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CN113666935A - 一种手性吲哚并吡咯类生物碱及其制备方法 - Google Patents

一种手性吲哚并吡咯类生物碱及其制备方法 Download PDF

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CN113666935A
CN113666935A CN202111038713.3A CN202111038713A CN113666935A CN 113666935 A CN113666935 A CN 113666935A CN 202111038713 A CN202111038713 A CN 202111038713A CN 113666935 A CN113666935 A CN 113666935A
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indolopyrrole
alkaloid
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丁同梅
王冠军
张书宇
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Shanghai Jiaotong University
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

本发明涉及一种手性吲哚并吡咯类生物碱及其制备方法，将吡唑啉酮亚胺与芳香胺类衍生物溶于溶剂中，在手性磷酸催化剂的作用下发生3+2串联环化反应，制备得到手性吲哚并吡咯类生物碱。与现有技术相比，本发明避免使用金属催化剂，可以高产率、高对映选择性地实现手性吲哚并吡咯类生物碱的合成，为肿瘤的治疗提供一种可能的潜在策略，具有较好的应用前景和一定的实际应用价值。

Description

一种手性吲哚并吡咯类生物碱及其制备方法
技术领域
本发明属于有机化学技术领域，尤其是涉及一种手性吲哚并吡咯类生物碱及其制备方法。
背景技术
吲哚并吡咯类生物碱在药物化学和有机化学领域都备受关注，其中，吲哚C-3位含有不同类型取代基的吲哚并吡咯化合物，其化学结构和生物活性的研究最为广泛。很多化合物的药理作用已经得到很好的认识和利用，包括肌肉松弛剂，钾离子通道阻滞剂以及抗癌活性。
在众多吲哚类生物碱的结构类型中，含有3α-氨基-六氢吡咯[2,3-b]吲哚结构的生物碱是其中很重要的一类。由于分子结构中存在C-3位氮杂季碳和C-2位两个相邻的手性中心，实现其化学合成极具难度，这就使得构建和拓展该类分子骨架的难度很大，从而大大制约了对这类化合物生物学功能和药学的研究利用。在构建含有3α-氨基-六氢吡咯[2,3-b]吲哚结构的生物碱时，往往利用的是吲哚环C-3位的亲核性，在已有吲哚环的基础上对其进行官能团化，通过亲电-环化过程实现氮杂季碳中心的构筑，这就限制了底物范围的多样性，并且难以合成多官能团的吲哚骨架(Angew.Chem.,Int.Ed.2011,50,2716；Angew.Chem.,Int.Ed.2014,53,5600)。而通过碳氢键活化实现吲哚环系的合成策略中往往需要金属催化剂的加入(ACS Catal.2016，6,4690)。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种有机催化剂参与、底物适用性广、产率高、对映选择性可控的手性吲哚并吡咯类生物碱及其制备方法。
本发明的目的可以通过以下技术方案来实现：
一种手性吲哚并吡咯类生物碱的制备方法，将吡唑啉酮亚胺与芳香胺类化合物溶于溶剂中，在手性磷酸催化剂的作用下发生3+2串联环化反应，制备得到手性吲哚并吡咯类生物碱。
合成路线如下：
Figure BDA0003248395890000021
所述催化剂包括：
Figure BDA0003248395890000022
R选自H或取代芳基。
优选地，所述手性磷酸催化剂为：
Figure BDA0003248395890000023
所述吡唑啉酮亚胺的化学结构式为：
Figure BDA0003248395890000024
所述芳香胺类化合物的化学结构式为：
Figure BDA0003248395890000025
制备得到的手性吲哚并吡咯类化合物的化学结构式为：
Figure BDA0003248395890000031
其中，R1选自芳基；R2选自烷基；R3选自芳基；R4选自烷基、支链烷基、杂原子，卤素或芳基。
所述溶剂包括二氯甲烷、甲苯、氯仿或四氢呋喃中的一种或几种，所述溶剂优选二氯甲烷和氯仿。
所述手性磷酸催化剂、吡唑啉酮亚胺、芳胺化合物的摩尔比为0.02-0.2:1.0:1.0-1.5。
所述吡唑啉酮亚胺在溶剂中的浓度为0.02～0.2mol/L。
反应的温度控制为-20～0℃，时间为12～18h。
