Method for producing cyclic oligosaccharides, cyclic oligosaccharides and inclusion agent

Abstract

To provide: a cyclic oligosaccharide manufacturing method with which it is possible to efficiently synthesize a cyclic oligosaccharide; and a novel cyclic oligosaccharide obtainable with the manufacturing method.SOLUTION: A method for manufacturing a cyclic oligosaccharide includes liquid-phase electrolytic reaction of a linear oligosaccharide in which five to 10 α-glucosamine or its derivatives are joined in series by 1,4-join.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a cyclic oligosaccharide, a novel cyclic oligosaccharide, and an inclusion agent using the oligosaccharide. [Background technology]

[0002] Cyclic oligosaccharides refer to molecules in which oligosaccharides consisting of multiple monosaccharides are cyclized. These molecules have a hydrophobic cavity in the molecule, and it is known that the cavity can encapsulate organic molecules or ions. A representative cyclic oligosaccharide is cyclodextrin (Non-Patent Document 1) (Formula 11). In addition, there are cyclic oligosaccharides such as cycloawaodrin (Non-Patent Document 2) synthesized by chemical synthesis (Formula 12). These molecules have the ability to encapsulate, and are therefore expected to be applied to foods, medicines, drug delivery systems, and the like. In addition, the size of the cavity may affect the molecules that can be encapsulated. Therefore, it is important to control the cavity of cyclic oligosaccharides, that is, to design and synthesize oligosaccharides. [ka] [Representative cyclic oligosaccharides] [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Ogawa, T.; Takahashi, Y. Carbohydr. Res1985, 138, C5. [Non-Patent Document 2] Nishizawa,M.;Imagawa,H.;Kan,Y.;Yamada,H.;Tetrahedron Lett.1991,32,5551. Summary of the Invention [Problem to be solved by the invention]

[0004] In recent years, the synthesis of small cyclodextrins, sterically distorted cyclodextrins CD3 and CD4, has been achieved (Ikuta, D.; Hirata, Y.; Wakamori, S.; Shimada, H.; Tomabechi, Y.; Kawasaki, Y.; Ikeuchi, K.; Hagimori, T.; Matsumoto, S.; Yamada, H. Science 2019, 364, 674.) (Formula 13, 14). In the development and application of the functions of these cyclic oligosaccharides, there are limitations to enzymatic synthesis alone, and the development of a chemical method that can stably supply them is strongly desired. [ka] (13) (14) Therefore, an object of the present invention is to provide a method for producing cyclic oligosaccharides that can efficiently synthesize cyclic oligosaccharides, and to provide novel cyclic oligosaccharides obtained through the method. [Means for solving the problem]

[0005] In light of the above-mentioned problems, the present inventors have conducted research and found that the desired cyclic oligosaccharides can be synthesized by using linear oligosaccharides linked in series via 1,4-bonds and performing liquid phase electrolysis. Specifically, the above problems were solved by the following means. [1] A method for producing cyclic oligosaccharides, comprising subjecting a linear oligosaccharide in which 5 to 10 α-glucosamine units or a derivative thereof are linked in series by 1,4-bonds to a liquid-phase electrolytic reaction. [2] The method for producing a cyclic oligosaccharide according to [1], wherein the linear oligosaccharide is represented by the following formula (1): Formula (1) [ka] (In formula (1), R 1 are each independently a protecting group having a formula weight of 500 or less, R 21 and R 22 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, R 3are each independently a protecting group having a formula weight of 300 or less, R 4 is a substituent, X is a sulfur atom, a selenium atom, or a tellurium atom, and n1 is an integer of 3 to 8. 22 and R 3 may be bonded to each other to form a ring. [3] The method for producing a cyclic oligosaccharide according to [1], wherein the linear oligosaccharide is represented by the following formula (1-1): Formula (1-1) [ka] (In formula (1-1), R 1 are each independently a protecting group having a formula weight of 500 or less, R 21 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, R 4 is a substituent, X is a sulfur atom, a selenium atom, or a tellurium atom, and n1 is an integer of 3 to 8. [4] A cyclic oligosaccharide represented by formula (2). Formula (2) [ka] (In formula (2), R 1 are each independently a protecting group having a formula weight of 500 or less, R 21 and R 22 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, R 31 Yes, that 3 -O- group, R 3 are each independently a protecting group with a formula weight of 300 or less, and n2 is an integer of 0 to 5. 22 and R 31 may be bonded to each other to form a ring. [5] A cyclic oligosaccharide represented by the formula (2-1). Formula (2-1) [ka] (In formula (2-1), R 1are each independently a protecting group having a formula weight of 500 or less, R 21 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, and n2 is an integer of 0 to 5. [6] A cyclic oligosaccharide represented by formula (3). Formula (3) [ka] (In formula (3), n2 represents an integer of 0 to 5, and Ac represents an acetyl group.) [7] A cyclic oligosaccharide represented by formula (4). Formula (4) [ka] (In formula (4), n2 represents an integer of 0 to 5.) [8] An inclusion agent comprising the compound according to [7]. [9] For a cyclic oligosaccharide represented by the following formula (2-1), the oxazolidinone ring is opened with a base, the resulting sugar is reacted with acetic anhydride to acetylate the ring-opened site, and further reacted with K2CO3 to return the acetyloxy group at the 3-position to a hydroxyl group to obtain a sugar, which is then reacted with an acid to obtain R 1 A method for producing a cyclic oligosaccharide of formula (3) in which the group at position (I) is replaced with a hydrogen atom and the 6-position substituent is replaced with a hydroxyl group. Formula (2-1) [ka] (In formula (2-1), R 1 are each independently a protecting group having a formula weight of 500 or less, R 21 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, and n2 is an integer of 0 to 5. Formula (3) [ka] (In formula (3), n2 represents an integer of 0 to 5, and Ac represents an acetyl group.) Effect of the Invention

[0006] According to the production method of the present invention, cyclic oligosaccharides can be efficiently synthesized, and novel cyclic oligosaccharides obtained through the production method can be provided. [Brief description of the drawings]

