomycin is clinically widely used as a therapeutic drug for malignant lymphoma and squamous cell carcinoma. Bleomycin, a glycopeptide, is produced by the divalent iron complex of its oligopeptide moiety, which is
It is said that it expresses antitumor activity by oxidatively cleaving glycerin and the sugar moiety consisting of D-manno-L-gulose is involved in cell membrane permeability. In addition, it has been shown that cobalt complexes of bleomycin are concentrated in cancer cells [eg J. Stubbe et al., Chem. Rev., 87, 1107 (198).
7).], The cancer cell recognition ability of the sugar moiety is suggested, and if a process capable of efficiently manufacturing the disaccharide moiety can be developed, its use as a recognition element of the targeting DDS is strongly expected. However, L-gulose is a rare sugar in nature, and an efficient production method for the above purpose is desired. So far
As a method for producing L-growth, (1) a method of reducing L-ascorbic acid [ML Wolfrom et al., J. Am. Chem. S.
oc., 74, 5583 (1952); GL Andrews et al., J. Or
g. Chem., 46, 2976 (1981); LM Lerner, Carbohydr.
Res., 44, 116 (1975).], (2) A method for synthesizing from D-glucose [eg, K. Katano et al., J. Org. Chem.,
50, 5807 (1985); T. Tsuchiya et al., Tetrahedron
Lett., 22, 1413 (1982).] Has been reported so far. However, it is considered difficult to introduce D-mannose at the 2-position from the skeleton of L-glopyranose [eg, V. Pozsgay et al., J. Org. Chem., 46, 37.
61 (1981).]. Furthermore, in the method (1), it is difficult to distinguish the 2-position hydroxyl group for introducing the D-mannose moiety from other hydroxyl groups, and in the method (2), a highly explosive azide compound or the like is used. Therefore, it is considered difficult to synthesize a large amount of L-gulose derivative for the above-mentioned purpose by these methods.

[0007]

DISCLOSURE OF THE INVENTION An object of the present invention is to aim at D-manno-L-growth, which is strongly expected to be used as a recognition element of a targeting DDS, and to aim for D-manno-L-gulose which is a rare sugar in nature. The development of efficient manufacturing methods.

[0008]

Means for Solving the Problems As a result of earnest studies on the development of an efficient method for producing L-growth, the present inventors have found that the compound of the present invention, 5-hydroxy-4- (1,2-dihydroxy). -3-butenyl) -1,3-dioxane derivative and 4- (1,
The 2-dihydroxy-3-butenyl) -1,3-dioxan-5-one derivative was found to be an extremely useful key intermediate, and the present invention was completed.

That is, the present invention has the following general formula:

[0010]

[Chemical 5]

[0011] (wherein, in the protecting group R ¹ and R ² together with the carbon atoms to which they are attached, to protect the two hydroxyl groups in a relationship of 1, 3 to each other, R ^3, R ⁴ and the R ⁷ the same or different, .R ⁵ represents a hydrogen atom or a hydroxyl-protecting group
And R ⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or an optionally protected carboxyl group)
Hydroxy-4- (1,2-dihydroxy-3-butenyl) -1,3-dioxane derivative, and the following general formula

[0012]

[Chemical 6]

[0013] (wherein, in the protecting group R ¹ and R ² together with the carbon atoms to which they are attached, to protect the two hydroxyl groups in a relationship of 1, 3 to one another, R ³ and R ⁴ Are the same or different and represent a hydrogen atom or a protective group for a hydroxyl group, R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or an optionally protected carboxyl group. And a 4- (1,2-dihydroxy-3-butenyl) -1,3-dioxan-5-one derivative represented by

R ¹ and R ² together with the carbon atom to which they are bonded protect two hydroxyl groups having a relationship of 1,3 with each other. Examples of such a protecting group include a methylene group. Alkylidene group such as ethylidene group, 2,2,2-trichloroethylidene group, isopropylidene group, butylidene group, cyclopentylidene group, cyclohexylidene group, cycloheptylidene group; benzylidene group, p-methoxybenzylidene group, Arylmethylidene group such as 2,4-dimethoxybenzylidene group, 3,4-dimethoxybenzylidene group, p-dimethylaminobenzylidene group, o-nitrobenzylidene group, phenanthridene group; and ethoxymethylene group,
Examples thereof include a 1-methoxyethylidene group, a 1,2-dimethoxyethylidene group and an α-methoxybenzylidene group.

As the hydroxyl-protecting groups R ³ , R ⁴ and R ⁷ in the above general formulas [II] and [III], methoxymethyl group, methylthiomethyl group, benzyloxymethyl group, 2-
Methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, tetrahydropyranyl group, 1-ethoxyethyl group, 1-methyl
-1-methoxyethyl group, 2,2,2-trichloroethyl group, 2-
Alkyl groups such as trimethylsilylethyl group and t-butyl group; benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, diphenylmethyl group, 5-dibenzosuberyl group Aryl groups such as phenyl group and triphenylmethyl group; silyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group; formyl group, acetyl group, trichloro Acetyl group, trifluoroacetyl group, pivaloyl group, benzoyl group, 2,4,6-trimethylbenzoyl group, 9-fluorenylmethylcarbonyl group, 2,2,2-trichloroethylcarbonyl group, benzyloxycarbonyl group, t Examples thereof include an acyl group such as a butoxycarbonyl group.

Examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isobutyl group and an isopentyl group.
Moreover, examples of the substituted or unsubstituted aryl group include a phenyl group, a p-tolyl group, a p-methoxyphenyl group, and a 2,4-dimethoxyphenyl group.

The protected carboxyl group means a carboxyl group esterified with a lower alkyl group or a carboxyl group neutralized with an alkali metal salt or amine.

In the above general formulas [II] and [III], R
¹ , R ² and the carbon atom to which they are bonded are preferably an arylmethylidene group as a unit that protects two hydroxyl groups having a relationship of 1, 3 with each other,
When R ³ and R ⁴ are hydroxyl-protecting groups, R ³ and R ⁴ are preferably arylmethyl groups. Further, in the above general formulas [II] and [III], if R ⁵ and R ⁶ are the same, cis and trans isomers do not exist, so that R ⁵ and R ⁶ are both hydrogen atoms or the same. preferable.

5-hydroxy-4- (1,2-dihydroxy-3-butenyl) -1,3 represented by the above general formulas [II] and [III]
The -dioxane derivative and the 4- (1,2-dihydroxy-3-butenyl) -1,3-dioxan-5-one derivative can be produced by the following synthetic steps.

[0020]

[Chemical 7]

[0021]

[Chemical 8]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷
Is the same as above. R ⁸ and R ⁹ represent a lower alkyl group, or a substituted or unsubstituted aryl group, and R ^{3 ′} represents a substituted or unsubstituted aryl group).

[First Step] In this step, an alkyl or aryl 1-thio-D-mannopyranoside represented by the general formula [IV] is treated with an aldehyde, a ketone,
Reacts with acetals and is represented by general formula [Va] 4,6-
The 1-thio-D-mannopyranoside derivative in which the hydroxyl group at the position is protected by an alkylidene group or an arylmethylidene group is produced. General formula [IV] used in this step
Alkyl or aryl 1-thio-D-mannopyranoside represented by, 1,2,3,4,6-penta-O-acetyl-D-mannopyranose in the presence of an acid catalyst to act thiols,
It is a compound which can be produced by derivatizing to 2,3,4,6-tetra-O-acetyl-1-thio-D-mannopyranoside and then subjecting the acetyl group, which is a hydroxyl-protecting group, to alkaline hydrolysis.

