CN115974883A - 一种合成手性七元环桥连3,4-稠合三环吲哚的方法 - Google Patents

一种合成手性七元环桥连3,4-稠合三环吲哚的方法 Download PDF

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CN115974883A
CN115974883A CN202310008359.2A CN202310008359A CN115974883A CN 115974883 A CN115974883 A CN 115974883A CN 202310008359 A CN202310008359 A CN 202310008359A CN 115974883 A CN115974883 A CN 115974883A
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谢明胜
侯晨颖
薛白玉
武晓霞
渠桂荣
郭海明
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Henan Normal University
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Abstract

本发明公开了一种合成手性七元环桥连3,4‑稠合三环吲哚的方法，属于有机合成技术领域。以N‑甲基‑4‑苄胺基吲哚1和β,γ‑不饱和α‑酮酸酯2为反应物，在Ni(II)‑PyBPI配合物催化下发生Friedel‑Crafts烷基化/N‑半缩醛化和脱水串联反应，得到了多种手性七元环桥接3,4‑稠合三环吲哚3。本发明中亲核试剂为N‑甲基‑4‑苄胺基吲哚1，反应同时还产生六元环桥接4,5‑稠合三环吲哚副产物4。该方法具有收率良好，区域选择性和对映选择性高等优势。

Description

一种合成手性七元环桥连3,4-稠合三环吲哚的方法
技术领域
本发明涉及一种合成手性七元环桥连3,4-稠合三环吲哚的方法，属于有机化学中不对称合成技术领域。
背景技术
手性3,4-稠合三环吲哚骨架在许多生物活性天然产物和药物中普遍存在其中，七元环桥接3,4-稠合三环吲哚因其生物活性和合成挑战而引起了人们的极大兴趣。
尽管人们可以用一些功能化吲哚衍生物作为起始材料或吲哚环形成策略来构建这些3,4-稠合三环吲哚，但开发一种高效的方法来构建手性七元环桥接3,4-稠合三环吲哚框架是非常可取的。
因此，发展有效的合成方法来制备手性七元环桥连3,4-稠合三环吲哚及其衍生物，具有重要的研究意义。
发明内容
为了解决上述技术问题，本发明公开了一种通过区域选择性和对映选择性的Friedel-Crafts烷基化/N-半缩醛化和脱水串联反应合成手性七元环桥连3,4-稠合三环吲哚的新方法。本发明中利用N-甲基-4-苄胺基吲哚作为1,4-双亲核试剂与β,γ-不饱和α-酮酸酯反应，以良好的收率和对映选择性得到手性七元环桥连3,4-稠合三环吲哚，同时该方法会产生六元环桥接的4,5-稠合三环吲哚副产物。
本发明所述合成手性七元环桥连的3,4-稠合三环吲哚的方法，包括如下步骤：以N-甲基-4-苄胺基吲哚1和β,γ-不饱和α-酮酸酯2为原料，在二价金属盐-PyBPI配体存在下有机溶剂中反应，得到手性七元环桥接3,4-稠合三环吲哚3。
反应方程式如下：
Figure BDA0004036611850000021
其中：R1选自苯基、取代苯基、噻吩；取代苯基中取代基为卤素、C1-C4烷基、苯基、C1-C4烷氧基中的一种或多种。在上述取代基中，优选情况下：R1为4-MeC6H4、3-MeC6H4、3-ClC6H4、4F-C6H4、4-BrC6H4、2-ClC6H4、3-ClC6H4等。
进一步地，在上述技术方案中，PyBPI配体，优选R＝2,6-iPr2C6H3。
进一步地，在上述技术方案中，有机溶剂选自三氟甲苯、氯苯、二氯甲烷或甲苯中的一种或多种。优选溶剂为三氟甲苯。
进一步地，在上述技术方案中，二价金属盐选自Co(ClO4)2-6H2O、Cu(OTf)2、Zn(OTf)2、Ni(OTf)2或Ni(ClO4)2-6H2O。
进一步地，在上述技术方案中，N-甲基-4-苄胺基吲哚1、β,γ-不饱和α-酮酸酯2与二价金属盐-PyBPI配体摩尔比为1-1.5:1:0.003-0.005。
进一步地，在上述技术方案中，反应温度为20-40℃。反应温度优选为30℃。
进一步地，在上述技术方案中，反应中加入添加剂，添加剂选自