本发明方法的设计思路是利用芳香胺类化合物(例如二苯胺)和吡唑啉酮亚胺与手性磷酸催化剂形成氢键，达到活化底物的作用，由于氮的孤电子对与苯基的共轭效应造成氮原子上电子云密度降低，进而减弱了氮的亲核性，同时由于氮的给电子诱导作用增强了邻位的反应活性，氮原子上的苯基取代基与手性磷酸催化剂邻位芳环体系存在π-π堆积相互作用，在这种协同作用下，很好地控制了第一步Friedel-Crafts反应的对映选择性。随后，在磷酸质子酸作用下发生氮对吡唑啉酮环内亚胺结构的进攻，进而完成整个催化循环。
与现有技术相比，本发明具有以下特点：
1)本发明采用有机小分子催化剂，无需金属催化剂的参与，有利于后续的分离提纯，简化衍生的步骤；
2)反应条件相对简单，催化剂的用量小，化学产率较高，对映选择性好，为手性吲哚并吡咯类生物碱的合成提供了新的思路；
3)合成的吲哚并吡咯环系是多种天然产物和药物分子的基本结构单元，从而丰富了该类化合物药物分子库。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
本实施方式中，化合物的氢核磁共振谱(1H NMR)由Bruker AVANCE III HD 400或Bruker AVANCE III HD 500测定；质谱(ESI-MS)由Waters ACQUITYTM UPLC&Q-TOF MSPremier测定；所用试剂均为市售试剂。
本发明的合成方法可以制备如下所示的吲哚并吡咯类化合物：
Figure BDA0003248395890000041
实施例1：
化合物1的制备
Figure BDA0003248395890000051
将0.10mmol二苯胺S1-1、0.11mmol吡唑啉酮亚胺S2、0.001mmol手性磷酸催化剂CPAⅠ、50mg分子筛、1.0mL氯仿加入反应瓶中，0℃下反应12h，反应完毕后，经硅胶柱分离得到白色固体1，收率为92％。
实施例2：
化合物2的制备
Figure BDA0003248395890000052
将0.10mmol 4-苯基二苯胺S1-2、0.11mmol吡唑啉酮亚胺S2、0.001mmol手性磷酸催化剂CPAⅠ、50mg分子筛、1.0mL氯仿加入反应瓶中，0℃下反应12h，反应完毕后，经硅胶柱分离得到黄色固体2，收率为90％。
化合物3-15由相应苯胺和吡唑啉酮亚胺按照上述方法制备获得。
实施例3：
化合物16的制备
Figure BDA0003248395890000053
将0.10mmol氮苯基2-萘胺S1-16、0.11mmol吡唑啉酮亚胺S2、0.001mmol手性磷酸催化剂CPA II、1.0mL DCM加入反应瓶中，-20℃下反应12h，反应完毕后，经硅胶柱分离得到白色固体16，收率为98％。
化合物17-25由相应萘胺与吡唑啉酮亚胺按照上述方法制备得到。
Figure BDA0003248395890000061
min.1H NMR(500MHz,acetone-d6):δ8.02(d,J＝10.0Hz,2H)7.58(d,J＝10.0Hz,2H),7.49-7.45(m,3H),7.39-7.30(m,3H),7.21(s,1H),7.13-7.07(m,2H),6.75(t,J＝10.0Hz,1H),6.44(d,J＝10.0Hz,1H),5.70(s,1H),1.43(s,9H),1.40(s,3H).13C NMR(126MHz,DMSO-d6):δ169.43,157.17,148.62,140.76,140.49,130.81,130.00,129.40,128.09,127.09,125.96,124.65,124.54,119.30,118.71,108.05,89.52,80.61,72.55,28.41,17.63.HRMS(ESI):m/z calculated for C27H28N4O3[M+H+]457.2234,found 457.2233.
Figure BDA0003248395890000062
hexane/i-PrOH＝80:20,1.0mL/min,254nm):tR(minor)＝6.1min,tR(major)＝8.7min.1HNMR(400MHz,acetone-d6):δ8.09(s,1H)7.88(d,J＝8.0Hz,2H),7.49-7.47(m,6H),7.28-7.25(m,1H),7.20(s,1H),7.12(t,J＝8.0Hz,1H),6.90(d,J＝4.0Hz,1H),6.33(d,J＝8.0Hz1H),6.15(s,1H),2.23(s,3H),1.41(s,9H),1.22(s,3H).13C NMR(100MHz,acetone-d6):δ168.30,156.37,147.81,139.98,137.34,133.27,129.96,129.19,129.04,127.32,126.27,125.17,123.82,118.45,117.98,107.17,88.73,79.75,71.70,27.58,19.98,16.80.HRMS(ESI):m/zcalculated for C28H30N4O3[M+H+]471.2391found 471.2388.
