CN106946968B - Synthetic method of isoastragaloside - Google Patents
Synthetic method of isoastragaloside Download PDFInfo
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- CN106946968B CN106946968B CN201710188497.8A CN201710188497A CN106946968B CN 106946968 B CN106946968 B CN 106946968B CN 201710188497 A CN201710188497 A CN 201710188497A CN 106946968 B CN106946968 B CN 106946968B
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- 229930186049 Isoastragaloside Natural products 0.000 title claims abstract description 20
- 238000010189 synthetic method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- WENNXORDXYGDTP-UOUCMYEWSA-N cycloastragenol Chemical compound O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O)C4(C)C)[C@H]4[C@@H](O)C[C@H]3[C@]2(C)C[C@@H]1O WENNXORDXYGDTP-UOUCMYEWSA-N 0.000 claims abstract description 24
- WENNXORDXYGDTP-UHFFFAOYSA-N cyclosiversigenin Natural products O1C(C(C)(O)C)CCC1(C)C1C2(C)CCC34CC4(CCC(O)C4(C)C)C4C(O)CC3C2(C)CC1O WENNXORDXYGDTP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 16
- QMNWISYXSJWHRY-XWJCTJPOSA-N astragaloside Chemical class O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)CO4)O)C4(C)C)C4[C@@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)CC3[C@]2(C)C[C@@H]1O QMNWISYXSJWHRY-XWJCTJPOSA-N 0.000 claims abstract description 15
- 125000006239 protecting group Chemical group 0.000 claims abstract description 15
- 229940126214 compound 3 Drugs 0.000 claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 34
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 24
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 238000004809 thin layer chromatography Methods 0.000 claims description 19
- 229940125782 compound 2 Drugs 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 14
- 229940125898 compound 5 Drugs 0.000 claims description 14
- SMDOOINVMJSDPS-UHFFFAOYSA-N Astragaloside Natural products C1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)OC2C(C(OC3C(C(O)C(O)C(CO)O3)O)C(O)C(CO)O2)O)=C1 SMDOOINVMJSDPS-UHFFFAOYSA-N 0.000 claims description 13
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- 239000000348 glycosyl donor Substances 0.000 claims description 12
- 238000006206 glycosylation reaction Methods 0.000 claims description 12
- 239000002808 molecular sieve Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- MSSYPWFHLFBMMP-BQAOMNQWSA-N Isoastragaloside IV Chemical compound C[C@]12CC[C@@]34C[C@@]35CC[C@@H](C([C@@H]5[C@H](C[C@H]4[C@@]1(C[C@@H]([C@@H]2[C@]6(CC[C@H](O6)C(C)(C)O[C@H]7[C@@H]([C@H]([C@@H]([C@H](O7)CO)O)O)O)C)O)C)O)(C)C)O[C@H]8[C@@H]([C@H]([C@@H](CO8)O)O)O MSSYPWFHLFBMMP-BQAOMNQWSA-N 0.000 claims description 10
- 229960000583 acetic acid Drugs 0.000 claims description 10
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- 239000002274 desiccant Substances 0.000 claims description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 8
- QMNWISYXSJWHRY-YLNUDOOFSA-N astragaloside IV Chemical compound O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)CO4)O)C4(C)C)[C@H]4[C@@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)C[C@H]3[C@]2(C)C[C@@H]1O QMNWISYXSJWHRY-YLNUDOOFSA-N 0.000 claims description 7
- QMNWISYXSJWHRY-BCBPIKMJSA-N astragaloside IV Natural products CC(C)(O)[C@@H]1CC[C@@](C)(O1)[C@H]2[C@@H](O)C[C@@]3(C)[C@@H]4C[C@H](O[C@@H]5O[C@H](CO)[C@H](O)[C@@H](O)[C@H]5O)[C@H]6C(C)(C)[C@H](CC[C@@]67C[C@@]47CC[C@]23C)O[C@@H]8OC[C@@H](O)[C@H](O)[C@H]8O QMNWISYXSJWHRY-BCBPIKMJSA-N 0.000 claims description 7
- PFKIBRPYVNVMRU-UHFFFAOYSA-N cyclosieversioside F Natural products CC(C)(O)C1COC(C)(C1)C2C(O)CC3(C)C4CC(OC5OC(CO)C(O)C(O)C5O)C6C(C)(C)C(CCC67CC47CCC23C)OC8OCC(O)C(O)C8O PFKIBRPYVNVMRU-UHFFFAOYSA-N 0.000 claims description 7
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 7
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical group CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000004756 silanes Chemical class 0.000 claims description 6
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- ZBKIUFWVEIBQRT-UHFFFAOYSA-N gold(1+) Chemical compound [Au+] ZBKIUFWVEIBQRT-UHFFFAOYSA-N 0.000 claims 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims 1
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 10
- 238000011160 research Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000011161 development Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 230000007246 mechanism Effects 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 241001061264 Astragalus Species 0.000 description 7
- 235000006533 astragalus Nutrition 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 210000004233 talus Anatomy 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 239000000386 donor Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 2
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- 238000005406 washing Methods 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
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-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
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- 241000220485 Fabaceae Species 0.000 description 1
