CN111662158A - 一种轴手性联芳基化合物及手性芴醇化合物的制备方法 - Google Patents

一种轴手性联芳基化合物及手性芴醇化合物的制备方法 Download PDF

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CN111662158A
CN111662158A CN202010617082.XA CN202010617082A CN111662158A CN 111662158 A CN111662158 A CN 111662158A CN 202010617082 A CN202010617082 A CN 202010617082A CN 111662158 A CN111662158 A CN 111662158A
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CN111662158B (zh
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周强辉
刘泽水
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Wuhan University WHU
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Abstract

本发明公开了一种轴手性联芳基化合物及手性芴醇化合物的制备方法。该制备方法以芳基碘化物、芳基溴化物和烯烃为起始原料，在钯催化剂、膦配体、手性降冰片烯衍生物以及碱的作用下，在50℃到150℃下于有机溶剂中搅拌反应，即可得到联芳基轴手性化合物及手性芴醇化合物。该方法所用的原料廉价易得，反应条件温和，底物普适性好，产率高，制备过程简单。所制备的联芳基轴手性化合物可应用于新型手性配体及手性催化剂的合成。

Description

一种轴手性联芳基化合物及手性芴醇化合物的制备方法
技术领域
本发明涉及一种轴手性联芳基化合物及手性芴醇化合物的制备方法，属于有机合成领域。
背景技术
轴手性联芳基骨架是一类非常重要的结构单元，广泛存在于具有生物活性的天然产物、药物分子以及手性材料中([1]Q.Li,L.Green,N.Venkataraman,I.Shiyanovskaya,A.Khan,A. Urbas,J.W.Doane,J.Am.Chem.Soc.2007,129,12908；[2]J.E.Smyth,N.M.Butler,P.A.Keller, Nat.Prod.Rep.2015,32,1562；[3]J.Clayden,W.J.Moran,P.J.Edwards,S.R.LaPlante,Angew. Chem.Int.Ed.2009,48,6398)。此外，以轴手性联芳基为骨架的手性配体和催化剂在不对称催化反应中具有重要作用([1]R.Noyori,H.Takaya,Acc.Chem.Res.1990,23,345；[2]Y.Chen,S. Yekta,A.K.Yudin,Chem.Rev.2003,103,3155；[3]D.Parmar,E.Sugiono,S.Raja,M.Rueping, Chem.Rev.2014,114,9047)。鉴于此类结构骨架的重要性，化学家发展了诸多合成方法，包括：(1)芳基-芳基的不对称交叉偶联或氧化自偶联([1]T.Hayashi,K.Hayashizaki,T.Kiyoi,Y. Ito,J.Am.Chem.Soc.1988,110,8153；[2]R.Giri,B.-F.Shi,K.M.Engle,N.Maugel,J.-Q.Yu, Chem.Soc.Rev.2009,38,3242)；(2)联芳基化合物的(动态)动力学拆分及去对称化([1]J. L.Gustafson,D.Lim,S.J.Miller,Science 2010,328,1251；[2]G.Ma,M.P.Sibi,Chem.Eur.J. 2015,21,11644)；(3)不对称构建联芳基中的一个芳环(A.Link,C.Sparr,Chem.Soc.Rev.2018, 47,3804)；(4)中心手性向轴手性的转变(A.Link,C.Sparr,Chem.Soc.Rev.2018,47,3804)； (5)张力二芳基环状化合物的不对称开环反应(K.Zhao,L.Duan,S.Xu,J.Jiang,Y.Fu,Z.Gu, Chem 2018,4,599)等。然而，这些方法大多需要预先合成特殊官能团的底物，或者需要较为复杂的催化剂，极大地限制了这些方法的使用范围。因此发展高效、简洁的合成新方法显得尤为重要。本发明以易得的芳基碘化物、芳基溴化物和烯烃为起始原料，在钯催化剂、膦配体、手性降冰片烯衍生物、碱的作用下，在50℃到150℃下于有机溶剂中搅拌反应，即可得轴手性联芳基化合物。该方法所用的原料廉价易得，反应条件温和，底物普适性好，产率高，制备过程简单。所制备的联芳基轴手性化合物可应用于新型手性配体及手性催化剂的合成。
