山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物及其制备方法及应用与流程
作者：NG体育 发布时间：2024-06-12 09:23:06
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本发明涉及化学技术和药学技术领域，尤其是一种山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物及其制备方法及应用。
背景技术：
根据药物设计的活性骨架拼接和迁越原理，把两个或多个具有生物活性骨架拼接成一个潜在生物活性的多骨架分子在有机化学和医药化学中是极其重要的研究领域。(1)螺六元碳环氧化吲哚广泛存在天然产物和合成药物分子中，吸引了许多化学工作者及医药化学团队的广泛关注，例如，天然产物或活性小分子螺六元碳环氧化吲哚satavaptan和progesteronereceptoragonistii表现明显的生物活性。(2)山酮素骨架也普遍存在天然产物和药物分子中。例如:天然产物分子ergochromedd，diversonol，desoxydiversonol，applanatinb和isocochlioquinonea共享一个山酮素分子单元，这些化合物在解除病痛、经济发展中起着重大作用。(3)异恶唑基团也普遍存在天然产物和药物分子中。例如:异噁唑基团也普遍存在天然产物和药物分子中。如:许多天然产物和药物(cloxacillinv,muscimolvi,isoxicamvii,leflunomideviii,等)。鉴于螺六元碳环氧化吲哚骨架、异噁唑骨架和山酮素骨架具有潜在的生物活性。因此，把螺六元碳环氧化吲哚骨架和异噁唑骨架拼接到山酮素骨架，合成一系列新的潜在多活性官能团的山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物，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(如图8所示)。
技术实现要素：
本发明的目的是：提供一种山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生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：一种山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物，该化合物具有如下通式(ⅰ)的结构：
式中，r1为甲氧基或氟或氢；r2为甲基或氟或氢；r3为甲基或苄基或乙基或苯基或氢；r4为甲基或氟或氯或溴或氢。
山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物的制备方法，将各种取代的双功能氧化吲哚-色酮合成子1、各种取代的3-异噁唑烯基氧化吲哚2在有机溶剂中，在有机小分子催化剂作用下，进行michael/michael环加成反应，获得山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物3。
合成路线举例如下：
其中合成路线中的化合物，其取代基满足r1为甲氧基或氟或氢；r2为甲基或氟或氢；r3为甲基或苄基或乙基或苯基或氢；r4为甲基或氟或氯或溴或氢。
反应机理以3a的合成举例如下：
所述的有机溶剂为乙腈、甲苯、二氯甲烷、或氯仿。
所述的有机小分子碱性催化剂为手性双功能金鸡纳碱衍生的硫脲或芳酰胺、环己基二胺衍生的硫脲或芳酰胺、1,2-二苯基二胺衍生的的硫脲或芳酰胺、等。
有机小分子碱性催化剂举例如下(但需强调的是本发明的有机小分子碱性催化剂不限于如下表示的内容)：
各种取代的双功能氧化吲哚-色酮合成子、各种取代的3-异噁唑烯基氧化吲哚在有机溶剂中的反应温度为-10℃至40℃，反应时间为1至7天。
山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生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，以各种取代的双功能氧化吲哚-色酮合成子1、各种取代的3-异噁唑烯基氧化吲哚2在有机溶剂中，在有机小分子催化剂作用下，进行michael/michael环加成反应，获得山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物3，该类化合物包含潜在的生物活性山酮素骨架、异噁唑骨架和螺环氧化吲哚化合物骨架，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。且该骨架化合物对人白血病细胞(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
图1及图2为本发明的实施例的化合物3a谱图数据；
图3为化合物3a液相谱图数据；
图4及图5为本发明的实施例的化合物3b谱图数据；
图6为化合物3b液相谱图数据；
图7为本发明的实施例的化合物3a和3v单晶图；
图8为本发明所合成的化合物的设计思路及其创造性。
具体实施方式
本发明的实施例：在反应管中依次加入39.1mg双功能氧化吲哚-色酮合成子1a(0.10mmol)，54.2mg3-异噁唑烯键氧化吲哚2a(0.15mmol)，6.2mg环己基二胺衍生的的硫脲催化剂c2(15mol％，0.015mmol)和0.9ml新蒸馏的氯仿溶液，40℃中搅拌反应3天，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64.7mg化合物3a，白色固体，熔点：161.2-163.0℃；产率86％；99％ee,>20:1dr,[α]d20＝-130.89(c0.30,ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝17.39min；τminor＝26.21min)。核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.67(s,9h),2.39(s,3h),2.44-2.48(m,1h),3.19-3.24(m,1h),4.19-4.25(m,1h),4.50(d,j＝15.5hz,1h),4.91(d,j＝15.5hz,1h),5.95-5.99(m,1h),6.24(d,j＝8.0hz,1h),6.32(d,j＝11.0hz,1h),6.77-6.80(m,2h),6.90-6.95(m,2h),7.02-7.06(m,1h),7.08-7.10(m,2h),7.14-7.17(m,1h),7.22-7.27(m,4h),7.34(d,j＝7.0hz,1h),7.41-7.45(m,1h),7.53(d,j＝8.0hz,1h),7.90-7.92(m,1h)；13cnmr(cdcl3,125mhz)δ:11.6,26.5,28.1,41.1,43.5,44.2,51.0,55.3,75.8,85.0,109.2,114.5,117.8,121.0,121.9,122.6,123.8,124.1,124.2,124.4,126.1,127.1,127.5,127.7,128.7,129.4,130.0,134.6,135.8,138.9,142.3,155.3,160.5,169.5,174.1,175.3,192.4；hrms(esi-tof)m/z:calcd.forc43h36n4nao9[m+na]+:775.2374；found:775.2377.
