Β(1→5)glucosylfranoside cyclic dimer and method for producing β(1→5)glucosylfranoside cyclic dimer

Abstract

To provide a β(1→5)glucosylfranoside cyclic dimer and a method for producing the β(1→5)glucosylfranoside cyclic dimer.SOLUTION: The β(1→5)glucosylfranoside cyclic dimer of the present invention is represented by the following formula (1).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a β(1→5) glucosyl furanoside cyclic dimer and a method for producing the β(1→5) glucosyl furanoside cyclic dimer. [Background technology]

[0002] Cyclic oligosaccharides have a cavity in their molecules, which allows them to incorporate certain compounds into that cavity (inclusion function). Utilizing this property makes it possible to stabilize volatile substances, stabilize oxidizing or photodegrading substances, and modify physical properties. Therefore, research into cyclic oligosaccharides is currently being actively conducted, primarily in the fields of food, pharmaceuticals, and cosmetics.

[0003] Specifically, applied research and practical application of cyclodextrin, a type of cyclic oligosaccharide, is progressing. Cyclodextrin is a cyclic oligosaccharide having a cyclic structure in which several molecules of D-glucose are linked by α(1→4) glycosidic bonds. Currently, α-cyclodextrin, which has a cyclic hexameric structure, β-cyclodextrin, which has a cyclic heptameric structure, and γ-cyclodextrin, which has a cyclic octameric structure, are produced by enzymatic methods and are commercially available (see Patent Documents 1 to 3).

[0004] Furthermore, chemical synthesis of "small cyclic oligosaccharides" of cyclic trimers and tetramers has been reported (see Patent Document 4).

[0005] On the other hand, cyclic dimers, which are "minimum cyclic oligosaccharides," are expected to have properties different from those of conventional cyclic oligosaccharides based on the results of chemical calculations and other methods. However, cyclic dimers could not be synthesized using conventional chemical and enzymatic methods. Therefore, verification of their properties has been difficult. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 5-292987 [Patent Document 2] Japanese Patent Application Laid-Open No. 2000-60590 [Patent Document 3] U.S. Patent No. 3,425,910 [Patent Document 4] Patent No. 6749644 Summary of the Invention [Problem to be solved by the invention]

[0007] In this situation, the problem to be solved by the present invention is to provide a method for chemically synthesizing β(1→5) glucosyl furanoside cyclic dimers, and to provide β(1→5) glucosyl furanoside cyclic dimers that have not been synthesized until now. [Means for solving the problem]

[0008] Such an object can be achieved by the present invention described below. The β(1→5) glucosyl furanoside cyclic dimer of the present invention is characterized by being represented by the following formula (1): [ka]

[0009] The β(1→5) glucosyl furanoside cyclic dimer of the present invention is characterized by being represented by the following formula (2): [ka] (In the formula, R 1 represents a bridging group.

[0010] The β(1→5) glucosyl furanoside cyclic dimer of the present invention is characterized by being represented by the following formula (3): [ka] (In the formula, R 1 indicates a bridging group, and R2 represents a protecting group for a hydroxyl group.

[0011] The method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention is characterized by comprising a cationic ring-opening polymerization step in which a 1,4-anhydrosugar represented by the following formula (4) is reacted by cationic ring-opening polymerization to obtain a β(1→5) glucosyl furanoside cyclic dimer represented by the following formula (3). [ka] (In the formula, R 1 indicates a bridging group, and R 2 represents a protecting group for a hydroxyl group. [ka] (In the formula, R 1 indicates a bridging group, and R 2 represents a protecting group for a hydroxyl group.

[0012] In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, 2 is preferably an allyl group, an acetyl group, a benzyl group or a benzyloxymethyl group.

[0013] In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, after the cationic ring-opening polymerization step, 2 It is preferable that the method further comprises a step of removing

[0014] In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, 1 is preferably represented by the following formula (5). -Ar 1 -L-Ar 2 - (5) (In the formula, Ar 1 , Ar 2 each independently represents an aromatic atomic group, and L represents a divalent substituent or a single bond.

[0015] In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, 1 is preferably represented by the following formula (6). [ka] (Wherein, p R 4 , q R 5 are each independently a hydrogen atom, a halogen atom, a halo-substituted or unsubstituted lower hydrocarbon group, a lower alkoxy group, a nitro group, or a di(lower alkyl)amino group, and L is a divalent substituent or a single bond. p and q are each independently an integer of 0 to 4. p R 4 Among them, adjacent R 4 may be bonded to each other to form a benzene ring, and q R 5 Among them, adjacent R 5 may be bonded to each other to form a benzene ring.

[0016] In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, the R 1 It is preferable that the method further comprises a step of removing

[0017] In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, it is preferable to use a silyl-based activator in the cationic ring-opening polymerization step.

[0018] In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, the 1,4-anhydrosugar represented by the above formula (4) is The hydroxyl groups at the 3 and 6 positions of the 1,2,4-orthoester are 1 crosslinking with forming a 1,4-anhydrosugar structure using an activating agent and protecting the 2-position with an acetyl group; and The acetyl group is protected by a protecting group R 2 and converting the resulting compound into a compound having the formula: [Effects of the Invention]

[0019] According to the present invention, a method for chemically synthesizing a β(1→5) glucosyl furanoside cyclic dimer and a β(1→5) glucosyl furanoside cyclic dimer that has not been synthesized until now can be provided. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 shows the 1H NMR and difference NOE NMR spectra of compound 12, a β(1→5) glucosyl furanoside cyclic dimer. [Figure 2] FIG. 1 shows the HMBC NMR spectrum of compound 12, a β(1→5) glucosyl furanoside cyclic dimer. [Figure 3] FIG. 1 is an ORTEP diagram of compound 12, a β(1→5) glucosyl furanoside cyclic dimer represented by formula (1). DETAILED DESCRIPTION OF THE INVENTION

[0021] Preferred embodiments of the present invention will be described in detail below. [1]β(1→5) glucosyl furanoside cyclic dimer First, the β(1→5) glucosyl furanoside cyclic dimer of the present invention will be explained.

[0022] The β(1→5) glucosyl furanoside cyclic dimer of the present invention is represented by the following formula (1).

[0023] [ka]

[0024] Another β(1→5) glucosyl furanoside cyclic dimer of the present invention is represented by the following formula (2):

[0025] [ka] (In the formula, R 1represents a bridging group.

[0026] Another β(1→5) glucosyl furanoside cyclic dimer of the present invention is represented by the following formula (3):

[0027] [ka] (In the formula, R 1 represents a bridging group, and R 2 represents a protecting group for a hydroxyl group.

[0028] The β(1→5) glucosyl furanoside cyclic dimers represented by the above formulae (1) to (3) have a cavity in their molecules and have the property of incorporating certain compounds into the cavity (inclusion function).

[0029] In particular, the β(1→5) glucosyl furanoside cyclic dimer of the present invention is a "minimum cyclic oligosaccharide" with a smaller inner cavity diameter (cavity) than conventional cyclic multimers, and based on results from chemical calculations, etc., it is expected that it may have properties different from conventional cyclic multimers, and can suitably encapsulate compounds smaller than those encapsulated by conventional cyclic multimers, such as single atoms, ions, protons, etc.

[0030] This property can be utilized to stabilize volatile substances, stabilize oxidizing substances or photodecomposing substances, and modify physical properties, and is therefore expected to be used in a variety of fields, including food, pharmaceuticals, pesticides, elemental refining, synthetic resins, fibers, and cosmetics.

[0031] The β(1→5) glucosyl furanoside cyclic dimers represented by the above formulas (1) to (3) can be suitably produced, for example, by the method described in detail below.

[0032] In particular, the compound represented by the formula (1) can be obtained by, for example, converting the compound represented by the formula (2) into R 1 from the compound represented by formula (3) 1 and R 2 It can be suitably produced by removing

[0033] The compound represented by the formula (2) can be obtained by, for example, converting the compound represented by the formula (3) into R 2 It can be suitably produced by removing

[0034] [2] Method for producing β(1→5) glucosyl furanoside cyclic dimer Next, the method for producing the β(1→5) glucosyl furanoside cyclic dimer of the present invention will be described.

[0035] The method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention is characterized by comprising a cationic ring-opening polymerization step in which a 1,4-anhydrosugar represented by the following formula (4) is reacted by cationic ring-opening polymerization to obtain a β(1→5) glucosyl furanoside cyclic dimer represented by the following formula (3).

[0036] [ka] (In the formula, R 1 represents a bridging group, and R 2 represents a protecting group for a hydroxyl group.

[0037] [ka] (In the formula, R 1 represents a bridging group, and R 2 represents a protecting group for a hydroxyl group.

[0038] As shown in the above formula (4), in 1,4-anhydrosugars in which the 1st and 4th positions are connected via an ether bond, the distance between the 1st and 4th positions is large, and the ring is distorted to form a Funa-type structure.

[0039] The degree of polymerization of the resulting cyclic oligosaccharides can be controlled by combining cationic ring-opening polymerization of 1,4-anhydrosugars with the softening phenomenon of sugars.

[0040] That is, the bridging group R 1Cationic ring-opening polymerization of 1,4-anhydrosugars containing the oxocarbenium cation intermediate with a flexible furanose ring is generated. The intermediates thus generated react with each other to form dimers. Subsequently, the bridging group R 1 Since the conformation is controlled by the above, an intramolecular reaction proceeds preferentially, resulting in cyclization, enabling the synthesis of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3), which is the precursor of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (1).

[0041] [2-1] 1,4-anhydrosugars The 1,4-anhydrosugar represented by the above formula (4) is a sugar in which the hydroxyl group at the 3-position and the hydroxyl group at the 6-position of D-glucose are linked by a bridging group R 1 The hydroxyl group at the 2nd position is R 2 It has a structure in which the hydroxyl groups at positions 1 and 4 are dehydrated within the molecule.

[0042] Bridging group R 1 may be any divalent substituent, for example, may have a structure in which multiple atoms are bonded only by single bonds, or may contain multiple bonds.

[0043] In particular, R 1 is preferably represented by the following formula (5). -Ar 1 -L-Ar 2 - (5) (In the formula, Ar 1 , Ar 2 each independently represents an aromatic atomic group, and L represents a divalent substituent or a single bond.

[0044] This allows the production of β(1→5) glucosyl furanoside cyclic dimers with a more suitably strained furanose ring due to steric constraints imposed by the substituents.

[0045] When L is a divalent substituent, L may be any divalent substituent, for example, L may have a structure in which multiple atoms are bonded only by single bonds, or may contain multiple bonds.

[0046] L is represented by, for example, ABCD, where A, B, C, and D are each independently CR 6 R 7 , N.R. 8 , oxygen atom, sulfur atom, SO, SO2 or single bond, provided that the number of single bonds does not exceed 3. 6 , R 7 and R 8 are each independently a hydrogen atom or a substituted or unsubstituted lower alkyl group.

[0047] In this specification, a "lower" functional group refers to a functional group containing 1 to 6 carbon atoms.

