CN112479920B - 一种类轴手性酰苯胺类化合物及制备方法和应用 - Google Patents

一种类轴手性酰苯胺类化合物及制备方法和应用 Download PDF

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CN112479920B
CN112479920B CN202011356807.0A CN202011356807A CN112479920B CN 112479920 B CN112479920 B CN 112479920B CN 202011356807 A CN202011356807 A CN 202011356807A CN 112479920 B CN112479920 B CN 112479920B
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张俊良
阳斌
杨俊锋
李志铭
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Abstract

本发明涉及一种类轴手性酰苯胺类化合物及制备方法和应用，其结构式为：
Figure DDA0002802832390000011
其中：R1为F、Cl、Br、C1～C12的烷烃基、苯基、取代苯基中的一种；R2为环烷基、苯基、取代苯基中的一种；R3为C1～C12的烷烃基、烯基、苯基、取代苯基、萘基、取代萘基、五元杂环基中的一种，与现有技术相比，本技术方案合成的该类化合物可能具有潜在生物活性，可用作手性配体骨架，同时该方法得到的产物具有非常高的对映选择性，在此类需求的药物、药物中间体和生物材料中均具有非常好的应用前景；避免了N‑末端官能团的催化反应，为C‑末端官能团进行催化反应制备阻转异构的酰苯胺类化合物建立了新的方向，可以实现工业化的推广。

Description

一种类轴手性酰苯胺类化合物及制备方法和应用
技术领域
本发明涉及化合物合成领域，尤其是涉及一种类轴手性酰苯胺类化合物及其制备方法和应用。
背景技术
手性是组成自然界物质的基本属性之一。近年来，具有C-N轴手性的结构经常出现在生物活性分子，天然产物和手性配体骨架中。1994年，Curran及其同事首次实现了轴向手性酰苯胺类化合物的不对称合成(J.Am.Chem.Soc.1994,116,3131)。从那时起，轴向手性酰苯胺的许多独特功能被用于不对称催化和生物活性化合物(如甲草胺和替硝西平)的开发以及类肽化学(Angew.Chem.Int.Ed.2009,48,6398；J.Med.Chem.2011,54,7005；J.Am.Chem.Soc.2011,133,10910)。但是，由于C-N手性轴的旋转势垒比其轴向手性联芳基类似物低，因此获得这些有用的结构仍然是一个挑战。
最初，研究人员采用手性池策略来制备轴手性酰苯胺类化合物，该策略需要当量的手性试剂。2002年，Taguchi和Curran分别报道了第一例通过Pd催化的N-烯丙基化进行的手性轴向酰苯胺类化合物的催化不对称合成方法(J.Org.Chem.2002,67,8682；Tetrahedron:Asymmetry 2003,14,587)。随后，包括Pd催化的N-芳基化，相转移催化的N-烷基化，路易斯碱催化的N-烯丙基烷基化，有机催化的不对称Friedel-Crafts胺化和Rh催化的不对称[2+2+2]环加成等方法相继被报道出来(J.Am.Chem.Soc.2006,128,12923；J.Am.Chem.Soc.2012,134,916；Angew.Chem.Int.Ed.2006,45,1147；J.Am.Chem.Soc.2018,140,40,12836；J.Am.Chem.Soc.2006,128,4586)。
在现有技术中的这些方法当中，大多数情况下，反应位点在N原子或其现有取代基上。一些例子是在C-N键生成过程中形成轴向手性，但因为旋转势垒而难以推广，然而，由C-末端官能团进行催化反应制备阻转异构的酰苯胺类化合物的方法仅有一例报道(10.1021/jacs.0c09400)，但该文献中的方法在其他场景中难以再现，较难实现推广。
发明内容
本发明的目的就是为了解决上述问题而提供一种类轴手性酰苯胺类化合物及其制备方法和应用，其中制备的该类轴手性酰苯胺类化合物是全新的结构，为C-末端官能团进行催化反应制备阻转异构的酰苯胺类化合物建立了新的方向。
本发明的目的通过以下技术方案实现：
本发明中要求保护的类轴手性酰苯胺类化合物的结构式为：
Figure BDA0002802832380000021
其中：
R1为F、Cl、Br、C1～C12的烷烃基、苯基、取代苯基中的一种；
R2为环烷基、苯基、取代苯基中的一种；
R3为C1～C12的烷烃基、烯基、苯基、取代苯基、萘基、取代萘基、五元杂环基中的一种。
进一步地，所述碳原子总数为1～12的烷基中，烷基的碳原子数优选为2～6；所述的取代苯基、取代萘基中的取代基为烷基、芳基、烷氧基、氟、氯、溴、酯基、氰基、二甲氨基中的至少一种。
