CN103275169A - 呋甾皂苷及其合成方法 - Google Patents
呋甾皂苷及其合成方法 Download PDFInfo
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- CN103275169A CN103275169A CN2013102095961A CN201310209596A CN103275169A CN 103275169 A CN103275169 A CN 103275169A CN 2013102095961 A CN2013102095961 A CN 2013102095961A CN 201310209596 A CN201310209596 A CN 201310209596A CN 103275169 A CN103275169 A CN 103275169A
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- Prior art keywords
- compound
- acid
- furostanol
- triflate
- tert
- Prior art date
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- 229930182490 saponin Natural products 0.000 title claims abstract description 35
- 235000017709 saponins Nutrition 0.000 title claims abstract description 35
- 150000007949 saponins Chemical class 0.000 title claims abstract description 34
- 238000001308 synthesis method Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 18
- 125000002252 acyl group Chemical group 0.000 claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims abstract description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims description 23
- -1 beta-D-galactopyranosyluronic acid Chemical class 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 7
- 239000012024 dehydrating agents Substances 0.000 claims description 7
- 239000002808 molecular sieve Substances 0.000 claims description 7
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 7
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical group OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 6
- 229910052710 silicon Inorganic materials 0.000 claims description 6
- 239000010703 silicon Substances 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 125000001483 monosaccharide substituent group Chemical group 0.000 claims description 5
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229960002246 beta-d-glucopyranose Drugs 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 claims description 3
- SHZGCJCMOBCMKK-PQMKYFCFSA-N alpha-D-rhamnose Chemical compound C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-HGVZOGFYSA-N alpha-L-mannose Chemical compound OC[C@@H]1O[C@@H](O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-HGVZOGFYSA-N 0.000 claims description 3
- SHZGCJCMOBCMKK-HGVZOGFYSA-N alpha-L-rhamnopyranose Chemical compound C[C@@H]1O[C@@H](O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-HGVZOGFYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-FPRJBGLDSA-N beta-D-galactose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-FPRJBGLDSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-RWOPYEJCSA-N beta-D-mannose Chemical compound OC[C@H]1O[C@@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-RWOPYEJCSA-N 0.000 claims description 3
- SRBFZHDQGSBBOR-KKQCNMDGSA-N beta-D-xylose Chemical compound O[C@@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-KKQCNMDGSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-YJRYQGEOSA-N beta-L-mannose Chemical compound OC[C@@H]1O[C@H](O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-YJRYQGEOSA-N 0.000 claims description 3
- JAMNHZBIQDNHMM-UHFFFAOYSA-N pivalonitrile Chemical compound CC(C)(C)C#N JAMNHZBIQDNHMM-UHFFFAOYSA-N 0.000 claims description 3
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 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 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 2
- SHZGCJCMOBCMKK-SXUWKVJYSA-N alpha-L-fucose Chemical compound C[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-SXUWKVJYSA-N 0.000 claims description 2
- 229940095564 anhydrous calcium sulfate Drugs 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N beta-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 claims description 2
- UCYRAEIHXSVXPV-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)indiganyl trifluoromethanesulfonate Chemical compound [In+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F UCYRAEIHXSVXPV-UHFFFAOYSA-K 0.000 claims description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- WGJJZRVGLPOKQT-UHFFFAOYSA-K lanthanum(3+);trifluoromethanesulfonate Chemical compound [La+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F WGJJZRVGLPOKQT-UHFFFAOYSA-K 0.000 claims description 2
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 150000003376 silicon Chemical class 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 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 description 2
- 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 description 2
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 claims description 2
