CN110437022B - 一种联苯类轴手性化合物及其合成方法 - Google Patents

一种联苯类轴手性化合物及其合成方法 Download PDF

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CN110437022B
CN110437022B CN201910711599.2A CN201910711599A CN110437022B CN 110437022 B CN110437022 B CN 110437022B CN 201910711599 A CN201910711599 A CN 201910711599A CN 110437022 B CN110437022 B CN 110437022B
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朱庭顺
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李文长
朱劭恒
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National Sun Yat Sen University
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Abstract

本发明公开了一种联苯类轴手性化合物及其合成方法，其结构如下所示：其中R1为芳香取代基，包括邻位、间位、对位取代和给电子、吸电子、卤素取代苯基；R2为芳香取代基，包括邻位、间位、对位取代和给电子、吸电子、卤素取代苯基；R3为芳香基或甲基取代基；R4为邻位吸电子基单取代或多取代基团。本发明建立了一种氮杂环卡宾有机小分子催化分子间[4+2]环加成形成阻转异构体芳烃的方法，制备得到了联苯类轴手性化合物。起始原料均易制备，实现了底物远距离反应位点的活化，一步构建出联苯类轴手性化合物，立体选择性表现优秀。本发明所制得的联苯类轴手性化合物可进行简单转化得到轴手性有机小分子配体，具有广泛的催化、配体应用前景。

Description

一种联苯类轴手性化合物及其合成方法
技术领域
本发明涉及一种联苯类轴手性化合物及其合成方法。
背景技术
阻转异构体芳烃化合物是一种具有限制旋转单键的特殊结构，广泛存在于天然产物、药物分子、催化剂和功能分子中(Nat.Prod.Rep.2015,32,1562-1583；J.Med.Chem.2011,54,7005-7022；Chem.Rev.2005,105,857-897)。随着人们对此类化合物的重视程度日益增加，开发合成轴手性分子的新方法也越来越有研究价值。迄今为止，最先进的几种合成阻转异构体芳烃的方法总结在图1中，主要包括通过金属催化交叉偶联对芳烃进行不对称修饰(Coord.Chem.Rev.2016,308, 131-190；Angew.Chem.Int.Ed.2018,57,12901-12905)、芳环的亲电取代反应(J. Am.Chem.Soc.2015,137,15062-15065；Angew.Chem.Int.Ed.2017,56,116-121； Nat.Chem.2018,10,58-64；Nat.Catal.2019,2,314-323)、由点手性-轴手性转移 (J.Am.Chem.Soc.2011,133,18-20；J.Am.Chem.Soc.2017,139,2140-2143)、去对称化取代(J.Am.Chem.Soc.2015,137,6766-6769；Angew.Chem.Int.Ed. 2018,57,17151-17155；ACS Catal.2019,9,4951-4957)、动力学拆分(Chem.Eur. J.2015,21,11644-11657；Angew.Chem.Int.Ed.2019,58,4596-4600)和一些其他方法(Nat.Chem.2017,9,558-562；J.Am.Chem.Soc.2018,140,7056-7060)。这类方法基于反应底物中已存在的芳香基团进行修饰、改造等来构建出手性轴。发展时间长但应用有所限制。