化合物3b至3x的制备方法同化合物3a，投料比与化合物3a相同，可得到化合物3b至3x，反应产率和dr值,ee值见表1和表2，但需强调的是本发明的化合物不限于表1和表2所表示的内容。
表1为一种山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物的制备方法的化学结构
表2为一种山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物的制备方法的化学结构
本实施例制备化合物3b:白色固体,熔点：170.9-172.8℃；产率82％；98％ee,>20:1dr,[α]d20＝-130.05(c0.41,ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝14.67min；τminor＝25.81min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.67(s,9h),2.38(s,3h),2.42-2.46(m,1h),3.02(s,3h),3.17-3.22(m,1h),4.17-4.23(m,1h),5.89-5.94(m,1h),6.28(d,j＝10.5hz,1h),6.37(d,j＝8.0hz,1h),6.76-6.78(m,1h),6.79-6.83(m,1h),7.00-7.06(m,3h),7.12-7.15(m,1h),7.24-7.26(m,1h),7.29-7.31(m,1h),7.41-7.44(m,1h),7.50-7.52(m,1h),7.89-7.92(m,1h)；13cnmr(cdcl3,125mhz)δ:11.6,26.0,26.9,28.1,40.9,43.5,51.0,55.2,75.8,84.9,108.0,114.4,117.8,121.0,121.8,122.6,123.5,123.7,124.1,124.2,126.2,127.1,129.4,130.0,132.2,135.8,138.9,142.8,148.5,155.2,160.5,169.6,174.0,175.3,192.4；hrms(esi-tof)m/z:calcd.forc37h32n4nao9[m+na]+:699.2061；found:699.2067.
本实施例制备化合物3c:白色固体,熔点：178.2-180.2℃；产率91％；95％ee,>20:1dr,[α]d20＝-100.21(c0.39,ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝12.61min；τminor＝21.23min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.11-1.14(m,3h),1.67(s,9h),2.38(s,3h),2.42-2.46(m,1h),3.19-3.25(m,1h),3.46-3.50(m,1h),3.67-3.75(m,1h),4.17-4.23(m,1h),5.89-5.94(m,1h),6.27(d,j＝11.0hz,1h),6.39(d,j＝7.5hz,1h),6.76-6.82(m,2h),6.98-7.06(m,3h),7.12-7.15(m,1h),7.28-7.32(m,2h),7.40-7.44(m,1h),7.52(d,j＝8.0hz,1h),7.89-7.91(m,1h)；13cnmr(cdcl3,125mhz)δ:11.5,11.8,26.4,28.1,34.7,41.0,43.5,50.8,55.0,75.8,84.9,108.1,114.4,117.8,121.0,121.8,122.4,123.8,124.1,124.3,124.4,126.2,127.1,129.4,130.0,132.2,135.8,138.9,141.9,148.5,155.2,160.5,169.6,173.6,175.3,192.4；hrms(esi-tof)m/z:calcd.forc38h34n4nao9[m+na]+:713.2218；found:713.2220.
本实施例制备化合物3d:白色固体,熔点：228.3-229.6℃；产率91％；>99％ee,>20:1dr,[α]d20＝-119.63(c0.27ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝16.47min；τminor＝26.36min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.67(s,9h),2.40(s,3h),2.43-2.49(m,1h),3.15-3.22(m,1h),4.19-4.26(m,1h),5.91-5.97(m,1h),6.23(d,j＝10.0hz,1h),6.34(d,j＝14.0hz,1h),6.77-6.85(m,2h),6.93-6.97(m,1h),7.00-7.07(m,2h),7.11(d,j＝9.5hz,2h),7.19-7.23(m,1h),7.31-7.37(m,2h),7.39-7.43(m,2h),7.48-7.52(m,2h),7.56-7.59(m,1h),7.87-7.89(m,1h)；13cnmr(cdcl3,125mhz)δ:11.7,26.9,28.2,41.4,43.6,51.1,55.4,76.0,85.1,109.4,114.7,117.9,121.1,123.9,124.1,124.5,124.6,126.3,126.7,127.2,128.9,129.7,129.9,130.1,133.4,139.2,143.2,148.6,155.6,160.6,169.8,173.5,175.4,192.4；hrms(esi-tof)m/z:calcd.forc42h34n4nao9[m+na]+:761.2218；found:761.2223.