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 2
- 150000002243 furanoses Chemical class 0.000 claims 3
- 239000000370 acceptor Substances 0.000 claims 2
- SRBFZHDQGSBBOR-SQOUGZDYSA-N beta-D-arabinopyranose Chemical compound O[C@@H]1CO[C@@H](O)[C@@H](O)[C@@H]1O SRBFZHDQGSBBOR-SQOUGZDYSA-N 0.000 claims 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
- VASOMTXTRMYSKD-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl)boronic acid Chemical compound OB(O)C1=C(F)C(F)=C(F)C(F)=C1F VASOMTXTRMYSKD-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- SRBFZHDQGSBBOR-MBMOQRBOSA-N alpha-D-arabinopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@@H]1O SRBFZHDQGSBBOR-MBMOQRBOSA-N 0.000 claims 1
- SRBFZHDQGSBBOR-QMKXCQHVSA-N alpha-L-arabinopyranose Chemical compound O[C@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-QMKXCQHVSA-N 0.000 claims 1
- SRBFZHDQGSBBOR-KLVWXMOXSA-N beta-L-arabinopyranose Chemical compound O[C@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-KLVWXMOXSA-N 0.000 claims 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims 1
- 239000000386 donor Substances 0.000 claims 1
- 238000005858 glycosidation reaction Methods 0.000 claims 1
- 239000000937 glycosyl acceptor Substances 0.000 claims 1
- 239000000348 glycosyl donor Substances 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 80
- 238000002360 preparation method Methods 0.000 abstract description 33
- 125000006239 protecting group Chemical group 0.000 abstract description 10
- 238000006206 glycosylation reaction Methods 0.000 abstract description 7
- 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 abstract description 5
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 abstract description 5
- 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 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000008103 glucose Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000013595 glycosylation Effects 0.000 abstract description 2
- 150000002463 imidates Chemical class 0.000 abstract 3
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 abstract 2
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 31
- 239000011734 sodium Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Steroid Compounds (AREA)
Abstract
本发明涉及一种如式（I）所示呋甾皂苷的化学合成方法，包括如下步骤：以化合物（II）作为原料，与酰基保护的单糖三氯亚胺酯给体反应得化合物（III），接着选择性地脱除其R1保护基得化合物（IV）；在糖苷化条件下，化合物（IV）与葡萄糖硫苷（V）反应得化合物（VI），接着脱除其R3保护基得化合物（VII）；化合物（VII）与鼠李糖三氯亚胺酯给体进行糖苷化反应得化合物（VIII），接着脱除其保护基R4和R5并选择性地引入保护基R3得化合物（IX）；化合物（IX）与酰基保护的单糖三氯亚胺酯给体进行糖苷化反应得化合物（X），然后脱除其酰基保护基得呋甾皂苷（I）。本发明所制备的呋甾皂苷可用于抗肿瘤和糖尿病药物的制备。
Description
技术领域
本发明属于药物合成领域，涉及一种呋甾皂苷及其化学合成方法。
技术背景
呋甾皂苷是一类呋甾皂苷元的3-OH和26-OH同时被糖基化修饰的双糖链甾体化合物，其中半缩酮型E环是其结构的独特之处。
呋喃皂苷具有多种生物活性。例如：原薯蓣皂苷（protodioscin，结构如下式所示）作为呋甾皂苷的典型代表，不仅是用于治疗冠心病、心绞痛等心血管疾病的临床药物—地奥心血康胶囊的有效成分之一，而且能够抑制白血病细胞MOLT-4、结肠癌细胞HCT-116、和SW-620、CNS癌细胞SNB-75以及肾癌细胞786-0等生长（GI50≤2.0μM）[(a)李伯刚，周正直新药与临床，1994，13，75-76;（b）Hu,K.;Yao,X.S.Planta Med.2002,68,297-301]；coreajaponin A（如下式）是新近由Lee小组从日本薯蓣的根茎中分离得到一个呋喃甾烷型皂苷，研究表明它能增加C6小鼠胶质瘤细胞的神经生长因子（NFG）的含量（Kim,K.H.;Kim,M.A.;Moon,E.J.;Kim,S.Y.;Choi,S.Z.;Son,M.W.;Lee,K.R.Bioorg.Med.Chem.Lett.2011,21,2075-2078）;parisaponin I（如下式）是Yoshikawa小组于2003年从我国用于治疗慢性支气管炎、乳腺炎、腮腺炎等疾病的传统中药—华重楼中首次分离得到的一个呋甾皂苷，具有保护胃黏膜的活性(Matsuda,H.;Pongpiriy-adacha,Y.;Morikawa,T.;Kishi,A.;Kataoka,K.;Yoshikawa,M.Bioorg.Med.Chem.Lett.2003,13,1101-1106)。另外，呋甾皂苷通常没有溶血活性，这些使其成为药物研发中理想的苗头化合物。
在植物体内，呋甾皂苷能够被呋甾-26-糖基水解酶特异性地酶解失去26位的糖基而转化为螺甾皂苷，同时由于它通常与其它皂苷伴生，这使得这类化合物的获得极其困难，从而限制了它们构效关系的研究，制约了其进一步开发和利用。
基于呋甾皂苷的独特结构、良好活性以及提取困难，多个小组对其开展了合成研究[(a)Yu,B.;Liao,J.C.;Zhang,J.B.;Hui,Y.Z.Tetrahedron Lett,2001,42,77-79;(b)Cheng,M.S.;Wang,Q.L.;Tian,Q.;Song,H.Y.;Liu,Y.X.;Li,Q.;Xu,X.;Miao,H.D.;Yao,X.S.;Yang,Z.J.Org.Chem.2003,68,3658-60;（c）Cheng,S.;Du,Y.;Ma,B.;Tan,D.Org.Biomel.Chem.2009,7,3112-3118;(D)Xu,Q.-C.;Liu,Y.;Liu,J.;He,C.-X.;Yan,M.-C.;Cheng,M.-S.Chem.Lett.2008,37,780-781;(e)Li,M.;Yu,B.Org.Lett.2006,8,2679-2682;(f)Hou,S.;Xu,P.;Zhou,L.;Yu,D.;Lei,P.Bioorg.Med.Chem.Lett.2006,16,2454-2458;(g)李明，俞飙中国发明专利，CN1763076A；（h）李明，俞飙中国发明专利，CN1763077A;(i)Cheng,S.;Du,Y.;Ma,B.-P.;Li,L.;Zhao,Y.WO2009/132478A1；（j）程水红，杜宇国，马百平，李鲁，赵阳中国发明专利，CN102076704A]。在已有的关于呋甾皂苷的合成方法中均以16,22-二-羰基-26-羟基胆甾烷型皂苷元作为关键的中间体，通过糖苷化反应先后引入26位和3位的糖基后，再选择性地还原16位的羰基而形成所需的半缩酮型E环。然而由于16,22-二-羰基-26位羟基裸露的胆甾烷型皂苷元的在溶剂中存在开链和环状两种形式，导致26-位的β-D-葡萄糖基引入的产率不高；再有，16位和22位的两个羰基的区域选择性还原反应难以控制，容易生成16和22位羰基均被还原的产物，降低了整个合成策略的效率。
发明内容
本发明的目的之一是提供以3-O-硅基或酰基-16-O-乙酰基-22-羰基-26-羟基胆甾烷和多种单糖糖基给体为原料合成的呋甾皂苷。
本发明的另一个目的是以3-O-硅基或酰基-16-O-乙酰基-22-羰基-26-羟基胆甾烷作为关键的中间体，采用逐步合成的策略，高效地实现26位和3位糖基的引入以及半缩酮型E环的形成，为上述呋甾皂苷的制备提供了一种新的化学合成方法。
本发明的呋甾皂苷结构如下式（I）所示：
其中，
虚线表示5，6位之间是单键或双键(Δ5)，并当其为单键时，5位氢原子位于α位或β位；
曲线表示22位碳的绝对构型是R或S；