相对而言，通过重建芳环制备阻转异构体的方法较少被人们所研究。通常来说，过渡金属催化不对称[2+2+2]环加成反应几乎是合成阻转异构体芳烃的唯一方法(Chem.Soc.Rev.2011,40,3430-3444；Asian J.Org.Chem.2018,7, 1706-1718)。近年来，Sparr教授课题组发展了一类手性胺催化分子内aldol缩合反应用于阻转异构体芳烃的构建(Angew.Chem.Int.Ed.2014,53,5458-5461； Angew.Chem.Int.Ed.2016,55,7261-7264)。该类反应中的底物设计巧妙，所以在应用时对底物α，β-不饱和醛酮的合成要求较高。因此，开发简单高效适用性广泛的合成轴手性化合物新方法是重建芳烃领域中值得研究的课题。
发明内容：
本发明的目的是克服现有技术的不足，提供一种联苯类轴手性化合物及其合成方法。
为了实现上述目的，本发明采用如下技术方案：
一种联苯类轴手性化合物，其结构如下所示：
Figure BDA0002153962620000022
其中R1为芳香取代基，包括邻位、间位、对位取代和给电子、吸电子、卤素取代苯基；R2为芳香取代基，包括邻位、间位、对位取代和给电子、吸电子、卤素取代苯基；R3为芳香基或甲基取代基；R4为邻位吸电子基单取代或多取代基团。
在上述的联苯类轴手性化合物中，作为优选的：
R1选自Ph、-Cl-Ph、-Br-Ph、-CF3-Ph、-OCH3-Ph、-CH3-Ph、-CH3-Ph、-CH3-Ph、 -Naphyl；
R2选自Ph、-Cl-Ph、-F-Ph、-CH3-Ph、-Cl-Ph、-Cl-Ph；
R3选自-CH3、-CH3-Ph、-CF3-Ph、-Br-Ph、-NO2-Ph、-NO2-Ph、-pyridyl、 -thiophenyl、-CN-Ph、-CF3-Ph、-Cl-Ph；
R4选自-NO2、-CH3、-CF3、-NO2(pyridyl)、-CN、-Br、-POPh2。
上述联苯类轴手性化合物的合成方法，包括如下步骤：在氮气条件下，将底物1和底物2溶于N-甲基吡咯烷酮和叔丁醇的混合溶剂中，加入催化剂C1，氧化剂B和有机碱1,4-二氮杂二环[2.2.2]辛烷(DABCO)在60℃的温度下搅拌8～ 18小时得到相应产物3；反应结构式如下所示：
Figure BDA0002153962620000031
其中R1、R2、R3、R4如前所述。上述反应中所得到的联苯类轴手性化合物 3的对映立体选择性比例(ee)可以达到90％～99％。光学纯度由高效液相色谱 (HPLC)和超高效合相色谱(UPCC)测得。
取代基R4的吸电子作用越强时，底物2中酮羰基的α-位越易发生去质子化，反应活性越高，所得产物的产率即越高。其中邻位取代基可替换成其他具有吸电子作用的基团，对该反应的立体选择性无影响。
本发明中，通过对底物基团的调控可实现在使用同一构型催化剂、同一催化反应条件时获得相反构型的轴手性化合物，如下反应式：
Figure BDA0002153962620000041
本发明得到的含硝基轴手性化合物可在铁、盐酸作用下还原为氨基，制得轴手性氨基化合物。氨基可进一步进行衍生化得到轴手性脲、硫脲催化剂、草酰二胺轴手性配体，立体选择性均保持不变。反应式如下：
Figure BDA0002153962620000042
当R4为氰基时，可还原制得轴手性羰基有机小分子催化剂，立体选择性保持不变。反应式如下：
Figure BDA0002153962620000051
取代基R4为二苯基磷氧基时，可还原得到轴手性有机磷配体，立体选择性保持不变。反应式如下：
Figure BDA0002153962620000052
与现有技术相比，本发明具有如下有益效果：本发明建立了一种氮杂环卡宾有机小分子催化分子间[4+2]环加成形成阻转异构体芳烃的方法，制备得到了联苯类轴手性化合物。本发明中所需的起始原料均易制备，实现了底物远距离反应位点的活化，一步构建出联苯类轴手性化合物，同时立体选择性表现优秀。在反应中即使是手性轴两侧的位阻基团相似的情况下仍可得到专一立体选择性的联苯类轴手性化合物。本发明方法中所制得的联苯类轴手性化合物可进行简单转化得到轴手性有机小分子配体，具有广泛的催化、配体应用前景。手性脲、硫脲催化剂小分子具有多氢键配位点，与底物通过氢键作用结合实现手性控制，从2003年Takemoto课题组(J.Am.Chem.Soc.2003,125,12672–12673) 第一次使用具有中心手性胺机构的硫脲作为双功能化催化剂催化Michael反应实现了高效的立体选择性之后，发展了更多不同手性结构的脲、硫脲小分子并在许多催化体系中已经达到了很好的效果(ChemCatChem 2017,9,718–727)。马大为教授课题组开发了一类新型的草酰二胺双齿配体，并高效应用于金属催化偶联反应中(Angew.Chem.Int.Ed.2017,56,16136–16179；J.Am.Chem.Soc. 2019,141,3541-3549)。