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本发明涉及化学技术领域，尤其是一种姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物及其制备方法及应用。
背景技术：
根据药物设计中药效团和骨架迁越原理,把具有生物活性基团拼接到具有活性分子骨架中在有机化学和医药化学中是极其重要的研究领域。(1)多官能团氧化吲哚广泛存在天然产物和合成药物分子中，其中，尤其3,3'-吡咯双螺环氧化吲哚因为具有广泛的生物活性，吸引了许多化学工作者及医药化学团队的广泛关注，例如，化合物i是具有抗细菌活性；化合物ii具有抗真菌活性，化合物iii具有抗肿瘤活性。(2)倍半萜姜黄酮turmeronei,(s)-芳姜黄酮(s)-ar-turmeroneii,姜黄酮衍生物iii-v从姜黄的根茎分离出来，被报道具有细胞毒、抗炎，抗癌和抗蛇毒活性。姜黄作为食品中的一种配料和调味品，也作为一种药物使用。因此,根据药物设计中药效团和骨架迁越原理,鉴于3,3'-吡咯双螺环氧化吲哚骨架化合物和姜黄酮具有潜在的生物活性。因此，把姜黄酮骨架拼接到3,3'-吡咯双螺环氧化吲哚骨架，合成一系列新的潜在多活性官能团的氧化吲哚衍生物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值(如附图8所示)。
技术实现要素：
本发明的目的是：提供一种姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物及其制备方法与应用，它是一类重要的医药中间体类似物和药物分子类似物，对药物筛选和制药行业具有重要的应用价值，且其合成方法非常经济简便。
本发明还发现该类化合物在制备防治肿瘤疾病药物中的应用。
本发明是这样实现的：姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物，该化合物具有如下通式(ⅰ)的结构：
式中，r1为苯基、乙基、甲基或苄基；r2为甲基、h或卤素；r3为甲基、乙基或苄基；r4为甲基、h或卤素；x为c或s。
将各种取代的靛红、二烯酮3-烯基氧化吲哚与脯氨酸或硫代脯氨酸或肌氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物。
合成路线如下：
其中各种取代的靛红1以及二烯酮3-烯基氧化吲哚2的结构式，其取代基满足r1为苯基、乙基、甲基或苄基；r2为甲基、h或卤素；r3为甲基、乙基或苄基；r4为甲基、h或卤素；x为c或s。
所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、乙醚、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
各种取代的靛红、二烯酮3-烯基氧化吲哚与脯氨酸或硫代脯氨酸或肌氨酸，在有机溶剂中反应温度为50-100℃，反应时间为5-20小时。
姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物在制备防治肿瘤疾病药物中的应用。
通过采用上述技术方案，以各种取代的靛红、二烯酮3-烯基氧化吲哚与脯氨酸或硫代脯氨酸或肌氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物，该类氧化吲哚骨架包含潜在的生物活性姜黄酮骨架，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。且该化合物对三种肿瘤细胞株如人前列腺(pc-3)，人肺癌细胞(a549)以及人白血病细胞(k562)具有抑制活性的作用。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。
附图说明
附图1及附图2为本发明的实施例1的化合物3aa谱图数据；
附图3及附图4为本发明的实施例2的化合物4aa谱图数据；
附图5及附图6为本发明的实施例3的化合物5aa谱图数据；
附图7为本发明的实施例化合物3aa,3ba和5ba单晶图；
附图8为本发明的实施例的化合物检测结果图。
具体实施方式
本发明的实施例1：在反应管中依次加入89.2mgn-甲基靛红1a(0.4mmol)，144.6mg二烯酮3-烯基氧化吲哚2a(0.6mmol)，92.0mg脯氨酸(0.8mmol)和10ml乙醇溶液，回流反应5h，tlc检测基本反应完全，直接上样经柱层析(洗脱剂：v(石油醚)：v(乙酸乙酯)＝4:1)纯化得化合物3aa，黄色固体，熔点：176.5-177.8℃，dr：20:1；产率89％。核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.43(s,3h),1.61(s,3h),2.05-2.10(m,2h),2.21-2.29(m,2h),2.47-2.53(m,1h),2.66-2.71(m,1h),2.88(s,3h),3.18(s,3h),4.58-4.63(m,2h),5.75(s,1h),6.39-6.41(m,1h),6.51-6.56(m,2h),6.60(d,j＝8.0hz,1h),7.03-7.13(m,2h),7.20-7.25(m,1h),7.77(d,j＝7.6hz,1h)；13cnmr(cdcl3,100mhz)δ:20.0,26.0,26.2,27.1,30.9,31.3,47.3,59.0,65.0,67.2,107.4,121.6,122.3,123.1,125.1,125.5,127.4,128.8,129.2,143.3,143.8,154.4,172.9,177.1,196.9；hrms(esi-tof)m/z:calcd.forc28h29n3nao3[m+na]+:478.2107；found:478.2109.
化合物3ba至3le的制备方法同化合物3aa，投料比与化合物3aa相同，可得到化合物3ba至3le，反应产率和非对映选择性见表1和表2，但需强调的是本发明的化合物不限于表1所表示的内容。
表1为一种姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物的化学结构
本实施例1制备化合物3ba：黄色固体；熔点：112.2-113.6℃；产率：83％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.40(s,3h),1.57(s,3h),2.02-2.08(m,2h),2.19-2.26(m,2h),2.50-2.55(m,1h),2.66-2.69(m,1h),2.87(s,3h),4.57-4.63(m,2h),4.76(d,j＝12.4hz,1h),4.94(d,j＝12.4hz,1h),5.74(s,1h),6.34-6.37(m,1h),6.41-6.44(m,1h),6.50(d,j＝6.0hz,1h),6.83-6.87(m,1h),7.05-7.08(m,1h),7.15-7.19(m,2h),7.23-7.26(m,2h),7.30-7.32(m,2h),7.73(d,j＝6.0hz,1h)；13cnmr(cdcl3,100mhz)δ:20.0,26.2,27.0,30.8,31.4,44.0,47.3,59.1,65.0,67.0,107.4,108.6,122.2,123.1,127.3,127.4,127.5,128.6,135.9,143.0,143.3,154.4,172.9,177.0,196.9；hrms(esi-tof)m/z:calcd.forc34h33n3nao3[m+na]+:554.2420；found:554.2423.
本实施例1制备化合物3ca：黄色固体；熔点：117.2-118.6℃；产率：61％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.47(s,3h),1.64(s,3h),2.08-2.16(m,2h),2.24-2.31(m,2h),2.66-2.71(m,1h),2.82-2.85(m,1h),2.96(s,3h),4.66-4.68(m,2h),5.80(s,1h),6.49-6.51(m,1h),6.56-6.63(m,3h),6.99-7.03(m,1h),7.14-7.17(m,1h),7.24-7.28(m,1h),7.38-7.41(m,1h),7.52-7.54(m,4h),7.83(d,j＝5.6hz,1h)；13cnmr(cdcl3,100mhz)δ:20.0,26.2,27.0,30.8,31.2,47.4,58.9,65.1,67.5,107.4,108.6,121.8,123.1,125.7,126.9,127.4,128.0,128.9,129.5,143.4,143.6,154.3,172.9,176.7,196.9；hrms(esi-tof)m/z:calcd.forc33h31n3nao3[m+na]+:540.2263；found:540.2265.