曲线表示25位碳的绝对构型是R或S；
S1是单糖取代基。
所述单糖取代基为β-D-吡喃葡萄糖(β-D-Glcp)、β-D-吡喃半乳糖(β-D-Galp)、β-D-吡喃甘露糖(β-D-Manp)、α-D-吡喃甘露糖(α-D-Manp)、β-L-吡喃甘露糖(β-L-Manp)、α-L-吡喃甘露糖(α-L-Manp)、β-D-吡喃木糖(β-D-Xylp)、β-D-吡喃氨基葡萄糖(β-D-GlcNACp)、α-L-吡喃鼠李糖(α-L-Rhap)、α-D-吡喃鼠李糖(α-D-Rhap)、β-D-吡喃/呋喃阿拉伯糖(β-D-Araf/p)、α-D-吡喃/呋喃阿拉伯糖(α-D-Araf/p)、α-L-吡喃/呋喃阿拉伯糖(α-L-Araf/p)、β-L-吡喃/呋喃阿拉伯糖(β-L-Araf/p)、α-L-吡喃岩藻糖(α-L-Fucp)、β-D-吡喃葡萄糖醛酸(β-D-GlcAp)、β-D-吡喃半乳糖醛酸(β-D-GalAp)中的一种。
上述呋甾皂苷的合成方法包括如下步骤：
以化合物（II）（中国发明专利，申请号：201310126415.9）作为原料，与酰基保护的单糖三氯亚胺酯给体反应得化合物（III），接着选择性地脱除其R1保护基得化合物（IV）；在糖苷化条件下，化合物（IV）与三氯亚胺酯给体（V）反应得化合物（VI），接着脱除其R3保护基得化合物（VII）；化合物（VII）与鼠李糖三氯亚胺酯给体进行糖苷化反应得化合物（VIII），接着脱除其保护基R4和R5并选择性地引入保护基R3得化合物（IX）；化合物（IX）与酰基保护的单糖三氯亚胺酯给体进行糖苷化反应得化合物（X），然后脱除其酰基保护基得呋甾皂苷（I）。
具体各步骤如下：
(1)化合物（III）的制备：
在溶剂中和脱水剂的存在下，于-78-150℃，以路易斯酸或质子酸为促进剂，化合物（II）与酰基保护的单糖三氯亚胺酯给体反应1-48小时得化合物（III），其中R1是酰基或硅基；化合物（II）与单糖三氯亚胺酯给体以及促进剂的摩尔比为1.0:(1.0-5.0):(0.05-3.0)；化合物（II）与脱水剂的质量比为1.0:(3.0-10.0)。
所述的溶剂是C1-C6的单卤代或多卤代烷烃、1,4-二氧六环、乙醚、乙腈、2,2,2–三甲基乙腈、四氢呋喃、N,N–二甲基甲酰胺、N,N–二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷-2-酮、二甲基亚砜、乙酸乙酯、甲苯、三氟甲苯、吡啶、甲醇、乙醇、异丙醇等C1-C6的烷基醇类、水中的一种或它们的混合物。
优选的溶剂是CH2Cl2、CHCl3、ClCH2CH2Cl、2,2,2-三甲基乙腈、三氟甲苯中的一种或它们两种或多种不同比例的混合溶剂。
所述的路易斯酸或质子酸是三甲基硅基三氟甲磺酸酯、三乙基硅基三氟甲磺酸酯、叔丁基二甲基硅基三氟甲磺酸酯、三氟化硼乙醚、三氟甲磺酸银、三氟甲磺酸铜、三氟甲磺酸锌、三氟甲磺酸钪、三氟甲磺酸镧、三氟甲磺酸镱、三氟甲磺酸铟、三氟甲磺酸、或高氯酸、四氟硼酸、四(五氟代苯基)硼酸、二(三氟甲磺酰)亚胺、三氯乙酸、三氟乙酸、甲酸、乙酸、SiO2-H2SO4、SiO2-HClO4、SiO2-HOTf中的一种或它们的混合物。
所述的硅基为甲基、乙基、异丙基、叔丁基、苯基等构成的三取代硅基；优选的硅基是叔丁基二甲基硅基或叔丁基二苯基硅基。
所述的脱水剂是
、
、
分子筛或AW-300分子筛或无水硫酸钠、无水硫酸钙、无水硫酸铜、无水硫酸镁中的一种或者它们的混合物；
所述的单糖基是S1；
所述R2是酰基保护的S1单糖取代基;
所述S1如步骤（1）所示；
所述的酰基为C2-C6的直链或支链脂肪族酰基或C6-C10的芳香酰基；优选的酰基是乙酰基、氯乙酰基、三氯乙酰基、特戊酰基、4-羰基戊酰基、2-氯-2-甲基-丙酰基、苯甲酰基、邻叠氮甲基苯甲酰基或2-(2-硝基苯基)-乙酰基。
(2)化合物(IV)的制备：
在碱存在下，在溶剂中于-78-150℃条件下脱除化合物（IV）中R1保护基得化合物(V)；碱与化合物（IV）的摩尔比为(0.1-5.0):1.0。
所述的碱可以是无机碱，如氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种；也可以是有机碱如叔丁醇钾、甲醇钠、乙醇钠、甲氧基镁、三乙胺、吡啶、4-N,N-二甲基吡啶、2,6-二甲基吡啶、2,4,6-三甲基吡啶、二异丙基乙基胺、四丁基氟化铵、水合肼、醋酸肼、硫脲中的一种；
所述溶剂如上；优选的溶剂是甲醇、乙醇、异丙醇等C1-C6的烷基醇类、C1-C6的单卤代或多卤代烷烃、乙酸乙酯、N,N–二甲基甲酰胺、N,N–二甲基乙酰胺、水中的一种或它们的混合物；
(3)化合物（VI）的制备：
与化合物（III）的制备条件类似，化合物（IV）与葡萄糖三氯亚胺酯（V）反应得化合物(VI)。
(4)化合物（VII）的制备：
在碱存在下，在溶剂中于-78-150℃条件下脱除化合物（VI）中R3保护基得化合物(VII)；碱与化合物（VII）的摩尔比为(0.1-5.0):1.0。
所述的溶剂如步骤（1）所示；
所述的碱如步骤（2）所示；
(5)化合物（VIII）的制备：
与化合物（III）的制备条件类似，化合物（VII）与鼠李糖三氯亚胺酯反应得化合物（VIII）；(6)化合物（IX）的制备：
在溶剂中和路易酸或质子酸存在的条件下，脱除化合物（VIII）中R4，R5保护基，接着与酰化试剂反应，选择性地在伯羟基上引入R3酰基保护基得化合物（IX）。
所述的R3为酰基；
所述的酰基如步骤（1）所示；
所述的R4，R5为苄叉或丙酮叉或对甲氧基苄叉；
R6为苄基或2-萘甲基或对甲氧苄基。
所述的酰化试剂是C2-C6的直链或支链脂肪族羧酸或C6-C10的芳香羧酸及其酰氯或酸酐。
优选的酰化试剂是乙酸、氯乙酸、三氯乙酸、特戊酸、4-羰基戊酸、2-氯-2-甲基-丙酸、苯甲酸、邻叠氮甲基苯甲酸、2-(2-硝基苯基)-乙酸及其酰氯或酸酐。
(7)化合物（X）的制备：
与化合物（III）的制备条件类似，化合物（IX）与酰基保护的单糖三氯亚胺酯反应得化合物(X)。
所述单糖取代基如步骤（1）所示；
所述酰基如步骤（1）所示。
(8)化合物（I）的制备：
在溶剂中，在-78-150℃，用碱脱除化合物（X）的酰基保护基，得呋甾皂苷（I）；其中碱与化合物（X）的摩尔比为(0.1–100.0):1.0。
所述碱如步骤（2）所示；
所述溶剂如步骤（1）所示；
优选的溶剂是甲醇、乙醇、异丙醇等C1-C6的烷基醇类、水或它们的混合物。
本发明的方法优选在惰性气体（如氩气、氮气等）保护下进行。
本发明提供了一种简便、高效、新颖的呋甾皂苷化学合成方法，克服了当前已有方法的局限性（如选择性还原16，22-位二羰基化合物中的16位羰基产率不高、难以控制等），具有较好的实用性。本发明所制备的呋甾皂苷具有较强的抗肿瘤活性和较好的抗糖尿病活性，可用于抗肿瘤和糖尿病药物的制备。
附图说明
图1是protodioscin、coreajaponin A和parisaponin I的合成路线图。
试剂和条件：(a)TMSOTf,
MS,CH2Cl2,rt,5h,90%;(b)Thiourea,C2H5OH,pyridine,70°C,1h,82%;TMSOTf,NIS,
MS,CH2Cl2,rt,5h,65%;c)pyridine,AcOH,NH2NH2·H2O,0°C,4h,91%;d)TMSOTf,
MS,CH2Cl2,rt,3h,98%;e)TFA,H2O,CH2Cl2,0°C,0.5h,100%;f)BzCl,CHCl3,collidine,40°C,4h,97%;g)TMSOTf,
MS,CH2Cl2,rt,4h,95%for9a;90%for9b;97%for9c;h)DDQ,CH2Cl2,H2O,3h,rt,93%for9a;96%for9b;95%for9c;i)LiOH·H2O,1,4-Dioxane,H2O,60°C。
具体实施方式
下面结合附图，以protodioscin11a、coreajaponin A 11b和parisaponin I 11c的合成作为具体实施例，对本发明进行详细说明，但本发明不限于以下内容。
（1）化合物2制备和数据
将化合物1（0.30g,0.54mmol），（中国发明专利，申请号：201310126415.9）苯甲酰基保护的葡萄糖三氯亚胺酯给体(Gauthier,C.;Legault,J.;Lebrun,M.;Dufour,P.;Pichette,A.Bioorg.Med.Chem.2006,14,6713-6725)(1.00g,1.35mmol,2.50equiv.)和MS(1.80g)混溶于6.00mL无水CH2Cl2中，室温下搅拌30分钟后，在冰浴中滴加TMSOTf(14.40μL,0.081mmol,0.15equiv.)。然后自然升至室温继续搅拌5小时后，TLC(Petroleum ether:AcOEt=2:1)显示反应完全。加入三乙胺淬灭反应，过滤掉分子筛，然后减压蒸除溶剂，所得残余物经硅胶柱层析(Petroleum ether:AcOEt=4:1)得到白色固体2(0.54g,0.48mmol,90%)。其数据如下：
[α]D 25=+10.3°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.02(d,J=6.6Hz,2H),7.95(d,J=7.7Hz,2H),7.90(d,J=7.7Hz,2H),7.83(d,J=6.6Hz,2H),7.56-7.26(m,14H),5.89(t,1H,J=9.9Hz,1H),5.67(t,J=9.9Hz,1H,)5.52(t,J=8.8Hz,1H),5.38(d,J=5.5Hz,1H),4.93(m,1H),4.82(d,J=7.7Hz,1H),4.70(m,1H),4.62(dd,J=12.1Hz,3.3Hz,1H),4.51(dd,J=12.1,5.5Hz,1H),4.15(m,1H),4.03(s,2H),3.73-3.37(m,2H),2.86(m,1H),2.48(m,1H),2.39-2.24(m,4H),1.91-1.85(m,8H),1.68-1.48(m,8H),1.26-0.76(m,19H),1.00(d,J=7.7Hz,3H),0.83(s,3H),0.78(d,J=6.6Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.8,166.7,166.1,165.8,165.2,165.0,139.1,133.4,133.2,133.15,133.11,129.77,129.69,129.67,129.5,129.3,128.76,128.73,128.40,128.36,128.34,128.24,122.7,101.4,75.9,75.6,75.2,72.9,72.1,71.8,69.8,63.2,54.9,53.8,49.7,43.3,41.8,41.1,39.5,38.5,37.7,36.7,36.4,34.8,32.9,31.5,31.2,27.5,27.0,21.1,20.7,19.2,16.6,13.2;
