CN113861246B - Stereoselective synthesis method of beta-D-arabinofuranoside bond - Google Patents
Stereoselective synthesis method of beta-D-arabinofuranoside bond Download PDFInfo
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- 230000000707 stereoselective effect Effects 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 28
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000000348 glycosyl donor Substances 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000012044 organic layer Substances 0.000 claims description 32
- 238000010791 quenching Methods 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 238000004440 column chromatography Methods 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- 230000000171 quenching effect Effects 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000004821 distillation Methods 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 239000000937 glycosyl acceptor Substances 0.000 claims description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 9
- 239000002808 molecular sieve Substances 0.000 claims description 9
- -1 o-dibromobenzyl Chemical group 0.000 claims description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 9
- 239000012312 sodium hydride Substances 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 7
- 230000007935 neutral effect Effects 0.000 claims description 7
- SRBFZHDQGSBBOR-OWMBCFKOSA-N L-ribopyranose Chemical compound O[C@H]1COC(O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-OWMBCFKOSA-N 0.000 claims description 6
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 6
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 5
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- OBAJXDYVZBHCGT-UHFFFAOYSA-N tris(pentafluorophenyl)borane Chemical group FC1=C(F)C(F)=C(F)C(F)=C1B(C=1C(=C(F)C(F)=C(F)C=1F)F)C1=C(F)C(F)=C(F)C(F)=C1F OBAJXDYVZBHCGT-UHFFFAOYSA-N 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- MOKYEUQDXDKNDX-DFLSAPQXSA-N [(2r,3r,4s,5r,6s)-6-methoxy-3,4,5-tris(phenylmethoxy)oxan-2-yl]methanol Chemical group O([C@@H]1[C@@H](CO)O[C@@H]([C@@H]([C@H]1OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)OC)CC1=CC=CC=C1 MOKYEUQDXDKNDX-DFLSAPQXSA-N 0.000 claims 1
- 238000006206 glycosylation reaction Methods 0.000 abstract description 15
- 150000002338 glycosides Chemical class 0.000 abstract description 11
- 229930182470 glycoside Natural products 0.000 abstract description 9
- 125000006239 protecting group Chemical group 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 150000002482 oligosaccharides Polymers 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000386 donor Substances 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000370 acceptor Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 230000013595 glycosylation Effects 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 210000002421 cell wall Anatomy 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 2
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 125000000328 arabinofuranosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- UHOVQNZJYSORNB-MICDWDOJSA-N deuteriobenzene Chemical compound [2H]C1=CC=CC=C1 UHOVQNZJYSORNB-MICDWDOJSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002243 furanoses Chemical class 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- SATHPVQTSSUFFW-UHFFFAOYSA-N 4-[6-[(3,5-dihydroxy-4-methoxyoxan-2-yl)oxymethyl]-3,5-dihydroxy-4-methoxyoxan-2-yl]oxy-2-(hydroxymethyl)-6-methyloxane-3,5-diol Chemical compound OC1C(OC)C(O)COC1OCC1C(O)C(OC)C(O)C(OC2C(C(CO)OC(C)C2O)O)O1 SATHPVQTSSUFFW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229920000189 Arabinogalactan Polymers 0.000 description 1
- 239000001904 Arabinogalactan Substances 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 229930182475 S-glycoside Natural products 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 235000019312 arabinogalactan Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical class [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940021993 prophylactic vaccine Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003569 thioglycosides Chemical class 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
Abstract
The invention belongs to the technical field of natural oligosaccharide chain synthesis, and particularly relates to a stereoselective synthesis method of beta-D-arabinofuranoside bonds. The method can effectively control the stereoselectivity of the glycosylation reaction with high selectivity, and has the advantages of wide substrate application range, convenient operation, easily obtained raw materials, less side reaction of the glycosylation reaction, high target yield and the like. The preparation method has the advantages that the reaction conditions of the glycosyl donor preparation process are simple and easy to control, the operation is convenient, the reaction raw materials are cheap and easy to obtain, the product yield of each stage is high, the selective removal of each protecting group of the glycosyl donor used in the preparation method can be realized under the acidic or alkaline condition, the flexibility and universality are high, and the method has very important significance for synthesizing the natural glycoside and the derivatives thereof.
Description
Technical Field
The invention belongs to the technical field of natural oligosaccharide chain synthesis, and particularly relates to a stereoselective synthesis method of beta-D-arabinofuranoside bonds.