Figure BDA0004036611850000022
MS、
Figure BDA0004036611850000023
MS或
Figure BDA0004036611850000024
MS。添加剂优选为
Figure BDA0004036611850000025
MS。
发明有益效果：
1、以N-甲基-4-氨基吲哚和β,γ-不饱和α-酮酸酯为原料，在M(II)-PyBPI配合物催化下，通过区域选择性和对映选择性Friedel-Crafts烷基化/N半缩醛化和脱水串联反应合成手性七元环桥连3,4-稠合三环吲哚3。该反应原料易得，反应收率和对映选择性最高分别可达91％和97％ee。
2、本发明中利用N-甲基-4-苄胺基吲哚为1,4-双亲核试剂，C-3和C-5位置为竞争亲核反应位点，副产物为六元环桥接4,5-稠合三环吲哚4。
具体实施方式
实施例1
以N-甲基-4-氨基吲哚1a和β,γ-不饱和α-酮酸酯2a为原料生成3aa为例，进行反应条件优化，反应方程式如下：
Figure BDA0004036611850000031
具体反应结果如下表所示：
Figure BDA0004036611850000032
Figure BDA0004036611850000041
[a]除非另有说明，反应条件:Ni(OTf)2/L(1:1,5mol％),1a(0.15mmol),2a(0.1mmol)在DCM(2.0mL)中30℃反应6小时；[b]核磁收率；[c]通过手性HPLC分析确定；[d]加入
Figure BDA0004036611850000042
MS(20mg)；[e]1a(0.13mmol)；[f]Ni(OTf)2/L1(2.5mol％),反应8小时。
在反应条件的筛选过程中，首先考察了金属对反应的影响(标号1-8)。同时通过对照不同配体、添加剂、溶剂、原料当量比和配体用量对反应的影响，最终确定L1为最佳配体，加入量为5mol％，三氟甲苯为最佳反应溶剂，
Figure BDA0004036611850000043
MS(20mg)为最佳反应条件。
在试管中加入L1和Ni(OTf)2(5mol％,1:1)。然后在空气气氛中加入β,γ-不饱和α-酮酸酯2a(0.1mmol,19.0mg)、
Figure BDA0004036611850000044
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3equiv,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2a消耗(TLC测定)。然后加入硅胶1.0g,30℃搅拌1.5h，使其完全脱水。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化，得到所需产物3aa，收率90％,91％ee。m.p.＝153.5–156.3℃.Rf＝0.28(Pet/EtOAc,8/1,v/v).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.012min,(minor)＝8.652min.[α]D 26＝-10.00(c＝0.72,CHCl3).1H NMR(400MHz,CDCl3)δ7.44–7.31(m,5H),7.24–7.17(m,5H),7.13(t,J＝8.0Hz,1H),6.95(d,J＝6.4Hz,1H),6.83(d,J＝8.0Hz,1H),6.67(d,J＝7.6Hz,1H),6.13(s,1H),5.28(d,J＝6.8,Hz,1H),4.85(d,J＝14.0Hz,1H),4.76(d,J＝13.6Hz,1H),3.64(s,3H),3.61(s,3H).13C{1H}NMR(100MHz,CDCl3)δ165.9,142.5,141.4,138.4,138.3,137.8,137.2,128.9,128.8,128.6,128.4,127.3,127.0,123.1,123.0,120.6,115.8,104.9,102.7,54.2,52.0,42.3,32.9.HRMS(ESI-TOF)m/z:[M+Na]+calcd for C27H24N2NaO2 +431.1730；found 431.1729.IR(neat):2922,1721,1635,1578,1496,1461,1421,1395,1322,1264,1227,1148,1070,1030,790,769,741,702cm-1.
