CN106632518A - 一种鬼臼毒素4‑oh衍生物的制备方法 - Google Patents
一种鬼臼毒素4‑oh衍生物的制备方法 Download PDFInfo
- Publication number
- CN106632518A CN106632518A CN201710034089.7A CN201710034089A CN106632518A CN 106632518 A CN106632518 A CN 106632518A CN 201710034089 A CN201710034089 A CN 201710034089A CN 106632518 A CN106632518 A CN 106632518A
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- Prior art keywords
- podophyllotoxin
- derivants
- preparation
- base
- glycosyl
- Prior art date
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- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 title claims abstract description 46
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229960001237 podophyllotoxin Drugs 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 230000004224 protection Effects 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 238000006206 glycosylation reaction Methods 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims abstract 2
- -1 glycosyl alkynes ester Chemical class 0.000 claims description 33
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- 239000002808 molecular sieve Substances 0.000 claims description 12
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- 238000000034 method Methods 0.000 claims description 9
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 7
- 239000002274 desiccant Substances 0.000 claims description 7
- 125000003147 glycosyl group Chemical group 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
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- 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 claims description 4
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- 229910019032 PtCl2 Inorganic materials 0.000 claims description 2
- 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 2
- HMFHBZSHGGEWLO-AIHAYLRMSA-N alpha-D-ribose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-AIHAYLRMSA-N 0.000 claims description 2
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- 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
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- AEMOLEFTQBMNLQ-DTEWXJGMSA-N beta-D-galacturonic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-DTEWXJGMSA-N 0.000 claims description 2
- 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 2
- HMFHBZSHGGEWLO-TXICZTDVSA-N beta-D-ribose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-TXICZTDVSA-N 0.000 claims description 2
- 125000003404 beta-D-xylosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 claims description 2
- SHZGCJCMOBCMKK-KGJVWPDLSA-N beta-L-fucose Chemical compound C[C@@H]1O[C@H](O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-KGJVWPDLSA-N 0.000 claims description 2
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- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 claims description 2
- RJHLTVSLYWWTEF-UHFFFAOYSA-K gold trichloride Chemical compound Cl[Au](Cl)Cl RJHLTVSLYWWTEF-UHFFFAOYSA-K 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
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- 230000035484 reaction time Effects 0.000 claims description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical group CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 2