Background
beta-D-arabinofuranoside linkages are widely available in nature and are important building blocks constituting the cell wall of mycobacteria. Two major polysaccharides on mycobacterial cell walls: arabinogalactan and lipoarabinomannan. Among them, lipoarabinomannan is the main antigenic component of mycobacterial cell walls, and plays a key role in numerous immunomodulatory events during disease progression. Thus, β -D-arabinofuranosides and derivatives thereof, which can be antigenic polysaccharides (or protein conjugates thereof) stimulate the production of protective antibodies in the body, are often developed as prophylactic vaccines. Meanwhile, because lipoarabinomannan biosynthesis enzymes are often acting targets of some antibiotics, beta-D-arabinofuranosides and derivatives thereof can be synthesized into novel oligosaccharide inhibitors of targeted enzymes. It can be seen that the beta-D-arabinofuranoside and the derivatives thereof have important biological functions, and the synthesis of the beta-D-arabinofuranoside has important guiding significance for preventing and treating mycobacterium tuberculosis.
Since the amount of beta-D-arabinofuranoside extracted in nature is limited, the research requirement can not be met far, and the beta-D-arabinofuranoside is prepared in a large amount by a chemical method to be an effective means for obtaining the compounds. Among them, the stereoselective synthesis of glycosidic bonds is the key to the synthesis of β -D-arabinofuranosides, and is also the most challenging part of glycosidic bond synthesis, mainly for the following reasons: (1) The involvement of an ortho group produces a 1, 2-trans glycoside, so a glycosyl donor having an acyloxy group at C2 cannot be used to synthesize a 1, 2-cis glycoside between substituents at C1 and C2; (2) In the absence of an ortho-group, both the steric and steric effects favor the formation of 1, 2-trans-glycosides, so that even donors with no participating groups on C2 are mainly synthesized to give 1, 2-trans-glycosides. (1) Kinetic studies have shown that the stereoselective reaction of β -D-arabinofuranosides proceeds through an ion pair SN1 mechanism, rather than SN2.
The existing synthesis method of the beta-D-arabinofuranoside mainly comprises the following steps: (1) Intramolecular Aglycone Delivery (IAD) method: a) IAD strategy based on 2-O-NAP (naphthylmethyl) protected D-arabinofuranosyl-sulfan donors for the stereoselective construction of beta-D-arabinofuranosyl bonds. B) Under oxidizing conditions, the 2-O-PMB protected arabinofuranosyl donor and the 2-OH derivative acceptor give mixed acetals in good yields. Subsequent intramolecular glycosylation using IDCP as an activator specifically yields 1, 2-linked β -arabinofuranosides. (2) Synthetic strategy with 2, 3-anhydrofuranosyl as acceptor: and (3) carrying out glycosylation reaction by taking 2, 3-dehydrated arabinofuranosyl sulfoxide as a donor, wherein the orientation of a glycosidic bond of a glycoside product is the same as that of epoxy, and then under the induction of chiral ligand, the 2, 3-epoxy undergoes stereoselective ring-opening reaction, and the generated 2-OH and the glycosidic bond are in cis form, so that the synthesis of the beta-D-arabinofuranoside is completed. (3) Locking the sugar ring conformation by a cyclic protecting group to control the configuration of the glycosidic bond: a) beta-D-arabinofuranosidization is realized by taking 2, 3-O-phthaloyl protected thioglycoside as a donor for glycosylation reaction. B) Direct intermolecular glycosylation protected by 3, 5-O-TIPDS. (4) Hydrogen-bond mediated aglycone delivery strategy (HAD): the quinoline-2-formyl (Quin) is used for protecting the 5-OH of an arabinofuranosyl donor, and hydrogen bonds can be formed between sp2 hybridized nitrogen atoms on the Quin of the protecting group and an acceptor in the glycosylation process, so that the acceptor is bound on the beta surface of a sugar ring, and the attack of the center of an acceptor terminal group occurs on the beta surface with high probability, so that a 1, 2-cis arabinofuranosyl bond is obtained. (5) The synthesis method using 2' -carboxybenzyl glycoside (CB) as furanose donor comprises the following steps: beta-D-arabinofuranoside was synthesized stereoselectively using 2' -carboxybenzyl glycoside (CB) as furanose donor. Although the method is simple and efficient, the stereoselectivity of the glycosylation reaction is greatly influenced by the acceptor protecting group, for example, a CB donor can show high stereoselectivity on an acyl-protected glycosyl acceptor; however, when the compound forms glycoside with a benzyl-protected receptor, the stereoselectivity has large fluctuation, so that the application of the compound is restricted. (6) Stereotactic furanosylation catalyzed by bis-thiourea hydrogen bond donors: the isomer phosphoric acid leaving group is combined with a hydrogen bond network on a double thiourea hydrogen bond donor catalyst, and interacts with amide on the catalyst to activate an acceptor, so that the 1, 2-cis-furanoside with high selectivity and high yield can be obtained.
