CN115286668A - Stereoselective synthesis method of beta-2, 6-dideoxy sugar and rhamnose bond - Google Patents
Stereoselective synthesis method of beta-2, 6-dideoxy sugar and rhamnose bond Download PDFInfo
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- CN115286668A CN115286668A CN202210987805.4A CN202210987805A CN115286668A CN 115286668 A CN115286668 A CN 115286668A CN 202210987805 A CN202210987805 A CN 202210987805A CN 115286668 A CN115286668 A CN 115286668A
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- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 235000000346 sugar Nutrition 0.000 title claims description 30
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 title claims description 18
- 230000000707 stereoselective effect Effects 0.000 title claims description 12
- 238000001308 synthesis method Methods 0.000 title description 3
- 239000000348 glycosyl donor Substances 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000000937 glycosyl acceptor Substances 0.000 claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 238000006206 glycosylation reaction Methods 0.000 claims abstract description 5
- 150000008265 rhamnosides Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 57
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical group C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 19
- 239000000386 donor Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 150000008163 sugars Chemical class 0.000 claims description 9
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- -1 p-methoxybenzyl Chemical group 0.000 claims description 6
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 230000013595 glycosylation Effects 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 229930182475 S-glycoside Natural products 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000009434 installation Methods 0.000 claims description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 150000003569 thioglycosides Chemical class 0.000 claims description 2
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 4
- 150000001720 carbohydrates Chemical class 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 239000004305 biphenyl Substances 0.000 abstract description 2
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 abstract 1
- 230000004071 biological effect Effects 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000002512 chemotherapy Methods 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 230000000269 nucleophilic effect Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- 239000000370 acceptor Substances 0.000 description 13
- 239000012230 colorless oil Substances 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005858 glycosidation reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 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
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 150000008131 glucosides Chemical group 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 150000002373 hemiacetals Chemical class 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
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- SIPDNGABPLZSKV-UHFFFAOYSA-N 1-phosphanylethanone Chemical group CC(P)=O SIPDNGABPLZSKV-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CGLATYVMTSUOJA-UHFFFAOYSA-N [Au+2].[N-](S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F.[N-](S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound [Au+2].[N-](S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F.[N-](S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 CGLATYVMTSUOJA-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- SHZGCJCMOBCMKK-PQMKYFCFSA-N alpha-D-rhamnose Chemical group C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 description 1
- 230000005490 anomeric effect Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229940097217 cardiac glycoside Drugs 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000008266 deoxy sugars Chemical class 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930014097 furanoid Natural products 0.000 description 1
- 125000004383 glucosinolate group Chemical group 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Substances Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- RYVMUASDIZQXAA-UHFFFAOYSA-N pyranoside Natural products O1C2(OCC(C)C(OC3C(C(O)C(O)C(CO)O3)O)C2)C(C)C(C2(CCC3C4(C)CC5O)C)C1CC2C3CC=C4CC5OC(C(C1O)O)OC(CO)C1OC(C1OC2C(C(OC3C(C(O)C(O)C(CO)O3)O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OCC(O)C(O)C1O RYVMUASDIZQXAA-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229930002534 steroid glycoside Natural products 0.000 description 1
- 150000008143 steroidal glycosides Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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 discloses a method for stereoselectively synthesizing beta-2, 6-dideoxyglycoside and beta-rhamnoside. According to the method, 2-diphenyl acetyl phosphine (DPPA) on a glycosyl donor is used as a remote guiding group, and a hydrogen bond is formed between phosphorus oxygen in the glycosyl donor and hydroxyl of a glycosyl acceptor, so that the glycosyl acceptor can only carry out nucleophilic attack on the anomeric position of the glycosyl donor from one side on the same side as the DPPA, and a glycosidic bond with high surface selectivity is formed. The method can efficiently control the stereoselectivity of the glycosylation reaction, and particularly shows great advantages in synthesizing challenging beta-configuration 2, 6-dideoxyglycoside and rhamnoside. The method has wide application range of the substrate, is convenient to operate, and is suitable for synthesizing various carbohydrate molecules with biological activity. In addition, the DPPA group can be in Ni (OTf) 2 The mild catalysis of the process realizes chemo-selective removal, and the process is used for further synthesizing uronic acid or high-deoxy sugarProviding the possibility of using the method.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a stereoselective synthesis method of beta-2, 6-dideoxy sugar and rhamnose glycosidic bond.
Background
Beta-2, 6-dideoxy sugar and rhamnose are widely present in many natural products and clinical reagents and are important building blocks constituting compounds such as various antibiotics (anthracyclines, macrolides, aureomycins), cardiac glycosides and the like. Because the compounds have numerous pharmacological activities, the efficient synthesis of the beta-2, 6-dideoxy glucoside and rhamnoside bond has great guiding significance for the development of new drugs.
2, 6-dideoxy sugar lacks an ortho group to participate in the group because of 2-position on the sugar ring, and the configuration of the glycosidic bond is mainly controlled by an anomeric effect, so that a thermodynamically stable alpha-isomer is mainly obtained. In addition, 2-position on the sugar ring lacks electron-withdrawing groups, and the density of anomeric carbon electron cloud is higher, so that 2, 6-deoxyglycosidic bond is unstable, is sensitive to acid, is easy to hydrolyze or isomerize anomeric position, and thus glycosidation and protecting group removal operation are required under mild conditions. For the synthesis of beta-2, 6-dideoxy sugars, there is mainly S N 2 or the like S N 2 reaction, I 2 Oxidation activation and sugar conformation control. However, most of these methods are complicated in operation, severe in conditions, poor in substrate applicability, and the like.