HR-ESIMS Calcd for C65H73ClO15Na(M+Na)+:1151.4530,found:1151.4504。
（2）化合物3的制备和数据
将化合物2(0.42g,0.37mmol)，硫脲(85.4mg,1.11mmol,3.00equiv.)溶于乙醇与吡啶体积比为5:1的混合溶液(6mL)中，在70°C条件下进行。搅拌一小时后，TLC(Petroleumether:AcOEt=1:1)显示反应完全。将反应液置于冰水中充分搅拌。使用CH2Cl2稀释，有机相依次使用1M稀盐酸溶液洗涤，饱和NaHCO3溶液，饱和食盐水溶液洗涤，然后收集有机相经无水Na2SO4干燥，过滤、减压浓缩，所得浆状物经硅胶柱层析(Petroleum ether:AcOEt=2:1)得到白色固体3(0.32g,0.30mmol,82%)。其数据如下：
[α]D 25=+14.5°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.02(d,J=7.1Hz,2H),7.95(d,J=7.1Hz,2H),7.90(d,J=7.1Hz,2H),7.81(d,J=7.1Hz,2H),7.55-7.26(m,14H),5.89(t,J=9.3Hz,1H),5.67(t,J=9.4Hz,1H)5.51(t,J=8.2Hz,1H),5.33(d,J=4.4Hz,1H),4.92(m,1H),4.81(d,J=8.2Hz,1H),4.62(dd,J=12.1,3.3Hz,1H),4.51(dd,J=12.1,3.3Hz,1H)，4.15(m,1H),3.73(m,1H),3.52(m,1H),3.37(m,1H),2.85(m,1H),2.49-2.21(m,6H),1.92-1.82(m,8H),0.83(s,3H),0.77(d,J=6.6Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.8,166.1,165.7,165.2,165.0,140.7,133.4,133.2,133.14,133.10,129.76,129.68,129.65,129.5,129.2,128.73,128.70,128.34,128.32,128.23,121.3,101.3,75.6,75.2,72.9,72.1,71.8,71.6,69.8,63.1,54.9,53.9,49.8,43.3,42.1,41.7,39.6,38.5,37.1,36.4,34.7,32.8,31.53,31.46,31.2,26.9,21.1,20.7,19.3,16.5,13.2;
HR-ESIMS Calcd for C63H72O14Na(M+Na)+:1075.4814,found:1075.4792。
（3）化合物4的制备和数据
将化合物3(0.10g,0.095mmol)，葡萄糖硫苷给体V(92.0mg,0.14mmol,1.50equiv.)和
MS(0.50g)混溶于4.00mL无水CH2Cl2中，室温下搅拌30分钟后，在冰浴中加入NIS(47.20mg,0.21mmol,2.25equiv.)，滴加TMSOTf(2.60μL,0.014mmol,0.10equiv.)，自然升至室温搅拌5小时后，TLC(Petroleum ether:AcOEt:CH2Cl2=2:1:1)显示反应完全。加入三乙胺淬灭反应，使用CH2Cl2稀释，有机相依次使用饱和的Na2S2O3溶液，饱和食盐水洗涤，收集有机相再用无水Na2SO4干燥，过滤、减压浓缩，所得浆状物经硅胶柱层析(Petroleum ether:AcOEt:CH2Cl2=3:1:1)得到白色固体4(97.0mg,0.062mmol,65%)。其数据如下：
[α]D 25=+17.8°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.02(d,J=9.0Hz,2H),7.94(d,J=9.1Hz,2H),7.90(d,J=9.1Hz,2H),7.83-7.71(m,6H),7.56-7.26(m,19H),6.91(d,J=10.3Hz,2H),5.89(t,J=11.5Hz,1H),5.67(t,J=11.6Hz,1H),5.52(m,2H),5.33(s,1H),4.99(m,2H),4.92(m,1H),4.86(d,J=14.8Hz,1H),4.81(d,J=9.4Hz,1H),4.62(dd,J=14.5,3.1Hz,1H),4.50(m,2H),4.31(m,1H),4.14(m,1H),3.82-3.71(m,6H),3.44-3.35(m,3H),2.85(m,1H),2.65-2.11(m,12H),1.91-1.84(m,8H),1.60-1.42(m,10H),1.25(s,4H),1.05-0.95(m,12H),0.82(s,4H),0.76(d,J=7.9Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,206.1,171.2,169.8,166.1,165.8,165.2,165.0,160.0,140.2,135.7,133.4,133.2,133.1,132.9,129.8,129.7,129.67,129.5,129.2,128.75,128.71,128.37,128.34,128.2,127.95,127.89,127.6,127.3,126.8,126.2,125.97,125.82,121.9,113.6,101.3,101.2,100.2,81.4,79.6,78.2,77.3,75.6,75.2,74.0,73.3,72.9,72.1,71.8,69.8,68.6,66.2,63.1,55.3,54.9,53.9,49.8,43.3,41.8,39.6,38.7,38.6,37.7,37.1,36.6,34.8,32.9,31.6,31.2,29.8,29.7,29.4,27.8,26.9,21.1,20.7,19.3,16.6,13.2;
HR-ESIMS Calcd for C93H103O22(M+H)+:1571.6936,found:1571.6907。
（4）化合物5的制备和数据
将化合物4(0.81g,0.52mmol)溶于6.00mL无水吡啶中与1.34mL乙酸的混合溶液中，在冰浴条件下搅拌5分钟后，滴加NH2NH2·H2O(162μL,3.64mmol,7.00equiv.)，自然升至室温搅拌4小时后，TLC(Petroleum ether:AcOEt:CH2Cl2=3:1:1)显示反应完全。将反应液置于冰水混合物中，使用CH2Cl2稀释，有机相依次使用1M稀盐酸溶液洗涤，饱和NaHCO3溶液，饱和食盐水溶液洗涤，收集有机相经无水Na2SO4干燥，过滤、减压浓缩，所得浆状物经硅胶柱层析(Petroleum ether:AcOEt:CH2Cl2=3:1:1)得到白色固体5(0.69g,0.47mmol,91%)。其数据如下：
[α]D 25=+8.5°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.02(d,J=7.1Hz,2H),7.94(d,J=7.1Hz,2H),7.90(d,J=7.1Hz,2H),7.84-7.79(m,5H),7.74(m,1H),7.55-7.26(m,18H),6.91(d,J=8.8Hz,2H),5.90(t,J=7.7Hz,1H),5.67(t,J=9.4Hz,1H),5.53(m,2H),5.34(d,J=2.8Hz,1H),5.11(d,J=12.1Hz,1H),5.00(d,J=12.1Hz,1H),4.99(m,2H),4.94(m,1H),4.82(d,J=7.7Hz,1H),4.64(dd,J=15.9,1.1Hz,1H),4.50(m,2H),4.31(m,1H),4.14(m,1H),3.82-3.71(m,6H),3.59(m,1H),3.43-3.36(m,2H),2.86(m,1H),2.49-2.26(m,6H),1.91-1.82(m,8H),1.60-0.76(m,30H),1.26(s,4H),0.82(s,4H),0.76(d,J=6.6Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,171.2,169.8,166.1,165.8,165.2,165.0,160.0,140.1,135.8,133.4,133.21,133.2,133.15,133.13,132.96,129.8,129.71,129.68,129.5,129.3,128.76,128.72,128.37,128.35,128.3,128.1,127.9,127.6,127.4,126.8,125.95,125.8,121.8,113.6,101.6,101.4,101.3,81.2,80.0,79.2,77.3,77.0,76.7,75.6,75.2,74.5,74.3,72.9,72.1,71.8,69.8,68.7,66.4,63.2,55.3,54.9,53.9,49.8,43.3,41.8,39.6,38.7,38.6,37.7,37.1,36.6,34.8,32.9,31.6,31.2,29.8,29.7,29.5,26.9,21.1,19.3,16.6,13.2;
HR-ESIMS Calcd for C88H96O20Na(M+Na)+:1495.6387,found:1495.6374。
（5）化合物6的制备和数据
将化合物5（0.22g,0.15mmol），苯甲酰基保护的鼠李糖三氯亚胺酯给体(Ziegler,T.;Bien,F.;Jurisch,C.Tetrahedron:Asymmetry1998,9,765-780)(0.14g,0.23mmol,1.50equiv.)和
MS(0.80g)混溶于6.00mL无水CH2Cl2中，室温下搅拌30分钟后，在冰浴中滴加TMSOTf(2.50μL,0.015mmol,0.10equiv.)，自然升至室温搅拌3小时后，TLC(petroleum ether:AcOEt:CH2Cl2=3:1:1)显示反应完全。加入三乙胺淬灭反应，使用CH2Cl2稀释，过滤掉分子筛，然后减压蒸除溶剂，所得残余物经硅胶柱层析(Petroleumether:AcOEt:CH2Cl2=3:1:1)得到白色固体6(0.27g,0.14mmol,98%)。其数据如下：