发明内容
为了解决现有技术中存在的不足，本发明提供一种轴手性联芳基化合物及手性芴醇化合物的制备方法。该方法所用的原料廉价易得，反应条件温和，底物普适性好，产率高，制备过程简单。这两类化合物具有相同的中间体——轴手性钯中间体，在外加终止试剂的条件下会形成轴手性联芳基化合物，当无外加终止试剂且底物中具有羰基结构时会发生分子内的终止反应，从而形成手性芴醇化合物。
本发明提供的技术方案具体如下：
本发明的目的之一在于提供一种轴手性联芳基化合物的制备方法，包括以下步骤：
在氩气保护下，以芳基碘化物A、芳基溴化物B和终止试剂C为起始原料，在钯催化剂 D、手性降冰片烯衍生物E、碱F的作用下，于有机溶剂G中搅拌反应直至反应结束，将反应混合物过滤、浓缩、柱层析纯化即得到如式I的轴手性联芳基化合物。
所述反应式如下：
Figure BDA0002561723400000021
其中：
R1-R5选自芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、烯基、炔基或卤素；
m表示R4的个数，0≤m≤3；当m≥2时，两个基团可以相同也可以不同；
n表示R5的个数，0≤n≤3；当n≥2时，两个基团可以相同也可以不同；
T表示终止试剂，包括烯烃、炔烃、硼酸、硼酸酯、氰化物、醇类；
Ar1和Ar2为芳烃及杂环芳烃。
本发明的目的之二在于提供一种手性芴醇化合物的制备方法，包括以下步骤：
在氩气保护下，以芳基碘化物A和芳基溴化物B为起始原料，在钯催化剂D、配体H、手性降冰片烯衍生物E、碱F的作用下，于有机溶剂G中搅拌反应至反应结束，将反应混合物过滤、浓缩、柱层析纯化即得到如式II的手性芴醇化合物；
反应式如下：
Figure BDA0002561723400000031
其中：
R1-R5为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、烯基、炔基、卤素中的一种或几种；
m表示R4的个数，0≤m≤3；当m≥2时，两个基团可以相同也可以不同；
n表示R5的个数，0≤n≤3；当n≥2时，两个基团可以相同也可以不同；
Ar1和Ar2为芳烃及杂环芳烃。
进一步，所述的轴手性联芳基化合物的制备方法中，终止试剂C选自烯烃、炔烃、芳基硼酸或硼酸酯、烷基硼酸或硼酸酯、氰化物、腈类化合物、酮类化合物。
进一步，所述的轴手性联芳基化合物或手性芴醇化合物的制备方法中，钯催化剂D选自 Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、PdI2、[Pd(allyl)Cl]2中的任意一种或几种。优选Pd(OAc)2。
进一步，所述的轴手性联芳基化合物或手性芴醇化合物的制备方法中，手性降冰片烯衍生物E的结构式为：
Figure BDA0002561723400000032
其中：
i)R6为左边五元环上的取代基，p代表取代基个数，0≤p≤8；R7为双键上的取代基，q 代表取代基个数，0≤q≤2；
ii)R6，R7选自芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、烯基、炔基或卤素中的任意一种或几种；
iii)左边五元环上取代基数目为2个及2个以上时，可以相同，也可以不相同；双键上的取代基数目为2个时，可以相同，也可以不相同；
iv)R6和R7取代基的种类可以相同，也可以不相同。
进一步，所述的轴手性联芳基化合物或手性芴醇化合物的制备方法中，碱F选自碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠中的任意一种或几种。优选碳酸钾。
进一步，所述的轴手性联芳基化合物或手性芴醇化合物的制备方法中，溶剂G选自甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、乙醚、二甲基乙二醚、甲基叔丁基醚、 1,4-二氧六烷、1,3-二氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、 C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N- 二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的任意一种或几种。优选乙腈。