本实施例制备化合物3da：黄色固体；熔点：185.4-186.8℃；产率：72％,13:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.45(s,3h),1.63(s,3h),2.05-2.11(m,2h),2.23-2.33(m,2h),2.46(s,3h),2.48-2.53(m,1h),2.69-2.72(m,1h),2.93(s,3h),3.49(s,3h),4.58-4.65(m,2h),5.76(s,1h),6.36(d,j＝5.6hz,1h),6.41-6.44(m,1h),6.56(d,j＝6.4hz,1h),6.80(d,j＝6.0hz,1h),7.10-7.13(m,1h),7.21-7.24(m,1h),7.77(d,j＝6.0hz,1h)；13cnmr(cdcl3,100mhz)δ:19.2,20.0,26.3,27.1,29.5,30.8,31.2,47.3,59.2,64.9,67.4,107.4,118.7,121.3,122.2,123.1,123.6,127.5,128.8,133.0,141.5,143.3,154.2,173.0,177.8,197.0；hrms(esi-tof)m/z:calcd.forc29h31n3nao3[m+na]+:492.2263；found:492.2265.
本实施例制备化合物3ea：黄色固体；熔点：106.8-108.5℃；产率：92％,20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.42(s,3h),1.60(s,3h),2.06-2.08(m,2h),2.22-2.25(m,2h),2.46-2.49(m,1h),2.65-2.68(m,1h),2.93(s,3h),3.56(s,3h),4.56-4.59(m,2h),5.72(s,1h),6.39-6.43(m,2h),6.55(d,j＝8.0hz,1h),6.95-6.98(m,1h),7.07-7.11(m,1h),7.18-7.25(m,1h),7.72-7.74(m,1h)；13cnmr(cdcl3,100mhz)δ:20.1,26.4,27.2,29.6,30.9,31.4,47.4,59.2,65.1,67.4,107.7,114.7,122.2,122.4,123.1,124.2,126.2,127.5,128.1,129.1,131.6,139.7,143.4,154.7,172.8,177.5,196.7；hrms(esi-tof)m/z:calcd.forc28h28cln3nao3[m+na]+:512.1717；found:512.1717.
本实施例制备化合物3fa：黄色固体；熔点：204.3-206.5℃；产率：82％,10:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.40(s,3h),1.57(s,3h),2.02-2.06(m,2h),2.17-2.24(m,2h),2.41-2.47(m,1h),2.63-2.67(m,1h),2.86(s,3h),3.12(s,3h),4.50-4.57(m,2h),5.70(s,1h),6.09-6.12(m,1h),6.46-6.49(m,1h),6.54(d,j＝7.5hz,1h),6.69-6.73(m,1h),7.07-7.10(m,1h),7.18-7.22(m,1h),7.70(d,j＝7.0hz,1h)；13cnmr(cdcl3,125mhz)δ:20.0,26.1,26.2,27.1,30.8,31.2,47.3,59.0,65.1,67.1,107.6,107.7,113.7(d,jcf＝25.0hz),115.3(d,jcf＝23.8hz),122.4,123.0,126.1,127.1,127.2,129.2,139.7,143.2,154.6,158.3(d,jcf＝238.8hz),172.6,176.8,196.6；hrms(esi-tof)m/z:calcd.forc28h28fn3nao3[m+na]+:496.2012；found:496.2015.
本实施例制备化合物3ga：黄色固体；熔点：243.3-245.5℃；产率：85％,19:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.48(s,3h),1.64(s,3h),2.08-2.12(m,2h),2.23-2.29(m,2h),2.48-2.53(m,1h),2.72-2.75(m,1h),2.93(s,3h),3.18(s,3h),4.58-4.61(m,2h),5.77(s,1h),6.49-6.51(m,2h),6.62(d,j＝6.4hz,1h),7.16-7.21(m,2h),7.27-7.31(m,1h),7.76(d,j＝6.0hz,1h)；13cnmr(cdcl3,100mhz)δ:20.0,26.1,26.2,27.1,30.8,31.3,47.3,58.9,65.2,67.2,107.7,108.7,114.3,122.4,122.9,127.2,128.8,129.2,131.9,142.7,143.2,154.6,172.6,176.5,196.6；hrms(esi-tof)m/z:calcd.forc28h28brn3nao3[m+na]+:556.1212；found:556.1214.
本实施例制备化合物3ha：黄色固体；熔点：204.4-205.6℃；产率：90％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.41(s,3h),1.57(s,3h),1.80(s,3h),2.03-2.08(m,2h),2.18-2.29(m,2h),2.51-2.56(m,1h),2.66-2.70(m,1h),2.87(s,3h),4.56-4.63(m,2h),4.75(d,j＝12.8hz,1h),4.91(d,j＝12.4hz,1h),5.74(s,1h),6.12(s,1h),6.23(d,j＝6.4hz,1h),6.49(d,j＝6.0hz,1h),6.64(d,j＝6.0hz,1h),7.06-7.09(m,1h),7.15-7.19(m,2h),7.22-7.26(m,2h),7.30(d,j＝5.6hz,2h),7.73(d,j＝5.6hz,1h)；13cnmr(cdcl3,100mhz)δ:20.0,20.7,26.2,27.0,30.8,31.4,44.1,47.4,59.1,65.2,67.0,107.4,108.2,122.1,123.1,126.5,127.3,127.4,127.5,128.5,128.7,129.2,130.9,136.1,154.3,173.0,176.8,197.0；hrms(esi-tof)m/z:calcd.forc35h35n3nao3[m+na]+:568.2576；found:568.2575.
本实施例制备化合物3ia：黄色固体；熔点：161.1-162.8℃；产率：88％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.47(s,3h),1.64(s,3h),2.08-2.15(m,2h),2.24-2.29(m,2h),2.53-2.59(m,1h),2.73-2.77(m,1h),2.95(s,3h),4.61-4.65(m,2h),4.81(d,j＝15.6hz,1h),4.97(d,j＝15.6hz,1h),5.79(s,1h),6.30-6.35(m,2h),6.59-6.62(m,1h),6.85-6.88(m,1h),7.13-7.17(m,1h),7.22-7.35(m,6h),7.75-7.77(m,1h)；13cnmr(cdcl3,100mhz)δ:20.2,26.3,27.2,30.9,31.5,44.3,47.4,59.2,65.3,67.1,107.9,109.6,123.1,126.2,127.1,127.2,127.3,127.6,127.7,128.8,129.1,129.3,135.6,154.8,172.8,176.7,196.7；hrms(esi-tof)m/z:calcd.forc34h32cln3nao3[m+na]+:588.2030；found:588.2032.