At present, a Guan-D-arabinofuranoside synthesis method is studied, although little progress has been made in aspects of stereoselectivity and the like, and the synthesis of some complex natural glycosides is realized, the problem of poor stereoselectivity of beta-D-arabinofuranoside bonds of a method is not eliminated all the time. Currently, the research on stereoselective synthesis of α -D-arabinofuranosides is mature, but in contrast, stereoselective synthesis of β -D-arabinofuranosides remains highly challenging. In addition, the current synthesis method of beta-D-arabinofuranoside has the problem of poor substrate applicability. And the existing method is only suitable for a certain type of glycosidic bond under a certain condition, and has poor universality. Therefore, it is necessary to develop a novel method for stereoselective synthesis of β -D-arabinofuranoside linkages to solve the problems of poor stereoselectivity of β -D-arabinofuranoside linkages and poor substrate applicability of the existing synthesis methods.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a stereoselective synthesis method of beta-D-arabinofuranoside bonds, which synthesizes beta-D-arabinofuranoside compounds by taking 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate as glycosyl donors, thereby solving the problems of poor stereoselectivity of beta-D-arabinofuranoside bonds and poor substrate applicability in the existing beta-D-arabinofuranoside synthesis method.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a stereoselective synthesis method of beta-D-arabinofuranoside bond, which comprises the following steps: 2-O-benzyl-3, 5-O-para-xylene-D-arabinofuranosyl trichloroacetimidate is taken as a glycosyl donor, the glycosyl donor, glycosyl acceptor and molecular sieve are dissolved in an organic solvent together, cooled to the temperature of between 70 ℃ below zero and 80 ℃ below zero, stirred and then added with a catalyst, stirred and reacted for 12 to 24 hours continuously, quenched and filtered and purified to obtain the beta-D-arabinofuranoside compound; the chemical structural formula of the 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate is shown as follows:
preferably, the molar ratio of the glycosyl donor, the glycosyl acceptor, the catalyst and the molecular sieve is 1.5-2.5: 1-2: 0.2 to 0.4:3 to 6.
Preferably, the glycosyl acceptor comprises natural steroid, pyran type sugar and furane type sugar, the molecular sieve comprises a 4A molecular sieve, the organic solvent comprises dichloromethane, and the catalyst comprises tris (pentafluorophenyl) borane.
Preferably, the preparation method of the 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate comprises the following steps of:
s1, adding D-arabinose into methanol, dropwise adding acetyl chloride under ice bath condition, heating to room temperature, stirring to react completely, quenching, concentrating, and drying to obtain a compound a;
s2, dissolving the compound a in pyridine under ice bath conditions, dropwise adding acetic anhydride, heating to room temperature, stirring and reacting to completion, separating and collecting an organic layer, and then washing and separating by column chromatography to obtain a compound b;
s3, dissolving the compound b in methylene dichloride under the ice bath condition, adding p-toluenesulfonic acid, fully stirring, then dropwise adding boron trifluoride-diethyl ether complex, heating to room temperature, reacting to completion, regulating the PH of a reaction system to be neutral after quenching reaction, separating and collecting an organic layer, and extracting, washing and separating the organic layer by column chromatography to obtain a compound c;
s4, dissolving the compound c in methanol, adding sodium methoxide, reacting at normal temperature until the reaction is completed, adjusting the pH of a reaction system to be neutral or slightly alkaline, and separating by distillation and column chromatography to obtain a compound d;
s5, dissolving the compound d in pyridine under ice bath condition, adding 1,3 dichloro-1, 3-tetraisopropyl disiloxane, stirring to react to completion after the temperature is up to room temperature, separating and collecting an organic layer after quenching reaction, and separating an organic phase through washing, distillation and column chromatography to obtain a compound e;
s6, adding N, N-dimethylformamide, sodium hydride and benzyl bromide into the compound e under ice bath condition, heating to a greenhouse, reacting to completion, quenching, separating and collecting an organic layer, and separating the organic layer by washing, distilling and column chromatography to obtain a compound f;
s7, adding tetrahydrofuran and tetrabutylammonium fluoride into the compound f under ice bath condition, heating to room temperature, reacting to completion, separating and collecting an organic layer, and separating by washing, distilling and column chromatography to obtain a compound g;
s8, adding N, N-dimethylformamide, sodium hydride and o-dibromobenzyl into the compound g under the ice bath condition, heating to room temperature, reacting to completion, separating and collecting an organic layer after quenching reaction, and separating the organic layer by washing, distilling and column chromatography to obtain a compound h;
s9, dissolving the compound h in an acetone-water solution under the ice bath condition, adding N-bromosuccinimide, heating to room temperature, reacting to completion, quenching, separating and collecting an organic layer, and separating the organic layer by washing and column chromatography to obtain a compound i;
s10, dissolving a compound i in methylene dichloride under ice bath condition, adding trichloroacetonitrile and 1, 8-diazabicyclo [5.4.0] undec-7-ene, heating to room temperature, reacting to completion, quenching, concentrating and separating by column chromatography to obtain the 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetyl imine ester.