[0048] For example, a lower alkyl group is an alkyl group having a linear, branched, or cyclic chemical structure and having from 1 to 6 carbon atoms, and more specific examples include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a neo-pentyl group, an n-hexyl group, an iso-hexyl group, a 3-methylpentyl group, and a cyclohexyl group. Among them, R 1 is preferably represented by the following formula (6).

[0049] [ka] (Wherein, p R 4 , q R 5 are each independently a hydrogen atom, a halogen atom, a halo-substituted or unsubstituted lower hydrocarbon group, a lower alkoxy group, a nitro group, or a di(lower alkyl)amino group, and L is a divalent substituent or a single bond. p and q are each independently an integer of 0 to 4. p R4 Among them, adjacent R 4 may be bonded to each other to form a benzene ring, and q R 5 Among them, adjacent R 5 may be bonded to each other to form a benzene ring.

[0050] This allows the production of β(1→5) glucosyl furanoside cyclic dimers with a more suitably strained furanose ring due to steric constraints imposed by the substituents.

[0051] When L is a divalent substituent, L may contain a multiple bond. When L is a divalent substituent, L is represented by, for example, ABCD, where A, B, C, and D are each independently CR 6 R 7 , N.R. 8 , oxygen atom, sulfur atom, SO, SO2 or single bond, provided that the number of single bonds does not exceed 3. 6 , R 7 and R 8 are each independently a hydrogen atom or a substituted or unsubstituted lower alkyl group.

[0052] In this specification, halogen atoms include fluorine atoms, chlorine atoms, bromine atoms and iodine atoms.

[0053] Examples of such lower hydrocarbon groups include various alkyl groups as saturated hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neo-pentyl, n-hexyl, isohexyl, 3-methylpentyl, and cyclohexyl groups, as well as unsaturated hydrocarbon groups in which at least one double bond or triple bond has been introduced into at least a portion of the above-mentioned alkyl groups.

[0054] Halo substitution refers to substitution with a halogen atom. The number of halogen atoms substituted is 1 or more, and the upper limit is the number of hydrogen atoms in the lower alkyl group or lower alkoxy group to be substituted (for example, 3 if the lower alkyl group is a methyl group, or 5 if the lower alkyl group is an ethyl group).

[0055] The lower alkoxy group may be an alkoxy group having from 1 to 6 carbon atoms, and is preferably a straight-chain or branched-chain alkoxy group having from 1 to 4 carbon atoms.

[0056] Examples of such lower alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, neo-pentoxy, n-hexyloxy, iso-hexyloxy, and 3-methylpentoxy.

[0057] Examples of the di(lower alkyl)amino group include a dimethylamino group, a diethylamino group, and a methylethylamino group.

[0058] A substituted lower alkyl group refers to a lower alkyl group having a substituent. Examples of the substituent include a lower alkenyl group, a lower alkoxy group, a lower alkylthio group, a di(lower alkyl)amino group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted arylthio group, and a substituted or unsubstituted arylamino group. The number of substituents is 1 to 3.

[0059] In the above formula (6), p R 4 Among them, adjacent R 4 are bonded to each other to form a benzene ring, for example, p R 4 Two adjacent R 4 are bonded to each other, R 4 is bonded to a benzene ring to form a naphthalene ring.

[0060] In the above formula (6), q R 5 Among them, adjacent R 5 are bonded to each other to form a benzene ring, for example, q R 5 Two adjacent R 5 are bonded to each other, R 5 is bonded to a benzene ring to form a naphthalene ring.

[0061] CR 6 R 7 Examples of NR include CH2, CH(CH3), CH(CH3)2, CH(CH=CH2), C(CH=CH2)2, CH(CH2-CH=CH2), and C(CH2-CH=CH2)2. 8 Examples of such groups include NH, N(CH), N(CH), and N(CHPh), where Ph represents a phenyl group.

[0062] Specific examples of L in the above formula (6) include a single bond, CH2, CH2-CH2, CH2-CH2-CH2, CH(CH2CH3)-CH2, C(CH3)2-CH2, O-CH2, S-CH2, NH-CH2, N(CH3)-CH2, N(C2H5)-CH2, CH2-CH2-CH2, CH2CH2CH2CH2, CH(CH3)-CH2-CH2, C(CH3)2-CH2-CH2, CH(C 2H5)-CH2-CH2, CH2-CH(CH3)-CH2, O-CH2-CH2, CH2-O-CH2, S-CH2-CH2, CH2-S-CH2, NH-CH2-CH2, N(CH3)-CH 2-CH2, N(C2H5)-CH2-CH2, CH2-CH2-CH2-CH2, CH(CH3)-CH2-CH2-CH2, CH(C2H5)-CH2-CH2-CH2, C(CH3)2-CH2 -CH2-CH2, CH2-CH(CH3)-CH2-CH2, O-CH2-CH2-CH2, O-CH(CH3)-CH2-CH2, CH2-O-CH2-CH2, CH(CH3)-O-CH2- CH2, O-CH2-CH2-O, S-CH2-CH2-CH2, CH2-S-CH2-CH2, S-CH2-CH2-S, NH-CH2-CH2-CH2, N(CH3)-CH2-CH2-CH2, Examples include CH2-NH-CH2-CH2, CH(CH3)-NH-CH2-CH2, CH(CH3)-N(CH3)-CH2-CH2, CH2-NH-CH(CH3)-CH2, NH-CH2-CH2-NH, N(CH3)-CH2-CH2-NH, N(CH3)-CH2-CH2-N(CH3), NH-CH(CH3)-CH2-NH, and the like, and among these, a single bond, CH2, and CH2-CH2 are preferred.

[0063] The values ​​of p and q in the above formula (6) are each an integer of 0 or more and 4 or less, preferably an integer of 0 or more and 2 or less, and more preferably 0 or 1.

[0064] R 4 and R 5 are bonded together with the carbon atoms to which they are attached to form a bridging group, the bridging group R 1 Examples of such measures include the following:

[0065] That is, the bridging group R 1 Examples of the bridging group include a bridging group in which L is CH2-CH2 and p and q are both 0, i.e., [1,1'-(ethane-1,2-diyl)dibenzene-2,2'-bis(methylene)]:

[0066] [ka] Examples include:

[0067] In addition, the bridging group R 1 Examples of the bridging group include a bridging group in which L is CH2 and p and q are both 0, i.e., [1,1'-(methane-1,2-diyl)dibenzene-2,2'-bis(methylene)]:

[0068] [ka] Examples include:

[0069] In addition, the bridging group R 1 Examples of the bridging group include a bridging group in which L is a single bond and p and q are both 0, i.e., [2,2'-dimethyl-1,1'-biphenyl]:

[0070] [ka] Examples include:

[0071] Among these, R 1 As the aryl group, [2,2'-dimethyl-1,1'-biphenyl] is preferred.

[0072] R 1By introducing [2,2'-dimethyl-1,1'-biphenyl] as a disaccharide, the conformation of the furanose ring can be controlled to more favorably, such as an envelope or half-chair conformation. This allows for the synthesis of β(1→5) glucosyl furanoside cyclic dimers, which are difficult to produce due to the highly distorted furanose ring, by cationic ring-opening polymerization of 1,4-anhydrosugars.

[0073] Furthermore, this cationic ring-opening polymerization allows for more suitable control of the degree of polymerization of the resulting cyclized product, and allows for the production of β(1→5) glucosyl furanoside cyclic dimers with higher selectivity.

[0074] Hydroxyl protecting group R 2 is any protecting group for a hydroxyl group, and for example, an existing protecting group for a hydroxyl group can be used.

[0075] More specifically, R 2Examples of the alkyl group include an allyl group; a methallyl group; a lower alkyl group which may have, as a substituent, one to five of at least one group selected from the group consisting of a halogen atom, a lower alkoxy group, and an aryloxy group; a phenyl group which may have, as a substituent, one to three of at least one group selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group on the aromatic ring; a benzyl group which may have, as a substituent, one to three of at least one group selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a nitro group on the aromatic ring; and a halogen atom, a lower alkyl group, and a lower alkoxy group as a substituent. a triphenylmethyl group which may have, on the aromatic ring, one to three of at least one group selected from the group consisting of: a formyl group; a lower alkanoyl group (acyl group) which may have, as a substituent, one to five of at least one group selected from the group consisting of a halogen atom, a lower alkoxy group, an aryl group, and an aryloxy group; a benzoyl group which may have, on the aromatic ring, one to three of at least one group selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group; and a silyl group in which three of at least one group selected from the group consisting of a lower alkyl group and an aryl group are substituted on the silicon atom.

[0076] More specifically, R 2 Examples of the alkyl group include an allyl group, a methallyl group, a methyl group, an ethyl group, a tert-butyl group, a methoxymethyl group, a 4-methoxyphenyl group, a benzyl group, a dimethylbenzyl group, a 4-methoxybenzyl group, a 2-nitrobenzyl group, a triphenylmethyl group, a formyl group, an acetyl group, a propionyl group, a tert-butylcarbonyl group, a benzoyl group, a tri-lower alkylsilyl group, and a tert-butyldiphenylsilyl group.

[0077] Among them, R 2is preferably an allyl group, an acetyl group, a propionyl group, a benzyl group, a dimethylbenzyl group, a benzyloxymethyl group, a 4-methoxybenzyl group, or a tri-lower alkylsilyl group, more preferably an allyl group, an acetyl group, a benzyl group, or a benzyloxymethyl group, and even more preferably an allyl group.

[0078] This allows for a higher yield of the target product. In particular, the allyl group has low steric hindrance in the cyclization reaction and is less affected by neighboring group participation, so the yield of the target product can be further increased.

[0079] [2-2] Cationic ring-opening polymerization process In this step, the 1,4-anhydrosugar represented by the above formula (4) is subjected to cationic ring-opening polymerization to obtain the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3).

[0080] This step is carried out, for example, by stirring the 1,4-anhydrosugar represented by the above formula (4) in a solvent in the presence of an activator.

[0081] Examples of the solvent include alcohol solvents such as methanol and ethanol; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and o-dichlorobenzene; ether solvents such as diethyl ether and tetrahydrofuran (THF); aromatic solvents such as benzene, toluene, and trifluoromethyltoluene (benzotrifluoride); and aprotic polar solvents such as N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). One or more solvents selected from these may be used in combination.

[0082] Among these, dichloromethane, 1,2-dichloroethane, and a mixed solvent of diethyl ether and an aromatic solvent such as benzene or toluene are preferred, and 1,2-dichloroethane is more preferred.

[0083] The solvent used in this step is preferably an anhydrous solvent. In this specification, an anhydrous solvent refers to a solvent having a water content of 200 ppm or less, and the water content in the anhydrous solvent is preferably 100 ppm or less, more preferably 50 ppm or less, and even more preferably 30 ppm or less.

[0084] The concentration of the 1,4-anhydrosugar represented by the above formula (4) in the solution used in the reaction in this step is preferably 0.01 M or more and 0.5 M or less, more preferably 0.03 M or more and 0.3 M or less, and even more preferably 0.05 M or more and 0.1 M or less.

