CN111892608B - 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用 - Google Patents

一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用 Download PDF

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CN111892608B
CN111892608B CN202010879146.3A CN202010879146A CN111892608B CN 111892608 B CN111892608 B CN 111892608B CN 202010879146 A CN202010879146 A CN 202010879146A CN 111892608 B CN111892608 B CN 111892608B
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CN111892608A (zh
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崔宝东
吴优彩
陈永正
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Zunyi Medical University
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

本申请公开的是有机合成领域中的一种具有光学活性的螺杂环2,3‑二氢苯并呋喃类化合物，具有如下结构：

Description

一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其 应用
技术领域
本发明涉及有机合成领域，更具体的，本发明为一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用。
背景技术
2,3-二氢苯并呋喃砌块广泛存在众多天然产物与药物分子中，尤其是螺环2,3-二氢苯并呋喃骨架由于其独特的三维空间结构更是构成许多天然分子与药物活性化合物的核心结构单元。
鉴于螺环2,3-二氢苯并呋喃类化合物在有机合成化学与药物化学中的潜在应用价值，获得更多的具有实际应用的手性螺环2,3-二氢苯并呋喃类化合物，对于有效丰富手性2,3-二氢苯并呋喃化合物的种类与开展相关领域的药物化学研究具有重要意义。
发明内容
本发明针对现有技术的不足，提供一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用，为开展相关领域的药物化学研究提供依据。
本发明的一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物，如下式所示：
Figure BDA0002653577710000011
式中：n为0或1。
本发明的化合物，一般为黄色或淡黄色固体，易溶于二氯甲烷、甲苯、乙醇、乙酸乙酯、丙酮、二甲基亚砜等有机溶剂，难溶于水，具有热力学稳定性的特点。
进一步，当n＝0时，R6各自独立地选自tBu或iPr；
相应的，R各自独立地选自Me、Et、nPr、iPr或Ph；
相应的，R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2；
相应的，R2各自独立地选自F、Cl或Br；
相应的，R3各自独立地选自Me、F、Cl或Br；
相应的，R1、R3也可以同时选自Me；
相应的，R4各自独立地选自Me、OMe、F、Cl或Br；
相应的，R5各自独立地选自Me、OMe、F、Cl或Br。
进一步，当n＝1时，R6各自独立地选自tBu或iPr；
相应的，R各自独立地选自Me、Et、nPr、iPr或Ph；
相应的，R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2；
相应的，R2各自独立地选自F、Cl或Br；
相应的，R3各自独立地选自Me、F、Cl或Br；
相应的，R1、R3也可以同时选自Me；
相应的，R4各自独立地选自Me、OMe、F、Cl或Br；
相应的，R5各自独立地选自Me、OMe、F、Cl或Br。
本发明的化合物是通过以下方法制备，包括：步骤一、向有机溶剂中加入杂环重氮化合物、对苯醌甲基化物以及手性膦酸或手性膦酰亚胺，在-20℃～40℃的反应温度下搅拌9～84h；
步骤二、分离得到具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物。
其中，杂环重氮化合物结构如下式所示：
Figure BDA0002653577710000021
式中：当n＝0时，
R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2；
R2各自独立地选自F、Cl或Br；
R3各自独立地选自Me、F、Cl或Br；
R1、R3也可以同时选自Me；
当n＝1时，R各自独立地选自Me、Et、nPr、iPr或Ph；
相应的，R1、R2、R3各自独立地为H；
对苯醌甲基化物结构如下式所示：
Figure BDA0002653577710000031
式中：当R6＝iPr时，R4各自独立地选自Me、OMe、F、Cl或Br；
相应的，R5各自独立地选自Me、OMe、F、Cl或Br；
当R6＝tBu时，R4各自独立地选自Me、OMe、F、Cl或Br；
相应的，R5各自独立地选自Me、OMe、F、Cl或Br。
例如：将0.1mmol对苯醌甲基化物、0.2mmol 3-重氮氧化吲哚/4-重氮氧化异喹啉和0.05mmol(3.0mg)(R)-螺环手性膦酸Cat.D溶解于1mL或2mL甲苯中，在0℃或25℃的反应温度下，搅拌48-84小时；然后，反应液直接用柱层析法进行分离，得到相应的具有光学活性的螺[二氢苯并呋喃-2,3'-氧化吲哚/2,4'-氧化异喹啉]化合物。