Aldehydes, ketones and acetals used in this step include formaldehyde dimethyl acetal, acetaldehyde diethyl acetal, acetone, 2,2-dimethoxypropane, 2,2-diethoxypropane, 3-pentanone, 3, 3-dimethoxypentane, cyclopentanone, 1,1-dimethoxycyclopentane, cyclopentanone ethylene ketal, cyclohexanone, 1,1-dimethoxycyclohexane, 1,1-diethoxycyclohexane, cyclohexanone ethylene ketal, cycloheptanone, 1, 1-dimethoxycycloheptane, benzaldehyde, benzaldehyde dimethyl acetal, benzaldehyde diethyl acetal, p-anisaldehyde, p-anisaldehyde dimethyl acetal, 2,4-dimethoxybenzaldehyde, 2,4-dimethoxy Lens dimethylacetal, acetophenone dimethylacetal, propiophenone, but propiophenone dimethyl acetal and the like, preferably dimethyl acetal are used. The acid catalyst used in this step includes hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrofluoric acid, tetrafluoroboric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphor. Sulfonic acid,
Examples include pyridinium p-toluene sulfonate, tetrafluoroborate diethyl ether complex, zinc chloride, aluminum chloride, iron trichloride, boron trifluoride ether complex, tin tetrachloride, titanium tetrachloride and the like, but preferably tetra A fluoroborate diethyl ether complex is used.

The reaction is generally carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably a hydrocarbon solvent such as pentane or hexane, ether, tetrahydrofuran, 1 , 2-
Ether solvents such as dimethoxyethane, dioxane,
Halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene,
An aromatic hydrocarbon solvent such as xylene, a ketone solvent such as acetone, 2-butanone, 3-pentanone, cyclopentanone, cyclohexanone, dimethylformamide, dimethyl sulfoxide, or the like is used, and more preferably, the acetal derivative used. The corresponding ketone solvent or dimethylformamide is used. Reaction is usually -20
Smooth progress from ℃ to 80 ℃. The introduction of these protecting groups is a known method [TW Greene et al., "Protective Group
s in Organic Synthesis "John Wiley & Sons, Inc., N
ewYork, 1991, pp118-142].

[Second Step] This step is for preparing a 1-thio-D-mannopyranoside derivative in which two hydroxyl groups at the 4- and 6-positions represented by the general formula [Va] are protected by an alkylidene group or an arylmethylidene group. A protective group is introduced into the 2- and 3-position hydroxyl groups to produce a 1-thio-D-mannopyranoside derivative represented by the general formula [Vb] in which the 2-, 3-, 4-, and 6-position hydroxyl groups are all protected. It is a thing.

As the protective groups R ³ and R ⁴ for the 2-hydroxyl group introduced in this step, those which are kept stable from the next step 3 to step 6 and which can be easily removed in the subsequent steps are selected. To be done. As the hydroxyl-protecting group satisfying such requirements, 2,2,2-trichloroethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, 2 Alkyl groups such as 1,2,2-trichloroethyl group and 2-trimethylsilylethyl group; arylmethyl groups such as benzyl group, p-methoxybenzyl group and 3,4-dimethoxybenzyl group; trimethylsilyl group, triethylsilyl group, triethylsilyl group Silyl groups such as isopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group; formyl group, acetyl group, trichloroacetyl group, trifluoroacetyl group, pivaloyl group, benzoyl group, 2,4,6-trimethyl A benzoyl group,
9-fluorenylmethylcarbonyl group, 2,2,2-trichloroethylcarbonyl group, benzyloxycarbonyl group, t-
Examples of the acyl group such as butoxycarbonyl group,
An arylmethyl group or a silyl group is preferably used. The introduction of protective groups for these hydroxyl groups is known in the art [T.
W. Greene et al., "Protective Groups in Organic Sy
nthesis "John Wiley & Sons, Inc., New York, 1991, p
p10-118]. When R ³ and R ⁴ are the same, the introduction of protecting groups is carried out simultaneously. When R ³ and R ⁴ are different from each other, the protecting groups R ³ and R ⁴ which are different in stages are utilized by taking advantage of the difference in the reactivity between the 2- and 3-position hydroxyl groups of the D-mannopyranoside derivative represented by the general formula [Va]. It is possible to introduce
Suitably, different protecting groups R ³ and R ⁴ can be introduced regioselectively by the methods shown in the following third to fifth steps.

[Third Step] In this step, a stannylene acetal derivative represented by the general formula [VI] is produced from a D-mannopyranoside derivative represented by the general formula [Va] and having two adjacent hydroxyl groups. Is.

Substituent of stannylene group introduced in this step
Examples of R ⁹ include a methyl group, an ethyl group, a butyl group, a t-butyl group, and a phenyl group. Stannylene acetalization reaction is carried out by adding D-mannopyranoside derivative represented by the general formula [Va] to dimethyltin dichloride, dimethyltin dibromide, dibutyltin dichloride, dibutyltin dibromide, di-t-butyltin dichloride in the presence of a base. , Diphenyltin dichloride, or a method of reacting the D-mannopyranoside derivative represented by the general formula [Va] with dibutyltin oxide. Suitably dibutyltin oxide is used [eg J. Alais et a
l., Tetrahedron Lett., 24, 2383 (1983).]. The reaction is usually carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction.
Preferably, pentane, a hydrocarbon solvent such as hexane, ether, tetrahydrofuran, 1,2-dimethoxyethane,
An ether solvent such as dioxane, a halogenated hydrocarbon solvent such as dichloromethane, chloroform and 1,2-dichloroethane, an aromatic hydrocarbon solvent such as benzene, toluene and xylene are used, and toluene is more preferably used. To be The reaction usually proceeds at 80 ° C. to 110 ° C., but preferably proceeds smoothly by heating and refluxing while removing the produced water by azeotropic distillation. The stannylene acetal derivative represented by the general formula [VI] obtained by the above method is used in the next fourth step without purification.

[Fourth Step] In this step, the stannylene acetal derivative represented by the general formula [VI] is arylmethylated to produce a D-mannopyranoside derivative represented by the general formula [Vc].

When a stannylene acetal derivative represented by the general formula [VI] is reacted with an electrophile such as arylmethyl halide, the reaction selectively proceeds on the 3-position oxygen atom and represented by the general formula [Vc]. The 2-hydroxyl group is not protected D-
A mannopyranoside derivative can be obtained. In addition, this reaction proceeds smoothly especially in the presence of fluoride ions [N.
Nagashima et al., Chem. Pharm. Bull., 39, 1972 (1
991).].

[Fifth Step] In this step, the 2-position hydroxyl group of the D-mannopyranoside derivative represented by the general formula [Vc] is protected, and the 2-position, the 3-position, the 4-position represented by the general formula [Vb], It is intended to produce a D-mannopyranose derivative in which the hydroxyl group at the 6-position is protected.

This step is similar to the second step in the known method [TW Greene et al., "Protective Groups in Organi".
c Synthesis "John Wiley & Sons, Inc., New York, 19
91, pp10-118].

[Sixth Step] In this step, the D-mannopyranose derivative represented by the general formula [Vb] in which the 2-, 3-, 4-, and 6-position hydroxyl groups are protected is hydrolyzed to give a compound of the general formula [Vb]. [VII]] to produce a D-mannopyranose derivative in which the 2-, 3-, 4-, and 6-hydroxyl groups are protected.

In this step, mercuric chloride-calcium carbonate, mercuric chloride-mercuric oxide-calcium sulfate, mercury perchlorate-calcium carbonate, thioglycoside derivative represented by the general formula [Vb] in the presence of water, Metal salts of silver nitrate, silver nitrate-silver oxide, silver perchlorate, cupric chloride-copper oxide, thallium nitrate, etc .; N-chlorosuccinimide-silver nitrate, N-bromosuccinimide, N-iodosuccinimide, etc. However, N-bromosuccinimide is preferably used. The reaction is usually carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but ether, tetrahydrofuran, dioxane and like ether solvents, acetone, 3-pentanone and the like are preferable. Ketone solvent, dichloromethane,
Chloroform, halogenated hydrocarbon solvents such as 1,2-dichloroethane, benzene, toluene, aromatic hydrocarbon solvents such as xylene, nitrile solvents such as acetonitrile and propionitrile, dimethylformamide, etc. are preferably used. Acetone is used for. The amount of water is 1-3
0 v / v% is used, but 2-10 v / v% is preferably used. The reaction usually proceeds smoothly at -20 ° C to 50 ° C.

