JP6455857B2 - Method for producing sugar chain compound - Google Patents

Description

  The present invention relates to a sugar chain compound that is an oligosaccharide or polysaccharide containing an amino sugar, and a method for producing a sugar chain compound.

  As sugar chains derived from biological resources including amino sugars, for example, chitin and chitosan, and heparosan, heparin and heparan sulfate are known.

  Chitin and chitosan are compounds having a molecular weight of several thousand to several tens of thousands, in which N-acetylglucosamine and glucosamine are respectively β1,4-linked, and are sugar chains derived from biological resources obtained from crustacean shells. Chitin and chitosan have features such as (i) no fear of depletion, (ii) high safety, and (iii) biodegradability, so that medical materials such as surgical threads, foods and cosmetics Has been applied.

  Heparin and heparan sulfate are polysaccharides having a basic skeleton of a repeating structure of glucuronyl- or iduronyl-β-1 → 4-N-acetylglucosamine disaccharide unit. -Many modifications such as sulfation have been made.

  Heparin is used as an anticoagulant, and generally heparin isolated and purified from the porcine intestinal tract is used as an anticoagulant. The heparin used is various such as unfractionated heparin, fractionated heparin, low molecular weight heparin, and ultra low molecular weight heparin. Among them, low molecular weight heparin has an advantage that there are few side effects such as bleeding.

Japanese Patent Publication “JP 2004-18840” International Publication No. 2011/0286668 US Patent Application Publication No. 2010/0036001 International Publication No. 2009/014559

Shino Manabe, et al., “N-Benzyl-2,3-Oxazolidinone as a Glycosyl Donor for Selective α-Glycosylation and One-Pot Oligosaccharide Synthesis Involving 1,2-cis-Glycosylation” J. Am. Chem. Soc. 2006 , 128, 10666-10667. Hiroko Satoh, et al., “Low Barrier Pathway for Endo-cleavage Induced Anomerization of Pyranosides with N-benzyl-2,3-trans Oxazolidinone” Eur. J. Org. Chem. 2009, 1127-1131. Shino Manabe, et al., “Evidence for Endocyclic Cleavage of Conformationally Restricted Glycopyranosides” Chem. Eur. J. 2009, 15, 6894-6901. Shino Manabe, et al., “Significant Solvent Effect in Anomerization Reaction of Pyranosides” Tetrahedron Lett. 2009, 50, 4827-4829. Shino Manabe, et al., “N-benzyl 2,3-trans CarbamatesBearing Glycosyl Donors for 1,2-cis Selective Glycosylation Reactions” Eur. J. Org. Chem. 2011, 497-516. Hiroko Satoh, et al., “EndocyclicCleavage in Glycosides with 2,3-trans Cyclic Protecting Groups” J. Am. Chem. Soc. 2011, 133, 5610-5619. Olsson, Johan D. M. et al., “Stereoselective Glycosylationsusing a 2-N-acyl-2N, 3O-oxazolidinone protected GlcNAc donor.” J. Org. Chem. 2008, 73 (18), 7181-7188. Boysen, Mike, et al., “Ethyl 2-acetamido-4,6-di-O-benzyl-2,3-N, O-carbonyl-2-deoxy-1-thio-β-D-glycopyranoside as a versatile GlcNAc donor. ”Chemical Communications (Cambridge, United Kingdom), 2005, (24), 3044-3046. Crich, D., et al., “6-O-Benzyl- and 6-O-Silyl-N-acetyl-2-amino-2-N, 3-O-carbonyl-2-deoxyglucosides: Effective Glycosyl Acceptors in the Glucosamine 4-OH Series. Effect of Anomeric Stereochemistry on the Removal of the Oxazolidinone Group. ”J. Org. Chem. 2005, 70, 1291-1296. Wei, P., et al., “Factors Affecting Stereocontrol during Glycosidation of 2,3-Oxazolidinone-Protected 1-Tolylthio-N-acetyl-d-glucosamine.” J. Org. Chem. 2005, 70, 4195-4198. Geng, Y., et al., “Pre-activation protocol leading to highly stereoselectivity-controllable glycosylations of oxazolidinoneprotected glucosamines.” Chem. Commun. 2008, 597-599. Barreteau, Helene, et al., “Production of intracellular heparosan and derived oligosaccharides by lyase expression in metabolically engineered E.coli K-12” Carbohydrate Research, 2012, 360, 19-24. Chavaroche, Anais A. E., et al., “Synthesis of heparosan oligosaccharides by Pasteurella multocida PmHS2 single-action transferases” Applied Microbiology and Biotechnology, 2012, 95 (5), 1199-1210. Liu, Yanfeng, et al., “Effects of carbon sources and feeding strategies on heparosan production by Escherichia coli K5” Bioprocess and Biosystems Engineering, 2012, 35 (7), 1209-1218. Zhang, Chunyu, et al., “Metabolic engineering of Escherichia coli BL21 for biosynthesis of heparosan, a bioengineered heparin precursor” Metabolic Engineering, 2012, 14 (5), 521-527. Chavaroche, Anais A. E., et al., “Production methods for heparosan, a precursor of heparin and heparan sulfate” Carbohydrate Polymers. Otto, Nigel J., et al., “Structure / Function Analysis of Pasteurellamultocida HeparosanSynthases: Toward Defining Enzyme Specificity and EngineeringNovel Catalysts” Journal of Biological Chemistry, 2012, 287 (10), 7203-7212. Chen, Xiang'e, et al., “Effects of heparosanand heparin on the adhesion and biofilm formation of several bacteria in vitro” Carbohydrate Polymers, 2012, 88 (4), 1288-1292. Masuko, Sayaka, et al., “Ozonolysis of the double bond of the unsaturated uronateresidue in low-molecular-weight heparin and K5 heparosan” Carbohydrate Research, 2011, 346 (13), 1962-1966. Higashi, Kyohei, et al., “Controlled photochemical depolymerizationof K5 heparosan, a bioengineered heparin precursor” Carbohydrate Polymers, 2011, 86 (3), 1365-1370. Wang, Zhenyu, et al., “Control of the heparosan N-deacetylation leads to an improved bioengineered heparin” Applied Microbiology and Biotechnology, 2011, 91 (1), 91-99. Chavaroche, Anais AE, et al., “Analysis of the Polymerization Initiation and Activity of Pasteurella multocida Heparosan Synthase PmHS2, and Enzyme with Glycosyltransferase and UDP-sugar Hydrolase Activity” Journal of Biological Chemistry, 2011, 286 (3), 1777-1785 . Wang, Zhenyu, et al., “E. coli K5 fermentation and the preparation of heparosan, a bioengineered heparin precursor” Biotechnology and Bioengineering, 2010, 107 (6), 964-973. Ly, Mellisa, et al., “Analysis of E. coli K5 capsular polysaccharide heparosan” Analytical and Bioanalytical Chemistry, 2011, 399 (2), 737-745. Chavaroche, Anais A. E., et al., “In vitro synthesis of heparosan using recombinant Pasteurella multocidaheparosan synthase PmHS2” Applied Microbiology and Biotechnology, 2010, 85 (6), 1881-1891. Legoux, Richard, et al., “N-Acetyl-heparosan lyase of Escherichia coli K5: gene cloning and expression” Journal of Bacteriology, 1996, 178 (24), 7260-7264. Wang Zhenyu, et al., “Escherichia coli K5 heparosanfermentation and improvement by genetic engineering” Bioengineered bugs, 2011, 2 (1), 63-67. Tojo Taira, “Preparation of low molecular weight K5 heparosan by photolysis”, Abstracts of the 132nd Annual Meeting of the Pharmaceutical Society of Japan, 2012, 132 (3), 183. Fumino Hatanabe et al., “1,2-cis aminoglycosideomer stereocontrol and synthesis of new sugar chains using endo-cleavage reaction”, 54th Natural Organic Compound Discussion, Proceedings, 2012.

  Cellulose composed of a glucose 1,4-β bond and amylose composed of a glucose 1,4-α bond are the same glucose with the same constitutional unit and the same binding position. However, since the stereochemistry at the anomeric positions is different from each other, the higher-order steric structures are different, and the physicochemical properties such as solubility are different. In sugar chain compounds composed of glucosamine units or N-acetylglucosamine units, there are chitin and chitosan which are sugar chain compounds consisting of 1,4-β bonds corresponding to cellulose, but glucosamine 1,4 corresponding to amylose. There are no known sugar chain compounds composed of -α bonds and sugar chain compounds composed of N-acetylglucosamine 1,4-α bonds.

  Acquire oligosaccharides composed of glucosamine 1,4-α bonds and oligosaccharides composed of N-acetylglucosamine 1,4-α bonds (hereinafter collectively referred to as 1,4-α (N-acetyl) glucosamine oligomers). As a method for this, a synthetic method in which a glycosylation reaction for generating a 1,4-α bond is repeatedly performed can be considered. However, for amino sugars such as acetylglucosamine and N-acetylglucosamine, it has been difficult to synthesize 1,4-α (N-acetyl) glucosamine oligomers because a complete α-selective glycosylation reaction has not been developed. There have been no reports of successful synthesis so far.

  In addition, commonly used heparin is a mixture of many compounds having different molecular weights and sulfation positions. Therefore, when heparin is used as an anticoagulant, problems of side effects and management after administration have been pointed out. In recent years, there has been an accident in which fatalities occur due to the presence of persulfated chondroitin sulfate in the preparation. Therefore, there is a demand for chemically synthesized products that can be strictly managed. So far, although fondaparinux, a chemically synthesized pentasaccharide, has been developed as the first synthetic drug that acts only on the coagulation factor Xa of the blood coagulation system, a new chemically synthesized product is still required.

  Heparin is considered to be biosynthesized with heparosan, which is a repeating structure of iduronyl- or glucuronyl-β-1 → 4-N-acetylglucosamine disaccharide unit, as a precursor. Therefore, it is considered that heparin or heparan sulfate can be synthesized through various enzyme reactions using heparosan as a starting material following the biosynthesis process. Since heparosan is found in the cell wall of the E. coli K5 strain, heparosan can be obtained by chemically and enzymatically degrading the E. coli cell wall. And low molecular weight heparosan can be acquired by reducing the molecular weight of heparosan obtained from the E. coli cell wall. However, even a compound obtained by the molecular weight reduction treatment does not have a sufficiently small molecular weight, that is, it does not have a molecular weight at the oligosaccharide level. In addition, no examples of successful synthesis of heparosan at the oligosaccharide level have been reported.

  Therefore, the present invention has been made in view of the above problems, and its object is to provide a novel oligosaccharide or polysaccharide containing a 1,2-cis-type amino sugar, which has not been synthesized until now. There is to do.

In order to solve the above problems, a first aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (a) or (b), wherein the sugar chain compound comprises a plurality of sugar residues. And a sugar chain compound containing one or more 1,2-cis sugar residues.
(A) A polysaccharide or oligosaccharide formed by repeatedly binding sugar units represented by the following formula (I) or (I ′).
(B) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (II) or (II ′).

(In the formulas (I) and (I ′), R ¹ and R ² are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, alkoxycarbonyl group, allyloxycarbonyl group or Represents an aryloxycarbonyl group, and R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, an acyl group, an allyl group, an aryl group, a hydroxyalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, Represents a benzoyloxycarbonyl group, a sulfo group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group, a carboxyfluoroalkyl group or a sulfo group, and the wavy line independently represents a bond having an equatorial or axial configuration. In the formula (I ′), R ²⁴ represents an alkyl group. Represents a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group or an aryloxycarbonyl group.)

(In the formulas (II) and (II ′), R ¹ and R ² are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, alkoxycarbonyl group, allyloxycarbonyl group or R ³ and R ⁵ each independently represent a hydrogen atom, an alkyl group, an acyl group, an allyl group, an aryl group, a hydroxyalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, Represents a benzoyloxycarbonyl group, a sulfo group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group, a carboxyfluoroalkyl group or a sulfo group, and the wavy line independently represents a bond having an equatorial or axial configuration. In the formula (II ′), R ²⁴ represents al Represents a kill group, haloalkyl group, allyl group, aryl group, acyl group, alkoxycarbonyl group, allyloxycarbonyl group or aryloxycarbonyl group.)
In order to solve the above problems, a second aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (c) or (d), wherein the sugar chain compound comprises a plurality of sugar residues. And a sugar chain compound containing one or more 1,2-cis sugar residues.
(C) An oligosaccharide formed by repeatedly binding sugar units represented by the following formula (III) or (III ′).
(D) An oligosaccharide formed by repeatedly binding sugar units represented by the following formula (IV) or (IV ′).

(In the formulas (III) and (III ′), R ¹ and R ² are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, alkoxycarbonyl group, allyloxycarbonyl group or R ³ , R ⁴ , R ⁶ and R ⁷ each independently represents a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxyalkyl group or an alkoxycarbonyl group. , Allyloxycarbonyl group, benzoyloxycarbonyl group, sulfo group, phosphoric acid group, alkylsilyl group, fluoroalkyl group, fluoroacyl group or carboxyfluoroalkyl group, R ⁸ represents —CH ₂ OR ⁹ or —COOR ^10. the stands, ^{R 9} is a hydrogen atom, an alkyl group, an acyl group, Ryl, aryl, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, allyloxycarbonyl, benzoyloxycarbonyl, phosphate, sulfo, alkylsilyl, fluoroalkyl, fluoroacyl or carboxyfluoroalkyl R ¹⁰ represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, an alkylsilyl group, a fluoroalkyl group or a tert-butyl group, and the wavy line independently represents a bond having an equatorial or axial configuration. In formula (III ′), R ²⁴ represents an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, or an aryloxycarbonyl group.

(In the formulas (IV) and (IV ′), R ¹ and R ² each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, or R ³ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxyalkyl group or an alkoxycarbonyl group. , Allyloxycarbonyl group, benzoyloxycarbonyl group, sulfo group, phosphoric acid group, alkylsilyl group, fluoroalkyl group, fluoroacyl group or carboxyfluoroalkyl group, R ⁸ represents —CH ₂ OR ⁹ or —COOR ^10. the stands, ^{R 9} is a hydrogen atom, an alkyl group, an allyl group, Ali Group, acyl group, hydroxyalkyl group, carboxyalkyl group, alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarbonyl group, phosphoric acid group, sulfo group, alkylsilyl group, fluoroalkyl group, fluoroacyl group or carboxyfluoroalkyl R ¹⁰ represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, an alkylsilyl group, a fluoroalkyl group or a tert-butyl group, and the wavy line independently represents a bond having an equatorial or axial configuration. In formula (IV ′), R ²⁴ represents an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, or an aryloxycarbonyl group.
A third aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (g) or (h) in order to solve the above-mentioned problem, wherein the sugar chain compound has a plurality of sugar residues. And a sugar chain compound containing one or more 1,2-cis sugar residues.
(G) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (V).
(H) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VI).

(In the formula (V), R ¹⁶ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphoric acid group, an alkoxycarbonyl group, an allyloxycarbonyl group, a trialkylsilyl group, or represents a tert-butyldiphenylsilyl group, and R ²³ represents an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group. (Represents a bond that exhibits an equatorial or axial configuration.)

(In the formula (VI), R ¹⁷ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphoric acid group, an alkoxycarbonyl group, an allyloxycarbonyl group, a trialkylsilyl group, or represents a tert-butyldiphenylsilyl group, and R ²³ represents an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group. (Represents a bond that exhibits an equatorial or axial configuration.)
A fourth aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (i) or (j) in order to solve the above-mentioned problem, wherein the sugar chain compound has a plurality of sugar residues. And a sugar chain compound containing one or more 1,2-cis sugar residues.
(I) An oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VII). (J) An oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VIII).

(In the formula (VII), R ¹⁶ and R ^{18 to} R ²⁰ are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, Represents an allyloxycarbonyl group, a trialkylsilyl group or a tert-butyldiphenylsilyl group, and R ²³ represents an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or 2,2,2-trichloroethoxycarbonyl. (The wavy line independently represents a bond exhibiting an equatorial or axial configuration.)

(In formula (VIII), R ^{17 to} R ²⁰ are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl. group, a trialkylsilyl group or tert- butyldiphenylsilyl ^{group, R 23} represents an acetyl group, methoxycarbonyl group, allyloxycarbonyl group, benzyloxycarbonyl group or 2,2,2-trichloroethoxycarbonyl group, (The wavy lines independently represent bonds exhibiting an equatorial or axial configuration.)
In order to solve the above problems, a method for producing a sugar chain compound according to the present invention is a method for producing a sugar chain compound containing a 1,2-cis sugar residue,
(I) a step of preparing a sugar chain compound according to the following (k), (l), (m) or (n);
(K) a polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (Ib),
(L) a polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (IIb);
(M) an oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (IIIb);
(N) an oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (IVb);

(In Formula (Ib), R ¹³ and R ¹⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, or a phosphate group, and R ¹⁵ and R ¹⁶ Are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group or tert-butyldiphenylsilyl. (The wavy line independently represents a bond exhibiting an equatorial or axial configuration.)