In the case of rhamnose, the alpha-glycosidic bond is mainly involved in the function of an ortho-group, and the function is usually realized by introducing an acyl group such as 2-OAc,2-OBz and the like on the sugar; the method for synthesizing pyranoside with 1, 2-cis glycosidic bond such as beta-rhamnose bond mainly comprises the following steps: (1) intramolecular aglycone release; (2) boronic acid catalyzed glycosidation of 1, 2-anhydrosugars; (3) The conformation of the glycosidation intermediate is controlled by protecting groups such as 4, 6-benzylidene and 2, 6-lactone. These methods have the disadvantages of low protecting group compatibility and narrow acceptor range.
The intramolecular aglycone delivery mediated by hydrogen bonds can skillfully avoid the defect that the 2-position on a sugar ring is lack of an ortho-group participating group, and the purpose of stereoselectivity control is achieved through excellent surface selectivity.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a method for stereoselectively synthesizing beta-2, 6-dideoxyglycoside and beta-rhamnoside, and solve the problems of poor stereoselectivity to glycosidic bonds, poor substrate applicability and the like in the conventional method.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for stereoselective synthesis of β -2, 6-dideoxy sugars with rhamnose linkages, said method comprising:
adding a glycosyl donor shown in a formula I, a glycosyl acceptor shown in a formula II and a freshly activated molecular sieve into an organic solvent, stirring at normal temperature, then placing a reaction system at a proper temperature, adding a catalyst, and reacting;
quenching with triethylamine after the reaction is completed, and obtaining the glycosylation product shown in the formula III after filtering, vacuum concentration and column chromatography;
the reaction formula is as follows:
wherein X is selected from H or OBn;
n =1 or 2;
the glycosyl acceptor in the formula II is ROH.
Further, the glycosyl donor is 2, 6-dideoxy sugar or rhamnose of furan type or pyran type sugar.
Further, the Protecting Group (PG) in the formula I and the formula III is any one or more of benzyl (Bn), p-methoxybenzyl (PMB), acetyl (Ac), allyl (All) or tert-butyldimethylsilyl ether (TBS), preferably, the protecting group PG in the formula I and the formula III is benzyl;
further, y in formula I and formula III is the number of protecting groups, and y =1 or 2;
further, the leaving group (Le) in the formula I is any one or more of N-phenyl-trifluoroacetimide ester, trichloroacetimide ester, thioglycoside (CAS number: 1384270-00-1) or o-alkynyl benzoate, and preferably, the leaving group Le in the formula I is N-phenyl-trifluoroacetimide ester or trichloroacetimide ester.
Further, the molecular sieve is
MS、
MS or
MS；
Further, the organic solvent is one of dichloromethane, toluene, trifluorotoluene, chlorobenzene, diethyl ether or acetonitrile, and is preferably trifluorotoluene or chlorobenzene.
Further, the stirring time is 0.5-1.5 h;
further, the catalyst is selected from TMSOTf, TBSOTf, tfOH, BF 3 ·Et 2 O or PPh 3 AuNTf 2 Preferably TMSOTf or TBSOTf;
further, the suitable temperature of the reaction is-78 ℃ to 25 ℃, and preferably, the suitable temperature of the reaction is-25 ℃ to 25 ℃.
Further, the installation of the phosphorus oxide side chain as the glycosyl donor is not limited to 3-OH, but is also applicable to 4-OH or 6-OH.
Further, the molar ratio of the glycosyl donor shown in the formula I to the glycosyl acceptor shown in the formula II is (1.2-2): (1-1.5);
furthermore, the molar volume ratio of the glycosyl acceptor shown in the formula II to the organic solvent is 0.01-0.1 mol/L;
furthermore, the molar addition amount of the catalyst is 5-100% of the molar amount of the glycosyl donor.
Further, the glycosyl donor represented by the formula I is selected from compounds represented by any one of the following structures I-1 to I-6:
the glycosyl acceptor of the invention can be routinely selected depending on the compound of interest.
Further, the R in the formulas II and III includes but is not limited to compounds of any structure shown in the following formulas II-1 to II-10:
further, the glycosylation product shown in the formula III is selected from compounds shown in any one of the following structures III-1 to III-12:
in certain specific embodiments, when the glycosyl donor is a D-rhamnose donor of a furanoid or pyranoid saccharide, the glycosyl donor intermediate is prepared as follows:
(1) Dissolving compound I-a, bnBr, TBAHSO4 in DCM, adding 5% aqueous NaOH solution. Reflux overnight with stirring at 50 ℃. After the reaction is completed, extracting, and carrying out silica gel column chromatography to obtain a compound I-b which is a white solid.
(2) Dissolving the compound I-b in DCM, and adding BF under the protection of N2 3 . THF was stirred at room temperature for 5min, TMSOTf was added, and the reaction was stirred at room temperature for 2h. Performing silica gel column chromatography to obtain compound I-c as colorless oily liquid.