进一步，所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物的光学纯度≧65％。
更进一步的，所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物的光学纯度≧80％。
再进一步的，所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物的光学纯度≧85％。
本发明目的在于，提供具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物作为活性成分在制备抗肿瘤药物中的应用。
具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物作为活性成分在制备抗肝癌药物中的应用的应用。
具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物作为活性成分在制备抗肺癌药物中的应用的应用。
经过抗肿瘤活性验证，本发明的化合物对肺癌细胞和肝癌细胞具有一定程度的抑制作用。
具体实施方式
本发明的化合物，反应原料的不同，生成的具体产物如下：
实施例1：
Figure BDA0002653577710000032
ee；[α]D 25＝57.3(c 0.55,CH2Cl2)；The ee was determined by HPLC(Chiralpak OD-H,i-PrOH/hexane＝10/90,flow rate 0.8mL/min,λ＝254nm,major diastereomer:tminor＝7.0min,tmajor＝9.7min).1H NMR(400MHz,CDCl3):major diastereomer:δ1.27(s,18H),2.62(s,3H),5.05(s,1H),5.14(s,1H),6.63(d,J＝7.6Hz,1H),6.72(s,2H),7.00-7.04(m,2H),7.17-7.22(m,2H),7.29(t,J＝8.2Hz,1H),7.37(t,J＝7.8Hz,1H),7.61(d,J＝7.2Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.3,30.3,34.3,60.1,92.2,107.8,110.3,121.5,123.2,124.2,124.5,125.0,125.2,128.1,128.2,129.0,130.5,135.5,144.5,153.5,160.9,172.9.HRMS(ESI-TOF)calcd.for C30H34NO3[M+H]+456.2533；found:456.2528.
实施例2：
Figure BDA0002653577710000041
major diastereomer:δ1.28(s,18H),2.40(s,3H),2.61(s,3H),5.04(s,1H),5.14(s,1H),6.53(d,J＝8.0Hz,1H),6.74(s,2H),7.00-7.03(m,2H),7.15-7.17(m,1H),7.20-7.22(m,1H),7.27-7.30(m,1H),7.43(s,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ21.3,25.3,30.3,34.3,60.0,92.2,107.6,110.3,121.5,124.7,124.9,125.0,125.2,128.1,128.2,129.0,130.6,132.8,135.5,142.0,153.5,161.0,172.9.HRMS(ESI-TOF)calcd.forC31H36NO3[M+H]+470.2690；found:470.2686.
实施例3：
Figure BDA0002653577710000042
MHz,CDCl3):major diastereomer:δ1.30(s,18H),2.60(s,3H),3.85(s,3H),5.04(s,1H),5.16(s,1H),6.56(d,J＝8.8Hz,1H),6.75(s,2H),6.91(dd,J＝2.6Hz,8.6Hz,1H),7.01-7.04(m,2H),7.21-7.24(m,2H),7.29(t,J＝7.8Hz,1H)；13C NMR(100MHz,CDCl3):majordiastereomer:δ25.3,30.3,34.3,56.2,60.3,92.4,108.3,110.3,111.1,115.2,121.5,124.5,125.0,125.2,128.1,129.0,129.4,135.5,137.8,153.5,156.5,160.8,172.7.HRMS(ESI-TOF)calcd.for C31H36NO4[M+H]+486.2639；found:486.2633.
实施例4：
Figure BDA0002653577710000051
5.17(s,1H),6.62(d,J＝8.4Hz,1H),6.72(s,2H),7.00-7.04(m,2H),7.20(d,J＝7.2Hz,1H),7.24-7.31(m,2H),7.54(d,J＝1.2Hz,1H)；13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.2,34.3,60.6,91.9,108.3,110.4,118.4,119.4,121.8,122.0,123.7,123.9,125.0,125.2,127.8,129.2,129.6,135.7,143.2,145.1(t,J＝2.0Hz,1C),153.7,160.6,172.8.HRMS(ESI-TOF)calcd.for C31H33F3NO4[M+H]+540.2356；found:540.2351.
