CN103923134A - 菲并吲哚里西啶生物碱糖基化产物及6-位衍生化产物及它们的制备、抗植物病毒活性 - Google Patents
菲并吲哚里西啶生物碱糖基化产物及6-位衍生化产物及它们的制备、抗植物病毒活性 Download PDFInfo
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Abstract
本发明涉及菲并吲哚里西啶生物碱糖基化产物和6-位衍生化产物及其制备和抗植物病毒活性,式中各基团的意义见说明书。本发明的菲并吲哚里西啶生物碱糖基化产物具有好的光稳定性,热稳定性和水溶性,表现出特别优异的抗植物病毒活性,糖基化产物和6-位衍生化产物均能很好地抑制烟草花叶病毒(TMV)。
Description
技术领域
本发明涉及6-O-脱甲基安托芬和14-羟基娃儿藤碱的糖基化产物、6-O-脱甲基安托芬的6-位衍生物,及其制备方法和抗植物病毒活性。
背景技术
菲并吲哚里西啶生物碱(Phenanthroindolizidine alkaloids)主要存在于萝藦科(Asclepiadaceae)、桑科(Moraceae)、爵床科(Acanthaceae)和樟科(Lauraceae)植物中。该类生物碱具有非常广泛的生物活性,尤其是其独特抗癌活性吸引了合成化学家和药物学家的广泛关注。其中(R)-6-O-脱甲基安托芬(1)展现出了比其它菲并吲哚里西啶生物碱更好的抗癌活性,而DCB-3503(3)则具有不同于以往抗癌药物的独特的作用机制。本课题组首次发现牛心朴子草的浸取物对危害极大的烟草花叶病毒(TMV)具有极高的抑制活性,进一步生物活性跟踪化学分离研究结果表明:其中抗TMV主要活性物质为菲并吲哚里西啶类生物碱-(R)-安托芬,同时还分离到了微量的(R)-6-O-脱甲基安托芬(1),它们比已见文献报道的植物病毒抑制剂活性高出很多。虽然菲并吲哚里西啶生物碱具有很好的生物活性,但是也存在中枢神经系统毒性较大、水溶性差、对光照和热不稳定的缺点,这影响它们的实际应用。
天然产物的糖基化就是指天然产物和糖相连形成糖缀合物的过程,在自然界中糖基化是一个非常普遍的生物转化,由八十多种糖基转移酶来完成。很多含糖的天然产物有很好的生物活性,可以作为药物进行开发,增加或者改变其中的糖基部分可以提高生物活性,产生新的生物活性,提高药物动力学参数,甚至改变分子作用机制等等。很多不含糖基的天然产物的生物活性很好,但是由于溶解性太差、毒性太大等等原因并不适合作为药物使用,对这些天然产物进行糖基化是解决这些问题的一个很好的途径。用化学方法对天然产物进行糖基化作为一个合理的结构改造的工具已经应用到药物化学上,可以开发天然产物的化学结构和生物活性的多样性。对菲并吲哚里西啶生物碱进行糖基化无疑可以增加其水溶性,同时还可以增加其分子极性,从而使其不易穿透血脑屏障,进而可以解决其中枢神经系统的毒性较大的缺点。
(R)-安托芬和(R)-6-O-脱甲基安托芬均具有很好的抗植物病毒活性,然而对于其中6-位取代基对活性的影响还没有进行研究过,对6-位进行衍生化的方法也缺乏报道。
发明内容
对天然产物进行糖基化,主要考虑糖基化的方式和糖基部分的选择。天然产物直接和糖通过糖苷键相连或者将天然产物衍生出一个连接臂再和糖进行糖苷化反应,得到的产物均称之为天然产物的糖基化产物。本发明选取不同的糖作为糖基部分,同时考察不同的糖基化方式对生物活性的影响。本发明针对菲并吲哚里西啶生物碱6-位和14-位进行糖基化,选取的生物碱是(R)/(S)-6-O-脱甲基安托芬(1,2)和14-羟基娃儿藤碱(3-6)。同时本发明还利用(R)/(S)-6-O-脱甲基安托芬(1,2)和α-溴代物的亲核取代反应制备了6-O-脱甲基6-位衍生物。所制备的化合物表现出了很好的抗植物病毒活性,能够很好的抑制烟草花叶病毒。
本发明的菲并吲哚里西啶生物碱糖基化产物及6-位衍生化产物是具有如下通式(I)所示结构的化合物:
R1和R2均代表甲氧基、R3代表O-Sugar;
R1和R2均代表甲氧基、R3代表
R1和R2均代表甲氧基、R3代表
R2和R3均代表氢、R1代表O-Sugar;
R2和R3均代表氢、R1代表
R2和R3均代表氢、R1代表
R2和R3均代表氢、R1代表OCH2R;
以上通式中包括所有13a位和14位的立体异构体。
本发明中以氧苷键进行连接的菲并吲哚里西啶生物碱的糖基化产物I可以按如下方法制备(路线一):
2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯(A),2,3,4,6-四-O-乙酰基-α-D-吡喃半乳糖三氯乙酰亚胺酯(B)和2,3,4,6-四-O-乙酰基-α-D-吡喃甘露糖三氯乙酰亚胺酯(C)作为糖基供体和6-O-脱甲基安托芬及14-羟基娃儿藤碱在BF3·Et2O做催化剂的条件下发生氧苷化反应,生成氧苷I。
本发明中以1,2,3-三唑作为连接臂的菲并吲哚里西啶生物碱的糖基化产物I可以按如下方法制备(路线二):
首先利用6-O-脱甲基安托芬及14-羟基娃儿藤碱DCB-3505的羟基和炔丙基溴反应,引入端炔,在Cu+催化下分别和2,3,4,6-四乙酰基-β-D-吡喃叠氮葡萄糖(D),2,3,4,6-四乙酰基-β-D-吡喃叠氮葡萄糖(E)和2,3,4,6-四乙酰基-β-D-吡喃叠氮葡萄糖(F)发生Huisgen 1,3-偶极环加成反应即点击化学反应可以高效地合成1,4-氮杂三唑糖苷,然后在碱性条件下脱除糖上的保护基可得目标产物I。
本发明中以氨基甲酰氧基作为连接臂的菲并吲哚里西啶生物碱的糖基化产物I可以按如下方法制备(路线三):
2-脱氧-2-异氰酰基-1,3,4,6-四-O-乙酰基-β-D-葡萄糖和6-O-脱甲基安托芬及14-羟基娃儿藤碱在Et3N做催化剂的条件下发生反应,一步生成目标产物I。
本发明中安托芬6-位衍生物I可以按如下方法制备(路线四):
利用(R)/(S)-6-O-脱甲基安托芬6-位酚羟基较高的反应活性,在碱性条件下可以和α-溴代物(溴乙腈、炔丙基溴、溴代乙酰胺和α-溴乙酸乙酯)发生亲核取代反应生成醚,从而在6-位引入一个侧链,可得目标化合物I,在侧链上引入乙氧甲酰氧基后还可以进一步发生还原反应。
本发明优选如下化学结构式的菲并吲哚里西啶生物碱糖基化产物及6-位衍生化产物(I):
具体实施方式
下述的实施例和生测试验结果可用来进一步说明本发明,但不意味着限制本发明。
实施例1:(S)-6-O-脱甲基安托芬氧苷I-1~I-4和14-羟基娃儿藤碱氧苷I-5~I-6的合成
(S)-6-O-脱甲基安托芬氧苷I-1~I-4的合成
向40mL二氯甲烷中加入(S)-6-O-脱甲基安托芬2(0.40g,1.15mmol),氩气保护下,加入分子筛,室温下搅拌0.5h。低温下加入0.2mL BF3·Et2O,搅拌0.5h,滴加糖三氯乙酰亚胺酸酯A(或B,C)(0.75g,1.20mmol)的二氯甲烷溶液,反应4h,TLC监测反应完全,加水淬灭反应,分液,二氯甲烷萃取水相,无水硫酸镁干燥,脱溶,柱层析(乙酸乙酯—二氯甲烷∶甲醇=30∶1),得全乙酰化糖苷。将所得的糖苷加入15mL甲醇中,加入甲醇钠至pH=9-12,室温搅拌1h,脱溶除去甲醇,加入水5mL,冷至0℃,过滤得产品I-1(或I-2,I-3),滤液中的产品用二氯甲烷∶甲醇=5∶1的混合液萃取滤液,脱溶即可得到滤液中的产品。I-4为I-3没有脱除乙酰基前的糖基化产物。
(13aS)-6-O-安托芬-β-D-半乳糖苷(I-1)白色固体,收率80%,熔点249-251℃;1H NMR(400MHz,DMSO-d6):δ8.28(s,1H),8.03(s,1H),7.84(d,J=8.8Hz,1H),7.35(s,1H),7.32(d,J=8.8Hz,1H),5.24(d,J=4.4Hz,1H),5.07(d,J=4.0Hz,1H),4.96(d,J=5.6Hz,1H),4.82(t,J=5.2Hz,1H),4.61(d,J=4.0Hz,1H),4.02(s,3H),3.96(s,3H),3.75-3.78(m,2H),3.67-3.70(m,1H),3.58-3.61(m,2H),3.41-3.50(m,3H),2.82-2.93(m,1H),2.22-2.24(m,1H),1.85-1.95(m,2H),1.68-1.85(m,1H).13C NMR(100MHz,DMSO-d6):δ155.6,149.3,148.4,129.6,126.4,126.2,126.0,124.1,124.0,123.0,116.8,108.3,104.2,101.8,75.9,73.5,70.4,68.5,60.9,59.9,55.7,55.4,54.5,53.3,33.1,31.0,21.2.HRMS(ESI):calcd.for C28H34NO8[M+H]+ 512.2279;found512.2284.