本发明要求保护的类轴手性酰苯胺类化合物的制备方法，所述类轴手性酰苯胺类化合物通过底物1、底物2和手性膦配体进行去对称化的sonogashira偶联反应，得到类轴手性酰苯胺类化合物3，反应过程为：
Figure BDA0002802832380000031
反应所采用的催化剂为钯盐催化剂和铜盐催化剂。
进一步地，进行去对称化的sonogashira偶联反应过程中：
先将钯盐催化剂与手性膦配体在溶剂中预先搅拌30min～1h，随后加入铜盐催化剂、底物1、底物2和碱，在反应温度下搅拌进行偶联反应，得到轴手性酰苯胺类化合物3。
进一步地，所述底物1和底物2的投料摩尔比为1:1～5；
底物1和底物2的投料摩尔比优选1:2。
所述钯盐催化剂的投料摩尔用量为底物1的投料摩尔用量的5％～50％；
优选为底物1的投料摩尔用量的10％。
所述手性膦配体的摩尔用量与钯盐催化剂摩尔用量之比为1:1～3；
优选为1:2。
所述铜盐催化剂的投料摩尔用量为底物1的投料摩尔用量1％～20％；
优选为5％。
所述碱的摩尔用量与底物1摩尔用量之比为1:1.1～3；
优选为1:2。
进一步地，所述钯盐催化剂为Pd(OAc)2、Pd(TFA)2、Pd2(dba)3、Pd2(dba)3 .CHCl3、Pd(dba)2、PdCl2中的一种或多种，优选Pd(OAc)2；
所述铜盐催化剂为CuCl、CuBr、CuI、CuBr.SMe2、CuTc、Cu(CH3CN)4PF6、Cu(CH3CN)4BF4、CuCl2、CuBr2、CuF2、Cu(OTf)2、Cu(acac)2中一种或多种，优选CuI。
进一步地，所述手性膦配体为L1～L19中一种或多种的混合物，L1～L19分别为：
Figure BDA0002802832380000041
进一步地，所述碱为醋酸铯、碳酸钾、碳酸钠、碳酸铯、N，N-二异丙基乙胺、1,4-二氮杂二环[2.2.2]辛烷、三乙胺中的一种，优选为醋酸铯、碳酸钾中的一种。
进一步地，所述溶剂为四氢呋喃、乙腈、1,4-二氧六环、二氯甲烷、甲苯、乙酸乙酯中的一种，优选四氢呋喃、乙腈、乙酸乙酯中的一种。
进一步地，所述偶联反应的反应温度为0℃～25℃，优选5℃～15℃，所述偶联反应的反应时间为18h～108h，优选为60h～108h。
进一步地，所述底物1和底物2均为所属领域的技术人员能够合成或者购买的化合物。
本发明具有以下技术优势：
1)本发明为合成新型轴手性酰苯胺类化合物提供了一种新的途径，该类化合物可能具有潜在生物活性，可用作手性配体骨架，同时该方法得到的产物具有非常高的对映选择性，在此类需求的药物、药物中间体和生物材料中均具有非常好的应用前景。
2)相对于现有技术，本技术方案避免了N-末端官能团的催化反应，为C-末端官能团进行催化反应制备阻转异构的酰苯胺类化合物建立了新的方向，通过一步法的催化反应过程即可实现，可以实现工业化的推广。
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，但绝不是对本发明的限制。
本发明提供的技术方案是：在氮气保护条件下，将钯盐催化剂与手性膦配体在溶剂中预先搅拌0.5h～1h，随后加入铜盐催化剂，底物1，底物2，碱，在合适的温度下搅拌进行偶联反应即可得轴手性酰苯胺类化合物3。其合成路线如下：
Figure BDA0002802832380000051
实施例1
Figure BDA0002802832380000052
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2a(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得95.0mg产品3aa,收率81％，HPLC测得97％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.74(d,J＝1.3,1H),7.65–7.59(m,6H),7.48(t,J＝7.5,2H),7.44(d,J＝1.2,1H),7.39(t,J＝7.3,1H),4.05(dd,J＝13.6,7.8,1H),2.99(dd,J＝13.6,5.2,1H),2.37(s,3H),2.08(d,J＝12.2,1H),1.85–1.73(m,1H),1.68–1.60(m,2H),1.60–1.50(m,2H),1.16(s,9H),1.14–1.05(m,3H),1.04–0.89(m,2H).13C NMR(101MHz,CDCl3)δ178.17,145.76,141.56,140.86,140.18,139.11,133.83,132.09,128.91,127.79,127.12,127.05,125.49,121.26,102.70,94.53,87.96,59.89,42.01,37.53,32.29,32.25,29.89,26.38,26.25,26.21,20.34.[α]20 D＝-58.9(c 0.6,CHCl3).