Figure BDA0003248395890000063
min,tR(minor)＝4.9min.1H NMR(400MHz,acetone-d6):δ8.05(d,J＝8.0Hz,2H),7.61(d,J＝8.0Hz,2H),7.52-7.48(m,2H),7.42-7.34(m,4H),7.18-7.12(m,2H),6.35(dd,J1＝4.0Hz,J2＝8.0Hz,1H),6.00(d,J＝4.0Hz,1H),5.70(s,1H),3.68(s,3H),1.46(s,9H),1.42(s,3H).13C NMR(126MHz,DMSO-d6):δ168.23,155.93,152.39,140.92,140.50,138.99,129.20,128.65,125.59,125.38,124.41,123.93,117.82,115.56,111.58,107.65,88.27,79.43,71.44,55.61,28.03,17.08.HRMS(ESI):m/z calculated for C28H30N4O4[M+H+]487.2340,found 487.2334.
Figure BDA0003248395890000071
min,tR(major)＝8.8min.1H NMR(500MHz,acetone-d6):δ8.02(d,J＝10.0Hz,2H)7.88(s,1H),7.57-7.47(m,5H),7.39-7.34(m,4H),7.13-7.10(m,1H),6.40(d,J＝10.0Hz,1H),5.73(s,1H),1.44(s,12H),1.32(s,12H).13C NMR(126MHz,acetone-d6):δ169.46,157.24,151.29,140.46,140.06,138.18,132.54,130.12,129.42,128.51,127.56,124.68,124.08,118.67,107.22,89.56,84.01,80.55,72.31,28.41,25.22,25.18,17.79.HRMS(ESI):m/z calculated for C33H39BN4O5[M+H+]583.3086,found 583.3084.
Figure BDA0003248395890000072
min,tR(minor)＝4.3min.1H NMR(500MHz,acetone-d6):δ8.02(d,J＝5.0Hz,2H)7.57-7.45(m,5H),7.39-7.36(m,2H),7.33-7.30(m,2H),7.14-7.10(m,2H),6.41(d,J＝10.0Hz,1H),5.73(s,1H),2.42(s,3H)1.44(s,9H),1.41(s,3H).13CNMR(126MHz,acetone-d6):δ169.16,157.13,147.35,140.51,140.36,132.38,130.03,129.41,127.98,127.37,127.19,126.83,125.50,124.74,118.71,108.62,89.80,80.72,72.42,28.39,18.50,17.58.HRMS(ESI):m/z calculated forC28H30N4O3S[M+H+]503.2111,found 503.2107.
Figure BDA0003248395890000073
min,tR(minor)＝6.0min.1H NMR(400MHz,acetone-d6):δ8.02(d,J＝8.0Hz,2H)7.58(d,J＝8.0Hz,2H),7.47(t,J＝8.0Hz,2H),7.39-7.31(m,4H),7.15-7.09(m,2H),6.32(dd,J1＝4.0Hz,J2＝8.0Hz,1H),5.97(d,J＝4.0Hz,1H),5.67(s,1H),3.65(s,3H),1.34(s,9H),1.39(s,3H).13C NMR(126MHz,acetone-d6):δ169.83,163.03,157.22,150.02,140.62,130.07,129.43,128.35,127.23,126.64,124.60,118.67,116.89,104.65,94.63,89.67,80.56,72.08,55.52,28.43,17.72.HRMS(ESI):m/z calculated for C28H30N4O4[M+H+]487.2340,found487.2334.
Figure BDA0003248395890000074
hexane/i-PrOH＝80:20,1.0 mL/min,254 nm):,tR(major)＝5.6min,tR(minor)＝8.3min.1H NMR(400MHz,acetone-d6):δ8.03(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,2H),7.48(m,2H)7.40-7.32(m,4H),7.18-7.10(m,2H),6.58(d,J＝8.0Hz,1H),6.28(s,1H),5.69(s,1H),2.18(s,3H),1.44(s,9H),1.39(s,3H).13C NMR(126MHz,acetone-d6):δ169.65,157.18,148.83,140.88,140.83,140.57,129.98,129.38,128.27,127.04,125.68,124.58,121.85,120.13,118.66,108.71,89.56,80.55,72.36,28.40,21.73,17.63.HRMS(ESI):m/zcalculated for C28H30N4O3[M+H+]471.2391,found 471.2385.