进一步，所述的轴手性联芳基化合物的制备方法中，膦配体H选自三芳基膦、三烷基膦、二环己基(2',4',6'-三异丙基-[1,1'-二苯基]-2-基)膦、二环己基(2',4',6'-三异丙基-3,6-二甲氧基- [1,1'-二苯基]-2-基)膦、二环己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦、2'-(二环己基膦基)-N,N- 二甲基-[1,1'-二苯基]-2-胺、二环己基(2',6'-二异丙氧基-[1,1'-二苯基]-2-基)膦、三(2-呋喃基)膦、 (3S,5S,7S)-金刚烷-1-基((1R,5S)-金刚烷-2-基)(丁基)膦中的任意一种或几种。优选三(2-呋喃基) 膦。
本发明的目的之三在于提供利用上述方法制备的轴手性联芳基化合物。
本发明的目的之四在于提供利用上述方法制备的手性芴醇化合物。
本发明所述的轴手性联芳基化合物或手性芴醇化合物的制备方法中，反应时间为1～48小时，反应温度为50～130℃。加热过程可采用油浴(如硅油、石蜡油等)或者其它加热方式。
本发明优选在反应完成后对反应产物进行后处理，包括抽滤、浓缩和纯化。所述抽滤过程可使用砂芯漏斗在减压的条件下过滤。所述浓缩过程可采用减压蒸馏等方法，例如用旋转蒸发仪减压浓缩。所述纯化方法可采用柱层析分离纯化。
本发明的方法可以高效地制备轴手性联芳基化合物及手性芴醇化合物，具有以下有益效果：
1、本发明所涉及的主要原料为芳基碘代物、芳基溴化物、烯烃，此原料可用商品化试剂，无需特殊处理，且价格低廉，种类繁多；
2、本发明方法具有非常好的对映选择性，所得产物的ee值高达99％。
3、本发明方法所涉及的反应使用的催化剂是较为廉价的金属钯盐，相比于其他催化剂或者络合物等是一个重要的补充；
4、本发明方法所涉及的反应使用的催化量的降冰片烯衍生物，相比于之前的反应使用的降冰片烯的用量大大减少；
5、本发明方法所涉及的反应对官能团具有很好的容忍性和普适性，取代基可以为烷基、烷氧基、氰基、酯基、硝基、卤原子(F、Cl、Br)等。
6、本发明方法可以大量(克级)制备轴手性联芳基化合物及手性芴醇化合物，为工业化生产奠定了良好的基础。
具体实施方式
下面通过实例对本发明给予进一步说明，值得注意的是，本发明不仅限于下述的实施例。
实施例1
化合物I-1的制备
Figure BDA0002561723400000051
在氩气保护下，向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg，0.01mmol)、碳酸钾(34.6mg,0.25mmol)和干燥的乙腈(1.0mL)，然后加入(1S,4R)-2-降冰片烯-2-甲酸乙酯(8.3mg，0.05mmol)、1-碘萘(38.1mg，0.15mmol)、2-溴-3-甲基苯甲酸甲酯(22.9mg， 0.1mmol)和丙烯酸叔丁酯(19.2mg，0.15mmol)。所得混合物于105℃在氩气保护氛围下反应24小时。反应结束后冷却至室温，混合物用硅藻土过滤，乙酸乙酯洗涤，减压蒸馏除去溶剂，柱层析分离纯化得化合物I-1(无色油状液体，78％产率，96％ee)。1H NMR(400MHz, CDCl3):δ8.23–8.20(m,1H),7.89–7.82(m,3H),7.71(d,J＝16.3Hz,1H),7.57–7.50(m,2H), 7.45–7.43(m,1H),7.38–7.34(m,1H),7.22(d,J＝8.4Hz,1H),5.93(d,J＝16.2Hz,1H),3.53(s, 3H),1.97(s,3H),1.44(s,9H)；13C NMR(100MHz,CDCl3):δ167.89,165.87,141.30,140.50, 138.02,137.18,133.89,133.04,131.34,130.84,130.30,128.74,128.71,127.90,127.63,127.22, 126.78,126.67,125.93,125.31,80.44,52.00,28.23,20.63；HRMS(ESI-TOF):calc’d for C26H26NaO4[M+Na]+425.1723,found 425.1728；HPLC:Daicel chiralpak AD-H column,2％iPrOH in nhexane,1mL/min,λ＝320nm,tR(major)＝9.61min,tR(minor)＝8.82min.