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-FCAWWPLPSA-N beta-L-ribose Chemical compound OC[C@@H]1O[C@H](O)[C@@H](O)[C@H]1O HMFHBZSHGGEWLO-FCAWWPLPSA-N 0.000 claims 1
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- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
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- 239000010703 silicon Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
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Abstract
一种鬼臼毒素4‑OH衍生物的制备方法，将化合物2和化合物3进行糖苷化反应，即可制得鬼臼毒素4‑OH衍生物1；其中，R1为本领域常用的羟基保护基，所述的保护基为苄基，叔丁基二甲基硅基,甲基的一种；NuH为具有亲核性的羟基，氨基，烷基，烯基或炔基中的一种，可适用于鬼臼毒素4‑OH衍生物的制备，且反应条件温和，绿色环保，产物的产率和纯度均较高。
Description
技术领域
本发明涉及化学领域，尤其涉及一种鬼臼毒素4-OH衍生物的制备方法。
背景技术
木质素类广泛存在于植物王国之中，作为二级代谢产物来源于苯丙素的氧化二聚，按照传统的分类方法木质素类化合物可以分成两大类，一类是经典木质素类即分子内含有β-β’(8-8’)连接的木质素类化合物，另一类是新型木质素类即结构中不含β-β’连接的苯丙素的二聚体，其中经典类木质素可以进一步细分为芳基四氢萘类(aryltetralinlignin)、二苄基丁烷类(dibenzylbutane lignan)、芳基萘类(arylnaphthalene lignan)及二苯并环辛二烯类(dibenzocyclooctadiene lignan)，生物活性测试显示木质素类化合物具有非常好的药用活性，主要包括抗肿瘤、抗感染、免疫抑制、心脑血管保护、抗氧化及抗病毒等，最为著名的木质素类化合物当属鬼臼毒素，早期临床试验发现鬼臼毒素确实对肿瘤的治疗非常高效，但遗憾的是其毒副作用太大，从而限制了其作为抗肿瘤药物使用，而鬼臼毒素4-OH进行衍生化后不仅提高了所需活性，而且毒副作用也大大降低。例如依托泊苷，替尼泊苷，NK-611等，[Botta,B.；Delle Monache,G.；Misiti,D.；Vitali,A.；Zappia,G.Curr.Med.Chem.2001,8,1363]。
其中鬼臼毒素4-OH(1-O-[2-脱氧-2-(二甲氨基)-4:6-O-亚乙基-D-吡喃葡萄糖基]-4'-去甲基-L-表鬼臼毒素)是一种活性非常好的抗肿瘤药物，已经处于临床二期，具有非常好的药用前景[Invest New Drugs,1998,16,319]，然而鬼臼毒素4-OH的衍生化是化学领域的难点，主要是由于该羟基处于富电子苯环的苄位，非常活泼，目前只有少数几位化学家完成了鬼臼毒素及其衍生物4-O-糖苷的合成[(a)Helv.Chim.Acta.1968,51,163,Helv.Chim.Acta.1968,51,1631.(b)Tetrahedron Lett.1991,32,1653(c)TetrahedronLett.1992,33,4831.(d)J.Org.Chem.1993,58,4175.(e)Eur.J.Med.Chem.2012,47,424.]，但这几种方法均具有产率低，构型不易控制，毒性较大等缺点，我们课题组在前期已经探索了利用鬼臼毒素4-OH与糖基炔酯给体制备糖基4-O-糖苷的方法[Org.Lett.2016,18,1294]，但是此方法只能用于合成4-O-糖苷类似物，而对于4-位N,C-等其他取代则无能为力，因此本发明主要提供一种鬼臼毒素及其类似物4-位炔酯给体与亲核试剂进行反应制备4-O-糖苷以及NK-611的方法，该方法不仅能用于合成4-O-糖苷键，而对于其他4-OH被N,C-等取代的类似物也可以高效地合成。
发明内容
本发明的目的在于提供一种鬼臼毒素4-OH衍生物的制备方法，解决了鬼臼毒素及其类似物4-OH被糖基、氨基、碳及烯烃等取代的化合物合成方法缺点大的问题。
所述鬼臼毒素4-OH全名为1-O-[2-脱氧-2-(二甲氨基)-4:6-O-亚乙基-D-吡喃葡萄糖基]-4'-去甲基-L-表鬼臼毒素。
本发明的制备方法可适用于鬼臼毒素4-OH衍生物的制备，且反应条件温和，绿色环保，产物的产率和纯度均较高。
本发明是这样实现的，它包含下列步骤：
将鬼臼毒素类糖基炔酯给体2和亲核试剂3进行糖苷化反应，即可制得鬼臼毒素4-OH衍生物1；
其中，R1为本领域常用的羟基保护基，所述的保护基为苄基(Bn，Cbz)，叔丁基二甲基硅基(TBS),甲基的一种；
NuH为具有亲核性的羟基，氨基，烷基，烯基或炔基中的一种，当NuH为糖基羟基时，所述的糖基包括β-D-葡萄糖基、α-D-葡萄糖基、β-D-半乳糖基、α-D-半乳糖基、β-D-甘露糖基、α-D-甘露糖基、β-D-木糖基、α-D-木糖基、β-D-2-氨基葡萄糖基、α-D-2-氨基葡萄糖基、α-L-鼠李糖基、β-L-鼠李糖基、α-D-核糖基、β-D-核糖基、α-L-核糖基、β-L-核糖基、α-D-阿拉伯糖基、β-D-阿拉伯糖基、α-L-阿拉伯糖基、β-L-阿拉伯糖基、α-L-岩藻糖基、β-L-岩藻糖基、β-D-葡萄糖醛酸基、α-D-葡萄糖醛酸基、β-D-半乳糖醛酸基、或者α-D-半乳糖醛酸基；
本发明中，所述的制备的鬼臼毒素4-OH衍生物的方法包含下列步骤：在有机溶剂中、在干燥剂存在下、惰性气体保护下，在亲炔基路易斯酸的作用下，将鬼臼毒素类糖基炔酯给体2和亲核试剂3进行糖苷化反应，直到反应完全为止；
所述的有机溶剂为干燥的二氯甲烷、甲苯、硝基甲烷和乙腈中的一种或多种。
所述的亲炔基路易斯酸为AuCl、AuCl3、AuLOTf、AuLNTf2、HgOTf和PtCl2中的一种或多种，其中，L为本领域常规的膦配体。
所述的膦配体为三丁基膦、三乙基膦、三苯基膦或三金刚烷基膦。
所述的亲炔基路易斯酸的用量为化合物2的摩尔量的0.2～0.3倍。
所述的糖苷化反应的温度为25～35℃。
所述的糖苷化反应时间为1～4小时。
所述的干燥剂的用量为鬼臼毒素类糖基炔酯给体2的摩尔量的1.0～4.0倍；所述的干燥剂为分子筛、分子筛、分子筛、酸洗的分子筛、酸洗的分子筛、酸洗的分子筛、无水硫酸钠、无水硫酸钙、无水硫酸铜和无水硫酸镁中的一种或多种。
本发明的技术效果是：可适用于鬼臼毒素4-OH衍生物的制备，且反应条件温和，绿色环保，产物的产率和纯度均较高。
具体实施方式
下面将结合实施例1-16详细说明本发明所具有的有益效果，旨在帮助阅读者更好地理解本发明的实质，但不能对本发明的实施和保护范围构成任何限定。
下述各实施例中涉及到的室温均为20～35℃。
实施例1
表鬼臼毒素4-O(甲基2,3,4-三-O-苯甲酰基-α-D-吡喃葡萄糖)表鬼臼毒素糖苷的制备，
步骤1:
鬼臼毒素4-O-邻环丙基乙炔基苯甲酸酯给体的合成：