本实施例制备化合物3ja：黄色固体；熔点：180.2-182.1℃；产率：88％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.47(s,3h),1.63(s,3h),2.09-2.14(m,2h),2.25-2.29(m,2h),2.54-2.58(m,1h),2.72-2.79(m,1h),2.95(s,3h),4.60-4.62(m,2h),4.79(d,j＝15.6hz,1h),4.96(d,j＝16.0hz,1h),5.78(s,1h),6.26(d,j＝8.4hz,1h),6.47(d,j＝2.4hz,1h),6.59-6.62(m,1h),6.99-7.02(m,1h),7.13-7.17(m,1h),7.23-7.34(m,6h),7.73-7.76(m,1h)；13cnmr(cdcl3,100mhz)δ:20.2,26.3,27.2,30.9,31.5,44.2,47.4,59.1,65.3,67.2,107.9,110.1,104.6,122.5,123.1,127.3,127.6,127.7,128.8,129.0,129.3,135.6,154.8,172.8,176.6,196.7；hrms(esi-tof)m/z:calcd.forc34h32brn3nao3[m+na]+:632.1525；found:632.1528.
本实施例制备化合物3ka：黄色固体；熔点：124.3-126.5℃；产率：80％,8:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.24-1.27(m,3h),1.47(s,3h),1.62(s,3h),1.92(s,3h),2.09-2.13(m,2h),2.25-2.28(m,2h),2.52-2.56(m,1h),2.69-2.73(m,1h),2.90(s,3h),3.63-3.67(m,1h),3.80-3.85(m,1h),4.61-4.65(m,2h),5.78(s,1h),6.20(s,1h),6.51-6.57(m,2h),6.84-6.87(m,1h),7.13-7.16(m,1h),7.23-7.27(m,1h),7.78(d,j＝6.0hz,1h)；13cnmr(cdcl3,100mhz)δ:12.4,19.9,20.7,26.1,27.0,30.8,31.3,34.5,47.3,58.9,65.2,67.1,107.0,107.3,122.0,123.1,126.6,127.3,128.7,129.2,130.6,140.3,143.3,154.1,172.8,176.3,197.1；hrms(esi-tof)m/z:calcd.forc30h33n3nao3[m+na]+:506.2420；found:506.2423.
本实施例制备化合物3la：黄色固体；熔点：206.6-207.3℃；产率：71％,8:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.23-1.27(m,3h),1.47(s,3h),1.64(s,3h),2.08-2.13(m,2h),2.22-2.28(m,2h),2.48-2.54(m,1h),2.70-2.75(m,1h),2.93(s,3h),3.62-3.68(m,1h),3.80-3.86(m,1h),4.58-4.62(m,2h),5.77(s,1h),6.37(s,1h),6.56(d,j＝8.0hz,1h),6.61(d,j＝8.0hz,1h),7.03-7.05(m,1h),7.14-7.18(m,1h),7.26-7.30(m,1h),7.76(d,j＝8.0hz,1h)；13cnmr(cdcl3,100mhz)δ:12.3,20.0,26.1,27.0,30.8,31.3,34.7,47.2,58.9,65.1,67.0,107.6,108.2,122.3,123.0,126.2,126.7,127.2,128.9,129.1,141.3,143.2,154.5,172.5,176.1,196.6；hrms(esi-tof)m/z:calcd.forc29h30cln3nao3[m+na]+:526.1873；found:526.1876.
本实施例制备化合物3ab：黄色固体；熔点：188.3-190.5℃；产率：71％,15:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.50(s,3h),1.64(s,3h),2.11-2.18(m,2h),2.25-2.36(m,2h),2.40(s,3h),2.54-2.61(m,1h),2.75-2.79(m,1h),3.17(s,3h),4.14(d,j＝16.0hz,1h),4.63-4.71(m,2h),5.20(d,j＝16.0hz,1h),5.82(s,1h),6.20(d,j＝7.6hz,1h),6.34-6.40(m,3h),6.59-6.63(m,1h),6.67(d,j＝7.6hz,1h),6.90(d,j＝7.6hz,1h),7.01-7.05(m,2h),7.08-7.12(m,1h),7.19-7.23(m,1h),7.60(s,1h)；13cnmr(cdcl3,100mhz)δ:20.0,21.4,26.0,27.1,30.9,31.4,43.1,47.5,58.7,65.5,67.3,77.8,107.5,108.3,121.7,123.1,125.7,125.8,126.9,127.9,128.5,129.1,129.3,131.7,135.0,154.1,172.9,177.0,197.2；hrms(esi-tof)m/z:calcd.forc35h35n3nao3[m+na]+:568.2576；found:568.2576.
本实施例制备化合物3ac：黄色固体；熔点：97.3-99.1℃；产率：68％,9:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.58(s,3h),1.67(s,3h),2.08-2.15(m,2h),2.22-2.34(m,2h),2.45-2.52(m,1h),2.69-2.73(m,1h),2.88(s,3h),3.17(s,3h),4.43-4.49(m,1h),4.65(d,j＝8.8hz,1h),5.79(s,1h),6.43-6.46(m,2h),6.58-6.63(m,2h),7.07-7.11(m,1h),7.36-7.38(m,1h),7.87(s,1h)；13cnmr(cdcl3,100mhz)δ:20.4,26.2,26.4,27.4,30.9,31.6,47.4,59.3,65.2,67.1,107.6,109.0,115.0,121.9,122.9,124.8,125.5,129.5,130.0,131.7,142.7,143.9,155.2,172.5,176.9；hrms(esi-tof)m/z:calcd.forc28h28brn3nao3[m+na]+:556.1212；found:556.1215.
本实施例制备化合物3dd：黄色固体；熔点：165.3-166.6℃；产率：89％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.46(s,3h),1.63(s,3h),2.08-2.16(m,2h),2.23-2.31(m,1h),2.33-2.38(m,1h),2.44(s,3h),2.51-2.58(m,1h),2.71-2.76(m,1h),3.42(s,3h),4.14(d,j＝16.0hz,1h),4.63-4.69(m,2h),5.25(d,j＝16.4hz,1h),5.81(s,1h),6.28-6.31(m,2h),6.36(d,j＝7.6hz,2h),6.42-6.46(m,1h),6.90-6.93(m,1h),7.01-7.11(m,5h),7.74-7.76(m,1h)；13cnmr(cdcl3,100mhz)δ:19.3,20.1,27.2,29.6,31.0,31.5,43.2,47.6,58.8,65.5,67.5,108.5,119.1,121.6,122.3,123.2,123.8,125.8,127.1,127.5,128.6,128.9,135.1,154.4,173.1,177.9,197.2；hrms(esi-tof)m/z:calcd.forc35h35n3nao3[m+na]+:568.2576；found:568.2577.