实施例2～19
化合物I-2～I-19的制备
操作步骤同实施例1，区别在于所使用的烯烃依次为：丙烯酸乙酯、丙烯酸苄酯、N,N-二甲基丙烯酰胺、N,-甲基-N-甲氧基丙烯酰胺、丙烯醛、乙烯基砜、乙烯基磷酸酯、乙烯基三甲基硅烷、乙烯基乙基醚、2-甲基-3-丁烯-2-醇、烯丙醇、高烯丙醇、5-己基-1-醇、苯乙烯、4-氟苯乙烯、4-甲氧基苯乙烯、4-硝基苯乙烯、3-乙烯基苯并噻吩。得到具有不同取代基终止的轴手性联芳基产物，结果见表1。
表1实施例2～19所得轴手性联芳基化合物结果
Figure BDA0002561723400000061
实施例20
化合物I-20的制备
Figure BDA0002561723400000071
操作步骤同实施例1，区别在于所使用的烯烃(52.9mg)结构如下所示,得化合物I-20 (黄色油状液体，96％产率，97％ee)。1H NMR(400MHz,CDCl3):δ8.31–8.27(m,1H),7.93 –7.89(m,1H),7.84(d,J＝8.4Hz,1H),7.80(dd,J＝8.1,1.2Hz,1H),7.76–7.72(m,2H),7.69–7.67(m,2H),7.56–7.50(m,2H),7.41(d,J＝7.2Hz,1H),7.36–7.32(m,3H),7.30–7.24(m,2H), 6.88–6.84(m,2H),6.67(d,J＝16.5Hz,1H),5.14–5.05(m,1H),3.53(s,3H),2.00(s,3H),1.66 (s,6H),1.21(s,3H),1.20(s,3H)；13C NMR(100MHz,CDCl3):δ195.01,173.31,168.25,159.55, 141.86,141.27,137.35,137.07,136.95,134.30,133.75,133.25,132.45,132.06,131.73,131.11, 130.80,130.41,128.69,127.67,127.62,127.42,127.37,126.42,126.11,125.80,125.61,117.23, 79.45,69.45,52.02,25.49,21.66,20.67；HRMS(ESI-TOF):calc’d for C41H38NaO6[M+Na]+ 649.2561,found 649.2559；HPLC:Daicel chiralpak AD-H column,15％iPrOH in nhexane,1 mL/min,λ＝320nm,tR(major)＝8.39min,tR(minor)＝7.19min.
实施例20所用的烯烃：
Figure BDA0002561723400000072
实施例21
化合物I-21的制备
Figure BDA0002561723400000073
操作步骤同实施例1，区别在于所使用的烯烃(40.1mg)结构如下所示,得化合物I-21(白色固体，88％产率，96％de)。1H NMR(400MHz,CDCl3):δ8.34–8.30(m,1H),7.93– 7.89(m,1H),7.83–7.80(m,2H),7.54–7.50(m,2H),7.41–7.38(m,1H),7.34–7.30(m,1H), 7.24(d,J＝8.4Hz,2H),7.16–7.09(m,2H),7.04(s,1H),6.60(d,J＝16.4Hz,1H),3.55(s,3H),2.91(dd,J＝9.2,4.2Hz,2H),2.53(dd,J＝18.8,8.6Hz,1H),2.45–2.40(m,1H),2.34–2.27(m, 1H),2.15(dd,J＝18.8,8.9Hz,1H),2.11–1.94(m,6H),1.70–1.40(m,6H),0.92(s,3H)；13C NMR (100MHz,CDCl3):δ220.99,168.27,142.14,139.41,137.37,136.69,135.24,135.06,133.68,133.23, 133.09,131.90,130.97,128.54,127.59,127.33,127.19,127.16,127.04,126.11,125.81,125.66, 125.60,124.50,123.80,123.77,51.94,50.53,48.06,44.54,38.21,35.96,31.65,29.47,26.55,25.78, 21.67,20.65,13.92；HRMS(ESI-TOF):calc’d for C39H38NaO3[M+Na]+577.2713,found 577.2711； HPLC:Daicel chiralpakAD-H column,5％iPrOH in nhexane,1mL/min,λ＝254nm,tR(major)＝ 13.87min,tR(minor)＝14.81min.
实施例21所用的烯烃：
Figure BDA0002561723400000081
实施例22
化合物I-22的制备
Figure BDA0002561723400000082
操作步骤同实施例1，区别在于所使用的烯烃(62.8mg)结构如下所示,得化合物I-22 (白色固体，81％产率，98％de)。1H NMR(400MHz,CDCl3):δ8.30–8.27(m,1H),7.95–7.87(m,3H),7.84(d,J＝8.4Hz,1H),7.78(dd,J＝7.8,1.4Hz,1H),7.57–7.49(m,2H),7.39(d,J＝7.3 Hz,1H),7.34–7.21(m,5H),6.65(d,J＝16.5Hz,1H),5.45(d,J＝5.1Hz,1H),4.85–4.81(m,1H), 3.52(s,3H),2.51–2.42(m,3H),2.18–2.06(m,2H),2.05–1.82(m,7H),1.78–1.62(m,4H),1.58 –1.44(m,2H),1.35–1.19(m,3H),1.12–1.04(m,4H),0.90(s,3H)；13C NMR(100MHz,CDCl3): δ221.25,168.20,165.82,141.93,141.82,140.02,137.32,137.06,134.29,133.72,133.24,132.41, 131.69,131.12,129.97,129.58,128.69,127.74,127.63,127.61,127.39,127.35,126.41,126.16, 125.79,125.60,122.13,74.35,52.00,51.80,50.24,47.66,38.30,37.08,36.90,35.98,31.59,31.52, 30.92,27.93,22.02,20.65,20.46,19.54,13.68；HRMS(ESI-TOF):calc’d for C47H48NaO5[M+Na]+ 715.3394,found 715.3390；HPLC:Daicel chiralpak AD-H column,15％iPrOH in nhexane,1 mL/min,λ＝320nm,tR(major)＝12.90min,tR(minor)＝9.92min.