[Seventh Step] In this step, D- in which the 2-, 3-, 4-, and 6-position hydroxyl groups represented by the general formula [VII] are protected
A 5-hydroxy-4- (1,2-dihydroxy-3-butenyl) -1,3 represented by the general formula [IIa] of the compound of the present invention is obtained by performing Wittig type reaction on the 1-position of the mannopyranose derivative.
-To produce a dioxane derivative.

As the method for obtaining the olefin compound represented by the general formula [IIa] from the hemiacetal derivative represented by the general formula [VII], methylenetriphenylphosphorane, ethylidenetriphenylphosphorane, propylidenetriphenylphosphorane, Wittig reaction using phosphonium ylides such as benzylidene triphenylphosphorane and methoxycarbonylmethylene triphenylphosphorane; Owner-Emmons type reaction using phosphonoacetic acid trimethyl ester, phosphonoacetic acid triethyl ester, etc .; Wittig reaction using diphenylphosphinomethyllithium, etc. Type reaction; Peterson elimination reaction using trimethylsilylmethyl lithium, etc .; Julia type reaction using α-lithiomethyl sulfone, etc.
The Wittig reaction with phosphonium ylide is preferably used. In this step, a base in an equimolar amount with hemiacetal is required to generate a formyl group from hemiacetal, and as the base used, phosphonium ylide which is a reaction agent can be used as it is.
Preferably, a method is used in which butyl lithium is allowed to act on the hemiacetal represented by the general formula [VII] as a base, and then phosphonium ylide is acted on. The reaction is usually carried out in a solvent, and any solvent that does not participate in the reaction can be used, but ether, tetrahydrofuran, dioxane and like ether solvents, benzene, toluene, xylene and the like are preferable. The aromatic hydrocarbon solvent, dimethyl sulfoxide, etc. are used, but tetrahydrofuran is preferably used. The reaction usually proceeds smoothly at -20 ° C to 30 ° C.

[Eighth Step] In this step, the 5-hydroxy group of the 5-hydroxy-4- (1,2-dihydroxy-3-butenyl) -1,3-dioxane derivative represented by the general formula [IIa] is oxidized. Then, the compound of the present invention produces a 4- (1,2-dihydroxy-3-butenyl) -1,3-dioxan-5-one derivative represented by the general formula [III].

For the oxidation of alcohol to ketone, a chromium-based oxidizing agent such as chromium trioxide, chromium trioxide pyridine complex, and pyridinium chlorochromate; dimethyl sulfoxide-oxalyl chloride triethylamine, dimethyl sulfoxide-dicyclohexylcarbodiimide, dimethyl sulfoxide- Acetic anhydride, dimethyl sulfoxide-trifluoroacetic anhydride, organic oxidants such as sulfur trioxide pyridine complex, and the like are exemplified, but dimethyl sulfoxide-is preferable.
Oxidation with oxalyl chloride-triethylamine is selected. The reaction is usually carried out in a solvent, any solvent can be used as long as it does not participate in the reaction, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, Pyridine or the like is used. The oxidation reaction proceeds smoothly at -50 ℃ to 0 ℃.

[Ninth Step] In this step, the carbonyl group of the 4- (1,2-dihydroxy-3-butenyl) -1,3-dioxan-5-one derivative represented by the general formula [III] is reduced. The compound of the present invention is represented by the general formula [IIb]: 5-hydroxy-4-
(1,2-dihydroxy-3-butenyl) -1,3-dioxane derivative is produced.

For reduction of ketone to alcohol, sodium borohydride, sodium trimethoxyborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, lithium tri-s-butylborohydride, Potassium tri-s-butyl borohydride, lithium trisiamyl borohydride, potassium trisiamyl borohydride, lithium triethyl borohydride, zinc borohydride, lithium aluminum hydride, lithium tri-t-butoxyaluminum hydride, Sodium bis (2-methoxyethoxy) aluminum hydride, aluminum hydride, diisobutylaluminum hydride, borane tetrahydrofuran complex, diciamylborane, diisopinocanphenylborane, 9-borabicyclo [3.3.1] nonane, etc. It is exemplified by the general formula [I
A sterically bulky reducing agent is selected for producing the alcohol derivative represented by b], and preferably hydrogenated tri-s-
Lithium butylboron is used. The reaction is usually carried out in a solvent, and any solvent that does not participate in the reaction can be used, but ether, tetrahydrofuran, dioxane and other ether solvents, benzene, toluene, xylene and the like are preferable. An aromatic hydrocarbon solvent or the like is used, and more preferably tetrahydrofuran is used. The reduction reaction proceeds smoothly at -78 ° C to 0 ° C.

The general formula [II] obtained by the above method
All of the compounds of the present invention represented by a], [IIb] and [III] are capable of removing a hydroxyl group-protecting group, exchanging it with another hydroxyl group-protecting group, or glycosylating a hydroxyl group according to known methods. It is possible to

The general formula [II
b] represented by 5-hydroxy-4- (1,2-dihydroxy-3-
The butenyl) -1,3-dioxane derivative is derived to L-growth represented by the formula [I] by the following synthetic steps.

[0044]

[Chemical 9]

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above.

[Tenth Step] This step is carried out by the general formula [IIb]
An aldehyde represented by the general formula [IX] by oxidatively cleaving the carbon-carbon double bond of the 5-hydroxy-4- (1,2-dihydroxy-3-butenyl) -1,3-dioxane derivative represented by Further, the aldehyde derivative [IX] is cyclized in the molecule to obtain an L-glopyranose derivative represented by the general formula [X].

In this step, olefin compound [IIb] is added to potassium permanganate, chromyl chloride, lead tetraacetate, osmium tetroxide, ruthenium tetroxide, selenium dioxide, hydrogen peroxide.
-Selenium dioxide, hydrogen peroxide-osmium tetroxide, hydrogen peroxide-vanadium oxide, hydrogen peroxide-tungstic acid, etc. to form α-glycol form, and then chromic acid, lead tetraacetate, periodic acid, periodic acid Method of reacting sodium or the like to cleave glycol; or ozone oxidation, potassium permanganate, potassium permanganate-periodate, chromic acid, osmium tetroxide-hydrogen peroxide, osmium tetroxide-periodate, It is carried out by a method such as oxidative cleavage with ruthenium tetraoxide; etc., but ozonolysis is preferably used. The reaction is usually carried out in a solvent, and any solvent that does not participate in the reaction can be used, but ether, tetrahydrofuran, dioxane and other ether solvents, methanol, ethanol and other alcohol solvents are preferred. A solvent, an ester solvent such as ethyl acetate, methyl acetate, or the like is used. The oxidative cleavage reaction proceeds smoothly at -80 ° C to 0 ° C.

[Eleventh Step] In this step, the protecting group for the hydroxyl group of the L-glopyranose derivative represented by the general formula [X] is removed to produce L-gulose represented by the formula [I]. .

The removal of protecting groups is carried out by known methods suitable for the protecting groups used [TW Greene et al., "Protective Groups
in Organic Synthesis "John Wiley & Sons, Inc., Ne
w York, 1991, pp. 118-142].

Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, but it goes without saying that the present invention is not limited thereto.