(In formula (IIb), R ¹³ and R ¹⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, or a phosphate group, and R ¹⁵ and R ¹⁷ Are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group or tert-butyldiphenylsilyl. (The wavy line independently represents a bond exhibiting an equatorial or axial configuration.)

(In Formula (IIIb), R ¹³ and R ¹⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, or a phosphate group, and R ¹⁵ , R ¹⁶ , R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group Or a tert-butyldiphenylsilyl group, R ²⁰ represents —CH ₂ OR ²¹ or —COOR ²² , and R ²¹ represents a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxy group, Alkyl group, alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarboni Group, a sulfo group, a phosphoric acid group, an alkyl silyl group, a fluoroalkyl group, fluoro acyl group, carboxyalkyl fluoroalkyl group, a trialkylsilyl group or tert- butyldiphenylsilyl group, R ²² represents a hydrogen atom, an alkyl group, (Represents a haloalkyl group, an allyl group, an aryl group, or an acyl group. The wavy line independently represents a bond having an equatorial or axial configuration.)

(In Formula (IV), R ¹³ and R ¹⁴ each independently represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, or a phosphate group, and R ¹⁵ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, alkyl group, allyl group, aryl group, acyl group, sulfo group, phosphoric acid group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group or tert- Represents a butyldiphenylsilyl group, R ²⁰ represents —CH ₂ OR ²¹ or —COOR ²² , and R ²¹ represents a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxyalkyl group, Alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarbonyl group, sulfo group, phosphorus Group, a sulfo group, an alkylsilyl group, fluoroalkyl group, fluoro acyl group, carboxyalkyl fluoroalkyl group, a trialkylsilyl group or tert- butyldiphenylsilyl group, R ²² represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl Represents a group, an aryl group or an acyl group, and a wavy line independently represents a bond having an equatorial or axial configuration.)
(Ii) introducing a carbamate group into the sugar chain compound prepared in the step (i), and
(Iii) reacting the sugar chain compound introduced with a carbamate group with hydrochloric acid, bis (trifluoromethylsulfonyl) imide or trifluoroacetic acid or a weakly acidic Lewis acid in an organic solvent;
A process for producing a sugar chain compound.

  According to the present invention, N-acetylglucosamine or a derivative thereof, or an oligosaccharide or polysaccharide in which glucosamine or a derivative thereof is α1,4-linked, which has not been known so far, can be provided.

  Moreover, according to the present invention, an oligosaccharide of heparosan that has not been known so far can be provided.

  Since no complete 1,2-cis-type selective glycosylation reaction has been developed for amino sugars, methods for producing oligosaccharides or polysaccharides of 1,2-cis-type amino sugars have not been known so far. As a result of intensive studies by the present inventors, the present inventors succeeded in producing oligosaccharides of 1,2-cis type amino sugars by isomerizing sugar chains consisting of 1,2-trans type amino sugars. The invention has been completed.

  One embodiment of a sugar chain compound and a method for producing a sugar chain compound according to the present invention will be described below.

[1. Sugar chain compound)
(First aspect)
A first aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (a) or (b), wherein the sugar chain compound has a plurality of sugar residues, -A sugar chain compound containing one or more cis-type sugar residues.
(A) A polysaccharide or oligosaccharide formed by repeatedly binding sugar units represented by the formula (I) or (I ′).
(B) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the formula (II) or (II ′).

In formulas (I) and (I ′) and formulas (II) and (II ′), R ¹ and R ² each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, An alkoxycarbonyl group, an allyloxycarbonyl group or an aryloxycarbonyl group is represented.

Examples of the alkyl group include an alkyl group having 1 to 20 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, an n-butyl group, an isobutyl group, and a pentyl group. Also,
Examples of the haloalkyl group include a group in which at least one hydrogen atom is substituted with a halogen atom in the above-described alkyl group, and examples thereof include a trifluoromethyl group.

  Examples of the aryl group include a benzyl group, a p-methoxybenzyl group, a naphthyl group, a tolyl group, and a p-nitrobenzyl group.

Examples of the acyl group include an acetyl group, Baie Nzoiru group, pivaloyl group and trifluoroacetyl group.

  Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, and a trichloroethoxycarbonyl group.

  As the aryloxycarbonyl group, a benzyloxycarbonyl group can be exemplified.

Alternatively, R ¹ and R ² may be bonded to form a cyclic structure together with the nitrogen atom. For example, a succinyl group and a phthaloyl group can be given as examples in which R ¹ and R ² which are acyl groups are bonded.

Among them, R ¹ and R ² are each independently preferably a hydrogen atom, an acyl group, an alkoxycarbonyl group, and an aryloxycarbonyl group, and each independently a hydrogen atom, an acetyl group, a trifluoroacetyl group, a methoxycarbonyl group, an ethoxy group. A carbonyl group, a benzyloxycarbonyl group, and a trichloroethoxycarbonyl group are more preferable, and a hydrogen atom and an acetyl group are particularly preferable.

In the formulas (I) and (I ′) and the formulas (II) and (II ′), R ³ represents a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxyalkyl group, an alkoxycarbonyl group. Represents a group, an allyloxycarbonyl group, a benzoyloxycarbonyl group, a sulfo group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group or a carboxyfluoroalkyl group.

  As an alkyl group, the above-mentioned C1-C20 alkyl group can be mentioned, for example.

  Examples of the acyl group include acetyl group, trifluoroacetyl group, pivaloyl group, p-methoxybenzoyl group, p-nitrobenzoyl group and benzoyl group.

  Examples of the aryl group include a benzyl group, a p-methoxybenzyl group, a naphthyl group, a tolyl group, and a p-nitrobenzyl group.

  As a hydroxyalkyl group, C1-C10 hydroxyalkyl groups, such as a hydroxyethyl group, a hydroxypropyl group, a glyceryl group, can be mentioned.

  Examples of the carboxyalkyl group include carboxyalkyl groups having 1 to 20 carbon atoms in the alkyl moiety such as a carboxymethyl group.

  Examples of the alkoxycarbonyl group include alkoxycarbonyl groups having 1 to 20 carbon atoms in the alkyl moiety such as an ethyloxycarbonyl group and a trichloroethyloxycarbonyl group.

  Examples of the alkylsilyl group include a tert-butylsilyl group and a triethylsilyl group.

  The fluoroalkyl group, the fluoroacyl group, and the carboxyfluoroalkyl group may be ones in which one or more hydrogen atoms are substituted with fluorine atoms in the above-described alkyl group, acyl group, and carboxyalkyl group, respectively.

Among them, R ³ is preferably a hydrogen atom, an acyl group or an aryl group, more preferably a hydrogen atom, an acetyl group or a benzyl group, and particularly preferably a hydrogen atom.

In the formulas (I) and (I ′), R ⁴ represents a hydrogen atom, alkyl group, allyl group, aryl group, acyl group, hydroxyalkyl group, carboxyalkyl group, alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarbonyl Represents a group, a sulfo group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group or a carboxyfluoroalkyl group. Any group can be exemplified by the same groups as those exemplified for R ³ . Among them, R ⁴ is preferably a hydrogen atom, an acyl group or an aryl group, more preferably a hydrogen atom, an acetyl group or a benzyl group, and particularly preferably a hydrogen atom.

In the formulas (II) and (II ′), R ⁵ represents a hydrogen atom, alkyl group, allyl group, aryl group, acyl group, hydroxyalkyl group, carboxyalkyl group, alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarbonyl Represents a group, a sulfo group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group or a carboxyfluoroalkyl group. Any group can be exemplified by the same groups as those exemplified for R ³ . Among them, R ⁵ is preferably a hydrogen atom, an acyl group or an aryl group, more preferably a hydrogen atom, an acetyl group or a benzyl group, and particularly preferably a hydrogen atom.

In the formulas (I ′) and (II ′), R ²⁴ represents an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group or an aryloxycarbonyl group. As the alkyl group, haloalkyl group, aryl group, acyl group, alkoxycarbonyl group and aryloxycarbonyl group, those exemplified in the description of R ¹ and R ² can be mentioned.

In formulas (I) and (I ′) and formulas (II) and (II ′), the wavy lines independently represent bonds that exhibit an equatorial or axial configuration. That is, with regard to the bond at the ^1st carbon atom, a bond that becomes a 1,2-cis type or a 1,2-trans type in relation to —NR ¹ R ² bonded to the 2nd carbon atom, It is a bond that becomes. The bond in the 1,2-cis form is a bond that generates an α1,4-bond in the case of the compound represented by formula (I), and α1,6 in the case of the compound represented by formula (II). A bond that causes a bond; The bond in the 1,2-trans form is a bond that generates a β1,4-bond in the case of the compound represented by the formula (I), and β1 in the case of the compound represented by the formula (II). , 6 is a bond that generates a bond. Similarly, with respect to the bond at the 4-position carbon atom, a bond that becomes a 2,4-cis type in relation to —NR ¹ R ² bonded to the 2-position carbon atom, or 2,4-trans It represents a bond that becomes a type. In other words, the 2,4-cis type bond represents the same configuration as glucosamine with respect to the 4-position bond, and the 2,4-trans type bond has the same configuration as galactosamine. Represents.

  In the sugar chain compound in this embodiment, it is sufficient that at least one 1,2-cis type sugar residue is contained, but 10% or more of the sugar residues in the sugar chain compound are 1,2 -Preferably it is cis, more preferably 15% or more of the sugar residues are 1,2-cis, more preferably 20% or more of the sugar residues are 1,2-cis. It is particularly preferred that all sugar residues are 1,2-cis.

  The sugar chain compound in this embodiment may be either an oligosaccharide or a polysaccharide. In the present specification, the oligosaccharide means a polymerized sugar in which monosaccharide units are polymerized in the range of 2 to 16 inclusive. Polysaccharide means a polymerized sugar in which 17 or more monosaccharide units are polymerized.

  When the sugar chain compound in this embodiment is an oligosaccharide, the number of sugar residues is preferably 2 or more, 16 or less, more preferably 2 or more and 10 or less, and particularly preferably 2 or more and 8 or less. .

  On the other hand, when the sugar chain compound in this embodiment is a polysaccharide, the mass average molecular weight is preferably 1,000 or more and 30,000 or less, more preferably 1,000 or more and 10,000 or less, and 1,000. It is particularly preferably 5,000 or more and 5,000 or less.

  In this embodiment, the reducing end and the non-reducing end of the sugar chain compound are each independently acetyl group; benzyl group; p-methoxyphenyl group; alkyl group including amino group; and allyl group; It may be modified with Alternatively, other monosaccharides may be bound.

  A more preferred form of the sugar chain compound in the first aspect of the sugar chain compound according to the present invention is an oligosaccharide (IX) represented by the following formula (IX).

Wherein ^(IX), the definition of R 1 to R ⁴ are as defined for ^R 1 to R ⁴ in formula (I). R ¹¹ represents a hydroxy group, an alkyl group, a haloalkyl group, an allyl group, an aryl group, glucosamine, glucuronic acid, iduronic acid or an acyl group, and R ¹² represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group , Glucosamine, glucuronic acid, iduronic acid or an acyl group, and n represents an integer of 2 to 16.

Among oligosaccharides (IX), R ¹ is a hydrogen atom, acyl group, alkoxycarbonyl group or aryloxycarbonyl group, R ² is a hydrogen atom, acetyl group or trifluoroacetyl group, benzoyl group or alkyl group, and R ³ is hydrogen More preferred are oligosaccharides having an atom, an acetyl group or a benzyl group, R ⁴ is a hydrogen atom, an acetyl group or a benzyl group, and n is an integer of 2 to 16, R ¹ is a hydrogen atom, R ² is a hydrogen atom or an acetyl group, An oligosaccharide in which R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, and n is an integer of 4 to 8 is particularly preferable.

  The sugar chain compound in this embodiment will be described later [2. It can be produced by the production method described in [Production method of sugar chain compound]. However, the production method of the sugar chain compound in this embodiment is not limited to the production method.

  The sugar chain compound according to the first aspect, like chitin and chitosan, is (i) a raw material for medical materials such as wound dressings, hemostatic agents, surgical sutures and artificial bones; (ii) antibacterial and Auxiliary raw materials for imparting moisture retention, (iii) Textile raw materials for textile products such as clothing, bedding, home appliances and baby products, (iv) Food additives such as sweeteners and thickening stabilizers or health Raw materials for food materials as food, (v) raw materials for agricultural supplies such as plant disease preventive agents, growth promoters, soil conditioners, feed additives and animal disease therapeutic agents, (vi) materials as wastewater treatment carriers , (Vii) a carrier that can be used in a drug delivery system, and (viii) a liquid crystal additive.

In addition, the 1st aspect of the sugar_chain | carbohydrate compound which concerns on this invention can also be expressed like the following (a ') and (b').
(A ′) a polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the formula (I) or (I ′), and comprising one or more α1,4-glycosidic bonds sugar.
(B ′) a polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the formula (II) or (II ′), and comprising one or more α1,6-glycosidic bonds sugar.

(Second embodiment)
A second aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (c) or (d), wherein the sugar chain compound has a plurality of sugar residues, -A sugar chain compound containing one or more cis-type sugar residues.
(C) An oligosaccharide formed by repeatedly bonding sugar units represented by the formula (III) or (III ′).
(D) An oligosaccharide formed by repeatedly bonding sugar units represented by the formula (IV) or (IV ′).

In formula (III) and (III ') and formula (IV) and ^(IV'), the definition of R 1 to R ³ and the wavy line, the above formula (I) and in ^R 1 to R ³ and the wavy line (II) Same as definition. In addition, the definition of R ⁴ in the formulas (III) and (III ′) and the definition of R ^{5 in} the formulas (IV) and (IV ′) are respectively defined as R ⁴ in the formula (I) and R in the formula (II). ^This is the same as the definition of ⁵ .

R ⁶ and R ⁷ in formulas (III) and (III ′) and formulas (IV) and (IV ′) are each independently a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, A carboxyalkyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, a benzoyloxycarbonyl group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group, or a carboxyfluoroalkyl group is represented.

  As an alkyl group, the above-mentioned C1-C20 alkyl group can be mentioned, for example.

  Examples of the acyl group include an acetyl group, a benzoyl group, a p-methoxybenzoyl group, a p-nitrobenzoyl group, and a pivaloyl group.

  As a hydroxyalkyl group, C1-C20 hydroxyalkyl groups, such as a hydroxyethyl group, a hydroxypropyl group, a glyceryl group, can be mentioned.

  Examples of the carboxyalkyl group include carboxyalkyl groups having 1 to 20 carbon atoms in the alkyl moiety such as a carboxymethyl group.

  Examples of the alkoxycarbonyl group include alkoxycarbonyl groups having 1 to 20 carbon atoms in the alkoxy moiety such as an ethyloxycarbonyl group, a trichloroethyloxycarbonyl group, and a benzyloxycarbonyl group.

  Examples of the alkylsilyl group include a tert-butylsilyl group and a triethylsilyl group.

  The fluoroalkyl group, the fluoroacyl group, and the carboxyfluoroalkyl group may be ones in which one or more hydrogen atoms are substituted with fluorine atoms in the above-described alkyl group, acyl group, and carboxyalkyl group, respectively.

Among them, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently preferably a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group and a phosphate group, and each independently, A hydrogen atom and an acyl group are more preferable, and independently of each other, a hydrogen atom and an acetyl group are more preferable, and a hydrogen atom is particularly preferable.

R ⁸ in formulas (III) and (III ′) and formulas (IV) and (IV ′) represents —CH ₂ OR ⁹ or —COOR ¹⁰ .

Here, R ⁹ is a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, a benzoyloxycarbonyl group, a sulfo group, or a phosphate group. Represents an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group or a carboxyfluoroalkyl group.

  As an alkyl group, the above-mentioned C1-C20 alkyl group can be mentioned, for example.

  Examples of the acyl group include an acetyl group, a benzoyl group, a p-methoxybenzoyl group, a p-nitrobenzoyl group, and a pivaloyl group.

  As a hydroxyalkyl group, C1-C20 hydroxyalkyl groups, such as a hydroxyethyl group, a hydroxypropyl group, a glyceryl group, can be mentioned.

  Examples of the carboxyalkyl group include carboxyalkyl groups having 1 to 20 carbon atoms in the alkyl moiety such as a carboxymethyl group.

  Examples of the alkoxycarbonyl group include alkoxycarbonyl groups having 1 to 20 carbon atoms in the alkyl moiety such as an ethyloxycarbonyl group and a trichloroethyloxycarbonyl group.

  Examples of the alkylsilyl group include a tert-butylsilyl group and a triethylsilyl group.

  The fluoroalkyl group, the fluoroacyl group, and the carboxyfluoroalkyl group may be ones in which one or more hydrogen atoms are substituted with fluorine atoms in the above-described alkyl group, acyl group, and carboxyalkyl group, respectively.

Among them, R ⁹ is preferably a hydrogen atom, a sulfo group, a phosphoric acid group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group, or a carboxyfluoroalkyl group, and more preferably a hydrogen atom.