本实施例制备化合物3e:白色固体,熔点：178.1-179.4℃；产率87％；95％ee,>20:1dr,[α]d20＝-112.93(c0.39,ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(95/5hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝25.36min；τminor＝32.03min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.68(s,9h),2.15(s,3h),2.38(s,3h),2.43-2.47(m,1h),3.20-3.26(m,1h),4.19-4.23(m,1h),4.54(d,j＝16.0hz,1h),4.83(d,j＝16.0hz,1h),5.95-6.00(m,1h),6.11(d,j＝8.0hz,1h),6.27(d,j＝11.0hz,1h),6.72(d,j＝8.0hz,1h),6.78(d,j＝7.5hz,1h),6.88-6.92(m,1h),7.02-7.08(m,3h),7.14-7.18(m,2h),7.22-7.26(m,4h),7.41-7.44(m,1h),7.53(d,j＝8.0hz,1h),7.89-7.92(m,1h)；13cnmr(cdcl3,125mhz)δ:11.5,21.0,26.6,28.1,41.2,43.5,44.1,50.9,55.3,75.8,85.0,108.8,114.3,117.8,121.0,121.8,124.3,124.4,124.7,126.3,127.1,127.4,127.6,128.7,129.3,130.2,132.4,134.7,135.8,148.6,155.2,160.6,169.5,174.0,175.2,192.4；hrms(esi-tof)m/z:calcd.forc44h38n4nao9[m+na]+:789.2531；found:789.2530.
本实施例制备化合物3f:白色固体,熔点：164.2-165.0℃；产率91％；94％ee,>20:1dr,[α]d20＝-119.21(c0.37ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝15.50min；τminor＝25.52min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.68(s,9h),2.43(s,3h),2.45-2.48(m,1h),3.18-3.23(m,1h),4.17-4.23(m,1h),4.48(d,j＝15.5hz,1h),4.93(d,j＝16.0hz,1h),5.91-5.96(m,1h),6.14-6.17(m,1h),6.29(d,j＝11.0hz,1h),6.62-6.66(m,1h),6.77-6.79(m,1h),6.94-6.97(m,1h),7.03-7.09(m,3h),7.14-7.21(m,2h),7.23-7.27(m,4h),7.42-7.45(m,1h),7.59(d,j＝8.0hz,1h),7.89-7.92(m,1h)；13cnmr(cdcl3,125mhz)δ:11.6,26.4,28.0,40.9,43.5,44.3,51.0,55.4,75.7,85.4,109.9(d,jcf＝7.5hz),112.2(d,jcf＝26.3hz),114.5,116.5(d,jcf＝22.5hz),117.8,121.0,121.9,124.2,124.5,125.8,127.1,127.4,127.8,128.8,129.6,134.3,135.9,138.3,138.9,148.4,155.4,158.6(d,jcf＝241.3hz),159.6,160.4,169.1,173.9,175.1,192.2；hrms(esi-tof)m/z:calcd.forc43h35fn4nao9[m+na]+:793.2280；found:793.2285.
本实施例制备化合物3g:白色固体,熔点：173.3-174.2℃；产率91％；93％ee,>20:1dr,[α]d20＝-114.13(c0.41,ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝12.14min；τminor＝15.46min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.68(s,9h),2.18(s,3h),2.38(s,3h),2.41-2.45(m,1h),3.00(s,3h),3.18-3.24(m,1h),4.17-4.23(m,1h),5.90-5.95(m,1h),6.23-6.25(m,2h),6.77(d,j＝8.0hz,1h),6.84(d,j＝8.0hz,1h),6.99-7.05(m,2h),7.12-7.16(m,2h),7.24-7.27(m,1h),7.40-7.44(m,1h),7.51(d,j＝8.0hz,1h),7.89-7.91(m,1h)；13cnmr(cdcl3,125mhz)δ:11.5,21.0,26.1,26.4,28.1,41.0,43.5,50.9,55.2,75.8,84.9,107.6,114.2,117.8,121.1,121.8,123.8,124.2,124.4,126.3,127.1,129.3,130.1,132.4,135.8,138.9,140.3,148.6,155.2,160.5,169.6,173.8,175.2,192.4；hrms(esi-tof)m/z:calcd.forc38h34n4nao9[m+na]+:713.2218；found:713.2224.
