CN114591179B - Photosensitive fluorine carrier and application thereof in efficient synthesis of oligosaccharide - Google Patents
Photosensitive fluorine carrier and application thereof in efficient synthesis of oligosaccharide Download PDFInfo
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- CN114591179B CN114591179B CN202210305868.7A CN202210305868A CN114591179B CN 114591179 B CN114591179 B CN 114591179B CN 202210305868 A CN202210305868 A CN 202210305868A CN 114591179 B CN114591179 B CN 114591179B
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- oligosaccharide
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- photosensitive fluorine
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- 229920001542 oligosaccharide Polymers 0.000 title claims abstract description 71
- 150000002482 oligosaccharides Chemical class 0.000 title claims abstract description 70
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 65
- 239000011737 fluorine Substances 0.000 title claims abstract description 65
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 23
- 238000006303 photolysis reaction Methods 0.000 claims abstract description 7
- 230000015843 photosynthesis, light reaction Effects 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 238000005859 coupling reaction Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000010168 coupling process Methods 0.000 claims description 14
- -1 polytetrafluoroethylene Polymers 0.000 claims description 14
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 14
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 14
- 235000000346 sugar Nutrition 0.000 claims description 14
- 239000002245 particle Substances 0.000 claims description 13
- 230000008878 coupling Effects 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 239000000348 glycosyl donor Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 230000001678 irradiating effect Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 230000004048 modification Effects 0.000 abstract description 2
- 150000002221 fluorine Chemical class 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 49
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 34
- 239000000047 product Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000012512 characterization method Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 6
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 5
- 238000010532 solid phase synthesis reaction Methods 0.000 description 5
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- AGCPPSNKHQEFRX-UHFFFAOYSA-N 1-azidoethanol Chemical compound CC(O)N=[N+]=[N-] AGCPPSNKHQEFRX-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WCQRWCFGZARAMR-UHFFFAOYSA-N [F].[F] Chemical compound [F].[F] WCQRWCFGZARAMR-UHFFFAOYSA-N 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- MGSDFCKWGHNUSM-QVPNGJTFSA-N alpha-L-Fucp-(1->2)-beta-D-Galp-(1->3)-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@@H]2[C@H]([C@H](O)O[C@H](CO)[C@H]2O)NC(C)=O)O[C@H](CO)[C@H](O)[C@@H]1O MGSDFCKWGHNUSM-QVPNGJTFSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000937 glycosyl acceptor Substances 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
- C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
- C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a photosensitive fluorine carrier and application thereof in high-efficiency synthesis of oligosaccharide, wherein the structural formula of the photosensitive fluorine carrier is shown in the specification
Wherein R is H or CH 3 . Compared with the reported fluorine carrier, the photosensitive fluorine carrier not only can facilitate the rapid separation of oligosaccharide, but also can be removed by ultraviolet photolysis, the removal condition is green and environment-friendly, and the harsh catalytic hydrogenolysis reaction and the use of expensive Pd catalyst are avoided. Meanwhile, the use of the photosensitive fluorine carrier is convenient for modification and convergent synthesis of the oligosaccharide, and the preparation efficiency of the oligosaccharide is greatly improved.
Description
Technical Field
The invention belongs to the technical field of oligosaccharide synthesis and separation, and particularly relates to a photosensitive fluorine carrier and application thereof in efficient oligosaccharide synthesis.
Background
The carbohydrate plays a crucial role in many biological processes, and the efficient acquisition of oligosaccharides and glycoconjugates is a prerequisite for the intensive study of carbohydrates on a molecular level. The direct separation and extraction from natural products is a traditional and important method for obtaining carbohydrate, but the structure of the obtained oligosaccharide has micro-heterogeneity, which is not favorable for the precise research of structure-activity relationship. With the development of sugar chemistry, chemical synthesis has become a powerful means to obtain structurally defined oligosaccharides. However, due to the characteristics of polyhydroxy and chiral centers of saccharides, oligosaccharides can be efficiently prepared, and three challenges are faced in efficient preparation of sugar modules, efficient and highly stereoselective construction of glycosidic bonds, and rapid purification during oligosaccharide assembly. In order to improve the synthesis efficiency of oligosaccharides, the efficient preparation of oligosaccharides is mainly achieved by reducing or simplifying the separation and purification processes in the oligosaccharide assembly process.