[0085] If the concentration of the 1,4-anhydrosugar represented by the above formula (4) is less than the lower limit, the substrate is less susceptible to the action of the activator, and the reaction does not proceed smoothly. On the other hand, if the concentration of the 1,4-anhydrosugar represented by the above formula (4) exceeds the upper limit, contact with the activator and water in the system increases, increasing reactivity and causing side reactions such as hydrolysis, which tends to significantly reduce the yield of the target product.

[0086] By setting the concentration of the 1,4-anhydrosugar represented by the above formula (4) to a value within the above range, the target reaction can be smoothly carried out while suppressing side reactions, thereby further increasing the yield of the target product.

[0087] In this step, it is preferable to use an activator. This can increase the yield of the desired β(1→5) glucosyl furanoside cyclic dimer.

[0088] Examples of the activating agent include silyl-based activating agents such as tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), trimethylsilyl trifluoromethanesulfonate (TMSOTf), triethylsilyl trifluoromethanesulfonate (TESOTf), and triisopropylsilyl trifluoromethanesulfonate (TIPSOTf); trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, diphenyl sulfoxide, tri-tert-butylphosphine, sulfuryl chloride, silver tetrafluoroborate (I), silver nitrate (I), N-iodosuccinimide, 1-fluoropyridinium trifluoromethanesulfonate, [bis( trifluoroacetoxy)iodo]benzene, boron trifluoride diethyl ether complex, aluminum chloride, diethylaluminum chloride, indium bromide (III), antimony chloride (V), phosphorus pentachloride, tin (IV) chloride, triphenylmethylium tetrakis(pentafluorophenyl)borate, tritylium tetrafluoroborate, 4-fluorophenylboronic acid, aluminum isopropoxide, scandium trifluoromethanesulfonate (III), silver trifluoromethanesulfonate (I), ytterbium trifluoromethanesulfonate (III), and the like can be used alone or in combination of two or more selected from these.

[0089] Among these activators, it is preferable to use a silyl-based activator, more preferably to use at least one selected from the group consisting of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), trimethylsilyl trifluoromethanesulfonate (TMSOTf), triethylsilyl trifluoromethanesulfonate (TESOTf), and triisopropylsilyl trifluoromethanesulfonate (TIPSOTf), and even more preferably to use tert-butyldimethylsilyl trifluoromethanesulfonate.

[0090] This makes it possible to further increase the yield of the desired β(1→5) glucosyl furanoside cyclic dimer.

[0091] The amount of activator used is preferably 2 to 10 moles, more preferably 2.5 to 8 moles, and even more preferably 3 to 5 moles, per mole of the 1,4-anhydrosugar represented by the above formula (4).

[0092] If the amount of activator used is less than the lower limit, the reaction will not proceed smoothly, whereas if the amount of activator used exceeds the upper limit, side reactions will be more likely to occur, resulting in a significant decrease in the yield of the target product.

[0093] By setting the amount of the activator used to a value within the above range, the target reaction can be favorably progressed while suppressing side reactions, and the yield of the target product can be further increased.

[0094] In this step, it is preferable to add an activator to a solution of the raw material compounds at a relatively low temperature, and then raise the temperature. This allows the reaction to proceed more smoothly, and the yield of the target product can be increased.

[0095] The temperature of the solution of the raw material compound when the activator is added is preferably -30°C or higher and 0°C or lower, more preferably -25°C or higher and -5°C or lower, and even more preferably -20°C or higher and -10°C or lower.

[0096] This allows the desired reaction to proceed favorably while suppressing side reactions, thereby increasing the yield of the desired product.

[0097] The temperature of the solution of the raw material compounds after adding the activator and heating is preferably 10°C or higher and 40°C or lower, more preferably 15°C or higher and 35°C or lower, and even more preferably 20°C or higher and 30°C or lower.

[0098] This allows the target reaction to proceed more favorably while suppressing side reactions, thereby increasing the yield of the target product.

[0099] The reaction time in this step is preferably from 1 hour to 30 hours, more preferably from 5 hours to 25 hours, and even more preferably from 10 hours to 20 hours.

[0100] This allows the target reaction to proceed sufficiently, making it possible to further increase the yield of the target product and further improve the productivity of the target product.

[0101] This step is preferably carried out in the presence of molecular sieves in the reaction system. This can further increase the yield of the desired product.

[0102] Such molecular sieves include, for example, molecular sieve 4A.

[0103] This allows the synthesis of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3).

[0104] The β(1→5) glucosyl furanoside cyclic dimer obtained by the above reaction may be separated from the reaction mixture and purified.

[0105] Such separation and purification can be suitably carried out by, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel permeation chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, or the like.

[0106] [2-3]R 2 Removal process In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, after the cationic ring-opening polymerization step, a protecting group R of the hydroxyl group is removed from the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3). 2 Remove R 2 A removal step may be further included.

[0107] As a result, the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (2) can be obtained.

[0108] R 2 The deprotection of can be carried out, for example, by stirring the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3) in a solvent in the presence of a palladium catalyst.

[0109] Examples of the solvent include alcoholic solvents such as methanol and ethanol; halogenated hydrocarbon solvents such as dichloromethane, chloroform, and carbon tetrachloride; acidic solvents such as formic acid and acetic acid; and ionic liquids. One or more selected from these may be used in combination.

[0110] Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium on carbon, palladium chloride, and the like, and one or more selected from these can be used in combination.

[0111] The amount of the palladium catalyst used is preferably 0.01 to 5 moles, more preferably 0.05 to 2 moles, per mole of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3).

[0112] This allows the desired reaction to proceed more efficiently while suppressing side reactions, and is also advantageous in terms of cost since the amount of palladium catalyst used can be reduced.

[0113] The reaction involves the removal of R 2 To capture R, such as 1,3-dimethylbarbituric acid 2 It is preferred to add a scavenger.

[0114] R 2The amount of the scavenger used is preferably 3 to 12 moles, more preferably 4 to 10 moles, per mole of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3).

[0115] This allows the desired reaction to proceed more efficiently while suppressing side reactions, and also allows post-reaction purification and other procedures to be carried out more efficiently.

[0116] The reaction temperature in this step is preferably 20°C or higher and 50°C or lower, more preferably 25°C or higher and 45°C or lower, and even more preferably 30°C or higher and 40°C or lower.

[0117] This allows the desired reaction to proceed favorably while suppressing side reactions, thereby increasing the yield of the desired product.

[0118] The reaction time in this step is preferably 1 hour or more and 5 hours or less, more preferably 1.5 hours or more and 4.5 hours or less, and even more preferably 2 hours or more and 4 hours or less.

[0119] This allows the target reaction to proceed sufficiently, making it possible to further increase the yield of the target product and further improve the productivity of the target product.

[0120] Also, R 2 When R is a substituent having a multiple bond such as an allyl group, 2 For the removal of the above, a two-step method of converting the compound into a vinyl ether accompanied by migration of the double bond and then removing the vinyl ether can be employed.

[0121] Also, R 2 The deprotection of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3) can be carried out by hydrogenolysis in the presence of a hydrogenation catalyst to remove R 2 This can be done by removing

[0122] This step is carried out, for example, by stirring the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3) in the presence of hydrogen in a solvent and in the presence of a hydrogenation catalyst.

[0123] Examples of the solvent include ether solvents such as diethyl ether and tetrahydrofuran; alcohol solvents such as methanol and ethanol; and acidic solvents such as formic acid and acetic acid. One or more selected from these can be used in combination.

[0124] Examples of the hydrogenation catalyst include palladium catalysts such as palladium(II) hydroxide / carbon (Pd(OH) / C) and palladium / carbon (Pd / C), and hydrogen-supporting metal catalysts such as Raney nickel, and one or more selected from these may be used in combination.

[0125] The amount of hydrogenation catalyst used is preferably 0.01 moles or more and 5 moles or less, more preferably 0.05 moles or more and 2 moles or less, per mole of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3).

[0126] This allows the desired reaction to proceed favorably while suppressing side reactions, thereby increasing the yield of the desired product.

[0127] The reaction temperature in this step is preferably 10°C or higher and 40°C or lower, more preferably 15°C or higher and 35°C or lower, and even more preferably 20°C or higher and 30°C or lower.

[0128] This allows the desired reaction to proceed favorably while suppressing side reactions, thereby increasing the yield of the desired product.

[0129] The reaction time in this step is preferably 3 hours or more and 30 hours or less, more preferably 5 hours or more and 25 hours or less, and even more preferably 10 hours or more and 20 hours or less.

[0130] This allows the target reaction to proceed more favorably while suppressing side reactions, thereby increasing the yield of the target product.

[0131] In addition, this step can also use hydrazine or a derivative thereof as a hydrogen source. Furthermore, in addition to using hydrogenation, the step can also be carried out using a method using an alkali metal or alkaline earth metal such as lithium, sodium, or calcium in a protic solvent such as ethanol or ammonia, or a method of oxidative removal using various reactants, electrolytic reactions, etc.

[0132] By the above reaction, the protecting group R 2 is removed, and the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (2) can be synthesized.

[0133] The β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (2) obtained by the above reaction may be separated and purified from the reaction mixture.

[0134] Such separation and purification can be suitably carried out by, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel permeation chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, or the like.

[0135] [2-4]R 1 Removal process In the method for producing a β(1→5) glucosyl furanoside cyclic dimer of the present invention, the R 1 Remove R 1 A removal step may be further included.

[0136] This allows for the favorable synthesis of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (1).

[0137] In particular, R 1The removal step may be carried out on the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (3). In the following explanation, however, 2 A representative example will be described below in which the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (2) obtained in the removal step is subjected to this process.

[0138] Bridging group R 1 The removal of the bridging group R can be achieved, for example, by using a hydrogenation catalyst. 1 This can be suitably carried out by hydrogenolysis of the above.

[0139] Hydrogenolysis of the bridging group R 1 The removal of R 2 This can be done by the same method as explained for deprotection of the compound (1).

[0140] This step is carried out, for example, by stirring the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (2) in the presence of hydrogen in a solvent and in the presence of a hydrogenation catalyst.

[0141] Examples of the solvent include ether solvents such as diethyl ether and tetrahydrofuran; alcohol solvents such as methanol and ethanol; and acidic solvents such as formic acid and acetic acid. One or more selected from these can be used in combination.

[0142] Examples of the hydrogenation catalyst include palladium catalysts such as palladium(II) hydroxide / carbon (Pd(OH) / C) and palladium / carbon (Pd / C), and hydrogen-supporting metal catalysts such as Raney nickel, and one or more selected from these may be used in combination.

[0143] The amount of hydrogenation catalyst used is preferably 0.01 to 5 moles, more preferably 0.05 to 2 moles, per mole of the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (2).

[0144] This allows the desired reaction to proceed favorably while suppressing side reactions, thereby increasing the yield of the desired product.