拆分条件：Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:21.79min(minor),30.34min(major).
实施例2
Figure BDA0002802832380000061
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2b(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得84.2mg产品3ab,收率82％，HPLC测得96％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.73(d,J＝1.3Hz,1H),7.55–7.50(m,2H),7.42(d,J＝1.2Hz,1H),7.38–7.32(m,3H),4.03(dd,J＝13.6,7.9Hz,1H),2.96(dd,J＝13.6,5.2Hz,1H),2.36(s,3H),2.04(d,J＝12.5Hz,1H),1.85–1.69(m,1H),1.67–1.57(m,2H),1.55–1.47(m,2H),1.14(s,9H),1.11–1.02(m,3H),1.02–0.85(m,2H).13C NMR(101MHz,CDCl3)δ178.11,145.76,140.85,139.09,133.85,131.65,128.86,128.45,125.45,122.40,102.69,94.54,87.25,59.87,41.97,37.50,32.26,32.22,29.86,26.36,26.18,20.32.[α]20 D＝-27.1(c 0.6,CHCl3).拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:16.90min(major),21.69min(minor).
实施例3
Figure BDA0002802832380000071
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2c(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得86.5mg产品3ac,收率82％，HPLC测得96％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.42–7.33(m,3H),7.14(d,J＝7.9Hz,2H),4.01(dd,J＝13.6,7.9Hz,1H),2.92(dd,J＝13.6,5.1Hz,1H),2.36(s,3H),2.33(s,3H),2.02(d,J＝12.4Hz,1H),1.79–1.68(m,1H),1.66–1.56(m,2H),1.54–1.45(m,2H),1.11(s,9H),1.09–1.00(m,3H),0.98–0.82(m,2H).13C NMR(101MHz,CDCl3)δ177.99,145.49,140.48,138.99,138.90,133.62,131.43,129.09,125.54,119.21,102.52,94.72,86.56,59.73,41.83,37.35,32.12,29.71,26.24,26.06,21.46,20.18.[α]20 D＝-20.2(c 0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:14.28min(major),19.32min(minor).
实施例4
Figure BDA0002802832380000081
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2d(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得95.7mg产品3ad收率84％，HPLC测得96％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.43(d,J＝8.2Hz,2H),7.38(s,1H),7.35(d,J＝8.3Hz,2H),3.97(dd,J＝13.6,7.8Hz,1H),2.97(dd,J＝13.6,5.2Hz,1H),2.33(s,3H),2.01(d,J＝11.9Hz,1H),1.78–1.67(m,1H),1.63–1.56(m,2H),1.54–1.44(m,2H),1.31(s,9H),1.11(s,9H),1.08–0.85(m,5H).13C NMR(101MHz,CDCl3)δ178.00,152.08,145.54,140.47,138.89,133.69,131.27,125.54,125.31,119.22,102.56,94.76,86.49,59.72,41.83,37.31,34.73,32.08,31.02,29.73,26.26,26.03,20.17.[α]20 D＝-28.4(c 0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:12.95min(major),20.13min(minor).