- 239000009636 Huang Qi Substances 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- DOXNDFPXMBXOKH-UHFFFAOYSA-N [Au+2] Chemical compound [Au+2] DOXNDFPXMBXOKH-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 229940107666 astragalus root Drugs 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000005858 glycosidation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
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- 238000004904 shortening Methods 0.000 description 1
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- 150000008163 sugars Chemical class 0.000 description 1
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
- C07J53/004—3 membered carbocyclic rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a method for synthesizing isoastragaloside, which comprises the following steps: protecting the 3-hydroxy group of cycloastragenol with a protecting group R1Protection of the hydroxyl groups at the 6-and 16-positions by protecting groups R2Protecting to obtain compound 3, and glycosidating compound 3And then removing the protecting group R at position 31The invention is a high-efficiency and high-stereoselectivity method for synthesizing the isoastragaloside, provides enough raw materials for the research and application of the isoastragaloside, provides a reference for the synthesis of the isoastragaloside compounds, fills the blank in the prior art, and greatly promotes the process of the research on the activity mechanism of the astragaloside compounds and the development of the medicaments thereof.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of isoastragaloside.
Background
Astragalus root, radix astragali, is the first tonic and belongs to the genus Astragalus of the family Leguminosae. With the development of modern separation and identification technology in recent years, a large amount of triterpenoid saponins, flavonoid compounds and polysaccharide components are separated from astragalus. Later-stage biochemical experiments show that the medicinal effect of the astragalus is mainly expressed by the astragaloside. Recent studies show that astragalosides show extremely favorable medicinal prospects in the aspects of immunoregulation, blood sugar reduction, improvement of insulin resistance activity, tumor resistance, cardiovascular system regulation, antivirus, antioxidant activity and the like, and among a plurality of astragalosides, the astragaloside IV and isoastragaloside IV have the best activity.
Although the extensive application prospect of the astragalosides promotes people to research the astragalosides continuously, the astragalosides used for activity test at present are mostly obtained by separating and extracting the astragalosides from the astragalus, and the astragalosides contained in the astragalus have various types and similar structures, so that great difficulty is brought to separation and purification. Some astragalosides are secondary saponins, the content of the astragalosides in astragalus is very low, and it is not easy to obtain enough amount for activity test, which becomes a bottleneck restricting the deep research of astragaloside activity, and almost no research on the chemical synthesis of astragalosides is reported so far.
The content of the isoastragaloside in the astragalus is particularly low, and the molecular structural formula is as follows:
the saponin part is cycloastragenol, because the 3,6, 16 and 25 positions of the cycloastragenol (compound 1) contain 4 inert OH groups, particularly the 25-position hydroxyl group is tertiary hydroxyl group, the activity is low, the glycosylation reaction is difficult, the prior reaction activities of the 4 inert OH groups are difficult to distinguish, and the selective glycosylation of part of the hydroxyl groups is more difficult.
The hydroxyl protection reaction of the cycloastragenol is difficult to carry out and the product is complex and variable, and the literature reports that under the action of excessive acetylation reagent, the fully acetylated cycloastragenol with the yield of 56 percent can be obtained only under the reaction time of 60 ℃ and as long as 50 days. Shortening the reaction time or lowering the reaction temperature results in a very complex reaction product, which is cycloastragenol in which 1 or 2 of the 4 hydroxyl groups are randomly protected. Therefore, the synthesis of the isoastragaloside is difficult, and the successful reports are not found at home and abroad.
Reference documents: a) mamedova, r.p.; agzamova, m.a.; isaev, m.i.chem.nat.compd.2001,37,533-536.b) Isaev, i.m.; iskenderov, d.a.; isaev, m.i.chem.nat.compd.2009,45,381-384.c) Isaev, i.m.; iskenderov, d.a.; isaev, m.i.chem.nat.compd.2010,46,407-411.d) Procopiou, p.a.; baugh, s.p.d.; flack, s.s.; inglis, G.G.J.org.chem.1998,63,2342-2347.
Disclosure of Invention
The invention provides a method for synthesizing isoastragaloside, which can synthesize the isoastragaloside with high efficiency and high selectivity, provide enough raw materials for the research and application of the isoastragaloside and provide reference for the synthesis of isoastragaloside compounds.