[α]D 25=+32.2°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.02(d,J=8.8Hz,2H),7.98-7.89(m,8H),7.83(d,J=8.6Hz,2H),7.72(m,1H),7.61-7.26(m,32H),6.90(d,J=9.6Hz,2H),5.91(t,J=11.3Hz,1H),5.83-5.79(m,2H),5.69-5.62(m,3H),5.55-5.51(m,2H),5.44(s,1H),5.07(d,J=13.1Hz,1H),4.97(d,J=12.6Hz,2H),4.82(d,J=9.4Hz,2H),4.71(d,J=8.8Hz,1H),4.64(d,J=13.5Hz,1H),4.52-4.50(dd,J=13.5,4.5Hz,1H),4.35-4.31(m,1H),4.15(m,1H),3.97-3.91(m,1H),3.86-3.71(m,10H),3.49(m,1H),3.37(m,1H),2.87(m,1H),2.61-2.43(m,4H),2.26-2.22(m,1H),2.06-1.85(m,9H),1.72-1.42(m,11H),1.34-1.26(m,11H),1.33(d,J=6.4Hz,3H),1.00(d,J=8.2Hz,3H),0.92(s,3H),0.83(s,3H),0.78(d,J=7.2Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.9,166.1,165.8,165.64,165.59,165.3,165.2,165.0,160.0,139.9,135.2,133.4,133.27,133.20,133.17,133.13,133.06,133.04,132.8,129.86,129.78,129.73,129.70,129.68,129.66,129.5,129.31,129.24,129.19,128.75,128.70,128.4,128.38,128.35,128.26,128.23,128.1,127.9,127.46,127.32,127.30,126.4,125.68,125.61,122.1,113.6,101.4,100.2,100.6,97.7,82.0,81.8,79.6,75.75,75.65,75.2,75.15,72.9,72.1,71.87,71.84,70.4,70.1,69.8,68.7,66.5,66.0,63.2,55.3,54.9,53.9,49.8,43.4,41.8,39.5,38.8,38.6,37.0,36.6,34.8,32.9,31.7,31.2,29.9,29.7,26.9,21.1,20.7,19.2,17.3,16.6,16.5,13.2;
HR-ESIMS Calcd for C115H119O27(M+H)+:1931.7933,found:1931.7882。
（6）化合物7的制备和数据
将化合物6(0.85g,0.44mmol)溶于8.00mL无水CH2Cl2中，冰浴条件下加入1.20mL的三氟乙酸与0.24mL的水的混合液中。室温下搅拌30分钟后，TLC(Petroleum ether:AcOEt=1:1)显示反应完全。使用CH2Cl2稀释，有机相依次使用蒸馏水，饱和NaHCO3溶液，饱和食盐水溶液洗涤，收集有机相用无水Na2SO4干燥，过滤、减压浓缩，所得浆状物经硅胶柱层析(Petroleum ether:AcOEt=1:1)得到白色固体7(0.79g,0.44mmol,100%)。其数据如下：
[α]D 25=+42.4°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.02(d,J=7.3Hz,2H),7.97-7.93(m,7H),7.90(d,J=7.4Hz,2H),7.84-7.80(m,5H),7.73-7.69(m,3H),7.59-7.26(m,29H),5.90-5.81(m,3H),5.69-5.66(m,2H),5.58(s,1H),5.52(t,J=8.5Hz,1H),5.43(s,1H),5.19(d,J=11.6Hz,1H),4.95(d,J=11.2Hz,2H),4.82(d,J=7.5Hz,2H),4.67-4.62(m,2H),4.51(dd,J=11.9,3.5Hz,1H),4.15(s,1H),3.87(d,J=10.0Hz,1H),3.79-3.66(m,6H),3.39(m,2H),2.87(m,1H),2.60-2.25(m,7H),2.12-1.85(m,10H),1.64-1.26(m,27H),1.00-0.77(m,22H),1.00(d,J=6.7Hz,3H),0.78(d,J=6.1Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.9,166.1,165.8,165.6,165.4,165.2,165.0,139.9,135.5,133.4,133.2,133.2,133.17,133.12,133.09,132.9,129.81,129.77,129.67,129.5,129.3,129.23,129.20,129.1,128.74,128.70,128.51,128.42,128.36,128.34,128.29,128.25,127.9,127.6,126.8,126.0,125.89,125.67,122.1,101.3,100.2,97.5,86.1,79.7,75.9,75.70,75.67,75.2,75.1,74.9,72.9,72.1,71.8,71.1,70.7,70.1,69.8,66.5,63.2,62.6,54.9,53.9,53.8,49.8,43.3,41.8,39.5,38.8,38.6,37.0,36.6,34.8,32.9,31.6,31.2,29.99,29.7,26.9,21.1,20.7,19.2,17.3,16.6,16.5,13.2;
HR-ESIMS Calcd for C107H112O26Na(M+Na)+:1835.7334,found:1835.7286。
（7）化合物8的制备和数据
将化合物7(0.72g,0.39mmol)溶于12.00mL无水CHCl3和4.00mL Collidine混合溶液中，冰浴条件下滴加苯甲酰氯(0.28mL,2.34mmol,6.00equiv.)在40°C条件下搅拌4小时后，TLC(petroleum ether:AcOEt=1:1)显示反应完全。将反应液减压蒸除溶剂，然后用CH2Cl2稀释，有机相依次使用1M稀盐酸、饱和食盐水溶液洗涤，收集有机相用无水Na2SO4干燥，过滤、减压浓缩，所得浆状物经硅胶柱层析(Petroleum ether:AcOEt=2:1)得到白色固体8(0.72g,0.37mmol,95%)。其数据如下：
[α]D 25=+84.2°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.07(d,J=9.3Hz,2H),8.03(d,J=9.4Hz,2H),7.97-7.89(m,7H),7.91(d,J=9.4Hz,2H),7.85-7.81(m,5H),7.71-7.67(m,3H),7.59-7.26(m,29H),5.91(t,J=11.6Hz,1H),5.84(m,2H),5.69-5.65(m,2H),5.57(s,1H),5.53(t,J=11.0Hz,1H),5.39(s,1H),5.17(d,J=13.8Hz,1H),5.03(d,J=13.8Hz,1H),4.94(m,1H),4.82(d,J=9.7Hz,2H),4.67-4.63(m,3H),4.56-4.50(m,2H),4.15(m,1H),3.82(d,J=10.2Hz,1H),3.76-3.62(m,5H),3.39(m,1H),2.90(m,1H),2.56-2.22(m,6H),2.04-1.86(m,7H),1.72-1.26(m,26H),1.00-0.77(m,14H),1.00(d,J=8.0Hz,3H),0.78(d,J=7.9Hz,3H);
13C NMR(150MHz,CDCl3)δ212.97,169.9,166.9,166.1,165.78,165.67,165.63,165.4,165.2,165.0,140.1,136.4,135.4,133.6,133.4,133.3,133.25,133.20,133.17,133.13,133.09,132.9,130.1,129.8,129.78,129.71,129.68,129.5,129.3,129.25,129.24,129.14,128.74,128.70,128.49,128.43,128.37,128.35,128.30,128.26,127.93,127.5,127.0,125.98,125.87,125.83,121.9,101.4,100.7,97.5,85.8,80.2,75.9,75.7,75.2,73.8,72.9,72.1,71.8,70.9,70.6,70.2,69.8,66.5,63.9,63.2,54.9,53.9,49.8,43.3,41.8,39.6,38.9,38.6,36.9,36.5,34.8,32.9,31.6,31.2,29.96,29.67,26.98,21.1,20.6,19.2,17.4,16.63,16.59,13.21;
HR-ESIMS Calcd for C114H116O26Na(M+Na)+:1939.7596,found:1939.7550。
（8）化合物9a的制备和数据
将化合物8(50.0mg,0.026mmol)，苯甲酰基保护的鼠李糖三氯亚胺酯给体(Ziegler,T.;Bien,F.;Jurisch,C.Tetrahedron:Asymmetry.1998,9,765-780)(40.3mg,0.065mmol,2.50equiv.)和
MS(0.20g)混溶于3.00mL无水CH2Cl2中，室温下搅拌30分钟后，在冰浴中滴加TMSOTf(2.50μL,0.015mmol,0.10equiv.)，自然升至室温搅拌4小时后，TLC(AcOEt:CH2Cl2=1:20)显示反应完全。加入三乙胺淬灭反应，过滤掉分子筛，滤液经减压蒸除溶剂，所得残余物经硅胶柱层析(AcOEt:CH2Cl2=1:35-1:20)得到白色固体9a(58.0mg,0.024mmol,95%)。其数据如下：