(3) Dissolving Compound I-c in dry toluene and then adding PPh 3 And imidazole. Stirring at 60 deg.C for 10min, adding I 2 Stirring at 60 ℃ for 2h. After the reaction is finished, the product is obtained by column chromatography separation, and the I-d is white solid.
(4) Dissolving the compound I-d in absolute ethyl alcohol, and adding Pd (OH) 2 and/C, reacting at 50 ℃ under hydrogen atmosphere overnight, and after the reaction is finished, performing column chromatography purification to obtain a compound I-e which is a white solid.
The intermediate I-e is an intermediate for preparing the compounds I-1 and I-2 of the invention.
In certain particular embodiments, when the glycosyl donor is a rhamnose donor of a furan-or pyran-type saccharide, the glycosyl donor intermediate is prepared as follows:
or is that
The above intermediates are useful as intermediates for preparing the compounds I-3, I-4 of the present invention.
In certain specific embodiments, when the glycosyl donor is a 2, 6-dideoxy sugar donor of a furan or pyran-type saccharide, the glycosyl donor intermediate is prepared as follows:
or the following steps:
the above intermediates are useful intermediates for preparing the compounds I-6 of the present invention.
In some embodiments, the method of optimized glycosyl donor preparation comprises the steps of:
(1) The corresponding alcohol and acid were dissolved in dry DCM at room temperature;
(2) Adding DMAP under the inert gas atmosphere, stirring for 5min, then adding EDCI, and stirring until TLC shows that the reaction is complete;
(3) Carrying out silica gel column chromatography after vacuum concentration on the mixture to obtain a phosphorus oxide side chain glucosinolate compound arranged at the 3-position;
(4) The above compounds in NBS and H 2 Under the action of O, removing glucosinolate to obtain corresponding hemiacetal, and for beta-2, 6-dideoxy sugar, using triphenyl hydrogen bromide to act on glycene to obtain corresponding hemiacetal;
(5) The corresponding hemiacetal compound obtained is dissolved in acetone and reacted with N-phenyl-trifluoroacetyl chloride using potassium carbonate or cesium carbonate as base to produce the corresponding glycosyl donor.
Compared with the prior art, the invention has the following beneficial effects:
(1) An easy to synthesize 2-Diphenylacetylphosphino (DPPA) group has been developed which can synthesize beta-2, 6-dideoxy sugars and rhamnosides with high surface selectivity by utilizing intramolecular aglycon delivery.
(2) DPPA groups are readily attached to the 3-OH and 4-OH groups of sugars, and catalytic amounts of Ni (OTf) can be utilized 2 Can remove chemically selectively without affecting acetyl, benzyl and the like. Catalytic amount of Ni (OTf) 2 The chemical selectivity removal has high flexibility and universality, and has very important significance for synthesizing natural glucoside and derivatives thereof.
(3) The method can efficiently and stereoselectively synthesize the beta-2, 6-dideoxyglycoside and the beta-rhamnoside bond, has mild reaction conditions and wide substrate application range
(4) The method can further extend the synthesis of oligosaccharide, uronic acid and other deoxy sugar connected by beta- (1 → 6) -glycosidic bond.
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. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
The DPPA of the invention refers to: 2-diphenyl acetyl phosphine group with the structural formula
The PG of the invention is as follows: a protecting group;
the Le in the invention refers to: a leaving group;
the OBn of the invention refers to: a benzyloxy group;
the Bn refers to: a benzyl group;
the PMB of the invention refers to: p-methoxybenzyl;
the Ac of the invention refers to: acetyl;
the All of the invention refers to: an allyl group;
the TBS of the invention is as follows: tert-butyl dimethyl silyl ether;
the STol of the present invention refers to: 4-methyl-benzene mercapto group with the structural formula
The Ph refers to: a benzene ring;
the TMSOTf provided by the invention refers to: trimethylsilyl trifluoromethanesulfonate (CAS #: 27607-77-8);
the TBSOTf of the invention refers to: tert-butyl dimethylsilyl trifluoromethanesulfonate CAS #:69739-34-0;
the TfOH of the invention refers to: trifluoromethanesulfonic acid;
BF of the invention 3 . Et 2 O is: boron trifluoride diethyl etherate solution;
the PPh of the present invention 3 AuNTf 2 The method comprises the following steps: triphenylphosphine bis (trifluoromethanesulfonimide) gold;
the Me of the invention refers to: a methyl group;
the Bz refers to the following components: a benzoyl group;
the acetone in the invention refers to: acetone;
the TLC of the invention refers to: thin layer chromatography;
all compounds of formula iii of the present invention are prepared according to the following route:
trifluoroacetimide ester donor (1.2eq, 20mM), glycosyl acceptor (1.0 eq) was dissolved in 0.1M anhydrous PhCF 3 In the presence of a catalyst, then activated
Molecular sieve, stirring at room temperature under the protection of nitrogenStirring for 1h. The reaction mixture was cooled to-25 ℃ and TMSOTf (0.12 eq) was added. The low temperature was turned off and stirring was continued until TLC showed complete consumption of starting material and quenched with triethylamine. The mixture was filtered and concentrated in vacuo. The corresponding product is obtained by silica gel column chromatography. The following glycosides were prepared following the above route without specific mention.