[0007] [Figure 1] NMR spectrum of compound 16 (part 1) [Diagram 2] NMR spectrum of compound 16 (part 2) [Diagram 3] NMR spectrum of compound 16 and its analysis diagram (part 3) [Figure 4] NMR spectrum of compound 16 and its analysis diagram (part 4) [Diagram 5] NMR spectrum of compound 21 (part 1) [Figure 6] NMR spectrum of compound 21 (part 2) [Figure 7] NMR spectrum of compound 21 and its analysis (part 3) [Figure 8] NMR spectrum of compound 21 and its analysis (part 4) [Figure 9] MALDI-TOF MS after quenching of reaction scheme (27) [Figure 10] MALDI-TOF MS after gel filtration of the reaction product (sugar 26) of reaction scheme (27). [Figure 11] 1H-NMR of the reaction product (sugar 26) of reaction scheme (27) after gel filtration [Figure 12] Mass spectrometry of intermediate sugar 24. [Figure 13] Mass spectrometry of the final product, sugar 26. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Hereinafter, an embodiment of the present invention (hereinafter, simply referred to as "the present embodiment") will be described in detail. Note that the present embodiment is an example for explaining the present invention, and the present invention is not limited to the present embodiment. In this specification, the use of "to" means that the numerical values ​​before and after it are included as the lower limit and upper limit. In this specification, various physical properties and characteristic values ​​are those at 23° C. unless otherwise specified. In the description of groups (atomic groups) in this specification, when the description does not indicate whether the group is substituted or unsubstituted, the description also includes groups (atomic groups) that have a substituent as well as groups (atomic groups) that have no substituent. For example, the term "alkyl group" includes not only alkyl groups that have no substituent (unsubstituted alkyl groups), but also alkyl groups that have a substituent (substituted alkyl groups). In this specification, when the description does not indicate whether the group is substituted or unsubstituted, the description is preferably unsubstituted. In cases where the standards shown in this specification differ depending on the year and the measurement method, etc., they shall be based on the standards as of January 1, 2021, unless otherwise stated.

[0009] Abbreviations for substituents and the like are: Et is an ethyl group, Bn is a benzyl group, Ar is an aryl group, Phth is a phthaloyl group, MeOH is methanol, Ph is a phenyl group, Ac is an acetyl group, DMPA is 4-dimethylaminopyridine, Tf is a trifluoromethanesulfonyl group, TfOH is trifluoromethanesulfonic acid, TMSOTf is trimethylsilyl trifluoromethanesulfonate, THF is tetrahydrofuran, Bu4NOTf is tetrabutylammonium triflate, TBDPS is a tert-butyldiphenylsilyl group, and DTBMP is 2,6-di-tert-butyl-4-methylpyridine.

[0010] First, we explain the synthetic route of monosaccharide building blocks, which have been considered as candidates for monomers in polymerization reactions (Reaction Scheme 1). Starting from glucosamine hydrochloride 1, the amino group was phthaloyl-protected with phthalic anhydride, followed by acetylation with Ac2O. It was then converted to thioglycoside 4 by reaction with 4-chlorothiophenol. This thioglycoside was deacetylated under acidic conditions, and benzylidene-protected with benzaldehyde dimethyl acetal to synthesize compound 6. The hydroxyl group at the 3-position was then acetylated again with acetic anhydride to obtain compound 7. Compound 7 was then treated with trimethylsilyl triflate in a borane-THF complex to cleave the benzylidene acetal, synthesizing monosaccharide building block 8. [ka] (1) [Synthesis of monosaccharide building blocks investigated so far (see the literature below)] ·Manmode,S.;Tanabe,S.;Yamamoto,T.;Sasaki,N.;Nokami,T.;Itoh,T.ChemistryOpen 2019,8,869. ·Yano,K.;Itoh,T.;Nokami.Carbohydr.Res.2020,492,108018.

[0011] Using the obtained monosaccharide building block 8, we attempted to synthesize cyclic sugars by electrochemical polymerization (reaction scheme 2). The reaction conditions were as follows: After electrochemical oxidation under constant current conditions at -60°C, the temperature was raised to -40°C and glycosylation reaction was carried out for 3600 seconds. The reaction was then stopped by adding Et3N. [ka] (2) Anodic oxidation: Anodic oxidation Glycosylation

[0012] When the reaction was carried out under these reaction conditions, it was not possible to obtain cyclic sugars with a cyclic trisaccharide or more, but 1,6-dehydrated sugar 9 and cyclic disaccharide 10 were obtained. The following mechanism is proposed as the reaction mechanism by which this 1,6-dehydrated sugar was obtained (Reaction Scheme 3). It is believed that the α-triflate intermediate generated during the electrolytic oxidation undergoes a conformational change and undergoes intramolecular glycosylation before coupling with other intermediates. Therefore, it is believed that preventing the conformational change that would generate 1,6-dehydrated sugars is important in obtaining larger cyclic sugars. [ka] (3) [Reaction mechanism of side reactions that may occur during electropolymerization]

[0013] Polymerization reactions using substrates with oxazolidinone protecting groups at the 2- and 3-positions and their problems In order to suppress side reactions due to the stereoinversion of the sugar pyranose ring, we attempted to introduce a protecting group that becomes bulky upon inversion at the 2- and 3-positions, which is the easiest to introduce (Reaction Scheme 4). We attempted synthesis using the monosaccharide building block 8 used above as the starting material. The 6-position of monosaccharide building block 8 was protected with a TBDPS group and converted to compound 11. Then, to remove the phthalimide protecting group, deprotection was performed using dehydrated ethylenediamine to obtain compound 12. At this time, the acetyl group at the 3-position was also deprotected at the same time. Next, oxazolidinone protection was performed at the 2- and 3-positions in CH2Cl2 and 10% NaHCO3 aqueous solution to convert to compound 13. Then, acetyl protection on the nitrogen was performed in DMF, and the TBDPS protecting group at the 6-position was deprotected to obtain oxazolidinone-protected compound 15 with an unprotected hydroxyl group at the 6-position. [ka] (4) [Synthesis of protected oxazolidinone]

[0014] This oxazolidinone-protected product 15 was used in a polymerization reaction by electrochemical oxidation (Reaction Scheme 5). As a result, cyclic disaccharide 16 was selectively obtained in 60% yield. However, cyclic sugars with cyclic trisaccharides or more were not obtained. This is because cyclization, which is an intramolecular reaction, is favored in the cyclization and elongation of glycans, and it was thought that electrochemical polymerization via the highly reactive primary hydroxyl group at the 6-position would not lead to the synthesis of macrocyclic oligosaccharides. [ka] (5) [Electropolymerization reaction using oxazolidinone-protected compounds]

[0015] Cyclic glycopolymerization of 1,4-linked glycoproteins using oxazolidinone substrates Since it was found that electrolytic glycosylation polymerization via 1,6-glycosidic bonds could not give large cyclic oligosaccharides, a different approach was taken (Reaction Scheme 6). In this approach, glycosylation via 1,4-glycosidic bonds gave large cyclic oligosaccharides. The outline is as follows:

[0016] [ka] (6) [Summary of the newly investigated synthesis of large cyclic oligosaccharides (see references below)] ·Nokami,T.;Shibuya,A.;Saigusa,Y.;Manabe,S.;Ito,Y.;Yoshida,J.BeilsteinJ.Org.Chem.2012,8,456. ·Benakli,K.;Zha,C.;Kerns,RJJAm.Chem.Soc.2001,123,9461.