(13aS)-6-O-安托芬-β-D-葡萄糖苷(I-2)白色固体,收率81%,熔点256-258℃;1H NMR(400MHz,DMSO-d6):δ8.25(s,1H),8.03(s,1H),7.83(d,J=9.2Hz,1H),7.33(s,1H),7.32(d,J=9.2Hz,1H),5.40(s,1H),5.18(s,1H),5.06-5.13(m,2H),4.71-4.78(m,1H),4.57(d,J=12.8Hz,1H),4.01(s,3H),3.95(s,3H),3.74-3.81(m,1H),3.46-3.55(m,3H),3.23-3.26(m,1H),3.13-3.23(m,1H),2.28-2.42(m,2H),2.14-2.21(m,1H),1.77-1.89(m,2H),1.59-1.68(m,1H).13C NMR(100MHz,DMSO-d6):δ155.5,149.2,148.3,129.5,126.3,126.2,126.0,124.1,124.0,123.0,116.7,108.1,104.1,104.1,101.1,77.3,76.7,73.4,70.0,60.9,59.8,55.6,55.4,54.4,53.3,33.0,30.9,21.2.HRMS(ESI):calcd.for C28H34NO8[M+H]+ 512.2279;found 512.2281.
(13aS)-6-O-安托芬-β-D-甘露糖苷(I-3)白色固体,收率78%,熔点258-260℃;1H NMR(400MHz,DMSO-d6):δ8.36(s,1H),8.06(s,1H),7.82(d,J=9.2Hz,1H),7.38(d,J=8.8Hz,1H),7.31(s,1H),5.58(s,1H),5.11(br,1H),4.84-4.99(m,2H),4.53-4.63(m,2H),4.02(s,3H),3.96(s,1H),3.94(s,3H),3.82(d,J=6.4Hz,1H),3.68(d,J=10.4Hz,1H),3.48-3.56(m,2H),2.71-2.77(m,1H),2.22-2.37(m,2H),2.06-2.18(m,1H),1.75-1.88(m,2H),1.59-1.64(m,1H).13C NMR(100MHz,DMSO-d6):δ154.4,149.1,148.2,129.5,126.1,126.1,126.0,124.2,123.9,122.9,116.8,109.7,104.2,103.9,99.4,74.8,70.6,70.1,66.8,61.0,59.6,55.6,55.2,54.3,53.1,32.9,30.7,21.0.HRMS(ESI):calcd.for C28H34NO8[M+H]+ 512.2279;found 512.2275.
(13aS)-6-O-安托芬-2,3,4,6-四-O-乙酰基-β-D-甘露糖苷(I-4)浅黄色固体,熔点186-188℃;1HNMR(400MHz,DMSO-d6):δ8.14(s,1H),7.88(s,1H),7.71(d,J=9.2Hz,1H),7.33(d,J=8.0Hz,1H),7.21(s,1H),5.73(s,1H),5.66(d,J=9.6Hz,1H),5.56(s,1H),4.42(t,J=10.0Hz,1H),4.93-4.96(m,1H),4.30-4.34(m,1H),4.18-4.21(m,1H),4.16(s,3H),4.09-4.12(m,2H),4.04(s,3H),3.39-3.42(m,1H),3.15-3.24(m,2H),2.36-2.41(m,1H),2.25(s,3H),2.15-2.17(m,1H),2.08(s,6H),1.95-2.03(m,3H),1.91(s,3H).HRMS(ESI):calcd.for C36H41NO12[M+H]+680.2702;found 680.2700.
14-羟基娃儿藤碱氧苷I-5~I-6的合成
向40mL二氯甲烷中加入14-羟基娃儿藤碱4(0.47g,1.15mmol),氩气保护下,加入分子筛,室温下搅拌0.5h。低温加入0.2mL BF3·Et2O,搅拌0.5h,滴加葡萄糖糖三氯乙酰亚胺酸酯A(0.75g,1.20mmol)的二氯甲烷溶液,反应4h,TLC监测反应完全,加水淬灭反应,分液,二氯甲烷萃取水相,无水硫酸镁干燥,脱溶,柱层析(乙酸乙酯—二氯甲烷∶甲醇=30∶1),得全乙酰化糖苷I-5。将所得的糖苷I-5加入15mL甲醇中,加入甲醇钠至pH=9-12,室温搅拌1h,脱溶除去甲醇,加入水5mL,冷至0℃,过滤得产品I-6,滤液中的产品用二氯甲烷∶甲醇=5∶1的混合液萃取滤液,脱溶即可得到滤液中的产品。
(13aR,14S)-14-O-2,3,6,7-四甲氧基菲并[9,10-b]吲哚里西啶-2,3,4,6-四-O-乙酰基-β-D-葡萄糖苷(I-5)浅黄色固体,熔点:160-162℃;1H NMR(400MHz,CDCl3):δ7.83(s,1H),7.77(s,1H),7.60(s,1H),7.18(s,1H),5.66(d,J=10.0Hz,1H),5.89-5.01(m,3H),4.72(d,J=10.0Hz,1H),4.48(d,J=20.0Hz,1H),4.18-4.25(m,2H),4.14(s,3H),4.10(s,3H),4.07(s,3H),4.01(s,3H),3.77-3.83(m,1H),3.63-3.67(m,1H),3.27-3.35(m,1H),2.77-2.91(m,1H),2.47-2.59(m,2H),2.12(s,1H),2.01-2.09(m,3H),1.96-1.99(m,6H),1.90(s,3H).
(13aR,14S)-14-O-2,3,6,7-四甲氧基菲并[9,10-b]吲哚里西啶-β-D-葡萄糖苷(I-6)白色固体,熔点:211-213℃;1H NMR(400MHz,DMSO-d6):δ8.00(s,1H),7.95(s,1H),7.93(s,1H),7.22(s,1H),5.76(d,J=6.4Hz,1H),4.97(t,J=6.0Hz,2H),4.93(d,J=4.8Hz,1H),4.77(t,J=6.0Hz,1H),4.60(d,J=7.2Hz,1H),4.52(d,J=15.2Hz,1H),4.03(s,3H),4.01(s,3H),3.93(s,3H),3.91(s,3H),3.78-3.83(m,1H),3.56(d,J=14.8Hz,1H),3.45-3.48(m,1H),3.01-3.07(m,1H),2.91-2.96(m,1H),2.37-3.46(m,2H),1.92-2.01(m,1H),1.79-1.86(m,2H).13C NMR(100MHz,DMSO-d6):δ155.6,149.3,148.4,129.6,126.4,126.2,126.0,124.1,124.0,123.0,116.8,108.3,104.2,101.8,75.9,73.5,70.4,68.5,60.9,59.9,55.7,55.4,54.5,53.3,33.1,31.0,21.2.HRMS(ESI):calcd.for C30H38NO10[M+H]+ 572.2490;found 572.2485.