在氮气保护下，将鬼臼毒素3.5g，8.5mmol及邻炔基苯甲酸2.4g12.75mmol溶于干燥的10mLDCM溶液中,然后加入DMAP(1.58g，12.75mmol)和DCC(3.5g，17.02mmol)，室温搅拌2小时，此时TLC显示所有起始原料消失，加入DCM(40mL)稀释反应混合物，所得溶液依次用水和饱和盐水洗涤，蒸发并减压浓缩，得到残余物，将其通过硅胶色谱法(洗脱剂系统：PE：EA＝3:1)进一步纯化,得到呈白色固体的(4.8g，97％)，[α]D 25＝-169.1(c 1,CHCl3)；1H NMR(400MHz,CDCl3)δ7.88(dd,J＝1.2,8.0Hz,1H),7.51-7.43(m,2H),7.35(dt,J＝1.6,7.6Hz,1H),6.95(s,1H),6.57(s,1H),6.46(s,2H),6.20(d,J＝8.0Hz,1H),5.98(dd,J＝1.6,3.6Hz,2H),4.65(d,J＝4.0Hz,1H),4.54(dd,J＝6.0,8.8Hz,1H),4.36(t,J＝8.8Hz,1H),3.79(s,3H),3.77(s,6H),3.12-3.06(m,1H),3.03(dd,J＝4.0,14.4Hz,1H),1.29-1.24(m,1H),0.85-0.79(m,2H),0.78-0.72(m,2H)；13C NMR(100MHz,CDCl3)δ173.3,166.6,152.2,147.7,147.2,136.6,134.4,134.0,132.0,131.5,130.8,129.4,128.0,126.8,124.1,109.3,107.5,107.1,101.2,99.2,73.9,73.7,71.1,60.3,55.7,45.2,43.4,38.3,8.34；HRMS(ESI)calcd for C34H31O9[M+H]+583.19626found 583.19679；
步骤2：
表鬼臼毒素4-O(甲基2,3,4-三-O-苯甲酰基-α-D-吡喃葡萄糖)表鬼臼毒素糖苷的制备，
在氮气保护下,将甲基2,3,4-三-O-苯甲酰基-α-D-吡喃葡萄糖基(30mg，0.05mmol)和鬼臼毒素4-O-邻-环丙基乙炔基苯甲酸酯给体(30mg，0.06mmol)溶解于干燥的的CH2Cl2(2mL)溶液中并加入加入将所得混合物在室温下搅拌30分钟，然后加入Ph3PAuNTf2(11mg，0.015mmol)，在室温下继续搅拌4小时(直到通过TLC监测)，将混合物过滤，将滤液在减压下浓缩，得到残余物，将其通过硅胶柱色谱法(石油醚/乙酸乙酯3:1)进一步纯化，得到白色固体41mg，92％，[α]D 25＝+7.0(c 1.05,CHCl3)；1H NMR(400MHz,CDCl3)δ7.90(dd,J＝1.2,8.0Hz,2H),7.87(dd,J＝1.2,8.0Hz,2H),7.78(dd,J＝1.2,8.0Hz,2H),7.47-7.39(m,2H),7.34-7.26(m,5H),7.21-7.17(m,2H),6.68(s,1H),6.42(s,1H),6.15(s,2H),6.09(t,J＝10.0Hz,1H),5.87(d,J＝1.6Hz,1H),5.81(d,J＝1.6Hz,1H),5.51(t,J＝9.6Hz,1H),5.20(dd,J＝3.6,10.0Hz,1H),5.14(d,J＝3.6Hz,1H),4.50(dd,J＝8.8,10.8Hz,1H),4.47(d,J＝1.6Hz,1H),4.36(d,J＝3.2Hz,1H),4.34(t,J＝8.0Hz,1H),4.12-4.08(m,1H),3.82(dd,J＝2.4,10.4Hz,1H),3.70(s,3H),3.64(s,6H),3.62(dd,J＝4.8,10.4Hz,1H),3.38(dd,J＝5.2,14.0Hz,1H),3.35(s,3H),2.85-2.76(m,1H)；13C NMR(100MHz,CDCl3)δ173.9,164.7(2C),164.3,151.4,147.4,145.5,136.1,134.4,132.5,132.3,132.0,131.5,128.8,128.7,128.6,128.1,127.9,127.8,127.4(2C),127.3,127.2,110.0,108.4,107.2,100.4,96.0,74.4,70.9,69.3,68.6,68.0,66.5,59.6,55.2,54.6,43.0,39.9,37.3。
实施例2
表鬼臼毒素4-O(甲基2,3,4-三-O-苯甲酰基-α-D-吡喃葡萄糖)表鬼臼毒素糖苷的制备，
步骤1：
如实施例1的步骤1所示，[α]D 25＝-50.8(c 1,CHCl3)；1H NMR(400MHz,CDCl3)δ7.89(dd,J＝1.2,8.0Hz,1H),7.49(dd,J＝1.6,8.0Hz,1H),7.45(td,J＝1.6,7.2Hz,1H),7.33(td,J＝1.6,8.0Hz,1H),7.00(s,1H),6.58(s,1H),6.46(d,J＝3.6Hz,1H),6.32(s,2H),6.00(d,J＝1.2Hz,1H),5.96(d,J＝1.6Hz,1H),4.72(d,J＝5.2Hz,1H),4.45(dd,J＝8.0,8.8Hz,1H),4.17(dd,J＝8.8,10.8Hz,1H),3.82(s,3H),3.76(s,6H),3.53(dd,J＝4.8,14.0Hz,1H),3.14-3.07(m,1H),1.40-1.36(m,1H),0.92-0.89(m,2H),0.81-0.73(m,2H)；13CNMR(100MHz,CDCl3)δ174.0,165.9,152.3,148.5,147.1,137.0,134.3(2C),132.6,131.7,130.4,130.2,127.5,126.9,124.1,109.7,109.5,107.8,101.2,99.3,76.8,74.3,68.6,67.4,60.4,55.9,43.6,41.5,36.6,8.54,8.50；HRMS(ESI)calcd for C34H31O9[M+H]+583.19626found 583.19683；
步骤2：
如实施例1的步骤2所示。
实施例3
表鬼臼毒素4-O(甲基2,3,4-三-O-苄基-α-D-吡喃葡萄)表鬼臼毒素糖苷的制备，
步骤1：
同实施例1中的步骤2所示，得到淡黄色的表鬼臼毒素4-O(甲基2,3,4-三-O-苄基-α-D-吡喃葡萄)表鬼臼毒素糖苷41mg,收率95％，[α]D 25＝-19.8(c 1,CHCl3)；1H NMR(400MHz,CDCl3)δ7.40-7.23(m,15H),6.81(s,1H),6.52(s,1H),6.22(s,2H),6.00(d,J＝1.6Hz,1H),5.95(d,J＝1.6Hz,1H),5.01(d,J＝10.8Hz,1H),4.90(d,J＝11.2Hz,1H),4.83(d,J＝12.0Hz,1H),4.82(d,J＝10.4Hz,1H),4.68(d,J＝12.4Hz,1H),4.57(d,J＝4.4Hz,1H),4.56(d,J＝1.2Hz,1H),4.55(d,J＝11.2Hz,1H),4.35(d,J＝3.2Hz,1H),4.32-4.24(m,2H),4.01(t,J＝9.2Hz,1H),3.79(s,3H),3.75(m,1H),3.73(s,6H),3.71(m,1H),3.61-3.51(m,1H),3.43-3.31(m,2H),3.34(s,3H),2.85-2.76(m,1H)；13C NMR(100MHz,CDCl3)δ175.0,152.5,148.4,146.7,138.6,138.2,138.1,137.2,135.4,132.5,129.0,128.5(2C),128.4,128.2,128.1(2C),128.0(3C),127.9,127.7,127.6,110.7,109.8,108.3,101.5,98.0,82.0,80.2,77.8,75.8,75.4,74.9,73.5,70.6,69.5,67.5,60.8,56.3,55.3,43.9,41.0,38.5；HRMS(ESI)calcd for C50H52O13Na[M+Na]+883.33001 found 883.33188。