R ¹⁰ represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, an alkylsilyl group, a fluoroalkyl group, or a tert-butyl group. Among them, as R ¹⁰ , a hydrogen atom, a methyl group and a benzyl group are preferable, and a hydrogen atom is more preferable.

As the ^{R 8, -COOR 10} is preferred.

In the formula (III ′) and the formula (IV ′), R ²⁴ represents an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group or an aryloxycarbonyl group. As the alkyl group, haloalkyl group, aryl group, acyl group, alkoxycarbonyl group and aryloxycarbonyl group, those exemplified in the description of R ¹ and R ² can be mentioned.

In formulas (III) and (III ′) and formulas (IV) and (IV ′), the wavy lines independently represent bonds that exhibit an equatorial or axial configuration. That is, in the formulas (III) and (IV), with respect to the bond at the 1st carbon atom of the left sugar (amino sugar), —NR ¹ R ² bonded to the 2nd carbon atom of the same sugar and Therefore, it represents a bond that becomes a 1,2-cis type or a bond that becomes a 1,2-trans type. The bond in the 1,2-cis form is a bond that generates an α1,4-bond in the sugar unit represented by the formula (III) in terms of the sugar unit represented by the formula (III). With regard to the saccharide unit represented by (), it is a bond that generates an α1,4-bond in the saccharide unit represented by the formula (IV). In addition, the bond in the 1,2-trans form is a bond that generates a β1,4-bond in the saccharide unit represented by the formula (III) in terms of the saccharide unit represented by the formula (I). With regard to the compound represented by (IV), it is a bond that generates a β1,4-bond in the sugar unit represented by the formula (IV). Similarly, in the formulas (III) and (IV), with respect to the bond at the 4-position carbon atom of the left sugar, in relation to -NR ¹ R ² bonded to the 2-position carbon atom, 2, It represents a 4-cis type bond or a 2,4-trans type bond. In other words, the 2,4-cis bond represents the same configuration as glucosamine with respect to the 4-position bond, and the 2,4-trans bond has the same configuration as galactosamine. Represents.

  In the sugar chain compound in this embodiment, it is sufficient that at least one sugar residue of 1,2-cis type is contained, but the formula (III) or (III ′) or Of the saccharide units represented by the formula (IV) or (IV ′), it is preferable that 10% or more of the saccharide units are saccharide units containing 1,2-cis type, and 30% or more of the saccharide units are 1,2 cis units. -It is more preferable that it is a saccharide unit containing a cis type, and it is particularly preferable that all the saccharide units are saccharide units containing a 1,2-cis type. In other words, among the saccharide units represented by formula (III) or (III ′) or formula (IV) or (IV ′), 10% or more of saccharide units are saccharide units composed of α1,4-linkages. Preferably, 30% or more of the saccharide units are saccharide units composed of α1,4-linkages, and all saccharide units are saccharide units composed of α1,4-linkages. Particularly preferred.

  In this embodiment, the reducing end and the non-reducing end of the sugar chain compound are each independently an acetyl group; a benzyl group; a p-methoxyphenyl group; an alkyl group containing an amino group; an allyl group; It may be modified. Alternatively, other monosaccharides may be bound.

A more preferable form in the second aspect of the sugar chain compound according to the present invention is specifically the sugar chain compound described in the following (e) or (f).
(E) An oligosaccharide formed by repeatedly binding sugar units represented by the formula (IIIa) or (IIIa ′).
(F) An oligosaccharide formed by repeatedly combining sugar units represented by the formula (IVa) or (IVa ′).

In the formulas (IIIa) and (IIIa ′), R ^{1 to} R ⁴ , R ^{6 to} R ⁸ and the wavy line are the same as defined in the above formula (III). Similarly, in the formulas (IVa) and (IVa ′), R ^{1 to} R ³ , R ^{5 to} R ⁸ and a wavy line are the same as defined in the above formula (IV). In formula (IIIa ′) and formula (IVa ′), R ²⁴ has the same definition as R ²⁴ in formula (III ′) and formula (IV ′), respectively.

  The oligosaccharide in this embodiment is an oligosaccharide having 4 to 16 sugar residues, more preferably 4 to 10 sugar residues, and particularly preferably 4 to 8 sugar residues. preferable.

  A more preferable form in the second aspect of the sugar chain compound according to the present invention is an oligosaccharide (X) represented by the following formula (X).

In formula ^(X), the definition of R 1 to R ⁴ and ^R 6 to R ⁸ are as defined for ^R 1 to R ⁴ and ^R 6 to R ⁸ in formula (III). Definition of R ¹¹ and ^{R 12} are as defined for ^{R 11} and ^{R 12} in formula (IX). m represents an integer of 2 to 8.

Among the oligosaccharides (X), R ¹ and R ² are each independently a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, R ³ , R ⁴ , R ⁶ and R ⁷ are each independently a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group or a phosphoric acid group, R ⁸ is a group represented by —COOR ¹⁰ , and R ¹⁰ is An oligosaccharide which represents a hydrogen atom, a methyl group or a benzyl group, and m is an integer of 2 to 8, is more preferable, R ¹ is a hydrogen atom, R ² is a hydrogen atom or an acetyl group, R ³ is a hydrogen atom, and R ⁴ is An oligosaccharide in which a hydrogen atom, R ⁶ is a hydrogen atom, R ⁷ is a hydrogen atom, R ⁸ is —COOH, and m is an integer of 2 to 4 is particularly preferable.

  The sugar chain compound in this embodiment will be described later [2. It can be produced by the production method described in [Production method of sugar chain compound]. However, the production method of the sugar chain compound in this embodiment is not limited to the production method.

  It can be used as a precursor for the synthesis of oxygen atoms and low-molecular-weight heparins of the sugar chain compound according to this embodiment. Therefore, low molecular weight heparin can be produced by chemical synthesis by using the sugar chain compound according to this embodiment. Therefore, contamination with foreign substances such as endotoxin derived from Escherichia coli can be prevented, and strict control over quality can be achieved.

In addition, the 2nd aspect of the sugar_chain | carbohydrate compound which concerns on this invention can also be expressed like the following (c ') and (d').
(C ′) An oligosaccharide formed by repeatedly binding sugar units represented by the formula (III) or (III ′), which contains one or more α1,4-glycoside bonds.
(D ′) An oligosaccharide formed by repeatedly bonding sugar units represented by the formula (IV) or (IV ′), which includes one or more α1,4-glycoside bonds.

[2. Method for producing sugar chain compound]
The method for producing a sugar chain compound of the present invention is a method capable of suitably producing the sugar chain compound according to the first aspect or the sugar chain compound according to the second aspect. This production method includes (i) a preparation step for preparing a sugar chain compound as a substrate, (ii) a carbamate group introduction step for introducing a carbamate group into the prepared sugar chain compound, and (iii) a sugar having a carbamate group introduced therein. It includes an isomerization step in which a chain compound is reacted with a specific acid in an organic solvent. The production method only needs to include these steps, and may include other steps such as a step of performing other modifications to the sugar chain compound. In the present embodiment, the details of each step will be described including (iv) a deprotection step in which deprotection is performed after the isomerization step.

(1. Preparation process)
The preparation step is a step of preparing the sugar chain compound described in the following (k), (l), (m) or (n).
(K) A polysaccharide or oligosaccharide formed by repeatedly bonding the saccharide units represented by the formula (Ib).
(L) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the formula (IIb).
(M) An oligosaccharide formed by repeatedly combining sugar units represented by the formula (IIIb).
(N) An oligosaccharide formed by repeatedly bonding sugar units represented by the formula (IVb).

In the formulas (Ib), (IIb), (IIIb) and (IVb), R ¹³ and R ¹⁴ are each independently a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group or Represents a phosphate group. Among them, R ¹³ and R ¹⁴ are each independently preferably a hydrogen atom and an acyl group, and each independently more preferably a hydrogen atom and an acetyl group.

In the formulas (Ib), (IIb), (IIIb) and (IVb), R ¹⁵ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphate group, or an alkoxycarbonyl group. Represents an allyloxycarbonyl group, a trialkylsilyl group or a tert-butyldiphenylsilyl group. Among these, R ¹⁵ is preferably a hydrogen atom or an acyl group, more preferably a hydrogen atom or an acetyl group.

In the formulas (Ib) and (IIIb), R ¹⁶ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphate group, an alkoxycarbonyl group, an allyloxycarbonyl group, or a trialkyl. It represents a silyl group or a tert-butyldiphenylsilyl group. Among them, R ¹⁶ is preferably an allyl group, an aryl group, an acyl group, a sulfo group, a phosphoric acid group, an alkoxycarbonyl group, an allyloxycarbonyl group, a trimethylsilyl group, or a tert-butyldiphenylsilyl group, an allyl group, a benzyl group, p -Methoxybenzyl group, acetyl group, benzoyl group, pivaloyl group, sulfo group, phosphoric acid group, methyloxycarbonyl group, trichloroethyloxycarbonyl group, tert-butyloxycarbonyl group, allyloxycarbonyl group, tert-dimethylbutylsilyl group And tert-butyldiphenylsilyl group is more preferable, benzyl group, acetyl group, benzoyl group, pivaloyl group and tert-butyldiphenylsilyl group are more preferable, benzyl group and tert-butyldiphenylsilyl group. Is particularly preferred, and a benzyl group is most preferred.

In the formulas (IIb) and (IVb), R ¹⁷ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphate group, an alkoxycarbonyl group, an allyloxycarbonyl group, or a trialkyl. It represents a silyl group or a tert-butyldiphenylsilyl group. Among them, R ¹⁷ is preferably a hydrogen atom, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, a trimethylsilyl group, or a tert-butyldiphenylsilyl group, and a hydrogen atom, an allyl group, a benzyl group, p-methoxy group. Benzyl group, acetyl group, benzoyl group, pivaloyl group, methyloxycarbonyl group, trichloroethyloxycarbonyl group, tert-butyloxycarbonyl group, allyloxycarbonyl group, tert-dimethylbutylsilyl group and tert-butyldiphenylsilyl group Preferably, a hydrogen atom and an acetyl group are more preferable, and a hydrogen atom is particularly preferable.

In the formulas (IIIb) and (IVb), R ¹⁸ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphate group, an alkoxycarbonyl group, an allyloxycarbonyl group, or a trialkyl. It represents a silyl group or a tert-butyldiphenylsilyl group. Among them, R ¹⁸ is preferably a hydrogen atom, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphoric acid group, an alkoxycarbonyl group, an allyloxycarbonyl group, a trimethylsilyl group, and a tert-butyldiphenylsilyl group, and a hydrogen atom, an allyl group Benzyl group, p-methoxybenzyl group, acetyl group, benzoyl group, pivaloyl group, sulfo group, phosphoric acid group, methyloxycarbonyl group, trichloroethyloxycarbonyl group, tert-butyloxycarbonyl group, allyloxycarbonyl group, tert -A dimethylbutylsilyl group and a tert-butyldiphenylsilyl group are more preferable, a hydrogen atom and an acetyl group are more preferable, and a hydrogen atom is particularly preferable.

In the formulas (IIIb) and (IVb), R ¹⁹ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphate group, an alkoxycarbonyl group, an allyloxycarbonyl group, or a trialkyl. It represents a silyl group or a tert-butyldiphenylsilyl group. Among them, R ¹⁹ is preferably an allyl group, an aryl group, an acyl group, a sulfo group, a phosphoric acid group, an alkoxycarbonyl group, an allyloxycarbonyl group, a trimethylsilyl group or a tert-butyldiphenylsilyl group, and an allyl group, a benzyl group, p- Methoxybenzyl group, naphthyl group, acetyl group, benzoyl group, pivaloyl group, sulfo group, phosphoric acid group, methyloxycarbonyl group, trichloroethyloxycarbonyl group, tert-butyloxycarbonyl group, allyloxycarbonyl group, tert-dimethylbutyl A silyl group and a tert-butyldiphenylsilyl group are more preferred, an allyl group, a benzyl group, a p-methoxybenzyl group and a naphthyl group are more preferred, an allyl group and a benzyl group are particularly preferred, and a benzyl group is most preferred.

In the formulas (IIIb) and (IVb), R ²⁰ represents —CH ₂ OR ²¹ or —COOR ²² .

Here, R ²¹ is a hydrogen atom, alkyl group, allyl group, aryl group, acyl group, hydroxyalkyl group, carboxyalkyl group, alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarbonyl group, sulfo group, phosphate group Represents an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group, a carboxyfluoroalkyl group, a trialkylsilyl group or a tert-butyldiphenylsilyl group. Among these, R ²¹ is preferably an allyl group, an aryl group, an acyl group and a tert-butyldiphenylsilyl group, more preferably a benzyl group, a tert-butyldiphenylsilyl group, a pivaloyl group, a benzoyl group, a p-methoxybenzyl group and an allyl group. , A benzyl group and a p-methoxybenzyl group are more preferable, and a benzyl group is particularly preferable.

R ²² represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group or an acyl group. Among these, R ²² is preferably a hydrogen atom, an alkyl group or an aryl group, more preferably a hydrogen atom, a methyl group or a benzyl group, and particularly preferably a hydrogen atom. ^As the ^{R _20,} -CH 2 ^{OR 21} is more preferable.

  The wavy lines independently represent bonds that exhibit an equatorial or axial configuration.

  When the sugar chain compound is an oligosaccharide among the compounds described in (k) or (l), the number of sugar residues is preferably 2 or more and 16 or less, more preferably 2 or more and 10 or less. 2 or more and 8 or less is particularly preferable.

  When the sugar chain compound is a polysaccharide of the compounds described in (k) or (l), the mass average molecular weight is preferably 1,000 or more and 30,000 or less, and 1,000 or more and 10,000 or less. More preferably, it is 1,000 or more and 5,000 or less.

  When the sugar chain compound is the oligosaccharide described in (m) or (n), the number of sugar residues is preferably 4 or more and 16 or less, more preferably 4 or more and 10 or less, and more preferably 4 or more and 8 or less. It is particularly preferred that

  The preparation of these sugar chain compounds is not particularly limited, such as preparation by chemical synthesis, purchase of commercial products, provision from others, and isolation and purification of naturally occurring ones. Further, by obtaining a derivative of the sugar chain compound described in (k), (l), (m) or (n) and subjecting this derivative to modification treatment or molecular weight reduction treatment, (k) , (L), (m) or (n) may be prepared. According to the preparation by chemical synthesis, contamination with foreign substances can be prevented.

(2. Carbamate group introduction step)
The carbamate group introduction step is a step of introducing a carbamate group into the prepared sugar chain compound. Examples of a method for introducing a carbamate group include a method of reacting a prepared sugar chain compound with triphosgene. The carbamate group includes —NR ¹³ R ¹⁴ (R ¹³ and R ¹⁴ are hydroxy groups) bonded to the 2nd carbon of the amino sugar and —OR ¹⁵ (R ¹⁵ is hydroxy group bonded to the 3rd carbon. ). Therefore, the carbamate group formed is a 2,3-trans carbamate group.

  The amount of triphosgene used for the reaction is, for example, 0.4 times mol to the sugar chain compound when the sugar chain compound to be subjected to the reaction is the sugar chain compound described in (k) or (l) above. It is 100 times mole, Preferably it is 0.4 times mole-20 times mole, More preferably, it is 0.4 times mole-10 times mole. On the other hand, when the sugar chain compound to be subjected to the reaction is the sugar chain compound described in the above (m) or (n), it is, for example, 0.7 times to 50 times mole with respect to the sugar chain compound. Is 0.7 times mole to 10 times mole, and more preferably 0.7 times mole to 5 times mole. Triphosgene may be added in multiple portions.

  As the solvent used, aprotic polar solvents such as acetonitrile, methylene chloride and toluene are used. Of these, acetonitrile and methylene chloride are preferable, and acetonitrile is particularly preferable. When acetonitrile is used, the reaction rate is faster than other solvents such as methylene chloride.

  The reaction temperature and reaction time can be appropriately set according to the type of solvent and sugar chain compound used. For example, the reaction temperature is −40 ° C. to 40 ° C., and preferably −30 ° C. to 0 ° C. The reaction time is, for example, 0.1 hour to 72 hours, preferably 0.1 hour to 12 hours.

  In addition, other methods for introducing a carbamate group include a method in which a sugar chain compound is reacted with p-nitroformate chloroester. In the case of p-nitroformate chloroester, the amount used is 2 to 10 moles relative to the sugar chain compound. As the solvent used at this time, acetonitrile, methylene chloride, or a two-phase solvent of toluene and water can be used. In particular, it is desirable to carry out in an acetonitrile-water system.

  By performing the carbamate group introduction step, in the sugar chain compound, the saccharide unit represented by the formula (Ib), the saccharide unit represented by the formula (IIb), the saccharide unit represented by the formula (IIIb), and the formula (IVb) Specifically, the saccharide units shown are the saccharide unit shown by the following formula (Vb), the saccharide unit shown by the formula (VIb), the saccharide unit shown by the formula (VIIb), and the formula (VIIIb), respectively. Converted to the indicated sugar unit.