实施例2:以1,2,3-三唑作为连接臂对(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱进行糖基化的方法。
(13aS)-6-O-炔丙基安托芬(I-28)的合成将(S)-6-O-脱甲基安托芬2(0.81g,2.33mmol)溶于15mL N,N-二甲基甲酰胺中,加入Cs2CO3(0.91g,2.79mmol),室温搅拌0.5h,缓慢滴加炔丙基溴(2.79mmol)的10mL N,N-二甲基甲酰胺溶液,反应直至TLC监测反应完全。加入30mL乙酸乙酯和30mL水,分液,乙酸乙酯萃取水相,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,脱溶,柱层析(乙酸乙酯做洗脱剂),可得白色固体产品I-28(0.77g),收率85%,熔点195-197℃;1H NMR(400MHz,CDCl3):δ8.04(br,1H),7.91(s,1H),7.83(d,J=9.2Hz,1H),7.31(s,1H),7.24-7.26(m,1H),4.90(s,2H),4.69(d,J=14.8Hz,1H),4.10(s,3H),4.06(s,3H),3.69(d,J=14.4Hz,1H),3.47(t,J=8.0Hz,1H),3.35(d,J=15.6,1H),2.87-2.93(m,1H),2.59(s,1H),2.44-2.52(m,2H),2.20-2.29(m,1H),2.00-2.06(m,1H),1.90-1.97(m,1H),1.74-1.82(m,1H).13C NMR(100MHz,CDCl3):δ155.4,149.5,148.4,130.1,127.1,126.6,126.1,124.7,124.3,123.5,115.1,106.6,104.0,103.8,78.7,75.8,60.2,56.3,56.0,55.9,55.1,53.9,33.8,31.3,21.6.HRMS(ESI):calcd.for C25H26NO3[M+H]+388.1907;found 388.1909.
(13aS,14S)-14-O-炔丙基-2,3,6,7-四甲氧基菲并[9,10-b]吲哚里西啶(7)的合成将DCB-3503(3)(0.83g,2.03mmol)溶于60mL N,N-二甲基甲酰胺中,加入氢化钠(0.49g,20.29mmol),反应1h,加入炔丙基溴(1.19g,10.15mmol),反应过夜。加入乙酸乙酯,滴加水分解掉氢化钠,分液,乙酸乙酯萃取水相,无水硫酸钠干燥,过滤,脱溶,柱层析(石油醚∶乙酸乙酯=1∶1),得白色固体产品7(0.73g),产率80%,熔点205-207℃;1H NMR(400MHz,CDCl3):δ7.87(s,1H),7.84(s,1H),7.82(s,1H),7.22(s,1H),5.29(s,1H),4.68(d,J=15.2Hz,1H),4.61(d,J=15.2Hz,1H),4.13(s,6H),4.08(s,3H),4.06(s,3H),3.81(d,J=15.6Hz,1H),3.53(d,J=15.2Hz,1H),3.43(t,J=8.0,1H),3.54-3.58(m,1H),3.33-3.43(m,2H),2.31(s,1H),1.92-2.05(m,3H).13C NMR(100MHz,CDCl3):δ149.5,149.3,149.0,130.5,126.3,125.0,124.1,124.0,123.6,105.3,103.7,103.4,103.1,81.6,73.3,71.2,65.4,56.2,56.1,55.5,54.5,54.4,24.6,22.0.HRMS(ESI):calcd.for C27H30NO5[M+H]+448.2118;found 448.2124.
以1,2,3-三唑作为连接臂对(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱进行糖基化的实验步骤将0.27mmol炔丙基生物碱7或I-28和0.29mmol全乙酰叠氮糖溶于20mL二氯甲烷中,加入20mL水,加入CuSO4.5H2O(0.02g,0.081mmol)和抗坏血酸钠Vc-Na(0.05g,0.27mmol),加热回流2h,冷至室温,分液,二氯甲烷萃取水相,合并有机相,饱和食盐水洗有机相,脱溶,柱层析,可得1,2,3-三唑为连接臂的糖基化产物I-7~I-9,I-13~I-15。将所得的糖基化产物加入20mL甲醇中,加入甲醇钠至pH=9-12,室温搅拌1h,脱溶除去甲醇,加入水5mL,冷至0℃,过滤即得脱保护的糖基化产品I-10~I-12,I-16~I-18,滤液中的产品用二氯甲烷∶甲醇=5∶1的混合液萃取,脱溶即可得到。
(13aS)-6-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖)-1H-1,2,3-三唑)甲基安托芬(I-7)柱层析(乙酸乙酯—二氯甲烷∶甲醇=25∶1),得浅黄色固体,收率94%,熔点204-206℃;1HNMR(400MHz,CDCl3):δ8.05(d,J=1.6Hz,1H),7.94(s,1H),7.92(s,1H),7.81(d,J=9.2Hz,1H),7.30(s,1H),7.24-7.26(m,1H),5.87(d,J=8.8Hz,1H),5.44(s,2H),5.37-5.44(m,1H),5.23(t,J=9.2Hz,1H),4.68(d,J=14.8Hz,1H),4.29(dd,J=12.8,5.2Hz,1H),4.14(s,3H),4.13(d,J=12.8Hz,1H),4.06(s,3H),3.96-3.99(m,1H),3.68(d,J=14.8Hz,1H),3.44-3.48(m,1H),3.34(dd,J=15.2,2.4Hz,1H),2.85-2.92(m,1H),2.41-2.52(m,2H),2.20-2.28(m,1H),2.06(s,7H),2.01(s,3H),1.89-1.94(m,1H),1.72-1.78(m,2H),1.67(s,3H).13C NMR(100MHz,CDCl3):δ170.5,169.9,169.3,168.9,155.9,149.4,148.5,145.2,130.1,127.0,126.6,125.9,124.4,124.3,123.6,121.3,115.6,106.0,103.9,103.8,85.8,75.2,72.6,70.2,67.7,62.2,61.5,60.2,56.0,55.9,55.1,53.9,33.8,31.3,21.6,20.7,20.5,20.5,19.9.HRMS(ESI):calcd.for C39H45N4O12[M+H]+ 761.3028;found 761.3033.
(13aS)-6-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃半乳糖)-1H-1,2,3-三唑)甲基安托芬(I-8)柱层析(乙酸乙酯—二氯甲烷∶甲醇=25∶1),得浅黄色固体,收率90%。熔点200-202℃;1HNMR(400MHz,CDCl3):δ8.06-8.08(m,1H),8.03(s,1H),7.93(s,1H),7.81(d,J=9.2Hz,1H),7.29(s,1H),7.25-7.28(m,1H),5.84(d,J=9.2Hz,1H),5.53-5.59(m,2H),5.45(s,2H),5.21-5.25(m,1H),4.69(d,J=15.2Hz,1H),4.17-4.22(m,1H),4.15(s,3H),4.10-4.13(m,1H),4.06(s,3H),3.70(d,J=14.8Hz,1H),3.47(t,J=6.8Hz,1H),3.34(dd,J=16.0Hz,2.8Hz,1H),2.87-2.95(m,1H),2.43-2.50(m,1H),2.23-2.26(m,1H),2.21(s,3H),2.03-2.07(m,1H),2.03(s,3H),1.99(s,3H),1.90-1.95(m,1H),1.78-1.83(m,1H),1.69-1.75(m,3H).13C NMR(100MHz,CDCl3):δ170.3,170.0,169.8,169.0,156.0,149.4,148.5,145.1,130.1,126.9,125.8,124.3,123.6,121.4,115.7,115.5,106.1,106.0,103.9,103.8,86.3,77.2,74.1,70.7,67.8,66.8,62.2,61.2,60.2,56.0,55.9,55.0,33.6,31.2,21.6,20.6,20.5,20.1,20.0.HRMS(ESI):calcd.forC39H45N4O12[M+H]+ 761.3028;found 761.3027.