[0145] The reaction temperature in this step is preferably 10°C or higher and 40°C or lower, more preferably 15°C or higher and 35°C or lower, and even more preferably 20°C or higher and 30°C or lower.

[0146] This allows the desired reaction to proceed favorably while suppressing side reactions, thereby increasing the yield of the desired product.

[0147] The reaction time in this step is preferably 3 hours or more and 30 hours or less, more preferably 5 hours or more and 25 hours or less, and even more preferably 10 hours or more and 20 hours or less.

[0148] This allows the target reaction to proceed more favorably while suppressing side reactions, thereby increasing the yield of the target product.

[0149] In addition, this step can also use hydrazine or a derivative thereof as a hydrogen source. Furthermore, in addition to using hydrogenation, the step can also be carried out using a method using an alkali metal or alkaline earth metal such as lithium, sodium, or calcium in a protic solvent such as ethanol or ammonia, or a method of oxidative removal using various reactants, electrolytic reactions, etc.

[0150] By the above reaction, the protecting group R 2 is removed, and the β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (1) can be synthesized.

[0151] The β(1→5) glucosyl furanoside cyclic dimer represented by the above formula (1) obtained by the above reaction may be separated and purified from the reaction mixture.

[0152] Such separation and purification can be suitably carried out by, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel permeation chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, or the like.

[0153] The above-mentioned production method has made it possible for the first time to synthesize the β(1→5) glucosyl furanoside cyclic dimer, which had not been possible to synthesize before.

[0154] [3] Manufacturing method for 1,4-anhydrosugar Next, a method for producing the 1,4-anhydrosugar represented by the above formula (4) will be described.

[0155] The 1,4-anhydrosugar represented by the above formula (4) can be prepared by converting the hydroxyl groups at the 3 and 6 positions of the 1,2,4-orthoester to the R 1 Crosslinking with R 1 a crosslinking step, a 1,4-anhydrosugar structure formation step in which a 1,4-anhydrosugar structure is formed using an activator and the 2-position is protected with an acetyl group, and a 1,4-anhydrosugar structure formation step in which the acetyl group is protected with a protecting group R 2 Convert to R 2 It can be produced by a method including an introduction step.

[0156] By using such a method, the 1,4-anhydrosugar represented by the above formula (4) can be produced with excellent productivity and high yield.

[0157] [3-1]R 1 Crosslinking process R 1 In the crosslinking step, as shown in the following reaction formula, the hydroxyl groups at the 3 and 6 positions of the 1,2,4-orthoester of D-glucose are converted to the R 1 Crosslinking is carried out with

[0158] [ka]

[0159] This step may involve, for example, reacting a 1,2,4-orthoester with a substituent R 1 The reaction is carried out by stirring with a compound having the formula:

[0160] Examples of the solvent include alcohol solvents such as methanol and ethanol; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and o-dichlorobenzene; ether solvents such as diethyl ether and tetrahydrofuran (THF); aromatic solvents such as benzene, toluene, and trifluoromethyltoluene (benzotrifluoride); and aprotic polar solvents such as N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). One or more solvents selected from these may be used in combination. The solvent used in this step is preferably an anhydrous solvent.

[0161] Substituent R 1 Examples of compounds having the formula include R 1 and halides such as bromides of the above.

[0162] Substituent R 1 The amount of the compound having the formula (I) used is, for example, preferably 0.01 moles or more and 10 moles or less, and more preferably 0.05 moles or more and 5 moles or less, relative to 1 mole of the 1,2,4-orthoester of D-glucose.

[0163] Examples of strong bases include sodium hydride and sodium methoxide, and one or more selected from these may be used in combination.

[0164] The amount of the strong base used is, for example, preferably 0.01 to 20 moles, more preferably 0.1 to 15 moles, and even more preferably 5 to 10 moles, relative to 1 mole of the 1,2,4-orthoester of D-glucose.

[0165] The temperature of the solution of the raw material compounds when the strong base is added is preferably -30°C or higher and 10°C or lower, more preferably -20°C or higher and 5°C or lower, and even more preferably -10°C or higher and 0°C or lower. After the strong base is added, the solution of the raw material compounds is preferably heated and refluxed.

[0166] The reaction time in this step is preferably from 10 minutes to 20 hours, more preferably from 30 minutes to 15 hours, and even more preferably from 1 hour to 10 hours.

[0167] By the above reaction, the hydroxyl groups at the 3 and 6 positions of the 1,2,4-orthoester are converted to R 1 It is possible to synthesize compounds crosslinked with

[0168] The compound obtained by the above reaction may be separated from the reaction mixture and purified. Such separation and purification can be suitably carried out by, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel permeation chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, or the like.

[0169] [3-2]1,4-Anhydrosaccharide structure formation step In the 1,4-anhydrosugar structure formation step, an activating agent is used to form a 1,4-anhydrosugar structure, and the 2-position is protected with an acetyl group, thereby obtaining an acetyl-protected product having a 1,4-anhydrosugar structure, i.e., a compound having a structure represented by the following formula (11).

[0170] [ka]

[0171] This step can be carried out, for example, by reacting R 1 R of the 1,2,4-orthoester of D-glucose obtained in the cross-linking step 1This is carried out by stirring the crosslinked product and the activator.

[0172] Examples of the solvent include alcohol solvents such as methanol and ethanol; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and o-dichlorobenzene; ether solvents such as diethyl ether and tetrahydrofuran (THF); aromatic solvents such as benzene, toluene, and trifluoromethyltoluene (benzotrifluoride); and aprotic polar solvents such as N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). One or more solvents selected from these may be used in combination.

[0173] Examples of the activating agent include silyl-based activating agents such as tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), trimethylsilyl trifluoromethanesulfonate (TMSOTf), triethylsilyl trifluoromethanesulfonate (TESOTf), and triisopropylsilyl trifluoromethanesulfonate (TIPSOTf); trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, diphenyl sulfoxide, tri-tert-butylphosphine, sulfuryl chloride, silver tetrafluoroborate (I), silver nitrate (I), N-iodosuccinimide, 1-fluoropyridinium trifluoromethanesulfonate, [bis( trifluoroacetoxy)iodo]benzene, boron trifluoride diethyl ether complex, aluminum chloride, diethylaluminum chloride, indium bromide (III), antimony chloride (V), phosphorus pentachloride, tin (IV) chloride, triphenylmethylium tetrakis(pentafluorophenyl)borate, tritylium tetrafluoroborate, 4-fluorophenylboronic acid, aluminum isopropoxide, scandium trifluoromethanesulfonate (III), silver trifluoromethanesulfonate (I), ytterbium trifluoromethanesulfonate (III), and the like can be used alone or in combination of two or more selected from these.

[0174] Among these activators, it is preferable to use a silyl-based activator, more preferably to use at least one selected from the group consisting of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), trimethylsilyl trifluoromethanesulfonate (TMSOTf), triethylsilyl trifluoromethanesulfonate (TESOTf), and triisopropylsilyl trifluoromethanesulfonate (TIPSOTf), and even more preferably to use tert-butyldimethylsilyl trifluoromethanesulfonate.

[0175] This makes it possible to further increase the yield of the acetyl-protected compound having a 1,4-anhydrosugar structure.

[0176] The amount of activator used is determined by the R 1 The amount is preferably 1.2 mol or more and 10 mol or less, and more preferably 1.5 mol or more and 5.0 mol or less, per mol of the crosslinked product.

[0177] If the amount of activator used is less than the lower limit, the reaction will not proceed smoothly, whereas if the amount of activator used exceeds the upper limit, side reactions will be more likely to occur, resulting in a significant decrease in the yield of the target product.

[0178] By setting the amount of the activator used to a value within the above range, the target reaction can be favorably progressed while suppressing side reactions, and the yield of the target product can be further increased.

[0179] The reaction time in this step is preferably from 10 minutes to 40 hours, more preferably from 0.5 hours to 24 hours.

[0180] The above reaction allows the synthesis of an acetyl-protected 1,4-anhydrosugar structure. In particular, the R 1 From the crosslinked product, an acetyl-protected product having a 1,4-anhydrosugar structure can be synthesized in one pot.

[0181] The acetyl-protected compound having a 1,4-anhydrosugar structure obtained by the above reaction may be separated from the reaction mixture and purified.

[0182] Such separation and purification can be suitably carried out by, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel permeation chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, or the like.

[0183] [3-3]R 2 Introduction process R 2 In the introduction step, the acetyl group of the acetyl-protected compound having a 1,4-anhydrosugar structure is converted into a protecting group R 2 Convert to.

[0184] In this step, multiple treatments may be carried out. For example, a process for removing the acetyl group of an acetyl-protected product having a 1,4-anhydrosugar structure and then converting the hydroxyl group at the 2-position from which the acetyl group has been removed to R 2 The process of protecting the image may be performed.

[0185] The treatment to remove the acetyl group from an acetyl-protected compound having a 1,4-anhydrosugar structure may be carried out under any conditions as long as the acetyl group at the 2-position can be selectively removed. For example, the treatment can be suitably carried out by reacting the compound with a metal alkoxide such as sodium methoxide in an alcoholic solvent such as methanol, followed by hydrolysis.

[0186] The amount of metal alkoxide used is preferably 1.2 to 10 moles, more preferably 1.5 to 5.0 moles, per mole of the acetyl-protected compound having a 1,4-anhydrosugar structure.

[0187] The above reaction yields a 1,4-anhydrosugar in which the hydroxyl group at the 2-position is not protected, that is, a compound having a structure represented by the following formula (12).

[0188] [ka]

[0189] The compound obtained by the above reaction may be separated from the reaction mixture and purified. Such separation and purification can be suitably carried out by, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel permeation chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, or the like.

[0190] The hydroxyl group at the 2nd position after the acetyl group is removed is R 2 The protection treatment with may be carried out under any conditions. For example, a 1,4-anhydrosugar in which the hydroxyl group at the 2-position is not protected and a substituent R 2 The reaction is carried out by stirring with a compound having the formula:

[0191] Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and o-dichlorobenzene; ether solvents such as diethyl ether and tetrahydrofuran (THF); aromatic solvents such as benzene, toluene, and trifluoromethyltoluene (benzotrifluoride); and aprotic polar solvents such as N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). One or more solvents selected from these may be used in combination. The solvent used in this step is preferably an anhydrous solvent.

[0192] Substituent R 2 Examples of compounds having the formula include R 2 and halides such as bromides of the above.

[0193] Substituent R 2The amount of the compound having the formula (I) used is, for example, preferably 1.01 mol or more and 2.00 mol or less, and more preferably 1.05 mol or more and 1.50 mol or less, relative to 1.00 mol of the 1,4-anhydrosugar in which the hydroxyl group at the 2-position is not protected.

[0194] Examples of strong bases include sodium hydride and sodium methoxide, and one or more selected from these may be used in combination.

[0195] The amount of the strong base used is, for example, preferably 1.01 mol or more and 2.50 mol or less, and more preferably 1.05 mol or more and 2.00 mol or less, per 1.00 mol of 1,4-anhydrosugar in which the hydroxyl group at the 2-position is not protected.