In the formulas (Vb), (VIb), (VIIb) and (VIIIb), R ²³ represents a hydrogen atom, an acetyl group, a benzyl group or a 2,2,2-trichloroethoxycarbonyl group.

Here, when a hydrogen atom is bonded to the nitrogen atom of the carbamate group of the sugar chain compound, that is, when R ²³ is a hydrogen atom, the hydrogen atom is acetylated before the reaction in the next isomerization step. Substituent, methoxycarbonyl group, allyloxycarbonyl group, benzyloxycarbonyl group, or 2,2,2-trichloroethoxycarbonyl group is preferable.

By making R ²³ an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group, 1, 2 can be efficiently used in the next isomerization step. -Isomerization from trans to 1,2-cis can be achieved.

  As a method for substituting a hydrogen atom with an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group, a method used in a known similar reaction Can be used.

  For example, as a method for replacing a hydrogen atom with an acetyl group, a method in which a sugar chain compound is reacted with acetic anhydride in the presence of pyridine or in the presence of pyridine and N, N-dimethyl-4-aminopyridine (DMAP). Is mentioned.

  Moreover, as a method of substituting a methoxycarbonyl group for a hydrogen atom, a method of synthesizing n-butyllithium with a sugar chain compound in tetrahydrofuran (THF) and adding methyl chloroformate can be mentioned.

  Moreover, as a method of substituting a hydrogen atom with an allyloxycarbonyl group, a method in which n-butyllithium is allowed to act on a sugar chain compound in THF and allyl chloroformate is added for synthesis.

  Moreover, as a method of substituting a benzyloxycarbonyl group for a hydrogen atom, a method in which n-butyllithium is allowed to act on a sugar chain compound in THF and benzyl chloroformate is added for synthesis.

  As a method for substituting a 2,2,2-trichloroethoxycarbonyl group for a hydrogen atom, n-butyllithium is allowed to act on a sugar chain compound in THF, and 2,2,2-trichloroethyl chloroformate is added. A synthesis method is mentioned.

(3. Isomerization process)
In the isomerization step, a sugar chain compound having a carbamate group introduced is reacted with hydrochloric acid, bis (trifluoromethylsulfonyl) imide or trifluoroacetic acid, or a weakly acidic Lewis acid in an organic solvent, and 1,2- The amino sugar moiety that was in the trans form is converted to a 1,2-cis amino sugar moiety. In this specification, this conversion is called isomerization.

In the present specification, the weakly acidic Lewis acid means a tin acid tetrachloride (SnCl ₄ ) and dimethyl boron bromide (SnCl ₄ ), which are Lewis acids conventionally used in the endo-cleavage reaction of pyranoside in an aprotic environment. This means a Lewis acid having a lower acidity than Me ₂ BBr). Examples of such Lewis acid include boron trifluoride diethyl ether complex (BF ₃ .OEt ₂ ), iron (III) chloride, and copper (II) trifluoromethanesulfonate (Cu (OTf) ₂ ).

  As the acid used for the isomerization reaction, a weakly acidic Lewis acid is preferable, and boron trifluoride diethyl ether complex is particularly preferable.

  The amount of acid used in the isomerization reaction is preferably 0.1-fold mol to 10-fold mol, and preferably 0.1-fold mol to 5-fold mol based on the sugar chain compound to be subjected to the reaction. More preferably, it is 0.1 times mole-2 times mole.

  Examples of the organic solvent used in the reaction include aprotic polar solvents such as acetonitrile, methylene chloride, and toluene. Of these, acetonitrile and methylene chloride are preferable, and acetonitrile is particularly preferable.

  The reaction temperature is preferably 25 ° C or lower, more preferably -40 ° C to 20 ° C, and particularly preferably -30 ° C to 0 ° C.

  The reaction time can be appropriately set according to the type of solvent and sugar chain compound used and the reaction temperature. For example, it is 0.1 hour to 72 hours, preferably 0.1 hour to 12 hours.

A sugar chain compound according to the following (g), (h), (i) or (j), which contains a 1,2-cis type sugar residue by a reaction up to the isomerization step A compound is obtained.
(G) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (V).
(H) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VI).
(I) An oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VII).
(J) An oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VIII).

In formula ^{(V), R 16} and ^{R 23} are each the same as ^{R 16} is and ^{R 23} in the formula (Vb). In Formula (VI), R ¹⁷ and R ²³ are the same as R ¹⁷ and R ²³ in Formula (VIb), respectively. Further, in the equation ^{(VII), R 16, R} 18, R 19, R 20 and ^{R 23} are each the same as ^{R 16, R 18, R 19} , R 20 and ^{R 23} in the formula (VIIb). Further, in the equation ^{(VIII), R 17, R} 18, R 19, R 20 and ^{R 23} are each the same as ^{R 17, R 18, R 19} , R 20 and ^{R 23} in the formula (VIIIb). In the formulas (V) to (VIII), the wavy line independently represents a bond having an equatorial or axial configuration.

  In particular, when the sugar chain compound is an oligosaccharide, the isomerization to 1,2-cis type is performed on all amino sugar moieties by carrying out the reaction with each condition set to a suitable condition. Can do.

  The sugar chain compound according to the above (g), (h), (i) or (j), which contains a 1,2-cis type sugar residue, is a sugar chain according to the present invention. Preferred intermediate compounds of the first and second aspects of the compound. Therefore, the sugar chain compound according to the above (g), (h), (i) or (j), which contains a 1,2-cis-type sugar residue, is also the present invention. It is included in the category. The preferred embodiments of the number of sugar residues and the amount of 1,2-cis sugar residues in the intermediate compound are the sugar residues in the first and second embodiments of the aforementioned sugar chain compound. And the preferred embodiment of the abundance of 1,2-cis sugar residues.

In order to effectively perform deprotection in the next deprotection step, R ¹⁶ and R ²⁰ are particularly preferably an acetyl group or a benzyl group.

  The α-type (1,2-cis type) has a 1H-NMR coupling constant of 1 to 3 (anomer position) of 2 to 3 Hz, whereas the β type (1,2-trans type) has an 8 to Since the chemical shift value is 10 Hz and the chemical shift value moves to a lower magnetic field than the β type, isomerization to the α type can be confirmed by confirming these.

(4. Deprotection step)
In the deprotection step, the protection applied to the hydroxy group and amino group is deprotected in the sugar chain compound obtained by the reaction up to the isomerization step. Thereby, among the sugar chain compounds according to the first aspect described above, in the formula (I), R ¹ , R ³ and R ⁴ are a hydrogen atom, R ² is a hydrogen atom or an acetyl group, and the formula Among the sugar chain compounds according to (II), in which R ¹ , R ³ and R ⁵ are hydrogen atoms, R ² is a hydrogen atom or an acetyl group, and the sugar chain compounds according to the first aspect described above, in formula (III) A sugar chain compound in which R ¹ , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁹ , and R ¹⁰ are a hydrogen atom, R ² is a hydrogen atom or an acetyl group, and R ¹ , R ³ in formula (IV) , R ⁵ , R ⁶ , R ⁷ , R ⁹ , and R ¹⁰ are hydrogen atoms, and R ² is a hydrogen atom or an acetyl group.

  For deprotection, a method used for a similar known reaction can be used. For example, deprotection can be performed by a method of methanol addition using sodium hydroxide-methanol or sodium methoxide and a method of hydrolysis using lithium hydroxide, sodium hydroxide or potassium hydroxide. .

  After the deprotection step, modification to the hydroxy group and the (N-acetyl) amino group may be performed. As the modification, a hydrogen atom of a hydroxy group or (N-acetyl) amino group is replaced with an alkyl group, a haloalkyl group, an acyl group, an allyl group, an aryl group, a hydroxyalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an allyloxycarbonyl group. Substituents such as a group, a benzoyloxycarbonyl group, a sulfo group, a phosphoric acid group, or an alkylsilyl group.

  A person skilled in the art can perform substitution of these groups for a hydrogen atom by appropriately setting conditions with reference to a conventionally known similar method.

(Summary)
A first aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (a) or (b), wherein the sugar chain compound has a plurality of sugar residues, and 1,2- It is a sugar chain compound containing a cis-type sugar residue.
(A) A polysaccharide or oligosaccharide formed by repeatedly binding sugar units represented by the following formula (I) or (I ′).
(B) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (II) or (II ′).

(In the formulas (I) and (I ′), R ¹ and R ² are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, alkoxycarbonyl group, allyloxycarbonyl group or Represents an aryloxycarbonyl group, and R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, an acyl group, an allyl group, an aryl group, a hydroxyalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, Represents a benzoyloxycarbonyl group, a sulfo group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group, a carboxyfluoroalkyl group or a sulfo group, and the wavy line independently represents a bond having an equatorial or axial configuration. In the formula (I ′), R ²⁴ represents an alkyl group. Represents a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group or an aryloxycarbonyl group.)

(In the formulas (II) and (II ′), R ¹ and R ² are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, alkoxycarbonyl group, allyloxycarbonyl group or R ³ and R ⁵ each independently represent a hydrogen atom, an alkyl group, an acyl group, an allyl group, an aryl group, a hydroxyalkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, Represents a benzoyloxycarbonyl group, a sulfo group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group, a carboxyfluoroalkyl group or a sulfo group, and the wavy line independently represents a bond having an equatorial or axial configuration. In the formula (II ′), R ²⁴ represents al Represents a kill group, haloalkyl group, allyl group, aryl group, acyl group, alkoxycarbonyl group, allyloxycarbonyl group or aryloxycarbonyl group.)
In the first embodiment of the sugar chain compound according to the present invention, an oligosaccharide is preferable.

  In the first aspect of the sugar chain compound according to the present invention, the number of sugar residues is preferably 2 to 16.

  In the first embodiment of the sugar chain compound according to the present invention, it is preferable that all sugar residues are 1,2-cis type.

  In the first embodiment of the sugar chain compound according to the present invention, 10% or more of the sugar residues are preferably 1,2-cis type.

A second aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (c) or (d), wherein the sugar chain compound has a plurality of sugar residues, and 1,2- A sugar chain compound containing one or more cis-type sugar residues.
(C) An oligosaccharide formed by repeatedly binding sugar units represented by the following formula (III) or (III ′).
(D) An oligosaccharide formed by repeatedly binding sugar units represented by the following formula (IV) or (IV ′).

(In the formulas (III) and (III ′), R ¹ and R ² are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, alkoxycarbonyl group, allyloxycarbonyl group or R ³ , R ⁴ , R ⁶ and R ⁷ each independently represents a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxyalkyl group or an alkoxycarbonyl group. , Allyloxycarbonyl group, benzoyloxycarbonyl group, sulfo group, phosphoric acid group, alkylsilyl group, fluoroalkyl group, fluoroacyl group or carboxyfluoroalkyl group, R ⁸ represents —CH ₂ OR ⁹ or —COOR ^10. the stands, ^{R 9} is a hydrogen atom, an alkyl group, an acyl group, Ryl, aryl, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, allyloxycarbonyl, benzoyloxycarbonyl, phosphate, sulfo, alkylsilyl, fluoroalkyl, fluoroacyl or carboxyfluoroalkyl R ¹⁰ represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, an alkylsilyl group, a fluoroalkyl group or a tert-butyl group, and the wavy line independently represents a bond having an equatorial or axial configuration. In formula (III ′), R ²⁴ represents an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, or an aryloxycarbonyl group.

(In the formulas (IV) and (IV ′), R ¹ and R ² each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, or R ³ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxyalkyl group or an alkoxycarbonyl group. , Allyloxycarbonyl group, benzoyloxycarbonyl group, sulfo group, phosphoric acid group, alkylsilyl group, fluoroalkyl group, fluoroacyl group or carboxyfluoroalkyl group, R ⁸ represents —CH ₂ OR ⁹ or —COOR ^10. the stands, ^{R 9} is a hydrogen atom, an alkyl group, an allyl group, Ali Group, acyl group, hydroxyalkyl group, carboxyalkyl group, alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarbonyl group, phosphoric acid group, sulfo group, alkylsilyl group, fluoroalkyl group, fluoroacyl group or carboxyfluoroalkyl R ¹⁰ represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, an alkylsilyl group, a fluoroalkyl group or a tert-butyl group, and the wavy line independently represents a bond having an equatorial or axial configuration. In formula (IV ′), R ²⁴ represents an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, or an aryloxycarbonyl group.
In the second aspect of the sugar chain compound according to the present invention, the sugar chain compound described in the following (e) or (f) is preferable.
(E) An oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (IIIa) or (IIIa ′).
(F) An oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (IVa) or (IVa ′).

(R ^{1 to} R ⁴ , R ^{6 to} R ^8, and wavy lines in Formulas (IIIa) and (IIIa ′) are the same as defined in Formulas (III) and (III ′) above. Also, Formula (IIIa ′) R ^{24 in} is the same as defined in formula (III ′) above.)

(R ^{1 to} R ³ , R ^{5 to} R ⁸ and the wavy line in the formulas (IVa) and (IVa ′) are the same as defined in the above formulas (IV) and (IV ′). Also, the formula (IVa ′) R ^{24 in} is the same as defined in formula (IV ′) above.)
In the second embodiment of the sugar chain compound according to the present invention, the number of sugar residues is preferably 4-15.

A third aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (g) or (h), the sugar chain compound having a plurality of sugar residues, A sugar chain compound containing one or more cis-type sugar residues.
(G) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (V).
(H) A polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VI).

(In the formula (V), R ¹⁶ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphoric acid group, an alkoxycarbonyl group, an allyloxycarbonyl group, a trialkylsilyl group, or represents a tert-butyldiphenylsilyl group, and R ²³ represents an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group. (Represents a bond that exhibits an equatorial or axial configuration.)

(In the formula (VI), R ¹⁷ represents a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, a phosphoric acid group, an alkoxycarbonyl group, an allyloxycarbonyl group, a trialkylsilyl group, or represents a tert-butyldiphenylsilyl group, and R ²³ represents an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group. (Represents a bond that exhibits an equatorial or axial configuration.)
A fourth aspect of the sugar chain compound according to the present invention is the sugar chain compound described in the following (i) or (j), wherein the sugar chain compound has a plurality of sugar residues, and 1,2- A sugar chain compound containing one or more cis-type sugar residues.
(I) An oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VII). (J) An oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (VIII).

(In the formula (VII), R ¹⁶ and R ^{18 to} R ²⁰ are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, Represents an allyloxycarbonyl group, a trialkylsilyl group or a tert-butyldiphenylsilyl group, and R ²³ represents an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or 2,2,2-trichloroethoxycarbonyl. (The wavy line independently represents a bond exhibiting an equatorial or axial configuration.)

(In formula (VIII), R ^{17 to} R ²⁰ are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl. group, a trialkylsilyl group or tert- butyldiphenylsilyl ^{group, R 23} represents an acetyl group, methoxycarbonyl group, allyloxycarbonyl group, benzyloxycarbonyl group or 2,2,2-trichloroethoxycarbonyl group, (The wavy lines independently represent bonds exhibiting an equatorial or axial configuration.)
The method for producing a sugar chain compound according to the present invention is a method for producing a sugar chain compound containing a 1,2-cis sugar residue,
(I) a step of preparing a sugar chain compound according to the following (k), (l), (m) or (n);
(K) a polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (Ib),
(L) a polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (IIb);
(M) an oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (IIIb);
(N) an oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (IVb);

(In Formula (Ib), R ¹³ and R ¹⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, or a phosphate group, and R ¹⁵ and R ¹⁶ Are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group or tert-butyldiphenylsilyl. (The wavy line independently represents a bond exhibiting an equatorial or axial configuration.)

(In formula (IIb), R ¹³ and R ¹⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, or a phosphate group, and R ¹⁵ and R ¹⁷ Are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group or tert-butyldiphenylsilyl. (The wavy line independently represents a bond exhibiting an equatorial or axial configuration.)

(In Formula (IIIb), R ¹³ and R ¹⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, or a phosphate group, and R ¹⁵ , R ¹⁶ , R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group Or a tert-butyldiphenylsilyl group, R ²⁰ represents —CH ₂ OR ²¹ or —COOR ²² , and R ²¹ represents a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxy group, Alkyl group, alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarboni Group, a sulfo group, a phosphoric acid group, an alkyl silyl group, a fluoroalkyl group, fluoro acyl group, carboxyalkyl fluoroalkyl group, a trialkylsilyl group or tert- butyldiphenylsilyl group, R ²² represents a hydrogen atom, an alkyl group, (Represents an allyl group, an aryl group, or an acyl group. Wavy lines independently represent a bond having an equatorial or axial configuration.)