The invention is realized by the following steps:
a synthetic method of isoastragaloside comprises the following steps:
(1) protecting the 3-position hydroxyl of the cycloastragenol with a protecting group R1 to obtain a compound 2;
(2) protecting hydroxyl groups at 6-position and 16-position of the compound 2 with a protecting group R2 to obtain a compound 3;
(3) carrying out glycosylation reaction on the compound 3 and a glycosyl donor compound 4 to obtain a compound 5;
(4) removing a protecting group R1 at the 3-position of the compound 5 to obtain a compound 6;
(5) carrying out glycosylation reaction on the compound 6 and a glycosyl donor compound 7 to obtain a compound 8;
(6) removing all protecting groups of the compound 8 to obtain the isoastragaloside IV;
wherein, R is1Selected from substituted or unsubstituted C1-C9 alkylsilyl; the R is2Selected from substituted or unsubstituted C2-C6 alkanoyl; the R is3Or R4Each independently selected from C1-C6 aroyl; x is selected from substituted or unsubstituted alkyne benzoyloxy.
X is
In the step (1), the protection method includes the following steps: at room temperature, dissolving cycloastragenol in a first solvent, adding halogenated silane and imidazole, slowly heating the reaction temperature to room temperature, and stirring until TLC (thin layer chromatography) tracking shows that the cycloastragenol completely reacts; the first solvent is one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether, the molar ratio of the cycloastragenol, halogenated silane and imidazole is 1:1: 1-1: 5:10, preferably 1:2: 3-1: 4:6, the concentration of the cycloastragenol in the first solvent is 0.1-1 mol/L, preferably 0.45-0.5 mol/L, and the halogenated silane is SCl, TESCl, TBDMSCl, DIDPSCl, SCl, DPSCl or TIPDSCl.
In the step (2), the protection method includes the following steps: dissolving the compound 2 in a second solvent at the temperature of below 0 ℃, adding pivaloyl chloride, slowly raising the reaction temperature to room temperature, then heating to 50 ℃, and continuing stirring until TLC tracking shows that the compound 2 is completely reacted, wherein the second solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether; the molar ratio of the compound 2 to the pivaloyl chloride is 1: 2-1: 20, preferably 1: 2-1: 10; the concentration of the compound 2 in the second solvent is 0.1-1 mol/L, preferably 0.108-0.5 mol/L.
In the step (3), the glycosylation reaction comprises the following steps: under the protection of inert gas, dissolving the compound 3 and the glycosyl donor compound 4 in a third solvent, adding a drying agent, stirring at room temperature for 0.5-2 hours, adding a catalyst, and continuously stirring at room temperature until TLC (thin layer chromatography) tracking shows that the compound 2 completely reacts; the third solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether, and the catalyst is a complex of monovalent gold, preferably PPh3AuNTf2Or PPh3AuOTf; the molar ratio of the compound 3, the glycosyl donor compound 4 and the catalyst is 1:1: 0.1-1: 5:0.8, preferably 1:1: 0.1-1: 2: 0.5; the concentration of the compound 3 in the third solvent is 0.001-1 mol/L, preferably 0.006-0.05 mol/L; the desiccant is a molecular sieve, preferably
Molecular sieves or acid-washed
Molecular sieves, more preferably 4A molecular sieves.
In the step (4), the protecting group R is1The removing method comprises the following steps: dissolving the compound 5 in a fourth solvent at room temperature, adding camphorsulfonic acid, and stirring until TLC tracking shows that the compound 5 is completely reacted; the fourth solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether, and the molar ratio of the compound 5 to camphorsulfonic acid is 1: 1-1: 10, preferably 1: 1-1: 4; the concentration of the compound 5 in the fourth solvent is 0.001-1 mol/L, preferably 0.001-0.004 mol/L.
In the step (5), the glycosylation reaction is carried outThe method comprises the following steps: dissolving a compound 6 and a glycosyl donor compound 7 in a fifth solvent, adding a drying agent, stirring at room temperature for 0.5-2 hours, adding a catalyst, and continuously stirring at room temperature until TLC tracking shows that the compound 6 completely reacts, wherein the fifth solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether; the molar ratio of the compound 6, the glycosyl donor compound 7 and the catalyst is 1:1: 0.1-1: 5:0.8, preferably 1:1: 0.1-1: 2.5: 1; the concentration of the compound 6 in the fifth solvent is 0.001-1 mol/L, preferably 0.001-0.003 mol/L; the catalyst is a complex of gold (II) and preferably PPh3AuNTf2Or PPh3AuOTf; the desiccant is a molecular sieve, preferably
Molecular sieves or acid-washed
Molecular sieves, more preferably 4A molecular sieves.