实施例5：
Figure BDA0002653577710000052
CDCl3):major diastereomer:δ1.30(s,18H),2.62(s,3H),5.02(s,1H),5.18(s,1H),6.58(dd,J＝3.8Hz,8.6Hz,1H),6.74(s,2H),7.01-7.11(m,3H),7.21(d,J＝7.2Hz,1H),7.30(t,J＝7.8Hz,1H),7.37(dd,J＝2.2Hz,7.4Hz,1H)；13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.3,34.3,60.4,92.1,108.4(d,J＝8.0Hz,1C),110.3,112.4(d,J＝25.0Hz,1C),116.6(d,J＝24.0Hz,1C),121.7,124.2,125.1,125.2,127.8,129.2,129.8(d,J＝8.0Hz,1C),135.6,140.4,153.6,159.5(d,J＝240.0Hz,1C),160.6,172.7.HRMS(ESI-TOF)calcd.for C30H33FNO3[M+H]+474.2439；found:474.2432.
实施例6：
Figure BDA0002653577710000053
CDCl3):major diastereomer:δ1.30(s,18H),2.62(s,3H),5.02(s,1H),5.18(s,1H),6.58(dd,J＝3.8Hz,8.6Hz,1H),6.74(s,2H),7.01-7.11(m,3H),7.21(d,J＝7.2Hz,1H),7.30(t,J＝7.8Hz,1H),7.37(dd,J＝2.2Hz,7.4Hz,1H)；13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.3,34.3,60.4,92.1,108.4(d,J＝8.0Hz,1C),110.3,112.4(d,J＝25.0Hz,1C),116.6(d,J＝24.0Hz,1C),121.7,124.2,125.1,125.2,127.8,129.2,129.8(d,J＝8.0Hz,1C),135.6,140.4,153.6,159.5(d,J＝240.0Hz,1C),160.6,172.7.HRMS(ESI-TOF)calcd.for C30H33ClNO3[M+H]+490.2143；found:490.2138.
实施例7：
Figure BDA0002653577710000061
CDCl3):major diastereomer:δ1.29(s,18H),2.61(s,3H),5.03(s,1H),5.17(s,1H),6.53(d,J＝8.0Hz,1H),6.74(s,2H),7.00-7.05(m,2H),7.20(d,J＝7.2Hz,1H),7.29(t,J＝7.8Hz,1H),7.50(dd,J＝2.0Hz,8.4Hz,1H),7.73(d,J＝2.0Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.3,34.3,60.3,91.8,109.2,110.3,115.5,121.8,124.3,125.1,125.2,127.4,127.7,129.2,130.4,133.2,135.6,143.4,153.6,160.6,172.5.HRMS(ESI-TOF)calcd.for C30H33BrNO3[M+H]+534.1638；found:534.1631.
实施例8：
Figure BDA0002653577710000062
CDCl3):major diastereomer:δ1.30(s,18H),2.60(s,3H),5.04(s,1H),5.18(s,1H),6.44(d,J＝8.4Hz,1H),6.75(s,2H),7.00-7.05(m,2H),7.21(d,J＝7.2Hz,1H),7.29(t,J＝7.8Hz,1H),7.70(dd,J＝1.6Hz,8.0Hz,1H),7.91(d,J＝1.6Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.3,30.3,34.3,60.3,91.6,109.8,110.3,121.7,124.2,125.0,125.1,127.7,129.1,130.6,132.9,135,6,139.1,144.1,153.6,160.5,172.3.HRMS(ESI-TOF)calcd.for C30H33INO3[M+H]+582.1500；found:582.1487.