实施例2
在试管中加入L1和Ni(OTf)2(5mol％,1:1)，然后在空气气氛中加入β,γ-不饱和α-酮酸酯2a-2o(0.1mmol)、
Figure BDA0004036611850000051
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3eq,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2a-2o消耗(TLC测定)。然后加入硅胶1.0g，30℃搅拌1.5h，使其完全脱水。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化，得到所需产物3aa-3ao。
具体结果如下：
Figure BDA0004036611850000061
代表性核磁表征数据如下：
Methyl(R)-1-benzyl-4-(2-fluorophenyl)-6-methyl-4,6-dihydro-1H-azepino[4,3,2-cd]indole-2-carboxylate(3ab)
Figure BDA0004036611850000062
黄色固体(33.3mg,78％yield,86％ee).m.p.74.5-76.5℃.Rf＝0.36(Pet/EtOAc,8/1).[α]D 26＝-19.63(c＝0.69,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝6.818min,(minor)＝7.745min.1HNMR(600MHz,CDCl3)δ7.36–7.29(m,2H),7.24–7.09(m,8H),6.92(dd,J＝6.6,1.8Hz,1H),6.87(d,J＝7.8Hz,1H),6.72(d,J＝7.8Hz,1H),6.27(s,1H),5.57(d,J＝6.6Hz,1H),4.87(d,J＝13.8Hz,1H),4.75(d,J＝13.8Hz,1H),3.64(s,3H),3.63(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.7,160.8(d,JC-F＝244.5Hz),141.5,138.6,138.4,137.5,135.4,130.21,130.18,129.4(d,JC-F＝13.5Hz),129.0,128.6(d,JC-F＝7.5Hz),128.4,127.4,124.4(d,JC-F＝3.0Hz),123.1,122.8,115.6(d,JC-F＝21.0Hz),113.7,104.8,102.8,54.1,52.0,35.3(d,JC-F＝3.0Hz),32.9.HRMS(ESI-TOF)m/z:[M+Na]+calcd for C27H23FN2NaO2 +449.1636；found 449.1628.IR(neat):3030,1716,1635,1582,1496,1454,1434,1420,1329,1230,1188,1148,1121,1051,932,752,730,700cm-1.
Methyl(S)-1-benzyl-4-(3-fluorophenyl)-6-methyl-4,6-dihydro-1H-azepino[4,3,2-cd]indole-2-carboxylate(3ac)
Figure BDA0004036611850000071
黄色固体(38.8mg,91％yield,95％ee).m.p.65.1-68.2℃.Rf＝0.36(Pet/EtOAc,8/1).[α]D 26＝-25.26(c＝0.69,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.225min,(minor)＝9.463min.1HNMR(600MHz,CDCl3)δ7.40-7.33(m,1H),7.25–7.18(m,3H),7.18–7.12(m,4H),7.09(dt,J＝10.2,2.4Hz,1H),7.04(td,J＝8.4,1.8Hz,1H),6.91(d,J＝6.6Hz,1H),6.86(d,J＝8.4Hz,1H),6.69(d,J＝7.8Hz,1H),6.21(s,1H),5.26(d,J＝6.0Hz,1H),4.85(d,J＝13.8,Hz,1H),4.77(d,J＝13.8,Hz,1H),3.66(s,3H),3.64(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,163.2(d,JC-F＝244.5Hz),145.22,145.18,141.2,138.8,138.4,137.6,135.9,130.1(d,JC-F＝9.0Hz),128.9,128.4,127.4,124.3(d,JC-F＝3.0Hz),123.1(d,JC-F＝3.0Hz),120.5,115.5(d,JC-F＝21.0Hz),114.8,113.9(d,JC-F＝21.0Hz),105.0,102.8,54.1,52.1,41.9,32.9.HRMS(ESI-TOF)m/z:[M+Na]+calcd forC27H23FN2NaO2 +449.1636；found 449.1633.IR(neat):3031,1717,1582,1496,1453,1231,1148,767,750,730,700cm-1.