[0051]

【Example】

 Reference example 1

[0052]

[Chemical 10]

Phenyl 4,6-O-benzylidene-1-thio-α-D
-Dissolve mannopyranoside (8.00 g, 22.2 mmol) in dimethylformamide (50 mL) under argon atmosphere, and
Underneath, sodium hydride (2.36 g, 59.1 mmol) was poured into a solution suspended in dimethylformamide (30 mL). 30
After stirring for a minute, benzyl bromide (7.14 mL, 59.
(9 mmol, 2.70 equivalents) was added dropwise, and the mixture was stirred at room temperature for 8 hours. Methanol (6 mL) was added at 0 ° C, the mixture was poured into water (600 mL), extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give phenyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-α-D-mannopyranoside (11.8 g, yield Rate 98%).

Mp 84-85 ° C. (recrystallized from ether / hexane) [α] _D ²⁰ + 107 ° (c 1.13, CHCl ₃ ). IR (neat): 3034, 2895, 2864, 1581, 1454, 1377, 136
. 5, 1213, 1163, 1105 cm -1 1 H-NMR (400MHz, CDCl 3): δ = 3.89 (1H, dd, J = 9.5,
9.5Hz, C (4) H), 3.97 (1H, dd, J = 3.2, 9.5 Hz, C (3)
H), 4.04 (1H, dd, J = 1.4, 3.2 Hz, C (2) H), 4.20 ~ 4.3
5 (3H, C (5) H, C (6) H _eq , C (6) H _ax ), 4.66 (1H, d, J = 1
2.2 Hz, PhCH ₂ ), 4.73 (2H, br.s, PhCH ₂ ), 4.83 (1H,
d, J = 12.2 Hz, PhCH ₂ ), 5.51 (1H, d, J = 1.4 Hz, C (1)
H), 5.65 (1H, s, PhCH), 7.25-7.41 (18H, aromatic),
7.52 (2H, m, aromatic). Elemental analysis (C ₃₃ H ₃₂ O ₅ S): Calculated; C 73.31, H 5.97, S
5.93: Found; C 73.33, H 6.06, S 5.92.

Reference Example 2

[0056]

[Chemical 11]

Phenyl 4,6-O-benzylidene-1-thio-α-
D-mannopyranoside (0.859 g, 2.38 mmol) and dibutyltin (IV) oxide (0.605 g, 2.43 mmol) were suspended in toluene (30 mL) under an argon atmosphere, and the mixture was heated under reflux for 3 hours while azeotropically removing water. The stannylene acetal body obtained by distilling off the solvent was dissolved in dimethylformamide (10 mL) under an argon atmosphere, and the mixture was poured into a reaction vessel containing cesium fluoride (0.369 g, 2.43 mmol) while stirring with ice cooling, Benzyl bromide (0.29 mL, 2.44 mmol) was added dropwise at the same temperature. After warming to room temperature and stirring for 12 hours, the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl ether, and washed with saturated brine. The solvent was evaporated and the residue was purified by silica gel chromatography (ethyl acetate / hexane) to give phenyl-3-O-benzyl-4,6-O-benzylidene-1-thio-α-D-mannopyranoside (0.981 g, yield Rate 9
1%) was obtained.

Mp 89-90 ° C. (recrystallized from ether / hexane) [α] _D ²⁰ + 228 ° (c 1.07, CHCl ₃ ). IR (KBr): 3454, 2899, 1736, 1375, 1246, 1213, 109
7, 1026 cm ^-1 .EI-MS: m / z = 451 (M + H ⁺ ), 450 (M ⁺ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ = 2.83 (1H, d, J = 1.3 H
z, OH), 3.86 (1H, dd, J = 10.3, 10.3 Hz, C (6) H _ax ),
3.97 (H, dd, J = 3.4, 9.5 Hz, C (3) H), 4.18 (1H, dd,
J = 9.5, 9.5 Hz, C (4) H), 4.21 (1H, dd, J = 4.9, 10.
3 Hz, C (6) H _eq ), 4.29 (1H, ddd, J = 1.0, 1.3, 3.4 H
z, C (2) H), 4.34 (1H, ddd, J = 4.9, 9.5, 10.3 Hz, C
(5) H), 4.75 (1H, d, J = 11.8 Hz, PhCH ₂ ), 4.90 (1H,
d, J = 11.8 Hz, PhCH ₂ ), 5.60 (1H, d, J = 1.0 Hz, C
(1) H), 5.63 (1H, s, PhCH), 7.28-7.53 (15H, aromatic). Elemental analysis (C ₂₆ H ₂₆ O ₅ S): Calculated value; C 69.31, H 5.82, S
7.12: Measured value; C 69.07, H 5.90, S 6.83.

Reference Example 3

[0060]

[Chemical 12]

Phenyl-3-O- synthesized by the method of Reference Example 2
Benzyl-4,6-O-benzylidene-1-thio-α-D-mannopyranoside (0.853 g, 1.89 mmol) was dissolved in dimethylformamide (6 mL) under argon atmosphere, and sodium hydride (83.5 mg, 2.09 mmol, 1.1 eq) was poured into a liquid suspended in dimethylformamide (1 mL) under an argon atmosphere, and further washed with dimethylformamide (3.0 mL). After stirring for 30 minutes, 4-methoxyphenyl chloride (0.29 mL, 2.06 mmol, 1.1 eq) was added dropwise at the same temperature, the temperature was gradually raised and the mixture was stirred at room temperature for 12 hours, and then a small amount of methanol was added to the reaction solution. , Water (30 mL) were sequentially added, extracted with ether, washed with saturated brine, and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel chromatography (ethyl acetate / hexane) and phenyl 3-O-benzyl-4,6-O-benzylidene-2-O- (4-methoxybenzyl) -1- Thio-α-D-mannopyranoside (1.019 g,
Yield 94%).

[Α] _D ²⁰ + 112 ° (c 0.66, CHCl ₃ ). IR (neat): 3063, 2901, 2864, 1612, 1249, 1099, 103
0, 746, 698 cm ^-1 .CI-MS: m / z = 571 (M + H ⁺ ), 570 (M ⁺ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ = 3.79 (3H, s, OMe), 3.8
8 (1H, dd, J = 9.5, 9.5Hz, C (4) H), 3.95 (1H, dd, J =
3.2, 9.5 Hz, C (3) H), 4.02 (1H, dd, J = 1.4,3.2 Hz,
C (2) H), 4.19-4.32 (3H, C (5) H, C (6) H _eq , C (6) H _ax ),
4.64 (1H, d, J = 12.1 Hz, PhCH ₂ ), 4.65 (2H, br.s, M
eOC ₆ H ₄ CH ₂ ), 4.81 (1H, d, J = 12.1 Hz, PhCH ₂ ), 5.46
(1H, d, J = 1.4 Hz, H-1), 5.64 (1H, s, PhCH), 6.84
(2H, m, MeOC ₆ H ₄ ), 7.25-7.40 (15H, aromatic), 7.52 (2
H, m, MeOC ₆ H ₄ ). Elemental analysis (C ₃₄ H ₃₄ O ₆ S): Calculated; C 71.56, H 6.0, S 5.
62: Measured value; C 71.28, H6.05, S 5.47.

Reference Example 4

[0064]

[Chemical 13]

Phenyl 2,3-synthesized by the method of Reference Example 1
Di-O-benzyl-4,6-O-benzylidene-1-thio-α-D-mannopyranoside (11.3 g, 20.9 mmol) was dissolved in a 4% aqueous acetone solution (80 mL), and N- Bromosuccinimide (22.2 g, 125 mmol) was added to a 4% aqueous acetone solution (170
The solution dissolved in (mL) was gradually added dropwise and reacted for 25 minutes.
The reaction was stopped by pouring a saturated aqueous solution of sodium sulfite, extraction with ether, washing with water and saturated saline in this order, and then drying over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate / hexane), and 2,3-di-O-benzyl-4,6-O-benzylidene-D-mannopyranose (5.80 g, Yield 62%) was obtained as a mixture of both anomers.

