WO2023047790A1 - 環状オリゴ糖の製造方法、環状オリゴ糖および包接剤 - Google Patents
環状オリゴ糖の製造方法、環状オリゴ糖および包接剤 Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 19
- 238000010668 complexation reaction Methods 0.000 title 1
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- 125000006239 protecting group Chemical group 0.000 claims description 55
- 235000000346 sugar Nutrition 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 28
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 18
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical group O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
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- 238000005481 NMR spectroscopy Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229960001911 glucosamine hydrochloride Drugs 0.000 description 1
- 239000000937 glycosyl acceptor Substances 0.000 description 1
- 239000000348 glycosyl donor Substances 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical group O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 150000003214 pyranose derivatives Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- YNJQKNVVBBIPBA-UHFFFAOYSA-M tetrabutylazanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[N+](CCCC)(CCCC)CCCC YNJQKNVVBBIPBA-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
- C07H5/06—Aminosugars
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a method for producing a cyclic oligosaccharide and a novel cyclic oligosaccharide. It also relates to an inclusion agent using the oligosaccharide.
- Cyclic oligosaccharides refer to molecules in which oligosaccharides composed of multiple monosaccharides are cyclized. It is known that these molecules have hydrophobic cavities in the molecules and can include organic molecules and ions in the cavities.
- Typical cyclic oligosaccharides include cyclodextrin (Non-Patent Document 1) (Formula 11).
- Non-Patent Document 2 cyclic oligosaccharides such as cycloawaodorin (Non-Patent Document 2) synthesized by chemical synthesis (Formula 12). These molecules are expected to be applied to foods, pharmaceuticals, drug delivery systems, etc., due to their inclusion ability.
- cyclic oligosaccharides that is, to design and synthesize oligosaccharides.
- an object of the present invention is to provide a method for producing a cyclic oligosaccharide that enables efficient synthesis of a cyclic oligosaccharide.
- Another object of the present invention is to provide a novel cyclic oligosaccharide obtained through the production method.
- a method for producing a cyclic oligosaccharide which comprises subjecting a linear oligosaccharide in which 5 to 10 ⁇ -glucosamine or a derivative thereof are linked in series via 1,4-bonds to a liquid-phase electrolysis reaction.
- R 3 are each independently a protecting group with a formula weight of 300 or less, R 4 is a substituent, X is a sulfur atom, selenium atom or tellurium atom, n1 is 3 to 8 is an integer, and R 22 and R 3 that are bonded to the same ring may be bonded to each other to form a ring.
- each R 1 is independently a protecting group with a formula weight of 500 or less
- each R 21 is independently a hydrogen atom or a protecting group with a formula weight of 300 or less
- R4 is a substituent
- X is a sulfur atom, selenium atom, or tellurium atom
- n1 is an integer of 3 to 8.
- formula (2) (In Formula (2), R 1 is each independently a protective group with a formula weight of 500 or less, and R 21 and R 22 are each independently a hydrogen atom or a protective group with a formula weight of 300 or less.
- R 31 is its R 3 —O— group, each R 3 is independently a protecting group with a formula weight of 300 or less, and n2 is an integer from 0 to 5. Bonded to the same ring R 22 and R 31 may combine with each other to form a ring.
- [5] A cyclic oligosaccharide represented by formula (2-1).
- Formula (2-1) (In formula (2-1), each R 1 is independently a protecting group with a formula weight of 500 or less, each R 21 is independently a hydrogen atom or a protecting group with a formula weight of 300 or less, n2 is an integer from 0 to 5.)
- Formula (3) (In formula (3), n2 represents an integer of 0 to 5, and Ac represents an acetyl group.) [7] A cyclic oligosaccharide represented by formula (4). Formula (4) (In formula (4), n2 represents an integer of 0 to 5.) [8] A clathrate containing the compound of [7]. [9] For a cyclic oligosaccharide represented by the following formula (2-1), the oxazolidinone ring is opened with a base, and the resulting sugar is reacted with acetic anhydride to acetylate the opened site.
- each R 1 is independently a protecting group with a formula weight of 500 or less
- each R 21 is independently a hydrogen atom or a protecting group with a formula weight of 300 or less
- n2 is an integer from 0 to 5.
- Formula (3) (In formula (3), n2 represents an integer of 0 to 5, and Ac represents an acetyl group.)
- cyclic oligosaccharides can be synthesized efficiently. Also, it is possible to provide a novel cyclic oligosaccharide obtained through the production method.
- NMR spectrum of compound 16 (part 1) NMR spectrum of compound 16 (part 2) NMR spectrum of compound 16 and its analysis diagram (Part 3) NMR spectrum of compound 16 and its analysis diagram (part 4) NMR spectrum of compound 21 (part 1) NMR spectrum of compound 21 (part 2) NMR spectrum of compound 21 and its analysis diagram (Part 3) NMR spectrum of compound 21 and its analysis diagram (part 4) MALDI-TOF MS after quenching reaction scheme (27) MALDI-TOF MS after gel filtration of the reaction product (sugar 26) of reaction scheme (27) 1 H-NMR after gel filtration of the reaction product (sugar 26) of reaction scheme (27). Graph showing the results of mass spectrometric measurement of sugar 24, which is an intermediate Graph showing the results of mass spectrometric measurement of sugar 26, the final product
- an "alkyl group” includes not only an alkyl group having no substituent (unsubstituted alkyl group) but also an alkyl group having a substituent (substituted alkyl group).