本发明制得该配体的轴手性化合物，具有潜在的应用价值。羰基化合物大多是作为反应底物存在，近年来研究者们发现羰基化合物通过不同的活化模式作用同样也可以作为催化剂存在于复杂的反应体系中(Angew.Chem.Int.Ed.2019,58,6818–6825)，不需要额外的保护和去保护操作羰基可以直接活化底物胺的α-位活性(Science 2018,360,1438–1442)。利用本发明可经过两步转化得到轴手性羰基化合物用于小分子催化。碳-氮偶联反应在药学、杂环合成、天然产物全合成中使用频率高，应用广泛，双芳基磷配体在钯催化碳- 氮偶联反应中有着独特优异的催化活性(Angew.Chem.Int.Ed.2008,47,6338– 6361；J.Am.Chem.Soc.2018,140,4721-4725)，轴手性磷配体在此类偶联反应时同样有着极高的应用价值。
附图说明：
图1为阻转异构体芳烃的传统合成方法。
具体实施方式：
实施例1：(R)-3a的合成：
在氮气条件下，将底物1a(58.5mg，0.25mmol)和底物2a(17.9mg，0.1 mmol)溶于1ml N-甲基吡咯烷酮和0.5ml叔丁醇的混合溶剂中，加入催化剂 C1(7.4mg，20mol％)，氧化剂B(142mg，0.35mmol)和有机碱1,4-二氮杂二环[2.2.2]辛烷(DABCO，6mg，0.05mmol))在60℃的温度下搅拌12小时。反应完全后，混合液加入乙酸乙酯和饱和氯化铵溶液萃取，水洗，饱和食盐水洗，干燥，减压蒸馏除去溶剂后进行柱层析分离得到产物3a。
Figure BDA0002153962620000061
133.4,132.7,129.4,128.9,128.2,127.9,127.9,127.6,127.3,126.8,126.6,124.4,20.9ppm.
实施例2：(R)-3b的合成：
将底物1换成R1＝4-Cl-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000071
127.7,126.9,126.3,124.4,20.9ppm.
实施例3：(R)-3c的合成：
将底物1换成R1＝4-Br-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000072
ppm.
实施例4：(R)-3d的合成：
将底物1换成R1＝4-CF3-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000073
JC-F＝4Hz),124.4,123.1(q,JC-F＝271Hz),20.9ppm.
实施例5：(R)-3e的合成：
将底物1换成R1＝4-OCH3-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000081
127.9,127.5,126.8,126.1,124.3,114.4,55.5,20.3ppm.
实施例6：(R)-3f的合成：
将底物1换成R1＝4-CH3-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000082
126.8,126.3,124.3,21.3,20.9ppm.
实施例7：(R)-3g的合成：
将底物1换成R1＝3-CH3-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000083
127.9,127.9,126.8,126.6,124.4,124.3,21.7,20.9ppm.
实施例8：(R)-3h的合成：
将底物1换成R1＝2-CH3-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000091
128.6,128.1,127.8,127.5,126.7,125.9,124.3,20.8,20.8ppm.
实施例9：(R)-3i的合成：
将底物1换成R1＝1-Naphyl，其余实验操作参照实施例1。
Figure BDA0002153962620000092
134.0,133.5,132.7,131.7,130.9,129.5,129.4,128.4,128.2,127.9,127.8,127.2,126.8,126.3,126.2,126.0,125.5,124.4,20.9ppm.