本实施例制备化合物3fd：黄色固体；熔点：204.3-205.8℃；产率：93％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.50(s,3h),1.64(s,3h),2.09-2.16(m,2h),2.23-2.35(m,2h),2.50-2.57(m,1h),2.72-2.76(m,1h),3.13(s,3h),4.20(d,j＝16.0hz,1h),4.59-4.69(m,2h),5.14(d,j＝16.0hz,1h),5.82(s,1h),6.07-6.10(m,1h),6.36-6.38(m,1h),6.46(d,j＝7.2hz,2h),6.53-6.56(m,1h),6.84-6.89(m,1h),7.03-7.15(m,5h),7.73-7.76(m,1h)；13cnmr(cdcl3,100mhz)δ:20.2,26.3,27.2,31.0,31.5,43.3,47.6,58.8,65.6,67.2,77.9,107.8,107.9,108.9,114.0(d,jcf＝26.0hz),115.5(d,jcf＝24.0hz),122.5,123.1,126.1,126.4,127.2,127.3,128.7,129.3,135.1,140.0,142.5,155.0,158.6(d,jcf＝239.0hz),172.8,176.8,196.8；hrms(esi-tof)m/z:calcd.forc34h32fn3nao3[m+na]+:572.2325；found:572.2327.
本实施例制备化合物3if：黄色固体；熔点：177.3-178.9℃；产率：67％,10:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.67(s,3h),1.71(s,3h),2.11-2.23(m,2h),2.28-2.41(m,2h),2.55-2.62(m,1h),2.78-2.83(m,1h),4.27(d,j＝16.0hz,1h),4.49-4.56(m,1h),4.75-4.80(m,2h),4.93(d,j＝15.6hz,1h),5.17(d,j＝16.0hz,1h),5.89(s,1h),6.31-6.36(m,3h),6.41(d,j＝8.0hz,2h),6.95-7.00(m,3h),7.06-7.15(m,5h),7.23-7.25(m,2h),7.72(s,1h)；13cnmr(cdcl3,100mhz)δ:20.6,27.5,30.9,31.8,43.5,44.3,47.5,59.1,65.7,67.0,109.9,110.0,122.7,126.0,127.1,127.3,127.4,127.5,127.6,127.9,128.7,128.8,134.5,135.1,156.0,172.4,176.5,196.3；hrms(esi-tof)m/z:calcd.forc40h35cl2n3nao3[m+na]+:698.1953；found:698.1954.
本实施例制备化合物3le：黄色固体；熔点：148.3-150.5℃；产率：84％,14:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:0.73-0.77(m,3h),1.20-1.24(m,3h),1.63-1.65(m,6h),2.02-2.15(m,2h),2.21-2.32(m,2h),2.44-2.51(m,1h),2.70-2.74(m,1h),3.27-3.32(m,1h),3.51-3.60(m,2h),3.81-3.87(m,1h),4.46-4.52(m,1h),4.59(d,j＝7.6hz,1h),5.80(s,1h),6.23(s,1h),6.50-6.53(m,2h),7.01-7.03(m,1h),7.23-7.25(m,1h),7.67(d,j＝1.6hz,1h)；13cnmr(cdcl3,100mhz)δ:12.1,12.4,20.5,27.4,30.9,31.7,34.7,34.8,47.4,58.4,65.6,67.1,108.3,108.6,122.8,126.1,126.9,127.4,127.5,128.9,129.1,141.1,141.4,155.9,171.6,175.9,196.3；hrms(esi-tof)m/z:calcd.forc30h31cl2n3nao3[m+na]+:574.1640；found:574.1638.
本发明的实施例2：在反应管中依次加入89.2mgn-甲基靛红1a(0.4mmol)，144.6mg二烯酮3-烯基氧化吲哚2a(0.6mmol)，硫代脯氨酸(0.8mmol)和10ml乙醇溶液，回流反应5h，tlc检测基本反应完全，直接上样经柱层析(洗脱剂：v(石油醚)：v(乙酸乙酯)＝3:1)纯化得化合物4aa，黄色固体，熔点：198.2-200.1℃，>20:1dr；产率72％。核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.56(s,3h),1.58(s,3h),2.89(s,3h),2.94(s,3h),2.95-2.98(m,1h),3.35-3.39(m,1h),3.63(d,j＝6.4hz,1h),3.84(d,j＝7.2hz,1h),3.91(d,j＝7.2hz,1h),5.26-5.31(m,1h),5.52(s,1h),6.61(d,j＝6.4hz,1h),6.67(d,j＝6.0hz,1h),7.01-7.04(m,1h),7.09-7.13(m,1h),7.19-7.22(m,1h),7.30-7.33(m,1h),7.62-7.64(m,1h),7.73-7.74(m,1h)；13cnmr(cdcl3,100mhz)δ:20.3,26.2,26.4,27.1,36.1,50.4,62.0,65.9,67.6,76.4,107.3,107.8,121.5,122.0,122.9,123.2,124.7,128.5,128.7,129.0,130.0,142.4,143.5,156.1,173.8,174.2；hrms(esi-tof)m/z:calcd.forc27h27n3nao3s[m+na]+:496.1671；found:496.1673.
化合物4da至4nh的制备方法同化合物4aa，投料比与化合物4aa相同，可得到化合物4da至4nh，反应产率和非对映选择性见表1和表2，但需强调的是本发明的化合物不限于表2所表示的内容。
表2为一种姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物的化学结构
本实施例制备化合物4da：黄色固体；熔点：174.4-176.8℃；产率：87％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.54(s,3h),1.61(s,3h),2.42(s,3h),2.90-2.93(m,1h),2.94(s,3h),3.30-3.34(m,1h),3.62(d,j＝6.0hz,1h),3.80(d,j＝7.2hz,1h),3.84(d,j＝6.0hz,1h),5.26-5.30(m,1h),5.48(s,1h),6.61(d,j＝6.0hz,1h),6.96-7.03(m,3h),7.18-7.21(m,1h),7.55-7.56(m,2h)；13cnmr(cdcl3,100mhz)δ:19.3,20.4,26.5,27.2,29.6,35.7,49.4,61.5,66.4,67.6,75.4,107.2,119.1,121.4,121.9,123.0,126.3,128.4,128.9,133.9,141.4,142.6,156.0,174.7,195.1；hrms(esi-tof)m/z:calcd.forc28h29n3nao3s[m+na]+:510.1827；found:510.1829.
本实施例制备化合物4ea：黄色固体；熔点：196.8-198.7℃；产率：71％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.55(s,3h),1.59(s,3h),2.90-2.94(m,1h),2.96(s,3h),3.23(s,3h),3.32-3.35(m,1h),3.57(d,j＝6.4hz,1h),3.77(d,j＝7.2hz,1h),3.87(d,j＝6.4hz,1h),5.23-5.27(m,1h),5.48(s,1h),6.64(d,j＝6.4hz,1h),6.99-7.04(m,2h),7.20-7.24(m,2h),7.55-7.57(m,1h),7.62-7.64(m,1h)；13cnmr(cdcl3,100mhz)δ:20.4,26.5,27.1,29.6,35.8,49.6,61.6,66.4,67.6,75.6,107.4,115.1,122.0,122.2,122.8,128.4,129.2,132.3,139.4,142.4,156.4,174.1,174.2,194.6；hrms(esi-tof)m/z:calcd.forc27h26cln3nao3s[m+na]+:530.1281；found:530.1280.