[0196] By the above reaction, the hydroxyl group at the 2-position becomes R 2 A 1,4-anhydrosugar protected by the formula (13) is obtained.

[0197] [ka]

[0198] The compound obtained by the above reaction may be separated from the reaction mixture and purified. Such separation and purification can be suitably carried out by, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel permeation chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, or the like.

[0199] Although the preferred embodiments of the present invention have been described above, the present invention is not limited to these.

[0200] For example, the β(1→5) glucosyl furanoside cyclic dimer of the present invention may be any dimer having a specific chemical structure, and is not limited to those produced by the methods described above.

[0201] Furthermore, the method for producing the β(1→5) glucosyl furanoside cyclic dimer may include steps other than the steps described above (for example, a pre-treatment step, an intermediate treatment step, a post-treatment step, etc.). [Example]

[0202] The present invention will be described in detail below based on specific synthesis examples, but the present invention is not limited to these.

[0203] [4] General conditions for synthesis and measurement In the following description, all commercially available reagents were used as received unless otherwise specified. 1,3-Dimethylbarbituric acid was purified by recrystallization from carbon tetrachloride and chloroform immediately before the reaction.

[0204] All moisture- and air-sensitive reactions were performed using glassware equipped with rubber septa (or septa) under positive argon or nitrogen pressure. When necessary, glassware was dried under reduced pressure by heating with a heat gun to evaporate solvents before use. When necessary, substrates were azeotropically dried by evaporating acetonitrile or toluene solutions several times to remove any traces of water that may have been present in the substrate.

[0205] Molecular sieves (MS) were heated with a heat gun and dried under reduced pressure before use. The reaction mixture was stirred magnetically and concentrated under reduced pressure.

[0206] The reaction was monitored by thin layer chromatography (TLC) and mass spectrometry (MS). After extraction, the organic layer was dried using anhydrous magnesium sulfate and removed by filtration through a cotton pad. The filtrate was concentrated and subjected to further purification procedures as needed. This series of procedures is referred to as "General Method Drying" in the following synthetic examples.

[0207] Thin-layer chromatography (TLC) was performed using Merck precoated silica gel 60 F-254 plates, ChemScene HPTLC silica gel 60GF254 plates, Merck RP-19 F-254 plates, or HPTLC silica gel 60F-254 plates.

[0208] Preparative thin-layer chromatography (PTLC) was performed using Merck PLC Silica Gel 60 F-254 plates (0.5 mm) or ChemScene PLC Silica Gel 60 GF254 (0.5 mm). Spots were visualized by exposure to UV light or by immersion in 2% anisaldehyde, 5% H2SO4 in ethanol, or 10% phosphomolybdic acid in ethanol, followed by heating at 200 °C for approximately 1 h.

[0209] Column chromatography was performed using Merck "Silica Gel 60" (63 μm-200 μm or 40 μm-63 μm) or Kanto Chemical "Silica Gel 60 N" (spherical, neutral, 40 μm-50 μm or 63 μm-210 μm) as the normal phase. Other carrier materials are described on an individual basis.

[0210] Automated flash column chromatography was performed using a Biotage Isolera® Prime.

[0211] Gel permeation chromatography (GPC) was performed using a Japan Analytical Industry Co., Ltd. (JAI) "LC-9260IINEXT / RI-700NEXT" column, "JAIGEL-1H-40" or "JAIGEL-2H-40," and chloroform (CHCl3) as the eluent.

[0212] Melting points were determined using a Mettler-Toledo FP90 as the central processor and a Mettler-Toledo FP81HT as the detector and are uncorrected.

[0213] The optical rotation was measured using a JASCO P-2100 polarimeter equipped with a 100 mm cell, transmitting a 589 nm halogen ray.

[0214] IR spectra were recorded on a JASCO FT / IR-4100 equipped with an attenuated total reflectance (ATR) sampling unit, and all major absorption bands were expressed in wavenumbers (cm -1 ) is shown.

[0215] High-resolution (HR) mass spectra were obtained using a JEOL JMS-T100LC or JMS-T100LP spectrometer for electrospray ionization (ESI). Data are presented in units of charged mass.

[0216] Nuclear magnetic resonance (NMR) spectra were measured using a JEOL JNM-ECX-400 / JNM-ECZ-400S / L1 ( 1 For H, 400MHz, 13 C, 101MHz), "JNM-ECX-500II" ( 1 For H, 500MHz, 13 C, 126MHz) or "JNM-ECZ-600R / S1" ( 1 For H, 600MHz, 13 For C, the data were acquired using a 151 MHz frequency. Either TMS (tetramethylsilane) or the residual proton of the deuterated solvent was used as the internal reference for each solvent indicated in parentheses. When deuterated water was used as the deuterated solvent, acetone was used as the internal reference.

[0217] 1 H NMR spectroscopic data are given as chemical shifts (δ), followed by multiplicity, coupling constants, integrals, and parenthetical assignments, in that order. Multiplicities are abbreviated as follows: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, and br: broad.

[0218] 13 C NMR spectroscopic data are given as chemical shifts (δ) with hydrogen multiplicities obtained from DEPT spectra and assignments in parentheses. Multiplicities are abbreviated as s:C, d:CH, t:CH, and q:CH. When multiple carbon atoms are present, the number is added in parentheses.

[0219] X-ray crystal structure analysis was carried out by measurement using "Saturn724 / Mo-V" manufactured by RIGAKU Corporation.

[0220] [5] Glycosylation Reaction Using DB-Group-Linked Linear Disaccharides [5-1] Determination of axial chirality of orthoesters incorporating DB groups (Synthesis Example 1) First, as shown in the following formula (9), DB groups were introduced into the 3- and 6-positions of the pyranose ring of compound 41.

[0221] [ka]

[0222] In this specification, the term "DB group" refers to a 2,2'-di(methyl)-1,1'-biphenyl group.

[0223] Synthesis of O-orthoacetyl-3,6-O-1,1'-dibenzene-2,2'-bis(methylene)-α-D-glucopyranose (compound 42) To a solution of compound 41 (1.00 g, 2.14 mmol) and sodium hydride (784 mg 60% in mineral oil, 471 mg as sodium hydride, 19.6 mmol) in tetrahydrofuran (490 mL), a solution of 1,1'-dibenzene-2,2'-bis(methylene)dibromide (1.83 g, 5.39 mmol) in tetrahydrofuran (270 mL) was added dropwise over 6.5 hours (72 mL / h) using a syringe pump under reflux. After the addition was complete, the mixture was stirred at the same temperature for an additional 30 minutes. The reaction was quenched at 0 °C by the addition of water (50 mL).

[0224] After removing tetrahydrofuran by evaporation, the aqueous mixture was extracted with diethyl ether (20 mL × 3). The combined organic layers were washed successively with water (30 mL × 2) and brine (30 mL). The crude product was obtained by drying in a conventional manner. The crude product was purified by column chromatography (silica gel 100 g, hexane / ethyl acetate = 9 / 1 to 6 / 1) to give (R)-Compound 42 (1.00 g, 2.63 mmol, 54% yield) as a white amorphous solid, and (S)-Compound 42 (602 mg, 1.57 mmol, 32% yield) as a white amorphous solid.

[0225] Data for (S)-compound 42: [α] 589 24 -144 (c 1.1, CHCl3). IR (ATR) 3015, 2863, 1475, 1405, 1308, 1193, 1092, 1058, 1002, 901, 851, 752, 668 cm -1 . 1 H NMR (400 MHz, acetone-d6, 19.7 ℃) δ 7.69 (m, 1H, DB), 7.48-7.34 (m, 6H, DB), 7.21 (m, 1H, DB), 5.59 (d, J = 4.9 Hz, 1H, H-1), 5.28 (d, J = 12.9 Hz, 1H, DB), 5.09 (d, J = 12.1 Hz, 1H, DB), 4.36 (ddd, J = 4.9, 2.0, 2.0 Hz, 1H, H-2), 4.33 (d, J = 12.1 Hz, 1H, DB), 4.24 (d, J = 12.9 Hz, 1H, DB), 4.22 (ddd, J = 10.5, 7.1, 1.2 Hz, 1H, H-5), 4.05 (ddd, J = 4.6, 2.0, 1.2 Hz, 1H, H-3), 3.42 (dd, J = 10.5, 7.9 Hz, 1H, H-6), 3.29 (dd, J = 4.6, 2.0 Hz, 1H, H-4), 3.19 (dd, J = 7.9, 7.1 Hz, 1H, H-6), 1.44 (s, 3H, Me).13 C NMR (101 MHz, acetone-d6, 18.6 ℃) δ 143.7 (s, 1C, DB), 140.9 (s, 1C, DB), 136.8 (s, 1C, DB), 135.1 (s, 1C, DB), 133.1 (d, 1C, DB), 132.1 (d, 1C, DB), 131.8 (d, 1C, DB), 130.3 (d, 1C, DB), 129.8 (d, 1C, DB), 129.0 (d, 1C, DB), 128.2 (d, 1C, DB), 128.0 (d, 1C, DB), 119.1 (s, 1C, orthoester), 98.4 (d, 1C, C-1), 75.5 (d, 1C, C-5), 75.1 (d, 1C, C-2), 72.3 (t, 1C, DB), 72.2 (t, 1C, DB), 71.8 (d, 1C, C-3), 71.0 (d, 1C, C-4), 67.1 (t, 1C, C-6), 20.6 (q, 1C, Me). HRMS (ESI) m / z [M + Na] + calcd for C 22 H 22 O6Na 405.1309, found 405.1311.

[0226] When DB groups were crosslinked at the 3 and 6 positions of the known 1,2,4-orthoacetylglucose, compound 41, two compounds, (R)-compound 42 and (S)-compound 42, were isolated.

[0227] [6] One-pot synthesis of compound 68 from (R)-compound 42 In order to synthesize compound 68 from (R)-compound 42 in one pot, the following investigations were carried out.

[0228] [ka]

[0229] (Synthesis Example 2-1) To a stirred mixture of MS4A (157 mg) and (R)-compound 42 (21.6 mg, 56.5 μmol) in dichloromethane (1 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (39.6 mg, 150 μmol). After stirring at −15° C. for 40 min, the reaction was quenched by the addition of 2 M ammonia in methanol (1 mL).

[0230] The mixture was filtered through a cotton Celite pad to remove MS4A. The pad was washed with dichloromethane. The crude product was purified by column chromatography (silica gel 2 g, toluene / diethyl ether = 6 / 1 to 0 / 1) to give compound 68 (11.9 mg, 31.1 μmol, 55% yield) as a colorless amorphous solid.

[0231] (Synthesis Example 2-2) To a stirred mixture of MS4A (155 mg) and (R)-compound 42 (19.4 mg, 51.0 μmol) in dichloromethane (1 mL) was added trimethylsilyl trifluoromethanesulfonate (33.3 mg, 150 μmol). After stirring at −40° C. for 50 min, the reaction was quenched by the addition of methanol (1 mL) and saturated aqueous sodium bicarbonate (1 mL).