实施例5
Figure BDA0002802832380000082
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2e(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得95.9mg产品3ae收率81％，HPLC测得94％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.72(d,J＝1.3Hz,1H),7.47(d,J＝8.5Hz,2H),7.38(d,J＝1.3Hz,1H),7.35(d,J＝8.5Hz,2H),3.98(dd,J＝13.6,7.8Hz,1H),2.93(dd,J＝13.6,5.2Hz,1H),2.34(s,3H),1.98(d,J＝12.0Hz,1H),1.76–1.65(m,1H),1.63–1.55(m,2H),1.53–1.45(m,2H),1.10(s,9H),1.08–1.00(m,3H),0.97–0.80(m,2H).13C NMR(101MHz,CDCl3)δ178.03,145.70,141.00,139.01,133.62,132.86,131.66,125.00,123.14,121.20,102.49,93.23,88.24,59.70,41.86,37.38,32.11,32.07,29.70,26.19,26.09,26.05,20.17.[α]20 D＝-37.6(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:16.67min(major),25.23min(minor).
实施例6
Figure BDA0002802832380000091
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2f(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得88.8mg产品3af收率81％，HPLC测得93％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.72(d,J＝1.3Hz,1H),7.46–7.40(m,2H),7.38(d,J＝1.2Hz,1H),7.34–7.29(m,2H),3.98(dd,J＝13.6,7.8Hz,1H),2.93(dd,J＝13.6,5.2Hz,1H),2.34(s,3H),1.98(d,J＝12.5Hz,1H),1.79–1.68(m,1H),1.63–1.56(m,2H),1.54–1.45(m,2H),1.10(s,9H),1.07–1.00(m,3H),0.98–0.81(m,2H).13C NMR(101MHz,CDCl3)δ178.04,145.68,140.97,139.01,134.86,133.62,132.68,128.73,125.00,120.74,102.48,93.17,88.06,59.70,41.85,37.38,32.11,32.06,29.70,26.19,26.08,26.06,20.18.[α]20 D＝-32.6(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:17.44min(major),24.94min(minor).
实施例7
Figure BDA0002802832380000101
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2g(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得80.4mg产品3ag收率74％，HPLC测得97％ee。
1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.43(d,J＝8.5Hz,2H),7.35(s,1H),6.85(d,J＝8.5Hz,2H),3.99(dd,J＝13.6,7.9Hz,1H),3.81(s,3H),2.93(dd,J＝13.6,5.1Hz,1H),2.32(s,3H),2.01(d,J＝12.2Hz,1H),1.77–1.68(m,1H),1.79–1.68(m,1H),1.66–1.55(m,2H),1.53–1.44(m,2H),1.11(s,9H),1.08–1.00(m,3H),0.98–0.79(m,2H).13C NMR(101MHz,CDCl3)δ178.02,159.94,145.35,140.27,138.88,133.40,133.05,125.68,114.37,113.98,102.48,94.65,86.01,59.72,55.18,41.82,37.37,32.13,32.10,29.71,26.24,26.06,20.18.[α]20 D＝-31.1(c＝0.6,CHCl3).
产物表征数据为：
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝93/7,0.3mL/min.Retention times:16.33min(major),22.31min(minor).
实施例8
Figure BDA0002802832380000111
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2h(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得90.1mg产品3ah收率81％，HPLC测得94％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.63(d,J＝1.1Hz,1H),7.37(d,J＝8.8Hz,2H),7.33(s,1H),[6.62(d,J＝8.8Hz),6.52(d,J＝8.6Hz),(2H)],4.00(dd,J＝13.6,7.9Hz,1H),[2.99(s),2.85(s),(6H)],2.93(dd,J＝13.6,5.2Hz,1H),2.31(s,3H),2.05(d,J＝10.4Hz,1H),1.81–1.70(m,1H),1.62–1.56(m,2H),1.55–1.46(m,2H),1.11(s,9H),1.08–0.99(m,3H),0.99–0.80(m,2H).13C NMR(101MHz,CDCl3)δ178.18,150.38,145.11,139.74,138.89,133.27,133.11,132.91,126.40,111.96,111.71,109.04,102.63,96.39,85.63,59.87,41.93,40.14,37.49,32.29,32.26,29.85,26.42,26.22,26.18,20.32.[α]20 D＝-30.6(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝93/7,0.3mL/min.Retention times:18.91min(major),29.91min(minor).