实施例9：
Figure BDA0002653577710000063
CDCl3):major diastereomer:δ1.24(s,18H),2.66(s,3H),5.06(s,1H),5.17(s,1H),6.68(s,2H),6.72(s,1H),6.98-7.04(m,2H),7.17(d,J＝7.2Hz,1H),7.22-7.28(m,1H),8.33(d,J＝8.4Hz,1H),8.48(s,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.8,30.3,34.3,60.6,91.2,107.4,110.2,110.5,120.2,122.1,123.9,125.1,125.2,127.3,127.5,129.4,135.8,143.7,149.9,153.8,160.3,173.2.HRMS(ESI-TOF)calcd.for C30H33N2O5[M+H]+501.2384；found:501.2380.
实施例10：
Figure BDA0002653577710000071
major diastereomer:δ1.31(s,18H),2.35(s,3H),2.38(s,3H),2.86(s,3H),4.99(s,1H),5.16(s,1H),6.74(s,2H),6.91(s,1H),6.99-7.03(m,2H),7.21(d,J＝7.6Hz,1H),7.26-7.30(m,2H)；13C NMR(100MHz,CDCl3):major diastereomer:δ18.7,20.9,28.6,30.3,34.3,60.5,91.9,110.2,119.2,121.4,122.6,124.7,125.0,125.2,128.2,128.9,132.6,134.4,135.4,139.5,153.4,160.9,173.7.HRMS(ESI-TOF)calcd.for C32H37NO3[M+H]+484.2846；found:484.2843.
实施例11：
Figure BDA0002653577710000072
1H),6.65(d,J＝2.0Hz,1H),6.75(s,2H),7.01-7.06(m,2H),7.18(dd,J＝1.8Hz,7.8Hz,1H),7.21-7.23(m,1H),7.28-7.32(m,1H),7.54(d,J＝8.0Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.2,34.3,60.3,91.7,108.5,110.3,121.7,122.9,124.1,125.0,125.1,125.2,126.5,127.9,129.1,135.7,136.3,145.7,153.6,160.7,172.8.HRMS(ESI-TOF)calcd.for C30H33ClNO3[M+H]+490.2143；found:490.2137.
实施例12：
Figure BDA0002653577710000073
major diastereomer:δ1.31(s,18H),2.60(s,3H),5.01(s,1H),5.20(s,1H),6.73(s,2H),6.80(s,1H),7.01-7.05(m,2H),7.21(d,J＝7.2Hz,1H),7.28-7.35(m,2H),7.48(d,J＝8.0Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.2,34.3,60.3,91.8,110.3,111.3,121.7,124.0,124.1,125.0,125.1,125.5,125.9,127.0,127.8,129.1,135.6,145.7,153.6,160.6,172.7.HRMS(ESI-TOF)calcd.for C30H33BrNO3[M+H]+534.1638；found:534.1635.
实施例13：
Figure BDA0002653577710000081
CDCl3):major diastereomer:δ1.25(s,18H),2.76(s,3H),4.94(s,1H),5.14(s,1H),6.67(s,2H),6.95-6.98(m,2H),7.05(d,J＝8.8Hz,2H),7.15(d,J＝5.2Hz,1H),7.24(t,J＝6.8Hz,1H),7.35(s,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ27.8,30.2(d,J＝12.0Hz,1C),34.3(d,J＝12.0Hz,1C),60.7,92.1,110.3,118.3,120.1,121.7,123.8,124.1,125.0,127.8,129.1,130.5,131.0,135.7,147.3(d,J＝237.1Hz,1C),153.7,160.7,172.6.HRMS(ESI-TOF)calcd.for C30H33FNO3[M+H]+474.2439；found:474.2432.
实施例14：
Figure BDA0002653577710000082
CDCl3):major diastereomer:δ1.32(s,18H),2.95(s,3H),4.98(s,1H),5.20(s,1H),6.72(s,2H),7.01-7.05(m,2H),7.09-7.12(m,1H),7.21(d,J＝8.0Hz,1H),7.28-7.32(m,2H),7.50-7.52(m,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ28.6,30.3,34.3,61.0,91.8,110.3,115.3,121.7,122.7,123.9,124.0,125.0,125.1,127.8,129.2,131.2,132.5,135.7,140.2,153.8,160.9,173.3.HRMS(ESI-TOF)calcd.for C30H33BrNO3[M+H]+490.2144；found:490.2141.