实施例10：(R)-3j的合成：
将底物1换成R2＝4-Cl-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000093
136.5,135.5,135.4,133.2,133.0,132.9,130.7,129.0,128.4,128.3,128.1,127.7,127.3,126.4,124.5,20.9ppm.
实施例11：(R)-3k的合成：
将底物1换成R2＝4-F-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000101
CDCl3)δ163.1(d,JC-F＝244Hz),149.5,140.9,140.5,137.2(d,JC-F＝3Hz),136.4, 135.7,135.6,133.3,132.8,131.0,130.9,128.9,128.3,128.1,127.7,127.3,126.6, 124.4,114.9(d,JC-F＝21Hz),20.9ppm；19F NMR(376MHz,CDCl3)δ-115.53.
实施例12：(R)-3l的合成：
将底物1换成R2＝4-CH3-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000102
138.3,136.4,136.3,135.9,135.6,133.4,132.7,129.2,128.9,128.6,128.1,127.7,127.6,127.3,126.7,124.4,21.2,20.9ppm.
实施例13：(R)-3m的合成：
将底物1换成R2＝3-Cl-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000111
MHz,CDCl3)δ149.5,143.1,141.0,140.4,140.1,136.5,135.5,135.3,133.7,133.2,132.8,129.5,129.1,129.0,128.5,128.4,127.7,127.6,127.3,127.0,126.4,124.4,20.8ppm.
实施例14：(R)-3n的合成：
将底物1换成R2＝2-Cl-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000112
140.0,138.5,136.4,136.2,135.2,133.6,133.1,132.9,132.4,132.2,131.0,129.8,129.0,128.9,128.8,128.3,127.6,127.3,127.0,126.5,126.4,125.6,124.7,124.1,21.3,20.7ppm.
实施例15：(S)-3o的合成：
将底物2换成R3＝4-CH3-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000113
141.0,140.9,140.4,138.0,136.6,136.0,134.7,132.2,129.6,129.5,129.0,128.8,128.3,128.0,128.0,127.8,127.7,127.4,126.9,124.2,21.3ppm.
实施例16：(S)-3p的合成：
将底物2换成R3＝4-CF3-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000121
129.9,129.6,129.1,128.9,128.2,128.1,128.0,127.4,127.2,125.6(q,JC-F＝271Hz),125.0(q,JC-F＝4Hz),124.4ppm；19F NMR(376MHz,CDCl3)δ-62.49；.
实施例17：(S)-3q的合成：
将底物2换成R3＝4-Br-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000122
141.1,140.6,140.5,140.1,140.0,135.4,134.5,134.5,132.4,131.2,129.6,129.0,128.5,128.0,127.9,127.3,127.1,124.3,121.4ppm.
实施例18：(S)-3r的合成：
将底物2换成R3＝4-NO2-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000123
141.4,140.2,139.8,139.5,134.9,134.5,134.4,132.6,130.5,129.5,129.4,129.1,128.4,128.2,127.8,127.4,127.3,124.5,123.3ppm.
实施例19：(S)-3s的合成：
将底物2换成R3＝3-NO2-Ph，其余实验操作参照实施例1。
Figure BDA0002153962620000131
CDCl3)δ149.6,147.9,142.7,142.2,141.5,140.4,139.8,139.2,135.7,134.8,134.6,134.4,132.6,129.6,129.2,129.1,129.1,128.4,128.1,127.9,127.4,127.3,124.4,124.4,122.1ppm.
实施例20：(S)-3t的合成：
将底物2换成R3＝3-pyridyl，其余实验操作参照实施例1。
Figure BDA0002153962620000132
CDCl3)δ149.6,147.8,142.1,141.4,140.4,139.9,137.8,137.3,137.0,134.9,134.8,134.5,132.5,129.5,129.1,129.1,128.4,128.2,128.1,128.1,127.4,127.2,124.4,123.2ppm.