实施例9
Figure BDA0002802832380000112
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2i(0.4mmol)与醋酸铯(0.4mmol)，置于15℃下搅拌60h。反应液浓缩，柱层析分离得84.5mg产品3ai收率74％，HPLC测得97％ee。
1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.4Hz,1H),7.75(d,J＝1.3Hz,1H),7.57(d,J＝8.4Hz,1H),7.42(d,J＝1.2Hz,1H),4.03(dd,J＝13.6,8.0Hz,1H),3.94(s,3H),2.93(dd,J＝13.6,5.1Hz,1H),2.36(s,1H),2.02(d,J＝12.7Hz,1H),1.76–1.66(m,1H),1.63–1.55(m,2H),1.53–1.46(m,2H),1.12(s,9H),1.10–1.01(m,3H),0.99–0.85(m,2H).13C NMR(101MHz,CDCl3)δ178.08,166.42,145.96,141.43,139.22,133.99,131.51,130.04,129.61,126.96,124.89,102.71,93.48,90.02,59.82,52.30,41.98,37.52,32.24,32.17,29.84,26.30,26.20,26.18,20.32.[α]20 D＝-32.7(c＝0.6,CHCl3).拆分条件:DaicelChiralpak ADH column；hexane/2-propanol＝93/7,0.3mL/min.Retention times:25.54min(major),39.22min(minor).
实施例10
Figure BDA0002802832380000121
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2j(0.4mmol)与醋酸铯(0.4mmol)，置于15℃下搅拌60h。反应液浓缩，柱层析分离得74.3mg产品3aj收率69％，HPLC测得97％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.62(d,J＝8.2Hz,2H),7.57(d,J＝8.2Hz,2H),7.40(s,1H),3.94(dd,J＝13.6,7.7Hz,1H),2.96(dd,J＝13.6,5.3Hz,1H),2.35(s,3H),1.94(d,J＝12.4Hz,1H),1.72–1.64(m,1H),1.61–1.54(m,2H),1.52–1.43(m,2H),1.08(s,9H),1.07–0.98(m,3H),0.98–0.82(m,2H).13C NMR(101MHz,CDCl3)δ178.21,146.18,141.86,139.31,133.95,132.19,132.04,127.19,124.43,118.35,112.15,102.66,92.41,91.35,59.82,42.03,37.55,32.23,32.15,29.84,26.26,26.23,26.17,20.32.[α]20 D＝-45.2(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝93/7,0.3mL/min.Retention times:24.18min(major),44.87min(minor).
实施例11
Figure BDA0002802832380000131
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2k(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得75.8mg产品3ak收率72％，HPLC测得98％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.69(d,J＝1.3Hz,1H),7.39(d,J＝1.2Hz,1H),7.36–7.29(m,2H),7.22(t,J＝7.8Hz,1H),7.15(d,J＝7.6Hz,1H),4.03(dd,J＝13.6,8.0Hz,1H),2.92(dd,J＝13.6,5.1Hz,1H),2.33(s,6H),2.06–2.01(m,1H),1.79–1.67(m,1H),1.65–1.56(m,2H),1.55–1.46(m,2H),1.12(s,9H),1.09–0.99(m,3H),0.98–0.79(m,2H).13C NMR(101MHz,CDCl3)δ177.95,145.54,140.62,138.94,137.99,133.79,131.94,129.66,128.71,128.21,125.41,122.09,102.61,94.66,86.79,59.74,41.82,37.34,32.13,32.07,29.72,26.25,26.06,21.14,20.18.[α]20 D＝-28.2(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:14.55min(major),18.29min(minor).
实施例12
Figure BDA0002802832380000141
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2l(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得83.2mg产品3ak收率76％，HPLC测得98％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.75(d,J＝1.3Hz,1H),7.49(t,J＝1.6Hz,1H),7.42–7.38(m,2H),7.36–7.32(m,1H),7.29(d,J＝7.6Hz,1H),4.04(dd,J＝13.6,8.1Hz,1H),2.92(dd,J＝13.6,5.0Hz,1H),2.36(s,3H),2.11–1.98(m,1H),1.81–1.67(m,2H),1.64–1.59(m,2H),1.56–1.50(m,2H),1.13(s,9H),1.11–1.03(m,3H),1.01–0.87(m,2H).13C NMR(101MHz,CDCl3)δ178.07,145.85,141.28,139.19,134.33,133.98,131.27,129.81,129.74,129.14,124.93,124.07,102.75,92.84,88.35,59.80,41.97,37.50,32.23,32.13,29.84,26.34,26.19,20.32.[α]20 D＝-31.5(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:16.38min(major),19.89min(minor).