EXAMPLE 1 Compound III-1
Glycosyl donor I-2:
glycosyl acceptor II-1:
compound III-1:
the donor I-2 (30mg, 0.04mmol) and the corresponding acceptor (12mg, 0.033mmol) were dissolved in 2mL PhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 37. Mu.L, 4.0. Mu. Mol) as catalyst, to give Compound III-1 (30mg, 89%; beta/. Alpha.) (II)>20: 1 H NMR(300MHz,CDCl 3 )δ7.74–7.62(m,4H),7.54–7.26(m,27H),7.25–7.20(m,4H),5.00(d,J＝10.8Hz,1H),4.89–4.73(m,4H),4.73–4.61(m,2H),4.60–4.50(m,3H),4.44(dd,J＝11.8,3.4Hz,2H),4.16(s,1H),4.08(dd,J＝10.5,2.0Hz,1H),4.02-3.96(m,1H),3.82–3.63(m,2H),3.57-3.51(m,1H),3.49–3.35(m,3H),3.31(s,3H),3.28–3.11(m,3H),1.30(d,J＝6.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ165.70,165.66,138.8,138.7,138.3,138.2,138.1,132.3,132.24,132.21,131.14,131.12,131.04,131.02,128.7,128.6,128.48,128.45,128.43,128.36,128.3,128.23,128.16,128.1,128.04,127.97,127.92,127.90,127.7,127.5,100.7,97.7,82.2,79.9,78.2,77.6,77.3,76.8,76.0,75.8,74.9,74.8,73.3,71.8,69.8,68.1,55.1,38.6,38.0,17.8；HRMS(ESI)calcd for C 64 H 65 O 12 PNa[M+Na] + 1055.4106,found 1055.4108.
EXAMPLE 2 Compound III-2
Glycosyl donor I-2:
glycosyl acceptor II-2:
compound III-2:
the donor I-2 (30mg, 0.04mmol) and the corresponding acceptor (20mg, 0.033mmol) were dissolved in 2mL of PhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 37 μ L,4.0 μmol) as catalyst, compound iii-2 (31mg, 87%, β) was obtained as a colorless oil: [ alpha ] to] D 20 ＝32.1(c＝0.1in CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.04–7.93(m,4H),7.93–7.84(m,2H),7.77–7.62(m,4H),7.57–7.28(m,23H),7.28–7.24(m,2H),6.22–6.11(m,1H),5.47(t,J＝9.9Hz,1H),5.30–5.20(m,2H),4.95(d,J＝12.2Hz,1H),4.75(dd,J＝9.8,3.2Hz,1H),4.59(dd,J＝11.8,3.4Hz,2H),4.51–4.41(m,2H),4.35–4.23(m,1H),4.12(dd,J＝10.9,1.9Hz,1H),4.01(d,J＝3.2Hz,1H),3.66(dd,J＝10.9,7.2Hz,1H),3.60-3.54(m,1H),3.44(s,3H),3.36–3.06(m,3H),1.27(d,J＝6.1Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ165.8,165.74,165.71,165.68,165.5,138.9,138.2,133.4,133.3,133.1,132.3,132.23,132.21,132.19,131.1,131.0,129.92,129.86,129.6,129.2,129.1,128.8,128.7,128.64,128.59,128.56,128.44,128.42,128.40,128.35,128.31,128.28,128.25,128.2,127.6,127.5,101.1,96.7,78.0,77.2,77.0,76.8,76.7,76.2,75.0,74.8,72.1,71.8,70.5,69.5,68.9,68.6,55.4,38.5,38.1,17.7；HRMS(ESI)calcd for C 62 H 59 O 15 PNa[M+Na] + 1097.3484,found 1097.3489.
EXAMPLE 3 Compounds III-3
Glycosyl donors I-2:
glycosyl acceptor II-3:
compound III-3:
the donor I-2 (30mg, 0.04mmol) and the corresponding acceptor (15mg, 0.033mmol) were dissolved in 2mL PhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 37 μ L,4.0 μmol) as catalyst, compound iii-3 (33mg, 97%, β) was obtained as a colorless oil: [ alpha ] to] D 20 ＝–3.2(c＝0.1in CHCl 3 )； 1 H NMR(300MHz,CDCl 3 )δ7.77–7.68(m,4H),7.53–7.28(m,24H),7.24–7.17(m,7H),5.13(d,J＝10.2Hz,1H),4.90(s,1H),4.80–4.71(m,2H),4.63(d,J＝3.5Hz,1H),4.60(d,J＝3.0Hz,1H),4.57(d,J＝3.5Hz,1H),4.55(d,J＝5.5Hz,1H),4.52–4.45(m,4H),4.24–4.10(m,2H),3.88(d,J＝3.2Hz,1H),3.73–3.65(m,2H),3.65–3.39(m,5H),3.32(s,3H),3.29–3.23(m,2H),1.24(d,J＝6.1Hz,3H)； 13 C NMR(150MHz,CDCl3)δ165.54,165.51,139.1,138.7,138.4,138.0,137.5,132.23,132.20,132.18,131.23,131.20,131.18,131.14,131.10,131.18,128.73,128.72,128.70,128.63,128.60,128.43,128.39,128.33,128.27,128.3,128.12,128.07,128.03,128.01,127.96,127.9,127.8,127.7,127.6,127.4,127.3,101.0,97.3,80.1,79.6,78.8,77.2,76.7,76.0,74.9,74.8,74.7,73.5,73.1,71.4,69.7,69.7,68.5,55.13,55.10,38.6,38.2,18.0.HRMS(ESI)calcd for C 62 H 65 O 12 PNa[M+Na] + 1055.4106,found 1055.4119.