实施例21：(S)-3u的合成：
将底物2换成R3＝2-thiophenyl，其余实验操作参照实施例1。
Figure BDA0002153962620000141
(100MHz,CDCl3)δ149.7,142.3,142.1,141.1,140.8,140.1,135.5,134.9,134.3, 132.5,129.5,129.0,128.7,128.6,128.3,128.0,127.9,127.4,127.4,127.1,127.0, 126.4,124.3ppm.
实施例22：(R)-3v的合成：
将底物2换成R4＝2-NO2,4-CH3，其余实验操作参照实施例1。
Figure BDA0002153962620000142
133.6,133.1,132.8,129.4,128.9,127.9,127.9,127.6,127.3,126.8,126.6,124.7,21.0,20.9ppm.
实施例23：(R)-3w的合成：
将底物2换成R4＝2-NO2,4-CF3，其余实验操作参照实施例1。
Figure BDA0002153962620000143
134.5,134.2,131.3(q,JC-F＝34Hz),129.3,129.0,129.0,128.1,127.8,127.3,127.2,126.8,124.3(q,JC-F＝271Hz),121.8(q,JC-F＝4Hz),20.9ppm；19F NMR(376MHz, CDCl3)δ-62.81.
实施例24：(R)-3x的合成：
将底物2换成R4＝2,4-NO2，其余实验操作参照实施例1。
Figure BDA0002153962620000151
141.8,141.3,140.4,140.1,135.8,134.9,133.6,129.3,129.0,128.2,128.2,127.9,127.4,127.3,126.8,126.6,119.9,20.8ppm.
实施例25：(R)-3y的合成：
将底物2换成R4＝2-NO2(pyridyl)，其余实验操作参照实施例1。
Figure BDA0002153962620000152
132.8,129.3,129.0,128.2,128.2,127.9,127.6,127.4,127.3,126.8,20.8ppm.
实施例26：(R)-3z的合成：
将底物2换成R4＝2-CN，其余实验操作参照实施例1。
Figure BDA0002153962620000153
129.7,128.9,128.1,127.7,127.6,127.4,127.3,126.7,118.2,114.0,20.8ppm.
实施例27：(R)-3z1的合成：
将底物2换成R4＝2-CF3,4-NO2，其余实验操作参照实施例1。
Figure BDA0002153962620000161
140.8,140.3,136.5,134.8,134.5,131.3(q,JC-F＝31Hz),129.7,129.0,127.9,127.9,127.7,127.3,127.1,126.7,125.6,124.1(q,JC-F＝273Hz),122.4(q,JC-F＝6Hz), 21.0ppm；19F NMR(376MHz,CDCl3)δ-60.19.
实施例28：(S)-3z2的合成：
将底物2换成R3＝4-CN-Ph，R4＝2-Br,4-NO2其余实验操作参照实施例1。
Figure BDA0002153962620000162
CDCl3)δ147.4,147.2,145.5,142.8,142.2,140.5,140.2,139.6,135.1,133.9,131.8,130.3,129.4,129.3,129.2,128.4,128.2,127.9,127.7,127.6,127.4,125.6,121.5,118.7,111.3ppm.
实施例29：(S)-3z3的合成：
将底物2换成R3＝4-CF3-Ph，R4＝2-POPh2其余实验操作参照实施例1。
Figure BDA0002153962620000171
145.9,145.2,142.5(d,JC-P＝51Hz),140.9,140.5(d,JC-P＝25Hz),135.8(d,JC-P＝11 Hz),134.2(d,JC-P＝13Hz),132.0,131.9,131.6,131.6,131.5,131.4,130.9,130.4, 130.1,128.8,128.5,128.4(d,JC-P＝3Hz),128.3(d,JC-P＝3Hz),127.8,127.5,127.5, 127.4,126.3,126.1,125.8(q,JC-F＝270Hz),124.2(q,JC-F＝3Hz)ppm；19F NMR (376MHz,CDCl3)δ-62.16；31P NMR(162MHz,CDCl3)δ29.42.