(In formula (IVb), R ¹³ and R ¹⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, an acyl group, a sulfo group, or a phosphate group, and R ¹⁵ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group Or a tert-butyldiphenylsilyl group, R ²⁰ represents —CH ₂ OR ²¹ or —COOR ²² , and R ²¹ represents a hydrogen atom, an alkyl group, an allyl group, an aryl group, an acyl group, a hydroxyalkyl group, a carboxy group, Alkyl group, alkoxycarbonyl group, allyloxycarbonyl group, benzoyloxycarbonyl Represents a sulfo group, a phosphoric acid group, sulfo group, alkyl silyl group, a fluoroalkyl group, fluoro acyl group, carboxyalkyl fluoroalkyl group, a trialkylsilyl group or tert- butyldiphenylsilyl group, R ²² represents a hydrogen atom, an alkyl Represents a group, a haloalkyl group, an allyl group, an aryl group or an acyl group, and a wavy line independently represents a bond having an equatorial or axial configuration.)
(Ii) introducing a carbamate group into the sugar chain compound prepared in the step (i), and
(Iii) reacting the sugar chain compound introduced with a carbamate group with hydrochloric acid, bis (trifluoromethylsulfonyl) imide or trifluoroacetic acid or a weakly acidic Lewis acid in an organic solvent;
A process for producing a sugar chain compound.

  In the method for producing a sugar chain compound according to the present invention, a hydrogen atom is bonded to the nitrogen atom of the carbamate group of the sugar chain compound obtained in the step (ii). Prior to the step, it is preferable to include replacing the hydrogen atom with an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group.

  Moreover, in the manufacturing method of the sugar_chain | carbohydrate compound which concerns on this invention, it is preferable to perform the process of said (iii) at 25 degrees C or less.

  In addition, the method for producing a sugar chain compound according to the present invention preferably further includes a step of deprotecting the protecting group of the sugar chain compound obtained in the step (iii).

  Moreover, in the manufacturing method of the sugar chain compound which concerns on this invention, it is preferable to make the said sugar chain compound react with the boron trifluoride diethyl ether complex which is weak acidic Lewis acid at the process of said (iii).

  Moreover, in the manufacturing method of the sugar chain compound which concerns on this invention, it is preferable that the acetyl group has couple | bonded with the nitrogen atom of the carbamate group of the said sugar chain compound used for reaction of the said (iii) process.

  Examples will be shown below, and the embodiments of the present invention will be described in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects are possible in detail. Further, the present invention is not limited to the above-described embodiments, and various modifications can be made within the scope shown in the claims, and the present invention is also applied to the embodiments obtained by appropriately combining the disclosed technical means. It is included in the technical scope of the invention. In addition, the Japanese patent application “Japanese Patent Application No. 2013-041312”, which is the basis of the priority claim of the present application, and all patent documents referred to in this specification, and other publications, are hereby incorporated by reference in their entirety. Incorporated in the description.

  In the chemical formulas shown in the examples, “NPhth” represents phthalimide, “MP” represents p-methoxyphenyl, “Bn” represents benzyl, “Bz” represents benzoyl, and “Ac” represents , Acetyl, “TBDPS” represents tert-butyldiphenylsilyl, “TBS” represents tert-butyldimethylsilyl, and “SPh” represents thiophenyl. The wavy line represents a bond showing an equatorial or axial configuration. The compound represented by the formula (1) is referred to as the compound (1), and the compound represented by the formula (2) is referred to as the compound (2). The same applies to the compounds after the formula (3).

[Example 1: Synthesis 1 of 1,4-α (N-acetyl) glucosamine oligomer 1]
(1-1: Synthesis of disaccharide)

A solution of compound (1) (0.74 g, 1.27 mmol) and compound (2) (0.63 g, 1.16 mmol) in methylene chloride (15 mL) was added to boron trifluoride diethyl ether complex (21 μL, 0 174 mmol) was added at -60 ° C. After 12 hours, triethylamine was added to the mixed solution to neutralize the mixed solution. The mixture was then diluted with chloroform and saturated sodium bicarbonate solution. The aqueous layer was extracted with chloroform and the combined layers were washed with brine, then dried over sodium sulfate and concentrated. The crude product was purified using silica gel column chromatography (toluene: ethyl acetate = 7: 3 to 1: 1) to obtain compound (3) (1.03 g, yield: 92%).
¹ H-NMR δ 7.82-7.79 (m, 4H), 7.71-7.58 (m, 4H), 7.42-7.10 (m, 8H), 6.76 (d, J = 9.2 Hz, 2H), 6.63 (d, J = 9.2 Hz, 2H), 5.82 (t, J = 9.6 Hz, 1H), 5.76 (d, J = 8.8 Hz, 1H), 5.71 (d, J = 5.2 Hz, 1H), 5.58 (d, J = 8.4 Hz , 1H), 5.47 (s, 1H), 4.39 (t, J = 8.8 Hz, 1H), 4.28-4.16 (m, 4H), 4.10 (t, J = 8.8 Hz, 1H), 3.71-3.69 (m, 3H), 3.67 (s, 3H), 3.58 (m, 2H), 1.95 (s, 3H), 1.85 (s, 3H); ¹³ C-NMR δ 170.2, 169.7, 167.9, 155.5, 150.5, 137.9, 136.7, 134.3, 131.4, 129.2, 129.0, 128.2, 128.2, 128.2, 127.5, 127.4, 126.2, 126.2, 125.3, 123.6, 119.0, 114.3, 101.7, 98.4, 97.4, 79.0, 75.5, 74.4, 72.7, 72.1, 69.6, 68.6, 67.3, 66.1, 55.7, 55.5, 54.9, 21.4, 20.8, 20.5; HRMS calcd for [C ₅₃ H ₄₈ N ₂ O ₁₆ + Na] ⁺ 991.2896, found 991.2908.
(1-2: Synthesis of tetrasaccharide)

To a solution of compound (3) (0.64 g, 0.67 mmol) in methylene chloride (20 mL) was added triethylsilane (1.2 mL, 7.51 mmol) and boron trifluoride diethyl ether complex (0.19 mL, 1 .33 mmol) was added at 4 ° C. After 2 hours, the mixture was diluted with saturated sodium bicarbonate solution and chloroform. The aqueous layer was extracted with chloroform, and the organic layer was washed with brine. The extract was dried over sodium sulfate and concentrated. The residue was purified using silica gel column chromatography (toluene: ethyl acetate = 7: 3 to 1: 1) to obtain compound (4) (0.55 g, yield: 82%).
¹ H-NMR δ 7.81 (m, 4H), 7.69 (m, 4H), 7.33-7.16 (m, 10H), 7.33-7.16 (m, 1H), 6.76 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.72 (t, J = 10.0 Hz, 1H), 5.69 (d, J = 8.4 Hz, 1H), 5.57 (t, J = 10.8 Hz, 1H), 5.46 (d , J = 8.4 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.42-4.27 (m, 3H), 4.14-4.09 (m, 2H) , 3.84-3.74 (m, 2H), 3.77-3.45 (m, 8H), 3.71 (s, 3H), 1.89 (s, 3H), 1.86 (s, 3H); ¹³ C-NMR δ 171.0, 170.0, 155.5 , 150.6, 138.1, 137.4, 134.2, 131.5, 128.5, 128.2, 127.9, 127.7, 127.4, 123.5, 118.9, 114.3, 97.4, 97.2, 74.5, 74.4, 73.6, 73.5, 73.2, 72.7, 71.6, 70.0, 67.5, 55.5 , 54.9, 20.6; HRMS calcd for [C ₅₃ H ₅₀ N ₂ O ₁₆ + Na] ⁺ 993.3053, found 993.3070.

Compound (4) (0.30 g, 0.309 mmol) was dissolved in pyridine (3 mL), and acetic anhydride (1 mL) was added thereto. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified using silica gel column chromatography (toluene: ethyl acetate = 4: 1) to obtain compound (5) (0.31 g, yield: 100%).
¹ H-NMR δ 7.81 (m, 4H), 7.70-7.69 (m, 4H), 7.35-7.17 (m, 10H), 6.76 (d, J = 9.2 Hz, 2H), 6.63 (d, J = 9.2 Hz , 2H), 5.73 (t, J = 8.8 Hz, 1H), 5.70 (d, J = 8.8 Hz, 1H), 5.57 (t, J = 9.2 Hz, 1H), 5.47 (d, J = 8.0 Hz, 1H ), 4.55 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.42-4.27 (m, 3H), 4.14-4.09 (m, 2H), 3.81 (t, J = 9.2 Hz, 1H), 3.76 (dd, J = 10.0, 4.4 Hz, 1H), 3.69-3.66 (m, 1H), 3.68 (s, 3H), 3.58 (m, 1H), 3.51-3.42 (m, 3H ), 1.88 (s, 3H), 1.85 (s, 3H); ¹³ C-NMR δ 171.0, 170.0, 155.5, 150.6, 138.1, 137.3, 134.2, 131.4, 128.5, 128.2, 127.9, 127.7, 127.4, 123.5, 118.9 , 114.3, 97.3, 97.2, 74.5, 74.4, 73.6, 73.5, 73.2, 72.7, 71.6, 71.4, 70.0, 67.5, 55.5, 54.9, 54.9, 21.6, 20.6; HRMS calcdfor [C ₅₅ H ₅₂ N ₂ O ₁₇ + Na ] ⁺ 1035.3158, found 1035.3168.

  To a solution of compound (5) (1.19 g, 1.18 mmol) in toluene (14 mL), acetonitrile (18 mL), water (14 mL) and ammonium hexanitratocerium (IV) acid (3.2 mL, 3. 66 mmol) was added at 4 ° C. After 2 hours, the mixture was diluted with water and chloroform. After the aqueous layer and the organic layer were separated, the aqueous layer was extracted with chloroform, and the combined layers were washed with brine. The combined layers were dried over sodium sulfate and concentrated. The residue was purified using silica gel column chromatography (toluene: ethyl acetate) to obtain hemiacetal.

  This hemiacetal was dissolved in methylene chloride (10 mL), and N, N-diethylaminosulfur trifluoride (0.23 mL) was added thereto. After 30 minutes, the reaction was stopped by adding saturated sodium bicarbonate solution. The aqueous layer was extracted with chloroform and the combined layers were washed with brine. After concentration, the residue was purified using silica gel column chromatography (toluene: ethyl acetate) to obtain 1.10 g of compound (6).

To a solution of compound (6) (1.22 g, 1.34 mmol) and compound (4) (0.97 g, 1.00 mmol) in methylene chloride (20 mL) was added hafnium trifluoromethanesulfonate (1.16 g, 1 .50 mmol) was added at -40 ° C. The mixture was stirred at −40 ° C. for 1 hour, then stirred at −20 ° C. for 1 hour, and further stirred at 0 ° C. for 3 hours. The reaction was then stopped by adding saturated sodium bicarbonate solution. Dilute with ethyl acetate and filter through celite. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After concentration, the residue was purified using silica gel column chromatography (toluene: ethyl acetate = 7: 3 to 1: 1) to obtain tetrasaccharide compound (7) (1.54 g, yield: 83). %).
¹ H-NMR δ 7.88-7.85 (m, 4H), 7.78-7.72 (m, 8H), 7.67-7.65 (m, 4H), 7.33-7.18 (m, 17H), 7.15-7.12 (m, 2H), 7.12-7.10 (m, 2H), 6.90 (m, 1H), 6.74-7.64 (m, 2H), 6.61-6.60 (m, 2H), 5.66-5.61 (m, 3H), 5.46-5.43 (m, 2H ), 5.33 (d, J = 8.4 Hz, 1H), 5.23-5.13 (m, 3H), 4.50-4.32 (m, 10H), 4.14-3.98 (m, 7H), 3.65 (s, 3H), 3.56- 3.46 (m, 4H), 3.40-3.32 (m, 4H), 3.26 (dd, J = 10.4, 8.4, Hz, 1H), 3.18 (dd, J = 10.4, 8.4 Hz, 1H), 3.00 (d, J = 10.0 Hz, 1H), 2.74 (d, J = 10.0 Hz, 1H), 1.83 (s, 3H), 1.78 (s, 3H), 1.78 (s, 3H), 1.77 (s, 3H), 1.63 (s , 3H); ¹³ C-NMR δ 170.3, 170.2, 169.4, 168.1, 167.2, 155.4, 150.6, 138.2, 138.1, 137.9, 137.6, 134.3, 131.4, 129.0, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.4 , 127.3, 127.2, 127.1, 126.9, 125.3, 123.6, 123.5, 118.8, 114.3, 97.4, 96.5, 96.4, 95.9, 74.4, 73.9, 73.6, 73.4, 73.3, 72.8, 72.6, 72.5, 72.2, 72.2, 72.1, 70.9 , 70.9, 70.7, 69.4, 55.5, 55.3, 55.2, 55.0, 54.8, 21.4, 20.6, 20.5, 20.4; [α] -3.2 (c 1.2, CHCl ₃ ); HRMS calcd for [C ₁₀₁ H ₉₄ N ₄ O ₃₁ + Na ] ⁺ 1181.5794, found 1881.5810.
(1-3: Introduction of carbamate group)

  Compound (7) (2.00 g, 1.08 mmol) was dissolved in a mixed solution of dimethylformamide (10 mL) and ethylenediamine (5 mL) and stirred at 80 ° C. for 2 days under a nitrogen atmosphere. After concentration, the crude product was purified using Sephadex LH-20 (chloroform: methanol = 1: 1) to obtain compound (8) (1.28 g, yield: 100%).

Compound (8) (430.0 mg, 0.381 mmol) and sodium bicarbonate (640 mg, 7.62 mmol) were dissolved in a mixed solution of acetonitrile (12 mL) and water (3 mL), where triphosgene (362.0 mg, 1.22 mmol) was added. After 12 hours, more triphosgene (180.0 mg, 0.61 mmol) and sodium bicarbonate (320.0 mg, 3.81 mmol) were added. The mixture was diluted with chloroform and brine and extracted with chloroform. The combined layers were washed with brine and dried over sodium sulfate. After concentration, the residue was purified using silica gel column chromatography (chloroform: methanol = 9: 1) to obtain compound (9) (303 mg, yield: 64%).
¹ H-NMR δ7.31-7.24 (m, 20H), 6.97 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.21 (s, 1H), 6.10 (s, 1H), 5.91 (s, 1H), 5.82 (s, 1H), 5.00 (d, J = 7.6 Hz, 1H), 4.69-4.43 (m, 11H), 4.21 (m, 2H), 4.20 (m, 2H ), 3.98-3.96 (m, 4H), 3.78-3.60 (m, 12H), 3.76 (s, 3H), 3.53-3.45 (m, 4H), 3.31-3.30 (m, 3H), 3.14 (s, 1H ), ¹³ C-NMR δ 159.2, 159.1, 154.9, 150.0, 138.8, 138.5, 138.4, 128.2, 128.2, 127.5, 118.1, 114.5, 100.2, 100.2, 98.9, 79.2, 78.8, 78.6, 77.1, 76.5, 74.4, 72.6 , 72.2, 68.1, 66.7, 58.7, 58.5, 55.4, 55.4; [α] -24.5 (c 0.60, CHCl ₃ ).

Compound (9) (39.0 mg, 0.0316 mmol) and N, N-dimethyl-4-aminopyridine (1.1 mg, 0.0063 mmol) were dissolved in pyridine (0.1 mL), and acetic anhydride (0 0.1 mL, 1.06 mmol) was added. The mixture was stirred overnight at room temperature. After concentration, the crude product was purified using silica gel column chromatography (toluene: ethyl acetate = 7: 3) to obtain compound (10) (31.9 mg, yield: 70%).
¹ H-NMR δ 7.38-7.26 (m, 20H), 7.09 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.54 (d, J = 6.4 Hz, 1H), 5.30-5.26 (m, 4H), 4.65-4.35 (m, 12H), 4.35-3.05 (m, 10H), 3.89-3.66 (m, 10H), 3.77 (s, 3H), 2.51 (s, 3H), 2.45 (s, 6H), 2.46 (s, 3H), 2.12 (s, 3H); ¹³ C-NMR δ 170.6, 170.4, 170.3, 169.8, 155.4, 153.2, 153.1, 153.1, 150.9, 138.0, 137.9, 137.8, 137.5, 128.4, 127.9, 127.8, 118.5, 114.6, 99.3, 99.3, 97.8, 96.9, 79.4, 78.5, 78.4, 78.4, 75.9, 75.8, 75.7, 75.5, 75.1, 74.9, 74.8, 73.6, 73.3, 71.2, 71.0, 70.9, 70.9, 70.4, 60.5, 60.4, 60.0, 55.7, 24.5, 24.4, 24.4, 10.8; [α]-110 (c 0.55, CHCl ₃ ).
(1-4: Isomerization reaction)

Boron trifluoride diethyl ether complex (11 μl, 0.0832 mmol) was added at 0 ° C. to a solution of compound (10) (60.0 mg, 0.0416 mmol) in acetonitrile (0.6 mL). The mixture was stirred at 0 ° C. for 10 hours, and then saturated sodium hydrogen carbonate solution was added to stop the reaction. The aqueous layer was extracted with chloroform and the combined layers were washed with brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified using silica gel column chromatography to obtain compound (11) (38.2 mg, yield: 54%).
¹ H-NMR δ7.31-7.21 (m, 20H), 6.94 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.17 (d, J = 3.2 Hz, 1H) , 6.02 (d, J = 2.8 Hz, 1H), 6.00 (d, J = 2.4 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 5.37 (t, J = 9.6 Hz, 1H), 4.79 (t, J = 12.0 Hz, 1H), 4.53-4.26 (m, 15H), 3.90-3.60 (m, 14H), 3.72 (s, 3H), 3.50 (t, J = 11.6 Hz, 1H), 3.35- 3.34 (m, 2H), 2.48 (s, 6H), 2.47 (s, 3H), 2.47 (s, 3H), 1.99 (s, 3H); ¹³ C-NMR δ 177.6, 171.5, 171.3, 171.1, 168.9, 155.8, 152.7, 152.5, 152.5, 152.5, 149.9, 137.7, 137.6, 137.4, 128.4, 128.4, 127.9, 127.8, 127.5, 127.4, 127.3, 118.7, 114.7, 95.8, 95.5, 95.5, 75.4, 75.2, 75.2, 74.6, 74.2, 73.9, 73.8, 73.5, 73.5, 73.0, 72.7, 72.1, 68.1, 67.8, 67.7, 67.6, 67.3, 59.9, 59.9, 59.8, 55.6, 23.7, 23.6, 20.6; HRMS calcd for [C ₇₃ H ₇₈ N ₄ O ₂₇ + Na] ⁺ 1465.4746, found 1465.4747.
[Example 2: Synthesis 2 of 1,4-α (N-acetyl) glucosamine oligomer 2]
The same procedure as in Example 1 was performed until the synthesis of compound (10).