- the notations that do not describe substituted and unsubstituted are preferably unsubstituted. If the standards shown in this specification differ from year to year in terms of measurement methods, etc., the standards as of January 1, 2021 shall be used unless otherwise specified.
- Et is an ethyl group
- Bn is a benzyl group
- Ar is an aryl group
- Phth is a phthaloyl group
- MeOH is methanol
- Ph is a phenyl group
- Ac is an acetyl group
- DMPA is 4-dimethylaminopyridine.
- Tf is trifluoromethanesulfonyl group
- TfOH is trifluoromethanesulfonic acid
- TMSOTf is trimethylsilyltrifluoromethanesulfonate
- THF is tetrahydrofuran
- Bu NOTf is tetrabutylammonium triflate
- TBDPS is tert-butyldiphenylsilyl group
- DTBMP 2,6 -di-tert-butyl-4-methylpyridine.
- reaction scheme 1 the synthesis route of the monosaccharide building block, which has been considered as a candidate monomer for polymerization reactions, will be described (reaction scheme 1).
- glucosamine hydrochloride 1 phthaloyl protection of the amino group with phthalic anhydride was performed, followed by acetylation with Ac2O . It was then converted to thioglycoside 4 by reaction with 4-chlorothiophenol. After deacetylating this thioglycoside under acidic conditions, benzylidene protection was performed with benzaldehyde dimethylacetal to synthesize compound 6. Then, the hydroxy group at the 3-position was acetylated again with acetic anhydride to obtain compound 7.
- reaction scheme 2 Using the obtained monosaccharide building block 8, an attempt was made to synthesize a cyclic sugar by electropolymerization (reaction scheme 2).
- the reaction conditions are as follows. After performing electrolytic oxidation under constant current conditions at ⁇ 60° C., the temperature was raised to ⁇ 40° C. and glycosylation reaction was performed for 3600 seconds. After that, Et 3 N was added to stop the reaction.
- Anodic oxidation Glycosylation Glycosylation Glycosylation
- reaction scheme 3 The reaction mechanism by which this 1,6-dehydrated sugar was obtained (reaction scheme 3).
- reaction scheme 3 We thought that the ⁇ -triflate intermediate generated during electrolytic oxidation undergoes a conformational change and undergoes intramolecular glycosylation before coupling with other intermediates. Therefore, we considered that it is important to prevent conformational changes that produce 1,6-dehydrated sugars in order to obtain larger cyclic sugars.
- the sugar chain is first elongated with ⁇ -1,4-glycosidic bonds by electropolymerization, and then the sugar chain is isomerized by the specific ⁇ -isomerization of the oxazolidinone protecting group. After that, cyclization is performed by performing electrolytic oxidation again.
- cyclization is performed by performing electrolytic oxidation again.
- Substrate 20 was synthesized by selectively opening the 4-position of 19 by a benzylidene ring-opening reaction. [Synthesis of protected 2,3-oxazolidinone with unprotected hydroxyl group at 4-position (see document below)] - Feng, J.; Hevey, R.; Ling, C.; Carbohydr. Res 2011, 346, 2650.
- Base Yield of oligosaccharide Yield of oligosaccharide
- a method for producing a cyclic oligosaccharide which comprises subjecting a linear oligosaccharide in which 5 to 10 ⁇ -glucosamine or its derivatives are linked in series via 1,4-bonds to a liquid-phase electrolysis reaction. rice field.
- the linear oligosaccharide is preferably represented by the following formula (1).
- formula (1) (In Formula (1), R 1 is each independently a protecting group with a formula weight of 500 or less, and R 21 and R 22 are each independently a hydrogen atom or a protecting group with a formula weight of 300 or less.
- R 3 are each independently a protecting group with a formula weight of 300 or less, R 4 is a substituent, X is a sulfur atom, selenium atom or tellurium atom, n1 is 3 to 8 is an integer, and R 22 and R 3 that are bonded to the same ring may be bonded to each other to form a ring.
- each R 1 is independently a protective group having a formula weight of 500 or less, and plays the role of a protective group that protects a hydroxyl group.
- a protective group having a formula weight of 500 or less By providing a protecting group, the progress of reactions other than cyclization can be suppressed, and the cyclization reaction can be effectively progressed.
- a protective group having a formula weight of 500 or less cyclization can be facilitated.
- the formula weight of R 1 is preferably 60 or more, more preferably 80 or more, still more preferably 90 or more, still more preferably 100 or more, and even more preferably 105 or more. preferable.