实施例13
Figure BDA0002802832380000142
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2m(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得81.7mg产品3am收率79％，HPLC测得95％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.68(dd,J＝1.9,0.6Hz,1H),7.45(dd,J＝7.6,1.7Hz,1H),7.42(dd,J＝1.9,0.6Hz,1H),7.30(ddd,J＝8.4,7.6,1.7Hz,1H),6.95–6.85(m,2H),3.94(dd,J＝13.6,7.5Hz,1H),3.88(s,3H),3.01(dd,J＝13.6,5.5Hz,1H),2.32(s,3H),2.04–1.93(m,1H),1.83–1.70(m,1H),1.69–1.63(m,1H),1.61–1.54(m,1H),1.51–1.44(m,2H),1.11(s,9H),1.09–0.81(m,5H).
13C NMR(101MHz,CDCl3)δ177.87,160.05,145.52,140.42,138.84,133.93,133.40,130.21,125.61,120.37,111.58,110.36,102.70,91.23,90.90,59.92,55.42,41.80,37.29,32.17,32.01,29.70,26.27,26.00,20.15.[α]20 D＝-5.6(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak IE column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:39.98min(minor),42.97min(major).
实施例14
Figure BDA0002802832380000151
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2n(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得90.7mg产品3an收率81％，HPLC测得96％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ8.40(d,J＝8.3Hz,1H),7.90–7.81(m,2H),7.79–7.71(m,2H),7.63(t,J＝7.6Hz,1H),7.59–7.51(m,2H),7.45(t,J＝7.7Hz,1H),3.98(dd,J＝13.6,7.3Hz,1H),3.13(dd,J＝13.6,5.6Hz,1H),2.38(s,3H),2.05–1.98(m,1H),1.89–1.79(m,1H),1.75–1.68(m,1H),1.59–1.54(m,1H),1.51–1,42(m,2H),1.16(s,9H),1.12–0.99(m,3H),0.98–0.83(m,2H).13C NMR(101MHz,CDCl3)δ178.08,145.62,140.84,139.05,133.93,133.04,133.00,130.84,129.27,128.31,126.85,126.43,125.92,125.39,125.29,119.89,102.77,92.83,91.92,60.00,41.93,37.47,32.21,32.17,29.83,26.19,26.00,20.24.[α]20 D＝-22.7(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:16.97min(major),21.35min(minor).
实施例15
Figure BDA0002802832380000161
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2o(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得90.0mg产品3ao收率80％，HPLC测得96％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.85–7.76(m,3H),7.72(s,1H),7.56(d,J＝8.5Hz,1H),7.50(d,J＝6.0Hz,1H),7.50(d,J＝6.1Hz,1H),7.45(s,1H),4.09(dd,J＝13.6,8.0Hz,1H),2.96(dd,J＝13.6,5.0Hz,1H),2.35(s,3H),2.20–2.03(m,1H),1.90–1.70(m,1H),1.66–1.56(m,2H),1.53–1.41(m,2H),1.16(s,9H),1.14–1.04(m,3H),1.03–0.89(m,2H).13C NMR(101MHz,CDCl3)δ178.03,145.62,140.77,139.01,133.82,132.94,132.83,131.64,128.07,128.00,127.83,127.68,126.90,126.58,125.38,119.58,102.63,94.85,87.51,59.78,41.89,37.44,32.21,32.11,29.77,26.23,26.12,26.08,20.22.[α]20 D＝-51.7(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:19.01min(major),31.11min(minor).
实施例16
Figure BDA0002802832380000171
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2p(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得83.4mg产品3ap收率80％，HPLC测得92％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.63(d,J＝1.4Hz,1H),7.24(d,J＝1.3Hz,1H),3.99(dd,J＝13.6,8.3Hz,1H),2.84(dd,J＝13.6,5.0Hz,1H),2.36(t,J＝7.3Hz,2H),2.28(s,3H),2.02–1.89(m,1H),1.73–1.63(m,3H),1.60–1.50(m,4H),1.46–1.35(m,2H),1.34–1.24(m,4H),1.19–1.11(m,3H),1.07(s,9H),0.99–0.84(m,5H).13C NMR(101MHz,CDCl3)δ177.95,145.66,140.11,138.88,134.07,126.13,102.58,96.20,78.31,59.63,41.84,37.27,32.12,32.07,31.33,29.76,28.84,28.39,26.47,26.41,26.26,22.55,20.25,19.61,14.06.