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 2.65 (1H,
d, J = 3.4 Hz, OH), 3.86 (2H, dd, J = 1.6, 3.1 Hz, C
(2) H, dd, J = 10.1, 10.1 Hz, C (6) H _ax ), 4.02 (2H, d
d, J = 3.1, 9.8 Hz, C (3) H, ddd, J = 4.6, 9.8, 10.1 H
z, C (5) H), 4.23 (1H, dd, J = 4.6, 10.1 Hz, C (6)
H _eq ), 4.26 (1H, dd, J = 9.8, 9.8 Hz, C (4) H), 4.67
(1H, d, J = 12.2 Hz, PhCH ₂ ), 4.73 (1H, d, J = 12.2 H
z, PhCH ₂ ), 4.83 (1H, d, J = 12.2 Hz, PhCH ₂ ), 4.84
(1H, d, J = 12.2 Hz, PhCH ₂ ), 5.19 (1H, dd, J = 1.6,
3.4 Hz, C (1) H), 5.64 (1H, s, PhCH), 7.26-7.41 (18
H, aromatic), 7.50 (2H, m, aromatic). CI-MS: m / z = 449 (M + H ⁺ ). Elemental analysis (C ₂₇ H ₂₈ O ₆ ): Calcd; C 72.30, H 6.29: Found; C 72.10, H 6.51.

Reference Example 5

[0068]

[Chemical 14]

Phenyl 3-O-benzyl-4,6-O-benzylidene-2-O- (4-methoxybenzyl) synthesized by the method of Reference Example 3
-1-Thio-α-D-mannopyranoside (388.6 mg, 0.68 mmo
l) in acetone (15 mL) and water (0.3 m
L), N-bromosuccinimide (127.3 mg, 0.72 mmol)
Were sequentially added and stirred for 30 minutes. The reaction was stopped by pouring a saturated aqueous solution of sodium sulfite, extraction with ether, washing with water and saturated saline in this order, and then drying over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate / hexane), and 3-O-benzyl-4,6-O-benzylidene-2-O- (4-methoxybenzyl) -D
-Mannopyranose (175.0 mg, 41% yield, recovered unreacted phenyl 3-O-benzyl-4,6-O-benzylidene-2-O- (4
-Methoxybenzyl) -1-thio-α-D-mannopyranoside (1
Corrected yield 90%) considering 58.2 mg) was obtained as a mixture of both anomers.

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 2.66 (1H,
d, J = 3.5Hz, OH), 3.78 (3H, s, OMe), 3.84 (1H, dd,
J = 1.6, 3.1 Hz, C (2) H), 3.85 (1H, dd, J = 10.2, 1
0.2 Hz, C (6) H _ax ), 4.00 (1H, dd, J = 3.1, 9.8 Hz, C
(3) H), 4.02 (1H, ddd, J = 4.8,9.7, 3.1 Hz, C (5) H),
4.22 (1H, dd, J = 4.8, 10.2 Hz, C (6) H _eq ), 4.24 (1H,
dd, J = 9.7, 9.8 Hz, C (4) H), 4.65 (1H, d, J = 12.2 H
z, PhCH ₂ ), 4.66 (1H, d, J = 12.0 Hz, PhCH ₂ ), 4.76
(1H, d, J = 12.0 Hz, PhCH ₂ ), 4.83 (1H, d, J = 12.2 H
z, PhCH ₂ ), 5.14 (1H, dd, J = 1.6, 3.5 Hz, C (1) H),
5.64 (1H, s, PhCH), 6.85 (2H, m, MeOC ₆ H ₄ ), 7.24-7.
52 (12H, aromatic).

Example 1

[0072]

[Chemical 15]

Methyltriphenylphosphonium bromide (1.
63 g, 4.57 mmol) was suspended in tetrahydrofuran (20 mL) under an argon atmosphere, and a butyllithium hexane solution (1.61 M, 2.70 mL, 4.35 mmol) was gradually added dropwise at -78 ° C, and the mixture was added at 5 ° C under the same temperature. Minutes, and further stirred in an ice-water bath for 10 minutes and at room temperature for 30 minutes to prepare a tetrahydrofuran solution of phosphonium ylide. Separately, 2,3-di-O synthesized in Reference Example 4
-Benzyl-4,6-O-benzylidene-α-D-mannopyranose (1.63 g, 3.62 mmol) in tetrahydrofuran (16 mL)
Butyllithium-hexane solution (1.61 M, 2.70 mL, 1.02 eq) at -78 ℃
Min, and the mixture was stirred in the ice-water bath for another 5 min. In this reaction solution,
A tetrahydrofuran solution of phosphonium ylide prepared previously and cooled to 0 ° C. again was added dropwise at −78 ° C., the temperature was gradually raised, and the reaction was carried out at room temperature for 30 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give (1'R, 2R, 2'R, 4R, 5R) -4
-(1,2-Dibenzyloxy-3-butenyl) -2-phenyl-1,3-
Dioxan-5-ol (1.06 g, yield 65%, considering recovered unreacted 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-mannopyranose (0.40 g) Then, a yield of 80%) was obtained.

Mp 85 ° C. (recrystallized from ether / hexane) [α] _D ²⁰ -48.2 ° (c 1.04, CHCl ₃ ). IR (KBr): 3476, 2903, 2870, 1643, 1452, 1394, 109
1, 1068, 1030, 1014 cm ^{- 1} .EI-MS: m / z = 446 (M ⁺ ), 445 (MH ⁺ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ = 1.70 (1H, d, J = 4.0 H
z, OH), 3.52 (1H, dd, J = 9.3, 9.4 Hz, C (4) H), 3.72
(3H, s, OMe), 3.84-3.94 (3H, C (1 ') H, C (5) H, C (6) H
_ax ), 4.22 (1H, dd, J = 4.8, 10.4 Hz, C (6) H _eq ), 4.23
(1H, dd, J = 6.8,7.4 Hz, C (2 ') H), 4.38 (1H, d, J =
11.7 Hz, PhCH ₂ ), 4.59 (1H, d, J = 11.7Hz, PhCH ₂ ),
4.66 (1H, d, J = 11.7 Hz, PhCH ₂ ), 4.79 (1H, d, J = 1
1.7 Hz, PhCH ₂ ), 5.37 (1H, s, PhCH), 5.44 (1H, ddd,
J = 0.6, 1.6, 10.3 Hz, C (4 ') H _B ), 5.47 (1H, ddd, J =
0.7, 1.6, 17.7 Hz, C (4 ') H _A ), 6.05 (1H, ddd, J = 7.
6, 10.3, 17.7 Hz, C (3 ') H _X ), 7.23-7.40 (15H, aromatic). Elemental analysis (C ₂₈ H ₃₀ O ₅ ): Calculated value; C 75.31, H 6.77: Measured value; C 75.40, H 6.82.

Example 2

[0076]

[Chemical 16]

3-O-benzyl-4,6-O- synthesized in Reference Example 5
A butyllithium hexane solution in tetrahydrofuran (1.61 M, 0.98 mL) was added to benzylidene-2-O- (4-methoxybenzyl) -D-mannopyranose (755.8 mg, 1.58 mmol) for lithiation, and then Example 1 Methyltriphenylphosphonium bromide (1.18 g, 3.31 mmol, 3.
1 equivalent) and butyl lithium hexane solution (1.61 M, 1.96
(1'R, 2R, 2'R, 4R, 5R) -4- [1-benzyloxy-2- (2) by reacting with phosphonium ylide prepared from (mL, 3.16 mmol)
(4-Methoxybenzyloxy) -3-butenyl] -2-phenyl-
1,3-dioxan-5-ol (68.6 mg, yield 45%) was obtained.