EXAMPLE 4 Compound III-4
Glycosyl donor I-4:
glycosyl acceptor II-1:
compound III-4:
the donor I-4 (30mg, 0.04mmol) and the corresponding acceptor (15mg, 0.033mmol) were dissolved in 2mL PhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 37 μ L,4.0 μmol) as catalyst, to give compound iii-4 (33mg, 96%, β) as a colorless oil: [ alpha ] to] D 20 ＝57.9(c＝0.1in CHCl 3 )； 1 H NMR(300MHz,CDCl 3 )δ7.74–7.62(m,4H),7.54–7.26(m,29H),7.23–7.18(m,2H),4.96(d,J＝11.0Hz,1H),4.90–4.75(m,4H),4.75–4.64(m,3H),4.61–4.51(m,4H),4.43(d,J＝11.4Hz,1H),4.22(dd,J＝11.2,3.0Hz,1H),4.01–3.90(m,2H),3.75–3.61(m,2H),3.62–3.51(m,2H),3.47(dd,J＝9.6,3.5Hz,1H),3.38–3.30(m,4H),3.29–3.04(m,2H),1.31(d,J＝6.1Hz,3H)； 13 C NMR(100MHz,CDC l3 )δ165.8,165.7,138.90,138.87,138.4,138.3,138.2,132.4,132.24,132.21,131.4,131.13,131.11,131.03,131.01,128.72,128.70,128.59,128.58,128.5,128.4,128.33,128.25,128.1,128.0,127.91,127.89,127.8,127.7,127.6,127.5,127.4,100.8,98.2,81.8,80.0,78.3,77.7,77.3,76.9,76.2,75.7,75.2,74.9,74.8,73.5,71.8,70.0,67.3,55.2,38.7,38.0,17.9；HRMS(ESI)calcd for C 62 H 65 O 12 PNa[M+Na] + 1055.4106,found 1055.4111.
EXAMPLE 5 Compounds III-5
Glycosyl donor I-4:
glycosyl acceptor II-2:
compound iii-5:
the donor I-4 (30mg, 0.04mmol) and the corresponding acceptor (20mg, 0.033mmol) were dissolved in 2mL of PhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 37 μ L,4.0 μmol) as catalyst, to give compound iii-5 (34mg, 97%, β) as a colorless oil: [ alpha ] of] D 20 ＝73.1(c＝0.1in CHCl 3 )； 1 H NMR(300MHz,CDCl 3 )δ8.00–7.86(m,6H),7.73–7.62(m,4H),7.56–7.29(m,23H),7.24–7.18(m,2H),6.17-6.10(m,1H),5.58-5.51(m,1H),5.29–5.15(m,2H),4.82(d,J＝12.4Hz,1H),4.70(dd,J＝9.8,3.1Hz,1H),4.55(d,J＝11.4Hz,1H),4.51–4.36(m,2H),4.31(d,J＝12.4Hz,1H),4.27–4.05(m,2H),3.80(d,J＝3.1Hz,1H),3.72(dd,J＝11.0,3.3Hz,1H),3.56-3.50(m,1H),3.42(s,3H),3.33-3.24(m,1H),3.24–2.99(m,2H),1.26(d,J＝6.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ165.9,165.8,165.7,165.6,165.2,139.0,138.3,133.3,133.1,132.5,132.2,131.5,131.15,131.05,129.9,129.8,129.7,129.3,129.1,129.1,128.69,128.67,128.6,128.55,128.50,128.4,128.33,128.28,128.2,128.1,127.9,127.6,127.4,100.8,96.9,78.1,77.4,77.3,77.1,76.7,76.2,74.8,74.8,72.1,71.8,70.5,70.1,68.6,68.3,55.6,38.6,37.9,17.8；HRMS(ESI)calcd for C 62 H 59 O 15 PNa[M+Na] + 1097.3484,found 1097.3488
EXAMPLE 6 Compounds III-6
Glycosyl donor I-4:
glycosyl acceptor II-3:
compound III-6:
the donor I-4 (30mg, 0.04mmol) and the corresponding acceptor (15mg, 0.033mmol) were dissolved in 2mL PhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 37. Mu.L, 4.0. Mu. Mol) as catalyst to give Compound III-6 (32mg, 95%β), as a colorless oil: [ alpha ] of] D 20 ＝–17.2(c＝0.1in CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.75–7.60(m,4H),7.57–7.43(m,3H),7.43–7.33(m,6H),7.32–7.28(m,7H),7.28–7.16(m,13H),7.16–7.07(m,2H),5.06(d,J＝10.6Hz,1H),4.90–4.71(m,4H),4.65–4.53(m,5H),4.52–4.38(m,3H),4.01–3.88(m,3H),3.79–3.53(m,5H),3.39(s,3H),3.32–3.11(m,3H),1.32(d,J＝6.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ165.91,165.86,139.1,138.9,138.4,138.3,138.0,132.4,132.28,132.26,132.2,132.1,131.4,131.14,131.12,131.08,131.04,131.02,128.72,128.69,128.60,128.57,128.4,128.3,128.2,128.14,128.08,128.0,127.91,127.87,127.8,127.68,127.66,127.6,127.32,127.29,98.6,97.4,80.8,78.3,78.0,77.2,76.3,75.1,75.0,74.9,74.7,73.5,72.0,70.0,68.5,55.1,38.6,38.0,18.0；HRMS(ESI)calcd for C 62 H 65 O 12 PNa[M+Na] + 1055.4106,found 1055.4111.
