CN110776455A - 一种钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法 - Google Patents

一种钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法 Download PDF

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CN110776455A
CN110776455A CN201910902124.1A CN201910902124A CN110776455A CN 110776455 A CN110776455 A CN 110776455A CN 201910902124 A CN201910902124 A CN 201910902124A CN 110776455 A CN110776455 A CN 110776455A
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史炳锋
刘蕾
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Abstract

本发明公开了一种以钯催化羧酸导向的芳基化为合成大位阻的氨基酸及短肽的方法，此方法的特点是在反应过程中底物不消旋，因此产物可以直接作为配体参与不对称催化反应。其中，钯催化芳基化反应是以双保护L‑叔亮氨酸,以及含有L‑叔亮氨酸的短肽化合物为底物，芳基碘为芳基化试剂，在氨基酸的γ位引入芳基以此合成大位阻的氨基酸及多肽。此反应在六氟异丙醇溶剂下进行，以醋酸钯为金属催化剂，乙酰基叔亮氨酸为助剂，以磷酸银、碳酸钾为添加剂。本发明能够高效合成多种支链大位阻的氨基酸及短肽化合物，该化合物是具有高活性、高选择性的手性配体，该配体在应用中展现出了较高的手性诱导。

Description

一种钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基 酸或多肽的方法
技术领域
本发明涉及一种钯催化C-H键芳基化合成大位阻氨基酸和多肽的方法，属于导向的过渡金属催化的碳氢键活化领域。
背景技术
氨基酸是组成蛋白质的基本结构单元，在生命活动中起着重要的作用。值得一提的是，大位阻的氨基酸及多肽在有机催化及天然产物、药物分子中普遍存在。特别地，近年来对于大位阻氨基酸的合成与应用备受关注。双保护的氨基酸作为手性配体参与不对称催化反应迅速发展成为不对称碳氢键活化的热门领域。与此同时，手性二铑催化剂，最常用的配体也是支链位阻比较大的手性纯的叔亮氨酸或者金刚烷甘氨酸。这些催化剂普遍存在以下问题，如较局限的修饰位点，只能在天然氨基酸的基础之上变换不同保护集团，对于侧链的修饰比较困难，尤其是将其修饰为更大的结构时。因此发展新的方法来合成手性纯的大位阻氨基酸及多肽化合物就显得尤为重要。
最近，羧酸导向的碳氢键活化由于其不用预先安装导向基，原子经济性、步骤经济性高等优点受到大家广泛关注，早在2010年，于金权课题组报道了羧酸导向的C(SP2)-H不对称芳基化(B.-F.Shi,Y.-H.Zhang,J K. Lam,D.-H.Wang,J.-Q.Yu,J.Am.Chem.Soc.2010,132,460)，基于以上的研究该课题组又报道了α氨基酸的β位C-H键的芳基化(G.Chen,Z,Zhuang, G.-C.Li,T.G.Saint-Denis,Y.Hsiao,C.L.Joe,J.-Q.Yu.Angew.Chem.Int.Ed.2017,56,1506)。与此同时，大位阻双保护的手性纯的叔亮氨酸作为配体的应用取得了突破性的进展。2019年，Matsunaga课题组报道了一例三价钴催化，手性氢化降冰片烯保护的L-叔亮氨酸为配体的C(SP3)-H不对称氨化反应(S.Fukagawa,Y.Kato,R,Tanaka,M.Kojima,T.Yoshino,S, Matsunaga,Angew.Chem.Int.Ed.2019,131,1165)，在这篇文章中，值得一提的是，手性配体的支链位阻对反应的对映选择性有较大影响，且支链位阻越大，产物ee值越高。尽管这类配体开创性的实现了不对称转化，但也存在一定的问题，如有限的修饰范围。为了快速、高效的构建这一类大位阻氨基酸化合物，基于以上的研究背景我们发展了叔亮氨酸的芳基化反应方法，该方法可以拓展到二肽三肽化合物。通过芳基化反应合成了一系列大位阻氨基酸配体，对于氨基酸为配体催化的不对称反应的发展等都有重要意义。