Figure BDA0003248395890000081
90:10,1.0mL/min,254 nm):tR(minor)＝9.3min tR(major)＝13.7min.1H NMR(500MHz,acetone-d6):δ8.01(d,J＝10.0Hz,2H)7.58(d,J＝10.0Hz,2H),7.46-7.43(m,2H),7.37-7.34(m,2H),7.30-7.27(m,1H),7.22(s,1H),7.15(s,1H),7.11-7.08(m,1H),6.31(s,1H),5.66(s,1H),2.17(s,3H),2.09(s,3H),1.43(s,9H),1.36(s,3H).13C NMR(126MHz,acetone-d6):δ169.71,157.13,146.77,141.37,140.59,139.05,129.89,129.34,127.67,127.09,126.83,126.62,124.51,122.01,118.62,109.70,89.51,80.49,72.50,28.39,20.26,19.22,17.53.HRMS(ESI):m/zcalculated for C29H32N4O3[M+H+]485.2547,found485.2542.
Figure BDA0003248395890000082
80:20,1.0 mL/min,254 nm):tR(minor)＝8.4min,tR(major)＝6.8min.1H NMR(400MHz,acetone-d6):δ7.94(d,J＝8.0Hz,2H),7.72(d,J＝8.0Hz,2H),7.46-7.42(m,4H),7.34(t,J＝8.0Hz,2H),7.25(t,J＝8.0Hz,1H),7.09(t,J＝8.0Hz,2H),6.73(t,J＝8.0Hz,1H),6.60(d,J＝8.0Hz,1H),5.69(s,1H),1.96(q,J＝8.0Hz,2H),1.44(s,9H),0.98(t,J＝8.0Hz,3H).13C NMR(100MHz,acetone-d6):δ168.80,156.38,148.03,139.75,139.32,129.70,128.84,128.36,125.72,125.21,124.54,124.19,123.68,118.06,117.74,106.31,90.07,79.60,71.39,27.40,24.74,6.79.HRMS(ESI):m/z calculated for C28H31N4O3[M+H+]471.2391,found471.2389.
Figure BDA0003248395890000083
min,tR(major)＝6.3min.1H NMR(400MHz,acetone-d6):δ7.89(d,J＝8.0Hz,2H),7.57(d,J＝8.0Hz,2H),7.48-7.45(m,3H),7.33-7.30(m,1H),7.20-7.17(m,3H),7.09(t,J＝8.0Hz,1H),6.74(t,J＝8.0Hz,1H),6.43(d,J＝8.0Hz,1H),5.66(s,1H),2.29(s,3H),1.43(s,9H),1.38(s,3H).13C NMR(100MHz,acetone-d6):δ168.10,156.17,147.61,139.78,137.14,133.07,129.76,128.99,128.84,127.12,126.07,124.97,123.62,118.37,118.25,117.78,106.97,88.53,79.55,71.50,27.38,19.78,16.60.HRMS(ESI):m/z calculated forC28H31N4O3[M+H+]471.2391,found 471.2396.
Figure BDA0003248395890000091
8.03(d,J＝8.0Hz,2H),7.55-7.54(m,2H),7.49-7.45(m,3H),7.49-7.38(m,2H),7.34-7.30(m,1H),7.26(s,1H),7.12-7.08(m,1H),6.75(t,J＝8.0Hz,1H),6.42(d,J＝8.0Hz,1H),5.76(s,1H),1.43(s,9H),1.39(s,3H).13C NMR(100MHz,acetone-d6):δ168.72,156.25,147.73,139.72,138.28,129.94,129.07,128.39,128.07,127.22,126.21,125.01,123.37,119.16,118.40,107.13,88.58,79.73,71.53,27.39,16.64.HRMS(ESI):m/z calculatedfor C27H28ClN4O3[M+H+]491.1844,found 491.1843.
Figure BDA0003248395890000092
min,tR(major)＝8.2min.1H NMR(400MHz,acetone-d6):δ7.92(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,2H),7.31(t,J＝8.0Hz,1H),7.18(s,1H),7.09(t,J＝8.0Hz,1H),6.94(d,J＝8.0Hz,2H),6.74(t,J＝8.0Hz,1H),6.44(d,J＝8.0Hz,1H),5.65(s,1H),3.77(s,3H),1.44(s,9H),1.38(s,3H).13C NMR(100MHz,acetone-d6):δ167.66,156.13,147.54,139.82,132.82,129.70,128.97,127.03,126.02,124.94,123.67,119.51,118.24,113.48,106.99,88.53,79.52,71.37,54.61,27.38,16.62.HRMS(ESI):m/z calculated for C28H31N4O4[M+H+]487.2340,found487.2346.