本实施例制备化合物3h:白色固体,熔点：169.9-171.0℃；产率90％；92％ee,>20:1dr,[α]d20＝-102.35(c0.47,ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝13.66min；τminor＝25.52min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.68(s,9h),2.42(s,3h),2.43-2.46(m,1h),3.03(s,3h),3.15-3.20(m,1h),4.15-4.20(m,1h),5.85-5.90(m,1h),6.24(d,j＝11.0hz,1h),6.30-6.33(m,1h),6.75-6.79(m,2h),7.01-7.06(m,2h),7.11-7.13(m,1h),7.13-7.18(m,1h),7.23-7.25(m,1h),7.41-7.45(m,1h),7.56(d,j＝8.0hz,1h),7.89-7.91(m,1h)；13cnmr(cdcl3,125mhz)δ:11.6,26.2,26.3,28.0,40.7,43.5,50.9,55.3,75.7,77.3,85.4,108.6(d,jcf＝7.5hz),112.0(d,jcf＝26.3hz),114.4,116.5(d,jcf＝23.8hz),117.8,121.0,121.9,123.7,124.3,125.9,127.1,129.6,135.9,138.9,148.5,155.4,158.7(d,jcf＝241.3hz),160.4,169.2,173.7,175.1,192.2；hrms(esi-tof)m/z:calcd.forc37h31fn4nao9[m+na]+:717.1967；found:717.1963.
本实施例制备化合物3i:白色固体,熔点：201.9-202.3℃；产率91％；96％ee,>20:1dr,[α]d20＝-119.21(c0.37ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝11.97min；τminor＝20.99min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.08-1.12(m,3h),1.66(s,9h),2.39(s,3h),2.40-2.44(m,1h),3.14-3.21(m,1h),3.42-3.48(m,1h),3.67-3.72(m,1h),4.12-4.19(m,1h),5.83-5.89(m,1h),6.21(d,j＝10.8hz,1h),6.30-6.33(m,1h),6.72-6.77(m,2h),6.97-7.03(m,2h),7.09-7.17(m,2h),7.25(s,1h),7.38-7.43(m,1h),7.55(d,j＝8.4hz,1h),7.87-7.89(m,1h)；13cnmr(cdcl3,100mhz)δ:11.6,11.8,26.5,28.1,34.9,41.0,43.5,50.8,55.2,75.8,85.4,108.7(d,jcf＝9.0hz),112.3(d,jcf＝26.5hz),114.5,116.6(d,jcf＝23.0hz),117.9,121.1,122.0,124.2,124.5,125.9,126.1,127.2,129.6,135.9,138.1,139.0,148.5,155.4,158.5(d,jcf＝241.3hz),160.5,169.3,173.4,175.2,192.3；hrms(esi-tof)m/z:calcd.forc38h33fn4nao9[m+na]+:731.2124；found:731.2130.
本实施例制备化合物3j:白色固体,熔点：165.3-166.2℃；产率87％；97％ee,>20:1dr,[α]d20＝-101.84(c0.46ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝24.25min；τminor＝11.35min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.65(s,9h),2.37(s,3h),2.41-2.46(m,1h),3.15-3.22(m,1h),4.16-4.23(m,1h),4.48(d,j＝15.6hz,1h),4.90(d,j＝15.6hz,1h),5.91-5.97(m,1h),6.22(d,j＝7.6hz,1h),6.30(d,j＝10.8hz,1h),6.74-6.79(m,2h),6.88-6.94(m,2h),7.06-7.09(m,2h),7.11-7.16(m,2h),7.20(d,j＝7.6hz,1h),7.23-7.25(m,3h),7.31(d,j＝7.6hz,1h),7.51-7.56(m,2h)；13cnmr(cdcl3,100mhz)δ:11.7,26.4,28.2,41.0,43.5,44.3,51.0,55.4,76.2,85.1,109.3,112.3(d,jcf＝23.8hz),114.6,119.6(d,jcf＝3.2hz),121.5(d,jcf＝2.8hz),122.8,123.8,124.0,124.2,124.6,126.1,127.5,127.9,128.9,129.5,130.2,134.6,139.0,142.3,148.5,155.4,156.8,157.1(d,jcf＝241.2hz),169.4,174.2,175.4,191.7；hrms(esi-tof)m/z:calcd.forc43h35fn4nao9[m+na]+:793.2280；found:793.2284.
本实施例制备化合物3k:白色固体,熔点：180.7-182.2℃；产率90％；95％ee,>20:1dr,[α]d20＝-101.65(c0.52ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝25.80min；τminor＝13.96min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.65(s,9h),2.36(s,3h),2.39-2.44(m,1h),3.00(s,3h),3.13-3.19(m,1h),4.13-4.21(m,1h),5.85-5.91(m,1h),6.25(d,j＝11.2hz,1h),6.35(d,j＝8.0hz,1h),6.72-6.77(m,1h),6.78-6.81(m,1h),6.97-7.05(m,2h),7.09-7.15(m,2h),7.21-7.28(m,2h),7.48-7.54(m,2h)；13cnmr(cdcl3,100mhz)δ:11.7,26.2,27.0,28.2,40.8,43.5,51.0,55.3,76.2,85.1,108.2,112.3(d,jcf＝24.4hz),114.6,119.6(d,jcf＝2.8hz),121.5(d,jcf＝2.8hz),122.8,123.3,123.5,123.6,123.7,124.1,124.4,126.1,129.6,130.2,139.0,142.8,148.5,155.4,156.8,157.4(d,jcf＝24.2hz),169.5,174.0,175.4,191.7；hrms(esi-tof)m/z:calcd.forc37h31fn4nao9[m+na]+:717.1967；found:717.1968.