[0017] In this approach, the glycan is first extended with β-1,4-glycosidic bonds by electrochemical polymerization, and then isomerized by the specific α-isomerization of the oxazolidinone protecting group. The glycan is then cyclized by electrochemical oxidation again. This approach has enabled the rapid and simple synthesis of cyclic oligosaccharides. It is particularly advantageous in that it can be performed in a one-pot synthesis. First, the synthesis of the substrate will be described (Reaction Scheme 7). Starting from the substrate 6 synthesized above, dephthaloylation was performed to obtain 17, which was then protected as 2,3-oxazolidinone to obtain 18. 18 was reacted with acetic anhydride in CH2Cl2 to obtain 19. Substrate 20 was synthesized by selectively opening the 4-position of 19 through a benzylidene ring-opening reaction. [ka] (7) [Synthesis of 2,3-oxazolidinone protected derivatives with an unprotected hydroxyl group at the 4-position (see the literature below)] ·Feng,J.;Hevey,R.;Ling,C.Carbohydr.Res 2011,346,2650.

[0018] Based on this substrate 20, the sugar chain elongation step was optimized (Table 1 below). In this study, we mainly examined the temperature during electrolytic oxidation and the presence or absence of a base. The supporting electrolyte was fixed with Bu4NOTf, the solvent was CH2Cl2, and the following conditions were examined. The bulky weak base DTBMP was used as the base.

[0019] [Optimization of glyco-elongation reaction conditions] [Table 1] Base: Yield of oligosaccharide: Yield of oligosaccharide

[0020] As a result, Entry 3 without a base was adopted as the subsequent conditions. The reason for this was that high temperatures without a base were more favorable for glycan elongation. These conditions were combined to perform one-pot polymerization (Reaction Scheme 8). First, electrolytic oxidation and glycosylation were performed at -40°C, and then the temperature was raised to room temperature. At this time, the glycan was isomerized for 1 hour using trifluoromethanesulfonic acid generated in the system by electrolytic oxidation. After that, the temperature was lowered again to -40°C, and electrolytic oxidation and glycosylation were performed. From this experiment, hexasaccharide cyclic oligosaccharide 21 (cyclic hexasaccharide 21) and heptasaccharide cyclic oligosaccharide 22 (cyclic heptasaccharide 22) were obtained with an isolation yield of 4.8% and 0.6%, respectively. In addition, all of the glycosidic bonds in the obtained cyclic oligosaccharides were α-linked. [ka] (8) isomerization: isomerization [Reaction conditions for one-pot cyclic oligosaccharide synthesis]

[0021] Next, the changes in the state of these sugar chains are shown (chemical formula and NMR spectrum 24). First, it can be seen that the peak of the α-anomeric hydrogen of the raw monosaccharide appears at around 6.1 ppm as measured by 1H NMR. When the sugar chain was extended by electrochemical polymerization, the α-anomeric hydrogen peak was split into two at around 6.0 ppm to 6.2 ppm, and the α-anomeric hydrogen peak was also confirmed at around 5.0 ppm. When this linear oligosaccharide was treated with acid isomerization, the α-anomeric hydrogen peak at around 5.0 ppm disappeared. Finally, when it was cyclized, the β-anomeric peak converged and shifted to around 5.8 ppm. It is known that the anomeric hydrogen peak shifts upfield when an oligosaccharide is cyclized (Wakao, M.; Fukase, K.; and Kusumoto, SJOrg.Chem.2002.67,8182.), and since this was in line with the above, it was determined to be a cyclic oligosaccharide.

[0022] [ka] [ 1 Measurement of glycan transitions by chemical shifts of anomeric hydrogens in H NMR]

[0023] As a result of the above development studies and the examples described below, the following invention has been completed. That is, a method for producing cyclic oligosaccharides has been invented, which comprises subjecting a linear oligosaccharide in which 5 to 10 α-glucosamine units or a derivative thereof are linked in series via 1,4-bonds to a liquid-phase electrolytic reaction. In this case, the linear oligosaccharide is preferably represented by the following formula (1). Formula (1) [ka] (In formula (1), R 1 are each independently a protecting group having a formula weight of 500 or less, R 21 and R 22 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, R 3 are each independently a protecting group having a formula weight of 300 or less, R 4 is a substituent, X is a sulfur atom, a selenium atom, or a tellurium atom, and n1 is an integer of 3 to 8. 22 and R 3 may be bonded to each other to form a ring.

[0024] In formula (1), R 1 are each independently a protecting group having a formula weight of 500 or less, and play the role of a protecting group for protecting a hydroxyl group. By providing a protecting group, the progress of reactions other than cyclization can be suppressed, and the cyclization reaction can be effectively promoted. In addition, by using a protecting group having a formula weight of 500 or less, cyclization can be facilitated. R 1The formula weight is preferably 60 or more, more preferably 80 or more, even more preferably 90 or more, still more preferably 100 or more, and even more preferably 105 or more. On the other hand, the upper limit is 500 or less, preferably 400 or less, more preferably 350 or less, still more preferably 300 or less, and even more preferably 280 or less. Preferred protecting groups include a Bn group, a benzoyl group (Bz), an acetyl group (Ac), a pivaloyl group (Piv), TBDPS, a tert-butyldimethylsilyl group (TBS), and a 9-fluorenylmethylcarboxy group (Fmoc), with Bn, TBDPS, and TBS being preferred, Bn and TBDPS being more preferred, and Bn being even more preferred. R 1 It may contain only one type, or may contain two or more types.

[0025] R 3 is a protecting group, and any protecting group can be used as long as it does not inhibit the cyclization of the α-1,4 chain sugar. In addition, the cyclization can be facilitated by using a protecting group with a formula weight of 300 or less. On the other hand, if the protecting group is too small, it may not be able to fulfill its role as a protecting group. In view of the above, R 3 The formula weight of R is preferably 20 or more, more preferably 30 or more, even more preferably 40 or more, and even more preferably 50 or more. On the other hand, the upper limit is 300 or less, preferably 250 or less, more preferably 200 or less, even more preferably 180 or less, and even more preferably 160 or less. 3 If the formula weight is too large, it will inhibit the cyclization reaction. On the other hand, if the substituent is too small, it may not be able to fully fulfill its role. Specific examples include Bn, Bz, Ac, Piv, TBDPS, TBS, and Fmoc, with Bz, Ac, Piv, and Fmoc being preferred, Bz and Ac being more preferred, and Ac being even more preferred. R 3 It may contain only one type, or may contain two or more types.

[0026] R21 and R 22 R is a hydrogen atom or a protecting group, and any group can be used as long as it does not inhibit the cyclization of the α-1,4 chain sugar. 21 and R 22 is preferably a protecting group. When it is a protecting group, the cyclization can be facilitated by using a protecting group having a formula weight of 300 or less. On the other hand, when it is a protecting group, if it is too small, it cannot fulfill its role as a protecting group. From this viewpoint, R 21 and R 22 When it is a protecting group, the formula weight is preferably 20 or more, more preferably 30 or more, even more preferably 40 or more, and even more preferably 50 or more. On the other hand, the upper limit is 300 or less, preferably 250 or less, more preferably 200 or less, even more preferably 180 or less, and even more preferably 160 or less. Preferred protecting groups include Bn, Bz, Ac, Piv, TBDPS, TBS, Fmoc, and a phthalic anhydride group (Phth), with Bn, Bz, Ac, Piv, TBDPS, TBS, Fmoc, and Phth being preferred, Bn, Ac, and Phth being more preferred, and Bn and Ac being even more preferred. R 21 and R 21 Each of these may contain only one type, or may contain two or more types.