Figure BDA0003248395890000093
(s,J＝1H)7.90(d,J＝5.0Hz,2H),7.40-7.50(m,7H),7.13-7.10(m,1H),6.88(d,J＝10Hz,1H),6.25(d,J＝10Hz,1H),6.06(s,1H),2.32(s,3H),2.23(s,3H),1.41(s,9H),1.21(s,3H).13C NMR(126MHz,DMSO-d6):δ168.59,156.06,145.37,139.18,137.33,135.16,130.25,129.86,128.74,126.71,126.46,126.20,123.95,117.87,106.59,88.13,79.33,71.39,28.15,20.75,20.44,17.21.HRMS(ESI):m/z calculated for C29H32N4O3[M+H+]485.2547,found 485.2547.
Figure BDA0003248395890000094
8.02(d,J＝8.0Hz,2H),7.43-7.09(m,7H),7.00(d,J＝4.0Hz,2H),6.70-6.68(m,1H),6.28(d,J＝8.0Hz,1H),5.60(s,1H),3.83(s,3H),3.74(s,3H),1.43(s,9H),1.33(s,3H).13C NMR(126MHz,acetone-d6):δ169.03,162.22,158.39,156.32,149.93,139.77,131.72,129.58,128.53,125.58,123.65,117.71,115.61,114.33,103.20,93.14,88.76,79.64,71.13,54.81,54.60,27.54,16.67.HRMS(ESI):m/zcalculated for C29H32N4O5[M+H+]517.2445,found 517.2446.
Figure BDA0003248395890000101
(d,J＝8.0Hz,2H),7.68-7.54(m,5H),7.39(t,J＝8.0Hz,3H),7.26(dd,J1＝4.0Hz,J2＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),6.46(d,J＝8.0Hz,1H),5.85(s,1H),1.44(s,12H).13CNMR(126MHz,acetone-d6):δ16877,157.09,147.29,140.20,139.62,133.54,133.27,129.82,129.49,128.97,124.95,120.13,118.77,110.10,109.85,89.88,80.88,72.26,28.35,17.59.HRMS(ESI):m/z calculated forC27H26Br2N4O3[M+H+]615.0424,found615.0421.
Figure BDA0003248395890000102
7.59-7.56(m,2H),7.47(d,J＝5.0Hz,1H),7.38-7.35(m,2H),7.26-7.21(m,3H),7.13-7.08(m,2H),6.77-6.74(m,1H),6.38(d,J＝5.0Hz,1H),5.70(s,1H),1.44(s,9H),1.41(s,3H).13C NMR(126MHz,acetone-d6):δ169.37,162.69,160.75,157.14,148.66,140.40,136.72(d,J＝2.5Hz),130.87,130.40(d,J＝8.8Hz),129.39,125.93,124.66,124.40,119.37,118.63,116.77,116.59,107.71,89.46,80.62,72.47,28.37,17.50.HRMS(ESI):m/zcalculated for C27H27FN4O3[M+H+]475.2140,found 475.2142.
Figure BDA0003248395890000103
(s,1H),7.85(d,J＝8.0Hz,2H),7.49(s,4H),7.38(t,J＝8.0Hz,2H),7.21(s,1H),7.12(t,J＝8.0Hz,1H),6.38(d,J＝8.0Hz,1H),6.20(s,1H),2.24(s,3H),1.41(s,9H),1.23(s,3H).13C NMR(126MHz,DMSO-d6):δ168.29,155.94,144.26,139.17,138.94,130.24,129.46,129.29,128.68,127.50,127.29,126.26,123.97,123.86,117.84,107.02,87.96,79.33,71.29,28.06,20.38,17.27.HRMS(ESI):m/zcalculated for C28H29ClN4O3[M+H+]505.2001,found 505.2001.
Figure BDA0003248395890000111
6.27(d,J＝8.0Hz,1H),5.83(s,1H),5.60(s,1H),3.84(s,3H),3.63(s,3H),1.42(s,9H),1.37(s,3H).13C NMR(126MHz,acetone-d6):δ169.92,163.11,159.28,157.21,150.82,140.66,132.61,130.47,129.42,126.47,124.54,118.60,116.50,115.22,104.09,94.03,89.65,80.53,72.02,55.70,55.49,28.43,17.56.HRMS(ESI):m/z calculated forC29H32N4O5[M+H+]517.2445,found 517.2445.