[α]D 25=+51.4°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.09(d,J=7.1Hz,2H),8.03(d,J=7.1Hz,2H),8.00(d,J=7.1Hz,2H),7.96(d,J=7.1Hz,2H),7.91(m,4H),7.83(m,4H),7.78(m,3H),7.57-7.12(m,40H),7.04(t,J=7.7Hz,2H),5.90(t,J=9.9Hz,1H),5.77-5.73(m,2H),5.69(m,2H),5.64(m,1H),5.59-5.51(m,3H),5.46(s,1H),5.37(m,2H),5.33(s,1H),5.20(d,J=12.1Hz,1H),4.96(m,2H),4.82(m,2H),4.71(d,J=7.1Hz,1H),4.65-4.63(m,2H),4.53(dd,J=12.1,5.5,1H),4.45(m,1H),4.16-4.13(m,2H),3.99-3.97(m,2H),3.90(m,1H),3.75(m,1H),3.64(m,1H),3.38(m,1H),2.87(m,1H),2.54-2.26(m,5H),1.98-1.87(m,8H),1.65-1.26(m,18H),1.04(dd,J=12.4,6.6Hz,9H),0.95-0.85(m,8H),0.84(s,4H),0.78(d,J=6.6Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.9,166.1,165.9,165.8,165.6,165.6,165.5,165.2,165.0,164.7,140.0,136.4,134.9,133.4,133.2,133.2,133.1,133.0,133.0,132.9,132.8,132.5,130.0,129.9,129.8,129.7,129.7,129.6,129.5,129.4,129.3,129.2,129.1,129.0,128.9,128.8,128.8,128.7,128.4,128.4,124.4,128.3,128.3,128.2,128.1,128.0,127.8,127.7,127.3,127.3,125.6,124.3,124.0,121.8,101.4,100.7,97.8,97.1,84.4,80.4,75.9,75.7,75.2,75.1,73.5,72.9,72.1,71.8,71.6,71.1,70.9,70.1,69.9,69.8,69.8,67.4,66.6,63.2,63.1,54.9,53.9,49.8,43.4,41.8,39.6,39.0,38.6,36.8,36.5,34.9,32.9,31.7,31.2,29.9,27.0,21.1,20.6,19.2,17.5,17.3,16.6,16.6,13.2;
HR-ESIMS Calcd for C141H138O34Na(M+Na)+:2397.8962,found:2397.8945。
（9）化合物9b的制备和数据
与化合物9a的制备类似，化合物8（0.10g,0.052mmol）与苯甲酰基保护的吡喃型阿拉伯糖三氯亚胺酯给体(Gauthier,C.;Legault,J.;Lebrun,M.;Dufour,P.;Pichette,A.Bioorg.Med.Chem.2006,14,6713-6725)(63.0mg,0.10mmol,2.00equiv.)得到白色固体9b(0.11g,0.047mmol,90%)。
[α]D 25=+73.5°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.07-7.81(m,22H),7.71(s,1H),7.62-7.19(m,40H),7.13(t,J=8.2Hz,1H),5.96-5.88(m,3H),5.79(dd,J=10.4,3.3Hz,1H),5.69(m,2H),5.58(m,2H),5.53(t,J=7.7Hz,1H),5.48(dd,J=10.0,3.5Hz,1H),5.40(d,J=9.9Hz,1H),5.34(m,1H),4.92(m,2H),4.87(d,J=7.7Hz,1H),4.82(d,J=7.9Hz,1H),4.76(m,1H),4.64(dd,J=12.1,3.3Hz,1H),4.56(m,2H),4.53-4.46(m,2H),4.29(dd,J=11.6,1.9Hz,1H),4.15(m,1H),4.10(t,J=9.4Hz,1H),3.87-3.83(m,2H),3.74-3.69(m,2H),3.62(m,2H),3.39(m,1H),2.88(m,1H),2.54-2.26(m,5H),1.93-1.85(m,7H),1.66-1.44(m,9H),1.29(d,J=6.6Hz,3H),1.00(d,J=7.1Hz,3H),0.87(s,4H),0.82(s,3H),0.78(d,J=6.6Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.8,166.1,165.9,165.7,165.6,165.5,165.56,165.4,165.3,165.2,165.04,165.02,140.0,134.8,133.4,133.33,133.28,133.2,133.15,133.11,133.0,132.7,129.82,129.80,129.77,129.67,129.52,129.32,129.25,129.22,129.0,128.7,128.55,128.43,128.36,128.34,128.29,128.24,128.18,127.84,127.78,127.2,126.3,125.4,121.9,101.4,101.36,100.6,97.6,83.6,80.3,77.8,76.0,75.7,75.2,75.1,72.9,72.8,72.1,71.8,71.5,70.3,70.2,69.8,68.8,66.4,64.3,63.15,62.98,54.9,53.9,49.8,43.3,41.7,39.5,38.8,38.6,36.9,36.5,34.8,32.9,31.6,31.2,29.8,29.6,27.0,21.1,20.6,19.1,17.3,16.6,13.2;
HR-ESIMS Calcd for C140H136O34Na(M+Na)+:2383.8805,found:2383.8855。
（10）化合物9c的制备和数据
与化合物9a的制备类似，化合物8（0.15g,0.078mmol），苯甲酰基保护的呋喃型阿拉伯糖三氯亚胺酯给体(Backinowsky,L.V.;Nepogodev,S.A.;Shashkov,A.S.Carbohydr.Res.1985,138,41-45)(0.12g,0.20mmol,2.50equiv.)反应得到白色固体9c(0.17g,0.074mmol,95%)。其数据如下：
[α]D 25=+61.1°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.04-8.02(m,4H),7.99(d,J=9.7Hz,2H),7.96(d,J=9.5Hz,2H),7.91-7.82(m,10H),7.78(d,J=9.2Hz,2H),7.63-7.60(m,2H),7.58-7.13(m,40H),5.90(t,J=11.5Hz,1H),5.75-5.66(m,3H),5.54-5.51(m,5H),5.45(s,1H),5.36(s,1H),5.26(d,J=14.0Hz,1H),5.02(d,J=14.0Hz,1H),4.93(m,2H),4.83-4.77(m,2H),4.68-4.50(m,6H),4.31(m,1H),4.16-4.11(m,2H),3.96-3.87(m,3H),3.76-3.73(m,1H),3.63(m,1H),3.98-3.37(m,1H),2.89(m,1H),2.53-2.22(m,5H),1.99-1.86(m,7H),1.65-1.26(m,16H),1.32(d,J=7.0Hz,3H),1.02(d,J=7.8Hz,3H),0.89(s,3H),0.83(s,3H),0.78(d,J=7.8Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.9,166.1,165.92,165.90,165.8,165.6,165.58,165.53,165.46,165.2,165.0,164.9,140.1,134.9,133.7,133.4,133.2,133.17,133.13,133.0,132.95,132.93,132.8,132.5,129.84,129.79,129.71,129.69,129.61,129.54,129.51,129.30,129.27,129.1,128.90,128.83,128.77,128.73,128.64,128.57,128.37,128.35,128.30,128.26,128.18,128.16,128.09,127.8,127.7,127.3,125.6,125.3,124.7,124.1,121.8,106.3,101.4,100.7,97.7,84.5,82.6,81.9,80.4,77.6,75.7,75.2,75.0,73.3,72.9,72.1,71.9,71.7,70.17,70.08,69.8,66.5,63.3,63.2,54.9,53.9,49.8,43.4,41.8,39.6,39.0,38.6,36.8,36.5,34.9,33.0,31.6,31.2,29.9,27.0,21.1,20.6,19.2,17.3,16.63,16.60,13.2;
HR-ESIMS Calcd for C140H136O34Na(M+Na)+:2383.8805,found:2383.8838。
（11）化合物10a的制备和数据
将化合物9a(70.0mg,0.029mmol)溶于5.00mL CH2Cl2和0.25mL水的混合溶液中，加入DDQ(40.1mg,0.18mmol，6.00equiv.),在室温下搅拌6小时后，TLC(Toluene:AcOEt=7:1)显示反应完全。加入饱和Na2S2O3溶液淬灭反应，CH2Cl2稀释，有机相依次使用饱和NaHCO3溶液，饱和食盐水溶液洗涤，有机相经无水Na2SO4干燥，过滤、减压浓缩，经硅胶柱层析(Toluene:AcOEt=7:1)得到白色固体10a(60.0mg,0.027mmol,93%)。其数据如下：