(13aS)-6-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃甘露糖)-1H-1,2,3-三唑)甲基安托芬(I-9)柱层析(乙酸乙酯—二氯甲烷∶甲醇=25∶1),得浅黄色固体,收率89%。熔点197-199℃;1HNMR(400MHz,CDCl3):δ8.05(d,J=12.0Hz,1H),7.88-7.91(m,2H),7.76(d,J=12.8Hz,1H),7.27(s,1H),7.20-7.22(m,1H),6.16(s,1H),5.73(s,1H),5.45(s,2H),5.26-5.36(m,2H),4.75(d,J=14.4Hz,1H),4.32(dd,J=12.4Hz,2.0Hz,1H),4.20(d,J=12.4Hz,1H),4.13(s,3H),4.06(s,3H),3.94-3.98(m,1H),3.77-3.86(m,1H),3.50-3.61(m,1H),3.67(d,J=15.2Hz,1H),3.00-3.06(m,1H),2.55-2.76(m,2H),2.25-2.33(m,1H),2.08(br,7H),1.97(s,4H),1.69-1.85(m,4H).13C NMR(100MHz,CDCl3):δ170.5,169.8,169.6,168.9,156.1,149.6,148.7,144.5,130.3,124.2,124.1,123.7,121.9,121.8,115.7,115.5,106.1,106.0,103.9,84.9,77.2,75.8,70.7,70.6,68.8,68.7,64.9,62.3,62.3,62.2,56.1,55.9,30.9,21.5,20.7,20.7,20.5,20.1.HRMS(ESI):calcd.for C39H45N4O12[M+H]+761.3028;found 761.3027.
(13S)-6-O-(4-取代-1-(β-D-吡喃葡萄糖)-1H-1,2,3-三唑)甲基安托芬(I-10)白色固体,收率95%。熔点259-261℃;1H NMR(400MHz,DMSO-d6):δ8.54(s,1H),8.34(s,1H),8.16(s,1H),7.85(d,J=8.8Hz,1H),7.36(br,2H),5.59(d,J=9.2Hz,1H),5.45(d,J=9.2Hz,1H),5.44(s,2H),5.34(d,J=4.4Hz,1H),5.21(d,J=5.2Hz,1H),4.78-4.81(m,1H),4.66(br,1H),4.05(s,3H),3.97(s,3H),3.78-3.84(m,1H),3.69-3.72(m,1H),3.41-3.52(m,4H),3.27-3.28(m,1H),2.94-2.98(m,1H),2.29(br,1H),1.97(br,1H),1.75-1.79(m,1H).13C NMR(100MHz,DMSO-d6):δ157.6,150.6,149.9,143.9,131.1,127.0,126.2,125.5,125.2,124.4,124.2,117.0,107.3,105.8,105.4,88.7,81.2,78.2,73.3,70.7,62.6,61.9,61.5,57.1,56.6,54.8,49.8,31.2,22.0.HRMS(ESI):calcd.for C31H37N4O8[M+H]+593.2606;found 593.2604.
(13aS)-6-O-(4-取代-1-(β-D-吡喃半乳糖)-1H-1,2,3-三唑)甲基安托芬(I-11)白色固体,收率94%。熔点234-236℃;1H NMR(400MHz,DMSO-d6):δ8.46(s,1H),8.30(s,1H),8.14(s,1H),7.83(d,J=8.8Hz,1H),7.33(br,2H),5.54(d,J=8.8Hz,1H),5.43(s,2H),5.33(d,J=2.4Hz,1H),4.72(br,2H),4.56(d,J=15.2Hz,1H),4.07-4.14(m,1H),4.05(s,3H),3.95(s,3H),3.74-3.78(s,2H),3.54(br,4H,OH),3.31(br,2H),2.72-2.79(m,1H),2.30-2.33(m,2H),2.14-2.15(m,1H),1.84(br,2H),1.62-1.66(m,2H).13C NMR(100MHz,DMSO-d6):δ156.1,149.3,148.3,142.9,129.7,126.3,125.6,124.2,123.6,123.5,123.0,115.6,105.9,104.6,104.1,88.1,78.4,73.7,69.3,68.4,61.3,60.4,59.8,55.8,55.4,54.4,53.3,33.0,30.9,21.2.HRMS(ESI):calcd.for C31H37N4O8[M+H]+ 593.2606;found 593.2605.
(13aS)-6-O-(4-取代-1-(β-D-吡喃甘露糖)-1H-1,2,3-三唑)甲基安托芬(I-12)白色固体,收率88%。熔点226-228℃;1H NMR(400MHz,DMSO-d6):δ8.42(s,1H),8.30(s,1H),8.13(s,1H),7.82(d,J=9.2Hz,1H),7.29-7.32(m,2H),6.06(s,1H),5.43(s,2H),5.08-5.15(m,1H),4.56(d,J=15.2Hz,1H),4.04(s,3H),3.94(s,3H),3.91(s,1H),3.75(d,J=11.6Hz,1H),3.61-3.64(m,1H),3.41-3.53(m,4H),3.31(br,1H),3.72-3.78(m,1H),2.27-2.35(m,2H),2.13-2.15(m,1H),1.98-1.89(m,2H),1.58-1.68(m,1H).13C NMR(100MHz,DMSO-d6):δ156.0,149.2,148.2,142.3,129.6,126.2,125.5,124.3,124.1,123.4,122.9,115.6,105.8,104.5,104.0,85.9,80.3,73.0,70.4,66.1,61.3,61.0,59.7,55.7,55.3,54.3,53.2,33.0,30.8,21.1.HRMS(ESI):calcd.forC31H37N4O8[M+H]+ 593.2606;found 593.2604.
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-13)柱层析(石油醚∶乙酸乙酯=1∶1-乙酸乙酯),得浅黄色固体,收率94%。熔点118-120℃;1H NMR(400MHz,CDCl3):δ7.84(s,1H),7.82(s,1H),7.80(s,1H),7.37(s,1H),7.22(s,1H),5.73(d,J=8.4Hz,1H),5.29-5.32(m,2H),5.26(s,1H),5.08-5.17(m,2H),4.70(d,J=15.2Hz,1H),4.21-4.27(m,2H),4.12(s,6H),4.05(s,3H),3.95(s,3H),3.86-3.89(m,1H),3.41-3.54(m,2H),2.55(br,1H),2.33-2.41(m,2H),2.07(s,3H),2.04(s,3H),2.00-2.02(m,2H),1.99(s,3H),1.90-1.97(m,2H).13C NMR(100MHz,DMSO-d6):δ170.6,167.0,169.4,168.8,149.4,149.2,148.9,148.8,147.3,130.4,126.1,124.9,124.3,124.0,123.5,120.3,105.2,103.7,103.4,103.1,85.6,75.0,72.8,71.6,70.2,67.8,65.9,65.4,61.7,60.3,56.1,56.1,55.4,54.4,24.6,22.0,20.7,20.6,20.6,20.2.HRMS(ESI):calcd.forC41H49N4O14[M+H]+ 821.3240;found 821.3237.
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃半乳糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-14)柱层析(石油醚∶乙酸乙酯=1∶1-乙酸乙酯),得浅黄色固体,收率96%。熔点117-119℃;1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.86(s,1H),7.84(s,1H),7.45(s,1H),7.26(s,1H),5.75(d,J=9.2Hz,1H),5.50(d,J=3.2Hz,1H),5.43(t,J=10.0Hz,1H),5.33(s,1H),5.18(dd,J=10.4Hz,3.2Hz,1H),5.13(d,J=12.0Hz,1H),4.75(d,J=14.8Hz,1H),4.31(d,J=12.4Hz,1H),4.16-4.20(m,2H),4.15(s,3H),4.13(s,3H),4.10(br,1H),4.08(s,3H),3.98(s,3H),3.59(d,J=15.2Hz,1H),3.47(t,J=7.6Hz,1H),2.62-2.65(m,1H),2.36-2.49(m,2H),2.20(s,3H),2.08-2.11(m,1H),2.05(s,3H),2.02-2.04(m,1H),1.98(s,3H),1.92-1.95(m,1H),1.81(s,3H).13C NMR(100MHz,CDCl3):δ170.4,170.1,169.9,169.0,149.4,149.2,148.9,148.8,147.3,130.5,126.2,124.9,124.3,124.0,123.6,120.5,105.3,103.7,103.4,103.2,86.2,73.9,71.7,71.0,67.8,66.9,65.4,61.2,60.3,56.2,56.1,55.5,54.4,24.6,22.0,20.7,20.7,20.6,20.3.HRMS(ESI):calcd.for C41H49N4O14[M+H]+821.3240;found 821.3236.