The solid-phase synthesis of sugar (Science 2001,291,1523) mainly uses some insoluble polymers and the like, introduces carriers onto glycosyl donors or glycosyl acceptors through connecting arms, and then can separate coupling products, byproducts and excessive reaction reagents only through washing. However, since solid-phase synthesis of sugars is carried out in heterogeneous systems, the coupling efficiency is difficult to predict. In order to maximize the efficiency of glycosylation, it is often necessary to use a large number of sugar modules in the reaction. The synthesis workload of the sugar module is large, the use of a large number of sugar modules greatly increases the synthesis cost of the oligosaccharide, and simultaneously causes a lot of waste. At the same time, the solid phase synthesis of sugars is not possible to monitor the course of the reaction by conventional analytical methods such as TLC, NMR, etc., and can be carried out by conventional methods after cleavage of the product from the support if the reaction is to be monitored.
The fluorine solid phase extraction (F-SPE) technology utilizes the action force of fluorine-fluorine between a highly fluorinated compound and fluorosilicone gel, so that the nonfluorinated compound can be removed only by washing with a fluorine-resistant solvent, and the rapid separation of the product is realized (Tetrahedron 2006,62,11837). The Pohl group applied this technique to the liquid phase automated synthesis of oligosaccharides (org. Lett.2015,17,2642). Since the synthesis of the fluorine carrier support is carried out in a homogeneous system, the glycosylation efficiency is generally not affected, and the reaction can be monitored by conventional means. Nevertheless, the cumbersome transfer steps in the F-SPE separation technique result in loss of compound and also limit the scale of the reaction. In addition, the fluorine carriers used in the Pohl group are not easily removed and have limited carrying capacity.
Based on the respective advantages and disadvantages of solid-phase synthesis and liquid-phase synthesis, the subject group of the inventor combines the advantages of solid-phase synthesis and liquid-phase synthesis, and establishes a polytetrafluoroethylene Particle (PTFE) assisted, rapid and low-cost liquid-phase reaction and solid-phase separation oligosaccharide synthesis strategy (org. Lett.2020,22,2564, ZL 2014107046792. In the oligosaccharide synthesis, double-side chain benzyl type fluorine carriers (ZL 2014105380632) are introduced onto sugar through conventional chemical reaction, polytetrafluoroethylene particles are added into a reaction mixture during separation and purification, and the rapid separation of fluorine-containing compounds and non-fluorine compounds can be realized through simple filtration and washing. Based on the method, the complex tumor associated antigen Globo-H hexaose supported by the fluorine carrier is synthesized by 5-step glycosylation reaction with the total yield of 48%. However, the double-side chain benzyl type fluorine carrier and a benzyl protecting group in the oligosaccharide can be removed together in the hydrogenolysis process, interference exists on the rapid modification of the terminal group of the oligosaccharide, and the influence is influenced and used in subsequent researches such as immunization, assembly, microarray and the like.
Disclosure of Invention
The invention aims to overcome the limitation of the conventional fluorine carrier in the aspects of bearing capacity or removal, and provides a photosensitive fluorine carrier capable of being removed through photolysis and application of the fluorine carrier in efficient oligosaccharide synthesis.