In the step (6), the reaction for removing the protecting group includes the following steps: dissolving the compound 8 in a sixth solvent, adding a reducing agent, and stirring at room temperature until TLC (thin layer chromatography) tracking shows that the compound 8 is completely reacted; the reducing agent is sodium borohydride, lithium aluminum hydride and borane; the eighth solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether, and preferably methanol.
Preferably, any one of the steps (1) to (6) is carried out under the protection of inert gas, and the inert gas is selected from nitrogen, argon or helium.
In the step (1), when the molar ratio of the cycloastragenol, the TBSCl and the imidazole is 1:20:20, the obtained compound is a compound with all protected hydroxyls at the 3-position and the 6-position of the cycloastragenol, and when the molar ratio of the cycloastragenol, the TBSCl and the imidazole is 1:2:2, other reaction parameters are the same, and the reaction yield is only 40%.
The invention has the technical effects that: the invention is a high-efficiency and high-stereoselectivity method for synthesizing the isoastragaloside, provides enough raw materials for the research and application of the isoastragaloside, provides reference for the synthesis of the isoastragaloside compounds, fills the blank of the prior art, and greatly promotes the process of the research on the activity mechanism of the astragaloside compounds and the development of the medicaments thereof.
Detailed Description
The present invention will be better understood from the following examples, however, those skilled in the art will readily appreciate that the examples are illustrative only and should not be construed to limit the invention as detailed in the claims.
The Bz protected sugars 4 and 7 were synthesized according to methods conventional in the art:
the synthesis method of the compound 4-1 is as follows:
dissolving all Bz glucose (100mg,0.17mmol) with a naked hydroxyl group at the anomeric position in dry dichloromethane (4mL) under the protection of nitrogen, adding ortho-alkynylbenzoic acid (37.4mg,0.2mmol), DMAP (28.1mg,0.23mmol), EDCI (43.9mg,0.23mmol), DIPEA (74 μ L) into the system, stirring overnight at room temperature until TLC tracking shows that the raw materials are completely reacted, extracting the reaction system with dichloromethane, washing with 1mol/L HCl, saturated sodium bicarbonate and saturated NaCl in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the crude product under reduced pressure, and then carrying out column chromatography to obtain a white solid compound 4-1(121mg, 93%):1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.5Hz,2H),7.92-7.87(m,6H),7.44-7.28(m,17H),6.94(d,J＝3.3Hz,1H),6.38(dd,J＝9.6,9.9Hz,1H),5.94(dd,J＝9.9,10.2Hz,1H),5.76(dd,J＝3.3,9.9Hz,1H),4.80-4.66(m,2H),4.54(dd,J＝3.3,6.0Hz,1H),1.56(m,1H),0.84(d,J＝6.6Hz,4H).
the synthesis method of the compound 7-1 is as follows:
in analogy to the synthesis of compound 4-1, compound 7-1(612mg, 89%) was obtained as a white solid from all Bz xylose with bare hydroxyl at the anomeric position: [ alpha ] to]D 25＝0.02(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ8.04-7.98(m,6H),7.90(dd,J＝1.2,8.0Hz,1H),7.58-7.51(m,3H),7.49-7.42(m,2H),7.38-7.30(m,6H),7.21(td,J＝1.6,7.6Hz,1H),6.42(d,J＝7.6Hz,1H),5.81(t,J＝5.2Hz,1H),5.58(dd,J＝4.0,5.2Hz,1H),5.36-5.32(m,1H),4.63(dd,J＝3.6,12.8Hz,1H),4.06(dd,J＝4.8,12.4Hz,1H),1.54-1.47(m,1H),0.90-0.84(m,4H)；13C NMR(100MHz,CDCl3)δ164.9,164.4,164.3,163.3,133.7,132.8,129.9,129.7,129.4,129.3,128.5,128.3,127.8(2C),126.3,124.7,99.7,91.4,73.6,67.8,67.6,67.2,60.9,8.2,-0.0；HRMS(ESI-TOF)m/z:[M+H]+calcd for C38H31O9 631.1968；found 631.1966.