The synthetic route of the preparation method specifically comprises the following steps:
according to the invention, the O-dibenzyl is arranged on the 3-position and 5-position hydroxyl on the D-arabinose by chemical reaction to prepare the 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate, the beta-surface steric hindrance of the sugar ring is larger due to the 3, 5-O-p-xylene, the conformation of the sugar ring of a donor can be controlled by utilizing the large steric hindrance cyclic protecting group effect, and the stereoselectivity of glycosylation reaction can be controlled with high selectivity, so that the synthesis of beta-configuration is realized. 2-O-benzyl-3, 5-O-para-xylene-D-arabinofuranosyl trichloroacetimide is used as glycosyl donor, under the existence of a catalyst, the beta-surface steric hindrance of a sugar ring is larger due to 3, 5-O-para-xylene, trichloroacetimide leaves, and finally a glycosyl acceptor is enabled to obtain a beta-configuration product under the action of the catalyst.
Further, in the step S1, the molar ratio of the D-arabinose to the acetyl chloride is 1.0-2.0:1.0-2.0.
Further, in the step S2, the molar ratio of the compound a to the acetic anhydride is 1.0-2.0:6.0-12.0.
Further, in the step S3, the molar ratio of the compound b, p-toluene thiophenol and boron trifluoride-diethyl etherate is 1.0 to 2.0: 1.0-2.0:2.0-4.0.
Further, in the step S4, the molar ratio of the compound c to the sodium methoxide is 1.0-2.0:0.2-0.4.
Further, in the step S5, the molar ratio of the compound d to the 1,3 dichloro-1, 3-tetraisopropyl disiloxane is 1.0-2.0:2.0-4.0.
Further, in step S6, the molar ratio of the compound e, benzyl bromide and sodium hydride is 1.0 to 2.0: 1.0-2.0:1.0-2.0.
Further, in the step S7, the molar ratio of the compound f to the tetrabutylammonium fluoride is 1.0-2.0:2.0-4.0.
Further, in the step S8, the molar ratio of the compound g, the o-dibromobenzyl and the sodium hydride is 1.0-2.0: 2.0-4.0:4.0-8.0.
Further, in the step S9, the molar ratio of the compound h to the N-bromosuccinimide is 1.0-2.0:3.0-6.0.
Further, in the step S10, the molar ratio of the compound i, the trichloroacetonitrile and the 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1.0-2.0: 10.0-20.0:0.5-1.0.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a stereoselective synthesis method of beta-D-arabinofuranoside bonds, which synthesizes beta-D-arabinofuranoside compounds by taking 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate as glycosyl donors, thereby realizing the stereoselective synthesis of the beta-D-arabinofuranoside bonds. The invention has the following advantages:
(1) The invention takes the compound 2-O-benzyl-3, 5-O-para-xylene-D-arabinofuranosyl trichloroacetimidate as glycosyl donor, carries out glycosylation reaction with other different glycosyl acceptors, and detects the products through TLC and NMR spectrum to obtain the products with high stereoselectivity beta configuration. The method can effectively control the stereoselectivity of the glycosylation reaction with high selectivity, has the advantages of wide substrate application range, convenient operation, easily available raw materials, less side reaction of the glycosylation reaction, high target yield and the like, and provides a new design idea for the research of the glycosylation reaction.