实施例4
表鬼臼毒素4-O(甲基-2,3-二-O-苯甲酰基-6-O-苄基-α-D-葡萄)表鬼臼毒素糖苷的制备，
步骤1、2同实施例1中步骤1和2所示，得到化合物41.2mg,93％的收率，[α]D 25＝-25.3(c 1.2,CHCl3)；1H NMR(400MHz,CDCl3)δ7.90(m,2H),7.60(dd,J＝1.2,8.0Hz,2H),7.48-7.40(m,4H),7.37-7.24(m,7H),6.81(s,1H),6.03(s,2H),5.86(d,J＝1.2,1H),5.82(d,J＝1.6Hz,1H),5.69(dd,J＝9.2,10.0Hz,1H),5.60(s,1H),5.25(dd,J＝3.6,10.0Hz,1H),5.15(d,J＝4.0Hz,1H),5.02(d,J＝12.0Hz,1H),4.55(d,J＝12.0Hz,1H),4.34(t,J＝9.6Hz,1H),4.18-4.10(m,3H),3.90-3.87(m,1H),3.80-3.73(m,2H),3.77(s,3H),3.72(s,6H),3.68(dd,J＝2.4,11.2Hz,1H),3.44(dd,J＝5.6,14.0Hz,1H),3.41(s,3H),2.41-2.32(m,1H)；13C NMR(100MHz,CDCl3)δ175.1,165.9,165.2,152.3,147.9,146.1,137.1,136.8,135.9,133.3,132.8,132.3,129.8,129.2(2C),129.1,129.0,128.6,128.5,128.4,127.9,111.0,109.5,108.4,101.2,97.2,74.2,71.8,71.4,71.3,71.1,70.3,67.2,66.8,60.7,56.3,55.5,43.7,39.6,38.1。
实施例5
1,2；5,6-二异亚丙基-3-O-鬼臼毒素-α-D-吡喃葡萄糖基和1,2；5,6-二异亚丙基-3-O-表鬼臼毒素-α-D-吡喃葡萄糖基的制备，
同实施例1中步骤1和2所示，得到两种化合物PPT和EPPT62.3mg(PPT:EPPT＝1.6：1)[α]D 25＝-80.3(c 1.26,CHCl3)；1H NMR(400MHz,CDCl3)δ6.87(s,1H),6.54(s,1H),6.25(s,2H),6.00(d,J＝1.6Hz,1H),5.99(d,J＝3.6Hz,1H),5.98(d,J＝3.6Hz,1H),4.60(d,J＝4.8Hz,1H),4.59(d,J＝3.6Hz,1H),4.54(d,J＝3.2Hz,1H),4.44(dd,J＝8.4,10.8Hz,1H),4.36(t,J＝8.0Hz,1H),4.27-4.22(m,2H),3.85(dd,J＝2.0,10.0Hz,1H),3.80(s,3H),3.74(s,6H),3.72-3.61(m,2H),3.45(dd,J＝5.2,14.0Hz,1H),2.91-2.82(m,1H)；1.49(s,3H),1.39(s,3H),1.36(s,3H),1.33(s,3H)；13C NMR(100MHz,CDCl3)δ175.1,152.5,148.5,146.7,137.2,135.5,132.4,129.0,112.3,110.8,109.7,108.3,106.4,101.5,101.1,84.0,79.5,75.0(2C),71.9,70.7,67.5,60.7,56.3,43.9,40.9,38.4,27.2,26.5,24.0；HRMS(ESI)calcd for C34H41O13[M+H]+657.25417 found 657.25374.For the polar EPPT-17:[α]D 25＝-58.2(c 0.9,CHCl3)；1H NMR(400MHz,CDCl3)δ6.98(s,1H),6.55(s,1H),6.22(s,2H),6.00(d,J＝3.6Hz,1H),5.98(d,J＝1.2Hz,1H),5.90(d,J＝4.0Hz,1H),4.73(d,J＝2.8Hz,1H),4.61(d,J＝5.6Hz,1H),4.57(d,J＝3.6Hz,1H),4.39(t,J＝8.0Hz,1H),4.31(dd,J＝8.4,10.8Hz,1H),4.21(d,J＝2.8Hz,1H),4.13-4.06(m,2H),4.03(dd,J＝5.6,8.4Hz,1H),3.95(dd,J＝4.4,5.2Hz,1H),3.80(s,3H),3.74(s,6H),3.52(dd,J＝5.6,14.0Hz,1H),3.00-2.91(m,1H),1.52(s,3H),1.35(s,3H),1.32(s,3H),1.26(s,3H)；13C NMR(100MHz,CDCl3)δ174.7,152.6,148.6,146.7,137.3,135.4,133.0,128.0,112.2,111.0,110.0,109.0,108.3,105.3,101.5,82.8,81.3,80.0,73.3,72.3,67.4,67.2,60.7,56.3,44.0,40.6,38.4,26.8,26.6,26.3,25.1,24.7；HRMS(ESI)calcd for C34H41O13[M+H]+657.25417 found 657.25318。
实施例6
表鬼臼毒素4-O胆固醇的制备，
同实施例1中步骤1和2所示，得到化合物56.4mg，收率100％。[α]D 25＝-56.8(c 1,CHCl3)；1H NMR(400MHz,CDCl3)δ6.84(s,1H),6.51(s,1H),6.27(s,2H),6.00(d,J＝1.2Hz,1H),5.95(d,J＝1.2Hz,1H),5.39(d,J＝5.2Hz,1H),4.65(d,J＝3.2Hz,1H),4.60(d,J＝5.2Hz,1H),4.40(t,J＝8.0Hz,1H),4.26(dd,J＝8.4,11.2Hz,1H),3.80(s,3H),3.73(s,6H),3.39(dd,J＝5.2,14.0Hz,1H),3.28-3.22(m,1H),2.88-2.80(m,1H),2.38-2.26(m,2H),2.07-1.79(m,5H),1.68-1.42(m,8H),1.37-1.22(m,5H),1.01(s,3H),0.93(d,J＝6.4Hz,3H),0.88(d,J＝1.6Hz,3H),0.86(d,J＝2.0Hz,3H),0.68(s,3H)；13C NMR(100MHz,CDCl3)δ175.0,152.6,148.2,147.1,140.3,137.2,135.3,132.2,130.5,122.2,110.4,109.3,108.3,101.4,79.2,71.3,67.8,60.7,56.8,56.3,56.2,50.2,43.9,42.4,41.2,39.8,39.5,39.4,38.5,37.2,36.9,36.2,35.8,31.9(2C),29.7,29.4,28.2,28.0,24.3,23.8,22.8,22.6,21.1,19.4,18.7,11.9；HRMS(ESI)calcd for C49H67O8[M+H]+783.48305found 783.48235。