实施例15：
Figure BDA0002653577710000083
CDCl3):major diastereomer:δ1.29(s,18H),2.93(s,3H),4.94(s,1H),5.18(s,1H),6.68(s,2H),6.98-7.02(m,3H),7.18(d,J＝7.2Hz,1H),7.26(t,J＝7.2Hz,1H),7.43-7.45(m,1H),7.51(d,J＝7.2Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ28.8,30.3,34.3,61.0,91.7,102.0,110.3,121.7,122.1,123.2,123.9,124.3,124.9,125.0,127.7,129.1,131.4,135.6,135.7,141.5,153.7,160.7,173.4.HRMS(ESI-TOF)calcd.forC30H33BrNO3[M+H]+534.1638；found:534.1636.
实施例16：
Figure BDA0002653577710000091
majordiastereomer:δ1.28(s,18H),4.06(d,J＝16.0Hz,1H),4.92(d,J＝16.0Hz,1H),5.15(s,1H),5.30(s,1H),6.34(d,J＝8.4Hz,1H),6.48-6.49(m,2H),6.90(s,2H),7.01-7.06(m,2H),7.15-7.19(m,4H),7.30(t,J＝7.8Hz,1H),7.35(dd,J＝1.8Hz,8.2Hz,1H),7.81(d,J＝2.0Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ30.4,34.4,43.9,59.7,91.5,110.2,110.7,115.7,121.8,124.0,124.8,126.2,126.4,127.4,127.7,128.8,129.0,129.2,129.8,133.3,134.8,135.8,143.2,153.9,160.2,172.7.HRMS(ESI-TOF)calcd.forC36H36BrNO3[M+H]+610.1952；found:610.1949.
实施例17：
Figure BDA0002653577710000092
CDCl3):major diastereomer:δ1.30(s,18H),1.39(s,9H),5.06(s,1H),5.19(s,1H),6.75(s,2H),6.99-7.06(m,2H),7.20(d,J＝7.2Hz,1H),7.30(t,J＝7.6Hz,1H),7.55-7.57(m,1H),7.75-7.80(m,2H)；13C NMR(100MHz,CDCl3):major diastereomer:δ28.0,30.3,34.4,61.2,84.1,91.0,110.3,117.0,118.0,121.9,123.7,125.1,125.2,127.0,127.2,129.4,129.6,133.6,136.0,139.5,148.5,153.8,160.4,170.5.HRMS(ESI-TOF)calcd.forC34H38BrNNaO5[M+Na]+642.1825；found:642.1824.
实施例18：
Figure BDA0002653577710000093
mg,51％yield；5:1dr,93％ee；[α]D 25＝-19.5(c 0.39,CH2Cl2)；The ee was determined byHPLC(Chiralpak OD-H,i-PrOH/hexane＝10/90,flow rate 1.0mL/min,λ＝254nm,majordiastereomer:tminor＝11.0min,tmajor＝5.7min).1H NMR(400MHz,CDCl3):majordiastereomer:δ1.29(s,18H),2.69(s,3H),4.97(s,1H),5.16(s,1H),6.52-6.61(s,3H),6.73(s,2H),7.07(dd,J＝0.8Hz,8.0Hz,1H),7.50(dd,J＝1.8Hz,8.2Hz,1H),7.72(d,J＝1.6Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.3,34.3,55.7,59.8,92.4,97.1,107.4,109.2,115.5,119.5,124.6,125.0,125.1,127.4,130.3,133.1,135.6,143.3,153.6,161.1,161.8,172.5.HRMS(ESI-TOF)calcd.for C31H34BrNNaO4[M+Na]+586.1563；found:586.1552.
实施例19：
Figure BDA0002653577710000101
NMR(400MHz,CDCl3):major diastereomer:δ1.29(s,18H),2.60(s,3H),4.97(s,1H),5.19(s,1H),6.53(d,J＝8.4Hz,1H),6.71(s,2H),7.00-7.02(m,2H),7.08-7.11(m,1H),7.51(dd,J＝2.0Hz,8.4Hz,1H),7.73(d,J＝2.0Hz,1H)；13C NMR(100MHz,CDCl3):majordiastereomer:δ25.5,30.3,34.3,59.7,92.5,109.4,111.2,115.6,122.0,123.6,125.1,125.5,126.7,127.5,129.7,133.4,134.5,135.7,143.4,153.8,161.3,172.1.HRMS(ESI-TOF)calcd.for C33H32BrClNO3[M+H]+568.1249；found:568.1242.