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:11.99min(major),14.87min(minor).
实施例17
Figure BDA0002802832380000181
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1a(0.2mmol)、底物2q(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得75.6mg产品3aq收率80％，HPLC测得92％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.63(d,J＝1.3Hz,1H),7.25(d,J＝1.3Hz,1H),6.29–6.10(m,1H),3.95(dd,J＝13.6,7.9Hz,1H),2.85(dd,J＝13.6,5.1Hz,1H),2.28(s,3H),2.19–2.07(m,4H),1.99–1.90(m,1H),1.71–1.54(m,9H),1.19–1.02(m,3H),1.07(s,9H),1.02–0.78(m,2H).13C NMR(101MHz,CDCl3)δ177.82,145.29,140.10,138.77,136.60,133.62,125.82,120.14,102.50,96.44,84.46,59.71,41.72,37.28,32.13,32.07,29.69,28.62,26.33,26.19,26.11,25.73,22.11,21.30,20.14.
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:13.59min(major),17.69min(minor).
实施例18
Figure BDA0002802832380000182
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1b(0.2mmol)、底物2a(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得98.1mg产品3ba收率78％，HPLC测得97％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.87(d,J＝1.8Hz,1H),7.64–7.54(m,7H),7.45(t,J＝7.6Hz,2H),7.36(t,J＝7.2Hz,1H),4.03(dd,J＝13.6,8.0Hz,1H),2.99(dd,J＝13.6,5.2Hz,1H),2.13–1.99(m,1H),1.86–1.74(m,1H),1.71–1.59(m,2H),1.57–1.49(m,2H),1.36(s,9H),1.14(s,9H),1.13–1.03(m,3H),1.03–0.90(m,2H).13C NMR(101MHz,CDCl3)δ178.03,152.32,145.52,141.40,140.04,137.50,131.97,130.32,128.78,127.66,126.98,126.92,125.06,121.15,102.81,94.09,88.26,59.68,41.85,37.43,34.46,32.13,32.04,31.02,29.73,26.27,26.13,26.09.[α]20 D＝-34.7(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak OZH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:13.08min(minor),15.77min(major).
实施例19
Figure BDA0002802832380000191
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1c(0.2mmol)、底物2a(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得86.5mg产品3ca收率71％，HPLC测得90％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.86(d,J＝2.1Hz,1H),7.65–7.53(m,7H),7.46(t,J＝7.5Hz,2H),7.37(t,J＝7.2Hz,1H),4.00(dd,J＝13.7,7.7Hz,1H),2.98(dd,J＝13.7,5.2Hz,1H),2.06–1.92(m,1H),1.80–1.73(m,1H),1.67–1.60(m,2H),1.58–1.50(m,2H),1.15(s,9H),1.12–1.02(m,1H),1.02–0.82(m,2H).13C NMR(101MHz,CDCl3)δ178.06,147.13,142.06,140.04,139.42,133.61,132.74,132.23,128.94,127.92,127.21,127.08,126.83,120.61,103.06,96.14,86.63,59.89,42.15,37.62,32.25,32.23,29.91,26.32,26.22,26.17.[α]20 D＝-42.8(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak ADH column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:21.24min(major),26.10min(minor).
实施例20
Figure BDA0002802832380000201
具体操作为：氮气保护下，往干燥的史莱克管中加入Pd(OAc)2(0.02mmol)、有机膦配体L19(0.04mmol)和2ml无水的乙酸乙酯，室温搅拌1h。再加入CuI(0.01mmol)、底物1d(0.2mmol)、底物2a(0.4mmol)与醋酸铯(0.4mmol)，置于5℃下搅拌60h。反应液浓缩，柱层析分离得72.3mg产品3da收率62％，HPLC测得91％ee。
产物表征数据为：
1H NMR(400MHz,CDCl3)δ7.70(d,J＝1.3Hz,1H),7.63–7.58(m,2H),7.54(d,J＝8.4Hz,2H),7.46(t,J＝7.6Hz,2H),7.41–7.34(m,3H),7.32–7.27(m,3H),7.10–7.07(m,3H),5.28(d,J＝13.8Hz,1H),4.45(d,J＝13.8Hz,1H),2.33(s,3H),1.14(s,9H).13C NMR(101MHz,CDCl3)δ178.55,144.26,141.33,140.53,140.26,139.24,136.62,133.20,132.18,130.93,128.91,127.84,127.75,127.35,127.05,126.86,125.92,121.31,102.40,94.38,87.43,55.65,42.11,29.80,20.39.[α]20 D＝-230.9(c＝0.6,CHCl3).