本实施例制备化合物3l:白色固体,熔点：153.8-155.2℃；产率87％；94％ee,>20:1dr,[α]d20＝-83.82(c0.42ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝10.80min；τminor＝23.23min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.08-1.12(m,3h),1.65(s,9h),2.35(s,3h),2.39-2.44(m,1h),3.15-3.22(m,1h),3.41-3.50(m,1h),3.66-3.72(m,1h),4.13-4.20(m,1h),5.85-5.91(m,1h),6.24(d,j＝10.8hz,1h),6.37(d,j＝8.0hz,1h),6.73-6.80(m,2h),6.96-7.05(m,2h),7.10-7.15(m,2h),7.25-7.29(m,2h),7.49-7.55(m,2h)；13cnmr(cdcl3,100mhz)δ:11.7,11.9,26.4,28.2,34.8,41.0,43.5,50.8,55.1,76.1,85.1,108.3,112.3(d,jcf＝24.0hz),114.5,119.6(d,jcf＝2.8hz),121.6(d,jcf＝2.8hz),122.6,123.4(d,jcf＝25.2hz),123.8,124.2,124.3,124.4,126.1,129.5,130.1,139.0,142.0,148.5,155.4,156.8,157.4(d,jcf＝241.0hz),169.5,173.6,175.5,191.8；hrms(esi-tof)m/z:calcd.forc38h33fn4nao9[m+na]+:731.2124；found:731.2130.
本实施例制备化合物3m:白色固体,熔点：182.4-183.9℃；产率88％；93％ee,>20:1dr,[α]d20＝-83.78(c0.28ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝29.44min；τminor＝10.66min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.69(s,9h),2.42(s,3h),2.43-4.27(m,1h),3.13-3.20(m,1h),4.14-4.21(m,1h),4.46(d,j＝15.6hz,1h),4.92(d,j＝15.6hz,1h),5.86-5.92(m,1h),6.14(d,j＝8.4hz,1h),6.26(d,j＝11.2hz,1h),6.74-6.78(m,1h),6.88-6.95(m,2h),7.04-7.06(m,2h),7.12-7.20(m,3h),7.24-7.26(m,3h),7.33(d,j＝2.4hz,1h),7.53-7.55(m,1h),7.59(d,j＝8.0hz,1h)；13cnmr(cdcl3,100mhz)δ:11.7,26.5,28.1,40.9,43.4,44.3,50.9,55.4,76.0,85.7,110.3,112.3(d,jcf＝23.2hz),114.6,119.7(d,jcf＝2.8hz),121.6(d,jcf＝2.8hz),123.5(d,jcf＝24.4hz),124.2,124.6,125.7,125.8,127.5,128.0,128.4,129.0,129.8,130.2,134.2,139.0,140.9,148.5,155.6,156.7,157.4(d,jcf＝241.0hz),168.9,173.8,175.0,191.5；hrms(esi-tof)m/z:calcd.forc43h34clfn4nao9[m+na]+:827.1891；found:827.1894.
本实施例制备化合物3n:白色固体,熔点：178.9-180.0℃；产率91％；93％ee,>20:1dr,[α]d20＝-87.72(c0.49ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝33.09min；τminor＝13.35min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.69(s,9h),2.40(s,3h),2.41-2.44(m,1h),3.00(s,3h),3.09-3.16(m,1h),4.11-4.19(m,1h),5.79-5.85(m,1h),6.19-6.26(m,2h),6.73-6.76(m,1h),6.98-7.02(m,1h),7.11-7.20(m,4h),7.42-7.43(m,1h),7.51-7.57(m,2h)；13cnmr(cdcl3,100mhz)δ:11.7,26.3,27.0,28.2,40.7,43.4,50.8,55.2,76.0,85.6,109.5,112.2(d,jcf＝23.3hz),114.6,115.6,119.6(d,jcf＝3.2hz),121.5(d,jcf＝2.4hz),123.6,124.4,125.7,126.2,127.1,129.8,133.1,139.0,141.9,148.5,155.5,156.7,157.7(d,jcf＝222.4hz),169.0,173.6,175.0,191.5；hrms(esi-tof)m/z:calcd.forc37h30brfn4nao9[m+na]+:795.1072；found:795.1076.