实施例20：
Figure BDA0002653577710000102
NMR(400MHz,CDCl3):major diastereomer:δ1.29(s,18H),2.61(s,3H),4.95(s,1H),5.20(s,1H),6.53(d,J＝8.4Hz,1H),6.71(s,2H),7.05(d,J＝7.6Hz,1H),7.15-7.17(m,2H),7.51(dd,J＝1.6Hz,8.4Hz,1H),7.73(d,J＝1.6Hz,1H)；13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.3,34.3,59.7,92.4,109.3,114.0,115.6,122.1,123.5,124.9,125.1,126.0,127.3,127.5,129.6,133.4,135.7,143.3,153.8,161.4,172.1.HRMS(ESI-TOF)calcd.for C30H32Br2NO3[M+H]+612.0743；found:612.0740.
实施例21：
Figure BDA0002653577710000111
NMR(400MHz,CDCl3):major diastereomer:δ1.30(s,18H),2.34(s,3H),2.60(s,3H),4.99(s,1H),5.17(s,1H),6.52(d,J＝8.0Hz,1H),6.74(s,2H),6.89(d,J＝8.0Hz,1H),7.02(s,1H),7.09(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,1H),7.72(s,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ21.1,25.4,30.3,34.3,60.4,91.9,109.2,109.8,115.5,124.3,125.2,125.6,127.4,127.7,129.5,130.4,131.1,133.1,135.6,143.4,153.6,158.5,172.6.HRMS(ESI-TOF)calcd.for C31H35BrNO3[M+H]+548.1795；found:548.1793.
实施例22：
Figure BDA0002653577710000112
min).1HNMR(400MHz,CDCl3):major diastereomer:δ1.27(s,18H),2.57(s,3H),3.75(s,3H),4.99(s,1H),5.16(s,1H),6.49(d,J＝8.0Hz,1H),6.73(s,2H),6.77-6.82(m,2H),6.89(d,J＝8.8Hz,1H),7.48(dd,J＝1.8Hz,8.2Hz,1H),7.72(d,J＝2.0Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.3,34.3,56.2,60.6,92.1,109.2,110.3,111.1,114.3,115.5,124.0,125.2,127.4,128.6,130.2,133.1,135.6,143.3,153.7,154.5,155.1,172.6.HRMS(ESI-TOF)calcd.for C31H35BrNO4[M+H]+564.1744；found:564.1742.
实施例23：
Figure BDA0002653577710000113
NMR(400MHz,CDCl3):major diastereomer:δ1.30(s,18H),2.60(s,3H),3.75(s,3H),5.01(s,1H),5.19(s,1H),6.52(d,J＝8.4Hz,1H),6.72(s,2H),6.89-6.92(m,2H),6.95-7.00(m,1H),7.51(dd,J＝1.8Hz,8.2Hz,1H),7.75(d,J＝2.0Hz,1H)；13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.3,34.3,60.3,92.4,109.3,110.5(d,J＝8.0Hz,1C),112.3(d,J＝26.0Hz,1C),115.3(d,J＝24.0Hz,1C),115.6,123.5,125.1,127.5,129.5(d,J＝9.0Hz,1C),129.8,133.3,135.8,143.4,153.8,156.4,158.3(d,J＝237.0Hz,1C),172.4.HRMS(ESI-TOF)calcd.for C30H32BrFNO3[M+H]+552.1544；found:552.1543.
实施例24：
Figure BDA0002653577710000121
NMR(400MHz,CDCl3):major diastereomer:δ1.28(s,18H),2.59(s,3H),4.98(s,1H),5.17(s,1H),6.50(d,J＝8.0Hz,1H),6.70(s,2H),6.90(d,J＝8.4Hz,1H),7.14(s,1H),7.21-7.24(m,1H),7.49(dd,J＝2.0Hz,8.4Hz,1H),7.71(d,J＝2.0Hz,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ25.5,30.3,34.4,60.2,92.4,109.4,111.2,115.6,123.4,125.1,125.2,126.7,127.5,129.1,129.7,130.1,133.4,135.8,143.4,153.9,159.2,172.2.HRMS(ESI-TOF)calcd.for C33H32BrClNO3[M+H]+568.1249；found:568.1245.