Methyl(S)-1-benzyl-4-(3-bromophenyl)-6-methyl-4,6-dihydro-1H-aze pino[4,3,2-cd]indole-2-carboxylate(3ae)
Figure BDA0004036611850000081
黄色固体(40.8mg,84％yield,95％ee).m.p.64.7-69.4℃.Rf＝0.35(Pet/EtOAc,8/1,v/v).[α]D 26＝-28.66(c＝0.67,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.308min,(minor)＝10.203min.1HNMR(600MHz,CDCl3)δ7.53(t,J＝1.8Hz,1H),7.47(dt,J＝7.8,1.2Hz,1H),7.30(dt,J＝7.8,1.2Hz,1H),7.27–7.19(m,4H),7.17–7.12(m,3H),6.89(d,J＝6.0Hz,1H),6.85(d,J＝7.8Hz,1H),6.68(d,J＝7.8Hz,1H),6.19(s,1H),5.22(d,J＝6.0,Hz,1H),4.84(d,J＝13.8Hz,1H),4.76(d,J＝13.8Hz,1H),3.66(s,3H),3.63(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,145.0,141.2,138.8,138.3,137.6,135.7,131.6,130.3,130.1,128.9,128.4,127.4,127.2,123.2,123.1,122.8,120.5,114.8,105.0,102.8,54.2,52.1,41.8,33.0.HRMS(ESI-TOF)m/z:[M+Na]+calcd for C27H23BrN2NaO2 +509.0835；found 509.0836.IR(neat):3030,2925,1717,1633,1580,1497,1461,1421,1399,1327,1231,1148,1072,1052,768,731,698cm-1.
Methyl(S)-1-benzyl-4-(4-bromophenyl)-6-methyl-4,6-dihydro-1H-aze pino[4,3,2-cd]indole-2-carboxylate(3af)
Figure BDA0004036611850000091
黄色固体(37.9mg,78％yield,96％ee).m.p.74.3-77.4℃.Rf＝0.37(Pet/EtOAc,8/1).[α]D 26＝-23.21(c＝0.95,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.683min,(minor)＝9.775min.1HNMR(600MHz,CDCl3)δ7.53–7.48(m,2H),7.25–7.18(m,5H),7.17–7.09(m,3H),6.90(d,J＝6.6Hz,1H),6.85(d,J＝8.4Hz,1H),6.68(d,J＝7.8Hz,1H),6.19(d,J＝1.2Hz,1H),5.20(d,J＝6.6Hz,1H),4.83(d,J＝13.8Hz,1H),4.75(d,J＝13.8Hz,1H),3.66(s,3H),3.63(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,141.7,141.2,138.8,138.4,137.6,135.9,131.8,130.3,128.9,128.4,127.4,123.2,123.1,120.7,120.5,114.9,105.0,102.8,54.1,52.1,41.5,33.0.HRMS(ESI-TOF)m/z:[M+Na]+calcd forC27H23BrN2NaO2 +509.0835；found509.0834.IR(neat):2925,1717,1633,1580,1497,1461,1421,1327,1231,1148,1072,1052,768,731,698cm-1.
Methyl(S)-1-benzyl-4-(3-chlorophenyl)-6-methyl-4,6-dihydro-1H-azepino[4,3,2-cd]indole-2-carboxylate(3ag)
Figure BDA0004036611850000101
浅黄色固体(35.8mg,81％yield,96％ee).Rf＝0.33(Pet/EtOAc,8/1).m.p.68.1-71.4℃.