Figure BDA0003248395890000112
11.8min.1H NMR(400MHz,acetone-d6):δ8.58(d,J＝8.0Hz,2H),8.00(d,J＝8.0Hz,2H),7.73(dd,J1＝8.0Hz,J2＝20Hz,2H),7.62-7.60(m,2H),7.53-7.44(m,3H),7.38-7.33(m,3H),7.24-7.20(m,1H),7.09(t,J＝8.0Hz,1H),6.84(d,J＝8.0Hz,1H),5.73(s,1H),1.49(s,9H),1.46(s,3H).13C NMR(126MHz,acetone-d6):δ169.33,156.66,147.78,140.67,140.58,132.26,132.07,130.16,129.42,129.35,128.15,127.35,127.28,124.82,124.60,122.86,118.78,113.76,111.74,89.81,80.51,74.46,28.47,18.07.HRMS(ESI):m/zcalculated for C31H30N4O3[M+H+]507.2391,found 507.2391.
Figure BDA0003248395890000113
＝13.0min.1H NMR(400MHz,acetone-d6):δ8.58(d,J＝10.0Hz,1H),8.01(d,J＝10.0Hz,2H),7.67(dd,J1＝10.0Hz,J2＝25Hz,2H),7.41-7.39(m,7H),7.37-7.34(m,2H),7.09(t,J＝10.0Hz,1H),6.83(d,J＝10.0Hz,1H),5.71(s,1H),2.39(s,3H),1.50(s,3H),1.46(9H).13CNMR(126MHz,DMSO-d6):δ168.21,155.63,146.38,139.41,139.16,138.68,131.12,129.24,128.57,128.43,127.05,126.34,124.03,123.76,121.79,117.79,112.86,110.68,88.12,79.12,73.20,28.11,21.12,17.80.HRMS(ESI):m/z calculated for C32H32N4O3[M+H+]521.2547,found 521.2547.
Figure BDA0003248395890000114
10.0min.1H NMR(500MHz,acetone-d6):δ8.65-8.62(m,1H),8.00(d,J＝10.0Hz,2H),7.69-7.59(m,3H),7.53-7.45(m,3H),7.38-7.34(m,4H),7.10(t,J＝10.0Hz,1H),6.89(d,J＝10.0Hz,1H),5.77(s,1H),1.48(s,9H),1.46(s,3H).13CNMR(126MHz,DMSO-d6):δ168.07,158.58,156.67,155.62,145.73,139.51,139.06,129.47,129.03(J＝7.56Hz),128.60,128.24,126.56,117.88,116.50(J＝25.2Hz),113.48,111.84,111.39(J＝20.16Hz),88.19,79.19,73.17,28.09,17.76.HRMS(ESI):m/z calculated for C31H29FN4O3[M+H+]525.2296,found 525.2296.
Figure BDA0003248395890000121
10.6min.1H NMR(400MHz,acetone-d6):δ8.56(d,J＝8.0Hz,1H),8.00(d,J＝8.0Hz,2H),7.69-7.51(m,7H),7.38-7.33(m,3H),7.09(t,J＝8.0Hz,1H),6.89-6.81(m,2H),5.87(d,J＝20.0Hz,1H),5.74(s,1H),5.23(d,J＝12.0Hz,1H),1.49(s,3H),1.46(s,9H).13C NMR(126MHz,acetone-d6):δ169.80,157.19,148.49,141.05,138.42,130.69,129.88,128.72,128.53,127.87,119.30,114.64,113.28,112.46,90.32,81.32,74.85,28.98,18.61.HRMS(ESI):m/z calculated forC33H32N4O3[M+H+]533.2547,found 533.2545.
Figure BDA0003248395890000122
min.1H NMR(400MHz,acetone-d6):δ8.70(d,J＝8.0Hz,1H),8.04-8.02(m,3H),7.85-7.76(m,4H),7.63-7.61(m,2H),7.54-7.33(m,10H),7.10(t,J＝8.0Hz,1H),6.87(d,J＝8.0Hz,1H),5.77(s,1H),1.51(s,3H),1.46(s,9H)13C NMR(126MHz,acetone-d6):δ169.35,156.73,141.84,140.61,132.58,130.49,130.20,129.71,129.39,128.17,127.74,127.57,127.36,127.06,118.79,113.77,112.16,89.89,80.63,74.44,28.49,18.13.HRMS(ESI):m/zcalculated for C37H34N4O3[M+H+]583.2704,found 583.2701.