本实施例制备化合物4fa：黄色固体；熔点：182.3-184.5℃；产率：74％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.57-1.58(m,6h),2.88(s,3h),2.88-2.95(m,1h),2.97(s,3h),3.35-3.38(m,1h),3.59(d,j＝8.5hz,1h),3.77(d,j＝9.0hz,1h),3.91(d,j＝8.5hz,1h),5.24-5.28(m,1h),5.52(s,1h),6.58-6.64(m,2h),7.01-7.05(m,2h),7.20-7.23(m,1h),7.54-7.56(m,1h),7.62(d,j＝7.5hz,1h)；13cnmr(cdcl3,125mhz)δ:20.3,26.4,26.5,27.1,36.1,50.4,62.0,65.8,67.6,76.4,107.4,108.0,116.1(d,jcf＝23.8hz),117.1(d,jcf＝26.3hz),122.0,122.7,124.4,128.5,129.1,139.4,142.4,156.4,158.2(d,jcf＝240.0hz),173.6,173.9,194.5；hrms(esi-tof)m/z:calcd.forc27h26fn3nao3s[m+na]+:514.1577；found:514.1580.
本实施例制备化合物4ma：黄色固体；熔点：198.3-199.7℃；产率：79％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.55(s,3h),1.60(s,3h),2.40(s,3h),2.85(s,3h),2.94(s,3h),2.95-2.97(m,1h),3.33-3.37(m,1h),3.63(d,j＝6.4hz,1h),3.82(d,j＝7.2hz,1h),3.87(d,j＝6.4hz,1h),5.27-5.31(m,1h),5.52(s,1h),6.55(d,j＝6.0hz,1h),6.60(d,j＝6.4hz,1h),6.98-7.02(m,1h),7.08-7.10(m,1h),7.17-7.21(m,1h),7.58-7.60(m,1h)；13cnmr(cdcl3,100mhz)δ:20.3,21.2,26.1,26.4,27.1,35.9,50.0,61.7,66.0,67.6,76.3,107.2,107.4,121.9,122.9,123.1,128.4,128.9,129.3,130.1,130.9,141.2,142.5,156.0,173.7,174.5,195.0；hrms(esi-tof)m/z:calcd.forc28h29n3nao3s[m+na]+:510.1827；found:510.1827.
本实施例制备化合物4ag：黄色固体；熔点：211.3-211.8℃；产率：70％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.48(s,3h),1.49(s,3h),2.27(s,3h),2.83(s,3h),2.84(s,3h),2.87-2.91(m,1h),3.29-3.33(m,1h),3.57(d,j＝7.2hz,1h),3.74(d,j＝7.2hz,1h),3.86(d,j＝6.4hz,1h),5.19-5.23(m,1h),5.44(s,1h),6.43(d,j＝6.4hz,1h),6.61(d,j＝6.4hz,1h),6.92(d,j＝6.4hz,1h),7.02-7.05(m,1h),7.23-7.26(m,1h),7.38(s,1h),7.67(d,j＝6.0hz,1h)；13cnmr(cdcl3,100mhz)δ:20.2,21.2,26.2,26.5,27.1,36.2,50.7,62.1,65.8,67.6,76.5,107.0,107.8,121.4,122.9,123.2,128.9,129.0,129.3,129.9,131.3,140.1,143.4,155.7,173.8,174.0,195.0；hrms(esi-tof)m/z:calcd.forc28h29n3nao3s[m+na]+:510.1827；found:510.1827.
本实施例制备化合物4mh：黄色固体；熔点：203.8-205.4℃；产率：93％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.52(s,3h),1.61(s,3h),2.33(s,3h),2.82(s,3h),2.87(s,3h),2.88-2.91(m,1h),3.27-3.30(m,1h),3.55(d,j＝6.4hz,1h),3.74(d,j＝6.8hz,1h),3.80(d,j＝6.4hz,1h),5.14-5.19(m,1h),5.47(s,1h),6.46-6.50(m,2h),7.03-7.05(m,1h),7.09-7.11(m,1h),7.42(s,1h),7.53(s,1h)；13cnmr(cdcl3,100mhz)δ:20.5,21.2,26.2,26.5,27.2,35.9,50.0,61.7,65.8,67.5,76.0,107.5,108.1,122.7,127.4,128.6,128.8,129.3,130.3,131.0,141.1,141.2,156.7,173.3,174.0,194.5；hrms(esi-tof)m/z:calcd.forc28h28cln3nao3s[m+na]+:544.1438；found:544.1435.
本实施例制备化合物4ng：黄色固体；熔点：214.2-215.6℃；产率：72％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.49(s,3h),2.27(s,3h),2.82(s,3h),2.87(s,3h),2.88-2.91(m,1h),3.29-3.32(m,1h),3.50(d,j＝7.2hz,1h),3.68(d,j＝7.2hz,1h),3.85(d,j＝7.2hz,1h),5.15-5.20(m,1h),5.45(s,1h),6.44(d,j＝6.0hz,1h),6.53(d,j＝7.2hz,1h),6.93-6.94(m,1h),7.20-7.23(m,1h),7.36(s,1h),7.70(s,1h)；13cnmr(cdcl3,100mhz)δ:20.3,21.2,26.3,26.5,27.1,36.3,50.9,62.0,65.7,67.7,76.4,107.1,108.5,122.8,124.4,129.1,129.4,129.5,129.8,131.4,140.1,141.9,156.0,173.5,173.7,194.7；hrms(esi-tof)m/z:calcd.forc28h28cln3nao3s[m+na]+:544.1438；found:544.1439.
本实施例制备化合物4nh:黄色固体；熔点：189.7-190.8℃；产率：90％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.54(s,3h),1.59(s,3h),2.85(s,3h),2.88-2.91(m,4h),3.29-3.32(m,1h),3.49(d,j＝7.2hz,1h),3.70(d,j＝7.2hz,1h),3.84(d,j＝7.2hz,1h),5.10-5.15(m,1h),5.49(s,1h),6.49(d,j＝6.4hz,1h),6.55(d,j＝6.8hz,1h),7.12-7.14(m,1h),7.22-7.24(m,1h),7.56(s,1h),7.66(s,1h)；13cnmr(cdcl3,100mhz)δ:20.5,26.4,26.6,27.2,36.3,50.7,62.0,65.5,67.5,76.1,108.2,108.7,122.6,124.4,127.2,128.8,129.1,129.3,130.0,141.0,141.9,157.0,173.0,173.4,194.0；hrms(esi-tof)m/z:calcd.forc27h25cl2n3nao3s[m+na]+:564.0891；found:564.0890.
本发明的实施例3：在反应管中依次加入89.2mgn-甲基靛红1a(0.4mmol)，144.6mg二烯酮3-烯基氧化吲哚2a(0.6mmol)，肌氨酸(0.8mmol)和10ml乙醇溶液，回流反应5h，tlc检测基本反应完全，直接上样经柱层析(洗脱剂：v(石油醚)：v(乙酸乙酯)＝3:1)纯化得化合物5aa，黄色固体；熔点：201.1-202.9℃；产率：82％,>20:1dr。核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.49(s,3h),1.80(s,3h),2.19(s,3h),2.84(s,3h),2.98(s,3h),3.38-3.42(m,1h),4.01-4.05(m,1h),4.51-4.54(m,1h),5.39(s,1h),6.55(d,j＝6.4hz,2h),6.87-6.91(m,1h),7.01-7.04(m,1h),7.11-7.14(m,1h),7.21-7.24(m,1h),7.28-7.31(m,1h),7.47(d,j＝6.4hz,1h)；13cnmr(cdcl3,100mhz)δ:20.5,25.3,26.3,27.1,35.3,52.9,55.8,61.8,78.6,107.1,107.5,121.7,122.1,123.9,124.8,126.2,127.8,128.6,129.5,143.2,144.1,155.3,173.8,176.9,195.6；hrms(esi-tof)m/z:calcd.forc26h27n3nao3[m+na]+:452.1950；found:452.1953.