[α]D 26＝-30.93(c＝0.72,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.178min,(minor)＝9.853min.1H NMR(600MHz,CDCl3)δ7.38(s,1H),7.34–7.31(m,2H),7.26–7.19(m,4H),7.17–7.12(m,3H),6.90(d,J＝6.6Hz,1H),6.85(d,J＝7.8Hz,1H),6.69(d,J＝7.8Hz,1H),6.19(d,J＝1.2Hz,1H),5.23(d,J＝6.6Hz,1H),4.84(d,J＝13.8Hz,1H),4.77(d,J＝13.8Hz,1H),3.66(s,3H),3.64(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,144.7,141.2,138.8,138.4,137.6,135.8,134.5,130.0,128.9,128.7,128.4,127.4,127.2,126.8,123.2,123.1,120.5,114.8,105.0,102.8,54.1,52.1,41.8,32.9.HRMS(ESI-TOF)m/z:[M+Na]+calcd for C27H23ClN2NaO2 +465.1340；found 465.1344.IR(neat):3359,2922,2852,1717,1632,1580,1497,1460,1421,1327,1229,1148,768,698cm-1.Methyl(S)-1-benzyl-4-(4-chlorophenyl)-6-methyl-4,6-dihydro-1H-azepino[4,3,2-cd]indole-2-carboxylate(3ah)
Figure BDA0004036611850000111
浅黄色固体(35.8mg,81％yield,96％ee).m.p.109.7-112.5℃.Rf＝0.32(Pet/EtOAc,8/1).[α]D 26＝-24.84(c＝0.72,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.463min,(minor)＝9.500min.1H NMR(600MHz,CDCl3)δ7.39–7.34(m,2H),7.33–7.28(m,2H),7.25–7.19(m,3H),7.17–7.10(m,3H),6.91(d,J＝6.0Hz,1H),6.85(d,J＝8.4Hz,1H),6.69(d,J＝7.8Hz,1H),6.18(s,1H),5.23(d,J＝6.6Hz,1H),4.84(d,J＝13.8Hz,1H),4.76(d,J＝13.8Hz,1H),3.66(s,3H),3.63(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,141.23,141.17,138.8,138.4,137.6,136.1,132.7,129.9,128.9,128.8,128.4,127.4,123.1,120.5,115.1,105.0,102.8,54.1,52.1,41.5,32.9.HRMS(ESI-TOF)m/z:[M+Na]+calcd forC27H23ClN2NaO2 +465.1340；found 465.1347.IR(neat):2920,1737,1712,1581,1498,1454,1393,1319,1262,1234,1188,1157,1047,1014,840,771,755,745,734,698cm-1.
实施例3
Figure BDA0004036611850000112
在试管中加入L1和Ni(OTf)2(5mol％，1:1)，在空气气氛中加入β,γ-不饱和α-酮酸酯2d(0.1mmol,20.0mg)、
Figure BDA0004036611850000113
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3eq,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2d消耗(TLC测定)。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化得到所需产物3ad，收率90％,92％ee。m.p.143.5-146.6℃.Rf＝0.30(Pet/EtOAc,8/1).[α]D 26＝-18.54(c＝0.71,CHCl3).HPLC CHIRALPAKID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.368min,(minor)＝9.503min.1H NMR(600MHz,CDCl3)δ7.36–7.32(m,2H),7.26–7.20(m,3H),7.19–7.13(m,3H),7.11–7.06(m,2H),6.91(d,J＝6.6Hz,1H),6.85(d,J＝8.4Hz,1H),6.69(d,J＝7.8Hz,1H),6.15(d,J＝1.2Hz,1H),5.26(d,J＝6.0Hz,1H),4.85(d,J＝13.8Hz,1H),4.77(d,J＝13.8Hz,1H),3.66(s,3H),3.63(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,161.9(d,JC-F＝243.0Hz),141.3,138.6,138.4,138.3(d,JC-F＝3.0Hz),137.7,136.6,130.0(d,JC-F＝7.5Hz),128.9,128.4,127.4,123.1,120.5,115.5(d,JC-F＝21.0Hz),104.9,102.8,54.2,52.1,41.5,32.9.HRMS(ESI-TOF)m/z:[M+Na]+calcd forC27H23FN2NaO2 +449.1636；found 449.1640.IR(neat):2922,2852,1716,1606,1497,1460,1262,1226,1187,1148,838,798,768,731,699cm-1.