发明内容
本发明的目的是提供一种以钯催化的芳基化反应合成大位阻的氨基酸及多肽的高效合成方法。该路线反应条件温和、操作简便、合成步骤较短，能够高效的合成的大位阻氨基酸及多肽，在反应过程中氨基酸及多肽并不消旋。
一种钯催化芳基化的方法，包括：
在钯催化剂、助剂和添加剂的作用下，N端双保护的L-叔亮氨酸，末端羧酸裸露的多肽与碘苯发生芳基化反应，反应结束后经过后处理得到N 端双保护的L-叔亮氨酸芳基化的产物，短肽芳基化的产物；
所述的添加剂由银盐和碱组成；
反应式如下(配体以乙酰基保护的叔亮氨酸为例)：
其中，R1独立地选自邻苯二甲酰基、取代的邻苯二甲酰基、1.8-二萘酰基、氢化降冰片烯二酰基或顺丁烯二酰基；
R2独立地选择烷氧羰基、酰基、烷氧基、卤素中的一个或多个；。
AA独立地选择氨基酸残基，
Figure BDA0002211684680000022
表示相互连接的两个或者两个以上的氨基酸残基；
本发明在反应过程中通过并不消旋，可以使得芳基化的产物具有 96％～99％ee值。
作为优选，R1独立地选自邻苯二甲酰基、取代的邻苯二甲酰基、1.8- 二萘酰基、氢化降冰片烯二酰基或顺丁烯二酰基；
R2独立地选择甲氧羰基、甲酰基、乙酰基、甲氧基、F、Cl、Br中的一个或多个。
AA独立地选择甘氨酸、L-缬氨酸、L-环己基甘氨酸、L-异亮氨酸、 L-亮氨酸、L-叔亮氨酸
作为优选，所述的钯催化剂为醋酸钯。
作为优选，所述的助剂为手性纯的乙酰基保护的氨基酸，优选为乙酰基保护的叔亮氨酸。
作为优选，所述的银盐为磷酸银、碳酸银、醋酸银、硝酸银、氧化银或三氟甲烷磺酸银；进一步优选为磷酸银。
所述的碱为碳酸钾、碳酸氢钾、碳酸铯、碳酸氢钠、磷酸二氢钠、磷酸氢二钠或磷酸钾；进一步优选为碳酸钾。
作为优选，反应在有机溶剂中进行，所述的有机溶剂为六氟异丙醇、醋酸、三氟乙醇或者其中的一种或几种；进一步优选为六氟异丙醇。
作为优选，反应温度为70℃，反应时间为48小时。
作为优选，氨基酸或者多肽、碘苯、钯催化剂、银盐、碱、助剂的摩尔比为1：3：0.1：1：1：0.3。
本发明的后处理方式优选为薄层硅胶板层析。
同现有技术相比，本发明的有益效果体现在：
(1)反应底物适用性广。
(2)反应条件温和，可以使产物不消旋具有很高的ee值。
(3)合成大位阻氨基酸及短肽效率高，在不对称催化氨化中体现出很高的活性，能够诱导出较高的ee。
附图说明
图1为实施例1得到的化合物1以及其消旋体的HPLC图谱，其中， HPLC图谱的条件为AD-H,n-hexane/2-propanol＝50/50,v＝0.5mL·min-1, λ＝254nm。
图2为化合物1’以及其消旋体的HPLC图谱。其中，HPLC图谱的条件为IC,n-hexane/2-propanol＝70/30,v＝0.8mL·min-1,λ＝254nm。
具体实施方式
以下结合具体实施例解释本发明，而不是对本发明进行限制。
实施例1
在反应器中，加入0.3毫摩尔邻苯二甲酰基保护的L型叔氨基酸、0.9 毫摩尔4-甲氧基碘苯、0.03毫摩尔醋酸钯催化剂、0.3毫摩尔磷酸银、0.3 毫摩尔乙酰基叔亮氨酸、0.3毫摩尔碳酸钾和3毫升六氟异丙醇，在70℃空气气氛中反应24小时后结束反应进行后处理，通过薄层硅胶板层析得到产物1和产物1’产率分别为58％、10％，ee值为99％、96％。化合物1、 1’以及其消旋体的HPLC图谱见图1、图2。
产物1结构如下(其中，Phth为邻苯二甲酰基)：
Figure BDA0002211684680000041
结构表征数据如下：