[α]D 25=+45.6°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.09-7.81(m,22H),7.59-7.24(m,33H),5.90(t,J=9.9Hz,1H),5.84-5.71(m,3H),5.72-5.62(m,5H),5.53(t,J=7.7Hz,1H),5.38(s,1H),5.22(s,1H),4.95(m,1H),4.83-4.78(m,3H),4.71-4.63(m,3H),4.53(dd,J=12.1,5.5,1H),4.47(m,1H),4.16-4.15(m,1H),3.99-3.98(m,2H),3.89(m,1H),3.79-3.71(m,3H),3.63(m,1H),3.39(m,1H),2.88(m,1H),2.54-2.26(m,5H),1.93-1.88(m,7H),1.65-1.26(m,24H),1.44(d,J=6.6Hz,3H),1.36(d,J=6.6Hz,3H),1.03(d,J=6.6Hz,3H),0.84(s,4H),0.78(d,J=6.6Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.9,166.1,165.99,165.8,165.67,165.63,165.52,165.45,165.3,165.2,165.0,140.2,133.5,133.4,133.23,133.20,133.18,133.13,133.0,132.9,130.0,129.98,129.90,129.85,129.79,129.70,129.65,129.5,129.4,129.3,129.27,129.27,129.02,129.00,128.77,128.73,128.55,128.48,128.45,128.36,128.29,128.22,121.8,101.4,100.7,99.2,97.5,82.2,80.6,75.9,75.7,75.2,75.1,72.9,72.1,71.8,71.2,70.8,70.4,70.2,69.8,69.3,68.5,66.5,63.2,54.9,53.9,49.8,43.4,41.8,39.6,39.0,38.6,36.8,36.5,34.9,32.9,31.7,31.2,29.97,27.0,21.1,20.6,19.1,17.5,16.6,16.6,13.2;
HR-ESIMS Calcd for C130H130O34Na(M+Na)+:2257.8336,found:2257.8385。
(12)化合物10b的制备和数据
与化合物10a的制备类似，化合物9b(30.0mg,0.012mmol)经脱除2-萘基甲基(Nap)保护基得到白色固体10b（27.0mg,0.012mmol,96%）。其数据如下：
[α]D 25=+77.2°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.09-8.07(m,4H),8.02(d,J=7.7Hz,2H),7.95-7.81(m,16H),7.61-7.25(m,33H),5.92-5.82(m,3H),5.73-5.65(m,5H),5.53-5.49(m,2H),5.36(d,J=1.6Hz,1H),4.93(m,1H),4.82(d,J=7.7Hz,1H),4.79(d,J=10.4Hz,1H),4.71(m,1H),4.64(dd,J=11.9,2.6Hz,1H),4.58(d,J=7.9Hz,1H),4.52(dd,J=13.2,7.7Hz,1H),4.38(m,2H),4.29(m,1H),4.16-4.11(m,2H),3.98-3.92(m,2H),3.77-3.57(m,5H),3.37(m,1H),2.88(m,1H),2.52-2.22(m,5H),1.92-1.85(m,8H),1.34(d,J=6.1Hz,3H),1.00(d,J=7.1Hz,3H),0.89(s,3H),0.82(s,3H),0.78(d,J=6.6Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.8,166.1,165.7,165.6,165.59,165.55,165.52,165.51,165.4,165.2,165.05,165.03,140.0,136.4,133.5–132.9,130.9,129.92,129.89,129.78,129.73,129.70,129.64,129.56,129.52,129.47,129.35,129.25,129.08,128.78–128.19,121.8,102.1,101.4,100.5,97.1,81.8,80.6,76.3,75.7,75.4,75.2,72.9,72.1,72.0,71.8,71.2,70.6,70.0,69.8,69.6,68.4,66.3,65.5,64.6,63.2,62.9,54.9,53.9,49.8,43.3,41.8,39.6,38.9,38.6,36.8,36.5,34.8,32.9,31.6,31.2,30.5,29.9,29.7,26.9,21.1,20.6,19.1,17.4,16.6,13.7,13.2;
HR-ESIMS Calcd for C129H128O34Na(M+Na)+:2243.8179,found:2243.8235。
(13)化合物10c的制备和数据
与化合物10a的制备类似，化合物9c（80.0mg,0.034mmol）经脱除2-萘基甲基(Nap)保护得到白色固体10c(72.0mg,0.032mmol,94%)。其数据如下：
[α]D 25=+43.5°(c1.0,CHCl3)；
1H NMR(600MHz,CDCl3)δ8.09-8.00(m,9H),7.96-7.75(m,11H),7.64-7.60(m,2H),7.55-7.47(m,10H),7.43-7.17(m,23H),5.90(t,J=11.6Hz,1H),5.83(m,2H),5.69-5.62(m,4H),5.54-5.41(m,2H),5.38-5.37(m,2H),4.95(m,1H),4.85-4.75(m,5H),4.66-4.62(m,4H),4.53(dd,J=14.7,6.2Hz,1H),4.17-4.12(m,2H),3.98(t,J=10.2Hz,1H),3.83-3.64(m,5H),3.38(m,1H),2.89(m,1H),2.57-2.22(m,5H),2.01-1.86(m,7H),1.73-1.41(m,11H),1.37(d,J=7.3Hz,3H),1.30-1.26(m,4H),1.02(d,J=8.1Hz,5H),0.92(s,3H),0.84(s,3H),0.78(d,J=7.9Hz,3H);
13C NMR(150MHz,CDCl3)δ212.9,169.9,166.1,166.02,166.00,165.8,165.60,165.61,165.59,165.41,165.35,165.2,165.0,140.1,133.8,133.6,133.4,133.3,133.2,133.1,133.0,132.9,130.9,129.9,129.8,129.7,129.6,129.5,129.4,129.3,128.8,128.7,128.6,128.5,128.4,128.3,128.2,121.8,108.0,101.4,100.7,97.3,82.3,81.4,81.3,80.6,75.7,75.5,75.2,72.9,72.1,72.0,71.9,70.4,70.2,69.8,66.4,65.5,63.7,63.5,63.2,55.0,53.9,49.8,43.4,41.8,39.6,39.1,38.6,36.9,36.5,34.9,32.9,31.7,31.2,30.5,30.0,27.0,21.1,20.7,19.2,17.5,16.63,16.60,13.2;
HR-ESIMS Calcd for C129H128O34Na(M+Na)+:2243.8179,found:2243.8242。
(14)化合物protodioscin11a的制备和数据
将化合物化合物10a(66mg,0.0295mmol)溶于2.00mL1,4-二氧六环和0.60mL水的混合溶液中，加入LiOH·H2O(22.3mg,0.53mmol，18equiv.),在60°C条件下搅拌反应。6小时后，TLC(Toluene:AcOEt=6:1)和(CH2Cl2:MeOH=2:1)显示反应完全。使用Dowex-50(H+)树脂调pH为5-6,过滤、减压浓缩。所得浆状物经高效液相色谱法(流动相为乙腈与水，设定波长为210nm)分离,得到白色固体protodioscin11a(15.1mg,0.0144mmol,49%)。其数据如下：
1H NMR(600MHz,pyridine-d5)δ6.43(s,1H),5.89(s,1H),5.31(d,J=4.4Hz,1H),5.00-4.95(m,3H),4.85-4.83(m,2H),4.70(s,1H),4.66(dd,J=9.2,3.3Hz,1H),4.58-4.55(m,2H),4.42-4.35(m,3H),4.26-4.22(m,4H),4.11-3.86(m,8H),3.71-3.62(m,2H),2.82-2.74(m,2H),1.78(d,J=6.2Hz,3H),1.67(d,J=6.1Hz,3H),1.35(d,J=6.9Hz,3H),1.07(s,3H),0.99(d,J=6.7Hz,3H),0.91(s,3H);
13C NMR(150MHz,pyridine-d5)δ141.2,122.2,111.0,105.3,103.3,102.4,100.7,81.5,79.0,78.9,78.5,78.4,78.2,77.3,75.7,75.6,74.5,74.3,73.2,73.1,72.9,72.1,70.8,69.9,64.2,63.2,61.7,57.0,50.7,41.2,41.1,40.3,39.4,37.9,37.6,37.5,34.7,32.9,32.7,32.1,30.6,28.8,21.5,19.8,19.0,18.9,17.9,16.9;
HRESI-MS Calcd for C51H84O22Na(M+Na)+:1071.5346,found:1071.5361。