实施例4
Figure BDA0004036611850000121
在试管中加入L1和Ni(OTf)2(5mol％，1:1)，在空气气氛中加入β,γ-不饱和α-酮酸酯2i(0.1mmol,22.6mg)、
Figure BDA0004036611850000131
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3equiv,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2i消耗(TLC测定)。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化得到所需产物3ai，收率62％,96％ee。m.p.69.4-73.7℃.Rf＝0.35(Pet/EtOAc,8/1).[α]D 26＝-33.93(c＝1.18,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-pro panol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(minor)＝7.273min,(major)＝9.675min.1H NMR(600MHz,CDCl3)δ7.25–7.19(m,3H),7.19–7.10(m,5H),7.09–7.05(m,1H),6.85(d,J＝7.2Hz,2H),6.68(d,J＝7.8Hz,1H),6.22(s,1H),5.18(d,J＝6.6Hz,1H),4.81(d,J＝13.8Hz,1H),4.76(d,J＝13.8Hz,1H),3.66(s,3H),3.65(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,150.5(dd,JC-F＝246.0,12.0Hz),149.4(dd,JC-F＝244.5,12.0Hz),141.2,139.7(t,JC-F＝3.0Hz),138.9,138.4,137.6,135.4,128.9,128.4,127.4,124.4(q,JC-F＝3.0Hz),123.2,123.1,120.4,117.4(t,JC-F＝18.0Hz),114.6,105.0,102.9,54.1,52.1,41.2,33.0.HRMS(ESI-TOF)m/z:[M+Na]+calcd for C27H22F2N2NaO2 +467.1542；found 467.1536.IR(neat):2922,1417,1633,1607,1580,1497,1460,1421,1326,1238,1149,1051,767,732cm-1.
实施例5
Figure BDA0004036611850000141
在试管中加入L1和Ni(OTf)2(5mol％，1:1)，在空气气氛中加入β,γ-不饱和α-酮酸酯2j(0.1mmol,25.8mg)、
Figure BDA0004036611850000142
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3equiv,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2j消耗(TLC测定)。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化得到所需产物3aj，收率75％,97％ee。m.p.73.7-82.7℃。Rf＝0.32(Pet/EtOAc,8/1).[α]D 26＝-45.55(c＝1.67,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.485min,(minor)＝10.175min.1H NMR(600MHz,CDCl3)δ7.46–7.42(m,2H),7.24–7.12(m,5H),7.09(dd,J＝7.2,2.4Hz,2H),6.89–6.83(m,2H),6.68(d,J＝7.8Hz,1H),6.24(s,1H),5.16(d,J＝6.6Hz,1H),4.81(d,J＝13.8Hz,1H),4.75(d,J＝13.8Hz,1H),3.67(s,3H),3.65(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,143.1,141.1,139.1,138.4,137.5,134.9,132.6,130.9,130.6,130.5,128.8,128.4,127.9,127.4,123.2,120.4,114.2,105.1,102.9,54.1,52.1,41.1,33.0.HRMS(ESI-TOF)m/z:[M+Na]+calcd for C27H22Cl2N2NaO2 +499.0951；found499.0951.IR(neat):2922,1717,1633,1580,1497,1462,1421,1401,1326,1231,1148,1053,1029,828,766,731,698cm-1.
实施例6
Figure BDA0004036611850000151
在试管中加入L1和Ni(OTf)2(5mol％,1:1)，在空气气氛中加入β,γ-不饱和α-酮酸酯2l(0.1mmol,20.4mg)、
Figure BDA0004036611850000152
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3equiv,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2l消耗(TLC测定)。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化得到黄色产物3al，收率90％,93％ee。m.p.111.6-114.2℃.Rf＝0.27(Pet/EtOAc,8/1).[α]D 26＝1.48(c＝1.44,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.098min,(minor)＝8.667min.1H NMR(600MHz,CDCl3)δ7.28–7.15(m,9H),7.11(t,J＝7.8Hz,1H),6.94(d,J＝6.0Hz,1H),6.81(d,J＝8.4Hz,1H),6.66(d,J＝7.8Hz,1H),6.12(s,1H),5.26(d,J＝6.0Hz,1H),4.85(d,J＝13.8Hz,1H),4.75(d,J＝13.8Hz,1H),3.63(s,3H),3.60(s,3H),2.40(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.9,141.4,139.4,138.4,138.3,137.9,137.7,136.5,129.4,128.9,128.5,128.4,127.3,123.1,123.0,120.7,116.0,104.8,102.7,54.2,52.0,42.0,32.9,21.3.HRMS(ESI-TOF)m/z:[M+Na]+calcd forC28H26N2NaO2 +445.1886；found445.1886.IR(neat):3029,2947,1717,1633,1607,1580,1497,1460,1421,1327,1231,1148,1072,768,732,698cm-1.