Figure BDA0003248395890000123
min.1HNMR(400MHz,acetone-d6):δ8.57(d,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,2H),7.70(dd,J1＝8.0Hz,J2＝20.0Hz,2H),7.59(d,J＝8.0Hz,2H),7.52-7.42(m,3H),7.35(t,J＝8.0Hz,1H),7.22-7.14(m,3H),6.83(d,J＝12.0Hz,1H),5.68(s,1H),2.27(s,3H),1.47(s,3H),1.44(s,9H).13C NMR(126MHz,acetone-d6):δ169.32,156.61,147.07,140.88,140.59,132.02,131.30,130.46,130.35,130.08,129.52,129.32,128.29,127.97,127.08,124.75,124.55,118.74,113.85,111.74,89.75,80.46,74.45,28.45,21.36,18.03.HRMS(ESI):m/zcalculated for C32H33N4O3[M+H+]521.2547,found 521.2540.
Figure BDA0003248395890000131
8.01(d,J＝10.0Hz,2H),7.70(dd,J1＝10.0Hz,J2＝25.0Hz,2H),7.47-7.31(m,7H),7.22-7.19(m,2H),7.09(t,J＝10.0Hz,1H),7.08(d,J＝10.0Hz,1H),5.69(s,1H),2.40(s,3H),1.48(s,3H),1.46(s,9H).13C NMR(126MHz,acetone-d6):δ169.54,156.82,148.27,140.77,137.99,137.21,132.42,132.21,130.87,130.20,129.57,129.49,128.50,127.47,124.90,124.71,122.85,118.90,89.97,80.63,74.57,28.62,21.26,18.16.HRMS(ESI):m/zcalculated for C32H32N4O3[M+H+]521.2547,found 521.2547.
Figure BDA0003248395890000132
7.39-7.36(m,2H),7.25-7.11(m,2H),6.83(d,J＝10.0Hz,1H),6.35(s,1H),1.46(s,9H),1.37(s,3H).13C NMR(126MHz,DMSO-d6):δ168.02,156.48,155.64,154.52,145.54,139.00,136.86(J＝5.04Hz),130.99,128.95,128.62(J＝10.08Hz),126.50,123.89,122.21,119.89,117.77,117.59,113.48,110.43,88.07,79.24,73.17,28.10,17.82.HRMS(ESI):m/z calculated for C31H28FN4O3[M+H+]559.1907,found 559.1905.
Figure BDA0003248395890000133
2H),7.47-7.45(m,3H),7.35-7.33(m,2H),7.07(t,J＝10.0Hz,1H),7.06-7.04(m,3H),6.71(d,J＝10.0Hz,1H),5.66(s,1H),3.85(s,3H),1.48(s,12H).13C NMR(126MHz,acetone-d6):δ169.55,159.47,156.81,148.65,140.74,132.91,132.37,132.22,130.39,130.05,129.54,129.46,127.42,124.77,124.64,122.68,118.82,115.44,113.15,119.49,89.99,80.61,74.48,55.84,28.59,18.08.HRMS(ESI):m/zcalculated for C32H32N4O3[M+H+]537.2496,found 537.2498.
Figure BDA0003248395890000134
16.9min 1H NMR(400MHz,acetone-d6):δ8.53(d,J＝8.0Hz,1H),7.91(d,J＝8.0Hz,2H),7.72-7.66(m,4H),7.49-7.41(m,3H),7.33-7.28(m,3H),7.21-7.17(m,3H),7.06(t,J＝8.0Hz,1H),6.95(d,J＝12.0Hz,1H),5.68(s,1H),2.12-1.98(m,2H),1.46(s,9H),1.07(t,J＝8.0Hz).13C NMR(100MHz,acetone-d6):δ168.71,155.83,147.40,139.51,139.33,131.02,128.98,128.36,128.31,126.23,125.58,123.91,123.60,121.69,117.71,113.23,110.20,90.18,79.50,73.32,27.46,25.16,6.87.HRMS(ESI):m/z calculated forC32H33N4O3[M+H+]521.2547,found521.2545.