- the upper limit is 500 or less, preferably 400 or less, more preferably 350 or less, even more preferably 300 or less, and even more preferably 280 or less.
- Preferred protective groups include Bn group, benzoyl group (Bz), acetyl group (Ac), pivaloyl group (Piv), TBDPS, tert-butyldimethylsilyl group (TBS), 9-fluorenylmethylcarboxy group (Fmoc). are exemplified, Bn, TBDPS and TBS are preferred, Bn and TBDPS are more preferred, and Bn is even more preferred.
- R 1 may contain only one type, or may contain two or more types.
- R 3 is a protecting group, and any group can be applied as long as it does not inhibit the cyclization of the ⁇ -1,4 chain sugar. Moreover, by using a protective group having a formula weight of 300 or less, cyclization can be facilitated. On the other hand, if the protecting group is too small, it may not play its role as a protecting group. From the above viewpoint, the formula weight of R 3 is preferably 20 or more, more preferably 30 or more, even more preferably 40 or more, and even more preferably 50 or more. On the other hand, the upper limit is 300 or less, preferably 250 or less, more preferably 200 or less, even more preferably 180 or less, and even more preferably 160 or less.
- R 3 If the formula weight of R 3 is too large, it inhibits the cyclization reaction. On the other hand, if the substituent is too small, it may not play its role sufficiently. Specifically, Bn, Bz, Ac, Piv, TBDPS, TBS and Fmoc are exemplified, Bz, Ac, Piv and Fmoc are preferred, Bz and Ac are more preferred, and Ac is even more preferred. Only one type of R 3 may be contained, or two or more types may be contained.
- R 21 and R 22 are hydrogen atoms or protecting groups, and any groups can be applied as long as they do not inhibit the cyclization of the ⁇ -1,4 chain sugar.
- R 21 and R 22 are preferably protecting groups. When it is a protective group, the use of a protective group having a formula weight of 300 or less can facilitate cyclization. On the other hand, when it is a protective group, if it is too small, it cannot fulfill its role as a protective group. From this point of view, the formula weight of R 21 and R 22 is preferably 20 or more, more preferably 30 or more, even more preferably 40 or more, and 50 or more when they are protecting groups. is more preferable.
- the upper limit is 300 or less, preferably 250 or less, more preferably 200 or less, even more preferably 180 or less, and even more preferably 160 or less.
- Preferred protective groups include Bn, Bz, Ac, Piv, TBDPS, TBS, Fmoc, and phthalic anhydride groups (Phth), preferably Bn, Bz, Ac, Piv, TBDPS, TBS, Fmoc, Phth, and Bn , Ac and Phth are more preferable, and Bn and Ac are more preferable.
- Each of R 21 and R 21 may contain only one type, or may contain two or more types.
- a 5- or 6-membered hetero ring is preferably formed, and a 5-membered hetero ring is more preferably formed. Specifically, it preferably forms a morpholine ring, a morpholinone ring, or an oxazolidinone ring, and particularly preferably an oxazolidinone ring.
- R 4 is a substituent, preferably electrochemically activated or X-activatable, such as sulfur.
- R 4 is particularly preferably one that does not interfere with the oxidation of sulfur atoms and the like.
- R4 should not be an electron-withdrawing group, preferably an electron-donating group. However, for the synthesis of chain-like oligosaccharides, slightly electron-withdrawing groups are preferable.
- the formula weight of R 4 is preferably 20 or more, more preferably 30 or more, even more preferably 40 or more, and even more preferably 50 or more.
- the upper limit is preferably 300 or less, more preferably 250 or less, even more preferably 200 or less, even more preferably 180 or less, and even more preferably 160 or less.
- Preferred protective groups include substituents, groups weaker in electron-withdrawing properties than nitro groups, and electron-donating groups. Specifically, phenyl group, 4-methylphenyl group, and 2,6-dimethylphenyl group. , 4-bromophenyl group, 4-chlorophenyl group and 4-fluorophenyl group are exemplified, preferably phenyl group, 2,6-dimethylphenyl group, 4-chlorophenyl group and 4-fluorophenyl group, and 2,6-dimethyl A phenyl group, a 4-chlorophenyl group and a 4-fluorophenyl group are more preferred, and a 4-chlorophenyl group and a 4-fluorophenyl group are even more preferred.
- n1 is an integer of 3-8, preferably an integer of 4-6.
- a cyclic or chain oligosaccharide may be a repeating structure of a single sugar or a repeating structure of different sugars, as long as the definition in the formula is satisfied. This also applies to the following formulas (1-1), (2), (2-1), (3) and (4).
- the linear oligosaccharide is preferably represented by the following formula (1-1).
- Formula (1-1) (In formula (1-1), each R 1 is independently a protecting group with a formula weight of 500 or less, each R 21 is independently a hydrogen atom or a protecting group with a formula weight of 300 or less, R4 is a substituent, X is a sulfur atom, selenium atom, or tellurium atom, and n1 is an integer of 3 to 8.)