The structural formula of the photosensitive fluorine carrier used for solving the technical problems is as follows:
wherein R is H or CH 3 。
When R is CH 3 The synthesis method of the photosensitive fluorine carrier comprises the following steps:
(1) Mixing the compound 2 with triphenylphosphine and the compound 1 according to the molar ratio of 1:1-2:1-2, dissolving the mixture with an aprotic solvent (toluene or tetrahydrofuran), adding an azo reagent (such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like) into the solution under stirring at 0 ℃ to room temperature, reacting for 5-10 hours at room temperature to 150 ℃, and separating and purifying a product to obtain a compound 3, wherein the reaction equation is as follows:
(2) Dissolving the compound 3 in a polar solvent (specifically, alcohol solvents such as ethanol, methanol and the like), adding sodium borohydride, and stirring at room temperature for 0.5-2 hours to obtain a photosensitive fluorine carrier I, wherein the reaction equation is as follows:
when R is H, the synthesis method of the photosensitive fluorine carrier is as follows:
(1) Dissolving the compound 4 and imidazole in the molar ratio of 1:2 in dichloromethane or tetrahydrofuran, adding tert-butyldimethylsilyl chloride under stirring at room temperature, reacting for 1-10 hours, and separating and purifying to obtain a compound 5;
(2) Mixing the compound 5 with triphenylphosphine and the compound 2 according to the molar ratio of 1:1-2:1-2, dissolving the mixture with an aprotic solvent (toluene or tetrahydrofuran), adding an azo reagent (such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like) into the obtained solution under stirring at 0 ℃ to room temperature, then reacting for 5-10 hours at room temperature to 150 ℃, and separating and purifying a product to obtain a compound 6, wherein the reaction equation is as follows:
(2) Dissolving a compound 6 in tetrahydrofuran and the like, adding a deprotection reagent tetrabutylammonium fluoride with the molar weight being 1-2 times that of the compound, reacting at room temperature for 2-24 hours to obtain a photosensitive fluorine carrier II, wherein the reaction equation is as follows:
the invention discloses an application of a photosensitive fluorine carrier in high-efficiency preparation of oligosaccharide, which comprises the following steps:
(1) Coupling a photosensitive fluorine carrier with a module corresponding to a first structural unit of the oligosaccharide, fully adsorbing a coupling product and polytetrafluoroethylene particles through acting force between fluorine and fluorine after the coupling reaction is finished, and filtering to obtain the coupling product; then removing the hydroxyl protecting group connected with the next structural unit in the coupled product, and purifying the product of removing the hydroxyl protecting group through polytetrafluoroethylene particles to ensure that the product is continuously coupled with the next structural unit; repeating the operation of coupling-deprotection-coupling to obtain photosensitive fluorine carrier supported oligosaccharide;
(2) Removing the photosensitive fluorine carrier in the oligosaccharide supported by the photosensitive fluorine carrier obtained in the step (1) through photolysis to obtain an oligosaccharide with a free hydroxyl at the end position, and chemically converting the oligosaccharide into a glycosyl donor through one step;
(3) Repeatedly carrying out coupling-deprotection operation by adopting the method in the step (1) to obtain the photosensitive fluorine carrier supported oligosaccharide with one or more hydroxyl protecting groups removed;
(4) Coupling the glycosyl donor obtained in the step (2) with the oligosaccharide obtained in the step (3) to obtain the photosensitive fluorine carrier supported oligosaccharide with more sugar units;
(5) And (4) repeating the steps (2) to (4) on the oligosaccharide supported by the photosensitive fluorine carrier with more sugar units obtained in the step (4), namely realizing the convergent synthesis of the oligosaccharide, and finally obtaining the target oligosaccharide.
The method for removing the photosensitive fluorine carrier comprises the following steps: dissolving the target oligosaccharide supported by the photosensitive fluorine carrier in a solvent, and irradiating for 10-60 minutes by ultraviolet light. Wherein the solvent is one or two of methanol, ethanol, tetrahydrofuran, diethyl ether, dichloromethane, dioxane, acetonitrile, etc.
Taking homopolymerized linear oligosaccharide as an example, the reaction process of the photosensitive fluorine carrier in oligosaccharide convergent synthesis is shown as follows, the photosensitive fluorine carrier is coupled with a module a1 corresponding to a first structural unit of a target oligosaccharide, and after the coupling reaction is finished, a solvent is changed to enable polytetrafluoroethylene particles and the photosensitive fluorine carrier supported oligosaccharide (hereinafter referred to as fluorine-supported oligosaccharide) to be fully adsorbed by the action force between fluorine and fluorine, so that a product a2 can be obtained only by filtration. Then, the protecting group of the group attached to the next structural unit in the product a2 is removed and a3 is obtained. And then, adding modules corresponding to other structural units for coupling reaction, after each coupling reaction, purifying the product by adopting an oligosaccharide separation method assisted by polytetrafluoroethylene particles, and repeating the operation of coupling-deprotection-coupling to obtain the fluorine-loaded oligosaccharide a4. On the other hand, b1 can be obtained by deprotecting a 4; on the other hand, the photosensitive fluorine carrier can be removed by photolysis to obtain oligosaccharide b2. Further, oligosaccharide b2 can be converted into a new glycosyl donor b3 by a further chemical reaction. By coupling b1 with b3, b4 can be obtained in a convergent manner. b4 can be converted into oligosaccharide b5 after deprotection. Likewise, oligosaccharide b4 can be photolyzed and further converted to glycosyl donor c 1. c1 can be continuously coupled with the fluoro-loaded oligosaccharide deprotected by b1 and the like to obtain the oligosaccharide with more sugar units. In addition, c1 can also be coupled to a linker such as azidoethanol to give compound c2. And carrying out full deprotection treatment on the c2 to obtain the oligosaccharide c 3. c3 can be further coupled with high molecular compounds such as protein, polymer and the like or other substances and used for some subsequent functional research of the oligosaccharide.