[0027] R 21 Or R 22 And, R 3 When the glycosidic bonds are bonded to each other to form a ring, the glycosidic bonds are easily isomerized to α-1,4 bonds, and cyclization is not affected, which is preferable. The ring formed may be any ring as long as it does not inhibit the cyclization of the chain sugars of α-1,4 bonds. As a specific ring formed, it is preferable to form a 5- or 6-membered heterocycle, and it is more preferable to form a 5-membered heterocycle. Specifically, it is preferable to form a morpholine ring, a morpholinone ring, or an oxazolidinone ring, and an oxazolidinone ring is particularly preferable.

[0028] R 4is a substituent, preferably one which can be electrochemically activated or where X, such as sulfur, can be activated. 4 In particular, R is preferably one that does not hinder the oxidation of sulfur atoms, etc. 4 is preferably not an electron-withdrawing group, and is preferably an electron-donating group. However, to synthesize linear oligosaccharides, a slightly electron-withdrawing group is preferable. From this viewpoint, R 4 The formula weight is preferably 20 or more, more preferably 30 or more, even more preferably 40 or more, and even more preferably 50 or more. On the other hand, the upper limit is preferably 300 or less, more preferably 250 or less, even more preferably 200 or less, even more preferably 180 or less, and even more preferably 160 or less. Preferred protecting groups include substituents, groups having weaker electron-withdrawing properties than a nitro group, and electron-donating groups, specifically exemplified by phenyl, 4-methylphenyl, 2,6-dimethylphenyl, 4-bromophenyl, 4-chlorophenyl, and 4-fluorophenyl groups, with phenyl, 2,6-dimethylphenyl, 4-chlorophenyl, and 4-fluorophenyl groups being preferred, with 2,6-dimethylphenyl, 4-chlorophenyl, and 4-fluorophenyl groups being more preferred, and 4-chlorophenyl and 4-fluorophenyl groups being even more preferred.

[0029] n1 is an integer of 3 to 8, and preferably an integer of 4 to 6. In the case of cyclic or linear oligosaccharides, the repeat structure may be a single sugar or different sugars, as long as the definition in the formula is satisfied. This also applies to the following formulae (1-1), (2), (2-1), (3), and (4).

[0030] The linear oligosaccharide is preferably represented by the following formula (1-1): Formula (1-1) [ka] (In formula (1-1), R 1are each independently a protecting group having a formula weight of 500 or less, R 21 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, R 4 is a substituent, X is a sulfur atom, a selenium atom, or a tellurium atom, and n1 is an integer of 3 to 8. R 1 , R 21 , R 4 The preferred ranges of X and n1 are the same as those defined in formula (1).

[0031] The liquid phase electrolytic reaction can be carried out by any known means so long as a linear oligosaccharide in which 5 to 10 α-glucosamine units or a derivative thereof are linked in series via 1,4-bonds is used. For example, the electrolyte may be CH2Cl2, acetonitrile, propionitrile, DMF, etc., with CH2Cl2 being preferred. The supporting electrolyte may be Bu4NOTf, Et4NOTf, Pr4NOTf, etc., with Bu4NOTf being preferred. The supporting electrolyte concentration is preferably in the range of 0.1 to 3.0 M, more preferably 0.5 to 2.0 M. The electrolytic oxidation temperature is preferably in the range of -100 to 0°C, more preferably -60 to -10°C.

[0032] The cyclic oligosaccharides obtained by the above-mentioned method for producing cyclic oligosaccharides include novel compounds. First, there is a cyclic oligosaccharide represented by the formula (2). Formula (2) [ka] (In formula (2), R 1 are each independently a protecting group having a formula weight of 500 or less, R 21 and R 22 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, R 31 Yes, that 3 -O- group, R 3 are each independently a protecting group with a formula weight of 300 or less, and n2 is an integer of 0 to 5.22 and R 31 may be bonded to each other to form a ring. In formula (2), R 1 , R 21 , R 3 The preferred range of R is the same as that shown in formula (1). 22 and R 31 The ring formed by these rings has the same meaning, and it is particularly preferred that they form an oxazolidinone ring.

[0033] Furthermore, an example of a novel compound is a cyclic oligosaccharide represented by the formula (2-1). Formula (2-1) [ka] (In formula (2-1), R 1 are each independently a protecting group having a formula weight of 500 or less, R 21 are each independently a hydrogen atom or a protecting group having a formula weight of 300 or less, and n2 is an integer of 0 to 5. R in formula (2-1) 1 , R 21 is defined as in formula (1). n2 is preferably an integer of 0 to 3, more preferably 1 or 2, and even more preferably 1.

[0034] Further novel compounds include cyclic oligosaccharides represented by formula (3). Formula (3) [ka] (In formula (3), n2 represents an integer of 0 to 5, and Ac represents an acetyl group.) n2 is preferably an integer of 0 to 3, more preferably 1 or 2, and even more preferably 1. The compound represented by formula (3) can be derived from the compound represented by formula (2-1). Specifically, first, the oxazolidinone ring is opened with a base (e.g., sodium hydroxide). The resulting sugar is reacted with acetic anhydride and DMAP (4-dimethylaminopyridine). It is then reacted with K2CO3 to return the acetyloxy group to a hydroxyl group to obtain a sugar. This is then reacted with an acid (preferably under a hydrogen atmosphere) to return the Bn (benzyl group) to a hydrogen atom, thereby obtaining the sugar of formula (3) in which the substituent at the 6-position is a hydroxyl group.

[0035] Further examples include cyclic oligosaccharides represented by the following formula (4). Formula (4) [ka] (In formula (4), n2 represents an integer of 0 to 5.) n2 is preferably an integer of 0 to 3, more preferably 1 or 2, and even more preferably 1. The compound represented by formula (4) can be obtained by deacetylation of the compound represented by formula (3). The deacetylation can be carried out by treatment with a base. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, and hydroxylamine.

[0036] The novel compounds represented by the above formulas (2) to (4) are useful as inclusion compounds. For example, they can be used in the same applications as cyclodextrin, and are useful as inclusion agents and encapsulating agents. In particular, those with 6- to 8-membered rings are widely synthesized and industrially used in cyclodextrin. The novel compounds represented by the above formulas (2) to (4) contain an amino group, and are therefore excellent in inclusion of those having an acidic substituent such as a carboxylic acid group. EXAMPLES

[0037] Liquid phase electrolysis automatic synthesis equipment In a preferred embodiment of the present invention, oligosaccharides are synthesized by liquid-phase electrolytic automated synthesis. In this method, glycosyl donors are activated by electrolytic oxidation (Reaction Scheme 9). Unlike conventional glycosylation methods such as Schmidt glycosylation, this method allows for the accumulation of intermediates, and therefore has the advantage of allowing for more precise reaction control. Taking advantage of this precision and reproducibility, we have developed an efficient method for synthesizing cyclic oligosaccharides based on electrolytic polymerization, in which a substrate serves as both a glycosyl donor and a glycosyl acceptor. [ka] (9) [Synthesis of oligosaccharides using an automated liquid-phase electrolytic synthesizer (see the literature below)] Nokami,T.;Shibuya,A.;Tsuyama,H.;Suga.S.;Albert A.Bowers,Crich,D.;Yoshida,JJAm.Chem.Soc.2007,129,10922.