  (2-1: Acetylation of compound (10))

A suspension of compound (10) (200 mg, 0.162 mmol) and 20% Pd (OH) ₂ / C (50 mg) in ethanol (8 mL) and acetic acid (8 mL) was stirred under a hydrogen atmosphere for 2 hours. The catalyst was filtered through filter paper and washed with acetic acid. After concentrating the reaction solution, a pentanol carbamate compound was obtained (71.0 mg, 52%). DMAP (1 mg, 0.008 mmol) was added to the resulting pentanol carbamate compound (35.3 mg, 0.0404 mmol), and pyridine (0.5 mL) and acetic anhydride (0.5 mL) were added thereto, and At rt overnight. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography to obtain compound (43) (39.7 mg, 78%).
¹ H-NMR δ 7.08 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.64 (d, J = 6.4 Hz, 1H), 5.31-5.28 (m, 3H), 5.14 (dd, J = 9.6, 3.2 Hz, 1H), 4.61-4.08 (m, 25H), 3.97 (dd, J = 12.8, 6.4 Hz, 1H), 3.90-3.83 (m, 2H), 3.77 (s, 3H), 2.52 (s, 12H), 2.14 (s, 3H), 2.12 (s, 12H); ¹³ C-NMR δ 170.4, 170.4, 169.6, 155.4, 153.0, 152.7, 152.7, 152.6, 150.7, 118.2, 114.5 , 98.9, 98.7, 98.2, 98.1, 78.3, 76.2, 76.1, 76.0, 75.9, 75.6, 74.6, 70.1, 64.5, 64.4, 64.3, 60.5, 55.7, 24.3, 21.0, 20.8.
(2-2: Isomerization reaction)

Boron trifluoride diethyl ether complex (9 μL, 0.0624 mmol) was added at 0 ° C. to a solution of compound (43) (39.0 mg, 0.320 mmol) in acetonitrile (0.3 mL). The mixture was stirred at 0 ° C. for 3 hours, and then saturated sodium hydrogen carbonate solution was added to stop the reaction. The aqueous layer was extracted with chloroform and the combined layers were washed with brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified using silica gel column chromatography to obtain compound (44) (32.2 mg, yield: 83%).
¹ H-NMR δ 6.96 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.17 (d, J = 2.4 Hz, 1H), 6.00 (d, J = 2.8 Hz, 1H), 5.98 (d, J = 2.4 Hz, 1H), 5.97 (d, J = 2.8 Hz, 1H), 5.32 (t, J = 9.6 Hz, 1H), 4.79 (t, J = 9.2 Hz, 1H) , 4.76-4.40 (m, 6H), 4.28-4.08 (m, 9H), 4.02-3.98 (m, 2H), 3.91-3.37 (m, 4H), 3.87-3.74 (m, 3H), 3.80 (s, 3H), 2.56 (s, 3H), 2.55 (s, 3H), 2.54 (s, 3H), 2.52 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H ), 2.09 (s, 3H); ¹³ C-NMR δ 171.9, 171.8, 171.8, 171.1, 170.5, 170.4, 170.3, 169.1, 156.0, 152.4, 152.3, 152.1, 149.7, 118.7, 114.7, 96.7, 96.6, 96.3, 95.4, 76.3, 75.9, 75.5, 75.0, 74.5, 74.4, 73.7, 71.9, 71.9, 71.3, 71.1, 67.7, 62.0, 61.8, 61.8, 61.4, 59.8, 59.8, 59.8, 59.7, 55.7, 23.7, 20.8, 20.7.
[Example 3: Synthesis of heparosan oligomer]
(3-1: Synthesis of disaccharide)

Compound (21) (1.00 g, 1.28 mmol), 3-phenylpropanol (350 μL, 2.56 mmol), N-iodosuccinimide (576 mg, 2.56 mmol) and molecular sieves (MS) 4A (1.00 g) To a stirred suspension in methylene chloride (10 mL) was added trifluoromethanesulfonic acid (35 μL) at 0 ° C. under an argon atmosphere. The mixture was stirred at 0 ° C. for 30 minutes under an argon atmosphere, the reaction was stopped by adding a 10% aqueous solution of sodium thiosulfate, and the mixture was filtered through a celite pad. The filtrate was then extracted with chloroform. The original layer was washed with saturated sodium bicarbonate solution and brine. The extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was purified using silica gel column chromatography (toluene: ethyl acetate = 97: 3-95: 5) to obtain compound (22) (854 mg, yield: 83%, colorless oil).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.06-8.04 (m, 2H), 7.68-7.63 (m, 4H), 7.57-7.55 (m, 1H), 7.46-7.31 (m, 8H), 7.19- 7.09 (m, 8H), 6.98-6.94 (m, 2H), 5.35 (dd, J = 9.6, 7.8 Hz, 1H), 5.26 (t, J = 9.6 Hz, 1H), 4.63 (d, J = 11.6 Hz , 1H), 4.56 (d, J = 8.0 Hz, 1H), 4.51 (d, J = 11.6 Hz, 1H), 3.91-3.85 (m, 2H), 3.73-3.68 (m, 2H), 3.65-3.60 ( m, 2H), 3.55-3.51 (m, 1H), 3.48-3.39 (m, 1H), 2.59-2.46 (m, 2H), 1.89-1.78 (m, 2H), 1.03 (s, 9H); ¹³ C -NMR (100 MHz, CDCl ₃ ) δ 165.6, 164.9, 141.5, 137.6, 135.6, 135.6, 133.2, 133.1, 129.7, 129.6, 128.4, 128.3, 128.3, 128.1, 128.0, 127.7, 127.6, 127.6, 125.6, 100.9, 80.1, 74.6, 73.8, 73.6, 71.3, 68.4, 62.6, 40.3, 31.8, 31.0, 26.6, 19.1; [α] ²⁰ _D +15.6 (c 0.68, CHCl ₃ ); HRMS calcd for [C ₄₇ H ₅₁ ClO ₇ Si + Na] ⁺ 829.2939, found 829.2932.

To a stirred solution of compound (22) (854 mg, 1.06 mmol) dissolved in a mixed solution of ethanol (20 mL) and pyridine (4 mL) was added 1,4-diazabicyclo [2.2.2] octane (593 mg, 5.29 mmol). ) Was added at room temperature. The mixture was stirred at 55 ° C. for 2.5 hours and then concentrated by vacuum drying. The residue was acidified with 0.5M HCl and extracted with ethyl acetate. The organic layer was washed with brine and the extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4-3: 7) to obtain Compound (23) (661 mg, yield: 86%, colorless amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J = 7.2 Hz, 2H), 7.72-7.70 (m, 4H), 7.58 (t, J = 7.6 Hz, 1H), 7.47-7.36 (m , 8H), 7.28-7.10 (m, 8H), 6.94 (d, J = 6.4 Hz, 2H), 5.28 (t, J = 8.4 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.52 (d, J = 8.0 Hz, 1H), 3.96-3.81 (m, 4H), 3.71 (t, J = 8.8 Hz, 1H), 3.29-3.44 (m, 1H), 3.41-3.37 (m, 1H), 2.84 (d, J = 1.6 Hz, 1H), 2.57-2.44 (m, 2H), 1.87-1.72 (m, 2H), 1.31-1.26 (m, 1H) , 1.07 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ165.2, 141.6, 138.0, 135.7, 135.6, 133.1, 133.0, 132.8, 130.0, 129.8, 129.8, 128.4, 128.4, 128.1, 128.0 , 127.8, 127.7, 125.6, 101.0, 82.3, 74.8, 74.4, 73.5, 72.2, 68.3, 64.5, 31.8, 31.0, 26.8, 19.2; [α] ²⁰ _D +3.4 (c 0.64, CHCl ₃ ); HRMS calcd for [ C ₄₅ H ₅₀ O ₇ Si + Na] ⁺ 753.3223, found 753.3220.

Compound (23) (1.01 g, 1.38 mmol), Compound (24) (1.10 g, 2.07 mmol), silver trifluoromethanesulfonate (532 mg, 2.07 mmol) and MS4A (2.00 g) were dissolved in methylene chloride. Phenylsulfenyl chloride (240 μL, 2.07 mmol) was added to the solution suspended in (10 mL) with stirring at −20 ° C. under an argon atmosphere. The mixture was stirred at −20 ° C. for 30 minutes under an argon atmosphere, and then saturated sodium bicarbonate solution was added to stop the reaction. After stirring at room temperature for 15 minutes, it was filtered through a celite pad. The filtrate was then extracted with chloroform. The organic layer was washed with brine and the extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1-3: 2) to obtain compound (25) (1.03 g, yield: 65%, colorless amorphous). .
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.00-7.96 (m, 2H), 7.77-7.71 (m, 6H), 7.68-7.65 (m, 2H), 7.53 (m, 1H), 7.47-7.41 ( m, 8H), 7.38-7.31 (m, 6H), 7.28-7.26 (m, 1H), 7.18-7.16 (m, 3H), 7.12-7.06 (m, 3H), 6.89-6.87 (m, 2H), 5.90 (t, J = 9.2 Hz, 1H), 5.73 (d, J = 8.4 Hz, 1H), 5.43 (s, 1H), 5.18 (t, J = 8.8 Hz, 1H), 4.86 (d, J = 11.6 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.44 (t, J = 8.8 Hz, 1H), 4.33-4.26 (m, 3H), 3.76-3.54 (m, 8H), 3.16-3.11 (m, 2H), 2.48-2.36 (m, 2H), 1.89 (s, 3H), 1.78-1.64 (m, 2H), 1.07 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.1, 167.6, 165.1, 141.6, 138.4, 136.9, 136.2, 135.8, 134.4, 133.6, 133.0, 132.9, 131.2, 130.1, 129.8, 129.7, 129.6, 129.1, 128.3, 128.3, 128.2, 128.1, 128.0, 127.7, 127.4, 127.4, 126.2, 125.6, 123.5, 101.6, 100.5, 96.8, 80.1, 79.4, 75.6, 74.2, 73.7, 73.2, 69.6, 68.6, 67.8, 66.0, 62.3, 56.1, 31.7, 30.9, 26.8, 20.6, 19.5; (α ] ²⁰ _D +13.1 (c 0.91, CHCl ₃ ); HRMS calcd for [C ₆₈ H ₆₉ NO ₁₄ Si + Na] ⁺ 1174.4385, found 1174.4387.
(3-2: Synthesis of trisaccharide)

To a stirred solution of compound (25) (3.62 g, 3.14 mmol) in methylene chloride (30 mL) was added boron trifluoride diethyl ether complex (890 μL, 6.28 mmol) and triethylsilane (6 mL, 37.7 mmol). Was added at 0 ° C. under an argon atmosphere. The mixture was stirred at 0 ° C. for 3.5 hours under an argon atmosphere, and then saturated sodium hydrogen carbonate solution was added to stop the reaction, followed by extraction with chloroform. The organic layer was washed with brine and the extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 7: 3 to 3: 2) to obtain compound (26) (3.43 g, yield: 94%, colorless amorphous). . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 8.0 Hz, 2H), 7.77-7.72 (m, 6H), 7.69-7.64 (m, 2H), 7.56-7.52 (m, 1H) , 7.45-7.40 (m, 5H), 7.36-7.26 (m, 15H), 7.19-7.15 (m, 4H), 7.09-7.06 (m, 6H), 6.89-6.87 (m, 2H), 5.77 (t, J = 8.8 Hz, 1H), 5.66 (d, J = 8.4 Hz, 1H), 5.18 (t, J = 7.6 Hz, 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.69 (d, J = 11.6 Hz, 1H), 4.48 (s, 2H), 4.41 (t, J = 8.8 Hz, 1H), 4.31 (d, J = 8.0 Hz, 1H), 4.24 (dd, J = 10.8, 8.4 Hz, 1H) , 3.84-3.70 (m, 5H), 3.63-3.60 (m, 3H), 3.16-3.11 (m, 2H), 2.47 -2.42 (m, 2H), 1.92 (s, 3H), 1.79-1.71 (m, 1H), 1.68-1.63 (m, 1H), 1.04 (s, 9H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.8, 167.7, 165.2, 141.6, 138.4, 137.4, 136.1, 135.8, 134.2, 133.7 , 132.9, 131.3, 130.1, 129.8, 129.6, 129.6, 128.5, 128.3, 128.3, 128.1, 128.1, 127.9, 127.7, 127.4, 127.2, 125.6, 123.5, 100.5, 96.4, 79.9, 75.6, 74.0, 73.7, 73.6, 73.2 , 73.0, 72.5, 70.4, 67.8, 62.3, 55.3, 31.7, 30.9, 26.8, 20.7, 19.5; [α] ²⁰ _D +18.4 (c 0.87, CHCl ₃ ); HRMS calcd for [C ₆₈ H ₇₁ NO ₁₄ Si + Na] ⁺ 1176.4 541, found 1176.4541.

Boron trifluoride diethyl ether complex (75 μL / mL) dissolved in methylene chloride was added to a stirred solution of compound (26) (309 mg, 0.268 mmol) and compound (27) (244 mg) dissolved in methylene chloride (1.9 mL). , 0.1 mL, 0.0536 mmol) was added at −40 ° C. under an argon atmosphere. The mixture was stirred at −40 ° C. for 1.5 hours under an argon atmosphere, and then saturated sodium hydrogen carbonate solution was added to stop the reaction, followed by extraction with chloroform. The organic layer was washed with brine and the extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to obtain compound (28) (349 mg, yield: 82%, colorless amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.91 (d, J = 7.2 Hz, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.72-7.62 (m, 8H), 7.54-7.47 (m , 4H), 7.41-7.22 (m, 21 H), 7.13-7.05 (m, 11 H), 7.00-6.94 (m, 3H), 6.86 (d, J = 8.0 Hz, 2H), 5.67 (dd, J = 10.4, 8.8 Hz, 1H), 5.55 (d, J = 6.0 Hz, 1H), 5.54 (s, 1H), 5.16 (d, J = 8.0 Hz, 1H), 5.13 (d, J = 8.0 Hz, 1H ), 4.85 (d, J = 11.6 Hz, 1H), 4.76 (d, J = 12.4 Hz, 1H), 4.68 (d, J = 12.4Hz, 1H), 4.67-4.63 (m, 2H), 4.51 (d , J = 12.0 Hz, 1H), 4.39-4.31 (m, 2H), 4.28-4.21 (m, 3H), 4.07 (t, J = 10.0 Hz, 1H), 3.77-3.57 (m, 7H), 3.47 ( dd, J = 11.6, 2.4 Hz, 1H), 3.36-3.24 (m, 3H), 3.13-3.07 (m, 2H), 2.43-2.37 (m, 2H), 1.86 (s, 3H), 1.73-1.61 ( m, 2H), 0.83 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ169.7, 167.6, 165.2, 164.4, 141.6, 138.4, 138.1, 137.9, 137.1, 136.1, 135.6, 134.2, 134.0 , 133.3, 133.2, 132.9, 131.4, 130.1, 129.8, 129.5, 129.4, 129.1, 128.5, 128.3, 128.3, 128.2, 128.2, 128.1, 127.9, 127.9, 127.8, 127.7, 127.5, 127.4, 127.1, 126.0, 125.
5, 123.6, 123.4, 101.3, 101.0, 100.5, 96.1, 81.7, 79.6, 77.7, 77.3, 75.6, 75.6, 74.5, 73.7, 73.5, 73.2, 73.1, 71.3, 68.7, 67.8, 66.6, 66.0, 62.3, 55.6, 31.7, 30.9, 26.5, 20.7, 19.3; [α] ²⁰ _D +36.6 (c 0.77, CHCl ₃ ); HRMS calcd for [C ₉₅ H ₉₅ NO ₂₀ Si + Na] ⁺ 1620.6115, found 1620.6125.
(3-3: Synthesis of tetrasaccharide)