实施例7
表鬼臼毒素4-O-(2-O-苯甲酰基-3,4,6-三-O-苄基-α/β-D-葡萄糖)表鬼臼毒素糖苷的制备，
同实施例1中步骤1和2所示，得到化合物81mg收率85％(α：β＝6:1)，[α]D 25＝+54.2(c 0.63,CHCl3)；1H NMR(400MHz,CDCl3)δ8.00(dd,J＝1.2,8.0Hz,2H),7.62-7.57(m,1H),7.48(t,J＝7.6Hz,2H),7.42-7.31(m,5H),7.27-7.25(m,3H),7.20-7.07(m,7H),6.49(s,1H),6.21(s,2H),5.96(d,J＝1.6Hz,1H),5.92(d,J＝1.2Hz,1H),5.34(d,J＝4.0Hz,1H),5.28(dd,J＝3.6,10.0Hz,1H),4.80-4.70(m,5H),4.63(d,J＝5.2Hz,1H),4.59(d,J＝12.0Hz,1H),4.46(d,J＝10.4Hz,1H),4.23(dd,J＝4.4,10.8Hz,1H),4.08(t,J＝9.6Hz,1H),4.01(t,J＝J＝8.0Hz,1H),3.84(t,J＝9.2Hz,1H),3.79(s,3H),3.71(s,6H),3.68-3.60(m,3H),3.45(dd,J＝5.6,14.0Hz,1H),2.86-2.77(m,1H)；13C NMR(100MHz,CDCl3)δ174.6,165.7,152.6,148.5,147.0,137.9(2C),137.6,137.3,135.1,133.8,132.5,129.6,129.0,128.9,128.8,128.5,128.4,128.3,128.2,128.0,127.9,127.8(2C),127.7,110.6,110.3,108.3,101.5,98.6,79.7,77.9,76.0,75.6,75.5,73.8,73.7,71.4,68.0,66.6,60.7,56.3,43.9,40.9,38.3；HRMS(ESI)calcd for C56H54O14Cl[M+Cl]-985.31966 found985.32226。
实施例8
表鬼臼毒素-2-O-苯甲酰基-3-O-苄基-4,6-O-亚苄基-α/β-D-葡萄糖苷的制备，
同实施例1中步骤1和2所示，得到化合物70.3mg，收率82％(α：β＝1.25:1)，[α]D 25＝+32.9(c 0.87,CHCl3)；1H NMR(400MHz,CDCl3)δ7.99(dd,J＝1.2,8.4Hz,2H),7.79(dd,J＝1.2,8.4Hz,1.6H),7.64-7.36(m,14.4H),7.23-7.09(m,9H),6.94(s,1H),6.66(s,0.8H),6.52(s,1H),6.27(s,0.8H),6.21(s,2H),6.13(s,1.6H),5.984(d,J＝1.6Hz,1H),5.976(d,J＝1.2Hz,1H),5.87(d,J＝1.6Hz,0.8H),5.69(d,J＝1.6Hz,0.8H),5.64(s,0.8H),5.60(s,1H),5.40(d,J＝3.6Hz,1H),5.26(dd,J＝7.2,9.2Hz,1H),5.25(dd,J＝4.0,9.2Hz,0.8H),4.89-4.80(m,3H),4.75-4.69(m,2.8H),4.66(d,J＝5.2Hz,1H),4.47-4.39(m,1.6H),4.32(d,J＝5.2Hz,0.8H),4.26(t,J＝8.0Hz,0.8H),4.20-4.06(m,3H),3.97(t,J＝8.0Hz,1H),3.91-3.79(m,4H),3.78(s,3H),3.76(s,2.4H),3.71(s,6H),3.69(s,4.8H),3.58-3.50(m,1H),3.42(dd,J＝5.2,14.0Hz,1H),3.16(dd,J＝5.6,14.0Hz,0.8H),2.86-2.76(m,1.8H)；13C NMR(100MHz,CDCl3)δ174.5(2C),165.8,164.9,152.6,152.5,148.6,148.4,146.9,146.6,137.9,137.8,137.3,137.2,137.1,137.0,135.2,135.1,133.9,132.9,132.6,129.7,129.6,129.5,129.2,129.1,128.8(2C),128.3(3C),128.2(2C),128.0,127.9,127.8,127.7,127.6,126.0,125.9,110.8,110.5,109.9,108.7,108.3,108.2,101.6,101.4,101.3(2C),100.0,99.1,82.2,81.7,75.4,74.8,73.9,73.8,73.4,68.6,68.5,67.6,66.5,66.4,63.1,60.7(2C),56.3,43.9,43.7,40.8,40.7,38.2,37.6；HRMS(ESI)calcd forC49H47O14[M+H]+859.29603 found 859.29484。
实施例9
表鬼臼毒素-4-O-金刚烷基的制备，
同实施例1中步骤1和2所示，得到化合物44.4mg,收率81％，[α]D 25＝-53.2(c1.26,CHCl3)；1H NMR(400MHz,CDCl3)δ6.96(s,1H),6.48(s,1H),6.25(s,2H),5.98(d,J＝1.6Hz,1H),5.94(d,J＝1.2Hz,1H),4.93(d,J＝3.6Hz,1H),4.59(d,J＝5.6Hz,1H),4.38(dd,J＝8.0,10.8Hz,1H),4.28(t,J＝8.0Hz,1H),3.80(s,3H),3.74(s,6H),3.41(dd,J＝5.2,13.6Hz,1H),2.84-2.75(m,1H),2.22(bs,3H),1.86(s,6H),1.71(q,J＝12.0Hz,6H)；13CNMR(100MHz,CDCl3)δ175.3,152.5,147.7,146.9,137.2,135.6,132.6,131.9,110.4,109.6,108.4,101.3,74.7,69.0,64.8,60.7,56.3,43.9,43.4,41.1,38.5,36.2,30.8。
实施例10
甲基-N-二苯基亚甲基-L-(4-O-表鬼臼毒素)苯基丙氨酸的制备，
同实施例1中步骤1和2所示，得到化合物70.2mg,收率93％，[α]D 25＝-124(c 1.26,CHCl3)；1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.8Hz,2H),7.42-7.29(m,6H),7.02(d,J＝8.4Hz,2H),6.78(d,J＝8.8Hz,2H),6.70(d,J＝7.2Hz,2H),6.64(s,1H),6.57(s,1H),6.30(s,2H),5.96(d,J＝1.2Hz,1H),5.92(d,J＝1.2Hz,1H),5.40(d,J＝3.6Hz,1H),4.69(d,J＝5.2Hz,1H),4.35(t,J＝8.0Hz,1H),4.28(dd,J＝4.4,9.2Hz,1H),4.13(dd,J＝8.4,10.8Hz,1H),3.81(s,3H),3.74(s,9H),3.46(dd,J＝5.2,14.0Hz,1H),3.27(dd,J＝4.4,13.6Hz,1H),3.20(m,1H),3.08-3.00(m,1H)；13C NMR(100MHz,CDCl3)δ174.5,172.2,170.9,157.0,152.7,148.8,147.2,139.3,137.3,136.0,134.8,132.4,132.2,131.7,131.3,130.4,130.0,128.8(2C),128.6,128.3,128.2,128.1,127.6,115.7,110.2,109.3,108.2,101.6,73.4,67.5,67.3,60.8,56.3,52.3,43.8,41.6,38.9,38.1；HRMS(ESI)calcd forC45H41NO10Na[M+Na]+778.26227found778.26218。