Example 1
The synthesis of the isoastragaloside IV,
(1) synthesizing a 3-hydroxyl protected cycloastragenol derivative 2,
under the protection of nitrogen, cycloastragenol (400mg,0.82mmol) is dissolved in dry DMF and TBSCl (489mg,3.3mmol), imidazole (333mg,4.9mmol) is added to the system, and the mixture is stirred at room temperature until TLC tracking shows that the raw materials are completely reacted, the reaction system is extracted with ethyl acetate and washed with 1mol/l HCl, saturated sodium bicarbonate and saturated NaCl in sequence, dried over anhydrous sodium sulfate, filtered, the crude product is concentrated under reduced pressure, and then column chromatography is carried out to obtain a white solid compound 2 (76.8%): [ alpha ] to]D 25＝30.5(c＝1,CHCl3)；1H NMR(400MHz,CDCl3)δ4.67(dd,J＝7.6,14.4Hz,1H),3.72(dd,J＝6.0,8.0Hz,1H),3.51(td,J＝3.6,9.6Hz,1H),3.25(dd,J＝4.8,10.0Hz,1H),2.59(dd,J＝10.4,21.6Hz,1H),2.31(d,J＝8.0Hz,1H),2.00-1.92(m,4H),1.76(dd,J＝4.0,12.0Hz,1H),1.25(s,3H),1.21(s,3H),1.17(s,3H),1.13(s,3H),1.11(s,3H),1.09(s,3H),0.91(s,3H),0.89(s,3H),0.85(s,9H),0.47(d,J＝4.0Hz,1H),0.31(d,J＝4.4Hz,1H),0.00(s,3H),-0.005(s,3H)；13C NMR(100MHz,CDCl3)δ87.1,81.4,78.8,73.4,71.8,68.9,57.5,53.7,46.9,46.5,46.0,45.0,42.1,37.7,34.4,33.0,32.1,31.4,30.8,29.4,28.6,27.9,27.7,26.4,25.9(2C),25.8,21.4,20.5,20.0,18.1,15.8；HRMS(ESI)calcd for C36H65O5Si[M+H]+605.4596,found 605.4599；
(2) The synthesis of 3,6 and 16-hydroxy protected cycloastragenol derivative 3,
under the protection of nitrogen and at the temperature of 0 ℃, dissolving a compound 2(300mg,0.5mmol) in dried pyridine (2ml), adding PivCl (50 mu L,4.96mmol) into the system, slowly raising the temperature to room temperature, heating to 50 ℃, stirring until TLC tracking shows that the raw materials are completely reacted, extracting the reaction system with ethyl acetate, washing with 1mol/L HCl, saturated sodium bicarbonate and saturated NaCl in sequence, drying with anhydrous sodium sulfate, performing suction filtration, concentrating a crude product under reduced pressure, and performing column chromatography to obtain a white solid compound 3 (94.9%): [ alpha ] to]D 25＝72.9(c＝1,CHCl3)；1H NMR(400MHz,CDCl3)δ5.31-5.26(m,1H),4.74-4.69(m,1H),3.74(t,J＝7.2Hz,1H),3.24(dd,J＝4.8,10.0Hz,1H),2.37(d,J＝8.0Hz,1H),2.08-2.00(m,2H),1.36(s,3H),1.31(s,3H),1.18(s,3H),1.16(s,9H),1.13(s,9H),1.07(s,3H),0.96(s,3H),0.85(s,12H),0.80(s,3H),0.54(d,J＝4.8Hz,1H),0.21(d,J＝4.8Hz,1H)；13C NMR(100MHz,CDCl3)δ178.2,177.7,85.5,83.3,78.5,75.7,71.2,69.7,57.5,49.2,46.7,46.2,45.1,43.0,41.9,38.6,38.2,32.5,31.9,31.4,27.8,27.4,27.3,27.2,27.1(2C),26.6,26.2,26.0,25.9,25.4,24.5,20.7,19.8,19.6,18.1,15.4；HRMS(ESI)calcdfor C64H81O7Si[M+H]+773.5746,found 773.5743；
(3) The synthesis of the 25-position glycosylation product 5,