本实施例制备化合物3o:白色固体,熔点：170.1-172.0℃；产率88％；98％ee,>20:1dr,[α]d20＝-80.45(c0.44ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(95/5hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝47.93min；τminor＝56.61min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.66(s,9h),2.29(s,3h),2.37(s,3h),2.42-2.46(m,1h),3.15-3.22(m,1h),4.14-4.21(m,1h),4.49(d,j＝15.2hz,1h),4.89(d,j＝16.0hz,1h),5.88-5.94(m,1h),6.22(d,j＝7.6hz,1h),6.29(d,j＝11.2hz,1h),6.66(d,j＝8.4hz,1h),6.75-6.79(m,1h),6.88-6.93(m,2h),7.06-7.09(m,2h),7.12-7.16(m,1h),7.16-7.26(m,5h),7.32(d,j＝7.6hz,1h),7.52(d,j＝8.4hz,1h),7.68(s,1h)；13cnmr(cdcl3,100mhz)δ:11.7,20.5,26.6,28.2,41.2,43.6,44.2,51.1,55.4,75.9,85.0,109.2,114.6,117.7,120.7,122.7,123.9,124.2,124.3,124.5,126.3,126.8,127.5,127.8,128.8,129.4,130.1,131.4,134.7,137.0,139.0,142.4,155.3,158.7,169.7,174.2,175.4,192.7；hrms(esi-tof)m/z:calcd.forc44h38n4nao9[m+na]+:789.2531；found:789.2537.
本实施例制备化合物3p:白色固体,熔点：175.6-177.4℃；产率86％；98％ee,>20:1dr,[α]d20＝-105.60(c0.43ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(95/5hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝38.57min；τminor＝60.41min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.67(s,9h),2.29(s,3h),2.41(s,3h),2.42-2.47(m,1h),3.14-3.20(m,1h),4.12-4.19(m,1h),4.46(d,j＝8.0hz,1h),4.91(d,j＝15.6hz,1h),5.85-5.91(m,1h),6.12-6.15(m,1h),6.26(d,j＝10.8hz,1h),6.60-6.67(m,2h),6.92-6.96(m,1h),7.05-7.07(m,2h),7.12-7.19(m,2h),7.21-7.25(m,5h),7.57(d,j＝8.4hz,1h),7.67(s,1h)；13cnmr(cdcl3,100mhz)δ:11.7,20.5,26.6,28.1,41.0,43.6,44.4,51.1,55.5,75.8,85.5,109.9(d,jcf＝3.2hz),112.3(d,jcf＝25.3hz),114.6,116.6(d,jcf＝23.4hz),117.7,120.7,124.3,124.6,126.0,126.8,127.5,127.9,128.9,129.7,131.4,134.4,137.0,138.4,139.0,148.5,155.5,158.6,158.7(d,jcf＝242.1hz),169.3,174.0,175.2,192.5；hrms(esi-tof)m/z:calcd.forc44h37fn4nao9[m+na]+:807.2437；found:807.2440.
本实施例制备化合物3q:白色固体,熔点：178.2-179.4℃；产率89％；98％ee,>20:1dr,[α]d20＝-103.17(c0.41ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝31.90min；τminor＝12.85min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.67(s,9h),2.13(s,3h),2.29(s,3h),2.36(s,3h),2.40-2.45(m,1h),3.17-3.23(m,1h),4.13-4.21(m,1h),4.53(d,j＝15.6hz,1h),4.82(d,j＝15.6hz,1h),5.89-5.95(m,1h),6.09(d,j＝8.0hz,1h),6.25(d,j＝10.8hz,1h),6.66(d,j＝7.6hz,1h),6.69-6.72(m,1h),6.87-6.91(m,1h),7.04-7.06(m,2h),7.12-7.16(m,2h),7.20-7.25(m,5h),7.52(d,j＝7.6hz,1h),7.67(d,j＝1.6hz,1h)；13cnmr(cdcl3,100mhz)δ:11.6,20.5,21.1,26.8,28.2,41.4,43.6,44.2,51.0,55.4,75.8,85.0,114.4,117.7,120.7,124.3,124.5,124.8,126.4,126.8,127.5,127.7,128.8,129.4,131.3,132.5,134.8,136.9,139.0,139.8,148.7,155.3,158.8,169.7,174.1,175.3,192.7；hrms(esi-tof)m/z:calcd.forc45h40n4nao9[m+na]+:803.2687；found:803.2690.
本实施例制备化合物3r:白色固体,熔点：182.6-184.1℃；产率91％；95％ee,>20:1dr,[α]d20＝-104.85(c0.49ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝20.28min；τminor＝26.86min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.65(s,9h),2.28(s,3h),2.35(s,3h),2.38-2.44(m,1h),2.99(s,3h),3.12-3.19(m,1h),4.11-4.18(m,1h),5.82-5.88(m,1h),6.24(d,j＝14.0hz,1h),6.33(d,j＝9.5hz,1h),6.64(d,j＝9.5hz,1h),6.76-6.80(m,1h),6.97-7.04(m,2h),7.09-7.13(m,1h),7.19-7.29(m,3h),7.48-7.50(m,1h),7.66-7.67(m,1h)；13cnmr(cdcl3,125mhz)δ:11.7,20.5,26.1,26.4,28.2,41.0,43.6,51.1,55.3,75.9,85.0,108.1,114.5,117.7,120.7,122.7,123.6,123.8,124.2,124.3,126.3,126.7,129.5,130.1,131.3,136.9,139.0,142.9,148.6,155.3,158.7,169.8,174.0,175.3,192.7；hrms(esi-tof)m/z:calcd.forc38h34n4nao9[m+na]+:713.2218；found:713.2222.