实施例30：(S)-3z4的合成：
将底物2换成R3＝4-Cl-Ph，R4＝2-NO2其余实验操作参照实施例1。
Figure BDA0002153962620000172
CDCl3)δ149.6,141.9,141.1,140.7,140.5,140.1,139.5,135.5,134.6,134.5,133.2,132.4,130.9,129.6,129.0,128.5,128.3,128.1,128.0,128.0,127.9,127.4,127.1,124.3ppm.
淡黄色固体(R)-4
Figure BDA0002153962620000173
128.2,128.2,127.7,127.5,127.3,127.0,126.7,125.8,118.3,115.0,20.7ppm.
白色固体(R)-5
Figure BDA0002153962620000181
132.4,132.2,132.1,129.4,129.1,128.9,128.5,128.0,127.9,127.1,127.1,127.0,124.9,124.6(q,JC-F＝271Hz),122.5,118.8,116.3,21.1ppm；19F NMR(376MHz, CDCl3)δ-63.03.
白色固体(R)-6
Figure BDA0002153962620000182
133.9,133.3,132.0,131.6,129.9,129.2,129.0,128.9,128.1,127.9,127.4,127.3,127.1,127.0,124.6,124.5(q,JC-F＝271Hz),123.3,118.6,21.4ppm；19F NMR(376 MHz,CDCl3)δ-62.94.
白色固体(R)-7
Figure BDA0002153962620000183
130.8,129.4,128.9,128.6,128.4,127.8,127.7,127.4,127.2,126.9,124.9,120.0,21.0ppm.
黄色油状液体(R)-8
Figure BDA0002153962620000191
132.1,129.7,129.0,128.0,128.0,127.8,127.7,127.3,127.3,126.8,126.5,21.6ppm.
白色固体(S)-9
Figure BDA0002153962620000192
CDCl3)δ145.8,145.4,143.4,141.8,141.6,140.5(d,JC-P＝21Hz),137.7(d,JC-P＝5 Hz),137.6(d,JC-P＝4Hz),137.1(d,JC-P＝12Hz),135.4(d,JC-P＝3Hz),133.9(d,JC-P＝20Hz),133.3,133.3,133.2,130.8,130.3,129.0,129.0,128.3,128.2,128.2,128.1, 127.8,127.6,127.5,127.3,126.4,125.8(q,JC-F＝270Hz),124.5(q,JC-F＝3Hz)ppm；19F NMR(376MHz,CDCl3)δ-62.26；31P NMR(162MHz,CDCl3)δ-14.67.
实施例1-30的汇总表如表1所示。
表1氮杂环卡宾不对称催化[4+2]环加成反应构建的轴手性化合物
Figure BDA0002153962620000201

Claims (2)

1.一种联苯类轴手性化合物，其结构如下所示：
Figure FDA0002808004580000011
其中R1选自Ph、4-Cl-Ph、4-Br-Ph、4-CF3-Ph、4-OCH3-Ph、4-CH3-Ph、3-CH3-Ph、2-CH3-Ph、1-萘基；
R2选自Ph、4-Cl-Ph、4-F-Ph、4-CH3-Ph、3-Cl-Ph、2-Cl-Ph；
R3选自-CH3、4-CH3-Ph、4-Br-Ph、4-NO2-Ph、3-NO2-Ph、3-吡啶、2-苯硫基、4-CN-Ph、4-CF3-Ph、4-Cl-Ph；
R4选自2-NO2、2-NO2-4-CH3、2-CF3-4-NO2、2-CN、2-Br-4-NO2、2-POPh2。
2.权利要求1所述联苯类轴手性化合物的合成方法，其特征在于包括如下步骤：在氮气条件下，将底物1和底物2溶于N-甲基吡咯烷酮和叔丁醇的混合溶剂中，N-甲基吡咯烷酮和叔丁醇的体积比为2:1，加入20mol％的催化剂C1，氧化剂B和0.5当量的有机碱1,4-二氮杂二环[2.2.2]辛烷在60℃的温度下搅拌8～18小时得到相应产物3；反应结构式如下所示：
Figure FDA0002808004580000012
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