- the preferred ranges of R 1 , R 21 , R 4 , X and n1 are the same as defined in formula (1) above.
- the above liquid phase electrolysis reaction can be carried out by other known means as long as a linear oligosaccharide in which 5 to 10 ⁇ -glucosamine or its derivatives are linked in series via 1,4-bonds.
- the electrolytic solution can be CH 2 Cl 2 , acetonitrile, propionitrile, DMF, etc., preferably CH 2 Cl 2 .
- Bu 4 NOTf, Et 4 NOTf, Pr 4 NOTf, etc. can be used as the supporting electrolyte, and Bu 4 NOTf is preferable.
- the supporting electrolyte concentration is preferably in the range of 0.1 to 3.0M, more preferably in the range of 0.5 to 2.0M.
- the electrolytic oxidation temperature is preferably in the range of -100 to 0°C, more preferably in the range of -60 to -10°C.
- cyclic oligosaccharides represented by formula (2) can be mentioned.
- formula (2) (In Formula (2), R 1 is each independently a protective group with a formula weight of 500 or less, and R 21 and R 22 are each independently a hydrogen atom or a protective group with a formula weight of 300 or less.
- R 31 is its R 3 —O— group, each R 3 is independently a protecting group with a formula weight of 300 or less, and n2 is an integer from 0 to 5.
- R 22 and R 31 may combine with each other to form a ring.
- R 1 , R 21 and R 3 are the same as in formula (1).
- the ring formed by R 22 and R 31 has the same meaning, and it is particularly preferable to form an oxazolidinone ring.
- novel compounds include cyclic oligosaccharides represented by formula (2-1).
- Formula (2-1) (In formula (2-1), each R 1 is independently a protecting group with a formula weight of 500 or less, each R 21 is independently a hydrogen atom or a protecting group with a formula weight of 300 or less, n2 is an integer from 0 to 5.) R 1 and R 21 in formula (2-1) are the same as those defined in formula (1). n2 is preferably an integer of 0 to 3, more preferably 1 or 2, and even more preferably 1.
- n2 represents an integer of 0 to 5
- Ac represents an acetyl group.
- n2 is preferably an integer of 0 to 3, more preferably 1 or 2, and even more preferably 1.
- Compounds of formula (3) can be derived from compounds of formula (2-1). Specifically, first, the oxazolidinone ring is opened with a base (eg, sodium hydroxide). The resulting sugar is reacted with acetic anhydride and DMAP (4-dimethylaminopyridine). Furthermore, it is reacted with K 2 CO 3 to obtain a sugar in which the acetyloxy group is converted back to a hydroxyl group. This is reacted with an acid (preferably under a hydrogen atmosphere) to return Bn (benzyl group) to a hydrogen atom to obtain a sugar of formula (3) having a hydroxyl group as the substituent at the 6-position. can.
- a base eg, sodium hydroxide
- DMAP 4-dimethylaminopyridine
- cyclic oligosaccharides represented by the following formula (4) are also included.
- Formula (4) (In formula (4), n2 represents an integer of 0 to 5.) n2 is preferably an integer of 0 to 3, more preferably 1 or 2, and even more preferably 1.
- Compounds of formula (4) can be obtained by deacetylation of compounds of formula (3). Deacetylation can be performed by base treatment. Examples of bases here include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, and hydroxylamine.
- novel compounds represented by formulas (2) to (4) above are useful as inclusion compounds.
- it can be used in the same applications as cyclodextrin, and is useful as an encapsulating agent and encapsulating agent.
- cyclodextrins with 6- to 8-membered rings are widely synthesized and industrialized. Since the novel compounds represented by the above formulas (2) to (4) contain an amino group, they are excellent in inclusion of those having an acidic substituent such as a carboxylic acid group.
- oligosaccharides are synthesized by an automatic liquid phase electrolytic synthesis method.
- the glycosyl donor is activated by electrolytic oxidation (Reaction Scheme 9).
- this method is advantageous in that the reaction can be controlled more precisely because intermediates can be accumulated. Taking advantage of this precision and reproducibility, we have developed an efficient method for synthesizing cyclic oligosaccharides based on electropolymerization, in which substrates act as both glycosyl donors and glycosyl acceptors.
- acetylated compounds are exemplified in the following examples, the acetylated compounds can be easily deacetylated by base treatment.
- Nuclear magnetic resonance spectra were measured on a Bruker AVANCE II 600 (1H NMR; 600 MHz, 13C NMR; 150 MHz) using CDCl3 as solvent at room temperature.
- Electrolytic oxidation was performed at 5066s, 8.0mA, -60°C.
- Glycosylation was performed at -40°C for 3600s. Quenched by adding 0.3 mL of Et 3 N to each of the cathode and anode. Concentrated, dried in vacuo, and water washed with H2O . The crude product obtained was dissolved in 3 mL of CH 2 Cl 2 and purified by GPC.
- the inside of the cell was replaced with argon, 10 mL of CH 2 Cl 2 was added to each of the cathode and anode, and TfOH (40 ⁇ L) was added to the cathode.