The invention has the following beneficial effects:
the photosensitive fluorine carrier not only inherits the characteristics of the fluorine carrier, but also can realize the liquid phase reaction and solid phase separation of oligosaccharide; meanwhile, the advantage of 'photosensitivity' can be developed, photolysis removal is easy, the removal condition is green and environment-friendly, and harsh catalytic hydrogenolysis reaction and use of expensive Pd catalyst are avoided. In addition, the photosensitive fluorine carrier supported oligosaccharide can be converted into a new glycosyl donor after photolysis for convergent synthesis and post-modification, so that the preparation efficiency of the oligosaccharide is greatly improved, and a foundation is laid for promoting further research and application of the oligosaccharide.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
1. 200mg (0.26 mmol) of the compound 2, 101mg (0.38 mmol) of triphenylphosphine and 75mg (0.35 mmol) of the compound 1 are dissolved in 3mL of dry toluene, cooled in an ice bath for 10 minutes, slowly dropped with 60 μ L of diethyl azodicarboxylate (DEAD), heated to 110 ℃ for reaction for 2 hours, cooled, concentrated, and subjected to silica gel column chromatography using a mixed solution of ethyl acetate and petroleum ether at a volume ratio of 1:3 as an eluent to obtain 129 mg compound 3 with a yield of 49%. The reaction equation is as follows:
the structural characterization data of the product is: 1 H NMR(300MHz,CDCl 3 )δ7.85(s,1H),6.76(s,1H), 4.66–4.49(m,1H),3.94(s,3H),3.87–3.62(m,8H),2.49(s,3H),2.54–2.25(m,4H)。
2. dissolving 120mg (0.12 mmol) of compound 3 in 1mL of methanol, adding 7mg (0.18 mmol) of sodium borohydride, stirring at room temperature for 1 hour, concentrating the reaction solution, and performing silica gel column chromatography with a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:2 as an eluent to obtain 106mg (0.11 mmol) of photosensitive fluorovector I with a yield of 88%. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(400MHz,CDCl 3 )δ7.78(s,1H),7.31(s,1H), 5.57(q,J＝6.3Hz,1H),4.51(p,J＝4.9Hz,1H),3.96(s,3H),3.86–3.68(m,8H),2.52– 2.29(m,4H),1.56(d,J＝6.3Hz,3H)。
example 2
1. 120mg (0.60 mmol) of Compound 4 are mixed with 79mg (1.16 mmol) of imidazole and dried CH in 5mL 2 Cl 2 Dissolved, stirred at room temperature, 117mg (0.78 mm) of the resulting solution was addedol) tert-butyldimethylsilyl chloride (TBSCl) and reacted for 5 hours, and the mixture of ethyl acetate and petroleum ether in a volume ratio of 1:5 was subjected to silica gel column chromatography to obtain 160mg (0.51 mmol) of compound 5, which was 85% in yield. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(600MHz,CDCl 3 )δ7.77(s,1H),7.26(s,1H), 5.65(s,1H),5.08(s,2H),4.00(s,3H),0.99(s,9H),0.15(s,6H)。
2. 86mg (0.27 mmol) of Compound 5, 143.4mg (0.18 mmol) of Compound 2 and 94mg (0.36 mmol) of triphenylphosphine were dissolved in 1mL of dry toluene, and 0.8mL of a toluene solution containing 56. Mu.L of diethyl azodicarboxylate (DEAD) was added dropwise to the resulting solution under cooling in an ice bath. After the addition was completed, the ice bath was removed, and the reaction mixture was heated to 100 ℃ to react for 8 hours, cooled, concentrated, and subjected to silica gel column chromatography using a mixture of ethyl acetate and petroleum ether at a volume ratio of 1. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(600MHz,CDCl 3 )δ7.93(s,1H),7.47(s,1H), 5.10(s,2H),4.51(p,J＝4.9Hz,1H),3.94(s,3H),3.85–3.71(m,8H),2.48–2.35(m, 4H),0.99(s,9H),0.15(s,6H)。