实施例11
表鬼臼毒素4-O-雌酚酮的制备，
同实施例1中步骤1和2所示，得到化合物55.3mg,收率83％，[α]D 25＝-42.2(c 1.1,CHCl3)；1H NMR(400MHz,CDCl3)7.24-7.22(d,J＝8.4Hz,2H),6.76-6.72(m,2H),6.70-6.68(M,1H),6.57(s,1H),6.32(s,2H),5.98(d,J＝1.6 1Hz 1H),5.94(d,J＝1.6 1H),5.46(d,J＝3.6Hz 1H),4.7(d,J＝4.8Hz,1H),4.36-4.30(t,J＝8.0Hz,1H),4.18-4.10(dd,J＝8.4,10.8Hz,1H),3.8-3.78(t,4H),3.7(s,6H),3.48-3.42(dd,J＝4.8,10.0Hz,1H),3.1.-3.02(m,1H),2.92-2.88(m,2H),2.56-2.48(m,1H),2.44-2.38(m,1H),2.30-2.22(m,1H),2.20-1.94(m,4H),1.7-1.42(m,7H)；13C NMR(100MHz,CDCl3)δ174.6,156.3,152.6,148.7,147.2,138.4,137.3,134.8,133.5,132.2,128.9,126.7,115.9,112.8,110.1,109.3,108.2,101.5,77.2,72.7,67.7,60.77,56.30,50.42,47.9,44.0,43.8,41.6,38.2,35.8,31.5,29.6,26.4,25.8,21.6,13.8。
实施例12
4-氟-苯胺-鬼臼毒素和4-氟-苯胺-表鬼臼毒素的制备，
同实施例1中步骤1和2所示，得到化合物50.7mg，收率100％,(EPPT/PPT＝5:1)。[α]D 25＝-104.4(c 0.66,CHCl3)；1H NMR(400MHz,CDCl3)δ7.15(s,0.25H),6.96-6.89(m,2.5H),6.76(s,1H),6.71(dd,J＝4.0,8.8Hz,0.5H),6.53(s,0.25H),6.52(2 1H),6.50(dd,J＝4.0,8.8Hz,2H),6.38(s,0.5H),6.32(s,2H),5.96-5.93(m,2.5H),4.64-4.58(m,2.5H),4.40(t,J＝8.0Hz,1H),4.26(dd,J＝7.2,8.8Hz,0.25H),4.01(dd,J＝8.4,10.4Hz,1.25H),3.80(s,3.75H),3.77(s,1.5H),3.75(s,6H),3.18(dd,J＝4.8,14.0Hz,1H),3.04-2.95(m,1H),2.91(dd,J＝4.8,14.0Hz,0.25H),2.75-2.65(m,0.25H),1.26(s,1.25H)；13C NMR(100MHz,CDCl3)δ174.7,174.3,157.3,155.0,152.6(2C),148.3,147.7,147.6,143.8,137.5,137.3,135.7,135.1,131.7,131.5,130.6,129.0,128.2,125.3,116.3,116.2,116.1,116.0,113.1,113.0,110.1,116.2,116.1,116.0,113.1,113.0,110.1,109.9,109.1,108.7,108.4,106.9,101.6,101.4,71.2,68.8,60.7,56.4,56.3,53.3,46.4,44.0,43.6,41.8,38.7。
实施例13
4-脱氧-4-烯丙基-表鬼臼毒素的制备，
步骤1：
在氮气保护下，将乙烯基三甲基硅烷和鬼臼毒素4-O-邻-环丙基乙炔基苯甲酸酯给体溶在干燥的CH2Cl2中，并且加入分子筛(酒精喷灯稍微除水即可)，搅拌30min后，加入PPh3AuNTf2，在常温下反应四个小时，TLC监控，得到化合物37mg,收率84％，[α]D 25＝-67.7(c 1,CHCl3)；1H NMR(400MHz,CDCl3)δ6.73(s,1H),6.47(s,1H),6.29(s,2H),5.95(d,J＝1.2Hz,1H),5.94(d,J＝1.2Hz,1H),5.84-5.78(m,1H),5.16-5.10(m,2H),4.57(d,J＝5.2Hz,1H),4.28-4.25(m,2H),3.80(s,3H),3.74(s,6H),3.31-3.26(m,1H),3.10(dd,J＝5.2,14.0Hz,1H),3.02-2.94(m,1H),2.62-2.54(m,1H),2.46-2.39(m,1H)；13C NMR(100MHz,CDCl3)δ175.0,152.4,147.1,146.9,137.1,136.7,136.1,133.1,130.9,116.9,110.1,108.7,108.4,101.2,69.0,60.7,56.2,44.1,42.3,38.5,37.7,36.2；HRMS(ESI)calcd forC25H27O7[M+H]+439.17513 found439.17474。
实施例14
4-脱氧-4-苯甲酰甲基表鬼臼毒素的制备，
步骤1：
同实施例13中步骤1所示，得到化合物51mg,收率100％，[α]D 25＝-27.9(c 1.26,CHCl3)；1H NMR(400MHz,CDCl3)δ7.98(dd,J＝1.2,8.4Hz,2H),7.63-7.59(m,1H),7.51(t,J＝7.6Hz,2H),6.70(d,1H),6.50(d,1H),6.32(s,2H),5.96(d,J＝1.6Hz,1H),5.94(d,J＝1.2Hz,1H),4.60(d,J＝4.8Hz,1H),4.35(dd,J＝7.6,9.2Hz,1H),4.07(qd,J＝2.0,6.0Hz,1H),3.81(s,3H),3.76(s,6H),3.60-3.49(m,2H),3.24(dd,J＝2.0,19.2Hz,1H),3.14-3.04(m,1H),2.94(dd,J＝4.8,14.0Hz,1H)；13C NMR(100MHz,CDCl3)δ198.0,174.8,152.5,147.5,147.1,137.1,135.9,135.8,133.9,133.0,131.1,128.9,128.0,110.2,108.4,108.3,101.4,70.2,60.8,56.2,44.1,42.9,41.9,35.2,34.2；HRMS(ESI)calcd for C30H29O8[M+H]+517.18569 found 517.18507。
实施例15
4-脱氧-4-(2-甲酰乙基)表鬼臼毒素的制备，
步骤1：