(2) The glycosyl donor compound 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate prepared by the invention contains O-dibenzyl on the 3-position and 5-position hydroxyl, and the structure has a large steric hindrance cyclic protecting group effect, so that the sugar ring conformation of the donor can be effectively controlled, the catalyst mainly attacks an olefinic bond from an alpha-surface to obtain an alpha-surface bridge halide ion intermediate, and finally an acceptor attacks from the back surface of the bridge halide ion, thereby realizing high stereoselective synthesis of beta-configuration. In addition, the reaction conditions in the preparation process of the donor are simple and easy to control, the operation is convenient, the reaction raw materials are cheap and easy to obtain, the yield of the products in each stage is high, the method has potential application value in medicine, materials and organic chemical industry, and a foundation is laid for the subsequent research of high-selectivity three-dimensional synthesis of glycosidic bonds.
(3) The donor compound 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate prepared by the invention can realize selective removal under acidic or alkaline conditions, has high flexibility and universality, and has very important significance for synthesizing natural glycoside and derivatives thereof.
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.
Example 12 Synthesis of O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate
The specific synthetic route is as follows:
the specific synthesis method comprises the following steps:
(1) D-arabinose (20.0 g,133.3 mmol) was weighed into a round bottom flask (500 mL), then anhydrous methanol (280 mL) was added thereto, acetyl chloride (10 mL) was added dropwise under ice bath, then stirred at room temperature for 3h, the reaction was judged to be complete by thin layer chromatography (dichloromethane: methanol=4:1), pyridine (80 mL) was added to quench the reaction, and the pH was brought to neutral or weakly alkaline, the excess solvent was removed by distillation under reduced pressure (-0.09 MPa,45 ℃ C.), and finally compound a (21.9 g,133.4 mmol) was obtained by spin-drying in 100% yield.
(2) The crude compound a (21.9 g,133.4 mmol) obtained in the previous step was added to pyridine (80 mL) under ice bath conditions, acetic anhydride (76.9 mL,813.8 mmol) was added dropwise after complete dissolution, stirring at room temperature for 16h, the reaction was judged to be complete by thin layer chromatography (dichloromethane: methanol=10:1), most of the pyridine was removed by distillation under reduced pressure (-0.09 MPa,45 ℃) and then diluted with dichloromethane, and washed with water 3 times, 1M hydrochloric acid 2 times, saturated copper sulfate 1 time, saturated sodium bicarbonate 1 time, saturated brine 1 time, dried over anhydrous sodium sulfate, distilled under reduced pressure (-0.09 MPa,45 ℃) to give crude product, and finally compound b (36.3 g,125 mmol) was obtained by separation by silica gel column chromatography (dichloromethane: methanol=10:1), with a yield of 94%.
(3) Compound b (36.3 g,125 mmol) was added to dry dichloromethane (200 mL) under ice bath conditions, after being fully dissolved, p-toluene thiophenol (18.6 g,150 mmol) was added, stirring was continued under ice bath conditions for 30min, boron trifluoride-diethyl ether complex (80.4 mL,637.5 mmol) was added dropwise, stirring was gradually warmed to room temperature and then reacted for 8h, the reaction was judged complete by thin layer chromatography (n-hexane: ethyl acetate=4:1), then quenched with triethylamine under ice bath conditions and adjusted to neutral PH, the excess solvent was removed by distillation under reduced pressure (-0.09 mpa,45 ℃) and diluted with ethyl acetate, then saturated ammonium chloride solution was added to neutralize the system to neutral, after delamination was allowed to remain the organic layer, the aqueous layer was extracted twice with ethyl acetate, the organic layer was combined, the obtained organic layer was washed once with saturated brine solution, dried over anhydrous sodium sulfate and distilled under reduced pressure (-0.09 mpa,45 ℃) was removed, the solvent was obtained, and finally the crude product was separated by silica gel column chromatography (ethyl acetate=4:1) to obtain compound (121.7 mmol) with a yield of 121.97%.
(4) Compound c (46.4 g,121.7 mmol) was added to anhydrous methanol (300 mL), dissolved with stirring, followed by sodium methoxide (1.31 g,24.3 mmol), reacted at room temperature for 1h, after the reaction was judged to be complete by thin layer chromatography (dichloromethane: methanol=10:1), the pH of the reaction solution was adjusted to neutrality by adding cation exchange resin IR120, and the solvent was distilled off under reduced pressure (-0.09 MPa,45 ℃ C.), and finally compound d (24.8 g,97 mmol) was obtained by separation by silica gel column chromatography (dichloromethane: methanol=10:1) in 80% yield.