化合物5ba至5oc的制备方法同化合物5aa，投料比与化合物5aa相同，可得到化合物5ba至5oc，反应产率和非对映选择性见表3，但需强调的是本发明的化合物不限于表3所表示的内容。
表3为一种姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物的化学结构
本实施例制备化合物5ba:黄色固体；熔点：203.7-204.9℃；产率：87％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.48(s,3h),1.81(s,3h),2.23(s,3h),2.99(s,3h),3.40-3.44(m,1h),4.06-4.10(m,1h),4.36(d,j＝12.8hz,1h),4.53-4.57(m,1h),4.84(d,j＝12.4hz,1h),5.38(s,1h),6.38(d,j＝6.0hz,1h),6.61(d,j＝6.4hz,1h),6.74(d,j＝5.2hz,2h),6.84-6.87(m,1h),6.98-7.01(m,1h),7.07-7.20(m,5h),7.33-7.35(m,1h),7.51-7.53(m,1h)；13cnmr(cdcl3,100mhz)δ:20.5,26.3,27.1,35.3,42.9,53.0,55.9,61.8,78.4,107.2,108.7,122.2,123.8,126.7,127.1,128.3,128.4,128.6,143.4,155.3,173.7,177.1,195.7；hrms(esi-tof)m/z:calcd.forc32h31n3nao3[m+na]+:528.2263；found:528.2265.
本实施例制备化合物5ca:黄色固体；熔点：191.4-193.2℃；产率：72％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.49(s,3h),1.86(s,3h),2.36(s,3h),3.00(s,3h),3.46-3.50(m,1h),4.03-4.06(m,1h),4.57-4.61(m,1h),5.41(s,1h),6.41(d,j＝6.0hz,1h),6.59(d,j＝6.4hz,1h),6.83-6.89(m,3h),7.02-7.05(m,1h),7.09-7.13(m,1h),7.15-7.21(m,2h),7.28-7.33(m,1h),7.36-7.39(m,2h),7.53-7.54(m,1h)；13cnmr(cdcl3,100mhz)δ:20.6,26.3,27.2,35.3,53.4,55.4,62.3,78.8,107.3,108.7,124.0,126.3,126.7,128.0,128.7,129.3,129.5,143.5,144.4,155.3,173.4,177.5,195.6；hrms(esi-tof)m/z:calcd.forc31h29n3nao3[m+na]+:514.2107；found:514.2109.
本实施例制备化合物5da:黄色固体；熔点：145.1-147.8℃；产率：86％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.49(s,3h),1.82(s,3h),2.19(s,3h),2.34(s,3h),2.97(s,3h),3.09(s,3h),3.37-3.42(m,1h),3.98-4.03(m,1h),4.49-4.54(m,1h),5.37(s,1h),6.56(d,j＝8.0hz,1h),6.86-6.94(m,3h),7.12-7.15(m,1h),7.25-7.32(m,2h)；13cnmr(cdcl3,100mhz)δ:19.0,20.5,26.3,27.1,28.7,35.3,52.9,55.6,62.0,77.9,107.1,118.8,121.6,121.8,123.9,124.0,127.7,128.5,133.3,141.8,143.2,155.2,174.5,177.0,195.7；hrms(esi-tof)m/z:calcd.forc27h29n3nao3[m+na]+:466.2107；found:466.2105.
本实施例制备化合物5ea:黄色固体；熔点：181.3-183.7℃；产率：83％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.49(s,3h),1.82(s,3h),2.19(s,3h),2.98(s,3h),3.19(s,3h),3.38-3.42(m,1h),3.97-4.02(m,1h),4.49-4.53(m,1h),5.35(s,1h),6.59(d,j＝7.6hz,1h),6.88-6.95(m,2h),7.13-7.18(m,2h),7.23(d,j＝7.6hz,1h),7.38(d,j＝7.6hz,1h)；13cnmr(cdcl3,100mhz)δ:20.6,26.3,27.2,28.7,35.2,53.0,55.6,62.1,78.1,107.3,114.8,121.9,122.7,123.8,124.8,128.8,131.9,139.9,143.1,155.6,174.1,176.8,195.4；hrms(esi-tof)m/z:calcd.forc26h26cln3nao3[m+na]+:486.1560；found:486.1560.
本实施例制备化合物5fa:黄色固体；熔点：187.7-189.3℃；产率：71％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.50(s,3h),1.81(s,3h),2.20(s,3h),2.84(s,3h),3.02(s,3h),3.36-3.40(m,1h),3.98-4.01(m,1h),4.49-4.53(m,1h),5.38(s,1h),6.47-6.49(m,1h),6.58(d,j＝7.5hz,1h),6.88-6.95(m,2h),7.13-7.16(m,1h),7.27-7.30(m,2h)；13cnmr(cdcl3,125mhz)δ:20.6,25.5,26.4,27.2,35.3,52.9,55.8,61.8,78.6,107.3,107.9,108.0,114.4(d,jcf＝26.3hz),115.8(d,jcf＝23.8hz),121.9,123.8,124.5,125.9,127.9,128.9,140.1,143.2,155.6,158.8(d,jcf＝238.8hz),173.6,176.7,195.4；hrms(esi-tof)m/z:calcd.forc26h26fn3nao3[m+na]+:470.1856；found:470.1859.
本实施例制备化合物5ga:黄色固体；熔点：203.3-205.8℃；产率：81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.48(s,3h),1.64(s,3h),2.07-2.11(m,2h),2.23-2.29(m,2h),2.48-2.53(m,1h),2.72-2.75(m,1h),2.93(s,3h),3.18(s,3h),4.58-4.63(m,2h),5.77(s,1h),6.49-6.51(m,2h),6.62(d,j＝6.4hz,1h),7.16-7.21(m,2h),7.27-7.31(m,1h),7.76(d,j＝6.0hz,1h)；13cnmr(cdcl3,100mhz)δ:20.0,26.1,26.2,27.1,30.8,31.3,47.3,58.9,65.2,67.2,107.7,108.7,114.3,122.4,122.9,127.2,128.8,129.2,131.9,142.7,143.2,154.6,172.6,176.5,196.6；hrms(esi-tof)m/z:calcd.forc26h26brn3nao3[m+na]+:530.1055；found:530.1057.