[0038] In 2019, the second generation of liquid-phase automatic electrolysis equipment was developed. This equipment has the advantage that the reaction conditions can be controlled more easily and the desired compound can be synthesized in larger quantities. In this invention, we used this second generation liquid-phase automatic electrolysis equipment to develop an efficient method for synthesizing cyclic oligosaccharides.

[0039] The present invention will be described in more detail below with reference to examples. The materials, amounts, ratios, processing contents, processing procedures, etc. shown in the following examples can be appropriately changed without departing from the spirit of the present invention. Therefore, the scope of the present invention is not limited to the specific examples shown below. If the measuring instruments used in the examples are difficult to obtain due to discontinuation or the like, measurements can be made using other instruments with equivalent performance. All reagents used were commercially available. All solvents used were dehydrated. For glycosylation reactions, 4 Å molecular sieves were added to the dehydrated solvent under an argon atmosphere to perform additional dehydration.

[0040] In the following examples, acetylated compounds are exemplified, but the acetylated compounds can be easily deacetylated by treating them with a base.

[0041] Nuclear magnetic resonance spectra were measured on a Bruker AVANCE II 600 (1H NMR; 600 MHz, 13C NMR; 150 MHz) using CDCl3 as a solvent at room temperature.

[0042] <Preparation Example 101> Synthesis of 1,3,4,6-penta-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (3) [ka] (10) Compound 1 (20.0g, 92.8mmol) was placed in a 500mL flask and dissolved in 120mL of 1M sodium hydroxide solution. Phthalic anhydride (16.32g, 110.7mmol) was then added and stirred overnight. The reaction was then confirmed to be complete by TLC (MeOH), and the mixture was concentrated and dried in vacuum. The mixture was then dissolved in pyridine (300mL) under an argon atmosphere, to which DMAP (1.22g, 9.9mmol) was added as a catalyst, and acetic anhydride (597.6mmol, 57.0mL) was added, and the reaction was carried out for two days. After that, the completion of the reaction was confirmed by TLC (Hexane: EtOAc = 1 / 1), and the reaction was stopped with MeOH. To remove the solvent, the crude product dissolved in EtOAc (ethyl acetate) was washed with 1M HClaq, NaHCO3aq, and H2O three times each, dried with Na2SO4, filtered, concentrated, and dried in vacuum. The obtained crude product was purified with a silica gel column (Hexane / EtOAc = 1 / 1) to obtain compound 3. Yield: 22.0g, 46.2mmol Yield: 50%

[0043] <Preparation Example 102> Synthesis of 4-Chlorophenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-β-D-gluco-pyranoside (4) [ka] (11) Compound 3 (22.04g, 46.7mmol) was added to a flask, 4-chlorothiophenol (8.04g, 55.4mmol) was added thereto, and the atmosphere was replaced with argon. CH2Cl2 (68.4 mL) was added and stirred. BF3 / OEt2 (8.55mL, 69.3mmol) was added dropwise at 0℃. Stirred at 50℃ overnight. TLC check (Hexane / EtOAc=1:1) was performed. NaHCO3aq was added to quench. The organic layer was extracted three times with CH2Cl2. The organic layer was washed three times with desalted water and dehydrated with Na2SO4. It was filtered and concentrated. It was dissolved in EtOAc, recrystallized with hexane, and the filtered product was dried in vacuum to obtain compound 4. Yield: 21.2g, 37.7mmol, 81% yield

[0044] <Preparation Example 103> Synthesis of 4-Chlorophenyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside (6) [ka] (12) Compound 4 (10.00 g, 17.8 mmol) was added to a recovery flask, the atmosphere was replaced with argon, and MeOH (87.0 mL) was added. 2.0 M HCl / Et2O was added and stirred for 3 days. The mixture was concentrated and dried in vacuum. The mixture was replaced with argon, and CH3CN (96.2 mL) was added. Benzaldehyde dimethyl acetal (65.2 mmol, 9.76 mL) was added dropwise and stirred for 2 days. A TLC check (Hexane / EtOAc=2:1) ​​was performed. Et3N (4.2 mL) was added to quench the mixture. The mixture was concentrated and separated using a silica gel column (Hexane / EtOAc=2:1). The mixture was concentrated and dried in vacuum. Yield 6.18g, 11.8 mmol Yield 66% (2 steps)

[0045] <Preparation Example 104> Synthesis of 4-Chlorophenyl-3-O-acetyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-β-Dglucopyranoside (7) [ka] (13) DMAP (0.14g, 1.22mmol) was added to a recovery flask containing compound 6 (5.84g, 11.4mmol) and the atmosphere was replaced with argon. CH2Cl2 (37.2mL) and pyridine (11.8mL) were added. Ac2O (72.2mmol, 6.69mL) was added dropwise and stirred at room temperature overnight. A TLC check (Hexane / EtOAc = 2:1) was performed. Methanol was added to stop the reaction. The mixture was concentrated and dried in vacuum. The mixture was dissolved in CH2Cl2 and recrystallized by adding hexane. The mixture was filtered and dried in vacuum to obtain compound 7. Yield 4.78g, 8.45mmol Yield 76%

[0046] <Preparation Example 105> Synthesis of 4-Chlorophenyl 3-O-acetyl-4-O-benzyl-2-deoxy-2-phtalimido-1-thio-β-Dglucopyranoside (8) [ka] (14) Compound 7 (4.78 g, 8.45 mmol) was placed in a recovery flask, and after drying in vacuum, BH3 / THF (21.2 mL) was added after argon replacement, and TMSOTf (2.12 mL) was added dropwise at 0°C. The mixture was stirred for 6 hours at 0°C. After confirming the completion of the reaction by TLC (Hexane / EtOAc = 2 / 1), Et3N (10 mL) and Methanol (24 mL) were added dropwise in that order to stop the reaction, and the mixture was concentrated and dried in vacuum. The crude product was dissolved in EtOAc, washed three times with NaHCO3aq and desalted water, and dried with Na2SO4. The mixture was filtered, concentrated, and dried in vacuum, and purified with a silica gel column (Hexane / EtOAc = 2 / 1 to 2 / 1) to obtain compound 8. Yield 2.80g, 49.4mmol Yield 58%

[0047] <Reference example 101> Electropolymerization using compound 8 [ka] (15) A 10 mL H-type separation electrolysis cell was purged with argon, Bu4NOTf (1.0 mmol, 0.392 g) was added to the anode, and 8 (0.40 mmol, 0.248 g) was added. Bu4NOTf (1.0 mmol, 0.392 g) was placed in the cathode. The cell was evacuated and vacuum dried overnight. The cell was purged with argon, 10 mL of CH2Cl2 was added to the cathode and anode, and TfOH (40 μL) was added to the cathode. Electrolytic oxidation was performed for 5066 s, 8.0 mA, and -60°C. Glycosylation was performed for 3600 s at -40°C. 0.3 mL of Et3N was added to the cathode and anode to quench. The mixture was concentrated, vacuum dried, and washed with H2O. The obtained crude product was dissolved in 3 mL of CH2Cl2 and purified by GPC.