- Electrolytic oxidation was performed at 5790s, 8.0mA, 0°C.
- Glycosylation was carried out at 0°C for 3600s. Quenched by adding 0.3 mL of Et 3 N to each of the cathode and anode. Concentrated, dried under vacuum, and washed with water three times with HClaq, NaHCO3aq and H2O .
- the crude product obtained was dissolved in 3 mL of CH 2 Cl 2 and purified by GPC. As a result, it was confirmed that disaccharide cyclic oligosaccharide 16 was produced (see the NMR spectrum below and FIGS. 1 to 4).
- Example 301 Electropolymerization using compound 20
- the interior of the 10 mL H-type separation electrolytic cell was replaced with argon, Bu 4 NOTf (1.0 mmol, 0.392 g) was added to the anode, and 8 (0.40 mmol, 0.185 g) was added.
- Bu4NOTf (1.0 mmol, 0.392 g) was placed in the cathode.
- the inside of the cell was evacuated and vacuum-dried overnight.
- the inside of the cell was replaced with argon, 10 mL of CH 2 Cl 2 was added to each of the cathode and anode, and TfOH (40 ⁇ L) was added to the cathode.
- Electrolytic oxidation was performed at 2895s, 8.0mA, -40°C. Glycosylation was performed at -40°C for 3600s. After that, the temperature was raised to room temperature and the mixture was stirred for 3600 seconds. Then, electrolytic oxidation was performed again at 2895 s, 8.0 mA, and -40°C. Glycosylation was performed at -40°C for 3600s. Et 3 N was quenched by adding 0.5 mL each to the cathode and anode. Concentrated, dried in vacuo, and water washed with H2O . The crude product obtained was dissolved in 3 mL of CH 2 Cl 2 and purified by GPC.
- FIG. 9 is MALDI-TOF MS after quenching of reaction scheme (27).
- FIG. 10 is MALDI-TOF MS after gel filtration (Sephadex LH-20, solvent: deionized water) of the product.
- FIG. 11 is 1 H-NMR of the product after gel filtration.
- Mass spectrometry data for the intermediate saccharide 24 are presented in FIG. The calculated values and measured values are as follows. Mass spectrometry (MALDI-TOF) C102H126N6NaO36 [M+Na+] calculated value: 2033.811, measured value: 2033.807
- Mass spectrometry data for the final product sugar 26 is presented in FIG. The calculated values and measured values are as follows. Mass spectrometry (MALDI-TOF) C48H78N6NaO30 [M+Na+] calculated value: 1241.466, measured value: 1241.466
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Abstract
Description
具体的には、下記の手段により、上記課題は解決された。
〔1〕5~10個のα-グルコサミンまたはその誘導体が1,4-結合により、直列に結合した直鎖状オリゴ糖を、液相電解反応させることを含む、環状オリゴ糖の製造方法。
〔2〕前記直鎖状のオリゴ糖が、下記式(1)で表される、〔1〕に記載の環状オリゴ糖の製造方法。
式(1)
〔3〕前記直鎖状のオリゴ糖が、下記式(1-1)で表される、〔1〕に記載の環状オリゴ糖の製造方法。
式(1-1)
〔4〕式(2)で表される環状オリゴ糖。
式(2)
〔5〕式(2-1)で表される環状オリゴ糖。
式(2-1)
〔6〕式(3)で表される環状オリゴ糖。
式(3)
〔7〕式(4)で表される環状オリゴ糖。
式(4)
〔8〕〔7〕に記載の化合物を含む包接剤。
〔9〕下記式(2-1)で表される環状オリゴ糖について、塩基によりそのオキサゾリジノン環を開環させ、得られた糖を、無水酢酸と反応させて、開環させた部位をアセチル化し、さらに、K2CO3と反応させ、3位のアセチルオキシ基をヒドロキシル基に戻した糖を得、これを酸と反応させR1の基を水素原子にし、6位の置換基をヒドロキシル基とした式(3)の糖を得る環状オリゴ糖の製造方法。
式(2-1)
式(3)
なお、本明細書において「~」とはその前後に記載される数値を下限値および上限値として含む意味で使用される。
本明細書において、各種物性値および特性値は、特に述べない限り、23℃におけるものとする。
本明細書における基(原子団)の表記において、置換および無置換を記していない表記は、置換基を有さない基(原子団)と共に置換基を有する基(原子団)をも包含する。例えば、「アルキル基」とは、置換基を有さないアルキル基(無置換アルキル基)のみならず、置換基を有するアルキル基(置換アルキル基)をも包含する。本明細書では、置換および無置換を記していない表記は、無置換の方が好ましい。
本明細書で示す規格が年度によって、測定方法等が異なる場合、特に述べない限り、2021年1月1日時点における規格に基づくものとする。
・Manmode,S.;Tanabe,S.;Yamamoto,T.;Sasaki,N.;Nokami,T.;Itoh,T.ChemistryOpen 2019,8,869.