拆分条件:Daicel Chiralpak IE column；hexane/2-propanol＝95/5,0.3mL/min.Retention times:22.34min(major),28.09min(minor).
上述的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 (7)

1.一种类轴手性酰苯胺类化合物的制备方法，其特征在于，所述类轴手性酰苯胺类化合物通过底物1、底物2和手性膦配体进行去对称化的sonogashira偶联反应，得到类轴手性酰苯胺类化合物3，反应过程为：
Figure DEST_PATH_IMAGE002
其中：
R1为F、Cl、Br、C1～C12的烷烃基、苯基、取代苯基中的一种；
R2为环烷基、苯基、取代苯基中的一种；
R3为C1～C12的烷烃基、烯基、苯基、取代苯基、萘基、取代萘基、五元杂环基中的一种；
所述手性膦配体为以下中的一种或多种的混合物：
Figure DEST_PATH_IMAGE004
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE010
；
反应所采用的催化剂为钯盐催化剂和铜盐催化剂。
2.根据权利要求1中所述类轴手性酰苯胺类化合物的制备方法，其特征在于，进行去对称化的sonogashira偶联反应过程中： 先将钯盐催化剂与手性膦配体在溶剂中预先搅拌30min～1h，随后加入铜盐催化剂、底物1、底物2和碱，在反应温度下搅拌进行偶联反应，得到类轴手性酰苯胺类化合物3。
3.根据权利要求2中所述类轴手性酰苯胺类化合物的制备方法，其特征在于，所述底物1和底物2的投料摩尔比为1:1～5；所述钯盐催化剂的投料摩尔用量为底物1的投料摩尔用量的5％～50％； 所述手性膦配体的摩尔用量与钯盐催化剂摩尔用量之比为1:1～3；所述铜盐催化剂的投料摩尔用量为底物1的投料摩尔用量1％～20％；所述碱的摩尔用量与底物1摩尔用量之比为1:1.1～3。
4.根据权利要求1中所述类轴手性酰苯胺类化合物的制备方法，其特征在于，所述钯盐催化剂为Pd(OAc)2、Pd(TFA)2、Pd2(dba)3、Pd2(dba)3·CHCl3、Pd(dba)2、PdCl2中的一种或多种；
所述铜盐催化剂为CuCl、CuBr、CuI、CuBr·SMe2、CuTc、Cu(CH3CN)4PF6、Cu(CH3CN)4BF4、CuCl2、CuBr2、CuF2、Cu(OTf)2、Cu(acac)2中一种或多种。
5.根据权利要求2中所述类轴手性酰苯胺类化合物的制备方法，其特征在于，所述碱为醋酸铯、碳酸钾、碳酸钠、碳酸铯、N，N-二异丙基乙胺、1,4-二氮杂二环[2.2.2]辛烷、三乙胺中的一种。
6.根据权利要求2中所述类轴手性酰苯胺类化合物的制备方法，其特征在于，所述溶剂为四氢呋喃、乙腈、1,4-二氧六环、二氯甲烷、甲苯、乙酸乙酯中的一种。
7.根据权利要求2中所述类轴手性酰苯胺类化合物的制备方法，其特征在于，所述偶联反应的反应温度为0℃～25℃，所述偶联反应的反应时间为18h～108h。
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A New Type of Chiral Sulfinamide Monophosphine Ligands: Stereodivergent Synthesis and Application in Enantioselective Gold(I)-Catalyzed Cycloaddition Reactions;Zhang, Zhan-Ming etal;《 Angewandte Chemie, International Edition》;20140320;全文 *
Pd/Cu-Catalyzed Enantioselective Sequential Heck/Sonogashira Coupling:Asymmetric Synthesis of Oxindoles Containing Trifluoromethylated Quaternary Stereogenic Centers;xingfeng Bai etal;《Angewandte Chemie, International Edition》;20191030;全文 *
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