本实施例制备化合物3s:白色固体,熔点：190.4-191.8℃；产率86％；98％ee,>20:1dr,[α]d20＝-113.38(c0.36ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝18.43min；τminor＝28.52min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.66(s,9h),2.28(s,3h),2.35(s,3h),2.36-2.44(m,1h),3.00(s,3h),3.10-3.17(m,1h),4.08-4.16(m,1h),5.79-5.85(m,1h),6.21(d,j＝11.2hz,1h),6.27-6.30(m,1h),6.64(d,j＝8.4hz,1h),6.72-6.77(m,1h),6.98-7.02(m,1h),7.08-7.16(m,2h),7.19-7.22(m,2h),7.54(d,j＝8.2hz,1h),7.66(s,1h)；13cnmr(cdcl3,100mhz)δ:11.7,20.5,26.3,28.1,40.8,43.5,51.0,55.4,55.5,75.7,85.5,108.6(d,jcf＝8.3hz),112.1(d,jcf＝26.5hz),114.5,116.6(d,jcf＝23.3hz),117.7,120.7,123.8,124.4,125.8,125.9,126.0,126.8,129.7,131.4,137.0,138.9,139.0,148.5,155.4,158.6,158.8(d,jcf＝242.5hz),169.4,173.8,175.1,192.5；hrms(esi-tof)m/z:calcd.forc38h33fn4nao9[m+na]+:731.2124；found:731.2126.
本实施例制备化合物3t:白色固体,熔点：162.3-163.7℃；产率89％；98％ee,>20:1dr,[α]d20＝-94.61(c0.38ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(85/15hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝22.89min；τminor＝11.83min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.66(s,9h),2.15(s,3h),2.28(s,3h),2.35(s,3h),2.37-2.43(m,1h),2.98(s,3h),3.14-3.20(m,1h),4.11-4.18(m,1h),5.83-5.89(m,1h),6.19-6.23(m,2h),6.64(d,j＝10.5hz,1h),6.79-6.82(m,1h),6.96-7.00(m,1h),7.10-7.13(m,2h),7.19-7.25(m,2h),7.49(d,j＝10.0hz,1h),7.66(s,1h)；13cnmr(cdcl3,125mhz)δ:11.6,20.5,21.1,26.1,26.6,28.2,41.1,43.6,51.0,55.3,75.8,85.0,107.7,114.3,117.7,120.7,123.9,124.3,124.5,126.4,126.7,129.4,130.2,131.3,132.5,136.9,139.0,140.4,148.7,155.3,158.7,169.8,173.9,175.3,192.8；hrms(esi-tof)m/z:calcd.forc39h36n4nao9[m+na]+:727.2374；found:727.2377.
本实施例制备化合物3u:白色固体,熔点：174.9-175.8℃；产率91％；97％ee,>20:1dr,[α]d20＝-83.16(c0.42ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝18.27min；τminor＝22.60min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,500mhz)δ:1.08-1.12(m,3h),1.65(s,9h),2.28(s,3h),2.35(s,3h),2.39-2.43(m,1h),3.14-3.21(m,1h),3.43-3.48(m,1h),3.66-3.71(m,1h),4.11-4.18(m,1h),5.83-5.89(m,1h),6.23(d,j＝13.5hz,1h),6.36(d,j＝10.0hz,1h),6.64(d,j＝10.5hz,1h),6.76-6.79(m,1h),6.95-7.04(m,2h),7.09-7.13(m,1h),7.19-7.22(m,1h),7.26-7.30(m,2h),7.50(d,j＝10.0hz,1h),7.67(d,j＝2.5hz,1h)；13cnmr(cdcl3,125mhz)δ:11.6,11.9,20.5,26.6,28.2,34.8,41.2,43.6,50.9,55.1,75.8,85.0,108.2,114.5,117.7,120.7,122.5,123.9,124.2,124.4,124.5,126.3,126.7,129.4,130.0,131.3,136.9,139.0,142.0,148.6,155.3,158.7,169.8,173.7,175.4,192.7；hrms(esi-tof)m/z:calcd.forc39h36n4nao9[m+na]+:727.2374；found:727.2378.