[0232] The mixture was filtered through a cotton Celite pad to remove MS4A. The pad was washed with diethyl ether. The aqueous filtrate was extracted with diethyl ether (3 mL × 3). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate (5 mL), water (5 mL), and brine (5 mL). The crude product was dried by a conventional method. The crude product was purified by column chromatography (silica gel 1 g, toluene / diethyl ether = 6 / 1) to give compound 68 as a colorless amorphous solid (6.7 mg, 17.5 μmol, 35% yield) and (R)-compound 42 (2.0 mg, 5.2 μmol, 10% yield) as a colorless amorphous solid.

[0233] (Synthesis Example 2-3) To a stirred mixture of MS4A (152 mg) and (R)-compound 42 (19.8 mg, 51.8 μmol) in dichloromethane (1 mL) was added boron trifluoride diethyl etherate (3.5 mg, 25 μmol) at −40° C. After stirring for 1 h, the mixture was warmed to −20° C. After stirring for 3.5 h, the mixture was warmed to 0° C. After stirring for 1.5 h, the mixture was warmed to 25° C. After stirring for 17 h, the mixture was warmed to reflux. After stirring for 2 h, an additional amount of boron trifluoride diethyl etherate (7.3 mg, 52 μmol) was added to the mixture at −40° C. After stirring for 1.5 h, the reaction was quenched by adding methanol (1 mL) and saturated aqueous sodium bicarbonate solution (1 mL).

[0234] The mixture was filtered through a cotton Celite pad to remove MS4A. The pad was washed with diethyl ether. The aqueous filtrate was extracted with diethyl ether (3 mL × 3). The combined organic layer was washed successively with saturated aqueous sodium bicarbonate (5 mL), water (5 mL), and brine (5 mL). The crude product was obtained by drying in a conventional manner. The crude product was purified by column chromatography (silica gel 1 g, hexane / ethyl acetate = 6 / 1 to 1 / 1) to obtain compound 68 (8.2 mg, 22 μmol, 41% yield) as a colorless amorphous solid. These results are shown in Table 1.

[0235] [Table 1]

[0236] The abbreviations for the compounds in the table are as follows: TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate TMSOTf: Trimethylsilyl trifluoromethanesulfonate BF3·OEt2: Boron trifluoride diethyl ether complex

[0237] When tert-butyldimethylsilyl trifluoromethanesulfonate was used as an activating agent, compound 68 was obtained in a 55% yield (Synthesis Example 2-1). When trimethylsilyl trifluoromethanesulfonate was used, compound 68 was obtained in a 35% yield, and the starting material (R)-compound 42 was recovered in a 10% yield (Synthesis Example 2-2). When boron trifluoride diethyl ether complex was used, compound 68 was obtained in a 41% yield (Synthesis Example 2-3).

[0238] These results confirmed that the 1,4-anhydrosugar compound 68 could be easily prepared in one pot from the DB-group-bridged (R)-compound 42.

[0239] [7]Conversion of protecting groups in 1,4-anhydrosugars Next, as shown in the following formula (16), the protecting group of the obtained compound 68 was converted to synthesize 1,4-anhydrosugars having different protecting groups at the 2-position.

[0240] [ka]

[0241] (Synthesis Example 3-1) Compound 52 was synthesized using compound 68 as the starting material as follows.

[0242] [ka]

[0243] A mixture of compound 68 (637 mg, 379 μmol) and sodium methoxide (45.0 mg, 833 μmol) in methanol (16.5 mL) was stirred at 20° C. for 17.5 hours. The reaction was quenched by the addition of Amberlite® (IR 120BHAG).

[0244] The mixture was filtered through a cotton pad to remove Amberlite®, and the filtrate was evaporated to give the crude product, which was purified by column chromatography (silica gel 10 g, hexane / ethyl acetate = 3 / 1 to 3 / 2) to give the product (556 mg, 1.63 mmol, 98% yield) as a colorless amorphous solid.

[0245] A mixture of the product (239 mg, 701 μmol), sodium hydride (34.5 mg 60% in mineral oil, 20.7 mg as sodium hydride, 863 μmol), and allyl bromide (93.2 mg, 770 μmol) was stirred in N,N-dimethylformamide (7 mL) at 0°C. After stirring for 5 minutes, the mixture was warmed to 20°C. After stirring for 2 hours, additional sodium hydride (62.7 mg 60% in mineral oil, 37.6 mg as sodium hydride, 1.57 mmol) and allyl bromide (186 mg, 1.54 mmol) were added to the mixture. After stirring for 1.5 hours, additional sodium hydride (61.5 mg 60% in mineral oil, 36.9 mg as sodium hydride, 1.54 mmol) and allyl bromide (186 mg, 1.54 mmol) were added to the mixture. After stirring for 17 hours, the reaction was quenched at 0° C. by the addition of water (7 mL).

[0246] The aqueous mixture was extracted with diethyl ether (10 mL × 3). The combined organic layers were washed successively with water (10 mL × 2) and brine (10 mL). The crude product was obtained by drying in a conventional manner. The crude product was purified by column chromatography (silica gel 10 g, hexane / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound 52 (207 mg, 544 μmol, 78% yield) as a colorless amorphous solid.

[0247] As described above, the acetyl group was removed from compound 68 and the 2-position was allyl-protected to give the 1,4-anhydrosugar compound 52 in a two-step yield of 78%.

[0248] (Synthesis Example 3-2) Compound 70 was synthesized using compound 68 as the starting material as follows.

[0249] That is, the same treatment as in Synthesis Example 3-1 was carried out, except that benzyl bromide was used instead of allyl bromide, and the temperature of the mixture after the addition of benzyl bromide was kept at 0°C and the reaction was carried out for 4.5 hours, thereby obtaining the 1,4-anhydrosugar compound 70 in a two-step yield of 71%.

[0250] (Synthesis Example 3-3) Compound 71 was synthesized using compound 68 as a starting material as follows.

[0251] That is, by carrying out the same treatment as in Synthesis Example 3-1 above, except that benzyloxymethyl chloride was used instead of allyl bromide and the reaction time was 18.5 hours, 1,4-anhydrosugar compound 71 was obtained in a two-step yield of 65%.

[0252] [8] Ring-opening polymerization of 1,4-anhydrosugars [8-1] Examination of activators To synthesize cyclic dimers using 1,4-anhydrosugars, we first investigated activators for ring-opening polymerization.

[0253] Synthesis of cyclobis-(1→5)-{2-O-allyl-3,6-O-[1,1'-dibenzene-2,2'-bis(methylene)]-β-D-glucofuranosyl} (Compound 48)

[0254] [ka]

[0255] (Synthesis Example 4-1) To a stirred mixture of MS4A (152 mg) and compound 52 (20.0 mg, 52.6 μmol) in dichloromethane (1 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (13.2 mg, 50.0 μmol). After stirring at −15° C. for 10 hours, the mixture was warmed to 0° C. After stirring for 16 hours, the mixture was warmed to 25° C. After stirring for 1 day, the mixture was warmed to reflux. After stirring for 1 day and 19 hours, the mixture was further treated with tert-butyldimethylsilyl trifluoromethanesulfonate (27.6 mg, 104 μmol) at 0° C. After stirring for 10 hours, the reaction was quenched by adding 2 M ammonia in methanol (1 mL).

[0256] The mixture was filtered through a cotton-Celite pad to remove MS4A. The pad was washed with dichloromethane. The resulting product was purified by column chromatography (silica gel 1 g, toluene / diethyl ether = 20 / 1 to 15 / 1) to give compound 48 (2.6 mg, 3.4 μmol, 14% yield) as a colorless amorphous solid, and the starting material compound 52 (13.0 mg, 34.2 μmol, 65% yield) was recovered as a colorless amorphous solid.

[0257] Data for compound 48: [α] 589 24 +4.2 (c 0.8, CHCl3). IR (ATR) 3015, 2923, 2859, 1477, 1349, 1216, 1092, 1044, 995, 929, 757, 668, 618 cm -1 . 1H NMR (500 MHz, acetone-d6, 18.3 ℃) δ 7.63 (ddd, J = 7.6, 0.8, 0.8 Hz, 2H, DB), 7.47-7.38 (m, 8H, DB), 7.35 (ddd, J = 7.6, 7.6, 1.0 Hz, 2H, DB), 7.16 (m, 2H, DB), 7.06 (dd, J = 7.6, 1.0 Hz, 2H, DB), 5.94 (ddt, J = 17.3, 10.6, 5.3, 5.3 Hz, 2H, Allyl), 5.33 (ddt, J = 17.3, 1.8, 1.8, 1.8 Hz, 2H, Allyl), 5.17 (ddt, J = 10.6, 1.8, 1.4, 1.4 Hz, 2H, Allyl), 4.83 (d, J = 3.0 Hz, 2H, H-1), 4.58 (d, J = 10.8 Hz, 2H, DB), 4.43 (d, J = 9.9 Hz, 2H, DB), 4.39 (d, J = 10.8 Hz, 2H, DB), 4.31 (dd, J = 7.8, 3.0 Hz, 2H, H-2), 4.30 (dd, J = 7.8, 3.3 Hz, 2H, H-4), 4.14 (ddd, J = 5.3, 1.8, 1.4 Hz, 4H, Allyl), 4.06 (ddd, J = 10.9, 7.3, 3.3 Hz, 2H, H-5), 4.01 (dd, J = 7.8, 7.8 Hz, 2H, H-3), 3.75 (d, J = 9.9 Hz, 2H, DB), 3.68 (dd, J = 7.8, 7.3 Hz, 2H, H-6), 3.58 (dd, J = 10.9, 7.8 Hz, 2H, H-6). 13C NMR (126 MHz, acetone-d6, 17.8 ℃) δ 141.9 (s, 2C, DB), 140.4 (s, 2C, DB), 137.8 (s, 2C, DB), 136.6 (s, 2C, DB), 135.9 (d, 2C, Allyl), 131.3 (d, 2C, DB), 130.6 (d, 2C, DB), 130.5 (d, 2C, DB), 129.0 (d, 2C, DB), 129.0 (d, 2C, DB), 128.8 (d, 2C, DB), 128.6 (d, 2C, DB), 128.1 (d, 2C, DB), 116.9 (t, 2C, Allyl), 105.3 (d, 2C, C-1), 87.7 (d, 2C, C-4), 86.9 (d, 2C, C-3), 77.9 (d, 2C, C-2), 73.0 (d, 2C, C-5), 72.2 (t, 2C, DB), 72.0 (t, 2C, DB), 71.4 (t, 2C, Allyl), 70.3 (t, 2C, C-6). HRMS (ESI) m / z [M + Na] + calcd for C 46 H 48 O5Na 783.3140, found 783.3161.