同实施例13中步骤1所示，得到化合物18mg,收率82％，[α]D 25＝-55.5(c 0.64,CHCl3)；1H NMR(400MHz,CDCl3)δ9.80(s,1H),6.63(s1H),6.47δ6.28(s,2H),5.95(d,J＝1.2Hz,1H),5.94(d,J＝1.2Hz,1H),4.56(d,1H),4.34-4.28(dd,1H),3.88-3.82(m,1H),3.74(s,6H),3.62-3.56(dd,J＝9.2,11.6 1H),3.10-2.97(m,2H),2.85-2.75(m,2H)；13CNMR(100MHz,CDCl3)δ199.5,174.5,152.5,147.5,147.1,137.2,135.6,132.2,131.0,110.2,108.3,108.0,101.4,77.3,77.2,77.0,76.7,69.7,60.7,56.45,48.09,44.483,41.92,34.92,32.89。
实施例16
鬼臼毒素4-OH的制备，
步骤1：化合物所需糖基受体的制备，
(1)
在氮气保护下将异头位TBS保护，二位叠氮保护，其他位置羟基裸露的β-D-葡萄糖500mg,1.57mmol和对甲苯磺酸27mg,0.16mmol溶解在10ml干燥的乙腈溶液中，搅拌30min后，加入0.5mL,4.71mmol二甲氧基乙烷，常温下反应4h,TLC监控原料反应完，用40ml乙酸乙酯稀释，用饱和NaHCO3洗，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩柱层析(PE:EA＝4:1)得化合物471mg，收率87％。[α]D 25＝-7(c 1.26,CHCl3)；1H NMR(400MHz,CDCl3)δ4.60(q,J＝4.8Hz,1H),4.45(d,J＝7.6Hz,1H),3.98(dd,J＝5.2,10.4Hz,1H),3.43(d,J＝10.4Hz,1H),3.38(d,J＝9.2Hz,1H),3.22(t,J＝9.2Hz,1H),3.15-3.09(m,3H),1.23(d,J＝5.2Hz,3H),0.77(s,9H),0.00(s,3H),-.002(s,3H)；13C NMR(100MHz,CDCl3)δ99.8,97.5,80.2,71.5,69.1,68.0,66.3,25.5,20.2,17.9,-4.4,-5.2；HRMS(ESI)calcd forC14H28N3O5Si[M+H]+346.17928 found 346.17955、
(2)
将(1)所得产物56mg,0.16mmol和AZMBOH57mg,0.32mmol溶解在3ml干燥的DCM中，然后加入DMAP39mg,0.32mmol和DCC66mg,0.32mmol，常温下反应4h,TLC监控原料反应完，用40ml乙酸乙酯稀释，用饱和NaHCO3洗，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩柱层析(PE:EA＝6:1)得化合物71mg，收率88％。[α]D 25＝-21.3(c 1,CHCl3)；1H NMR(400MHz,CDCl3)δ7.84(dd,J＝1.6,8.0Hz,1H),7.43(td,J＝1.2,7.6Hz,1H),7.36(dd,J＝1.6,8.0Hz,1H),7.28(td,J＝1.6,7.6Hz,1H),5.10(t,J＝10.0Hz,1H),4.67-4.56(m,2H),4.52(q,J＝5.2Hz,1H),4.00(dd,J＝4.8,10.4Hz,1H),3.45-3.32(m,3H),3.26-3.19(m,1H),1.13(d,J＝5.2Hz,3H),0.76(s,9H),0.00(s,3H),-0.01(s,3H)；13C NMR(100MHz,CDCl3)δ165.6,137.3,132.9,130.8,129.8,128.7,128.2,99.8,97.7,78.4,71.8,68.0,67.2,66.6,53.5,52.9,25.5,20.3,17.9,-4.4,-5.2；HRMS(ESI)calcd C22H33N6O6Si[M+H]+505.22254found 505.22266、
(3)
将(2)所得产物128.4mg,0.255mmol,溶解在2ml干燥的吡啶中，反应在塑料反应器里面进行，在0℃条件下缓慢滴加HF-Pyr溶液0.32mL,3.57mmol，在0℃条件下搅拌3h,TLC监控原料反应完全。用40ml乙酸乙酯稀释，用饱和1M HCl洗，饱和NaHCO3洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩柱层析(PE:EA＝3:1)得化合物94.5mg，收率95％。[α]D 25＝+16.9(c1,CHCl3)；1H NMR(400MHz,CDCl3)δ8.02(d,J＝4.4Hz,1H),8.00(d,J＝4.0Hz,1H),7.62-7.42(m,6H),5.81(t,J＝10.0Hz,1H),5.44(d,J＝3.2Hz,1H),5.34(t,J＝10.0Hz,1H),4.89(d.J＝8.0Hz,1H),4.85-4.70(m,6H),4.23(dd,J＝4.4,10.4Hz,1H),4.17-4.10(m,2H),3.63-3.45(m,6H),3.44(dd,J＝3.6,10.4Hz,1H),1.34(d,J＝4.8Hz,3H),1.32(d,J＝4.8Hz,3H)；13C NMR(100MHz,CDCl3)δ166.1,165.7,137.3,133.0,130.8,129.8,128.6,128.1,99.9,96.8,93.2,79.1,78.2,72.0,69.7,68.3,68.0,66.0,65.7,62.6,62.2,52.7,20.2HRMS(ESI)calcd C16H18N6O6Na[M+Na]+413.11800 found 413.11818；
步骤2：
4'-脱甲基-4'-O-(苄氧羰基)表鬼臼毒素4-O-邻-环丙基乙炔基苯甲酸酯
将4’去甲氧基表鬼臼毒素10mg,0.1mmol溶于干燥的DCM中，加入三乙胺0.02ml，0.15mmol,加入氯甲酸苄酯0.02ml,o.15mmol,室温反应3h,TLC监控反应结束，柱层析得到化合物，然后在氮气保护下，将得到的化合物及邻炔基苯甲酸516mg,1.87mmol溶于干燥的4mLDCM溶液中,然后加入DMAP(229mg,1.87mmol)和DCC(516mg,2.5mmol)，室温搅拌2小时，此时TLC显示所有起始原料消失，加入DCM(40mL)稀释反应混合物，所得溶液依次用水和饱和盐水洗涤，减压浓缩，得到残余物，将其通过硅胶色谱法(洗脱剂系统：PE：EA＝4:1)进一步纯化,得到呈白色固体的(577.6mg,66％两步总收率)；
步骤3：
糖苷键的构建
同实施例1中步骤2所示，得到化合物33.6mg,收率74％，[α]D 25＝-17.2(c 0.53,CHCl3)；1H NMR(400MHz,CDCl3)δ8.00(dd,J＝1.6,8.0Hz,1H),7.62(td,J＝1.6,7.6Hz,1H),7.53(d,J＝7.6Hz,1H),7.46-7.32(m,6H),6.83(s,1H),6.57(s,1H),6.27(s,2H),6.03(d,J＝1.2Hz,1H),6.01(d,J＝1.2Hz,1H),5.29(t,J＝10.0Hz,1H),5.26(s,2H),5.00(d,J＝3.2Hz,1H),4.84-4.70(m,4H),4.68(d,J＝5.2Hz,1H),4.44(dd,J＝8.8,10.8Hz,1H),4.32-4.23(m,2H),3.67(s,6H),3.65-3.55(m,3H),3.49-3.43(m,1H),3.40(dd,J＝5.6,14.0Hz,1H),2.96-2.88(m,1H)；13C NMR(100MHz,CDCl3)δ174.2,165.7,153.0,151.5,149.0,147.4,138.1,137.2,134.9,132.9,132.4,130.9,129.9,128.5,127.3,111.1,108.8,107.8,101.8,100.5,100.0,77.1,73.5,71.7,70.3,68.0,67.4,66.6,65.0,56.2,43.8,40.9,37.5,20.2HRMS(ESI)calcd C45H43N6O15[M+H]+907.27809 found 907.27910；