Mp 100-102 ° C. (recrystallized from ether / hexane) [α] _D ²⁰ -56.2 ° (c 1.35, CHCl ₃ ). IR (KBr): 3437, 2932, 2866, 1612, 1249, 1091, 105
9, 987, 696 cm ^-1 .CI-MS: m / z = 476 (M ⁺ ), 475 (MH ⁺ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ = 1.71 (1H, d, J = 4.0 H
z, OH), 3.51 (1H, dd, J = 9.5, 10.8 Hz, C (4) H), 3.7
2 (3H, s, OMe), 3.80-3.90 (3H, C (1 ') H, C (5) H, C (6) H
_ax ), 4.22 (1H, dd, J = 4.8, 10.4 Hz, C (6) H _eq ), 4.23
(1H, dd, J = 6.8, 7.7 Hz, C (2 ') H), 4.31 (1H, d, J =
11.4 Hz, ArCH ₂ ), 4.58 (1H, d, J = 11.7Hz, ArCH ₂ ),
4.59 (1H, d, J = 11.4 Hz, ArCH ₂ ), 4.76 (1H, d, J = 1
1.7 Hz, ArCH ₂ ), 5.35 (1H, s, PhCH), 5.44 (1H, dd,
J = 1.7 Hz, 9.8 Hz, C (4 ') H _B ), 5.47 (1H, dd, J = 1.7
Hz, 17.4 Hz, C (4 ') H _A ), 6.03 (1H, ddd, J = 7.6 Hz,
9.8Hz, 17.4 Hz, C (3 ') H _X ), 6.79 (2H, m, MeOC ₆ H ₄ ),
7.22 (2H, m, MeOC ₆ H ₄ ), 7.31-7.39 (10H, aromatic). Elemental analysis (C ₂₉ H ₃₂ O ₆ ): Calculated; C 73.09, H 6.77: Found; C 72.69, H 6.60. .

Example 3

[0080]

[Chemical 17]

Dichloromethane (1.5 m
L) dissolve oxalyl chloride (0.17 mL, 1.95 mmol)-
After stirring for 5 minutes at 50 ° C, dimethyl sulfoxide (0.28
(mL, 3.95 mmol) was gradually added dropwise. After stirring at the same temperature for 15 minutes, the compound was synthesized by the method of Example 1 (1'R, 2R, 2'R, 4
R, 5R) -4- (1,2-Dibenzyloxy-3-butenyl) -2-phenyl-1,3-dioxan-5-ol (369.7 mg, 0.828 mmol)
Was dissolved in dichloromethane (1.5 mL), and the mixture was stirred at the same temperature for 30 minutes. After further stirring at -18 ° C for 15 minutes, triethylamine (1.20 mL, 8.61 mmol) was added dropwise.
The mixture was stirred at -18 ° C for 10 minutes and at 0 ° C for 10 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, extracted with ether, washed with saturated brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered, and the solvent was evaporated under reduced pressure to give crude (1'R, 2R, 2'R, 4S) -4- (1,2-dibenzyloxy-3-butenyl) -2-phenyl- 1,3-dioxan-5-one was obtained. This product was used in the next step without purification.

Crude (1'R, 2R, 2'R, 4S)-prepared by the above method
4- (1,2-dibenzyloxy-3-butenyl) -2-phenyl-1,3
-Dioxan-5-one (370 mg, 0.83 mmol) was dissolved in tetrahydrofuran (4 mL) under an argon atmosphere, and the temperature was -78 ° C.
After stirring for 5 minutes at room temperature, tri-sec-butylhydroborohydride tetrahydrofuran solution (1.0 M, 1.0 mL, 1.0 mm
ol) was added dropwise and the mixture was stirred at -78 ° C for 90 minutes and at 0 ° C for 30 minutes.
Saturated saline was poured into the reaction solution, which was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give (1'R, 2R, 2'R, 4R, 5S) -4- (1,2-dibenzyloxy-3-butenyl) -2- Phenyl-1,3-dioxan-5-ol (279.5
mg, yield of 2 steps 76%) was obtained.

Mp 101-102 ° C. (recrystallized from ether / hexane) [α] _D ²⁰ -30.6 ° (c 0.98, CHCl ₃ ). IR (KBr): 3485, 2914, 2872, 1496, 1454, 1388, 136
5, 1151, 1086, 1024, 960 cm ^-1 .EI-MS: m / z = 447 (M + H ⁺ ), 446 (M ⁺ ), 445 (MH ⁺ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ = 3.13 (1H, d, J = 9.6 H
z, OH), 3.65 (1H, dddd, J = 1.1, 1.4, 2.0, 9.6 Hz, C
(5) H), 3.98 (1H, dd, J = 4.2, 7.3 Hz, C (1 ') H), 4.00
(1H, dd, J = 1.4, 11.9 Hz, C (6) H _ax ), 4.03 (1H, dd,
J = 1.1, 7.3 Hz, C (4) H), 4.12 (1H, dd, J = 4.2, 8.1
Hz, C (2 ') H), 4.18 (1H, dd, J = 2.0, 11.9 Hz, C (6) H
_eq ), 4.43 (1H, d, J = 11.8 Hz, PhCH ₂ ), 4.66 (1H, d,
J = 11.8 Hz, PhCH ₂ ), 4.75 (1H, d, J = 11.0 Hz, PhCH
₂ ), 4.80 (1H, d, J = 11.0 Hz, PhCH ₂ ), 5.35 (1H, dd
d, J = 0.9, 1.7 Hz, 17.3 Hz, C (4 ') H _A ), 5.40 (1H, dd
d, J = 0.6, 1.7, 10.3 Hz, C (4 ') H _B ), 5.57 (1H, s, PhC
H), 6.04 (1H, ddd, J = 8.1Hz, 10.3 Hz, 17.3 Hz, C
(3 ') H _X ), 7.23-7.40 (13H, aromatic), 7.50 (2H, m, aromatic). Elemental analysis (C ₂₈ H ₃₀ O ₅ ): Calculated value; C 75.31, H 6.77: Measured value. C 75.33, H 6.75.

Example 4

[0085]

[Chemical 18]

Synthesized by the method of Example 2 (1′R, 2R, 2′R, 4
R, 5R) -4- (1-Benzyloxy-2- (4-methoxybenzyloxy) -3-butenyl) -2-phenyl-1,3-dioxan-5-ol (52.0 mg, 0.11 mmol), Oxalyl chloride (48.2 μL, 0.55 mmol), dimethyl sulfoxide (78.4 μL, 1.09 mmol) and triethylamine (0.18 mL, 1.31 mmol) were allowed to act in the same manner as in Example 3 to obtain crude (1′R, 2R, 2′R). , 4S)-
3- (2-benzyloxy-3- (4-methoxybenzyloxy) -3
-Butenyl) -2-phenyl-1,3-dioxan-5-one (47.8
mg) and further reacted with tri-sec-butylhydroboronated lithium tetrahydrofuran solution (1.0 M, 0.13 mL, 0.13 mmol) in the same manner as in Example 3 (1′R, 2R,
2'R, 4R, 5S) -3- [2-Benzyloxy-3- (4-methoxybenzyloxy) -3-butenyl] -2-phenyl-1,3-dioxane-
5-ol (40.9 mg, 79% yield for 2 steps) was obtained.