[0258] (Synthesis Example 4-2) To a stirred mixture of MS4A (165 mg) and compound 52 (20.8 mg, 54.7 μmol) in dichloromethane (1.5 mL) was added trimethylsilyl trifluoromethanesulfonate (36.5 mg, 164 μmol). After stirring at −15° C. for 22.5 h, the mixture was warmed to 0° C. After stirring for 7 h, the reaction was quenched by the addition of 2 M ammonia in methanol (1.5 mL).

[0259] The mixture was filtered through a cotton Celite pad to remove MS4A. The pad was washed with dichloromethane. The crude product was purified by column chromatography (silica gel 1 g, toluene / diethyl ether = 20 / 1 to 15 / 1) to give compound 48 (14 mg, 1.8 μmol, 7% yield) as a colorless amorphous solid, and the starting material compound 52 (5.0 mg, 13 μmol, 24% yield) was recovered as a colorless amorphous solid.

[0260] (Synthesis Example 4-3) To a stirred mixture of MS4A (153 mg) and compound 52 (15.0 mg, 39.4 μmol) in dichloromethane (1 mL) was added triethylsilyl trifluoromethanesulfonate (13.5 mg, 50.9 μmol). After stirring at −15° C. for 19 hours, the mixture was warmed to 0° C. After stirring for 1 day, additional triethylsilyl trifluoromethanesulfonate (26.9 mg, 102 μmol) was added to the mixture at −15° C. After stirring for 1 day, additional triethylsilyl trifluoromethanesulfonate (26.9 mg, 102 μmol) was added to the mixture at −15° C. After stirring for 10 minutes, the mixture was warmed to 25° C. After stirring for 1 hour, the mixture was warmed to reflux. After stirring for 2 hours, the reaction was quenched at 0° C. by the addition of 2 M ammonia in methanol (1 mL).

[0261] The mixture was filtered through a cotton Celite pad to remove MS4A. The pad was washed with dichloromethane. The crude product was purified by column chromatography (silica gel 1 g, toluene / diethyl ether = 20 / 1 to 15 / 1) to give compound 48 (1.2 mg, 1.6 μmol, 8% yield) as a colorless amorphous solid, and the starting material, compound 52 (8.1 mg, 21 μmol, 54% yield), was recovered as a colorless amorphous solid.

[0262] (Synthesis Example 4-4) To a stirred mixture of MS4A (155 mg) and compound 52 (20.6 mg, 54.1 μmol) in dichloromethane (1 mL) was added triphenylmethylium tetrakis(pentafluorophenyl)borate (5.0 mg, 5.4 μmol). After stirring at −30° C. for 2 hours, the mixture was warmed to 0° C. After stirring for 3 hours, the mixture was warmed to 20° C. After stirring for 1 day, additional triphenylmethylium tetrakis(pentafluorophenyl)borate (5.6 mg, 6.1 μmol) was added to the mixture. After stirring for 17 hours, the mixture was warmed to reflux. After stirring for 3.5 hours, additional triphenylmethylium tetrakis(pentafluorophenyl)borate (6.5 mg, 7.0 μmol) was added to the mixture. After stirring for 2 hours, additional triphenylmethylium tetrakis(pentafluorophenyl)borate (47.1 mg, 51.1 μmol) was added to the mixture. After stirring for 22.5 hours, the reaction was quenched by adding a small amount of methanol (1 mL) and saturated aqueous sodium bicarbonate solution (1 mL).

[0263] The mixture was filtered through a cotton Celite pad to remove MS4A. The pad was washed with diethyl ether. The aqueous filtrate was extracted with diethyl ether (5 mL × 3). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate (7 mL), water (7 mL), and brine (7 mL). The crude product was obtained by drying in a conventional manner. The crude product was purified by column chromatography (silica gel 2 g, toluene / diethyl ether = 19 / 1 to hexane / ethyl acetate = 1 / 1) to obtain compound 48 (1.3 mg, 1.7 μmol, 6% yield) as a colorless amorphous solid. These results are shown in Table 2.

[0264] [Table 2]

[0265] The abbreviations for the compounds in the table are as follows: TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate TMSOTf: Trimethylsilyl trifluoromethanesulfonate TESOTf: Triethylsilyl trifluoromethanesulfonate Ph3CB(C6F5)4: Triphenylmethylium tetrakis(pentafluorophenyl)borate

[0266] [8-2] Consideration of protecting groups and concentrations First, we investigated the effects of the protecting group at the 2-oxygen position and the concentration of the compound.

[0267] [ka]

[0268] (Synthesis Example 5-1) Synthesis was carried out in the same manner as in Synthesis Example 4-1 above, except that the starting material was changed to Compound 70 (197 mg, 457 μmol).

[0269] The crude product was purified by column chromatography (silica gel 15 g, toluene / diethyl ether = 20 / 1 to 15 / 1) to give compound 78 (4.1 mg, 4.8 μmol, yield 2%) as a colorless amorphous solid, and the starting material compound 70 (175 mg, 406 μmol, yield 89%) was recovered as a colorless amorphous solid.

[0270] Data for compound 78: [α] 589 25 +2.8 (c 0.5, CHCl3). IR (ATR) 3026, 2870, 1454, 1340, 1093, 1047, 996, 757, 699, 615 cm -1 . 1H NMR (400 MHz, acetone-d6, 22.8 ℃) δ 7.68 (ddd, J = 7.6, 1.0, 1.0 Hz, 2H, DB), 7.49-7.33 (m, 18H, Ar), 7.27 (dddd, J = 8.0, 6.4, 1.7, 1.7 Hz, 2H, DB), 7.15 (m, 2H, DB), 7.06 (dd, J = 7.6, 1.0 Hz, 2H, DB), 4.85 (d, J = 3.0 Hz, 2H, H-1), 4.64 (d, J = 12.4 Hz, 2H, Bn), 4.61 (d, J = 12.4 Hz, 2H, Bn), 4.57 (d, J = 10.5 Hz, 2H, DB), 4.42 (d, J = 10.0 Hz, 2H, DB), 4.40 (d, J = 10.5 Hz, 2H, DB), 4.29 (dd, J = 7.6, 3.0 Hz, 2H, H-2), 4.28 (dd, J = 7.6, 3.0 Hz, 2H, H-4), 4.04 (ddd, J = 11.1, 7.6, 3.0 Hz, 2H, H-5), 4.03 (dd, J = 7.6, 7.6 Hz, 2H, H-3), 3.75 (d, J = 10.0 Hz, 2H, DB), 3.62 (dd, J = 7.6, 7.6 Hz, 2H, H-6), 3.55 (dd, J = 11.1, 7.6 Hz, 2H, H-6), 13C NMR (101 MHz, acetone-d6, 19 ℃) δ 141.9 (s, 2C, DB), 140.5 (s, 2C, DB), 139.5 (s, 2C, Bn), 137.8 (s, 2C, DB), 136.8 (s, 2C, DB), 131.3 (d, 2C, DB), 130.6 (d, 4C, Ar), 129.1 (d, 2C, DB), 129.1 (d, 4C, Bn), 129.0 (d, 6C, Ar), 128.7 (d, 2C, DB), 128.6 (d, 2C, DB), 128.3 (d, 2C, DB), 128.1 (d, 2C, DB), 105.1 (d, 2C, C-1), 87.9 (d, 2C, C-4), 86.9 (d, 2C, C-3), 77.9 (d, 2C, C-2), 73.0 (d, 2C, C-5), 72.6 (t, 2C, Bn), 72.2 (t, 2C, DB), 72.1 (t, 2C, DB), 70.3 (t, 2C, C-6) HRMS (ESI) m / z [M + Na] + calcd for C 54 H 52 O 10 Na 883.3453, found 883.3482.

[0271] (Synthesis Example 5-2) Synthesis was carried out in the same manner as in Synthesis Example 4-1 above, except that the concentration of the starting material was changed to 0.5M.

[0272] The crude product was purified by column chromatography (silica gel 8 g, toluene / diethyl ether = 20 / 1 to ethyl acetate only) to give compound 48 (14.2 mg, 18.7 μmol, yield 13%) as a colorless amorphous solid, and the starting material compound 52 (7.2 mg, 19 μmol, yield 7%) was recovered as a colorless amorphous solid. These results are shown in Table 3.

[0273] [Table 3]

[0274] In the previous case where the concentration of the starting material was 0.05 M and the protecting group at the 2-oxygen position was an allyl group, the target product, Compound 48, was obtained in a yield of 14%, while the raw material, Compound 52, was recovered in a yield of 65% (Synthesis Example 4-1).

[0275] When the protecting group at the 2-position was a benzyl group and tert-butyldimethylsilyl trifluoromethanesulfonate was used as an activating agent, the target product, Compound 78, was obtained in a yield of 2%, and the starting material, Compound 70, was recovered in a yield of 89% (Synthesis Example 5-1).

[0276] These results suggest that the ease of cyclization changes depending on the bulkiness of the protecting group at the 2-position. In other words, it is thought that protecting groups such as allyl groups provide little steric hindrance during cyclization and do not have the effect of neighboring group participation, resulting in high yields of the product.

[0277] [9] Synthesis and structure determination of compound 12 [9-1] Synthesis of Compound 12 As shown in the formula below, Compound 48 and Compound 78 were converted to Compound 12, a β(1→5) glucosyl furanoside cyclic dimer.

[0278] [ka]

[0279] (Synthesis Example 6-1) First, the 2-benzyl-protected compound 78 was catalytically hydrogenated using Pearlman's catalyst to remove the benzyl and DB groups, giving the β(1→5) glucosyl furanoside cyclic dimer 12 in 86% yield.

[0280] [ka]

[0281] A mixture of compound 78 (8.0 mg, 9.3 μmol) and palladium hydroxide on carbon (20 wt% palladium hydroxide, 6.5 mg of 50% wet, 0.65 mg as palladium hydroxide, 4.6 μmol) was stirred in tetrahydrofuran (1.1 mL) under a hydrogen atmosphere at 25° C. for 1 hour.

[0282] The mixture was filtered through a cotton celite pad to remove the catalyst and carbon. The filtrate was concentrated to obtain the crude product. The crude product was purified by passing a solution of the crude product in distilled water through a cotton celite pad to remove water-insoluble by-products. The filtrate was concentrated to obtain compound 12 (2.6 mg, 8.0 μmol, 86% yield) as a white powder.

[0283] Data for compound 12: [α] 589 24 -56 (c 0.3, MeOH). 1 H NMR (600 MHz, D2O, 19.6 ℃) δ 5.02 (br s, 2H, H-1), 4.39 (dd, J = 5.6, 2.6 Hz, 2H, H-4), 4.27 (d, J = 5.6 Hz, 2H, H-3), 4.24 (br s, 2H, H-2), 4.15 (ddd, J = 7.0, 4.5, 2.6 Hz, 2H, H-5), 3.78 (dd, J = 11.7, 4.5 Hz, 2H, H-6), 3.74 (dd, J = 11.7, 7.0 Hz, 2H, H-6). 13 C NMR (151 MHz, D2O, 19.9 ℃) δ 107.5 (d, 2C, C-1), 81.5 (d, 2C, C-5), 80.8 (d, 2C, C-4), 80.4 (d, 2C, C-2), 77.1 (d, 2C, C-3), 61.9 (t, 2C, C-6). HRMS (ESI) m / z [M + Na] + calcd for C 12 H 20 O 10 Na 347.0949, found 347.0930.