本实施例制备化合物3v:白色固体,熔点：173.8-175.7℃；产率91％；97％ee,>20:1dr,[α]d20＝-87.66(c0.38ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝30.24min；τminor＝12.87min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.06-1.09(m,3h),1.66(s,9h),2.15(s,3h),2.27(s,3h),2.34(s,3h),2.37-2.43(m,1h),3.15-3.22(m,1h),3.41-3.46(m,1h),3.62-3.67(m,1h),4.10-4.18(m,1h),5.83-5.89(m,1h),6.18(d,j＝11.2hz,1h),6.24(d,j＝8.0hz,1h),6.64(d,j＝8.8hz,1h),6.79-6.82(m,1h),6.95-6.98(m,1h),7.09-7.13(m,2h),7.18-7.21(m,1h),7.25-7.28(m,1h),7.49(d,j＝8.4hz,1h),7.66(s,1h)；13cnmr(cdcl3,100mhz)δ:11.6,11.9,20.5,21.1,26.7,28.2,34.7,41.3,43.6,50.8,55.1,75.8,85.0,107.8,114.3,117.7,120.7,124.3,124.6,124.8,126.4,126.7,129.3,130.2,131.2,132.2,136.9,138.9,139.5,148.7,155.2,158.8,169.8,173.5,175.4,192.8；hrms(esi-tof)m/z:calcd.forc40h38n4nao9[m+na]+:741.2531；found:741.2538.
本实施例制备化合物3w:白色固体,熔点：143.3-144.5℃；产率84％；98％ee,>20:1dr,[α]d20＝-68.65(c0.21ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiccolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝22.54min；τminor＝12.35min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.65(s,9h),2.38(s,3h),2.44-2.49(m,1h),3.13-3.20(m,1h),4.15-4.22(m,1h),4.55(d,j＝15.6hz,1h),4.92(d,j＝15.6hz,1h),5.89-5.96(m,1h),6.24-6.31(m,2h),6.76-6.80(m,2h),6.86-6.95(m,2h),7.01-7.10(m,4h),7.23-7.31(m,4h),7.40-7.44(m,1h),7.53-7.56(m,1h),7.90(d,j＝8.0hz,1h)；13cnmr(cdcl3,100mhz)δ:11.7,27.0,28.2,41.2,43.5,44.4,51.2,55.3,75.8,85.3,109.6,112.1,116.2(d,jcf＝24.1hz),117.9,121.1,122.0,122.9,123.8,123.9,127.2,127.3,127.9(d,jcf＝25.2hz),129.0,130.3,132.3,134.5,136.0,142.3,148.5,155.4,159.5(d,jcf＝264.1hz),160.6,169.4,174.0,175.0,192.3；hrms(esi-tof)m/z:calcd.forc43h35fn4nao9[m+na]+:793.2280；found:793.2285.
本实施例制备化合物3x:白色固体,熔点：182.4-184.0℃；产率79％；97％ee,>20:1dr,[α]d20＝-104.17(c0.21ch2cl2)；theeewasdeterminedbyhplcanalysisusingachiralpakiacolumn(90/10hexane/i-proh；flowrate:1.0ml/min；λ＝254nm；τmajor＝36.04min；τminor＝16.31min)；核磁共振和高分辨质谱测试等结果如下：1hnmr(cdcl3,400mhz)δ:1.65(s,9h),2.37(s,3h),2.44-2.49(m,1h),3.16-3.23(m,1h),3.59(s,3h),4.17-4.24(m,1h),4.62(d,j＝15.6hz,1h),4.86(d,j＝16.0hz,1h),5.89-5.96(m,1h),6.20(d,j＝8.0hz,1h),6.31(d,j＝10.8hz,1h),6.69-6.72(m,1h),6.76-6.80(m,2h),6.88-6.94(m,2h),7.01-7.05(m,3h),7.22-7.24(m,3h),7.33(d,j＝7.6hz,1h),7.40-7.44(m,1h),7.47(d,j＝8.4hz,1h),7.89(d,j＝8.0hz,1h)；13cnmr(cdcl3,100mhz)δ:11.7,26.4,28.2,41.4,43.6,44.2,51.2,55.5,75.9,84.9,109.5,110.0,114.9,115.8,117.9,121.1,122.0,122.8,123.9,127.0,127.2,127.5,127.7,128.9,130.1,132.3,134.6,136.0,142.4,148.6,155.4,156.9,160.6,169.6,174.2,175.5,192.5；hrms(esi-tof)m/z:calcd.forc44h38n4nao10[m+na]+:805.2480；found:805.2486.
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)肿瘤细胞的细胞毒性试验表明：此类式(1)所示结构的山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生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3f,3h,3m,3n和3w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3f,3h,3m,3n和3w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3f,3h,3m,3n和3w对pc-3细胞半抑制浓度ic50由spss软件(19版本)分析得到。化合物3f对k562肿瘤细胞的ic50为41.4μmol/l；化合物3h对k562肿瘤细胞的ic50为34.5μmol/l；化合物3m对k562肿瘤细胞的ic50为48.1μmol/l；化合物3n对k562肿瘤细胞的ic50为56.4μmol/l；化合物3w对k562肿瘤细胞的ic50为35.3μmol/l；而阳性对照顺铂对k562肿瘤细胞的ic50为21.5μmol/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)所示的山酮素骨架拼接异噁唑与双螺环氧化吲哚衍生物对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，值得继续深入研究下去。