Figure BDA0003248395890000141
14.7min,tR(major)＝18.0min.1H NMR(400MHz,acetone-d6):δ8.57(d,J＝8.0Hz,1H),7.89(d,J＝8.0Hz,2H),7.70(dd,J1＝8.0Hz,J2＝20.0Hz,2H),7.61-7.59(m,2H),7.52-7.42(m,3H),7.37-7.32(m,1H),7.22-7.18(m,1H),6.92-6.88(m,2H),6.83(d,J＝12.0Hz,1H),5.67(s,1H),3.75(s,3H),1.47(s,3H),1.44(s,9H).13C NMR(100MHz,acetone-d6):δ167.74,156.23,146.81,139.82,133.03,131.38,131.05,129.26,129.23,128.49,127.21,126.40,126.31,123.94,121.92,119.70,113.56,113.06,110.84,88.90,79.53,73.39,54.73,27.55,17.14.HRMS(ESI):m/z calculated for C33H33N4O4[M+H+]537.2496,found537.2499.
Figure BDA0003248395890000142
8.57(d,J＝10.0Hz,1H),8.01(d,J＝10.0Hz,2H),7.70(dd,J1＝8.0Hz,J2＝20.0Hz,2H),7.60-7.57(m,2H),7.53-7.44(m,3H),7.38-7.35(m,3H),7.24-7.20(m,1H),6.82(d,J＝8.0Hz,1H),5.80(s,1H),1.49(s,3H),1.45(s,9H).13C NMR(100MHz,acetone-d6):δ168.51,155.70,146.82,139.58,138.33,131.19,129.18,128.44,128.30,127.96,127.20,126.39,126.36,123.74,121.90,119.15,112.52,110.75,88.83,79.60,73.39,27.43.HRMS(ESI):m/z calculated for C31H30ClN4O3[M+H+]541.2001,found 541.2006.
上述对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。

Claims (10)

1.一种手性吲哚并吡咯类生物碱的制备方法，其特征在于，将吡唑啉酮亚胺与芳香胺类化合物溶于溶剂中，在手性磷酸催化剂的作用下发生串联反应，制备得到手性吲哚并吡咯类生物碱。
2.根据权利要求1所述的一种手性吲哚并吡咯类生物碱的制备方法，其特征在于，所述手性磷酸催化剂包括：
Figure FDA0003248395880000011
其中，R选自H或取代芳基。
3.根据权利要求1所述的一种手性吲哚并吡咯类生物碱的制备方法，其特征在于，所述手性磷酸催化剂为：
Figure FDA0003248395880000012
4.根据权利要求1所述的一种手性吲哚并吡咯类生物碱的制备方法，其特征在于，所述吡唑啉酮亚胺的化学结构式为：
Figure FDA0003248395880000013
所述芳香胺类化合物的化学结构式为：
Figure FDA0003248395880000014
制备得到的手性吲哚并吡咯类生物碱的化学结构式为：
Figure FDA0003248395880000021
其中：
R1选自芳基；
R2选自烷基；
R3选自芳基；
R4选自烷基、支链烷基、杂原子或卤素。
5.根据权利要求1所述的一种手性吲哚并吡咯类化合物的制备方法，其特征在于，所述溶剂包括二氯甲烷、甲苯、氯仿或四氢呋喃中的一种或几种。
6.根据权利要求1或5所述的手性吲哚并吡咯类化合物及其制备方法，其特征在于，所述溶剂优选为二氯甲烷或氯仿。
7.根据权利要求1所述的一种手性吲哚并吡咯类化合物的制备方法，其特征在于，所述手性磷酸催化剂、吡唑啉酮亚胺与芳香胺类化合物的摩尔比为0.02-0.2:1.0:1.0-1.5。
8.根据权利要求1所述的一种手性吲哚并吡咯类化合物及其制备方法，其特征在于，所述吡唑啉酮亚胺在溶剂中的浓度为0.02～0.2mol/L。
9.根据权利要求1所述的一种手性吲哚并吡咯类化合物的制备方法，其特征在于，所述串联反应的温度控制为-20～0℃，时间为12～18h。
10.一种手性吲哚并吡咯类生物碱，其特征在于，采用如权利要求1-9任意一项所述的制备方法制备得到，该手性吲哚并吡咯类生物碱的化学结构式为：
Figure FDA0003248395880000022
其中：
R1选自芳基；
R2选自烷基；
R3选自芳基；
R4选自烷基、支链烷基、杂原子或卤素。
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