3. 900mg (0.83 mmol) of Compound 6 was dissolved in 5mL of tetrahydrofuran, 1.4mL of 1mol/L tetrahydrofuran solution of tetrabutylammonium fluoride was added, and after 4 hours of reaction at room temperature, TLC indicated that the reaction was complete. Adding 15mL of ethyl acetate into the reaction mixture, pouring the mixture into water for liquid separation extraction, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography separation by using a eluent which is a mixed solution of 1:2 in the volume ratio of ethyl acetate to petroleum ether to obtain 637mg (0.66 mmol) of the photosensitive fluorine carrier II with the yield of 79%. The reaction equation is:
the structural characterization data of the product is: 1 H NMR(600MHz,CDCl 3 )δ7.85(s,1H),7.11(s,1H), 4.89(d,J＝5.9Hz,2H),4.45(p,J＝4.9Hz,1H),3.78–3.63(m,8H),2.54(t,J＝6.4Hz, 1H),2.39–2.28(m,4H)。
example 3
Taking photosensitive fluorine carrier II as an example, mannuronic acid oligosaccharide is synthesized. The specific method comprises the following steps:
1. after 47mg (0.071 mmol) of compound 7 and 43mg (0.045 mmol) of the photosensitive fluorocarrier II were dissolved in 3mL of dry dichloromethane, and cooled at-40 ℃ for 10 minutes, a solution of trifluoromethanesulfonic acid (TfOH) in dichloromethane (which was obtained by dissolving 5. Mu.L of TfOH in 1mL of dichloromethane) was slowly added dropwise, and after 0.5 hour of the reaction, the reaction was completed by TLC, and 30. Mu.L of triethylamine was added to quench the reaction. 807mg of polytetrafluoroethylene particles were added to the reaction mixture, the reaction mixture was concentrated, 5mL of a 60% by volume aqueous acetone solution was added to the mixture, the mixture was stirred uniformly, the mixture was filtered, and the mixture was washed twice with a 60% by volume aqueous acetone solution (5 mL each), and then the product was desorbed with pure acetone and dried by spinning to obtain 59mg (0.041 mmol) of compound 8, which was 91% in yield. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(600MHz,CDCl 3 )δ7.90(s,1H),7.40–7.35(m, 3H),7.33–7.24(m,8H),5.62(t,J＝8.1Hz,1H),5.29(d,J＝15.4Hz,1H),5.10(d,J＝ 15.4Hz,1H),4.86(d,J＝12.0Hz,1H),4.82(d,J＝12.0Hz,1H),4.77(s,1H),4.58(d,J ＝12.5Hz,1H),4.55(d,J＝12.4Hz,1H),4.50–4.46(m,1H),3.99(d,J＝7.9Hz,1H), 3.98–3.96(m,1H),3.83–3.72(m,8H),3.66–3.63(m,4H),3.61(s,3H),2.72(t,J＝6.5 Hz,2H),2.61–2.51(m,2H),2.46–2.35(m,4H),2.17(s,3H)。
2. 42mg (0.029 mmol) of compound 8 was dissolved in 1mL of dichloromethane, 460. Mu.L of 0.1mol/L hydrazine acetate solution in methanol was added thereto with stirring at room temperature, the reaction was allowed to proceed for 2.5 hours, TLC showed completion of the reaction, 400mg of polytetrafluoroethylene particles were added to the reaction system, the mixture was concentrated to remove the organic solvent, 5mL of 50% by volume aqueous acetone was added to the mixture and stirred uniformly, the mixture was filtered, and after washing twice with 50% by volume aqueous acetone (5 mL each), the product was desorbed with pure acetone and spin-dried to obtain 41mg (0.029 mmol) of compound 9 in 100% yield. The reaction equation is as follows:
the structural characterization data of the product is: 1 H NMR(600MHz,CDCl 3 )δ7.91(s,1H),7.40(d,J＝ 6.5Hz,2H),7.35–7.24(m,9H),5.28(d,J＝15.0Hz,1H),5.11(d,J＝15.0Hz,1H),4.99 (d,J＝12.0Hz,1H),4.84(d,J＝12.0Hz,1H),4.68(s,1H),4.60(d,J＝12.1Hz,1H), 4.57(d,J＝12.0Hz,1H),4.53–4.48(m,1H),4.32(t,J＝9.7Hz,1H),4.00(d,J＝2.8Hz, 1H),3.85–3.71(m,15H),3.44(dd,J＝9.4,2.9Hz,1H),2.93(s,1H),2.46–2.36(m, 4H)。
3. after 41mg (0.029 mmol) of Compound 9 and 38mg (0.058 mmol) of Compound 7 were dissolved in 0.7mL of dry dichloromethane, and cooled at-40 ℃ for 10 minutes, a TfOH solution (obtained by dissolving 5. Mu.L of TfOH in 1mL of dichloromethane) was slowly dropped, and after 1 hour of the reaction, the reaction was completed by TLC, and the reaction was quenched by adding 10. Mu.L of triethylamine. After 800mg of polytetrafluoroethylene particles were added to the reaction mixture, the reaction mixture was concentrated, 5mL of a 60% by volume aqueous acetone solution was added to the mixture, the mixture was stirred uniformly, filtered, washed twice with a 60% by volume aqueous acetone solution (5 mL each), and the product was desorbed with pure acetone and dried by spinning to obtain 50.6mg (0.028 mmol) of compound 10, which was 97% in yield. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(600MHz,CDCl 3 )δ7.92–7.89(m,1H),7.37 (d,J＝7.1Hz,2H),7.35–7.30(m,5H),7.29–7.20(m,14H),5.46(t,J＝9.6Hz,1H), 5.36(d,J＝15.6Hz,1H),5.06(d,J＝15.6Hz,1H),4.83–4.77(m,2H),4.76–4.72(m, 2H),4.65(d,J＝10.2Hz,2H),4.54–4.49(m,2H),4.49–4.45(m,1H),4.44(d,J＝12.4 Hz,1H),4.03(d,J＝6.7Hz,1H),3.96–3.93(m,1H),3.86(dd,J＝7.3,2.9Hz,1H),3.83 (d,J＝2.7Hz,1H),3.81–3.68(m,9H),3.64(d,J＝4.7Hz,1H),3.62(d,J＝3.3Hz,1H), 3.58(s,3H),3.53(t,J＝3.8Hz,6H),3.46(dd,J＝9.6,2.7Hz,1H),2.69(t,J＝6.8Hz, 2H),2.59–2.49(m,2H),2.45–2.35(m,4H),2.16(s,3H)。
4. 50mg (0.028 mmol) of Compound 10 are dissolved in 2.8mL of tetrahydrofuran and the reaction is complete by TLC after 10 minutes of irradiation with a 365nm UV lamp. Concentrating, eluting with 1:2 volume ratio of ethyl acetate and petroleum ether to obtain 20mg (0.024 mmol) of compound 11 with 86% yield. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(600MHz,CDCl 3 )δ7.33–7.13(m,20H),5.48 –5.41(m,2H),4.75(d,J＝12.4Hz,1H),4.66(d,J＝12.4Hz,1H),4.57–4.52(m,3H), 4.48(d,J＝12.0Hz,1H),4.44(d,J＝12.4Hz,1H),4.41(dd,J＝4.9,3.6Hz,1H),4.36(d, J＝3.4Hz,1H),4.34(d,J＝12.3Hz,1H),4.13(dd,J＝4.7,2.7Hz,1H),3.82(d,J＝2.5 Hz,1H),3.78(d,J＝9.3Hz,1H),3.59–3.51(m,5H),3.47(s,3H),3.42(dd,J＝9.5,2.8 Hz,1H),3.09(d,J＝4.7Hz,1H),2.68–2.60(m,2H),2.55–2.41(m,2H),2.10(s,3H)。
5. 242mg (0.28 mmol) of compound 11 and 112mg (0.54 mmol) of N-phenyltrifluoroacetyl chloride are dissolved in 3mL of acetone, 77mg (0.56 mmol) of potassium carbonate are added while stirring at room temperature, after 2 hours of reaction, the reaction is detected to be complete by TLC, concentration is carried out, and 280mg (0.27 mmol) of compound 12 is obtained by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:2 (wherein triethylamine in an amount of 5% of the volume of the mixture is added), and the yield is 97%. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(600MHz,CDCl 3 )δ7.38(d,J＝7.0Hz,2H), 7.36–7.30(m,3H),7.30–7.20(m,17H),7.09(t,J＝7.5Hz,1H),6.82(d,J＝7.5Hz, 2H),6.47(s,1H),5.51(t,J＝9.5Hz,1H),4.81(d,J＝12.3Hz,1H),4.76(d,J＝12.4Hz, 1H),4.69(d,J＝11.9Hz,1H),4.64(s,1H),4.59(d,J＝12.0Hz,1H),4.57–4.52(m,3H), 4.46(t,J＝9.4Hz,2H),4.36(d,J＝3.8Hz,1H),4.17(s,1H),3.87(d,J＝2.4Hz,1H), 3.86–3.79(d,J＝9.4Hz,2H),3.64(s,3H),3.56(s,3H),3.49(dd,J＝9.5,2.8Hz,1H), 2.72(t,J＝6.7Hz,2H),2.63–2.48(m,2H),2.17(s,3H)。