・Yano,K.;Itoh,T.;Nokami.Carbohydr.Res.2020,492,108018.
Glycosylation:グリコシル化
糖ピラノース環の立体反転による副反応を抑制するため、最も導入しやすい、2,3位に反転時に嵩高くなる保護基、すなわち2,3-オキサゾリジノン保護の導入を試みた(反応スキーム4)。上記で用いた単糖ビルディングブロック8を出発原料として合成を試みた。単糖ビルディングブロック8の6位をTBDPS基による保護を行い、化合物11へと変換した。その後、フタルイミド保護基の脱保護を行うため、脱水エチレンジアミンを用いて脱保護を行い、化合物12を得た。この時3位のアセチル基も同時に脱保護された。次に、CH2Cl2と10%NaHCO3水溶液中にて、2,3位オキサゾリジノン保護を行い化合物13へと変換した。そして、DMF中にて、窒素上のアセチル保護を行った後に、6位のTBDPS保護基を脱保護することで、6位の水酸基が無保護のオキサゾリジノン保護体15を得た。
1,6-グリコシド結合による、電解グリコシル化重合では、大きな環状オリゴ糖を得られないと判明したため、アプローチを変更した(反応スキーム6)。このアプローチでは、1,4-グリコシド結合によるグリコシル化で大きな環状オリゴ糖を得ることができた。以下がその概要である。
・Nokami,T.;Shibuya,A.;Saigusa,Y.;Manabe,S.;Ito,Y.;Yoshida,J.BeilsteinJ.Org.Chem.2012,8,456.
・Benakli,K.;Zha,C.;Kerns,R.J.J.Am.Chem.Soc.2001,123,9461.
初めに、基質の合成について述べる(反応スキーム7)。上記で合成した基質6を出発原料として、脱フタロイル化を行い、17を得た後に2,3-オキサゾリジノン保護を、行い18を得た。この18をCH2Cl2中で無水酢酸に作用させることで19を得た。この19をベンジリデン開環反応で4位選択的に開環することで、基質20を合成した。
・Feng,J.;Hevey,R.;Ling,C.Carbohydr.Res 2011,346,2650.
[ワンポット環状オリゴ糖合成の反応条件]
これを電解重合によって、糖鎖伸長すると、6.0ppmから6.2ppm付近にαアノマー水素のピークが2種に分裂すると同時に、5.0ppm付近にαアノマー水素のピークも確認できる。そして、この鎖状オリゴ糖を酸による異性化で処理をすると、5.0ppm付近のαアノマー水素のピークが消失した。最後に、環化すると、βアノマーピークが収束し、5.8ppm付近へとシフトした。オリゴ糖が環状化することで、アノマー水素のピークは高磁場シフトすることが知られており(Wakao,M.;Fukase,K.;and Kusumoto,S.J.Org.Chem.2002.67,8182.)、これに沿っているため、環状オリゴ糖であると判断した。
すなわち、5~10個のα-グルコサミンまたはその誘導体が1,4-結合により、直列に結合した直鎖状オリゴ糖を、液相電解反応させることを含む、環状オリゴ糖の製造方法が発明された。
このとき前記直鎖状のオリゴ糖が下記式(1)で表されることが好ましい。
式(1)
R1の式量は、60以上であることが好ましく、80以上であることがより好ましく、90以上であることがさらに好ましく、100以上であることが一層好ましく、105以上であることがより一層好ましい。一方、上限は500以下であり、400以下であることが好ましく、350以下であることがより好ましく、300以下であることがさらに好ましく、280以下であることが一層好ましい。好ましい保護基としては、Bn基、ベンゾイル基(Bz)、アセチル基(Ac)、ピバロイル基(Piv)、TBDPS、tert-ブチルジメチルシリル基(TBS)、9-フルオレニルメチルカルボキシ基(Fmoc)が例示され、Bn、TBDPS、TBSが好ましく、Bn、TBDPSがさらに好ましく、Bnが一層好ましい。
R1は1種のみ含んでいてもよいし、2種以上含んでいてもよい。
上記の観点から、R3の式量は、20以上であることが好ましく、30以上であることがより好ましく、40以上であることがさらに好ましく、50以上であることが一層好ましい。一方、上限は300以下であり、250以下であることが好ましく、200以下であることがより好ましく、180以下であることがさらに好ましく、160以下であることが一層好ましい。R3は、式量が大きすぎると環化反応の阻害となる。一方、置換基が小さすぎるとその役割を十分に果たせないことがある。具体的には、Bn、Bz、Ac、Piv、TBDPS、TBS、Fmocが例示され、Bz、Ac、Piv、Fmocが好ましく、Bz,Acがより好ましく、Acがさらに好ましい。
R3は1種のみ含んでいてもよいし、2種以上含んでいてもよい。
R21およびR21は、それぞれ、1種のみ含んでいてもよいし、2種以上含んでいてもよい。
環状もしくは鎖状のオリゴ糖においては、式中の定義を満たす限り、単一の糖の繰返し構造であっても、異なる糖の繰返し構造であってもよい。このことは、下記の式(1-1)、式(2)、式(2-1)、式(3)、式(4)についても同様である。
式(1-1)
R1、R21、R4、Xおよびn1の好ましい範囲は前記式(1)で示したものと同義である。