To a stirred solution of compound (28) (3.90 g, 2.44 mmol) dissolved in acetic acid (72 mL), water (18 mL) was added at 60 ° C. The mixture was stirred at 60 ° C. for 23 hours and then concentrated by vacuum drying. The residue was purified using silica gel column chromatography (chloroform: ethyl acetate = 7: 3 to chloroform: methanol = 97: 3) to obtain compound (29) (2.81 g, yield: 76%, colorless) Amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.92 (dd, J = 8.0, 1.2 Hz, 2H), 7.82 (dd, J = 8.0, 0.8 Hz, 2H), 7.69-7.62 (m, 8H), 7.54 -7.49 (m, 2H), 7.41-7.13 (m, 22H), 7.09-7.05 (m, 3H), 7.00-6.94 (m, 3H), 6.85 (dd, J = 8.0, 2.0 Hz, 2H), 5.67 (dd, J = 10.8, 8.8 H, 1H), 5.54 (d, J = 8.4 Hz, 1H), 5.15 (t, J = 8.0 Hz, 1H), 5.12 (t, J = 8.0 Hz, 1H), 4.86 (d, J = 10.8 Hz, 1H), 4.70-4.63 (m, 3H), 4.55 (d, J = 12.4 Hz, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.37 (t, J = 8.8 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 4.28-4.23 (m, 2H), 4.09 (t, J = 9.2 Hz, 1H), 3.86 (dd, J = 12.0, 3.2 Hz, 1H), 3.73-25.57 (m, 6H), 3.51-3.47 (m, 2H), 3.42 (d, J = 10.8 Hz, 1H), 3.38-3.28 (m, 2H), 3.13-3.07 (m, 2H) , 2.44-2.44 (m, 3H), 1.86 (s, 3H), 1.73-1.63 (m, 4H), 0.82 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.1, 167.7, 165.2 , 164.4, 141.6, 138.4, 138.1, 137.8, 136.1, 135.7, 134.3, 134.0, 133.3, 133.3, 132.9, 132.8, 131.4, 130.1, 129.8, 129.7, 129.5, 129.3, 128.5, 128.5, 128.3, 128.2, 128.1, 128.0 , 128.0, 127.9, 127.9, 127.8, 127.7, 127.4 , 127.1, 125.5, 123.5, 100.5, 100.2, 96.1, 82.5, 79.7, 75.6, 75.2, 74.7, 74.4, 73.8, 73.6, 73.4, 73.3, 73.1, 71.4, 70.8, 67.8, 66.8, 62.8, 62.3, 55.7, 31.7 , 30.9, 26.5, 20.6, 19.3; [α] ²⁰ _D +19.0 (c 0.88, CHCl ₃ ); HRMS calcd for [C ₈₈ H ₉₁ NO ₂₀ Si + Na] ⁺ 1532.5802, found 1532.5798.

To a stirred solution of compound (29) (450 mg, 0.298 mmol) in methylene chloride (3 mL) was added 2,6-lutidine (100 μL, 0.894 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonic acid (140 μL, 0 .596 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 10 minutes, and then saturated ammonium chloride solution was added to stop the reaction, followed by extraction with chloroform. The organic layer was washed with brine and the extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain compound (30) (415 mg, yield: 86%, colorless amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.91 (dd, J = 8.4, 1.2 Hz, 2H), 7.77 (dd, J = 8.4 0.8Hz, 2H), 7.71 (m, 8H), 7.54-7.47 ( m, 2H), 7.40-7.21 (m, 15H), 7.15-7.04 (m, 10H), 6.99-6.93 (m, 3H), 6.85 (dd, J = 7.6, 2.0 Hz, 2H), 5.64 (dd, J = 10.8, 8.8 Hz, 1H), 5.54 (d, J = 8.4 Hz, 1H), 5.14 (t, J = 8.0 Hz, 1H), 5.07 (dd, J = 9.2, 8.0 Hz, 1H), 4.86 ( d, J = 11.6 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 11.2 Hz, 1H), 4.58 (d, J = 12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.38 (t, J = 8.8 Hz, 1H), 4.32 (d, J = 12.4 Hz, 1H), 4.26-4.20 (m, 2H), 4.04 (t, J = 9.2 Hz, 1H), 3.93 (dd, J = 10.0, 4.4 Hz, 1H), 3.79-3.57 (m, 6H), 3.54-3.46 (m, 2H), 3.37 (m , 1H), 3.26-3.20 (m, 3H), 3.12-3.07 (m, 2H), 2.42-2.37 (m, 2H), 1.86 (s, 3H), 1.74-1.59 (m, 4H), 0.89 (s , 9H), 0.80 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.9, 167.6, 165.2, 164.4, 141.6, 138.4, 138.2 , 138.2, 136.1, 135.6, 134.2, 133.9, 133.2, 133.0, 132.9, 132.8, 131.5, 131.4, 130.1, 129.8, 129.7 , 129.5, 128.5, 128.3, 128.2, 128.1, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 127.4, 127.1, 125.5, 123.6, 123.4, 100.5, 100.3, 96.1, 81.9, 79.6, 75.6, 75.1, 74.6, 74.1 , 73.9, 73.7, 73.6, 73.5, 73.4, 73.1, 72.9, 71.0, 67.7, 66.7, 64.9, 62.3, 55.7, 31.7, 30.9, 26.5, 25.8, 20.7, 19.3, 18.2, -5.5, -5.6; [α] ²⁰ _D +20.6 (c 0.82, CHCl ₃ ); HRMS calcd for [C ₉₄ H ₁₀₅ NO ₂₀ Si ₂ + Na] ⁺ 1646.6666, found 1646.6659.

Boron trifluoride was added to a stirred solution of compound (30) (1.23 g, 0.757 mmol) and compound (31) (752 mg, 1.14 mmol) in methylene chloride (10 mL) at −40 ° C. under an argon atmosphere. Diethyl ether complex (20 μL, 0.151 mmol) was added. The mixture was stirred at −40 ° C. for 1 hour under an argon atmosphere, then heated to −20 ° C. and further stirred for 1.5 hours. After stirring, saturated sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with brine and the extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 7: 3 to 1: 1) and gel filtration chromatography (Bio-Beads SX-3, BIO-RAD, toluene: ethyl acetate = 1: 1). To give compound (32) (1.15 g, yield: 71%, colorless amorphous). Unreacted compound (30) was recovered (203 mg, yield: 17%, colorless amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 7.6 Hz, 2H), 7.80-7.60 (m, 9H), 7.52-7.49 (m , 2H), 7.40-7.02 (m, 35H), 7.00-6.90 (m, 3H), 6.85 (dd, J = 6.0, 2.0 Hz, 2H), 5.76 (dd, J = 10.8, 8.8, Hz, 1H) , 5.62 (dd, J = 10.8, 8.8, Hz, 1H), 5.51 (d, J = 8.8 Hz, 1H), 5.42 (d, J = 8.4 Hz, 1H), 5.19 (t, J = 9.6 Hz, 1H ), 5.14 (t, J = 8.0 Hz, 1H), 5.01 (t, J = 7.6 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 7.6 Hz, 1H), 4.43 (d, J = 8.0 Hz, 1H), 4.38- 4.26 (m, 4H), 4.23 (d, J = 8.0 Hz, 1H), 4.16 (d, J = 12.4 Hz, 1H), 4.07 (dd, J = 10.8, 8.4 Hz, 1H), 3.97 (t, J = 8.0 Hz, 1H), 3.83-3.53 (m, 10H), 3.46-3.31 (m, 4H), 3.24 (d, J = 12.0 Hz, 1H), 3.10-3.04 (m, 3H), 2.45-2.30 ( m, 2H), 1.83 (s, 3H), 1.73 (s, 3H), 1.50-1.80 (m, 2H), 0.84 (s, 18H), 0.00 (s, 3H), -0.09 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.2, 169.9, 167.6, 166.3, 165.2, 164.6, 141.6, 138.4, 138.2, 138.1, 137.5, 136.1, 135.7, 134. 5, 133.4, 133.1, 132.9, 132.8, 130.1, 129.8, 129.7, 129.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.7, 127.5, 127.4, 127.3, 127.0, 125.5, 123.5, 100.5, 100.0, 96.5, 96.0, 80.1, 79.5, 76.3, 75.6, 75.3, 74.7, 74.4, 73.7, 73.6, 73.5, 73.4, 73.2, 73.1, 73.0, 72.4, 71.9, 71.4, 70.3, 68.8, 67.7, 62.3, 55.7, 55.3, 40.5, 31.7, 30.9, 26.6, 25.8, 20.6, 20.4, 19.3, 18.0, -5.3, -5.3; [α] ²⁰ _D +21.6 (c 0.55, CHCl ₃ ); HRMS calcd for [C ₁₁₉ H ₁₂₇ ClN ₂ O ₂₈ Si ₂ + Na] ⁺ 2145.7700, found 2145.7690.
(3-4: Introduction of carbamate group)

Compound (32) (2.73 g, 1.28 mmol) was dissolved in 40% methylamine in methanol (500 mL) and stirred at 40 ° C. for 3 days. Next, the mixture was concentrated by vacuum drying, and the residue was purified using gel filtration chromatography (LH-20, GE Healthcare Biosciences, chloroform: methanol = 1: 1) to obtain compound (33). Obtained (1.72 g, yield: 90%, colorless amorphous).
¹ H-NMR (400 MHz, CD ₃ OD) δ 7.64-7.60 (m, 5H), 7.34-7.26 (m, 10H), 7.18-7.02 (m, 30H), 4.97 (d, J = 11.2 Hz, 1H ), 4.85 (d, J = 11.2 Hz, 1H), 4.69 (dd, J = 12.0, 4.0 Hz, 1H), 4.57 (d, J = 7.6 Hz, 1H), 4.43 (d, J = 12.4 Hz, 1H) ), 4.42 (d, J = 12.4 Hz, 1H), 4.39 (d, J = 12.0 Hz, 1H), 4.26-4.08 (m, 7H), 3.97-3.59 (m, 7H), 3.56 (d, J = 5.2 Hz, 1H), 3.43 (dd, J = 9.6, 2.0 Hz, 1H), 3.42-3.28 (m, 16Hz, 1H), 3.19-3.09 (m, 3H), 2.63-2.59 (m, 3H), 2.54 (t, J = 8.4 Hz, 1H), 1.84 (m, 2H), 0.90 (s, 9H), 0.79 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); ¹³ C-NMR (100 MHz, CD ₃ OD) δ 143.3, 140.7, 140.6, 140.1, 140.0, 137.2, 136.8, 135.1, 134.2, 130.8, 129.5, 129.4, 129.2, 129.2, 129.0, 129.0, 128.9, 128.8, 128.7, 128.6, 128.3 , 128.2, 128.2, 126.8, 105.0, 104.3, 102.9, 102.8, 84.4, 83.8, 82.2, 77.8, 77.2, 76.8, 76.3, 76.1, 75.6, 75.5, 75.3, 75.0, 74.9, 74.8, 74.6, 74.5, 72.2, 70.9 , 70.0, 69.8, 63.6, 62.9, 59.2, 58.9, 33.3, 32.7, 27.5, 26.6, 20.3, 19.2, -4.9, -5.0; [α] ²⁰ _D +2.6 (c 0.83, MeOH); HRMS calcd f or [C ₈₃ H ₁₁₀ N ₂ O ₁₉ Si ₂ + Na] ⁺ 1517.7139, found 1517.7146.

To a stirred solution of compound (33) (540 mg, 0.3361 mmol) dissolved in a mixed solution of acetonitrile (10 mL) and water (2.5 mL), sodium hydrogen carbonate (152 mg, 1.81 mmol) and triphosgene (85.7 mg, 0.289 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 2.5 hours, then diluted with brine and extracted with chloroform. The organic layer was washed with brine and the extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was purified using silica gel column chromatography (chloroform: methanol = 97: 3-95: 5) to obtain compound (34) (536 mg, yield: 96%, colorless amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.61-7.58 (m, 4H), 7.32-7.09 (m, 31H), 6.15 (bs, 1H), 5.18 (bs, 1H), 4.91-4.87 (m, 2H), 4.83 (d, J = 8.0 Hz, 1H), 4.74-4.69 (m, 2H), 4.64 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.37 ( d, J = 11.6 Hz, 1H), 4.34 (d, J = 12.0 Hz, 1H), 4.26 (d, J = 12.0 Hz, 1H), 4.17 (d, J = 8.0 Hz, 1H), 4.13 (d, J = 7.2 Hz, 1H), 4.03-4.89 (m, 3H), 3.86-3.73 (m, 9H), 3.65-3.39 (m, 4H), 3.44-3.10 (m, 12H), 2.62-2.60 (m, 2H), 1.93-1.85 (m, 2H), 0.96 (s, 9H), 0.79 (s, 9H), 0.00 (s, 6H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 158.9, 158.9, 141.6 , 138.9, 138.6, 137.6, 137.2, 135.9, 135.4, 133.2, 132.4, 130.0, 129.9, 128.5, 128.4, 128.0, 127.9, 127.9, 127.8, 127.7, 127.6, 125.9, 102.8, 102.4, 101.4, 100.8, 83.5, 82.4 , 81.4, 81.0, 76.3, 75.6, 75.3, 75.1, 75.0, 74.6, 74.3, 74.0, 73.7, 73.5, 70.3, 70.1, 68.8, 62.1, 61.2, 60.2, 59.8, 32.3, 31.2, 26.8, 26.0, 19.3, 18.4 , -4.9, -5.2; [α] ²⁰ _D +3.5 (c 0.64, CHCl ₃ ); HRMS calcd for [C ₈₅ H ₁₀₆ N ₂ O ₂₁ Si ₂ + Na] ⁺ 1570.6754, found 1570.67 54.

To a stirred solution of compound (34) (519 mg, 0.335 mmol) in tetrahydrofuran (1 mL) was added acetic acid (50 μL, 0.838 mmol) and tetra-n-butylammonium fluoride (1.0 M THF solution, 0.84 mL, 0.84 mmol) was added. The mixture was stirred at room temperature for 16 hours and then quenched with 1M HCl and acetic acid. Subsequently, it is purified using gel filtration chromatography (LH-20, GE Healthcare Biosciences, chloroform: methanol = 1: 1) and silica gel column chromatography (chloroform: methanol = 97: 3-93: 7), Compound (35) was obtained (323 mg, yield: 81%, colorless amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.24-7.06 (m, 25H), 6.93 (bs, 1H), 6.84 (bs, 1H), 4.83-4.69 (m, 5H), 4.44-4.32 (m, 4H), 4.14 (d, J = 7.2 Hz, 1H), 3.95 (m, 2H), 3.84-3.31 (m, 21H), 3.22-3.16 (m, 5H), 2.58 (t, J = 7.6 Hz, 2H ), 1.87-1.79 (m, 2H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ159.8, 159.5, 141.5, 138.6, 138.4, 137.6, 137.5, 128.5, 128.4, 128.4, 128.1, 127.9, 127.8, 127.8, 127.7, 127.6, 125.9, 102.9, 102.7, 101.6, 101.2, 83.6, 83.4, 81.6, 80.6, 75.0, 74.8, 74.7, 74.5, 74.4, 74.1, 73.8, 73.6, 69.7, 69.4, 69.0, 68.3, 60.3, 60.1, 60.0, 32.0, 30.9; [α] ²⁰ _D -3.7 (c 0.40, CHCl ₃ ); HRMS calcdfor [C ₆₃ H ₇₄ N ₂ O ₂₁ + Na] ⁺ 1217.4681, found 1217.4712.