under the protection of nitrogen, the compound 3 and the glucose alkyne ester donor 4-1 are dissolved in dry dichloromethane, and a 4A molecular sieve is added, and the mixture is stirred at room temperature for half an hour, and then the catalyst Ph is added3PAuNTf2(0.2eq), stirring at room temperature was continued until TLC tracking indicated complete reaction of starting material, the crude product was concentrated under reduced pressure and then column chromatographed to give compound 5 (91.6%) as a white solid: [ alpha ] to]D 25＝40.3(c＝1,CHCl3)；1H NMR(400MHz,CDCl3)δ8.02-7.96(m,4H),7.91(dd,J＝1.2,8.0Hz,2H),7.86(dd,J＝1.2,8.4Hz,2H),7.54-7.48(m,4H),7.43-7.34(m,7H),7.31(t,J＝8.0Hz,1H),5.90(t,J＝9.6Hz,1H),5.53(dd,J＝9.2,10.0Hz,1H),5.48(dd,J＝7.6,9.2Hz,1H),5.35(d,J＝8.0Hz,1H),5.23-5.18(m,1H),4.76(dd,J＝6.8,14.4Hz,1H),4.60(dd,J＝2.8,12.0Hz,1H),4.44(dd,J＝7.2,12.0Hz,1H),4.13-4.08(m,1H),3.72(dd,J＝4.8,8.4Hz,1H),3.20(m,1H),2.42(d,J＝7.6Hz,1H),2.14-2.06(m,2H),1.37(s,3H),1.33(s,3H),1.18(s,9H),1.17(s,9H),1.16(s,3H),1.13(s,3H),0.98(s,3H),0.86(s,12H),0.80(s,3H),0.56(d,J＝4.8Hz,1H),0.27(d,J＝4.8Hz,1H)；13C NMR(100MHz,CDCl3)δ178.0,177.7,165.9,165.8,165.4,164.9,134.2,134.1,133.5,133.2,133.1(2C),129.8(2C),129.7(2C),129.6,129.3,129.2,129.0,128.8,128.4,128.3(2C),96.2,86.0,84.1,80.1,78.3,76.1,73.1,72.1(2C),70.5,69.8,63.9,57.8,49.1,46.8,46.3,45.2,43.2,41.9,38.6,38.5,38.2,32.6,32.1,31.2,30.5,27.8,27.4,27.2(2C),25.9,25.5,24.0,21.7,20.6,19.7,19.6,18.1,15.4,-3.9,-4.9；HRMS(ESI)calcd for C80H107O16Si[M+H]+1351.73229,found 1351.73310；
(4) Synthesizing a naked product 6 of hydroxyl at the 3-position,
compound 5(20mg,0.03mmol) was dissolved in dry methanol (2.0mL) under nitrogen, camphorsulfonic acid (26mg,0.11mmol) was added at room temperature, stirred until TLC tracking indicated complete reaction of starting material, the crude product was concentrated under reduced pressure, and then column chromatographed to give compound 6 as a white solid (82.9%): [ alpha ] to]D 25＝20.5(c＝1,CHCl3)；1H NMR(400MHz,CDCl3)δ8.00-7.96(m,4H),7.91(dd,J＝1.2,8.0Hz,2H),7.85(dd,J＝1.2,8.0Hz,2H),7.54-7.49(m,3H),7.45-7.33(m,7H),7.31-7.27(m,2H),5.91(t,J＝9.6Hz,1H),5.54(t,J＝10.1Hz,1H),5.48(dd,J＝8.0,9.6Hz,1H),5.27(d,J＝8.0Hz,1H),5.23-5.18(m,1H),4.78-4.73(m,1H),4.59(dd,J＝3.2,12.0Hz,1H),4.44(dd,J＝7.2,11.6Hz,1H),4.14-4.08(m,1H),3.72(dd,J＝4.8,8.4Hz,1H),3.24(dd,J＝4.8,11.6Hz,1H),2.43(d,J＝8.0Hz,1H),2.16(dd,J＝7.6,13.6Hz,1H),2.05-2.01(m,1H),1.36(s,3H),1.33(s,3H),1.18(s,12H),1.17(s,9H),1.11(s,3H),1.00(s,3H),0.91(s,3H),0.89(s,3H),0.56(d,J＝4.8Hz,1H),0.30(d,J＝4.4Hz,1H)；13C NMR(100MHz,CDCl3)δ178.1,177.7,166.0,165.8,165.4,164.9,133.5,133.2(2C),133.1,129.8(2C),129.7(2C),129.6(2C),128.9,128.8,128.4,128.3(2C),96.2,86.0,84.1,80.1,77.9,76.1,73.1,72.1,72.0,70.4,69.9,63.9,57.8,49.2,46.8,46.3,45.4,43.7,41.3,38.6,38.5,38.3,32.3(2C),31.3,30.0,28.0,27.3,27.2,27.1,26.9,26.1,25.9,25.6,23.8,22.0,20.8,19.8,19.7,15.0；HRMS(ESI)calcdfor C74H93O16[M+H]+1237.64581,found 1237.64675；
(5) Synthesis of glycosylation products 8 at 3, 25-positions,
compound 6 and the xylosylene ester donor 7 were dissolved in dry dichloromethane under nitrogen and the 4A molecular sieve was added, stirred at room temperature for half an hour and the catalyst Ph was added3PAuNTf2(0.2eq) and continued at room temperatureStirring was continued until TLC tracking indicated complete reaction of the starting material, and the crude product was concentrated under reduced pressure and then column chromatographed to give compound 8 (83.2%) as a white solid: [ alpha ] to]D 25＝25.2(c＝0.3,CHCl3)；1H NMR(400MHz,CDCl3)δ8.02-7.94(m,10H),7.92(dd,J＝1.2,8.0Hz,2H),7.86(dd,J＝1.2,8.0Hz,2H),7.55-7.43(m,7H),7.41-7.27(m,14H),5.91(t,J＝10.0Hz,1H),5.80(t,J＝8.0Hz,1H),5.52-5.42(m,3H),5.32-5.27(m,2H),5.23-5.18(m,1H),4.80(d,J＝6.4Hz,1H),4.65-4.58(m,2H),4.42-4.33(m,2H),4.14-4.09(m,1H),3.73(dd,J＝4.8,8.4Hz,1H),3.62(dd,J＝7.6,12.0Hz,1H),3.15(dd,J＝4.4,11.2Hz,1H),2.44(d,J＝7.6Hz,1H),2.13-2.03(m,2H),1.35(s,3H),1.33(s,3H),1.19(s,3H),1.17(s,9H),1.13(s,3H),1.08(s,9H),0.97(s,3H),0.78(s,3H),0.64(s,3H),0.52(d,J＝4.8Hz,1H),0.26(d,J＝4.8Hz,1H)；13C NMR(100MHz,CDCl3)δ178.0,177.5,166.0,165.9,165.6(2C),165.4,165.1,164.9,133.6,133.4,133.3,133.2(2C),133.1,129.9,129.8,129.7(2C),129.6(2C),129.4,129.2,129.1,128.9,128.8,128.5,128.4(2C),128.3(2C),102.6,96.2,88.6,86.1,84.2,80.2,76.1,73.1,72.1(2C),71.2,71.0,70.4,69.6,69.3,63.9,61.7,57.8,49.2,46.8,46.3,45.2,42.9,41.4,38.5,38.3,32.5,31.8,31.1,28.6,27.4,27.2,27.1,26.6,26.2,25.9,25.6,24.0,21.9,20.7,19.7,19.6,15.6；HRMS(ESI)calcd for C100H116O23N[M+NH4]+1699.79666,found 1699.79904；
(6) The synthesis of the isoastragaloside IV,
compound 13(70mg,0.042mmol) was dissolved in dry THF under nitrogen protection at 0 ℃, lithium aluminum hydride (25mg,0.67mmol) was added slowly to the system, and then warmed to room temperature slowly with stirring until TLC tracking showed completion of the starting material reaction, the crude product was concentrated under reduced pressure, and then column chromatography gave the white solid compound isoastragaloside (yield: 75.6%): : [ alpha ] to]D 25＝7.9(c＝0.25,CH3OH)；1H NMR(400MHz,C5D5N)δ5.08(d,J＝7.6Hz,1H),4.93(d,J＝7.2Hz,1H),4.45(dd,J＝3.6,11.6Hz,1H),4.40(dd,J＝4.8,11.2Hz,1H),4.32(dd,J＝4.8,11.6Hz,1H),4.25-4.15(m,4H),4.09-4.00(m,3H),3.92-3.88(m,2H),3.81-3.72(m,2H),3.64-3.61(m,1H),2.85(dd,J＝11.6,19.6Hz,1H),2.48(d,J＝7.6Hz,1H),2.00(s,3H),1.67(s,3H),1.42(s,3H),1.35(s,3H),1.33(s,3H),1.29(s,3H),0.94(s,3H),0.56(d,J＝3.2Hz,1H),0.28(d,J＝4.0Hz,1H)；13C NMR(100MHz,C5D5N)δ107.4,98.6,88.4,87.0,81.8,78.3,77.8,75.4,75.0,73.3,71.1,71.0,67.7,66.8,62.5,57.9,53.8,46.6,45.9,45.8,45.0,42.5,38.4,34.8,33.2,32.2,30.3,30.1,29.3,28.7,27.6,26.0,25.7,25.4,22.8,21.3,20.7,19.8,16.4；HRMS(ESI)calcd for C41H68O14Na[M+Na]+807.4501,found 807.4498。
Comparative example 1: in the step (3) or (5), trichloroacetimidate donor is used to replace alkyne ester donor for glycosidation reaction, the reaction system is very complicated, the product is few, and the alkyne ester donor is more superior in synthesizing isoastragaloside.
Comparative example 2: in the step (1), when the molar ratio of the cycloastragenol to the halosilane to the imidazole is 1:20:20, other reaction parameters are the same, and the reaction is a product with 3-and 6-hydroxy groups protected simultaneously.
Comparative example 3: in the step (1), when the molar ratio of the cycloastragenol, the TBSCl and the imidazole is 1:2:2, other reaction parameters are the same, and the reaction yield is only 40%.
Comparative example 4: in the step (2), when the concentration of the compound 2 is 0.001mol/L, other reaction parameters are the same, and only 6 hydroxyl of the compound 2 is protected.