例えば、電解液は、CH2Cl2、アセトニトリル、プロピオニトリル、DMF等を用いることができ、CH2Cl2が好ましい。支持電解質は、Bu4NOTf、Et4NOTf、Pr4NOTf等を用いることができ、Bu4NOTfが好ましい。支持電解質濃度は、0.1~3.0Mの範囲で行うことが好ましく、0.5~2.0Mの範囲で行うことがより好ましい。電解酸化温度は、-100~0℃の範囲で行うことが好ましく、-60~-10℃の範囲で行うことがより好ましい。
式(2)
式(2)中、R1、R21、R3の好ましい範囲は式(1)で示したものと同義である。R22とR31とで形成する環も同義であり、特にオキサゾリジノン環を形成することが好ましい。
式(2-1)
式(2-1)中のR1、R21は式(1)で定義したものと同義である。
n2は、0~3の整数が好ましく、1または2がより好ましく、1がよりさらに好ましい。
式(3)
n2は、0~3の整数が好ましく、1または2がより好ましく、1がよりさらに好ましい。
式(3)で表される化合物は、式(2-1)で表される化合物から誘導することができる。具体的には、まず、塩基(例えば、水酸化ナトリウム)によりオキサゾリジノン環を開環する。得られた糖を、無水酢酸とDMAP(4-ジメチルアミノピリジン)と反応させる。さらに、K2CO3と反応させ、アセチルオキシ基をヒドロキシル基に戻した糖を得る。これを酸と反応させ(好ましくは、水素雰囲気下で酸と反応させ)Bn(ベンジル基)を水素原子に戻し、6位の置換基をヒドロキシル基とした式(3)の糖を得ることができる。
式(4)
n2は、0~3の整数が好ましく、1または2がより好ましく、1がよりさらに好ましい。
式(4)で表される化合物は、式(3)で表される化合物の脱アセチル化によって得ることができる。脱アセチル化は、塩基処理によって行うことができる。ここでの塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、ナトリウムメトキシド、ヒドロキシアミンが例示される。
本発明の好ましい実施形態においては、液相電解自動合成法によるオリゴ糖の合成が行われる。この方法では、グリコシルドナーを電解酸化することで活性化を行っている(反応スキーム9)。旧来のSchmidtグリコシル化などのグリコシル化方法と違い、中間体の蓄積が可能となっているため、より精密に反応を制御できる点がメリットである。この精密性と再現性を利用し、基質にグリコシルドナーとグリコシルアクセプターの両方の役割を担わせる電解重合法に基づいて、環状オリゴ糖の効率的な合成法を開発した。
Nokami,T.;Shibuya,A.;Tsuyama,H.;Suga.S.;Albert A.Bowers,Crich,D.;Yoshida,J.J.Am.Chem.Soc.2007,129,10922.
実施例で用いた測定機器等が廃番等により入手困難な場合、他の同等の性能を有する機器を用いて測定することができる。
試薬はすべて市販されている試薬を使用した。溶媒はすべて脱水された溶媒を使用した。グリコシル化反応時には、脱水溶媒にアルゴン雰囲気下で4Åのモルキュラーシーブスを加え、追加の脱水を行った。
1,3,4,6-penta-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (3)の合成
その後、TLC(Hexane:EtOAc=1/1)で反応終了を確認し、MeOH で反応を停止させた。溶媒を取り除くため、EtOAc(酢酸エチル)に溶解させた粗生成物を1MのHClaq、NaHCO3aq、H2Oの順でそれぞれ3回ずつ分液洗浄を行い、Na2SO4 で乾燥させ、ろ過、濃縮、真空乾燥を行った。得られた粗生成物を、シリカゲルカラム(Hexane/EtOAc=1/1)で生成し、化合物3を得た。
収量22.0g,46.2mmol 収率50%
4-Chlorophenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-β-D-gluco-pyranoside (4)の合成
収量21.2g,37.7mmol 収率81%
4-Chlorophenyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside(6)の合成
収量6.18g,11.8 mmol 収率66% (2 steps)
4-Chlorophenyl-3-O-acetyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-β-Dglucopyranoside(7)の合成
収量4.78g,8.45mmol 収率76%
4-Chlorophenyl 3-O-acetyl-4-O-benzyl-2-deoxy-2-phtalimido-1-thio-β-Dglucopyranoside(8)の合成
収量2.80g,49.4mmol 収率58%
化合物8を使った電解重合
4-Chlorophenyl 3-O-acetyl-4-O-benzyl-6-O-tert-butyldimethyldiphenylsilyl-2-deoxy-2-phtalimido1-thio-β-D-glucopyranoside(11)の合成
収量4.52g,5.60mmol 収率93%
4-Chlorophenyl 2-amino-6-O-tert-butyldimethyldiphenylsilyl-2-deoxy-1-thio-β-D-glucopyranoside(12)の合成
収量3.07g,4.77mmol 収率85%