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃甘露糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-15)柱层析(石油醚∶乙酸乙酯=1∶1-乙酸乙酯),得浅黄色固体,收率92%。熔点139-141℃;1H NMR(400MHz,CDCl3):δ7.86(s,2H),7.84(s,1H),7.38(s,1H),6.05(s,1H),5.60(s,1H),5.34(s,1H),5.26(s,1H),5.28(t,J=9.6Hz,1H),5.20(d,J=9.6Hz,1H),5.09(d,J=12.0Hz,1H),4.74(d,J=15.2Hz,1H),4.34(d,J=12.8Hz,1H),4.27-4.30(m,1H),4.19(d,J=12.8Hz,1H),4.15(s,3H),4.14(s,3H),4.08(s,3H),3.99(s,3H),3.88-3.92(m,1H),3.58(m,d,J=15.2Hz,1H),3.46-3.49(m,2H),2.61-2.65(m,1H),2.36-2.42(m,2H),2.09(s,6H),1.98-2.06(m,3H),1.96(s,3H),1.79(s,3H).13C NMR(100MHz,DMSO-d6):δ170.7,169.8,169.7,169.1,149.5,149.1,149.0,148.9,146.9,130.6,126.1,124.8,124.3,124.0,123.6,121.2,105.3,103.7,103.3,103.0,84.7,75.7,71.7,70.9,68.9,65.3,65.1,62.4,60.4,56.2,56.1,56.1,55.5,54.4,24.6,22.0,20.8,20.8,20.6,20.3.HRMS(ESI):calcd.forC41H49N4O14[M+H]+ 821.3240;found 821.3236.
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(β-D-吡喃葡萄糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-16)白色固体,收率95%。熔点172-174℃;1H NMR(400MHz,DMSO-d6):δ8.04(s,1H),8.03(s,1H),8.02(s,1H),7.74(s,1H),7.26(s,1H),5.46(d,J=9.2Hz,1H),5.30(d,J=3.6Hz,1H),5.25(d,J=4.4Hz,1H),5.11-5.14(m,1H),4.96(d,J=11.6Hz,1H),4.72(d,J=7.6Hz,1H),4.58(m,1H),4.05(s,6H),3.94(s,3H),3.87(s,3H),3.66-3.69(m,2H),3.38-3.44(m,3H),3.19-3.23(m,1H),2.35-2.37(m,1H),2.23-2.38(m,2H),1.86-1.93(m,3H).13C NMR(100MHz,DMSO-d6):δ149.2,148.7,148.6,144.9,129.9,125.4,124.3,123.8,123.5,122.8,122.4,105.2104.1,103.9,87.4,79.9,77.0,72.0,70.5,69.6,64.9,60.8,59.8,55.9,55.9,55.5,55.3,54.8,53.7,24.1,21.4.HRMS(ESI):calcd.for C33H41N4O10[M+H]+653.2817;found 653.2812.
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(β-D-吡喃半乳糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-17)白色固体,收率93%。熔点177-179℃;1H NMR(400MHz,DMSO-d6):δ8.06(s,1H),8.05(s,1H),8.03(s,1H),7.80(s,1H),7.31(s,1H),5.41(d,J=9.2Hz,1H),5.23(s,1H),5.01(d,J=11.6Hz,1H),4.78(d,J=16.0Hz,1H),3.35-3.39(m,1H),4.05(s,6H),3.96(s,3H),3.89(s,3H),3.74(s,1H),3.65-3.67(m,1H),3.47-3.53(m,4H),3.43-3.45(m,3H),2.29-2.36(m,2H),1.88-1.99(m,3H).13C NMR(100MHz,DMSO-d6):δ149.2,148.6,145.0,129.9,125.5,124.3,123.9,123.5,122.8,122.0,105.2,104.1,104.0,88.0,79.2,78.3,73.7,70.5,69.3,68.5,65.0,60.4,60.0,55.9,55.5,55.3,54.8,53.7,24.1,21.4.HRMS(ESI):calcd.for C33H41N4O10[M+H]+653.2817;found 653.2816.
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(β-D-吡喃甘露糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-18)白色固体,收率95%。熔点171-173℃;1H NMR(400MHz,DMSO-d6):δ8.05(s,1H),8.03(s,1H),7.97(s,1H),7.28(s,1H),5.92(s,1H),5.20-5.22(m,2H),4.94-5.06(m,3H),4.75(d,J=15.6Hz,1H),4.58-4.59(m,1H),4.05(s,7H),3.95(s,3H),3.88(s,3H),3.81(br,1H),3.70-3.74(m,1H),3.57(br,1H),3.45-3.47(m,2H),2.37-2.44(m,1H),2.26-2.29(m,2H),1.80-1.99(m,3H).13C NMR(100MHz,DMSO-d6):δ149.2,148.6,144.6,129.9,125.4,124.3,123.8123.5,122.8,122.7,105.1,104.1,103.9,85.8,80.3,73.2,70.5,70.4,66.2,64.9,61.1,60.0,55.9,55.9,55.5,55.3,54.8,53.7,29.6,24.1,21.4.HRMS(ESI):calcd.forC33H41N4O10[M+H]+ 653.2817;found 653.2812.
实施例3:以氨基甲酰氧基作为连接臂对(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱进行糖基化的方法。
将生物碱(R)-6-O-脱甲基安托芬(1)或(S)-6-O-脱甲基安托芬(2)(0.18g,0.52mmol)溶于二氯甲烷(40mL)中,加入2-脱氧-2-异氰酰基-1,3,4,6-四-O-乙酰基-β-D-葡萄糖(G)(0.27g,0.62mmol),加入0.4mL三乙胺,TLC检测反应完全,脱溶,常压柱层析(乙酸乙酯——二氯甲烷∶甲醇=10∶1),得产品I-19或I-20。
将14-羟基生物碱3(或4,5,6)(0.18g,0.44mmol)溶于二氯甲烷(40mL)中,加入2-脱氧-2-异氰酰基-1,3,4,6-四-O-乙酰基-β-D-葡萄糖(G)(0.76g,1.76mmol),加入0.4mL三乙胺,TLC检测反应完全,脱溶,常压柱层析(乙酸乙酯∶石油醚=10∶1),得产品I-21(或I-22,I-23,I-24)。
(13aS)-6-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧安托芬(I-19)白色固体,收率92%。熔点196-198℃;1H NMR(400MHz,CDCl3):δ8.16(s,1H),7.86(s,1H),7.84(d,J=13.2Hz,1H),7.31(s,1H),7.28(d,J=13.2Hz,1H),5.87(d,J=8.4Hz,1H),5.43(d,J=8.4Hz,1H),5.33-5.38(m,1H),5.17(t,J=9.6Hz,1H),4.67(d,J=14.8Hz,1H),4.28-4.32(m,1H),4.13(s,1H),4.10(s,3H),4.06(s,3H),3.96-4.02(m,1H),3.82-3.84(m,1H),3.68(d,J=14.8Hz,1H),3.44-3.49(m,1H),3.33-3.37(m,1H),2.89-2.95(m,1H),2.42-2.53(m,2H),2.23-2.25(m,1H),2.19(s,3H),2.14(s,3H),2.10(s,3H),2.06(s,3H),1.91-2.02(m,2H),1.76-1.82(m,1H).13CNMR(100MHz,CDCl3):δ171.0,170.7,169.4,154.4,149.6,148.6,129.8,127.8,127.1,126.9,126.5,124.0,123.7,119.7,114.1,103.9,92.5,72.8,72.4,67.9,65.8,61.6,60.1,55.9,55.9,55.4,55.0,53.8,33.8,31.3,29.7,21.6,21.0,20.8,20.7,20.6,15.3.HRMS(ESI):calcd.for C37H43N2O13[M+H]+ 723.2760;found 723.2765.
(13aR)-6-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧安托芬(I-20)白色固体,收率93%;熔点203-205℃;1H NMR(400MHz,CDCl3):δ8.19(s,1H),7.85-7.91(m,2H),7.30-7.34(m,2H),5.88(d,J=8.8Hz,1H),5.33-5.38(m,1H),5.18(t,J=9.6Hz,1H),4.70(d,J=14.8Hz,1H),4.29-4.33(m,1H),4.14(s,1H),4.11(s,3H),4.07(s,3H),3.98-4.00(m,1H),3.83-3.85(m,1H),3.70(d,J=14.8Hz,1H),3.46-3.47(m,1H),3.35-3.36(m,1H),2.90-2.96(m,1H),2.46-2.50(m,2H),2.24-2.27(m,1H),2.20(s,3H),2.14(s,3H),2.10(s,3H),2.06(s,3H),2.03-2.04(m,1H),1.91-1.95(m,2H),1.78-1.81(m,1H).13C NMR(100MHz,CDCl3):δ171.0,170.7,169.4,154.5,149.6,148.6,148.5,129.8,127.8,127.1,126.8,126.4,124.1,123.6,119.7,114.1,103.9,103.8,92.4,72.8,72.4,67.9,61.6,60.1,55.9,55.9,55.4,55.0,53.8,33.7,31.3,21.6,21.0,20.8,20.7,20.6.HRMS(ESI):calcd.for C37H43N2O13[M+H]+723.2760;found 723.2765.