1H NMR(400MHz,CDCl3)δ7.92–7.82(m,2H),7.79–7.70(m,2H), 7.09(d,J＝8.6Hz,2H),6.82(d,J＝8.6Hz,2H),4.86(s,1H),3.79(s,3H), 3.01(d,J＝13.3Hz,1H),2.83(d,J＝13.3Hz,1H),1.17(s,3H),1.01(s,3H). 13C NMR(101MHz,CDCl3)δ172.84,168.21,158.29,134.44,131.98, 131.76,129.98,123.81,113.47,59.25,55.33,44.68,39.48,24.89,24.76. HRMS(EI-TOF)calcd for C22H21NO5(M-H+):366.1347,found:366.1347.
化合物1ee值的测定:HPLC with a Daicel Chiralpak AD-H, n-hexane/2-propanol＝50/50,v＝0.5mL·min-1,λ＝254nm,t(minor)＝18.0 min,t(major)＝22.6min,99％ee；
产物1’结构如下：
Figure BDA0002211684680000042
1H NMR(400MHz,CDCl3)δ7.89–7.78(m,2H),7.76–7.70(m,2H), 7.16(d,J＝8.5Hz,2H),7.07(d,J＝8.5Hz,2H),6.90–6.78(m,4H),5.02(s, 1H),3.7997(s,3H),3.7993(s,3H),3.47(d,J＝13.7Hz,1H),3.39(d,J＝13.4 Hz,1H),3.18(d,J＝13.5Hz,1H),2.54(d,J＝13.6Hz,1H),0.87(s,3H).13C NMR(101MHz,CDCl3)δ173.82,168.25,158.38,158.11,134.40,132.30, 131.71,131.67,130.07,129.58,123.74,113.81,113.31,56.65, 55.31,55.26,42.75,42.39,42.04,22.74.HRMS(EI-TOF)calcd for C28H27NO6(M-H+):472.1765,found:472.1767.
化合物1’ee值的测定，通过将化合物1’中的羧酸衍生为羧酸苄酯: HPLC with aDaicel Chiralpak IC,n-hexane/2-propanol＝70/30,v＝0.8 mL·min-1,λ＝254nm,t(minor)＝9.8min,t(major)＝14.6min,96.2％ee；
实施例2～15
操作步骤同实施例1，区别在于：改变原料碘苯上的取代基，则可以得到不同的芳基化的产物(见表1)。
表1实施例2～15合成大位阻氨基酸的实验结果
Figure DEST_PATH_IMAGE001
实施例16
加入0.3毫摩尔L型3-溴邻苯二甲酰基叔氨基酸、0.9毫摩尔4-甲氧基碘苯、0.03毫摩尔醋酸钯催化剂、0.3毫摩尔磷酸银、0.3毫摩尔乙酰基叔亮氨酸、0.3毫摩尔碳酸钾和3毫升六氟异丙醇，在70℃空气气氛中反应24小时后结束反应进行后处理，通过薄层硅胶板层析得到产物16和产物16’产率分别为61％、15％。
产物16结构如下：
Figure BDA0002211684680000071
产物表征数据如下：
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.87(d,J＝7.7,1H),7.72(d, J＝7.9Hz,1H),7.08(d,J＝8.2Hz,2H),6.82(d,J＝8.1Hz,2H),4.83(s,1H), 3.79(s,3H),3.00(d,J＝13.3Hz,1H),2.81(d,J＝13.3Hz,1H),1.16(s,3H), 0.99(s,3H).13C NMR(101MHz,CDCl3)δ173.09,167.22,166.68, 158.17,137.32,134.29,133.23,131.82,130.11,129.69,129.31,127.04, 125.04,123.67,113.36,55.20,44.56,39.34,28.01,24.78,24.64.HRMS(EI-TOF)calcd for C21H20BrNO5(M-H+):444.0452,found:444.0452.