6. dissolving 116mg (0.064 mmol) of compound 10 in 2mL of dichloromethane, stirring at room temperature, adding 0.26mL of 0.5mol/L hydrazine acetate in methanol, reacting at room temperature for 2 hours, TLC indicating that the reaction is complete, adding 1g of polytetrafluoroethylene particles to the reaction system, concentrating to remove the organic solvent, adding 5mL of 50% by volume aqueous acetone to the mixture, stirring uniformly, filtering, washing twice (5 mL each) with 50% by volume aqueous acetone, desorbing the product with pure acetone, and spin-drying to obtain 112mg (0.065 mmol) of compound 12 with a yield of 100%. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(400MHz,CDCl 3 )δ7.90(s,1H),7.40–7.19(m, 21H),5.36(d,J＝15.7Hz,1H),5.06(d,J＝15.6Hz,1H),4.85–4.79(m,3H),4.75–4.68(m,3H),4.67–4.62(m,2H),4.59–4.55(m,3H),4.49–4.45(m,1H),4.23(t,J＝ 9.5Hz,1H),4.07(d,J＝6.5Hz,1H),3.96(s,1H),3.89(dd,J＝7.1,2.9Hz,1H),3.83(d, J＝2.4Hz,1H),3.82–3.69(m,9H),3.64(s,3H),3.56(d,J＝9.1Hz,1H),3.54(s,3H), 3.52(s,3H),3.33(dd,J＝9.4,2.7Hz,1H),2.96(s,1H),2.50–2.30(m,4H)。
7. after 112mg (0.066 mmol) of compound 13 and 186mg (0.18 mmol) of compound 12 were dissolved in 1mL of dry dichloromethane, and cooled at-40 ℃ for 10 minutes, a solution of TfOH in dichloromethane (which is obtained by dissolving 10. Mu.L of TfOH in 1mL of dichloromethane, and taking 100. Mu.L of the solution) was slowly dropped, the reaction was completed by TLC after 1 hour, and the reaction was quenched by adding 20. Mu.L of triethylamine. Adding 3g of polytetrafluoroethylene particles into the reaction solution, concentrating the reaction solution, adding 10mL of 65 vol% acetone aqueous solution into the mixture, uniformly stirring, filtering, washing twice (10 mL each) with 65 vol% acetone aqueous solution, then washing once with 10mL of 70 vol% acetone aqueous solution, desorbing the product with pure acetone, and performing spin drying to obtain 170mg (0.066 mmol) of compound 14, wherein the yield is 100%. The reaction equation is as follows:
the structural characterization data for the product is: 1 H NMR(600MHz,CDCl 3 )δ7.90(s,1H),7.37–7.18(m, 41H),5.40(t,J＝9.8Hz,1H),5.35(d,J＝15.5Hz,1H),5.04(d,J＝15.5Hz,1H),4.83– 4.75(m,4H),4.74–4.67(m,6H),4.66–4.58(m,4H),4.57–4.51(m,3H),4.50–4.45 (m,2H),4.40(d,J＝12.4Hz,2H),4.36(t,J＝9.0Hz,1H),4.29(t,J＝9.3Hz,1H),4.02 (d,J＝6.6Hz,1H),3.92(s,1H),3.84–3.70(m,12H),3.67–3.63(m,2H),3.61–3.57(m, 1H),3.56–3.52(m,3H),3.52(s,3H),3.51(s,3H),3.50(s,3H),3.43(s,3H),3.40(dd,J ＝9.7,2.8Hz,1H),2.69–2.65(m,2H),2.57–2.47(m,2H),2.46–2.35(m,4H),2.15(s, 3H)。
Claims (4)
1. a photosensitive fluorine carrier, characterized in that the structural formula of the fluorine carrier is as follows:
wherein R is H or CH 3 。
2. The use of the photosensitive fluorine carrier of claim 1 in the synthesis of oligosaccharides, the specific method is as follows:
(1) Coupling a photosensitive fluorine carrier with a module corresponding to a first structural unit of the oligosaccharide, fully adsorbing a coupling product and polytetrafluoroethylene particles through acting force between fluorine and fluorine after the coupling reaction is finished, and filtering to obtain the coupling product; then removing a hydroxyl protecting group connected with the next structural unit in the coupled product, and purifying the product of which the hydroxyl protecting group is removed by polytetrafluoroethylene particles to ensure that the product is continuously coupled with the next structural unit; repeating the operation of coupling-deprotection-coupling to obtain photosensitive fluorine carrier supported oligosaccharide;
(2) Removing the photosensitive fluorine carrier in the oligosaccharide supported by the photosensitive fluorine carrier obtained in the step (1) through photolysis to obtain an oligosaccharide with a free hydroxyl at the end position, and chemically converting the oligosaccharide into a glycosyl donor through one step;
(3) Repeatedly carrying out coupling-deprotection operation by adopting the method in the step (1) to obtain the photosensitive fluorine carrier supported oligosaccharide with one or more hydroxyl protecting groups removed;
(4) Coupling the glycosyl donor obtained in the step (2) with the oligosaccharide obtained in the step (3) to obtain the photosensitive fluorine carrier supported oligosaccharide with more sugar units;
(5) And (4) repeating the steps (2) to (4) on the oligosaccharide supported by the photosensitive fluorine carrier with more sugar units obtained in the step (4), namely realizing the convergent synthesis of the oligosaccharide, and finally obtaining the target oligosaccharide.
3. The use of a photosensitive fluorine carrier according to claim 2 for the synthesis of oligosaccharides, wherein the photosensitive fluorine carrier is removed by a method comprising: dissolving the photosensitive fluorine carrier supported oligosaccharide in a solvent, and irradiating for 10-60 minutes by ultraviolet light.
4. The use of the photosensitive fluorine carrier in the synthesis of oligosaccharide according to claim 3, wherein the solvent used for removing the photosensitive fluorine carrier is any one or a mixture of two of methanol, ethanol, tetrahydrofuran, diethyl ether, dichloromethane, dioxane and acetonitrile.
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| CN104355972A (en) * | 2014-10-13 | 2015-02-18 | 陕西师范大学 | Benzyl type fluoride carrier provided with double side chains and applications of fluoride carrier |
| CN104497058A (en) * | 2014-11-27 | 2015-04-08 | 陕西师范大学 | Method for synthesizing fluorine-supported biomolecule by utilizing polytetrafluoroethylene particle |
| CN112940058A (en) * | 2021-01-27 | 2021-06-11 | 山东大学 | Fluorine label, preparation method thereof and auxiliary method for synthesizing oligosaccharide chain by enzyme method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104355972A (en) * | 2014-10-13 | 2015-02-18 | 陕西师范大学 | Benzyl type fluoride carrier provided with double side chains and applications of fluoride carrier |
| CN104497058A (en) * | 2014-11-27 | 2015-04-08 | 陕西师范大学 | Method for synthesizing fluorine-supported biomolecule by utilizing polytetrafluoroethylene particle |
| CN112940058A (en) * | 2021-01-27 | 2021-06-11 | 山东大学 | Fluorine label, preparation method thereof and auxiliary method for synthesizing oligosaccharide chain by enzyme method |
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