(13aS,14S)-2,3,6,7-四甲氧基-14-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧菲并[9,10-b]吲哚里西啶(I-21)白色固体,收率86%;熔点200-202℃;1H NMR(400MHz,CDCl3):δ7.80(s,1H),7.78(s,1H),7.52(s,1H),7.06(s,1H),6.57(s,1H),5.72(d,J=8.4Hz,1H),5.09-5.17(m,2H),4.64-4.73(m,1H),4.28(dd,J=13.4Hz,2.4Hz,1H),4.16(br,1H),4.13(s,3H),4.10(s,3H),4.04-4.06(m,1H),3.98(br,6H),3.82-3.84(m,1H),3.63-3.67(m,1H),3.50-3.57(m,1H),2.74-2.78(m,1H),2.46-2.56(m,1H),2.14(s,3H),2.10(br,4H),2.03(br,2H),2.00(s,3H),1.87-1.90(m,2H),1.77(s,3H).13C NMR(100MHz,CDCl3):δ170.8,170.5,169.6,169.2,156.7,149.7,149.4,149.0,148.9,125.2,125.1,124.2,124.1,123.3,104.1,103.6,103.4,103.3,92.9,72.8,71.78,68.3,63.9,61.9,61.8,61.8,56.2,56.2,56.1,55.0,54.7,53.6,24.7,21.5,20.9,20.7,20.1.HRMS(ESI):calcd.for C39H47N2O15[M+H]+783.2971;found 783.2979.
(13aR,14S)-2,3,6,7-四甲氧基-14-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧菲并[9,10-b]吲哚里西啶(I-22)白色固体,收率83%;熔点205-207℃;1H NMR(400MHz,CDCl3):δ7.77(s,1H),7.68(s,1H),7.21(s,1H),6.97(s,1H),6.55(d,J=7.2Hz,1H),5.62(d,J=8.8Hz,1H),5.09-5.11(m,2H),4.38(d,J=14.8Hz,1H),4.24(dd,J=14.8Hz,4.4Hz,1H),4.13(s,3H),4.08-4.10(m,2H),4.05(s,3H),3.98(s,3H),3.81(s,3H),3.72-3.76(m,1H),3.47-3.52(m,1H),3.30-3.34(m,1H),2.46-2.56(m,2H),2.20(s,3H),2.12-2.17(m,1H),2.09(s,3H),2.01(s,3H),1.89-1.98(m,3H),1.83(s,3H).13C NMR(100MHz,CDCl3):δ170.5,170.4,169.7,169.4,156.7,148.6,148.1,147.8,147.7,129.4,125.1,124.3,124.0,123.6,122.6,103.9,103.3,103.0,102.7,93.6,75.1,72.7,71.3,69.0,65.9,65.2,62.4,55.8,55.6,55.0,54.3,54.1,53.1,29.7,21.9,21.1,20.7,20.6,19.8.HRMS(ESI):calcd.for C39H47N2O15[M+H]+783.2971;found 783.2969.
(13aR,14R)-2,3,6,7-四甲氧基-14-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧菲并[9,10-b]吲哚里西啶(I-23)白色固体,收率89%;熔点205-207℃;1H NMR(400MHz,CDCl3):δ7.73(s,1H),7.64(s,1H),7.34(s,1H),6.85(s,1H),6.51(s,1H),5.48-5.59(m,2H),5.16(t,J=9.6Hz,1H),5.06(t,J=9.6Hz,1H),4.38(d,J=11.6Hz,1H),4.20-4.27(m,1H),4.14(s,3H),4.08-4.13(m,1H),4.05(s,3H),3.91(s,3H),3.83-3.86(m,1H),3.75(s,3H),3.38-3.39(m,1H),2.73(br,1H),2.37(d,J=8.0Hz,1H),2.11(s,3H),2.07(s,3H),2.04(br,1H),2.00(s,3H),2.00(s,3H),1.91(br,2H),1.75(s,2H).13C NMR(100MHz,CDCl3):δ170.8,170.4,169.5,169.2,157.1,149.3,148.9,148.7,148.5,128.9,125.2,124.9,124.2,124.0,123.3,104.0,103.5,103.3,103.2,92.2,73.7,72.9,68.0,63.4,61.6,60.5,56.1,56.0,55.8,55.1,54.1,53.7,24.8,21.6,21.2,20.9,20.7,20.3.HRMS(ESI):calcd.for C39H47N2O15[M+H]+783.2971;found 783.2979.
(13aS,14R)-2,3,6,7-四甲氧基-14-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧菲并[9,10-b]吲哚里西啶(I-24)白色固体,收率83%;熔点206-208℃;1H NMR(400MHz,CDCl3):δ7.61(s,1H),7.40(s,1H),6.83(s,1H),6.44(s,1H),6.43(d,J=7.2Hz,1H),5.66(d,J=8.8Hz,1H),5.17(t,J=9.6Hz,1H),5.05(t,J=10.0Hz,1H),4.44-4.48(m,1H),4.16-4.22(m,2H),4.16(s,3H),4.03-4.08(m,3H),3.99(s,3H),3.86-3.89(m,1H),3.76(s,3H),3.39(s,3H),3.16(br,1H),2.60-2.61(m,1H),2.29-2.34(m,1H),2.19(s,3H),2.08-2.14(m,2H),2.06(s,3H),1.99(s,3H),1.88(s,3H),1.80-1.87(m,4H).13C NMR(100MHz,CDCl3):δ170.9,170.6,169.3,169.3,156.8,148.8,148.4,147.9,147.9,125.2,124.4,124.1,123.8,122.8,104.2,103.3,103.1,102.8,91.8,74.4,72.9,67.9,65.2,61.4,56.0,55.9,55.8,55.0,54.5,54.0,29.5,22.1,21.0,20.8,20.7,20.3.HRMS(ESI):calcd.for C39H47N2O15[M+H]+ 783.2971;found 783.2960.
实施例4:安托芬6-位衍生物I-25~I-36的制备
6-O-脱甲基安托芬6-位衍生物I-25~I-34的制备
将(R)/(S)-6-O-脱甲基安托芬1或2(0.81g,2.33mmol)溶于15mL N,N-二甲基甲酰胺中,加入Cs2CO3(0.91g,2.79mmol),室温搅拌0.5h,冰浴条件下缓慢滴加2.79mmol溴乙烷或α-溴代物(溴乙腈、炔丙基溴、溴代乙酰胺和α-溴乙酸乙酯)的10mL N,N-二甲基甲酰胺溶液,缓慢升至室温,室温下反应直至TLC监测反应完全。加入30mL乙酸乙酯和30mL水,分液,乙酸乙酯萃取水相,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,脱溶,柱层析(乙酸乙酯做洗脱剂),可得产品I-25~I-34。
(R)-6-O-乙基安托芬(I-25)白色固体,收率88%,熔点211-213℃;1H NMR(400MHz,CDCl3):δ7.86(s,2H),7.76(d,J=8.8Hz,1H),7.25(s,1H),7.16(d,J=9.2Hz,1H),4.64(d,J=15.2Hz,1H),4.21(q,J=6.8Hz,2H),4.07(s,3H),4.03(s,3H),3.62(d,J=15.2Hz,1H),3.43(t,J=8.4Hz,1H),3.66(d,J=15.6Hz,1H),2.80-2.87(m,1H),2.36-2.43(m,2H),2.15-2.25(m,1H),1.98-2.03(m,1H),1.83-1.90(m,1H),1.67-1.75(m,1H),1.51(t,J=6.8Hz,1H).13C NMR(100MHz,CDCl3):δ155.7,148.2,147.2,129.1,126.8,126.0,125.6,124.8,124.4,123.1,123.0,122.4,114.0,104.5,102.8,102.7,62.6,59.1,54.9,54.8,54.0,52.8,32.6,30.2,20.5,14.0.HRMS(ESI):calcd.for C24H28NO3[M+H]+ 378.2064;found 378.2069.