Example 7 Compounds III-7
Glycosyl donor I-5:
glycosyl acceptor II-1:
compound III-7:
the donor I-5 (30mg, 0.04mmol) and the corresponding acceptor (15mg, 0.033mmol) were dissolved in 2.5mLPhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 46 μ L,5.0 μmol) as catalyst, compound iii-7 (25mg, 87%, β) was obtained as a colorless oil: [ alpha ] to] D 20 ＝–36.5(c＝0.2in CHCl 3 )； 1 H NMR(300MHz,CDCl 3 )δ＝7.81–7.68(m,4H),7.59–7.41(m,7H),7.40–7.27(m,17H),7.23(d,J＝1.8,2H),5.00(d,J＝10.9,1H),4.89–4.83(m,2H),4.83–4.75(m,2H),4.66(d,J＝12.2,1H),4.60–4.48(m,4H),4.08(dd,J＝9.8,2.0,1H),4.03–3.93(m,2H),3.73–3.65(m,1H),3.55–3.44(m,3H),3.41(s,1H),3.35(s,3H),3.32(s,1H),3.28–3.17(m,1H),3.05–2.95(m,1H),1.90–1.82(m,1H),1.35–1.30(m,1H),1.24(d,J＝6.3,3H)； 13 C NMR(125MHz,CDCl 3 )δ165.4,165.3,138.8,138.3,138.1,132.4,132.3,132.0,131.5,131.20,131.16,131.12,131.09,131.05,131.01,130.97,128.9,128.8,128.7,128.5,128.42,128.38,128.2,128.1,127.98,127.97,127.9,127.8,127.7,127.6,99.0,98.0,82.2,81.7,79.7,76.4,75.7,74.90,74.85,74.6,73.4,69.6,67.5,55.1,39.3,38.9,36.1,18.0；HRMS(ESI)calcd for C 55 H 59 O 11 PNa[M+Na] + 949.3687,found 949.3685.
EXAMPLE 8 Compounds III-8
Glycosyl donors I-5:
glycosyl acceptor II-2:
compound III-8:
the donor I-5 (30mg, 0.046 mmol) and the corresponding acceptor (17mg, 0.033mmol) were dissolved in 2.5mL of HCl CF 3 In TMSOTf (0.11M PhCF) 3 Solution, 46. Mu.L, 5.0. Mu. Mol) as catalyst, to give compound III-8 (31mg, 90%, beta./. Alpha.)>20, 1) as a colorless oil: 1 H NMR(300MHz,CDCl 3 )δ＝8.02–7.88(m,5H),7.90–7.71(m,7H),7.60–7.44(m,10H),7.43–7.35(m,4H),7.34–7.27(m,5H),6.14(t,J＝9.6,1H),5.52(d,J＝9.9,1H),5.30–5.19(m,2H),4.90–4.79(m,1H),4.64–4.49(m,2H),4.44–4.34(m,1H),4.27–4.16(m,1H),4.01(dd,J＝11.3,2.0,1H),3.59(dd,J＝11.2,6.2,1H),3.46(s,3H),3.43(s,1H),3.39–3.24(m,2H),3.07–2.98(m,1H),2.14–2.03(m,1H),1.38–1.29(m,1H),1.22(d,J＝6.1,3H)； 13 C NMR(125MHz,CDCl 3 )δ165.84,165.79,138.3,133.4,133.3,133.1,132.40,132.38,132.35,131.24,131.20,131.16,131.1,131.01,129.95,129.89,129.85,129.72,129.67,129.3,129.1,128.80,128.77,128.74,128.77,128.67,128.48,128.44,128.42,128.4,0 128.33,128.28,127.8,127.7,127.6,127.5,99.6,96.8,81.7,74.8,74.5,72.1,71.2,70.64,70.6,69.3,68.9,67.9,55.6,55.5,39.4,38.9,36.1,18.0,17.9；HRMS(ESI)calcd for C 55 H 54 O 14 PNa[M+Na] + 991.3065,found 991.3062.