Mp 109-110 ° C. (recrystallized from ether / hexane) [α] _D ²⁰ -33.8 ° (c 0.88, CHCl ₃ ). IR (KBr): 3489, 2905, 2068, 1614, 1518, 1452, 138
8, 1255, 1099, 1022, 819 cm ^-1 .CI-MS: m / z = 476 (M ⁺ ), 475 (MH ⁺ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ = 3.17 (1H, d, J = 9.6 H
z, OH), 3.65 (1H, dddd, J = 1.1, 1.4, 2.0, 9.6 Hz, C
(5) H), 3.79 (3H, s, OMe), 3.93 (1H, dd, J = 4.6, 7.
1 Hz, C (1 ') H), 4.00 (1H, dd, J = 1.4, 11.9 Hz, C (6) H
_ax ), 4.03 (1H, dd, J = 1.1, 7.1 Hz, C (4) H), 4.10 (1
H, dd, J = 4.6, 8.0 Hz, C (2 ') H), 4.19 (1H, dd, J =
2.0, 11.9 Hz, C (6) H _eq ), 4.36 (1H, d, J = 11.6 Hz, A
rCH ₂ ), 4.59 (1H, d, J = 11.6 Hz, ArCH ₂ ), 4.73 (1H,
d, J = 11.0 Hz, ArCH ₂ ), 4.77 (1H, d, J = 11.0 Hz, ArC
H ₂ ), 5.34 (1H, ddd, J = 0.8, 1.7 Hz, 17.3 Hz, C (4 ')
H _A ), 5.40 (1H, dd, J = 0.6, 1.7, 10.3 Hz, C (4 ') H _B ),
5.57 (1H, s, PhCH), 6.03 (1H, ddd, J = 8.0 Hz, 10.3
Hz, 17.3 Hz, C (3 ') H _X ), 6.85 (2H, m, MeOC ₆ H ₄ ), 7.25-
7.38 (10H, aromatic), 7.56 (2H, m, MeOC ₆ H ₄ ).

Example 5

[0089]

[Chemical 19]

Synthesized by the method of Example 4 (1'R, 2R,
2'R, 4R, 5S) -3- [2-Benzyloxy-3- (4-methoxybenzyloxy) -3-butenyl] -2-phenyl-1,3-dioxane-5-
All (79.0 mg, 0.17 mmol) was dissolved in pyridine (1 mL), acetic anhydride (0.80 mL) was added at 0 ° C, and further at room temperature.
It was stirred for 2 hours. The reaction mixture was diluted with ether (30 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give (1'R, 2R, 2'R, 4R, 5S) -5-acetoxy-3- [2-benzyloxy-3- (4-methoxy) Benzyloxy) -3-butenyl] -2-phenyl-1,3-dioxane (71.1 mg, yield 83
%) Was obtained.

[Α] _D ²⁰ -6.87 ° (c 1.25, CHCl ₃ ). IR (neat): 2914, 2866, 1738, 1612, 1514, 1454, 137
3, 1246, 1097, 1053, 698 cm ^-1 .EI-MS: m / z = 519 (M + H ⁺ ), 518 (M ⁺ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ = 1.99 ( 3H, s, CH ₃ CO),
3.79 (1H, dd, J = 3.1, 8.1 Hz, C (2 ') H), 3.80 (3H,
s, OMe), 3.95 (1H, dd, J = 3.1, 8.4 Hz, C (1 ') H), 4.
00 (1H, dd, J = 1.6, 13.0 Hz, C (6) H _ax ), 4.07 (1H, d
d, J = 1.6, 8.4 Hz, C (4) H), 4.28 (1H, dd, J = 1.6, 1
3.0 Hz, C (6) H _eq ), 4.31 (1H, d, J = 11.8 Hz, ArCH ₂ ),
4.57 (1H, d, J = 11.8 Hz, ArCH ₂ ), 4.72 (1H, ddd, J
= 1.6, 1.6,1.6 Hz, C (5) H), 4.79 (1H, d, J = 11.3 H
z, ArCH ₂ ), 4.82 (1H, d, J = 11.3 Hz, ArCH ₂ ), 5.30
(1H, ddd, J = 0.8, 1.5 Hz, 17.4 Hz, C (4 ') H _A ), 5.37
(1H, ddd, J = 0.6, 1.5 Hz, 10.3 Hz, C (4 ') H _B ), 5.59
(1H, s, PhCH), 5.96 (1H, ddd, J = 8.1 Hz, 10.4 Hz, 1
7.4 Hz, C (3 ') H _X ), 6.87 (2H, m, MeOC ₆ H ₄ ), 7.21-7.40
(10H, aromatic), 7.51 (2H, m, MeOC ₆ H ₄ ).

Example 6

[0093]

[Chemical 20]

Synthesized by the method of Example 5 (1′R, 2R,
2'R, 4R, 5S) -5-Acetoxy-3- [2-benzyloxy-3- (4-
(Methoxybenzyloxy) -3-butenyl] -2-phenyl-1,3
-Dioxane (67.5 mg, 0.13 mmol) was dissolved in 5% water-containing dichloromethane solution (1 mL), and 2,3-dichloro-5,6-under 0 ° C.
After adding dicyano-1,4-benzoquinone (35.5 mg, 0.16 mmol), the mixture was further stirred at room temperature for 3 hours. After diluting the reaction solution with dichloromethane (15 mL), the insoluble matter was filtered off,
The solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane) to give (1'R, 2R, 2'R, 4S, 5S) -5-acetoxy-3- [2-benzyloxy-3-hydroxy. -3-Butenyl] -2-phenyl-1,
3-dioxane (45.5 mg, yield 88%) was obtained.

[Α] _D ²⁰ + 22.5 ° (c 1.12, CHCl ₃ ). IR (neat): 3452, 3034, 2862, 1738, 1496, 1454, 124
4, 1151, 1095, 1047, 1026 cm ^-1 .CI-MS: m / z = 399 (M + H ⁺ ), 398 (M ⁺ ), 397 (MH ⁺ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ = 2.18 (3H, s, CH ₃ CO),
2.36 (1H, br, OH), 3.93 (1H, dd, J = 3.7, 8.4 Hz, C
(1 ') H), 4.04 (1H, dd, J = 1.6, 13.1 Hz, C (6) H _{a x} ),
4.09 (1H, m, C (2 ') H), 4.12 (1H, dd, J = 1.6, 8.4 H
z, C (4) H), 4.31 (1H, dd, J = 1.6, 13.1 Hz, C (6)
H _eq ), 4.69 (1H, d, J = 11.3 Hz, PhCH ₂ ), 4.80 (1H, d
dd, J = 1.6, 1.6, 1.6 Hz, C (5) H), 4.95 (1H, d, J = 1
1.3 Hz, PhCH ₂ ), 5.26 (1H, ddd, J = 1.1, 1.2 Hz, 10.
4 Hz, C (4 ') H _B ), 5.35 (1H, ddd, J = 1.2,1.2 Hz, 17.3
Hz, C (4 ') H _A ), 5.63 (1H, s, PhCH), 5.97 (1H, ddd,
J = 7.2 Hz, 10.4 Hz, 17.3 Hz, C (3 ') H _X ), 7.27-7.41 (8
H, aromatic), 7.52 (2H, m, aromatic).

Reference Example 6

[0097]

[Chemical 21]

Synthesized by the method of Example 6 (1'R, 2R, 2'R, 4
S, 5S) -5-Acetoxy-3- [2-benzyloxy-3-hydroxy-3-butenyl] -2-phenyl-1,3-dioxane (42.9 mg,
0.11 mmol) and 2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyltrichloroacetimidate (259.4 mg,
0.38 mmol) under argon atmosphere with dichloromethane (2.5 m
L), and at 0 ° C., boron trifluoride diethyl etherate complex (23.8 μL, 0.19 mmol) was added and reacted for 10 minutes. The reaction mixture was diluted with dichloromethane (30 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / hexane) (1'S, 2R, 2'R, 4S, 5
S) -5-acetoxy-3- [2-benzyloxy-3- (2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyloxy) -3-butenyl] -2 -Phenyl-1,3-dioxane (60.1 mg, yield 61
%) Was obtained.