(5) After compound d (24.8 g,97 mmol) was added to pyridine (100 mL) under ice bath, stirred for sufficient dissolution, 1,3 dichloro-1, 3-tetraisopropyl disiloxane (61.9 mL,194 mmol) was added, stirred at room temperature for 3h, after completion of the reaction as judged by thin layer chromatography (n-hexane: ethyl acetate=10:1), the reaction was quenched with saturated sodium bicarbonate, the aqueous layer was extracted three times with dichloromethane, the organic layers were combined, then washed with water 3 times, 1M hydrochloric acid 1 time, saturated sodium bicarbonate 1 time, saturated brine 1 time, dried with anhydrous sodium sulfate, and excess solvent was removed by distillation under reduced pressure (-0.09 MPa,45 ℃) to give crude product, which was finally separated by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give compound e (33.8 g,67.8 mmol) in 70% yield.
(6) N, N-dimethylformamide (100 mL) was added to compound e (33.8 g,67.8 mmol) under ice-bath conditions, 60% sodium hydride (3.0 g,74.5 mmol) and benzyl bromide (8.5 mL,71.2 mmol) were gradually warmed to room temperature under stirring and reacted for 3 hours, after completion of the reaction as judged by thin layer chromatography (N-hexane: ethyl acetate=15:1), methanol was added to quench the reaction under ice-bath conditions, water was added to the system, extraction was performed 3 times with methylene chloride, the organic layers were combined, each of which was washed with water 3 times, saturated saline water 1 time, dried with anhydrous sodium sulfate, and the excess solvent was removed by distillation under reduced pressure (-0.09 MPa,45 ℃ C.) to give crude product, which was finally separated by silica gel column chromatography (petroleum ether: ethyl acetate=15:1) to give compound f (31 g,52.6 mmol) in 77.7% yield.
(7) Tetrahydrofuran (90 mL) was added as a solvent to compound f (31 g,52.6 mmol) under ice-bath conditions, a tetrahydrofuran solution of tetrabutylammonium fluoride (1M, 108.6mL,105 mmol) was added, the reaction was gradually warmed to room temperature under stirring, 2h was allowed to react, after the completion of the reaction was judged by thin layer chromatography (n-hexane: ethyl acetate=1:1), water was added to the system, extraction was performed 3 times with methylene chloride, the organic layers were combined, each organic layer was washed with water 3 times and saturated common salt for 1 time, after washing, dried over anhydrous sodium sulfate, and the excess solvent was removed by distillation under reduced pressure (-0.09 MPa,45 ℃) to give a crude product, which was finally separated by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound g (17.3 g,50 mmol) in 95% yield.
(8) N, N-dimethylformamide (50 mL) and 60% sodium hydride (8.0 g,200 mmol) were added to the compound g (17.3 g,50 mmol) under ice-bath conditions, stirred thoroughly for 30min under ice-bath conditions, then o-dibromobenzyl (26.4 g,100 mmol) was added, the reaction was allowed to proceed to room temperature gradually after stirring, 3h was allowed to proceed, after completion of the reaction as judged by thin layer chromatography (N-hexane: ethyl acetate=4:1), methanol was added under ice-bath conditions to quench the reaction, water was added to the system, extraction was performed 3 times with dichloromethane, the organic layers were combined, each of which was washed with water 3 times and saturated brine for 1 time, dried over anhydrous sodium sulfate, distilled under reduced pressure (-0.09 MPa,45 ℃ C.) to give a crude product, and finally, the compound h (7.8 g,17.5 mmol) was obtained by separation by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) in 35% yield.
(9) Compound h (7.8 g,17.5 mmol) was dissolved in acetone under ice bath: to a mixture (50 mL) of water (20:1), N-bromosuccinimide (9.3 g,52.4 mmol) was added, and after stirring gradually to room temperature, the mixture was reacted for 1 hour, and after completion of the reaction as judged by thin layer chromatography (N-hexane: ethyl acetate=1:1), saturated sodium thiosulfate was added to quench the reaction, acetone was removed by distillation under reduced pressure (-0.09 MPa,45 ℃ C.) and extracted 3 times with methylene chloride, the organic layers were combined, the obtained organic layers were washed with saturated common salt, washed with water and dried over anhydrous sodium sulfate to give a crude product, and finally, the compound i (5.3 g,15.1 mmol) was isolated by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) and the yield was 87%.