To a stirred solution of compound (35) (307 mg, 0.257 mmol) in pyridine (2 mL) was added acetic acid (2 mL) and N, N-dimethyl-4-aminopyridine (9.4 mg, 0.0771 mmol) at 0 ° C. Was added. The mixture was stirred at room temperature for 15 hours and then concentrated by vacuum drying. The residue was purified using silica gel column chromatography (chloroform: ethyl acetate = 7: 3 to 2: 3) to obtain Compound (36) (323 mg, yield: 84%, yellowish white amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.33-7.14 (m, 25H), 5.28 (d, J = 6.4 Hz, 1H), 5.18 (d, J = 6.8 Hz, 1H), 5.03-4.97 (m , 2H), 4.91 (t, J = 8.4 Hz, 1H), 4.84 (d, J = 11.2H, 1H), 4.83 (d, J = 10.8 Hz, 1H), 4.58 (d, J = 11.2 Hz, 1H ), 4.53-4.35 (m, 6H), 4.24 (d, J = 8.0 Hz, 1H), 4.16-4.06 (m, 5H), 4.00 (m, 1H), 3.92-3.78 (m, 8H), 3.76- 3.72 (m, 3H), 3.71-3.65 (m, 2H), 3.54 (dd, J = 10.4, 4.8 Hz, 1H), 3.48-3.36 (m, 3H), 2.67-2.56 (m, 2H), 2.44 ( s, 6H), 2.08 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 1.94 (s, 3H), 1.90-1.80 (m, 2H), 1.77 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.1, 170.9, 170.6, 170.2, 169.8, 169.3, 169.3, 153.2, 153.0, 141.7, 138.5, 138.3, 137.8, 137.6, 128.5, 128.5, 128.4, 128.3, 127.9, 127.6 , 127.6, 127.5, 127.4, 125.8, 100.6, 99.8, 99.7, 99.1, 81.3, 80.9, 78.4, 77.9, 76.5, 76.4, 75.6, 75.1, 74.2, 74.1, 73.4, 73.3, 73.1, 73.1, 73.0, 70.7, 70.1 , 68.6, 63.3, 63.2, 61.6, 61.3, 31.9, 31.1, 24.5, 24.4, 21.0, 20.9, 20.7, 20.7; [α] ²⁰ _D -28.0 (c 0.40, CHCl ₃ ); HRMS calcd for [C ₇₇ H ₈₈ N ₂ O ₂₈ + Na] ⁺ 1512.5421, found 1512.5410.
(3-5: Isomerization reaction)

Boron trifluoride diethyl ether complex (34 μL, 0.242 mmol) was added to a stirred solution of compound (36) (180 mg, 0.121 mmol) in acetonitrile (1.2 mL) at −20 ° C. under an argon atmosphere. . The mixture was stirred at −20 ° C. for 10 minutes under an argon atmosphere, and then saturated sodium hydrogen carbonate solution was added to stop the reaction, followed by extraction with chloroform. The organic layer was washed with brine and the extract was dried over sodium sulfate and then concentrated by vacuum drying. The residue was purified by silica gel column chromatography (ethyl acetate: toluene = 3: 7) to obtain Compound (37) (165 mg, yield: 92%, colorless amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.27-7.09 (m, 25H), 6.16 (d, J = 2.4 Hz, 1H), 6.00 (d, J = 2.4 Hz, 1H), 5.35 (t, J = 10.4 Hz, 1H), 5.00 (t, J = 8.0 Hz, 1H), 3.97 (t, J = 7.6 Hz, 1H), 4.75 (t, J = 12.0 Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 4.59-4.49 (m, 8H), 4.46-4.36 (m, 4H), 4.31 (d, J = 8.0 Hz, 1H), 4.18-4.12 (m, 2H), 4.08 (t, J = 9.6 Hz, 1H), 3.98 (t, J = 8.8 Hz, 1H), 3.81-3.76 (m, 3H), 3.67-3.44 (m, 12H), 3.39-3.33 (m, 1H), 2.64-2.52 (m , 2H), 2.22 (s, 3H), 2.09 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.96 (s, 2H), 1.87 (s, 3H), 1.84-1.82 ( m, 3H), 1.78 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.6, 171.3, 170.4, 170.4, 169.3, 169.2, 169.0, 152.7, 152.6, 141.6, 137.9, 137.9, 137.7, 137.4, 128.5, 128.4, 128.4, 128.3, 128.0, 127.8, 127.8, 127.7, 127.6, 127.3, 127.1, 125.8, 100.6, 99.8, 95.9, 95.2, 82.0, 81.7, 76.0, 75.1, 74.9, 74.3, 74.0, 74.0, 73.8, 73.6, 73.1, 73.0, 73.0, 73.0, 72.9, 72.2, 68.5, 68.3, 67.5, 67.2, 62.9, 62.2, 60.2, 60.0, 31.9, 31.1, 23.4, 23.3, 20.8, 20.7, 20.6; [α] ²⁰ _D +7 2.9 (c 0.55, CHCl ₃ ); HRMS calcd for [C ₇₇ H ₈₈ N ₂ O ₂₈ + Na] ⁺ 1512.5421, found 1512.5422.
(3-6: Conversion from cyclic protecting group to acetamide group)

Compound (37) (1.76 g, 1.18 mmol) was dissolved in allyl alcohol (20 mL), LiOH.H ₂ O (1.98 g, 47.2 mmol) was added at room temperature, and the mixture was stirred for 3.5 hours. The reaction solution was passed through LH-20 (Sephadex, MeOH / CHCl ₃ : 9/1) as it was to remove LiOH to obtain a mixture of allyl carbamate and acetamide. The obtained mixture of allyl carbamate and acetamide was dissolved in pyridine (10 mL), and acetic anhydride (10 mL) was added. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ / MeOH: 97/3). Palladium (II) acetate (79.5 mg, 0.354 mmol) was dissolved in methylene chloride (3 mL), and triethylamine (150 μL, 1.06 mmol) and triethylsilane (1.7 mL, 10.6 mmol) were added thereto. The mixture was stirred at room temperature for 15 minutes under an argon atmosphere. A solution of purified allyl carbamate and acetamide dissolved in methylene chloride (9 mL) was added to the solution. After the reaction solution was stirred for 11 hours, 50% aqueous acetic acid solution (1.7 mL) was added, concentrated under reduced pressure, and dried under high vacuum. The residue was dissolved in pyridine (5 mL), acetic anhydride (5 mL) was added, reacted at room temperature for 1.5 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ / AcOEt: 2/3 to 1/9) to obtain diacetamide. The obtained diacetamide was dissolved in a mixed solution of tetrahydrofuran (6 mL) and methanol (6 mL), sodium methoxide (28% methanol solution, 40 μL, 0.0710 mmol) was added in the presence of phenolphthalein, and the mixture was stirred overnight. . Amberlyst 15E was added to the reaction solution to stop the reaction, and then Amberlyst 15E was filtered and concentrated to obtain compound (38) (833 mg, 62%, 5 steps) (colorless amorphous).
¹ H-NMR (CD ₃ OD) δ 7.40-7.14 (m, 25H), 5.44 (d, J = 3.6 Hz, 1H), 5.40 (d, J = 4.0 Hz, 1H), 5.10 (d, J = 10.0 Hz, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.64-4.55 (m, 6H), 4.36 (d, J = 8.0 Hz, 1H), 4.30 (d, J = 7.6 Hz, 1H) , 4.07-3.30 (m, 35H), 2.73 (t, J = 8.0 Hz, 2H), 1.97-1.89 (m, 2H), 1.78 (s, 3H), 1.77 (s, 3H); ¹³ C-NMR ( CD ₃ OD) δ 173.4, 173.3, 143.3, 139.7, 139.6, 139.4, 120.5, 129.5, 129.4, 129.4, 129.3, 129.0, 128.8, 128.7, 128.6, 126.8, 104.6, 104.5, 99.0, 98.5, 86.1, 85.8, 81.0 , 76.7, 76.5, 76.2, 75.9, 75.4, 75.4, 75.5, 74.5, 74.1, 73.9, 73.9, 73.2, 72.5, 72.2, 71.3, 70.8, 70.0, 69.7, 62.2, 62.1, 55.0, 54.7, 33.1, 32.7, 22.6 , 22.6; [
α] ²⁰ _D +40.4 (c 0.80, MeOH).
(3-7: Conversion to uronic acid)

Compound (38) (20 mg, 0.0163 mmol) and 15% aqueous sodium hydrogen carbonate solution (50 μL) were dissolved in acetone (0.15 mL), and 2,2,6,6-tetramethylpiperidine 1-oxyl was dissolved therein. (TEMPO) (0.5 mg, 0.0326 mmol) and trichloroisosialic acid (7.6 mg, 0.0326 mmol) were added at 4 ° C. After the addition, the reaction solution was stirred at room temperature for 2 hours, and the reaction was stopped with isopropanol. Purification by LH-20 (Sephadex, CHCl ₃ / MeOH: 1/1) and silica gel column chromatography (CHCl ₃ / MeOH: 4/1 to 1/1) gave Compound (39).
¹ H-NMR (CD ₃ OD) δ 7.38-7.13 (m, 25H), 5.49 (d, J = 3.6 Hz, 1H), 5.44 (d, J = 3.2 Hz, 1H), 5.03 (d, J = 10.4 Hz, 1H), 5.08 (d, J = 10.0 Hz, 1H), 4.68-4.50 (m, 8H), 4.31 (d, J = 8.0 Hz, 1H), 4.27 (d, J = 7.6 Hz, 1H), 4.08 (d, J = 9.6 Hz, 1H), 3.99-3.46 (m, 24H), 2.71 (t, J = 7.6 Hz, 2H), 2.01 (s, 3H), 1.93 (s, 3H), 1.90-1.87 (m, 2H).
[Example 4: Synthesis of 1,4-α (N-acetyl) glucosamine polymer]

  1.0 g of chitosan (5 to 20 mPa · s, manufactured by Tokyo Chemical Industry Co., Ltd.) (compound (43)) was dissolved in 1-butyl-methylimidazolium chloride (10 mL), and triethylamine (1 mL) was added thereto, Stir at 100 ° C. After the mixture was cooled to room temperature, triphosgene (0.5 g) was added. The mixture was stirred at 100 ° C. for 2 days and the mixture was suspended in methanol. After centrifugation, the residue was washed with methanol and diethyl ether. The brown precipitate (1.2 g) was dissolved in 1-butyl-methylimidazolium chloride (10 mL), and pyridine (5 mL), acetic anhydride (5 mL) and DMAP (100 mg) were added thereto at 60 ° C. Stir. After stirring, the mixture was suspended in methanol. Centrifugation gave compound (44) (1.4 g). The obtained compound (44) was suspended in methylene chloride (30 mL), and then boron trifluoride diethyl ether complex (1 mL) was added at −20 ° C. After the mixture was stirred for 5 hours, diethyl ether (30 mL) and triethylamine (1 mL) were added. Centrifugation collect | recovered the precipitate (1.0g) of brown solid, and the rough body of the compound (45) was obtained.

  [Example 5: Examination of isomerization reaction in monosaccharides by the difference in substituents on the carbamate group nitrogen]

  Various substituents R on the carbamate group nitrogen of the compound (40) were designed, and the efficiency of the isomerization reaction from 1,2-trans type to 1,2-cis type was examined. The isomerization reaction was carried out by adding a 2-fold molar amount of boron trifluoride diethyl ether complex at −30 ° C. to a solution of the compound (40) of 1,2-trans type in methylene chloride. Added and allowed to stir for 12 hours. After stirring, saturated sodium bicarbonate solution was added to stop the reaction. After extraction with chloroform, drying over sodium sulfate and concentration, the residue was purified. The amount of the compound (β1) in the 1,2-trans form (that is, the compound (40) that has not undergone isomerization) in the obtained sample, and 1,2 resulting from the isomerization of the compound (40) -The abundance of the compound (α1) which is a cis type was measured to examine the efficiency of the isomerization reaction.

In the compound (40), the substituent R on the carbamate group nitrogen is an acetyl group (Ac), a methoxycarbonyl group (CO ₂ Me), an allyloxycarbonyl group (CO ₂ All), a benzyloxycarbonyl group (CO ₂ Bn). ), 2,2,2-trichloroethoxycarbonyl group (CO ₂ CH ₂ CCl ₃ ), benzyl group (Bn), p-methoxybenzyl group (PMB), o-nitrobenzyl group, acetonitrile group (CH ₂ CN), Alternatively, a compound that is a hydrogen atom (H) was used. The results are shown in Table 1.

  As shown in Table 1, when the substituent R on the carbamate group nitrogen is an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group It was shown that the compound (β1) as a starting material was completely isomerized without producing.

  [Example 6: Examination of isomerization reaction in disaccharide by difference of substituents on carbamate group nitrogen]

  Various substituents R on the carbamate group nitrogen of the compound (41) were designed, and the efficiency of the isomerization reaction from 1,2-trans type to 1,2-cis type in the amino sugar moiety was examined. . The isomerization reaction was performed in the same manner as in Example 3 except that the compound (41) was used instead of the compound (40). In the finally obtained sample, the amount of the compound (β2) (compound (41) that did not cause isomerization) in the 1,2-trans form, and 1, 2 produced by isomerization of the compound (41), The abundance of the compound (α2) which is a 2-cis type was measured to examine the efficiency of the isomerization reaction.

  As the compound (41), a compound in which the substituent R on the carbamate group nitrogen is an acetyl group, a benzyl group, or a hydrogen atom was used. The results are shown in Table 2.

  As shown in Table 2, when the substituent R on the carbamate group nitrogen is an acetyl group, the isomerization reaction in the disaccharide completely isomerizes without generating the starting compound (β2). Was shown to do.

  [Example 7: Examination of isomerization reaction in monosaccharides depending on the amount of acid used]

  Various amounts of boron trifluoride diethyl ether complex used for the isomerization reaction were set, and the efficiency of the isomerization reaction of the compound (42) from the 1,2-trans type to the 1,2-cis type was examined. It was. In the isomerization reaction, the compound (42) was used instead of the compound (40), and the amount of boron trifluoride diethyl ether complex to be added was 2 times, 1 time, and 0.5 times mole. Otherwise, the same procedure as in Example 3 was performed except that the molar amount was 0.1 times. In the test using 0.1 times the amount of boron trifluoride diethyl ether complex, the case where the stirring time was 72 hours was also examined. The amount of the compound (β3) in the 1,2-trans form (that is, the compound (42) that has not undergone isomerization) in the obtained sample, and 1,2 resulting from the isomerization of the compound (42) -The abundance of the compound (α3) which is a cis type was measured to examine the efficiency of the isomerization reaction. The results are shown in Table 3.

  The present invention can be used in various technical fields such as pharmaceutical and medical materials, cosmetics, clothing, food, and agriculture.

Claims (4)

A method for producing a sugar chain compound containing a 1,2-cis sugar residue,
The sugar chain compound is a polysaccharide or oligosaccharide comprising one or more 1,2-cis-type sugar residues formed by repeatedly binding sugar units represented by the following formula (I) or (I ′): And

(In the formulas (I) and (I ′), R ¹ and R ² are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, benzyl group, acyl group, alkoxycarbonyl group, allyloxy group. Represents a carbonyl group, an aryloxycarbonyl group, or a benzyloxycarbonyl group, and R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, an allyl group, an aryl group, a benzyl group, an acyl group, a hydroxyalkyl group, a carboxy group, Represents an alkyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, a benzoyloxycarbonyl group, a sulfo group, a phosphate group, an alkylsilyl group, a fluoroalkyl group, a fluoroacyl group, or a carboxyfluoroalkyl group. Or show axial configuration During represents a slip. Formula (I '), R ²⁴ represents an alkyl group, a haloalkyl group, an allyl group, an aryl group, a benzyl group, an acyl group, an alkoxycarbonyl group, an allyloxycarbonyl group, an aryloxycarbonyl group, or benzyloxy, The glycan end forms a reducing end or a non-reducing end and is independently modified with an acetyl group; a benzyl group; a p-methoxyphenyl group; an alkyl group including an amino group; and an allyl group. May be.)
(I) a step of preparing the sugar chain compound described in (k) below,
(K) a polysaccharide or oligosaccharide formed by repeatedly bonding sugar units represented by the following formula (Ib),

(In the formula ^{(Ib), R 13} and ^{R 14} each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an allyl group, an aryl group, a benzyl group, an acyl group, a sulfo group or a phosphoric acid ^{group, R 15} And R ¹⁶ are each independently a hydrogen atom, alkyl group, haloalkyl group, allyl group, aryl group, benzyl group, acyl group, sulfo group, phosphate group, alkoxycarbonyl group, allyloxycarbonyl group, trialkylsilyl group. or tert. wavy line representing a butyldiphenylsilyl group is independently a bond showing the configuration of an equatorial or axial.)
(Ii) introducing a carbamate group into the sugar chain compounds prepared in the above described process (i), to form a 2,3 Toransuka Le Bameto group process and,
(Iii) reacting the sugar chain compound introduced with a carbamate group with hydrochloric acid, bis (trifluoromethylsulfonyl) imide or trifluoroacetic acid or a weakly acidic Lewis acid in an organic solvent,
Including
A step of deprotecting the protecting group of the sugar chain compound obtained in the step (iii),
In the case where a hydrogen atom is bonded to the nitrogen atom of the carbamate group, prior to the step (iii), the hydrogen atom bonded to the nitrogen atom of the carbamate group is replaced with an acetyl group, a methoxycarbonyl group, an allyloxycarbonyl group. , A benzyloxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group. The method for producing a sugar chain compound according to claim 1 , wherein the step (iii) is performed at 25 ° C or lower. The method for producing a sugar chain compound according to claim 1 or 2 , wherein in the step (iii), the sugar chain compound is reacted with a boron trifluoride diethyl ether complex which is a weakly acidic Lewis acid. The production of a sugar chain compound according to any one of claims 1 to 3 , wherein an acetyl group is bonded to a nitrogen atom of the carbamate group of the sugar chain compound subjected to the reaction in the step (iii). Method.