(15)化合物coreajaponin A11b的制备和数据
化合物10b(89.0mg,0.040mmol),得到白色固体coreajaponin A11b(26mg,0.025mmol,63%)。
1H NMR(600MHz,pyridine-d5)δ6.28(s,1H),5.29(d,J=4.0Hz,1H),4.98-4.94(m,4H),4.84-4.82(m,2H),4.63(dd,J=9.2,3.3Hz,1H),4.57(dd,J=11.8,2.4Hz,1H),4.53(dd,J=12.1,3.8Hz,1H),4.48-4.35(m,4H),4.29-4.21(m,7H),4.12(dd,J=9.2,3.3Hz,1H),4.05(m,1H),3.96-3.87(m,3H),3.81-3.76(m,2H),3.63(dd,J=9.4,5.9Hz,1H),2.76-2.72(m,2H),1.78(d,J=6.2Hz,3H),1.33(d,J=6.8Hz,3H),1.06(s,3H),0.99(d,J=6.7Hz,3H),0.90(s,3H);
13C NMR(150MHz,pyridine-d5)δ141.1,122.2,111.0,106.3,105.4,102.4,100.4,81.8,81.5,79.0,78.9,78.6,77.9,77.7,76.7,75.6,75.0,74.6,73.2,72.9,72.1,70.0,68.3,64.3,63.2,62.0,57.0,50.7,41.2,41.1,40.3,39.4,37.9,37.6,37.5,34.7,32.9,32.7,32.1,30.6,28.8,21.5,19.8,19.1,17.9,16.9;
HRESI-MS Calcd for C50H82O22Na(M+Na)+:1057.5190,found:1057.5195。
(16)化合物parisaponin I11c的制备和数据
其制备方法类似于化合物11c，化合物3-53(49.0mg,0.022mmol),得到白色固体parisaponin I11c(14mg,0.0135mmol,62%)。
1H NMR(600MHz,pyridine-d5)δ6.30(s,1H),5.94(s,1H),5.30(s,1H),4.97-4.94(m,3H),4.87-4.80(m,5H),4.63(dd,J=9.1,2.9Hz,1H),4.57(d,J=9.9Hz,1H),4.38-4.18(m,12H),4.05(t,J=7.9Hz,1H),3.96-3.88(m,3H),3.78(d,J=8.6Hz,1H),3.63(dd,J=9.2,4.9Hz,1H),2.78-2.73(m,2H),1.78(d,J=6.1Hz,3H),1.33(d,J=6.7Hz,3H),1.06(s,3H),0.99(d,J=6.6Hz,3H),0.90(s,3H);
13C NMR(150MHz,pyridine-d5)δ141.1,122.2,111.0,109.99,105.3,102.3,100.6,87.1,83.1,81.5,79.0,78.9,78.5,78.3,78.1,77.8,77.4,77.1,75.7,75.6,74.5,73.2,72.8,72.1,69.9,64.2,63.2,62.9,56.9,50.7,41.2,41.1,40.3,39.4,37.9,37.6,37.5,34.7,32.9,32.7,32.1,30.6,28.8,21.5,19.8,19.1,17.9,16.8;
HRESI-MS Calcd for C50H82O22Na(M+Na)+:1057.5190,found:1057.5195。
(17)化合物protodioscin11a、coreajaponin11b和parisaponin11c的抗肿瘤活性测试
采用MTT法，以阿霉素作为阳性对照，分别测试了化合物protodioscin11a、coreajaponin11b和parisaponin11c对肿瘤细胞株A-549，Hela和K562的抑制活性，结果如表1所示。Protodioscin11a和parisaponin11c显示了较强的抗肿瘤活性，而coreajaponin11b的抗肿瘤活性较弱。
表1：protodioscin11a、coreajaponin11b和parisaponin11c的抗肿瘤活性（IC50）
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。
Claims (10)
1.呋甾皂苷，其特征在于其结构通式如下式（I）所示：
其中，
虚线表示5，6位之间是单键或双键；
曲线表示22位碳的绝对构型是R或S；
曲线表示25位碳的绝对构型是R或S；
S1是单糖取代基。
2.根据权利要求1所述的呋甾皂苷，其特征在于所述单糖取代基为β-D-吡喃葡萄糖、β-D-吡喃半乳糖、β-D-吡喃甘露糖、α-D-吡喃甘露糖、β-L-吡喃甘露糖、α-L-吡喃甘露糖、β-D-吡喃木糖、β-D-吡喃氨基葡萄糖、α-L-吡喃鼠李糖、α-D-吡喃鼠李糖、β-D-吡喃/呋喃阿拉伯糖、α-D-吡喃/呋喃阿拉伯糖、α-L-吡喃/呋喃阿拉伯糖、β-L-吡喃/呋喃阿拉伯糖、α-L-吡喃岩藻糖、β-D-吡喃葡萄糖醛酸、β-D-吡喃半乳糖醛酸中的一种。
3.根据权利要求1所述的呋甾皂苷，其特征在于所述结构通式中5，6位之间为单键时，5位氢原子位于α-位或β-位。
4.一种如权利要求1所述的呋甾皂苷的合成方法，其特征在于该方法包括如下步骤:
5.如权利要求4所述的呋甾皂苷的合成方法，其特征在于所述的糖苷化条件为在溶剂中和脱水剂的存在下，于-78-150℃，以路易斯酸或质子酸为促进剂，糖基受体与三氯亚胺酯给体反应1-48小时，其中受体与糖基给体以及促进剂的摩尔比为1.0:(1.0-5.0):(0.05-3.0)；受体与脱水剂的质量比为1.0:(3.0-10.0)。
6.如权利要求4或5所述的呋甾皂苷的合成方法，其特征在于所述溶剂是C1-C6的单卤代或多卤代烷烃、1,4-二氧六环、乙醚、乙腈、2,2,2–三甲基乙腈、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷-2-酮、甲苯、三氟甲苯、吡啶、C1-C6的烷基醇类、水中的一种或其混合物。
7.如权利要求4所述的呋甾皂苷的合成方法，其特征在于所述的酰基为C2-C6的直链或支链脂肪族酰基或C6-C10的芳香酰基；优选的是乙酰基、氯乙酰基、三氯乙酰基、特戊酰基、4-羰基戊酰基、2-氯-2-甲基-丙酰基、苯甲酰基、邻叠氮甲基苯甲酰基、2-(2-硝基苯基)-乙酰基；硅基为甲基、乙基、异丙基、叔丁基、苯基构成的三取代硅基，优选的是叔丁基二甲基硅基、叔丁基二苯基硅基。
8.如权利要求4或5所述的呋甾皂苷的合成方法，其特征在于所述的路易斯酸或质子酸是三甲基硅基三氟甲磺酸酯、三乙基硅基三氟甲磺酸酯、叔丁基二甲基硅基三氟甲磺酸酯、三氟化硼乙醚、三氟甲磺酸银、三氟甲磺酸铜、三氟甲磺酸锌、三氟甲磺酸钪、三氟甲磺酸镧、三氟甲磺酸镱、三氟甲磺酸铟、三氟甲磺酸、或高氯酸、四氟硼酸、四(五氟代苯基)硼酸、二(三氟甲磺酰)亚胺、三氟乙酸、甲酸、乙酸、SiO2-H2SO4、SiO2-HClO4、SiO2-HOTf中的一种或其混合物。
9.如权利要求5所述的呋甾皂苷的合成方法，其特征在于所述的脱水剂是
、
、
分子筛或AW-300分子筛或无水硫酸钠、无水硫酸钙、无水硫酸铜、无水硫酸镁中的一种或者它们的混合物。
10.如权利要求4所述的呋甾皂苷的合成方法，其特征在于所述的碱指氢氧化物、氢化物或碳酸盐或叔丁醇钾、叔丁醇钠、叔丁基锂、甲醇钠、乙醇钠、甲氧基镁、吡啶、4-N,N-二甲基吡啶、2,6-二甲基吡啶、2,4,6-三甲基吡啶、四丁基氟化铵中的一种或其混合物。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037480A (zh) * | 2015-06-24 | 2015-11-11 | 中国海洋大学 | 呋甾皂苷及其作为α-糖苷酶抑制剂在抗糖尿病药物中的应用 |
| CN105175478A (zh) * | 2015-09-16 | 2015-12-23 | 华东师范大学 | 表雄酮和去氢表雄酮糖基化衍生物及其制备方法和应用 |
| CN112094310A (zh) * | 2020-09-01 | 2020-12-18 | 南京师范大学 | 硫代糖苷键甾醇糖苷和硫代糖苷键甾烷醇糖苷及其制备方法和应用 |
| WO2023245847A1 (zh) * | 2022-06-22 | 2023-12-28 | 中山大学 | 一种硼酸类小分子化合物在制备增强免疫检查点抑制剂疗效及治疗白血病药物中的应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1763076A (zh) * | 2005-09-22 | 2006-04-26 | 中国科学院上海有机化学研究所 | 呋甾皂苷及其衍生物的化学合成方法 |
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| CN1763076A (zh) * | 2005-09-22 | 2006-04-26 | 中国科学院上海有机化学研究所 | 呋甾皂苷及其衍生物的化学合成方法 |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037480A (zh) * | 2015-06-24 | 2015-11-11 | 中国海洋大学 | 呋甾皂苷及其作为α-糖苷酶抑制剂在抗糖尿病药物中的应用 |
| CN105175478A (zh) * | 2015-09-16 | 2015-12-23 | 华东师范大学 | 表雄酮和去氢表雄酮糖基化衍生物及其制备方法和应用 |
| CN112094310A (zh) * | 2020-09-01 | 2020-12-18 | 南京师范大学 | 硫代糖苷键甾醇糖苷和硫代糖苷键甾烷醇糖苷及其制备方法和应用 |
| CN112094310B (zh) * | 2020-09-01 | 2022-05-03 | 南京师范大学 | 硫代糖苷键甾醇糖苷和硫代糖苷键甾烷醇糖苷及其制备方法和应用 |
| WO2023245847A1 (zh) * | 2022-06-22 | 2023-12-28 | 中山大学 | 一种硼酸类小分子化合物在制备增强免疫检查点抑制剂疗效及治疗白血病药物中的应用 |
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