[0284] (Synthesis Example 6-2) Synthesis of cyclobis-(1→5)-{3,6-O-[1,1'-dibenzene-2,2'-bis(methylene)]-β-D-glucofuranosyl} (compound 83) On the other hand, the 2-allyl protected compound 48 was treated with 1,3-dimethylbarbituric acid and tetrakis(triphenylphosphine)palladium(0) to remove the 2-allyl group, yielding the 2-unprotected compound 83 in 46% yield.

[0285] [ka]

[0286] More specifically, a mixture of compound 48 (46.6 mg, 61.2 μmol), 1,3-dimethylbarbituric acid (70.6 mg, 452 μmol), and tetrakis(triphenylphosphine)palladium(0) (16.9 mg, 14.6 μmol) was stirred in a mixture of dichloromethane (305 μL) and methanol (305 μmol) at 25° C. for 13 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (1 mL).

[0287] The aqueous mixture was then extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed successively with saturated aqueous ammonium chloride (5 mL), water (5 mL), and brine (5 mL). The crude product was obtained by drying in a conventional manner. The crude product was purified by column chromatography (silica gel 1 g, hexane / ethyl acetate = 3 / 1 to 1 / 1) followed by recycling GPC (flow rate 14.0 mL / min, pressure 2.0 MPa, 2 cycles) to obtain compound 83 (19.1 mg, 28.1 μmol, yield 46%) as a colorless amorphous solid.

[0288] Data for compound 83: [α] 589 23-27 (c 0.9, CHCl3). IR (ATR) 3456, 3060, 3018, 2903, 2865, 1478, 1444, 1395, 1346, 1217, 1088, 1038, 1000, 949, 804, 753, 717, 666, 617 cm -1 . 1 H NMR (400 MHz, acetone-d6, 18.7 ℃) δ 7.67 (d, J = 7.6 Hz, 2H, DB), 7.48-7.32 (m, 10H, DB), 7.15 (m, 2H, DB), 7.05 (dd, J = 7.6, 1.0 Hz, 2H, DB), 4.72 (d, J = 5.1 Hz, 2H, OH), 4.71 (d, J = 3.0 Hz, 2H, H-1), 4.57 (d, J = 10.5 Hz, 2H, DB), 4.44 (ddd, J = 8.2, 5.1, 3.0 Hz, 2H, H-2), 4.43 (d, J = 10.0 Hz, 2H, DB), 4.39 (d, J = 10.5 Hz, 2H, DB), 4.24 (dd, J = 7.5, 3.2 Hz, 2H, H-4), 4.02 (ddd, J = 10.9, 7.1, 3.2 Hz, 2H, H-5), 3.87 (dd, J = 8.2, 7.5 Hz, 2H, H-3), 3.73 (d, J = 10.0 Hz, 2H, DB), 3.60 (dd, J = 7.9, 7.1 Hz, 2H, H-6), 3.54 (dd, J = 10.9, 7.9 Hz, 2H, H-6). 13C NMR (101 MHz, acetone-d6, 19.4 ℃) δ 141.8 (s, 2C, DB), 140.4 (s, 2C, DB), 138.0 (s, 2C, DB), 136.8 (s, 2C, DB), 131.3 (d, 2C, DB), 130.5 (d, 4C, DB), 129.2 (d, 2C, DB), 128.9 (d, 2C, DB), 128.7 (d, 2C, DB), 128.5 (d, 2C, DB), 128.0 (d, 2C, DB), 106.8 (d, 2C, C-1), 88.3 (d, 2C, C-3), 81.2 (d, 2C, C-2), 77.7 (d, 2C, C-4), 72.8 (d, 2C, C-5), 72.3 (t, 2C, DB), 72.2 (t, 2C, DB), 70.4 (t, 2C, C-6). HRMS (ESI) m / z [M + Na] + calcd for C 40 H 40 O 10 Na 703.2514, found 703.2526.

[0289] (Synthesis Example 6-3) Synthesis of β(1→5) glucosyl furanoside cyclic dimer (compound 12) Next, using the compound 83 obtained as above as a starting material, compound 12 was produced as a β(1→5) glucosyl furanoside cyclic dimer.

[0290] [ka]

[0291] More specifically, first, a mixture of compound 83 (15.0 mg, 22.0 μmol) and palladium hydroxide on carbon (20 wt% palladium hydroxide, 6.5 mg of 50% wet, 0.65 mg as palladium hydroxide, 4.6 μmol) was stirred in a mixed solvent of tetrahydrofuran (550 μL) and methanol (550 μL) under a hydrogen atmosphere at 25° C. for 1 hour.

[0292] The mixture was then filtered through a cotton celite pad to remove palladium hydroxide and carbon. The filtrate was concentrated to obtain a crude product. The crude product was purified by passing a solution of the crude product in distilled water through a cotton celite pad to remove water-insoluble by-products. The filtrate was concentrated to obtain compound 12 (10.0 mg, quantitative, containing a small amount of by-products) as a white powder.

[0293] [9-2] Structure determination of compound 12 We attempted to determine the structure of compound 12, a β(1→5) glucosyl furanoside cyclic dimer that we had successfully synthesized.

[0294] First, the peaks obtained by mass spectrometry ([M+Na] + :347.0930) is the molecular weight of compound 12 ([M+Na] + :347.0949), which was essentially the same.

[0295] Next, difference NOE spectra were measured to find protons that were spatially close to each other. FIG. 1 shows the structure of compound 12, a β(1→5) glucosyl furanoside cyclic dimer. 1 1 H NMR and difference NOE NMR spectra.

[0296] Figure 1 confirms a correlation between irradiation of the proton at position 1 and irradiation of the proton at position 5, and between irradiation of the proton at position 5 and the proton at position 1. Therefore, it is believed that compound 12 has furanose rings in which the 1- and 5-positions of the furanose rings can be close to each other.

[0297] FIG. 2 shows the HMBC NMR spectrum of compound 12, a β(1→5) glucosyl furanoside cyclic dimer.

[0298] As shown in Figure 2, two-dimensional NMR also confirmed that compound 12 has a β-1,5 bond. From the HMBC of compound 12, correlation between the 1st and 4th positions was observed, suggesting that compound 12 has a furanose ring in which the 1st and 4th carbons are bonded via an oxygen atom. Correlation between the 1st and 5th positions was also observed, suggesting that compound 12 has a β-1,5 bond in which the 1st and 5th carbons are bonded via an oxygen atom.

[0299] Based on the above results, compound 12 was identified as a cyclized compound having a β-1,5-linked furanose ring, and the world's first synthesis of compound 12 was achieved.

[0300] Furthermore, X-ray crystal structure analysis was performed on Compound 12. Figure 3 is an ORTEP diagram of Compound 12, which is a β(1→5) glucosyl furanoside cyclic dimer represented by formula (1).

[0301] FIG. 3 also confirms that compound 12 is a cyclized compound having a β-1,5-bonded furanose ring. [Industrial Applicability]

[0302] The β(1→5) glucosyl furanoside cyclic dimer of the present invention is a novel compound that is expected to have properties different from those of conventional cyclic oligosaccharides. Furthermore, the method for producing the β(1→5) glucosyl furanoside cyclic dimer of the present invention is a method that can suitably produce novel compounds that are expected to have properties different from those of conventional cyclic oligosaccharides. Therefore, the β(1→5) glucosyl furanoside cyclic dimer and the method for producing the β(1→5) glucosyl furanoside cyclic dimer of the present invention have industrial applicability.

Claims

1. A β(1→5) glucosyl furanoside cyclic dimer characterized by being represented by the following formula (1): 【Chemical 1】

2. A β(1→5) glucosyl furanoside cyclic dimer characterized by being represented by the following formula (2): 【Chemistry 2】 (In the formula, R １ represents a bridging group.)

3. A β(1→5) glucosyl furanoside cyclic dimer characterized by being represented by the following formula (3): 【Chemistry 3】 (In the formula, R １ represents a bridging group, and R ２ represents a protecting group for a hydroxyl group.)

4. A method for producing a β(1→5) glucosyl furanoside cyclic dimer, comprising a cationic ring-opening polymerization step of reacting a 1,4-anhydrosugar represented by the following formula (4) with a β(1→5) glucosyl furanoside cyclic dimer represented by the following formula (3): 【Chemistry 4】 (In the formula, R １ represents a bridging group, and R ２ represents a protecting group for a hydroxyl group.) 【Chemistry 5】 (In the formula, R １ represents a bridging group, and R ２ represents a protecting group for a hydroxyl group.)

5. The R ２ The method for producing a β(1→5) glucosyl furanoside cyclic dimer according to claim 4, wherein is an allyl group, an acetyl group, a benzyl group, or a benzyloxymethyl group.

6. After the cationic ring-opening polymerization step, ２ The method for producing a β(1→5) glucosyl furanoside cyclic dimer according to claim 4 or 5, further comprising a step of removing

7. The R １ The method for producing a β(1→5) glucosyl furanoside cyclic dimer according to claim 4 or 5, wherein is represented by the following formula (5): -Ar １ -L-Ar ２ - (5) (In the formula, Ar １ , Ar ２ each independently represents an aromatic atomic group, and L represents a divalent substituent or a single bond.

8. The R １ The method for producing a β(1→5) glucosyl furanoside cyclic dimer according to claim 7, wherein is represented by the following formula (6): 【Chemistry 6】 (Wherein, p R ４ , q R ５ are each independently a hydrogen atom, a halogen atom, a halo-substituted or unsubstituted lower hydrocarbon group, a lower alkoxy group, a nitro group, or a di(lower alkyl)amino group, and L is a divalent substituent or a single bond. p and q are each independently an integer of 0 to 4. ４ Among them, adjacent R ４ may be bonded to each other to form a benzene ring, and q R ５ Among them, adjacent R ５ may be bonded to each other to form a benzene ring.)

9. After the cationic ring-opening polymerization step, １ The method for producing a β(1→5) glucosyl furanoside cyclic dimer according to claim 4 or 5, further comprising a step of removing

10. The method for producing a β(1→5) glucosyl furanoside cyclic dimer according to claim 4 or 5, wherein a silyl activator is used in the cationic ring-opening polymerization step.

11. The 1,4-anhydrosugar represented by the above formula (4) is The hydroxyl groups at the 3 and 6 positions of the 1,2,4-orthoester are １ crosslinking with forming a 1,4-anhydrosugar structure using an activating agent and protecting the 2-position with an acetyl group; and The acetyl group is protected by a protecting group R ２ The method for producing a β(1→5) glucosyl furanoside cyclic dimer according to claim 4 or 5, which is produced by a method comprising the step of converting the β(1→5) glucosyl furanoside cyclic dimer into

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