本实施例制备化合物5ia:黄色固体；熔点：174.7-175.9℃；产率：71％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.50(s,3h),1.81(s,3h),2.24(s,3h),3.04(s,3h),3.39-3.44(m,1h),4.04-4.08(m,1h),4.36(d,j＝16.0hz,1h),4.50-4.55(m,1h),4.82(d,j＝16.0hz,1h),5.38(s,1h),6.30(d,j＝8.4hz,1h),6.64(d,j＝8.0hz,1h),6.71(d,j＝6.4hz,2h),6.85-6.89(m,1h),7.05-7.07(m,1h),7.11-7.22(m,4h),7.31(d,j＝7.2hz,1h),7.53(s,1h)；13cnmr(cdcl3,100mhz)δ:20.6,26.4,27.1,35.3,43.1,53.0,55.8,61.8,78.3,107.3,109.6,122.2,123.8,126.7,126.9,127.3,128.6,128.8,129.4,141.8,143.4,155.7,173.2,176.8,195.4；hrms(esi-tof)m/z:calcd.forc32h30cln3nao3[m+na]+:562.1873；found:562.1875.
本实施例制备化合物5ja:黄色固体；熔点：151.3-153.9℃；产率：88％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.50(s,3h),1.82(s,3h),2.24(s,3h),3.04(s,3h),3.40-3.43(m,1h),4.03-4.07(m,1h),4.36(d,j＝12.8hz,1h),4.50-4.54(m,1h),4.81(d,j＝12.8hz,1h),5.38(s,1h),6.24(d,j＝6.8hz,1h),6.64(d,j＝6.4hz,1h),6.71(d,j＝5.6hz,2h),6.85-6.88(m,1h),7.12-7.22(m,5h),7.28-7.31(m,1h),7.66(s,1h)；13cnmr(cdcl3,100mhz)δ:20.6,26.4,27.2,35.4,43.1,53.1,55.7,61.9,78.4,107.4,110.2,115.2,122.3,123.9,124.7,126.4,126.7,127.4,128.3,128.6,128.8,129.6,132.4,134.9,142.4,143.4,155.7,173.1,176.9,195.4；hrms(esi-tof)m/z:calcd.forc32h30brn3nao3[m+na]+:606.1368；found:606.1369.
本实施例制备化合物5ma:黄色固体；熔点：188.2-189.6℃；产率：89％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.50(s,3h),1.81(s,3h),2.19(s,3h),2.34(s,3h),2.82(s,3h),2.98(s,3h),3.37-3.41(m,1h),4.01-4.04(m,1h),4.49-4.53(m,1h),5.40(s,1h),6.43(d,j＝6.4hz,1h),6.55(d,j＝6.0hz,1h),6.86-6.90(m,1h),7.01-7.02(m,1h),7.11-7.14(m,1h),7.28-7.30(m,2h)；13cnmr(cdcl3,100mhz)δ:20.5,21.0,25.3,26.2,27.1,35.3,52.9,55.6,61.8,78.6,107.1,107.2,121.7,123.9,126.8,127.8,128.5,129.7,131.5,141.6,143.1,155.2,173.6,177.0,195.6；hrms(esi-tof)m/z:calcd.forc27h29n3nao3[m+na]+:466.2107；found:466.2108.
本实施例制备化合物5na:黄色固体；熔点：170.2-171.7℃；产率：93％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:0.83-0.86(m,3h),1.49(s,3h),1.83(s,3h),2.19(s,3h),2.98(s,3h),3.23-3.30(m,1h),3.38-3.42(m,1h),3.54-3.61(m,1h),4.01-4.05(m,1h),4.52-4.55(m,1h),5.38(s,1h),6.55-6.58(m,2h),6.86-6.89(m,1h),6.99-7.03(m,1h),7.11-7.14(m,1h),7.19-7.23(m,1h),7.29-7.30(m,1h),7.48-7.50(m,1h)；13cnmr(cdcl3,100mhz)δ:12.2,20.5,26.2,27.1,33.7,35.2,53.0,55.6,61.8,78.2,107.1,107.5,121.7,121.8,123.9,124.7,126.4,127.9,128.5,129.4,143.1,143.2,155.2,173.3,177.2,195.7；hrms(esi-tof)m/z:calcd.forc27h29n3nao3[m+na]+:466.2107；found:466.2107.
本实施例制备化合物5oa:黄色固体；熔点：181.1-182.5℃；产率：77％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.49(s,3h),1.75(s,3h),2.21(s,3h),2.98(s,3h),3.37-3.41(m,1h),4.05-4.09(m,1h),4.49-4.53(m,1h),4.67(d,j＝15.5hz,1h),4.80(d,j＝15.5hz,1h),5.37(s,1h),6.62(d,j＝8.0hz,1h),6.85-6.99(m,5h),7.13-7.20(m,4h),7.33(d,j＝7.5hz,2h)；13cnmr(cdcl3,125mhz)δ:20.5,26.4,27.1,35.3,44.7,52.7,56.0,61.9,78.4,107.2,117.7(d,jcf＝18.8hz),122.2,122.6,123.6,124.7,127.1,128.3(d,jcf＝16.3hz),128.8,136.8,143.2,146.8(d,jcf＝242.5hz),155.6,173.3,176.5,195.4；hrms(esi-tof)m/z:calcd.forc32h30fn3nao3[m+na]+:546.2169；found:546.2172.
本实施例制备化合物5pa:黄色固体；熔点：131.3-132.8℃；产率：77％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.48(s,3h),1.78(s,3h),2.02(s,3h),2.25(s,3h),3.03(s,3h),3.40-3.44(m,1h),4.06-4.10(m,1h),4.51-4.54(m,1h),4.70(d,j＝13.6hz,1h),5.03(d,j＝13.6hz,1h),5.38(s,1h),6.62-6.66(m,3h),6.79-6.82(m,1h),6.88-6.95(m,2h),7.11-7.19(m,4h),7.27(d,j＝6.0hz,1h),7.43(d,j＝6.0hz,1h)；13cnmr(cdcl3,100mhz)δ:18.6,20.5,26.3,27.1,35.3,44.2,52.9,55.9,61.9,77.6,107.1,118.9,122.1,122.2,123.8,124.5,125.3,126.6,128.4,128.5,128.6,133.6,137.4,155.2,174.5,177.2,195.7；hrms(esi-tof)m/z:calcd.forc33h33n3nao3[m+na]+:542.2420；found:542.2423.
本实施例制备化合物5ai:黄色固体；熔点：138.0-139.8℃；产率：87％,19:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:0.81-0.83(m,3h),1.38(s,3h),1.74(s,3h),2.14(s,3h),2.16(s,3h),2.74(s,3h),3.27-3.34(m,2h),3.61-3.66(m,1h),3.91-3.95(m,1h),4.45-4.49(m,1h),5.27(s,1h),6.37(d,j＝6.4hz,1h),6.45(d,j＝6.4hz,1h),6.83(d,j＝6.4hz,1h),6.91-6.95(m,1h),7.04(s,1h),7.11-7.14(m,1h),7.41-7.43(m,1h)；13cnmr(cdcl3,100mhz)δ:12.2,20.5,20.9,25.1,27.1,34.5,35.4,53.2,55.9,61.7,78.7,106.9,107.3,122.1,134.0,125.2,126.6,128.6,128.8,129.4,130.8,140.0,144.2,154.8,174.1,176.6,195.9；hrms(esi-tof)m/z:calcd.forc28h31n3nao3[m+na]+:480.2263；found:480.2265.