4-Chlorophenyl 6-O-tert-butyldimethyldiphenylsilyl-2-deoxy-2,3-N,O-carbonyl-1-thio-β-D-glucopyranoside(13)の合成
収量2.89g,4.37mmol 収率92%
4-Chlorophenyl 2-acetamido-6-O-tert-butyldimethyldiphenylsilyl-2-deoxy-2,3-N,Ocarbonyl-1-thio-β-D-glucopyranoside(14)の合成
4-Chlorophenyl 2-acetamido-2-deoxy-2,3-N,O-carbonyl-1-thio-β-D-glucopyranoside(15)の合成
収量0.94g,2.03mmol 収率62%
化合物15を使った電解重合
[α]24D = 43.5 (c = 0.7, CHCl3). 1H-NMR (600 MHz, CDCl3): δ 7.38-7.35 (m, 4 H), 7.33-7.30 (m, 1 H), 5.25-5.23 (d, J = 5.7 Hz, 1 H), 4.91-4.89 (d, J = 11.4 Hz, 1 H), 4.63-4.61(d, J = 11.2 Hz, 1 H), 4.33-4.29 (dd, J = 12.5, 9.8 Hz, 1 H), 4.19-4.17 (dd, J = 9.6, 4.3 Hz,1 H), 4.15-4.14 (dd, J = 2.4, 1.0 Hz, 1 H), 4.14 (m, 1 H), 4.02-4.00 (dd, J = 10.9, 2.5 Hz,1 H), 3.95-3.92 (dd, J = 12.5, 5.8 Hz, 1 H), 3.60-3.58 (d, J = 10.5 Hz, 1 H), 2.53 (s, 3 H).13C-NMR (150 MHz, CDCl3): δ 170.6, 153.7, 137.3, 128.5, 128.0, 127.9, 97.0, 81.7, 73.1,63.8, 62.0, 24.5; HRMS (ESI) m/z calcd for C32H34KN2O12[M+K]+, 677.1744; found,677.1735.
4-Chlorophenyl 2-amino-4,6-O-benzylidene-2-deoxy-1-thio-β-D-glucopyranoside(17)の合成
収量6.56g,16.7mmol 収率98%
4-Chlorophenyl 4,6-O-benzylidene-2-deoxy-2,3-N,O-carbonyl-1-thio-β-D-glucopyranoside(18)の合成
収量5.34g,12.7mmol 収率76%
収量3.80g,8.22mmol 収率65%
4-Chlorophenyl 2-acetamido-6-O-benzyl-2-deoxy-2,3-N,O-carbonyl-1-thio-β-D-glucopyranoside(20)の合成
収量2.44g,5.25mmol 収率69%
化合物20を使った電解重合
環状6 糖21
1H-NMR (600 MHz, CDCl3): δ 7.33-7.26 (m, 5 H), 5.80-5.80 (d, J = 2.4 Hz, 1 H), 4.54-4.49 (m, 2 H), 4.44-4.42 (d, J = 11.8 Hz, 1 H), 4.18-4.15 (pseudo-t, J = 9.0 Hz, 1 H), 3.81-3.79 (dd, J = 10.7, 4.5 Hz, 1 H), 3.77-3.75 (dd, J = 9.2, 4.9 Hz, 1 H), 3.71-3.69 (dd, J =12.2, 2.3 Hz, 1 H), 3.64-3.62 (d, 10.0 Hz, 1 H), 2.53 (s, 3 H). 13C-NMR (150 MHz, CDCl3):δ 172.1, 152.3, 137.4, 128.5, 128.0, 127.8, 98.0, 77.7, 74.8, 74.4, 73.7, 68.0, 59.6, 23.5;HRMS (ESI) m/z calcd for C96H102N6NaO36[M+Na]+, 1938.6261; found, 1938.6140.
質量分析(MALDI-TOF)C102H126N6NaO36 [M+Na+] 計算値:2033.811, 実測値:2033.807
質量分析(MALDI-TOF)C48H78N6NaO30 [M+Na+] 計算値:1241.466, 実測値:1241.466
Claims (9)
- 5~10個のα-グルコサミンまたはその誘導体が1,4-結合により、直列に結合した直鎖状オリゴ糖を、液相電解反応させることを含む、環状オリゴ糖の製造方法。
- 請求項7に記載の化合物を含む包接剤。
- 下記式(2-1)で表される環状オリゴ糖について、塩基によりそのオキサゾリジノン環を開環させ、得られた糖を、無水酢酸と反応させて、開環させた部位をアセチル化し、さらに、K2CO3と反応させ、3位のアセチルオキシ基をヒドロキシル基に戻した糖を得、これを酸と反応させR1の基を水素原子にし、6位の置換基をヒドロキシル基とした式(3)の糖を得る環状オリゴ糖の製造方法。
式(2-1)
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