[0048] <Preparation Example 201> Synthesis of 4-Chlorophenyl 3-O-acetyl-4-O-benzyl-6-O-tert-butyldimethyldiphenylsilyl-2-deoxy-2-phtalimido1-thio-β-D-glucopyranoside (11) [ka] (16) Compound 8 (3.42 g, 6.02 mmol) and imidazole (0.89 g, 12.0 mmol) were placed in a recovery flask, dried in vacuum, substituted with argon, and dissolved in DMF (21.8 mL) at 0 ° C. Then, TBDPSCl (2.64 mL) was added dropwise and stirred at room temperature overnight. After confirming the completion of the reaction by TLC (Hexane: EtOAc = 3 / 1), it was diluted with EtOAc, washed with NaHCO3aq H2O three times each, and dried with Na2SO4. Then, it was filtered, concentrated, dried in vacuum, and purified with a silica gel column (Hexane: EtOAc = 3 / 1) to obtain compound 11. Yield 4.52g, 5.60mmol Yield 93%

[0049] <Preparation Example 202> Synthesis of 4-Chlorophenyl 2-amino-6-O-tert-butyldimethyldiphenylsilyl-2-deoxy-1-thio-β-D-glucopyranoside (12) [ka] (17) Compound 11 (4.52 g, 5.60 mmol) was placed in a recovery flask, dried under vacuum, substituted with argon, and dissolved in n-butanol (37.5 mL). Then, ethylene diamine anhydrous (9.37 mL) was added dropwise, and the temperature was raised to reflux in the order of 30 ° C, 50 ° C, 80 ° C, and 100 ° C. Then, the mixture was stirred overnight, and the end of the reaction was confirmed by TLC (Hexane / EtOAc = 1 / 2). Then, the solvent was concentrated and dried under vacuum, and the crude product was purified with a silica gel column (Hexane / EtOAc = 1 / 2) to obtain compound 12. Yield 3.07g, 4.77mmol Yield 85%

[0050] <Preparation Example 203> Synthesis of 4-Chlorophenyl 6-O-tert-butyldimethyldiphenylsilyl-2-deoxy-2,3-N,O-carbonyl-1-thio-β-D-glucopyranoside (13) [ka] (18) Compound 12 (3.02 g, 4.77 mmol) and Triphosgene (0.56 g, 1.90 mmol) were placed in a recovery flask and dissolved in CH2Cl2 (133.3 mL) under air. 10% NaHCO3aq (99.7 mL) was then added and stirred overnight. Then, it was diluted with CH2Cl2 and extracted. The extract was washed with H2O and dried with Na2SO4. Then, it was filtered, concentrated, and dried in vacuum to obtain compound 13. Yield 2.89g, 4.37mmol Yield 92%

[0051] <Preparation Example 204> Synthesis of 4-Chlorophenyl 2-acetamido-6-O-tert-butyldimethyldiphenylsilyl-2-deoxy-2,3-N,Ocarbonyl-1-thio-β-D-glucopyranoside (14) [ka] (19) Compound 13 (2.89 g, 4.37 mmol) and 60% NaH (1.22 g, 51.2 mmol) were placed in a recovery flask, dried under vacuum, and argon-substituted. Then, it was dissolved in DMF (24.3 mL), and acetyl chloride (2.4 mL) was added dropwise at 0°C, and the mixture was stirred overnight. Then, the reaction was confirmed to be complete by TLC (Hexane / EtOAc = 3 / 1), and the mixture was quenched with NaHCO3aq. Then, the mixture was diluted with CH2Cl2, and washed three times with NaHCO3aq and H2O, and dried with Na2SO4. Then, the mixture was concentrated, dried under vacuum, and purified with a silica gel column (Hexane / EtOAc = 3 / 1) to obtain compound 14.

[0052] <Preparation Example 205> Synthesis of 4-Chlorophenyl 2-acetamido-2-deoxy-2,3-N,O-carbonyl-1-thio-β-D-glucopyranoside (15) [ka] (20) Compound 14 (2.30 g, 3.28 mmol) was placed in a plastic flask, dried under vacuum, purged with argon, pyridine was added, and 30% HF / pyridine was added dropwise at 0°C. After stirring for 4 hours, NaHCO3aq was added to quench. Then, it was dissolved in EtOAc, washed with H2O, and dried with Na2SO4. Filtration, concentration, and vacuum drying were performed, and compound 15 was obtained by purifying with a silica gel column (Hexane / EtOAc = 3 / 1). Yield: 0.94g, 2.03mmol, 62%

[0053] <Reference example 201> Electropolymerization using compound 15 [ka] (twenty one) The atmosphere in a 10 mL H-type separation electrolysis cell was replaced with argon, Bu4NOTf (1.0 mmol, 0.392 g) and DTBMP (2.0 mmol, 0.410 g) were added to the anode, and 8 (0.40 mmol, 0.185 g) was added. Bu4NOTf (1.0 mmol, 0.392 g) was placed in the cathode. The cell was evacuated and vacuum dried overnight. The atmosphere in the cell was replaced with argon, and 10 mL of CH2Cl2 was added to the cathode and anode, and TfOH (40 μL) was added to the cathode. Electrochemical oxidation was performed at 5790 s, 8.0 mA, and 0°C. Glycosylation was performed at 3600 s and 0°C. 0.3 mL of Et3N was added to the cathode and anode, respectively, to quench. The mixture was concentrated, vacuum dried, and washed three times with HClaq, NaHCO3aq, and H2O. The resulting crude product was dissolved in 3 mL of CH2Cl2 and purified by GPC, which confirmed that disaccharide cyclic oligosaccharide 16 was produced (see the NMR spectrum and Figures 1 to 4 below).