实施例25：
Figure BDA0002653577710000122
NMR(400MHz,CDCl3):major diastereomer:δ1.29(s,18H),2.61(s,3H),5.00(s,1H),5.19(s,1H),6.52(d,J＝8.4Hz,1H),6.71(s,2H),6.88(d,J＝8.4Hz,1H),7.30(s,1H),7.38(d,J＝8.4Hz,1H),7.51(d,J＝8.4Hz,1H),7.73(s,1H)；13C NMR(100MHz,CDCl3):majordiastereomer:δ25.5,30.3,34.3,60.1,92.3,109.4,111.9,113.8,115.6,123.3,125.1,127.5,128.0,129.6,130.5,132.0,133.4,135.8,143.4,153.8,159.7,172.1.HRMS(ESI-TOF)calcd.for C30H32Br2NO3[M+H]+612.0743；found:612.0744.
实施例26：
Figure BDA0002653577710000123
major diastereomer:δ0.78(t,J＝7.2Hz,3H),1.32(s,18H),3.06-3.14(m,1H),3.22-3.31(m,1H),4.80(s,1H),5.24(s,1H),6.64(s,2H),7.02(t,J＝7.4Hz,1H),7.08(d,J＝8.0Hz,1H),7.13(d,J＝8.4Hz,1H),7.32-7.36(m,1H),7.56-7.60(m,1H),7.74-7.78(m,1H),7.85-7.87(m,1H),8.18-8.21(m,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ13.0,30.1,34.4,35.9,65.9,91.5,109.8,121.8,124.7,125.0,125.2,125.3,125.5,126.7,128.4,129.1,129.4,134.6,136.3,140.2,154.2,161.2,163.0,169.6.HRMS(ESI-TOF)calcd.for C32H35NO4[M+H]+498.2639；found:498.2636.
实施例27：
Figure BDA0002653577710000131
NMR(400MHz,CDCl3):major diastereomer:δ0.77(t,J＝7.2Hz,3H),1.32(s,18H),3.07-3.15(m,1H),3.23-3.31(m,1H),4.74(s,1H),5.26(s,1H),6.60(s,2H),6.96-7.02(m,2H),7.13(d,J＝1.6Hz,1H),7.57-7.62(m,1H),7.75-7.84(m,2H),8.19-8.21(m,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ12.9,30.0,34.3,35.8,65.1,92.1,110.6,121.9,124.2,124.5,125.0,125.3,125.5,125.6,128.3,129.1,134.5,134.6,136.3,139.4,154.2,161.8,162.7,169.4.HRMS(ESI-TOF)calcd.for C32H34ClNO4[M+H]+532.2249；found:532.2248.
实施例28：
Figure BDA0002653577710000132
NMR(400MHz,CDCl3):major diastereomer:δ0.77(t,J＝7.0Hz,3H),1.32(s,18H),3.07-3.15(m,1H),3.20-3.31(m,1H),4.72(s,1H),5.26(s,1H),6.60(s,2H),6.92-6.94(m,1H),7.14-7.17(m,1H),7.28-7.32(m,1H),7.58-7.62(m,1H),7.75-7.83(m,2H),8.19-8.21(m,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ13.0,30.1,34.4,35.9,65.4,92.1,113.5,122.4,124.3,124.7,124.9,125.1,125.5,126.2,126.3,128.4,129.3,134.7,136.4,139.6,154.4,162.0,162.8,169.5.HRMS(ESI-TOF)calcd.for C32H34BrNO4[M+H]+576.1744；found:576.1744.