(10) Compound i (5.3 g,15.1 mmol) was dissolved in dry dichloromethane (50 mL) under ice bath conditions, and trichloroacetonitrile (15.3 mL,151 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.1 mL,7.55 mmol) were added, and after stirring gradually to room temperature, the reaction was allowed to proceed for 4h, and after judging by thin layer chromatography (n-hexane: ethyl acetate=4:1), the reaction was quenched with triethylamine, concentrated under reduced pressure (-0.09 MPa,10 ℃) and separated by flash column chromatography on silica gel (n-hexane: ethyl acetate=10:1) to give the product j: 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimide (7.5 g,15.5 mmol) in 81% yield. The profile information of the product is as follows:
1 H NMR(400MHz,Benzene-d 6 )δ7.96(s,1H),6.83–6.73(m,2H),6.71(s,12H),6.70(s,1H),6.70–6.60(m,2H),6.56(t,J＝7.5Hz,1H),6.46(t,J＝7.5Hz,1H),6.20(d,J＝7.6Hz,1H),6.07(s,1H),4.38(d,J＝11.8Hz,1H),4.25(d,J＝11.8Hz,1H),4.08(d,J＝3.6Hz,1H),4.06(s,2H),3.92(d,J＝13.7Hz,1H),3.89–3.78(m,2H),3.68(dd,J＝7.3,3.5Hz,1H),3.31(dd,J＝11.7,4.7Hz,1H),3.01(dd,J＝11.7,9.7Hz,1H),1.20(s,0H),0.87(s,2H),0.47(d,J＝7.3Hz,1H)。
EXAMPLE 2 stereoselective Synthesis of beta-D-arabinofuranoside linkage by glycosylation
The glycosyl donor 2-O-benzyl-3, 5-O-p-xylene-D-arabinofuranosyl trichloroacetimidate (50 mg,0.1 mmol), glycosyl acceptor 2,3, 4-tri-O-benzyl-alpha-D-glucopyranoside (31.8 mg,0.068 mmol) and freshly activated 4A molecular sieve (1.4 g) prepared in example 1 were dissolved together in dry dichloromethane (13.6 mL), cooled to-78℃and the suspension stirred for 15 min, then the catalyst tris (pentafluorophenyl) borane (7 mg,0.0136 mmol) was added and the resulting reaction mixture was stirred at-78℃for 12h and then quenched with triethylamine. Filtration through celite and concentration in vacuo followed by purification on a thin layer chromatography silica gel plate (n-hexane: ethyl acetate=3:1) gave the highly stereoselective beta configuration of the glycosylation product 2-O-benzyl-3, 5-O-p-xylene-beta-D-arabinofuranosyl-2, 3, 4-tri-O-benzyl-alpha-D-glucopyranoside (45.9 mg, 85%). The profile information of the product is as follows:
1 H NMR(400MHz,Benzene-d 6 )δ6.06(d,J＝7.4Hz,2H),5.96(dt,J＝14.8,6.9Hz,7H),5.83(d,J＝8.8Hz,12H),5.77(td,J＝4.8,2.4Hz,3H),5.77–5.65(m,1H),5.59(t,J＝7.4Hz,1H),5.36(d,J＝7.5Hz,1H),3.65(t,J＝10.9Hz,2H),3.61–3.22(m,11H),3.17(d,J＝11.9Hz,1H),3.07(d,J＝12.0Hz,1H),2.95–2.85(m,2H),2.69(ddd,J＝17.0,9.3,5.3Hz,3H),2.61–2.52(m,2H),2.55–2.46(m,1H),2.43(dd,J＝11.2,5.4Hz,1H),2.26(dd,J＝10.5,3.9Hz,1H),2.17(dd,J＝9.6,3.5Hz,1H),1.81(s,3H). 13 C NMR(101MHz,C 6 D 6 )δ139.55,139.39,139.04,138.70,138.42,138.01,132.97,128.57,128.41,128.17,128.15,128.10,127.94,127.70,127.46,127.31,127.12,127.07,100.05,98.07,85.01,83.53,81.94,80.95,78.72,77.98,75.08,74.58,73.34,72.61,72.32,71.94,70.23,69.48,66.38,54.61,29.85。
the embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, and yet fall within the scope of the invention.
Claims (10)
1. A stereoselective synthesis method of beta-D-arabinofuranoside bond, characterized by that, dissolve glycosyl donor, glycosyl acceptor and molecular sieve in the organic solvent together, the said glycosyl acceptor is methyl-2, 3, 4-tri-O-benzyl-alpha-D-glucopyranoside, cool to-70 deg.C to-80 deg.C, stir and then add catalyst, the said catalyst is tris (pentafluorophenyl) borane, continue stirring and react for 12 h-24 h, quench and react, filter and purify and get beta-D-arabinofuranoside compound; the structure of the glycosyl donor is shown as a formula j, and the structure of the beta-D-arabinofuranoside compound is shown as a formula k:
2. the method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 1, wherein the molar ratio of the glycosyl donor, glycosyl acceptor, catalyst and molecular sieve is from 1.5 to 2.5: 1-2: 0.2 to 0.4:3 to 6.