(S)-6-O-乙基安托芬(I-26)白色固体,收率89%,熔点212-214℃;1H NMR,13C NMR andHRMS(ESI)同I-25。
(R)-6-O-炔丙基安托芬(I-27)白色固体,收率85%,熔点197-199℃;1H NMR,13C NMR andHRMS(ESI)同I-28(实例2)。
(R)-6-O-氰基甲基安托芬(I-29)黄色固体,收率93%,熔点228-230℃;1H NMR(400MHz,DMSO-d6):δ8.03(d,J=2.0Hz,1H),7.88(s,1H),7.87(d,J=7.6Hz,1H),7.32(s,1H),7.23-7.26(m,1H),4.96(s,2H),4.69(d,J=14.8Hz,1H),4.12(s,3H),4.07(s,3H),3.70(d,J=14.8Hz,1H),3.47(t,J=8.0Hz,1H),3.34-3.38(m,1H),2.88-2.96(m,2H),2.42-2.51(m,1H),2.21-2.29(m,1H),2.01-2.07(m,1H),1.91-1.97(m,1H),1.75-1.82(m,1H).13C NMR(100MHz,DMSO-d6)δ154.6,149.8,148.7,130.2,127.3,127.1,126.7,125.7,124.9,123.5,115.5,114.9,107.3,104.1,103.8,60.3,56.1,56.0,55.2,54.5,53.9,33.9,31.4,21.7.HRMS(ESI):calcd.forC24H25N2O3[M+H]+ 389.1860;found 389.1858.
(S)-6-O-氰基甲基安托芬(I-30)黄色固体,收率92%,227-229℃;1H NMR,13C NMR,HRMS和I-29相同。
(R)-6-O-氨基甲酰基甲基安托芬(I-31)浅黄色固体,收率92%,熔点232-234℃;1H NMR(400MHz,DMSO-d6):δ8.13(d,J=2.4Hz,1H),8.06(s,1H),7.84(d,J=9.2Hz,1H),7.66(s,1H),7.50(s,1H),7.34(s,1H),7.21(dd,J=9.2Hz,2.4Hz,1H),4.69(s,2H),4.60(d,J=15.2Hz,1H),4.02(s,3H),3.95(s,3H),3.60(d,J=15.2Hz,1H),3.34-3.37(m,2H),2.75-2.82(m,1H),2.38-2.47(m,2H),2.14-2.18(m,1H),1.82-1.88(m,2H),1.63-1.68(m,1H).13C NMR(100MHz,DMSO-d6):δ170.2,155.8,149.3,148.4,129.7,126.3,125.7,124.3,123.6,123.0,116.0,105.9,104.5,104.2,67.2,59.9,55.8,55.4,54.4,53.1,32.8,30.8,21.2.HRMS(ESI):calcd.forC24H27N2O4[M+H]+ 407.1965;found 407.1959.
(S)-6-O-氨基甲酰基甲基安托芬(I-32)浅黄色固体,收率92%,熔点230-232℃;1H NMR,13CNMR,HRMS(ESI)和I-31相同。
(R)-6-O-乙氧基甲酰基甲基安托芬(I-33)白色固体,收率96%,熔点174-176℃;1H NMR(400MHz,CDCl3):δ7.98(s,1H),7.89(s,1H),7.83(d,J=8.8Hz,1H),7.32(s,1H),7.21(dd,J=1.6,8.8Hz,1H),4.82(s,2H),4.67(d,J=15.2Hz,1H),4.32(q,J=7.2Hz,2H),4.11(s,3H),4.07(s,3H),3.69(d,J=15.2Hz,1H),3.46(t,J=8.0Hz,1H),3.33-3.38(m,1H),2.86-2.93(m,1H),2.42-2.50(m,2H),2.21-2.29(m,1H),1.99-2.06(m,1H),1.87-1.95(m,1H),1.74-1.82(m,1H),1.32(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ169.2,155.8,149.7,148.6,130.3,127.3,126.8,126.3,125.0,124.6,123.6,114.8,106.7,104.2,104.0,66.1,61.6,60.4,56.2,56.1,55.2,54.0,34.0,31.5,21.8,14.4.HRMS(ESI):calcd.for C26H30NO5[M+H]+ 436.2118;found 436.2124.
(S)-6-O-乙氧基甲酰基甲基安托芬(I-34)白色固体,收率96%,173-175℃;1H NMR,13C NMR,HRMS(ESI)和I-33相同。
6-O-脱甲基安托芬6-位衍生物I-35、I-36的制备
将(R)/(S)-6-O-乙氧基甲酰基甲基安托芬(I-33、I-34)(0.42g,0.97mmol)溶于THF(15mL)中,冰浴下加入四氢铝锂(0.11g,2.90mmol),升至室温反应,冰浴下加入水分解掉四氢铝锂,用二氯甲烷萃取,无水硫酸钠干燥,过滤,脱溶,可得(R)/(S)-6-O-(2-羟基乙基)安托芬(I-35、I-36)。
(R)-6-O-(2-羟基乙基)安托芬(I-35)白色固体,收率97%,熔点214-216℃;1H NMR(400MHz,CDCl3):δ8.09(d,J=1.6Hz,1H),8.07(s,1H),7.81(d,J=8.8Hz,1H),7.32(s,1H),7.23(dd,J=1.6,8.8Hz,1H),4.55(d,J=15.2Hz,1H),4.24(t,J=4.8Hz,2H),4.02(s,3H),3.94(s,3H),3.82(q,J=4.8Hz,1H),3.52(d,J=14.8Hz,1H),3.27-3.33(m,2H),2.72-2.78(m,1H),2.28-2.39(m,2H),2.11-2.19(m,1H),1.79-1.90(m,2H),1.61-1.68(m,1H).13C NMR(100MHz,CDCl3):δ156.7,149.3,148.3,129.8,126.4,126.4,125.5,124.2,123.3,123.0,115.7,105.6,104.5,104.1,69.8,59.9,59.8,55.8,55.4,54.5,53.3,33.1,30.9,21.2.HRMS(ESI):calcd.for C24H28NO4[M+H]+ 394.2013;found 394.2010.
(S)-6-O-(2-羟基乙基)安托芬(I-36)白色固体,收率97%,熔点216-218℃;1H NMR,13C NMR,HRMS(ESI)和I-35相同。
实施例5:6-O-脱甲基安托芬和14-羟基娃儿藤碱糖基化产物(I)的理化性质研究
上述优选化合物与各自的对照样品(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱相比,其特征在于优选化合物与已知化合物相比具有突出优点,具体表现在:(1)上述优选化合物I-1~I-36与各自的对照样品(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱相比,化学稳定性明显增强,同等条件下室温放置或者日光照射同等时间,变质速度明显比他们慢;(2)上述优选化合物糖基化产物I-1~I-3,I-6,I-10~I-12,I-16~I-18与各自的对照样品(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱相比,水溶性明显增强,(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱不溶于水,而以上脱除糖上保护基的糖基化产物的水溶性均大于4mg/mL;上述两点对化合物在农药上的应用具有至关重要的作用。
实施例6:抗烟草花叶病毒活性的测定,测定程序如下:
1、病毒提纯及浓度测定:
病毒提纯及浓度测定参照南开大学元素所生测室编制烟草花叶病毒SOP规范执行。病毒粗提液经2次聚乙二醇离心处理后,测定浓度,4℃冷藏备用。
2、化合物溶液配制:
称量后,原药加入DMF溶解,制得1×105μg/mL母液,后用含1‰吐温80水溶液稀释至所需浓度;宁南霉素制剂直接兑水稀释。
3、离体作用:
摩擦接种珊西烟适龄叶片,用流水冲洗,病毒浓度10μg/mL。收干后剪下,沿叶中脉对剖,左右半叶分别浸于1‰吐温水及药剂中,30min后取出,于适宜光照温度下保湿培养,每3片叶为1次重复,重复3次。3d后记录病斑数,计算防效。
4、活体保护作用:
选长势均匀一致的3-5叶期珊西烟,全株喷雾施药,每处理3次重复,并设1‰吐温80水溶液对照。24h后,叶面撒布金刚砂(500目),用毛笔蘸取病毒液,在全叶面沿支脉方向轻擦2次,叶片下方用手掌支撑,病毒浓度10μg/mL,接种后用流水冲洗。3d后记录病斑数,计算防效。
5、活体治疗作用:
选长势均匀一致的3-5叶期珊西烟,用毛笔全叶接种病毒,病毒浓度为10μg/mL,接种后用流水冲洗。叶面收干后,全株喷雾施药,每处理3次重复,并设1‰吐温80水溶液对照。3d后记录病斑数,计算防效。
6、活体钝化作用:
选长势均匀一致的3-5叶期珊西烟,将药剂与等体积的病毒汁液混合钝化30min后,摩擦接种,病毒浓度20μg/mL,接种后即用流水冲洗,重复3次,设1‰吐温80水溶液对照。3d后数病斑数,计算结果。
抑制率(%)=[(对照枯斑数-处理枯斑数)/对照枯斑数]×100%
表1 部分菲并吲哚里西啶生物碱糖基化产物及6-位衍生化产物抗TMV活性测试结果:
从表1可见,合成的菲并吲哚里西啶生物碱糖基化产物及6-位衍生化产物大部分都表现出了很好的离体和活体抗烟草花叶病毒(TMV)活性,尤其是糖基化产物I-2,I-3和安托芬6-位衍生化产物I-27,I-28,I-29,I-31,I-35的抗烟草花叶病毒活性比商品化品种宁南霉素的活性更好,具有极大的开发价值。
Claims (9)
1.如下通式所示结构的菲并吲哚里西啶生物碱糖基化及6-位衍生化产物(I)
R1和R2均代表甲氧基、R3代表O-Sugar;
R1和R2均代表甲氧基、R3代表
R1和R2均代表甲氧基、R3代表
R2和R3均代表氢、R1代表O-Sugar;
R2和R3均代表氢、R1代表
R2和R3均代表氢、R1代表
R2和R3均代表氢、R1代表OCH2R;
以上通式中包括所有13a位和14位的立体异构体。
2.优选的通式I所示的化合物是:
(13aS)-6-O-安托芬-β-D-葡萄糖苷(I-1);
(13aS)-6-O-安托芬-β-D-半乳糖苷(I-2);
(13aS)-6-O-安托芬-β-D-甘露糖苷(I-3);
(13aS)-6-O-安托芬-2,3,4,6-四-O-乙酰基-β-D-甘露糖苷(I-4);
(13aR,14S)-14-O-2,3,6,7-四甲氧基菲并[9,10-b]吲哚里西啶-2,3,4,6-四-O-乙酰基-β-D-葡萄糖苷(I-5);
(13aR,14S)-14-O-2,3,6,7-四甲氧基菲并[9,10-b]吲哚里西啶-β-D-葡萄糖苷(I-6);
(13aS)-6-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖)-1H-1,2,3-三唑)甲基安托芬(I-7);
(13aS)-6-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃半乳糖)-1H-1,2,3-三唑)甲基安托芬(I-8);
(13aS)-6-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃甘露糖)-1H-1,2,3-三唑)甲基安托芬(I-9);
(13aS)-6-O-(4-取代-1-(β-D-吡喃葡萄糖)-1H-1,2,3-三唑)甲基安托芬(I-10);
(13aS)-6-O-(4-取代-1-(β-D-吡喃半乳糖)-1H-1,2,3-三唑)甲基安托芬(I-11);
(13aS)-6-O-(4-取代-1-(β-D-吡喃甘露糖)-1H-1,2,3-三唑)甲基安托芬(I-12);
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-13);
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃半乳糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-14);
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(2,3,4,6-四-O-乙酰基-β-D-吡喃甘露糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-15);
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(β-D-吡喃葡萄糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-16);
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(β-D-吡喃半乳糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-17);
(13aS,14S)-2,3,6,7-四甲氧基-14-O-(4-取代-1-(β-D-吡喃甘露糖)-1H-1,2,3-三唑)甲基菲并[9,10-b]吲哚里西啶(I-18);
(13aR)-6-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧安托芬(I-19);
(13aS)-6-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧安托芬(I-20);
(13aS,14S)-2,3,6,7-四甲氧基-14-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧菲并[9,10-b]吲哚里西啶(I-21);
(13aR,14S)-2,3,6,7-四甲氧基-14-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧菲并[9,10-b]吲哚里西啶(I-22);
(13aR,14R)-2,3,6,7-四甲氧基-14-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧菲并[9,10-b]吲哚里西啶(I-23);
(13aS,14R)-2,3,6,7-四甲氧基-14-(1,3,4,6-四-O-乙酰基-β-D-葡萄糖-2-脱氧-2-氨基)甲酰氧菲并[9,10-b]吲哚里西啶(I-24);
(R)-6-O-乙基安托芬(I-25);
(S)-6-O-乙基安托芬(I-26);
(R)-6-O-炔丙基安托芬(I-27);
(S)-6-O-炔丙基安托芬(I-28);
(R)-6-O-氰基甲基安托芬(I-29);
(S)-6-O-氰基甲基安托芬(I-30);
(R)-6-O-氨基甲酰基甲基安托芬(I-31);
(S)-6-O-氨基甲酰基甲基安托芬(I-32);
(R)-6-O-乙氧基甲酰基甲基安托芬(I-33);
(S)-6-O-乙氧基甲酰基甲基安托芬(I-34);
(R)-6-O-(2-羟基乙基)安托芬(I-35);
(S)-6-O-(2-羟基乙基)安托芬(I-36)。
3.权利要求1和2所述的菲并吲哚里西啶生物碱糖基化及6-位衍生化产物(I),其特征在于优选化合物与已知化合物相比具有突出优点,具体表现在:(1)上述优选化合物I-1~I-36与各自的对照样品(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱相比,化学稳定性明显增强,同等条件下室温放置或者日光照射同等时间,变质速度明显比他们慢;(2)上述优选化合物糖基化产物I-1~I-3,I-6,I-10~I-12,I-16~I-18与各自的对照样品(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱相比,水溶性明显增强,(R)/(S)-6-O-脱甲基安托芬和14-羟基娃儿藤碱不溶于水,而以上脱除糖上保护基的糖基化产物的水溶性均大于4mg/mL;上述两点对化合物在农药上的应用具有至关重要的作用。
4.制备6-O-脱甲基安托芬和14-羟基娃儿藤碱氧苷的方法(路线一)
路线一
2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯(A),2,3,4,6-四-O-乙酰基-α-D-吡喃半乳糖三氯乙酰亚胺酯(B)和2,3,4,6-四-O-乙酰基-α-D-吡喃甘露糖三氯乙酰亚胺酯(C)作为糖基供体和6-O-脱甲基安托芬及14-羟基娃儿藤碱在BF3·Et2O做催化剂的条件下发生氧苷化反应,生成氧苷I。
5.以1,2,3-三唑作为连接臂为连接臂对6-O-脱甲基安托芬和14-羟基娃儿藤碱进行糖基化的方法进行糖基化的方法(路线二)
首先利用6-O-脱甲基安托芬及14-羟基娃儿藤碱DCB-3505的羟基和炔丙基溴反应,引入端炔,在Cu+催化下分别和2,3,4,6-四乙酰基-β-D-吡喃叠氮葡萄糖(D),2,3,4,6-四乙酰基-β-D-吡喃叠氮葡萄糖(E)和2,3,4,6-四乙酰基-β-D-吡喃叠氮葡萄糖(F)发生Huisgen 1,3-偶极环加成反应即点击化学反应可以高效地合成1,4-氮杂三唑糖苷,然后在碱性条件下脱除糖上的保护基可得目标产物I。
6.以氨基甲酰氧基作为连接臂对6-O-脱甲基安托芬和14-羟基娃儿藤碱进行糖基化的方法(路线三)
2-脱氧-2-异氰酰基-1,3,4,6-四-O-乙酰基-β-D-葡萄糖和6-O-脱甲基安托芬及14-羟基娃儿藤碱在Et3N做催化剂的条件下发生反应,一步生成目标产物I。
7.安托芬6-位衍生物I制备方法(路线四):
利用(R)/(S)-6-O-脱甲基安托芬6-位酚羟基较高的反应活性,在碱性条件下可以和α-溴代物(溴乙腈、炔丙基溴、溴代乙酰胺和α-溴乙酸乙酯)发生亲核取代反应生成醚,从而在C6位引入一个侧链,可得目标化合物I,在侧链上引入乙氧甲酰氧基后还可以发生还原反应。
8.权利要求1所述的菲并吲哚里西啶生物碱糖基化产物I的应用,其特征在于它们的抗植物病毒活性,能很好地抑制烟草花叶病毒(TMV)。
9.按照权利要求7所述的菲并吲哚里西啶生物碱糖基化产物I的应用,其特征在于化合物I-2,I-3,I-27,I-28,I-29,I-31,I-35具有特别优异的抗植物病毒活性。
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