EXAMPLE 9 Compounds III-9
Glycosyl donor I-5:
glycosyl acceptor II-3:
compound III-9:
the donor I-5 (30mg, 0.046 mmol) and the corresponding acceptor (15mg, 0.033mmol) were dissolved in 2.5mLPhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 46. Mu.L, 5.0. Mu. Mol) as catalyst, to give Compound III-9 (29mg, 88%; beta/. Alpha.)>20, 1) as a colorless oil: 1 H NMR(400MHz,CDCl 3 )δ＝7.81–7.68(m,4H),7.53–7.37(m,7H),7.35–7.26(m,15H),7.24(dd,J＝4.2,1.9,2H),7.17–7.07(m,2H),4.88(d,J＝3.5,1H),4.87–4.77(m,2H),4.74(d,J＝1.8,2H),4.65–4.57(m,3H),4.54–4.43(m,3H),3.93(dd,J＝9.9,8.8,1H),3.77–3.59(m,5H),3.42–3.36(m,4H),3.34–3.25(m,2H),3.07(d,J＝9.1,1H),2.09–2.02(m,1H),1.54–1.44(m,1H),1.26–1.24(m,3H)； 13 C NMR(100MHz,CDCl 3 )δ165.32,165.26,138.3,138.21,138.19,138.18,137.9,132.4,132.3,132.0,131.2,131.19,131.1,131.0,130.9,129.8,128.7,128.6,128.4,128.37,128.0,127.94,127.88,127.8,127.8,127.7,100.7,99.5,81.53,81.5,80.6,77.9,75.9,75.0,74.8,74.5,73.5,71.3,70.0,68.4,55.1,39.4,38.8,36.3,18.1；HRMS(ESI)calcd for C 55 H 59 O 11 PNa[M+Na] + 949.3687,found 949.3691.
EXAMPLE 10 Compounds III-10
Glycosyl donor I-6:
glycosyl acceptor II-1:
compound iii-10:
the donor I-6 (30mg, 0.046 mmol) and the corresponding acceptor (15mg, 0.033mmol) were dissolved in 2.5mLPhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 46 μ L,5.0 μmol) as catalyst, compound iii-10 (24mg, 78%, β) was obtained as a colorless oil: [ alpha ] of] D 20 ＝–33.8(c＝0.2in CHCl3)； 1 H NMR(300MHz,CDCl 3 )δ＝7.86–7.73(m,4H),7.52–7.40(m,7H),7.39–7.28(m,14H),7.23(d,J＝5.0,6H),5.11(d,J＝2.9,1H),5.00(d,J＝10.8,1H),4.91–4.76(m,3H),4.70–4.47(m,4H),4.33(d,J＝12.3,1H),4.11–3.96(m,3H),3.80–3.72(m,1H),3.63–3.44(m,5H),3.38(s,3H),3.34–3.28(m,1H),1.70–1.54(m,2H),1.00(d,J＝6.5,3H)；13C NMR(125MHz,CDCl 3 )δ165.92,165.87,138.8,138.5,138.1,137.9,135.9,132.2,132.1,131.3,131.23,131.1,128.8,128.7,128.66,128.6,128.48,128.46,128.43,128.4,128.2,128.0,127.9,127.8,127.7,127.6,100.3,98.0,82.2,79.9,77.7,75.8,74.8,73.6,73.4,72.1,70.1,69.8,69.4,69.2,67.5,66.9,55.2,38.8,38.7,32.8,16.4；HRMS(ESI)calcd for C 55 H 59 O 11 PNa[M+Na] + 949.3687,found 949.3691.
EXAMPLE 11 Compounds III-11
Glycosyl donor I-6:
glycosyl acceptor II-2:
compound III-11:
the donor I-6 (30mg, 0.046 mmol) and the corresponding acceptor (17mg, 0.033mmol) were dissolved in 2.5mL of HCl F 3 In TMSOTf (0.11M PhCF) 3 Solution, 46. Mu.L, 5.0. Mu. Mol) as catalyst, to give compound III-11 (25mg, 80%; beta/. Alpha.) (>20, 1) as a colorless oil: 1 H NMR(300MHz,CDCl 3 )δ＝8.02–7.73(m,11H),7.57–7.34(m,15H),7.30(dd,J＝7.5,2.9,5H),6.18-6.12(m,1H),5.55-5.49(m,1H),5.34–5.23(m,2H),5.13(d,J＝3.0,1H),4.52(d,J＝12.2,1H),4.43–4.24(m,3H),4.08(dd,J＝11.4,2.1,1H),3.66–3.54(m,3H),3.48(s,3H),3.45–3.35(m,2H),2.06–1.97(m,1H),1.74–1.61(m,1H),0.97(d,J＝6.4,3H)； 13 CNMR(150MHz,CDCl 3 )δ165.88,165.86,165.80,165.5,137.9,133.5,133.5,133.4,133.1,132.23,132.20,132.18,132.17,132.15,132.08,131.3,131.25,131.21,131.18,131.14,131.11,129.9,129.8,129.7,129.28,129.25,129.1,129.0,128.8,128.69,128.66,128.6,128.5,128.4,128.4,128.3,127.7,127.6,100.8,96.8,73.7,72.1,70.6,70.1,69.4,69.2,68.9,67.8,55.52,55.47,38.7,38.2,32.7,16.4；HRMS(ESI)calcd for C 55 H 53 O 14 PNa[M+Na] + 991.3065,found 991.3064
EXAMPLE 12 Compounds III-12
Glycosyl donor I-6:
glycosyl acceptor II-4:
compound III-12:
the donor I-6 (30mg, 0.046 mmol) and the corresponding acceptor (15mg, 0.033mmol) were dissolved in 2.5mLPhCF 3 In TMSOTf (0.11M PhCF) 3 Solution, 46. Mu.L, 5.0. Mu. Mol) as catalyst, to give compound III-12 (24mg, 83%; beta/. Alpha. /)>20: 1 H NMR(400MHz,CDCl 3 )δ＝7.77–7.67(m,4H),7.52–7.44(m,3H),7.39(dd,J＝7.6,3.9,4H),7.35–7.27(m,15H),7.25–7.20(m,4H),5.11(dd,J＝6.6,3.6,2H),4.77(dd,J＝9.8,2.1,1H),4.67–4.56(m,4H),4.52–4.46(m,2H),4.40-4.28(m,2H),4.22-4.17(m,1H),3.75–3.67(m,2H),3.66–3.47(m,5H),3.42-3.30(m,5H),1.96–1.86(m,1H),1.65–1.53(m,1H),0.99(d,J＝6.4,3H)； 13 C NMR(100 MHz,CDCl 3 )δ165.98,165.92,139.1,138.6,138.0,137.98,137.86 132.69,132.55,132.5,132.1,132.2,131.0,131.4,131.34,131.30,131.1,131.0,128.6,128.7,128.58,128.55,128.5,128.41,128.39,128.24,128.19,128.15,128.0,127.9,127.74,127.69,127.6,101.1,97.7,80.2,79.5,77.3,76.0,74.7,74.1,73.5,73.4,70.2,69.9,69.6,69.1,68.9,68.5,55.1,38.7,38.0,33.5,16.6；HRMS(ESI)calcd for C 55 H 59 O 11 PNa[M+Na] + 949.3687,found 949.3722.