[0054] Cyclic disaccharides 16 [α] 24 D = 43.5 (c = 0.7, CHCl3). 1 H-NMR (600 MHz, CDCl3): δ 7.38-7.35 (m, 4 H), 7.33-7.30 (m, 1 H), 5.25-5.23 (d, J = 5.7 Hz, 1 H), 4.91-4.89 (d, J = 11.4 Hz, 1 H), 4.63-4.61(d, J = 11.2 Hz, 1 H), 4.33-4.29 (dd, J = 12.5, 9.8 Hz, 1 H), 4.19-4.17 (dd, J = 9.6, 4.3 Hz,1 H), 4.15-4.14 (dd, J = 2.4, 1.0 Hz, 1H), 4.14 (m, 1H), 4.02-4.00 (dd, J = 10.9, 2.5 Hz,1 H), 3.95-3.92 (dd, J = 12.5, 5.8 Hz, 1 H), 3.60-3.58 (d, J = 10.5 Hz, 1 H), 2.53 (s, 3 H). 13C-NMR (150 MHz, CDCl3): δ 170.6, 153.7, 137.3, 128.5, 128.0, 127.9, 97.0, 81.7, 73.1,63.8, 62.0, 24.5; HRMS (ESI) m / z calcd for C 32 H 34 KN2O 12 [M+K] + , 677.1744; found,677.1735.

[0055] <Preparation Example 301> Synthesis of 4-Chlorophenyl 2-amino-4,6-O-benzylidene-2-deoxy-1-thio-β-D-glucopyranoside (17) [ka] (twenty two) Compound 6 (8.96 g, 17.1 mmol) was placed in a recovery flask, dried under vacuum, substituted with argon, and dissolved in ethanol (90 mL). Ethylene diamine anhydrous (18.6 mL) was then added dropwise, and the temperature was raised to reflux at 30°C, 50°C, 80°C, and 100°C in that order. The mixture was then stirred overnight, and the completion of the reaction was confirmed by TLC (CH2Cl2 / MeOH=8 / 1). The solvent was then concentrated and dried under vacuum, and the crude product was purified using a silica gel column (CH2Cl2 / MeOH=8 / 1) to obtain 17. Yield: 6.56g, 16.7mmol, 98% yield

[0056] <Preparation Example 302> Synthesis of 4-Chlorophenyl 4,6-O-benzylidene-2-deoxy-2,3-N,O-carbonyl-1-thio-β-D-glucopyranoside (18) [ka] (twenty three) 17 (6.56 g, 16.7 mmol) and Triphosgene (1.69 g, 5.68 mmol) were placed in a recovery flask and dissolved in CH2Cl2 (250 mL) under air atmosphere. 10% NaHCO3aq (187 mL) was then added and stirred overnight. Then, it was diluted with CH2Cl2 and extracted. The extract was washed with H2O and dried over Na2SO4. Then, it was filtered, concentrated, and dried in vacuum to obtain 18. Yield: 5.34g, 12.7mmol, 76% yield

[0057] <Preparation Example 303> [ka] (twenty four) Compound 18 (5.34 g, 12.7 mmol) and DMAP (0.31 g, 2.54 mmol) were placed in a recovery flask, dried under vacuum, substituted with argon, and CHCl (38 mL) and pyridine (12.3 mL) were added. Acetic anhydride (11.8 mL) was then added dropwise and stirred overnight. The reaction was then confirmed to be complete by TLC (Hexane / EtOAc = 2:1), and quenched with MeOH. The mixture was then concentrated and dried under vacuum. A small amount of MeOH was added to the obtained crude product, which was left for one day, washed, and purified to obtain compound 19. Yield: 3.80g, 8.22mmol Yield: 65%

[0058] <Preparation Example 304> Synthesis of 4-Chlorophenyl 2-acetamido-6-O-benzyl-2-deoxy-2,3-N,O-carbonyl-1-thio-β-D-glucopyranoside (20) [ka] (twenty five) Compound 19 (3.51 g, 7.61 mmol) was placed in a recovery flask, dried under vacuum, and replaced with argon. CHCl (119.9 mL) and triethyl silane (14.6 mL) were added. BF·EtO (1.4 mL) was then added dropwise and stirred for 4 hours. NaHCOaq was then added to quench the mixture, which was then washed with HO and dried with NaSO. The mixture was then filtered, concentrated, dried under vacuum, and purified with a silica gel column (Hexane / EtOAc = 2 / 1) to obtain compound 20. Yield 2.44g, 5.25mmol Yield 69%

[0059] <Example 301> Electropolymerization using compound 20 [ka] (26) The atmosphere in a 10 mL H-type separation electrolysis cell was replaced with argon, Bu4NOTf (1.0 mmol, 0.392 g) was added to the anode, and 8 (0.40 mmol, 0.185 g) was added. Bu4NOTf (1.0 mmol, 0.392 g) was added to the cathode. The cell was evacuated and vacuum dried overnight. The atmosphere in the cell was replaced with argon, 10 mL of CH2Cl2 was added to the cathode and anode, and TfOH (40 μL) was added to the cathode. Electrochemical oxidation was performed at 2895 s, 8.0 mA, and -40°C. Glycosylation was performed at 3600 s and -40°C. The mixture was then warmed to room temperature and stirred for 3600 s. Then, electrochemical oxidation was performed again at 2895 s, 8.0 mA, and -40°C. Glycosylation was performed at 3600 s and -40°C. The mixture was quenched by adding 0.5 mL of Et3N to the cathode and anode, respectively. The mixture was concentrated, dried in vacuum, and washed with H2O. The resulting crude product was dissolved in 3 mL of CH2Cl2 and purified by GPC. The resulting fraction containing the cyclic hexasaccharide was dissolved in CH3Cl and separated by preparative TLC (Hexane: EtOAc = 2:3), and the area around Rf = 0.7 was scraped off and eluted with CH3Cl. As a result, it was confirmed that cyclic oligosaccharide 21 of hexasaccharide was produced (see the NMR spectrum and Figures 5 to 8 below). Cyclic hexasaccharide 21 1H-NMR (600 MHz, CDCl3): δ 7.33-7.26 (m, 5 H), 5.80-5.80 (d, J = 2.4 Hz, 1 H), 4.54-4.49 (m, 2 H), 4.44-4.42 (d, J = 11.8 Hz, 1 H), 4.18-4.15 (pseudo-t, J = 9.0 Hz, 1 H), 3.81-3.79 (dd, J = 10.7, 4.5 Hz, 1 H), 3.77-3.75 (dd, J = 9.2, 4.9 Hz, 1 H), 3.71-3.69 (dd, J =12.2, 2.3 Hz, 1 H), 3.64-3.62 (d, 10.0 Hz, 1 H), 2.53 (s, 3 H). 13 C-NMR (150 MHz, CDCl3): δ 172.1, 152.3, 137.4, 128.5, 128.0, 127.8, 98.0, 77.7, 74.8, 74.4, 73.7, 68.0, 59.6, 23.5; HRMS (ESI) m / z calcd for C 96 H 102 N6NaO 36 [M+Na] + , 1938.6261; found, 1938.6140.