[Α] _D ²⁰ + 51.4 ° (c 0.89, CHCl ₃ ). IR (neat): 3452, 3065, 2918, 1739, 1496, 1454, 136
. 9, 1230, 1097, 1026 cm -1 1 H-NMR (400MHz, CDCl 3): δ = 2.12 (3H, s, CH 3 CO),
3.63 (1H, dd, J = 1.5,10.6 Hz, ManC (6) H), 3.64 (1H,
dd, J = 1.5, 3.0 Hz, ManC (2) H), 3.70 (1H, ddd, J =
1.5, 4.2, 9.6 Hz, ManC (5) H), 3.76 (1H, dd, J = 4.2,
10.6 Hz, ManC (6) H '), 3.87 (1H, dd, J = 3.0, 9.6 H
z, ManC (3) H), 3.91 (1H, m, C (1 ') H), 3.93 (1H, dd, J
= 1.6, 13.1 Hz, C (6) H _ax ), 3.94 (1H, dd, J = 1.6, 8.3
Hz, C (4) H), 4.04 (1H, dd, J = 9.6, 9.6 Hz, ManC (4)
H), 4.15 (1H, dd, J = 1.0, 7.5 Hz, C (2 ') H), 4.31 (1
H, dd, J = 1.4, 13.1 Hz, C (6) H _eq ), 4.50 (1H, d, J =
11.4Hz, PhCH ₂ ), 4.52 (1H, d, J = 11.0 Hz, PhCH ₂ ),
4.55 (1H, d, J = 13.2 Hz, PhCH ₂ ), 4.60 (1H, d, J = 1
3.2 Hz, PhCH ₂ ), 4.61 (1H, d, J = 12.9 Hz, PhCH ₂ ), 4.
62 (1H, m, C (5) H), 4.63 (1H, d, J = 12.9 Hz, PhC
H ₂ ), 4.67 (1H, d, J = 12.5 Hz, PhCH ₂ ), 4.68 (1H, d,
J = 11.4 Hz, PhCH ₂ ), 4.72 (1H, d, J = 12.5 Hz, PhCH
₂ ), 4.86 (1H, d, J = 11.0 Hz, PhCH ₂ ), 5.02 (1H, d,
J = 1.5 Hz, ManC (1) H), 5.18 (1H, dd, J = 1.3 Hz, 10.
4 Hz, C (4 ') H _B ), 5.22 (1H, dd, J = 1.3,17.4 Hz, C
(4 ') H _A ), 5.55 (1H, s, PhCH), 5.93 (1H, ddd, J = 7.5
Hz, 10.4 Hz, 17.5 Hz, C (3 ') H _X ), 7.17 (2H, m, aromatic), 7.20-7.42 (26H, aromatic), 7.52 (2H, m, aromatic).

Example 7

[0101]

[Chemical formula 22]

Synthesized by the method of Example 3 (1'R, 2R, 2'R, 4
R, 5S) -4- (1,2-Dibenzyloxy-3-butenyl) -2-phenyl-1,3-dioxan-5-ol (194.5 mg, 0.44 mmol)
Was dissolved in methanol (10 mL), and ozone was passed through at −78 ° C. for 40 minutes. Excessive ozone dissolved was removed through argon gas, dimethyl sulfide (0.30 mL) was added, and the temperature was raised to room temperature. After evaporating the solvent, the residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 2,3-di-O-benzyl-4,6-O-benzylidene-L-glopyranose (168.5 mg, yield 86%) was obtained as a mixture of both anomers.

Α-anomer: ¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 3.94 (1H, dd, J = 3.2 Hz, 3.2 Hz, C (2) H), 4.01
(1H, m, C (5) H), 4.08 (2H, dd, J = 1.6, 12.5 Hz, C
(6) H _ax , m, C (3) H), 4.16 (1H, dd, J = 1.1, 3.6 Hz, C
(4) H), 4.30 (1H, dd, J = 1.4, 12.5 Hz, C (6) H _eq ), 4.
57 (1H, d, J = 11.6 Hz, PhCH ₂ ), 4.71 (1H, d, J = 11.
6 Hz, PhCH ₂ ), 4.72 (1H, d, J = 11.5 Hz, PhCH ₂ ), 4.8
6 (1H, d, J = 11.5 Hz, PhCH ₂ ), 5.32 (1H, d, J = 10.0
Hz, OH), 5.40 (1H, ddd, J = 1.2, 3.2, 10.0 Hz, C (1)
H), 5.52 (1H, s, PhCH), 7.28-7.47 (15H, aromatic).

Example 8

[0105]

[Chemical formula 23]

2,3-di-O-benzyl-4 synthesized in Example 7
6-O-benzylidene-L-glopyranose (157.1 mg, 0.35
mmol) was dissolved in dichloromethane (1.5 mL), triethylamine (0.30 mL) and acetic anhydride (0.20 mL) were sequentially added at 0 ° C., and the mixture was reacted at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / hexane) 2.
3-Di-O-benzyl-4,6-O-benzylidene-L-glopyranosyl acetate (151.2 mg, 88% yield) was obtained as a mixture of both anomers.

Β-anomer; ¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 2.10 (1H, s, CH ₃ CO), 3.88 (1H, dd, J = 2.9 Hz,
8.6 Hz, C (2) H), 3.96 (1H, m, C (5) H), 4.02 (2H, d
d, J = 1.8, 12.6 Hz, C (6) H _ax , dd, J = 2.9 Hz, 3.4 H
z, C (3) H), 4.05 (1H, dd, J = 1.3, 3.4 Hz, C (4) H),
4.29 (1H, dd, J = 1.3, 12.6 Hz, C (6) H _eq ), 4.63 (1H,
d, J = 12.0 Hz, PhCH ₂ ), 4.69 (1H, d, J = 12.0 Hz, Ph
CH ₂ ), 4.71 (1H, d, J = 12.0 Hz, PhCH ₂ ), 4.86 (1H,
d, J = 12.0 Hz, PhCH ₂ ), 5.50 (1H, s, PhCH), 6.16 (1
H, d, J = 8.4 Hz, C (1) H), 7.27-7.48 (15H, aromatic).

2,3-di-O-benzyl-synthesized by the above method
4,6-O-benzylidene-β-L-glopyranosyl acetate (15.2 mg, 0.03 mmol) was dissolved in methanol (10 mL), formic acid (0.1 mL), 20% palladium hydroxide / carbon (15.0 mg) ) Were sequentially added, and then hydrogen at 20 atm was sealed in the autoclave and stirred for 3 hours. The catalyst was removed by filtration, and the solvent was distilled off to obtain crude L-glopyranosyl acetate at room temperature, methanol (20 mL) saturated with ammonia was added, and the mixture was stirred for 8 hours, and L-growth (3.1 mg, 56%) was obtained.

¹ H-NMR (400 MHz, CD ₃ OD): δ = 3.56 (1H,
dd, J = 3.3, 8.2 Hz, C (2) H), 3.68 (1H, dd, J = 5.5, 1
1.3 Hz, C (6) H), 3.71 (1H, m, C (4) H), 3.73 (1H, dd,
J = 6.5, 11.3 Hz, C (6) H '), 3.92 (1H, ddd, J = 1.0,
5.5, 6.5 Hz, C (5) H), 3.95 (1H, dd, J = 3.3, 3.3 Hz,
C (3) H), 4.80 (1H, d, J = 8.2 Hz, C (1) H).

[0110]

As a result of the completion of the present invention, an L-gulose derivative can be efficiently produced from inexpensive D-mannose.

Claims (2)

[Claims] 1. The following general formula: (In the formula, R ¹ and R ² are a protecting group that protects two hydroxyl groups having a relationship of 1,3 together with the carbon atom to which they are bonded, and includes R ³ , R ⁴ and R ⁷ Are the same or different and represent a hydrogen atom or a protective group for a hydroxyl group, R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or an optionally protected carboxyl group. 5-hydroxy-4-represented by
(1,2-Dihydroxy-3-butenyl) -1,3-dioxane derivative. 2. The following general formula: (In the formula, R ¹ and R ² are a protecting group that protects two hydroxyl groups having a relationship of 1,3 together with the carbon atom to which they are bonded, and R ³ and R ⁴ are the same or And R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or an optionally protected carboxyl group. ) 4- (1,2-dihydroxy-3-
Butenyl) -1,3-dioxan-5-one derivative.