Claims (9)
1. a method for stereoselectively synthesizing beta-2, 6-dideoxy sugar and rhamnose glycosidic bonds is characterized by comprising the following steps:
adding a glycosyl donor shown in a formula I, a glycosyl acceptor shown in a formula II and a freshly activated molecular sieve into an organic solvent, and stirring at normal temperature;
then placing the reaction system at a proper temperature, adding a catalyst, and reacting;
after the reaction is completed, triethylamine is used for quenching, and a glycosylation product shown in a formula III is obtained after filtration, vacuum concentration and column chromatography;
the general reaction formula is as follows:
wherein X is selected from H or OBn;
n =1 or 2;
the glycosyl acceptor shown in the formula II is ROH.
2. The method for the stereoselective synthesis of β -2, 6-dideoxy sugar with rhamnose linkage according to claim 1, characterized in that the sugar-based donor is 2, 6-dideoxy sugar or rhamnose of furan-or pyran-type sugars.
3. The method for the stereoselective synthesis of beta-2, 6-dideoxy sugar and rhamnose linkage according to claim 1, wherein the protecting group PG in formula i and formula iii is any one or more of benzyl, p-methoxybenzyl, acetyl, allyl or tert-butyldimethylsilyl ether, preferably the protecting group PG in formula i and formula iii is benzyl;
in the formulas I and III, y is the number of protecting groups, and y =1 or 2;
the leaving group Le in the formula I is selected from any one or more of N-phenyl-trifluoroacetimide ester, trichloroacetimide ester, thioglycoside or o-alkynyl benzoate, and preferably, the leaving group Le in the formula I is N-phenyl-trifluoroacetimide ester or trichloroacetimide ester.
4. The method of stereoselective synthesis of beta-2, 6-dideoxy sugar and rhamnose linkage according to claim 1, wherein said molecular sieve is
Or
The organic solvent is dichloromethane, toluene, trifluorotoluene, chlorobenzene, diethyl ether or acetonitrile, preferably trifluorotoluene or chlorobenzene;
the stirring time is 0.5-1.5 h;
the catalyst is selected from TMSOTf and TBSOTf、TfOH、BF 3 ·Et 2 O or PPh 3 AuNTf 2 Preferably TMSOTf or TBSOTf;
the suitable temperature of the reaction is-78-25 ℃, and preferably-25 ℃.
5. The method for stereoselective synthesis of beta-2, 6-dideoxy sugars with rhamnoside linkages according to claim 1, wherein the installation of the phosphorus oxide side chain as the glycosyl donor is not limited to 3-OH, as it applies to 4-OH or 6-OH.
6. The method for stereoselective synthesis of beta-2, 6-dideoxy sugar and rhamnose linkage according to claim 1, wherein the molar ratio of the glycosyl donor of formula I to the glycosyl acceptor of formula II is (1.2-2): (1-1.5);
the molar volume ratio of the glycosyl acceptor shown in the formula II to the organic solvent is 0.01-0.1 mol/L;
the molar addition of the catalyst is 5-100% of the molar amount of the glycosyl donor.
7. The method for stereoselective synthesis of beta-2, 6-dideoxy sugars with rhamnose linkage according to claim 1, wherein the glycosyl donor of formula I is selected from compounds of any one of the structures I-1 to I-6:
8. the method for the stereoselective synthesis of beta-2, 6-dideoxy sugars with rhamnose linkages according to claim 1, wherein said R in formulae II and iii includes, but is not limited to, compounds of any of the structures shown in formulae II-1 to II-10 below:
9. the method for stereoselective synthesis of beta-2, 6-dideoxy sugars with rhamnose linkages of claim 1 wherein the glycosylation product of formula iii is selected from compounds of any one of the following structures iii-1 to iii-12:
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