产物16’结构如下：
Figure BDA0002211684680000072
产物表征数据如下
1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.86(d,J＝7.9Hz,1H),7.69 (d,J＝7.9Hz,1H),7.15(d,J＝8.2Hz,2H),7.05(d,J＝8.2Hz,2H),6.82(dd, J＝8.5,2.4Hz,4H),4.98(s,1H),3.79(s,3H),3.78(s,3H),3.44(d,J＝13.7 Hz,1H),3.35(d,J＝13.5Hz,1H),3.12(d,J＝13.5Hz,1H),2.54(d,J＝13.7 Hz,1H),0.85(s,3H).13C NMR(101MHz,CDCl3)δ173.30,167.42,166.89, 158.48,158.23,137.42,133.36,132.30,131.72,130.23,129.95,129.50, 129.42,127.11,125.11,113.87,113.40,56.96,55.34,55.30,42.80, 42.47,42.09,22.78.HRMS(EI-TOF)calcd for C28H26BrNO6(M-H+): 550.0871,found:550.0870.
实施例16～24
17-24操作步骤同实施例16，区别在于：改变叔亮氨酸的保护基，则可以得到不同保护基的叔亮氨酸芳基化的产物(见表2，NPG的结构见表 2)。
表2实施例16～24合成不同保护基团的大位阻氨基酸的实验结果
Figure DEST_PATH_IMAGE002
实施例25
在50mL反应器中，加入0.1毫摩尔甘氨酸-L-叔亮氨酸的二肽、0.3 毫摩尔4-碘苯甲酸甲酯、0.015毫摩尔醋酸钯催化剂、0.1毫摩尔硫酸银、 0.1毫摩尔乙酰基叔亮氨酸、0.1毫摩尔碳酸钾和1毫升六氟异丙醇，在70℃空气气氛中反应24小时后结束反应进行后处理，通过薄层硅胶板层析得到产物25和产物25’产率分别为42％、11％。
产物25结构如下：
Figure BDA0002211684680000082
1H NMR(400MHz,CDCl3)δ7.87(d,J＝7.6Hz,2H),7.82–7.78(m, 2H),7.72–7.59(m,2H),7.17(d,J＝7.9Hz,2H),6.79–6.58(b,1H),4.59– 4.36(m,3H),3.87(s,3H),2.66(s,2H),0.99(s,3H).0.97(s,3H).13C NMR (101MHz,CDCl3)δ173.94,168.09,167.37,167.12,143.17,134.43, 131.91,131.00,129.25,128.21,123.74,60.21,52.20,44.55,40.71,38.49, 23.66,23.22.HRMS(EI-TOF)calcd for C24H24N2O7(M-H+):451.1511, found:451.1512.
产物25’结构如下：
Figure BDA0002211684680000091
1H NMR(400MHz,CDCl3)δ7.88(d,J＝4.4Hz,2H),7.86(d,J＝4.3 Hz,2H),7.81–7.76(m,2H),7.66–7.59(m,2H),7.22(d,J＝8.0Hz,2H), 7.15(d,J＝8.1Hz,2H),7.08(d,J＝8.4Hz,1H),4.53(d,J＝8.6Hz,1H), 4.47(d,J＝16.3Hz,1H),4.35(d,J＝16.3Hz,1H),3.88(s,3H),3.87(s,3H), 3.00(d,J＝13.1Hz,1H),2.87(d,J＝13.1Hz,1H),2.72(d,J＝13.2Hz,1H), 2.51(d,J＝13.1Hz,1H),0.84(s,3H).13C NMR(101MHz,CDCl3)δ173.74,168.03,167.54,167.11,142.54,142.40,134.45,131.92,131.28,131.09, 129.52,129.48,128.66,128.60,126.02,123.79,58.08,52.23,52.21, 42.48,41.80,40.71,21.91.HRMS(EI-TOF)calcd for C32H30N2O9(M-H+): 585.1878,found:585.1877.