Claims (8)
1. A synthetic method of isoastragaloside is characterized by comprising the following steps:
(1) protecting the 3-position hydroxyl of the cycloastragenol with a protecting group R1 to obtain a compound 2;
(2) protecting hydroxyl groups at 6-position and 16-position of the compound 2 with a protecting group R2 to obtain a compound 3;
(3) carrying out glycosylation reaction on the compound 3 and a glycosyl donor compound 4 to obtain a compound 5;
(4) removing a protecting group R1 at the 3-position of the compound 5 to obtain a compound 6;
(5) carrying out glycosylation reaction on the compound 6 and a glycosyl donor compound 7 to obtain a compound 8;
(6) removing all protecting groups of the compound 8 to obtain the isoastragaloside IV,
wherein, R is1Selected from TBS, TES, TBDMS, TBDPS, DIPS, DPS or TIPDS; the R is2Is pivaloyl; the R is3Is benzoyl; x is
2. The method for synthesizing astragaloside IV according to claim 1, wherein in the step (1), the protection method comprises the following steps: at room temperature, dissolving cycloastragenol in a first solvent, adding halogenated silane and imidazole, slowly heating the reaction temperature to room temperature, and stirring until TLC (thin layer chromatography) tracking shows that the cycloastragenol completely reacts; the first solvent is one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether, the halogenated silane is TBSCl, TESCl, TBDMSCl, TBDPSCl, DIPSl, DPSCl or TIPDSCl, and the molar ratio of cycloastragenol, halogenated silane and imidazole is 1:1: 3-1: 5: 10; the concentration of the cycloastragenol in the first solvent is 0.1-1 mol/L.
3. The method for synthesizing astragaloside IV according to claim 1, wherein in the step (2), the protection method comprises the following steps: dissolving the compound 2 in a second solvent at the temperature of below 0 ℃, adding pivaloyl chloride, slowly raising the reaction temperature to room temperature, then heating to 50 ℃, and continuing stirring until TLC tracking shows that the compound 2 is completely reacted, wherein the second solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether; the molar ratio of the compound 2 to the pivaloyl chloride is 1: 2-1: 20; the concentration of the compound 2 in the second solvent is 0.1-1 mol/L.
4. The method for synthesizing astragaloside IV according to claim 1, wherein in the step (3), the glycosylation reaction comprises the following steps: under the protection of inert gas, dissolving the compound 3 and the glycosyl donor compound 4 in a third solvent, adding a drying agent, stirring at room temperature for 0.5-2 hours, adding a catalyst, and continuously stirring at room temperature until TLC (thin layer chromatography) tracking shows that the compound 3 completely reacts; the third solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether, and the molar ratio of the compound 3, the glycosyl donor compound 4 and the catalyst is 1:1: 0.1-1: 5: 0.8; the concentration of the compound 3 in the third solvent is 0.001-1 mol/L; the catalyst is selected from a complex of gold (I) valency; the desiccant is selected from molecular sieves.
5. The method for synthesizing astragaloside IV according to claim 1, wherein in the step (4), the protecting group R1The removing method comprises the following steps: dissolving the compound 5 in a fourth solvent at room temperature, adding camphorsulfonic acid, and stirring until TLC tracking shows that the compound 5 is completely reacted; the fourth solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether, and the molar ratio of the compound 5 to camphorsulfonic acid is 1: 1-1: 10; said compound 5 being in the second placeThe concentration of the quaternary solvent is 0.001-1 mol/L.
6. The method for synthesizing astragaloside IV according to claim 1, wherein in the step (5), the glycosylation reaction comprises the following steps: dissolving a compound 6 and a glycosyl donor compound 7 in a fifth solvent, adding a drying agent, stirring at room temperature for 0.5-2 hours, adding a catalyst, and continuously stirring at room temperature until TLC tracking shows that the compound 6 completely reacts, wherein the fifth solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether; the molar ratio of the compound 6, the glycosyl donor compound 7 and the catalyst is 1:1: 0.1-1: 5: 0.8; the concentration of the compound 6 in the fifth solvent is 0.001-1 mol/L; the catalyst is selected from a complex of gold (I) valency; the desiccant is selected from molecular sieves.
7. The method for synthesizing astragaloside IV according to claim 1, wherein the reaction for removing the protecting group in the step (6) comprises the following steps: dissolving the compound 8 in a sixth solvent, adding a reducing agent, and stirring at room temperature until TLC (thin layer chromatography) tracking shows that the compound 8 is completely reacted; the reducing agent is sodium borohydride, lithium aluminum hydride and borane; the sixth solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or diethyl ether.
8. The method for synthesizing astragaloside according to claim 1, wherein any of the steps (1) to (6) is carried out under an inert gas atmosphere.
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