[0060] <Example 302> Synthesis of Cyclic 6 sugar 21からCyclic 6 sugar 26

change

[0061] Synthesis of Cyclohexakis-(1,4)-(2-amino-6-O-benzyl-2-deoxy-α-D-glucopyranosyl)(23)

change

[0062] Synthesis of Cyclohexakis-(1,4)-(2-acetamide-3-O-acetyl-6-O-benzyl-2-deoxy-α-D-glucopyranosyl) (24) [ka] The solid (85.7 mg) containing sugar 23 and DMAP (5.61 mg, 3.04 mmol) were placed in a glass eggplant flask, dried in vacuum, and replaced with argon. 3.0 mL of pyridine was added thereto, and 0.28 mL of acetic anhydride was added dropwise, and the mixture was stirred at 45°C for about 7 days. Then, MeOH was added to quench the mixture. Then, the mixture was concentrated and dried in vacuum. The obtained solid was dissolved in EtOAc and washed with H2O. The organic layer was dried with Na2SO4, concentrated, and dried in vacuum to obtain 47.2 mg of crude product. This crude product was purified by column chromatography (Hexane / EtOAc (volume ratio) = 2:1, then CH2Cl2 / MeOH (volume ratio) = 1:1) to obtain sugar 24 (22.4 mg, 0.0111 mmol) in 56% yield (2 steps).

[0063] Synthesis of Cyclohexakis-(1,4)-(2-acetamide-6-O-benzyl-2-deoxy-α-D-glucopyranosyl) (25) [ka] Sugar 24 (22.4 mg, 0.0111 mmol) and K2CO3 (14.8 mg, 0.111 mmol) were placed in a glass recovery flask, dried under vacuum, and replaced with argon. 2.32 mL of a mixed solvent of CH2Cl2 / MeOH (1:2) was added and stirred for one day. After confirming the progress of the reaction by MALDI-TOF-MS, the mixture was concentrated and dried under vacuum to obtain a solid (46.2 mg) containing the target compound 25.

[0064] Synthesis of Cyclohexakis-(1,4)-(2-acetamide-2-deoxy-α-D-glucopyranosyl)(26) [ka] The solid containing sugar 25 in a glass eggplant flask was dried in vacuum and replaced with argon. 1.00 mL of a mixed solvent of THF / H2O (1:1) was added to the flask. The mixture was then frozen once, 70 mg of Pd(OH)2 / C was added, dried in vacuum, and replaced with hydrogen. The mixture was stirred for 7 days, and the progress of the reaction was confirmed by MALDI-TOF-MS. The mixture was then concentrated and dried in vacuum to obtain a solid containing the target product. The solid was purified by gel filtration column chromatography on Sphadex LH-20 to obtain sugar 26 (1.6 mg, 0.0013 mmol) in a yield of 12% (2 steps).

[0065] Figure 9 shows the MALDI-TOF MS after the reaction of reaction scheme (27) was stopped. Figure 10 shows the MALDI-TOF MS after gel filtration of the product (Sephadex LH-20, solvent: ion-exchanged water). Figure 11 shows the MALDI-TOF MS after gel filtration of the product. 1 H-NMR. These results show that the desired product (compound of formula (3)) has been obtained.

[0066] Mass spectrometry data for intermediate saccharide 24 is shown in Figure 12. The calculated and measured values ​​are as follows: Mass spectrometry (MALDI-TOF) C102H126N6NaO36 [M+Na+] Calculated value: 2033.811, Found value: 2033.807

[0067] Mass spectrometry data for the final product, sugar 26, is shown in Figure 13. The calculated and measured values ​​are as follows: Mass spectrometry (MALDI-TOF) C48H78N6NaO30 [M+Na+] calculated value: 1241.466, found value: 1241.466

Claims

1. The method includes subjecting a linear oligosaccharide represented by the following formula (1) to a liquid phase electrolytic reaction, A method for producing cyclic oligosaccharides, wherein the liquid-phase electrolysis reaction is carried out by applying an electric current in a separate electrolysis cell, thereby carrying out an electrochemical oxidation reaction. Formula (1) 【Chemistry 1】 (In formula (1), R １ are each independently a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ２１ and R ２２ are each independently a hydrogen atom, a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ３ are each independently a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ４ is a phenyl group, a 4-methylphenyl group, a 2,6-dimethylphenyl group, a 4-bromophenyl group, a 4-chlorophenyl group, or a 4-fluorophenyl group, X is a sulfur atom, and n1 is an integer of 3 to 8. ２２ and R ３ may be bonded to each other to form a 5- or 6-membered heterocycle.

2. The method for producing a cyclic oligosaccharide according to claim 1, wherein the linear oligosaccharide represented by the formula (1) is represented by the following formula (1-1): Formula (1-1) 【Chemistry 2】 (In formula (1-1), R １ are each independently a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ２１ are each independently a hydrogen atom, a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ４ is a phenyl group, a 4-methylphenyl group, a 2,6-dimethylphenyl group, a 4-bromophenyl group, a 4-chlorophenyl group, or a 4-fluorophenyl group, X is a sulfur atom, and n1 is an integer of 3 to 8.

3. A cyclic oligosaccharide represented by formula (2): Formula (2) 【Chemistry 3】 (In formula (2), R １ are each independently a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ２１ and R ２２ are each independently a hydrogen atom, a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ３１ Each independently represents R ３ is an —O— group, and R ３ are each independently a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group, and n2 is an integer of 0 to 5. ２２ and R ３１ may be bonded to each other to form a 5- or 6-membered heterocycle.

4. A cyclic oligosaccharide represented by the formula (2-1): Formula (2-1) 【Chemistry 4】 (In formula (2-1), R １ are each independently a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ２１ are each independently a hydrogen atom, a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group, and n2 is an integer of 0 to 5.

5. A cyclic oligosaccharide represented by formula (3): Formula (3) 【Chemistry 5】 (In formula (3), n2 represents an integer of 0 to 5, and Ac represents an acetyl group.)

6. An inclusion agent comprising the oligosaccharide according to any one of claims 3 to 5.

7. A cyclic oligosaccharide represented by the following formula (2-1) is subjected to a ring-opening of the oxazolidinone ring with a base, and the resulting sugar is reacted with acetic anhydride to acetylate the ring-opened site. ２ CO ３ This is reacted with an acid to give a sugar having the 3-acetyloxy group converted back to a hydroxyl group, and the sugar is reacted with an acid to give R １ The method for producing a cyclic oligosaccharide, comprising the steps of: Formula (2-1) 【Chemistry 6】 (In formula (2-1), R １ are each independently a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group; R ２１ are each independently a hydrogen atom, a benzyl group, a benzoyl group, an acetyl group, a pivaloyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, or a 9-fluorenylmethylcarboxy group, and n2 is an integer of 0 to 5. Formula (3) 【Chemistry 7】 (In formula (3), n2 represents an integer of 0 to 5, and Ac represents an acetyl group.)

8. A linear oligosaccharide represented by formula (5). Formula (5) 【Chemistry 8】 (In formula (5), Ar is 4-ClC ６ H ４ where Ac represents an acetyl group, Bn represents a benzyl group, and n represents an integer of 0 to 4.

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