实施例7
Figure BDA0004036611850000161
在试管中加入L1和Ni(OTf)2(5mol％,1:1)，在空气气氛中加入β,γ-不饱和α-酮酸酯2m(0.1mmol,22.0mg)、
Figure BDA0004036611850000162
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3equiv,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2m消耗(TLC测定)。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化得到浅黄色固体产物3am，收率67％,95％ee。m.p.168.3-171.4℃.Rf＝0.18(Pet/EtOAc,8/1,v/v).[α]D 26＝-5.49(c＝0.60,CHCl3).HPLCCHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝8.547min,(minor)＝10.473min.1H NMR(400MHz,CDCl3)δ7.32–7.28(m,2H),7.25–7.16(m,5H),7.12(t,J＝8.0Hz,1H),6.98–6.89(m,3H),6.82(d,J＝8.0Hz,1H),6.66(d,J＝7.6Hz,1H),6.13(d,J＝1.2Hz,1H),5.25(d,J＝6.4,1H),4.86(d,J＝14.0Hz,1H),4.76(d,J＝14.0Hz,1H),3.85(s,3H),3.64(s,3H),3.60(s,3H).13C{1H}NMR(100MHz,CDCl3)δ165.9,158.7,141.4,138.4,138.2,137.9,137.7,134.6,129.6,128.9,128.4,127.3,123.1,123.0,120.6,116.2,114.1,104.8,102.7,55.5,54.2,52.0,41.6,32.9.HRMS(ESI-TOF)m/z:[M+Na]+calcd for C28H26N2NaO3 +461.1836；found 461.1841.IR(neat):2924,1717,1633,1581,1497,1460,1421,1327,1230,1148,1071,1052,768,732cm-1.
实施例8
Figure BDA0004036611850000171
在试管中加入L1和Ni(OTf)2(5mol％,1:1)。然后在空气气氛中加入β,γ-不饱和α-酮酸酯2n(0.1mmol,26.6mg)、
Figure BDA0004036611850000172
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3equiv,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2m消耗(TLC测定)。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化得到所需产物3an，收率73％,95％ee。m.p.89.9-94.1℃.Rf＝0.32(Pet/EtOAc,8/1).[α]D 26＝-17.14(c＝1.65,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝8.448min,(minor)＝11.053min.1H NMR(600MHz,CDCl3)δ7.70–7.61(m,4H),7.52–7.44(m,4H),7.43–7.36(m,1H),7.24–7.12(m,6H),7.01(d,J＝6.6Hz,1H),6.86(d,J＝8.4Hz,1H),6.70(d,J＝7.8Hz,1H),6.25(d,J＝1.2Hz,1H),5.33(d,J＝6.6,Hz,1H),4.88(d,J＝13.8Hz,1H),4.79(d,J＝13.8Hz,1H),3.67(s,3H),3.64(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.9,141.7,141.4,141.1,140.0,138.5,138.4,137.7,136.8,128.98,128.95,128.9,128.4,127.5,127.4,127.3,127.2,123.2,123.1,120.7,115.5,104.9,102.7,54.2,52.0,41.8,32.9.IR(neat):2924,1717,1633,1580,1497,1460,1421,1327,1232,1071,1052,768,732,698cm-1.