步骤4：
保护基的脱除，
将化合物4'-脱甲基-4'-O-苄氧羰基)表鬼臼毒素4-O-2“-脱氧-2”-叠氮基-3“-O-(叠氮甲基)苯甲酰-4'，6”-二-O-亚乙基-β-D-吡喃葡萄糖苷20mg溶解在2ml的甲醇溶液中，然后加入20mgPd(OH)2/C,在反应容器浸没后，将容器抽真空，然后用H2再填充,这个过程重复三次，然后在氢气保护下反应12h，TLC检测，得到化合物10.9mg,收率85％，[α]D 25＝-78.4(c 0.5,CHCl3)；1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,C5D5N)δ7.33(s,1H),6.8(s,1H),6.78(s,2H),5.96(s,1H),5.71(s,1H),5.06-5.02(m,4H),4.91-4.86(m,2H),4.72-4.66(m,1H),4.38-4.32(m,2H),4.09-4.07(t,J＝9.2Hz 1H),3.77(s,6H),3.75-3.59(m,5H),3.30-3.22(m 2H),1.45-1.40(d,J＝4.80H),13C NMR(100MHz,C5D5N)δ175.1,148.3,147.5,137.1,133.3,130.1,110.6,109.0,105.2,101.9,99.8,82.0,74.54,73.45,68.28,67.1,59.1,56.22,44.1,41.8,38.0,20.4HRMS(ESI)calcd C29H34NO12[M+H]+588.20755 found588.20679；
步骤5：
鬼臼毒素4-OH的制备，
操作步骤：在氮气保护下，将4'-脱甲基-表鬼臼毒素4-O-2“-脱氧-2”-氨基-4“，6”-二-O-亚乙基-β-D-吡喃葡萄糖苷56mg溶解在2ml甲醇溶液中，加入20mg氰基硼氢化钠，然后再加入甲醛水溶液0.084ml，之后反应体系在常温下搅拌4h，TLC监控，反应结束后，减压浓缩，柱层析(CH2Cl2:MeOH＝20:1)得到化合物52mg,收率84％。[α]D 25＝-32.3(c 1.26,CHCl3)；1H NMR(400MHz,CDCl3)δ6.73(s,1H),6.47(s,1H),6.29(s,2H),5.95(d,J＝1.2Hz,1H),5.94(d,J＝1.2Hz,1H),5.42(s,1H),5.0(d,J＝2.8Hz 1H),4.9-4.86(d,J＝8.4Hz,1H),4.81-4.76(dd,J＝4.8,10.0Hz 1H),4.66-4.63(d,J＝5.6Hz 1H),4.40-4.34(dd,J＝8.8,10.4Hz 1H),4.3-4.24(t,J＝8.0,8.4 1H),4.22-4.16(dd,J＝4.8,10.4Hz,1H),3.76(s,1H),3.68-3.58(m,2H),3.44-3.30(m,3H),2.95-2.87(m 1H),2.52-2.44(m 1H)2.32(s6H)；13C NMR(100MHz,CDCl3)δ174.6,148.8,147.1,146.5,134.3,133.1,130.5,127.6,111.2,108.8,107.7,101.7,99.84,97.8,80.77,77.0,71.4,68.1,67.6,66.5,56.4,43.7,41.1,37.4,20.4；HRMS(ESI)calcd C31H37NO12Na[M+Na]+638.22080 found 638.21931。
以上所述的实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案作出的各种变形和改进，均应落入本发明权利要求书确定的保护范围内。
Claims (9)
1.一种鬼臼毒素4-OH衍生物的制备方法，其特征在于，将鬼臼毒素类糖基炔酯给体2和亲核试剂3进行糖苷化反应，即可制得鬼臼毒素4-OH衍生物1；
其中，R1为本领域常用的羟基保护基，所述的保护基为苄基，叔丁基二甲基硅基,甲基的一种；
NuH为具有亲核性的羟基，氨基，烷基，烯基或炔基中的一种。
2.根据权利要求1所述的一种鬼臼毒素4-OH衍生物的制备方法，其特征在于：当NuH为糖基羟基时，所述的糖基包括β-D-葡萄糖基、α-D-葡萄糖基、β-D-半乳糖基、α-D-半乳糖基、β-D-甘露糖基、α-D-甘露糖基、β-D-木糖基、α-D-木糖基、β-D-2-氨基葡萄糖基、α-D-2-氨基葡萄糖基、α-L-鼠李糖基、β-L-鼠李糖基、α-D-核糖基、β-D-核糖基、α-L-核糖基、β-L-核糖基、α-D-阿拉伯糖基、β-D-阿拉伯糖基、α-L-阿拉伯糖基、β-L-阿拉伯糖基、α-L-岩藻糖基、β-L-岩藻糖基、β-D-葡萄糖醛酸基、α-D-葡萄糖醛酸基、β-D-半乳糖醛酸基、或者α-D-半乳糖醛酸基。
3.根据权利要求1所述的一种鬼臼毒素4-OH衍生物的制备方法，其特征在于：所述的制备的鬼臼毒素4-OH衍生物的方法包含下列步骤：在机溶剂中、在干燥剂存在下、惰性气体保护下，在亲炔基路易斯酸的作用下，将鬼臼毒素类糖基炔酯给体2和亲核试剂3进行糖苷化反应，直到反应完全为止。
4.根据权利要求1所述的一种鬼臼毒素4-OH衍生物的制备方法，其特征在于：所述的制备的鬼臼毒素4-OH衍生物中的有机溶剂为干燥的二氯甲烷、甲苯、硝基甲烷和乙腈中的一种或多种。
5.根据权利要求1所述的一种鬼臼毒素4-OH衍生物的制备方法，其特征在于：所述的制备的鬼臼毒素4-OH衍生物中的亲炔基路易斯酸为AuCl、AuCl3、AuLOTf、AuLNTf2、HgOTf和PtCl2中的一种或多种，其中，L为本领域常规的膦配体。
6.根据权利要求5所述的一种鬼臼毒素4-OH衍生物的制备方法，其特征在于：所述的膦配体为三丁基膦、三乙基膦、三苯基膦或三金刚烷基膦。
7.根据权利要求1所述的一种鬼臼毒素4-OH衍生物的制备方法，其特征在于：所述制备的鬼臼毒素4-OH衍生物的糖苷化反应中，所述的亲炔基路易斯酸的用量为鬼臼毒素类糖基炔酯给体2的摩尔量的0.2～0.3倍。
8.根据权利要求1所述的一种鬼臼毒素4-OH衍生物的制备方法，其特征在于：所述制备的鬼臼毒素4-OH衍生物的糖苷化反应的温度为25～35℃；所述的制备鬼臼毒素4-OH衍生物的糖苷化反应反应的时间为1～4小时。
9.根据权利要求1所述的一种鬼臼毒素4-OH衍生物的制备方法，其特征在于：所述制备的鬼臼毒素4-OH衍生物的糖苷化反应在干燥剂的存在下进行，干燥剂的用量为鬼臼毒素类糖基炔酯给体2的摩尔量的1.0～4.0倍；所述的干燥剂为分子筛、分子筛、分子筛、酸洗的分子筛、酸洗的分子筛、酸洗的分子筛、无水硫酸钠、无水硫酸钙、无水硫酸铜和无水硫酸镁中的一种或多种。
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