实施例26～32
26-32操作步骤同实施例25，区别在于：改变短肽的种类，则可以得到不同短肽的芳基化产物(见表3)。
表3实施例26～32短肽芳基化的实验结果
Figure DEST_PATH_IMAGE003

Claims (8)

1.一种钯催化的羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法，其特征在于，包括：
在钯催化剂、助剂和添加剂的作用下，N端双保护的L-叔亮氨酸，末端羧酸裸露的多肽与碘苯发生芳基化反应，反应结束后经过后处理得到N端双保护的L-叔亮氨酸芳基化的产物，多肽芳基化的产物；
所述的添加剂由银盐和碱组成；
反应式如下：
其中，R1独立地选自取代或者未取代的邻苯二甲酰基、1.8-二萘酰基、氢化降冰片烯二酰基或顺丁烯二酰基；
R2独立地选择烷氧羰基、酰基、烷氧基、卤素中的一个或多个；
AA独立地为氨基酸残基。
2.根据权利要求1所述的钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法，其特征在于，R2独立地选择甲氧羰基、甲酰基、乙酰基、甲氧基、F、Cl、Br中的一个或多个。
3.根据权利要求1所述的钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法，其特征在于，所述的钯催化剂为醋酸钯。
4.根据权利要求1所述的钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法，其特征在于，所述的助剂为乙酰基保护的氨基酸。
5.根据权利要求1所述的钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法，其特征在于，所述的银盐为磷酸银、碳酸银、醋酸银、硝酸银、氧化银或三氟甲烷磺酸银；
所述的碱为碳酸钾、碳酸氢钾、碳酸铯、碳酸氢钠、磷酸二氢钠、磷酸氢二钠或磷酸钾。
6.根据权利要求1所述的钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法，其特征在于，反应在有机溶剂中进行，所述的有机溶剂为六氟异丙醇、醋酸、三氟乙醇中的一种或几种。
7.根据权利要求1所述的钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法，其特征在于，反应温度为60～80℃，反应时间为12～24小时。
8.根据权利要求1所述的钯催化羧酸导向的γ-C(sp3)-H键芳基化合成大位阻氨基酸或多肽的方法，其特征在于，氨基酸或者多肽、碘苯、钯催化剂、银盐、碱、助剂的摩尔比为1：3：0.1：1：1：0.3。
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Publication number Priority date Publication date Assignee Title
CN113527121A (zh) * 2021-06-09 2021-10-22 河北科技大学 一种C(sp3)-C(sp2)键的构建方法与β-芳基氨基酸的制备方法
CN113731506A (zh) * 2021-09-28 2021-12-03 常州大学 杯[4]芳烃酰胺化合物协助钯催化脂肪醛c-h芳基化反应的方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113527121A (zh) * 2021-06-09 2021-10-22 河北科技大学 一种C(sp3)-C(sp2)键的构建方法与β-芳基氨基酸的制备方法
CN113527121B (zh) * 2021-06-09 2023-01-17 河北科技大学 一种C(sp3)-C(sp2)键的构建方法与β-芳基氨基酸的制备方法
CN113731506A (zh) * 2021-09-28 2021-12-03 常州大学 杯[4]芳烃酰胺化合物协助钯催化脂肪醛c-h芳基化反应的方法
CN113731506B (zh) * 2021-09-28 2023-05-26 常州大学 杯[4]芳烃酰胺化合物协助钯催化脂肪醛c-h芳基化反应的方法

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