3. The method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 1, wherein said molecular sieve is a 4A molecular sieve and said organic solvent is methylene chloride.
4. The method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 1, wherein the glycosyl donor is synthesized by a route comprising:
the preparation method of the glycosyl donor comprises the following steps:
s1, adding D-arabinose into methanol, dropwise adding acetyl chloride under ice bath condition, heating to room temperature, stirring to react completely, quenching, concentrating, and drying to obtain a compound a;
s2, dissolving the compound a in pyridine under ice bath conditions, dropwise adding acetic anhydride, heating to room temperature, stirring and reacting to completion, separating and collecting an organic layer, and then washing and separating by column chromatography to obtain a compound b;
s3, dissolving the compound b in methylene dichloride under the ice bath condition, adding p-toluenesulfonic acid, fully stirring, then dropwise adding boron trifluoride-diethyl ether complex, heating to room temperature, reacting to completion, regulating the PH of a reaction system to be neutral after quenching reaction, separating and collecting an organic layer, and extracting, washing and separating the organic layer by column chromatography to obtain a compound c;
s4, dissolving the compound c in methanol, adding sodium methoxide, reacting at normal temperature until the reaction is completed, adjusting the pH of a reaction system to be neutral or slightly alkaline, and separating by distillation and column chromatography to obtain a compound d;
s5, dissolving the compound d in pyridine under ice bath condition, adding 1,3 dichloro-1, 3-tetraisopropyl disiloxane, heating to room temperature, stirring to react completely, quenching, separating and collecting an organic layer, and separating an organic phase through washing, distillation and column chromatography to obtain a compound e;
s6, adding N, N-dimethylformamide, sodium hydride and benzyl bromide into the compound e under ice bath condition, heating to a greenhouse, reacting to completion, quenching, separating and collecting an organic layer, and separating the organic layer by washing, distilling and column chromatography to obtain a compound f;
s7, adding tetrahydrofuran and tetrabutylammonium fluoride into the compound f under ice bath condition, heating to room temperature, reacting to completion, separating and collecting an organic layer, and separating by washing, distilling and column chromatography to obtain a compound g;
s8, adding N, N-dimethylformamide, sodium hydride and o-dibromobenzyl into the compound g under the ice bath condition, heating to room temperature, reacting to completion, separating and collecting an organic layer after quenching reaction, and separating the organic layer by washing, distilling and column chromatography to obtain a compound h;
s9, dissolving the compound h in an acetone-water solution under the ice bath condition, adding N-bromosuccinimide, heating to room temperature, reacting to completion, quenching, separating and collecting an organic layer, and separating the organic layer by washing and column chromatography to obtain a compound i;
s10, dissolving a compound i in dichloromethane under ice bath condition, adding trichloroacetonitrile and 1, 8-diazabicyclo [5.4.0] undec-7-ene, heating to room temperature, reacting to completion, quenching the reaction, concentrating and separating by column chromatography to obtain the glycosyl donor.
5. The method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 4, wherein in step S1, the molar ratio of D-arabinose to acetyl chloride is 1.0 to 2.0:1.0 to 2.0.
6. The method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 4, wherein in step S2, the molar ratio of said compound a to acetic anhydride is 1.0 to 2.0:6.0 to 12.0.
7. The method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 4, wherein in step S3, the molar ratio of said compound b, p-tolylthio and boron trifluoride-diethyl etherate is 1.0 to 2.0: 1.0-2.0:2.0-4.0.
8. The method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 4, wherein in step S4, the molar ratio of compound c to sodium methoxide is 1.0 to 2.0:0.2 to 0.4.
9. The method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 4, wherein in step S5, the molar ratio of said compound D to 1,3 dichloro-1, 3-tetraisopropyl disiloxane is 1.0 to 2.0:2.0 to 4.0.
10. The method for stereoselective synthesis of β -D-arabinofuranoside linkages according to claim 4, wherein in step S6, the molar ratio of said compound e, benzyl bromide and sodium hydride is from 1.0 to 2.0: 1.0-2.0:1.0-2.0.
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