实施例29：
Figure BDA0002653577710000133
was determined by HPLC(Chiralpak OD-H,i-PrOH/hexane＝5/95,flow rate 0.5mL/min,λ＝254nm,major diastereomer:tminor＝5.8min,tmajor＝10.5min).1H NMR(400MHz,CDCl3):major diastereomer:δ0.78(t,J＝7.0Hz,3H),1.33(s,18H),2.32(s,3H),3.06-3.15(m,1H),3.22-3.31(m,1H),4.76(s,1H),5.23(s,1H),6.64(s,2H),6.90(s,1H),7.02(d,J＝8.4Hz,1H),7.13(d,J＝8.0Hz,1H),7.55-7.59(m,1H),7.73-7.77(m,1H),7.84-7.86(m,1H),8.18-8.20(m,1H)；13C NMR(100MHz,CDCl3):major diastereomer:δ13.1,21.0,30.2,34.4,35.9,66.0,91.6,109.3,124.7,125.1,125.3,125.5,125.8,126.6,128.3,129.0,129.8,131.2,134.6,136.3,140.4,154.2,159.2,163.0,170.0.HRMS(ESI-TOF)calcd.for C33H37NO4[M+H]+512.2796；found:512.2795.
抗肿瘤活性验证：
选取实施例21～25的化合物为代表，以人源肺癌细胞株(A549)和人源肝癌细胞株(HepG2)为受体，测试其体外抗肿瘤活性(MTT比色法)。
以实施例21的化合物为例进行说明，具体实验操作如：
(1)取对数生长期的人源肺癌细胞株(A549)或人源肝癌细胞株(HepG2)，用含10％胎牛血清的新鲜DMEM培养基将细胞密度调至1×105cells·mL-1，接种于96孔板内，100μL/well，于37℃，5％CO2的培养箱内培养。
(2)细胞贴壁培养24h后换成无血清的新鲜培养液，同时进行加药处理。样品设剂量0.4,2,10和50μmol/mL，同时设空白对照组。
(3)细胞加药后继续培养48h后，将MTT染色液(10μL,0.5mg/mL)加入到培养基中，细胞于37℃下继续培养4小时。
(4)移去培养基，加入100μL二甲基亚砜用于溶解福尔马赞晶体，用酶标仪(ELx800,Bio-Tek,Winooski,VT,USA)在570nm下测定OD值，并计算实施例21化合物的IC50值。
实施例22～25化合物的肿瘤细胞抑制活性实验按照与实施例21类似的方法操作。
表1为实施例21～25的化合物对人肝癌细胞和人肺癌细胞增殖的抑制作用。
Figure BDA0002653577710000141
Figure BDA0002653577710000151
通过以上实验，结果表明本发明所涉及的化合物对肺癌细胞和肝癌细胞具有一定程度的抑制作用。

Claims (7)

1.一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物，其特征在于：如下式所示：
Figure DEST_PATH_FDA0002653577700000011
式中：n=0，R6各自独立地选自 t Bu或 i Pr；
相应的，R各自独立地选自Me、Et、 n Pr、 i Pr或Ph；
相应的，R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2；
相应的，R2各自独立地选自F、Cl或Br；
相应的，R3各自独立地选自Me、F、Cl或Br；
相应的，R4各自独立地选自Me、OMe、F、Cl或Br；
相应的，R5各自独立地选自Me、OMe、F、Cl或Br。
2.根据权利要求1所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物，其特征在于：所述化合物的光学纯度≧65%。
3.根据权利要求2所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物，其特征在于：所述化合物的光学纯度≧80%。
4.根据权利要求3所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物，其特征在于：所述化合物的光学纯度≧85%。
5.根据权利要求1~4任一所述的化合物作为活性成分在制备抗肿瘤药物中的应用。
6.根据权利要求1~4任一所述的化合物作为活性成分在制备抗肝癌药物中的应用。
7.根据权利要求1~4任一所述的化合物作为活性成分在制备抗肺癌药物中的应用。
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Time-Economical Synthesis of Bis-Spiro Cyclopropanes via Cascade 1,6-Conjugate Addition/Dearomatization Reaction of para-Quinone Methides with 3-Chlorooxindoles;Jing-Ru Zhang等;《Eur.J.Org.Chem.》;20200624;第4988-4994页 *

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