本实施例制备化合物5aj:黄色固体；熔点：214.5-215.1℃；产率：75％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.47(s,3h),1.71(s,3h),2.11(s,3h),2.30(s,3h),2.77(s,3h),3.18(s,3h),3.28-3.32(m,1h),3.96-3.99(m,1h),4.41-4.44(m,1h),5.36(s,1h),6.52(d,j＝6.4hz,1h),6.69-6.72(m,1h),6.78(d,j＝5.6hz,1h),6.96-6.99(m,1h),7.11(d,j＝5.6hz,1h),7.16-7.21(m,1h),7.38-7.40(m,1h)；13cnmr(cdcl3,100mhz)δ:19.1,20.5,25.5,27.2,29.8,35.4,52.7,56.1,61.4,78.8,107.6,118.3,121.5,122.0,123.9,125.9,126.3,129.4,132.4,140.9,144.0,155.0,173.7,177.4,195.7；hrms(esi-tof)m/z:calcd.forc27h29n3nao3[m+na]+:466.2107；found:466.2109.
本实施例制备化合物5dh:黄色固体；熔点：185.8-187.2℃；产率：93％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.47(s,3h),1.82(s,3h),2.11(s,3h),2.29(s,3h),2.89(s,3h),3.07(s,3h),3.32-3.36(m,1h),3.87-3.91(m,1h),4.40-4.43(m,1h),5.35(s,1h),6.41(d,j＝7.2hz,1h),6.81-6.84(m,1h),6.87(d,j＝6.4hz,1h),7.04-7.06(m,1h),7.20-7.22(m,2h)；13cnmr(cdcl3,100mhz)δ:19.0,20.6,26.4,27.2,28.8,35.2,52.9,55.6,61.9,77.8,108.0,119.0,122.0,123.8,124.0,127.1,128.0,128.5,133.5,141.8,142.0,156.0,174.4,176.7,195.3；hrms(esi-tof)m/z:calcd.forc27h28cln3nao3[m+na]+:500.1717；found:500.1719.
本实施例制备化合物5nb:黄色固体；熔点：200.2-201.8℃；产率：79％,20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.34(s,3h),1.72(s,3h),2.12(s,3h),2.16(s,3h),2.75(s,3h),3.32-3.35(m,1h),3.95-3.99(m,1h),4.41(d,j＝12.0hz,1h),4.45-4.49(m,1h),4.95(d,j＝12.4hz,1h),5.24(d,j＝14.0hz,1h),6.24(d,j＝6.4hz,1h),6.43(d,j＝6.4hz,1h),6.72(d,j＝6.4hz,1h),6.80(d,j＝2.8hz,2h),7.03(s,1h),7.11-7.13(m,3h),7.15-7.17(m,1h),7.49(s,1h)；13cnmr(cdcl3,100mhz)δ:20.5,21.0,25.4,27.1,35.4,43.8,53.2,56.5,61.8,78.5,108.1,108.4,123.8,126.3,126.8,127.4,128.1,128.5,128.6,129.0,129.4,131.4,135.5,140.3,155.3,173.7,177.0,195.5；hrms(esi-tof)m/z:calcd.forc33h32cln3nao3[m+na]+:576.2030；found:576.2032.
本实施例制备化合物5oc:黄色固体；熔点：195.3-196.9℃；产率：75％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.47(s,3h),1.84(s,3h),2.15(s,3h),2.95(s,3h),3.34-3.37(m,1h),3.91-3.94(m,1h),4.29(d,j＝12.4hz,1h),4.41-4.45(m,1h),4.83(d,j＝12.8hz,1h),5.34(s,1h),6.26-6.29(m,1h),6.45(d,j＝6.4hz,1h),6.72-6.76(m,3h),7.11-7.13(m,3h),7.20-7.22(m,1h),7.26-7.28(m,1h),7.41(s,1h)；13cnmr(cdcl3,100mhz)δ:20.8,26.5,27.3,35.3,43.3,53.0,55.9,61.6,78.3,108.8,109.3,109.4,114.5,114.7,115.1,116.0,116.2,123.6,126.8,126.9,127.5,128.7,131.4,131.7,135.1,142.6,156.6,158.0,159.9,173.2,176.5,195.0；hrms(esi-tof)m/z:calcd.forc32h29brfn3nao3[m+na]+:624.1274；found:624.1275.
本发明的式(1)化合物具有重要的生物活性，体外对人白血病细胞(k562)的细胞毒性试验表明：此类式(1)所示的结构的姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。但需强调的是本发明的化合物不限于人白血病细胞(k562)表示的细胞毒性。
药理实施例：化合物3le,3fa,3la,3ia,3fd,4da,5ia,5ba,5oa和5pa对k562细胞的细胞毒性
k562(人慢性髓系白血病细胞)用rpmi-1640培养基培养，培养基中含10％的胎牛血清，100u/ml的青霉素和100u/ml链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5％co2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良mtt法。细胞经过24小时的孵育后，分别将新配的化合物3le,3fa,3la,3ia,3fd,4da,5ia,5ba,5oa和5pa的二甲基亚砜溶液以浓度梯度加入到各孔中，使孔中化合物最终浓度分别为5μmol/l,10μmol/l,20μmol/l,40μmol/l和80μmol/l。48小时后，每孔加入10μlmtt(5mg/ml)的磷酸盐缓冲液，再继续在37℃培养4小时后，离心5分钟除去未转化的mtt，每孔中加入150μl二甲基亚砜。以溶解还原的mtt晶体甲臜(formazan)，用酶标仪在490nm波长测定od值。其中化合物3le,3fa,3la,3ia,3fd,4da,5ia,5ba,5oa和5pa对k562细胞半抑制浓度ic50由spss软件(19版本)分析得到。化合物3le对k562肿瘤细胞的ic50为43.5μmol/l；化合物3fa对k562肿瘤细胞的ic50为51.3μmol/l；化合物3la对k562肿瘤细胞的ic50为33.8μmol/l；化合物3ia对k562肿瘤细胞的ic50为78.8μmol/l；化合物3fd对k562肿瘤细胞的ic50为62.3μmol/l；化合物4da对k562肿瘤细胞的ic50为38.5μmol/l；化合物5ia对k562肿瘤细胞的ic50为49.4μmol/l；化合物5ba对k562肿瘤细胞的ic50为79.0μmol/l；化合物5oa对k562肿瘤细胞的ic50为22.3μmol/l；化合物5pa对k562肿瘤细胞的ic50为27.6μmol/l；而阳性对照顺铂对k562肿瘤细胞的ic50为24.7μmol/l。
实验结论：k562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的姜黄酮拼接3,3'-吡咯双螺环氧化吲哚化合物对k562细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。
从以上药理实施例中我们可以看出这些化合物对人白血病细胞(k562)显示有一定的细胞毒性。可见这些化合物具有开发成为抗肿瘤药物的潜力，值得继续深入研究下去。