实施例9
Figure BDA0004036611850000181
在试管中加入L1和Ni(OTf)2(5mol％,1:1)。然后在空气气氛中加入β,γ-不饱和α-酮酸酯2o(0.1mmol,19.6mg)、
Figure BDA0004036611850000182
MS(20mg)和PhCF3(2.0mL)。在30℃搅拌0.5小时后，加入N-苄基-1-甲基-1H-吲哚-4-胺1a(1.3equiv,30.7mg)。反应混合物在30℃搅拌至β,γ-不饱和α-酮酸酯2o消耗(TLC测定)。最后对反应混合物进行过滤浓缩，残渣直接用快速柱层析(Pet/EtOAc,500/1～100/1,v/v)洗脱纯化得到所需产物3ao，收率82％,88％ee。m.p.89.9-94.1℃.m.p.65.4-71.5℃.Rf＝0.26(Pet/EtOAc,8/1).[α]D 26＝-12.03(c＝1.69,CHCl3).HPLC CHIRALPAK ID,n-hexane/2-propanol＝70/30,flow rate 0.8mL/min,λ＝254nm,retention time:(major)＝7.647min,(minor)＝8.822min.1H NMR(600MHz,CDCl3)δ7.28(dd,J＝4.8,1.2Hz,1H),7.25–7.17(m,5H),7.13(t,J＝7.8Hz,1H),7.06–7.01(m,2H),6.92(d,J＝6.6Hz,1H),6.84(d,J＝7.8Hz,1H),6.67(d,J＝7.8Hz,1H),6.45(s,1H),5.61(d,J＝6.6Hz,1H),4.84(d,J＝13.8Hz,1H),4.80(d,J＝13.8Hz,1H),3.67(s,3H),3.65(s,3H).13C{1H}NMR(150MHz,CDCl3)δ165.8,145.7,141.0,138.5,138.3,137.7,136.5,128.8,128.4,127.3,126.9,125.4,124.0,123.14,123.11,120.3,115.1,105.0,102.8,54.1,52.1,37.3,33.0.HRMS(ESI-TOF)m/z:[M+Na]+calcd for C25H22N2NaO2S+437.1294；found437.1291.IR(neat):2920,2851,1716,1580,1496,1460,1421,1325,1239,1148,1069,767,732,697cm-1.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (7)

1.一种合成手性七元环桥连3,4-稠合三环吲哚的方法，其特征在于，包括如下步骤：以N-甲基-4-苄胺基吲哚1和β,γ-不饱和α-酮酸酯2为原料，在二价金属盐-PyBPI配体存在下有机溶剂中反应，得到手性七元环桥接3,4-稠合三环吲哚3；反应方程式如下：
Figure QLYQS_1
其中：R1选自苯基、取代苯基、噻吩；取代苯基中取代基为卤素、C1-C4烷基、苯基、C1-C4烷氧基中的一种或多种。
2.根据权利要求1所述合成手性七元环桥连3,4-稠合三环吲哚的方法，其特征在于：PyBPI配体中，R＝2,6-iPr2C6H3。
3.根据权利要求1所述合成手性七元环桥连3,4-稠合三环吲哚的方法，其特征在于：有机溶剂选自三氟甲苯、氯苯、二氯甲烷或甲苯中的一种或多种。
4.根据权利要求1所述合成手性七元环桥连3,4-稠合三环吲哚的方法，其特征在于：二价金属盐选自Co(ClO4)2-6H2O、Cu(OTf)2、Zn(OTf)2、Ni(OTf)2或Ni(ClO4)2-6H2O。
5.根据权利要求1所述合成手性七元环桥连3,4-稠合三环吲哚的方法，其特征在于：N-甲基-4-苄胺基吲哚1、β,γ-不饱和α-酮酸酯2与二价金属盐-PyBPI配体摩尔比为1-1.5:1:0.003-0.005。
6.根据权利要求1-5任意一项所述合成手性七元环桥连的3,4-稠合三环吲哚的方法，其特征在于：反应温度为20-40℃。
7.根据权利要求1-5任意一项所述合成手性七元环桥连3,4-稠合三环吲哚的方法，其特征在于：反应中加入添加剂，添加剂选自
Figure QLYQS_2
MS、
Figure QLYQS_3
MS或
Figure QLYQS_4
MS。
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHAOMIN CHEN: "4-Aminoindoles as 1, 4-bisnucleophiles for diversity-oriented synthesis of tricyclic indoles bearing 3, 4-fused seven-membered rings", 《ORG. BIOMOL. CHEM.》, vol. 17, 30 May 2019 (2019-05-30), pages 5982 *
ZAHID SHAFIQ: "A Highly α-Regioselective AgOTf-Catalyzed Nucleophilic Substitution of the Baylis-Hillman Acetates with Indoles", 《ORG. LETT.》, vol. 9, no. 13, 23 May 2007 (2007-05-23) *

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