实施例22所用的烯烃：
Figure BDA0002561723400000091
实施例23
化合物I-23的制备
Figure BDA0002561723400000092
在氩气体保护下，向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg，0.01mmol)、碳酸钾(34.6mg,0.25mmol)和干燥的乙二醇二甲醚(1.0mL)，然后加入(1S,4R)-2-降冰片烯-2-甲酸乙酯(8.3mg，0.05mmol)、1-碘萘(38.1mg，0.15mmol)、2-溴-3-甲基苯甲酸甲酯 (22.9mg，0.1mmol)和三异丙基硅基乙炔(36.5mg，0.2mmol)。所得混合物于105℃在氩气保护氛围下反应24小时。反应结束后冷却至室温，混合物用硅藻土过滤，乙酸乙酯洗涤，减压蒸馏除去溶剂，柱层析分离纯化得化合物I-23(黄色油状液体，70％产率，99％ee)。1HNMR(400MHz,CDCl3):δ8.42(d,J＝8.2Hz,1H),7.89–7.85(m,3H),7.60–7.56(m,1H),7.53 –7.50(m,1H),7.43(d,J＝7.5Hz,1H),7.34–7.27(m,2H),3.52(s,3H),2.05(s,3H),0.94(s,21H)；13C NMR(100MHz,CDCl3):δ167.60,143.15,142.27,137.87,133.82,133.69,132.21,130.23, 128.34,128.02,127.99,127.40,126.96,126.92,126.69,126.16,119.32,103.23,99.22,51.84,20.57, 18.67,11.28；HRMS(ESI-TOF):calc’d for C30H36NaO2Si[M+Na]+479.2377,found 479.2374；HPLC:所得产物的ee值通过四丁基氟化铵脱除硅保护基后测得,Daicel chiralpak AD-H column,2％iPrOH in nhexane,1mL/min,λ＝254nm,tR(major)＝8.42min.
实施例24
化合物I-24的制备
Figure BDA0002561723400000101
在氩气保护下，向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg，0.01mmol)、碳酸钾(34.6mg,0.25mmol)和干燥的四氢呋喃(1.0mL)，然后加入(1S,4R)-2-降冰片烯-2- 甲酸乙酯(8.3mg，0.05mmol)、1-碘萘(38.1mg，0.15mmol)、2-溴-3-甲基苯甲酸甲酯(22.9 mg，0.1mmol)和甲基硼酸(12mg，0.2mmol)。所得混合物于105℃在氩气保护氛围下反应24小时。反应结束后冷却至室温，混合物用硅藻土过滤，乙酸乙酯洗涤，减压蒸馏除去溶剂，柱层析分离纯化得化合物I-24(白色固体，43％产率，99％ee)。1H NMR(400MHz,CDCl3) δ8.07(d,J＝9.8Hz,1H),7.87(d,J＝7.4Hz,1H),7.79(d,J＝9.4Hz,1H),7.73(d,J＝8.4Hz,1H), 7.56–7.52(m,1H),7.51–7.45(m,2H),7.38–7.34(m,1H),7.16(d,J＝8.4Hz,1H),3.48(s,3H), 2.34(s,3H),1.98(s,3H)；13C NMR(100MHz,CDCl3)δ168.38,142.42,137.80,136.93,133.43, 132.94,132.83,131.21,130.99,128.72,127.47,127.24,127.22,125.98,125.86,125.37,124.51, 51.93,20.56,15.65；HRMS(ESI-TOF):calc’dfor C20H18NaO2[M+Na]+313.1199,found 313.1195； HPLC:Daicel chiralpak IE column,2％iPrOH in nhexane,1mL/min,λ＝230nm,tR(major)＝6.54 min,tR(minor)＝6.22min.
实施例25
化合物I-25的制备
Figure BDA0002561723400000111
操作步骤同实施例24，区别在于所使用的硼酸为苯硼酸(24.4mg),得化合物I-25(无色油状液体，88％产率，95％ee)。1H NMR(400MHz,CDCl3)δ7.94–7.91(m,2H),7.63– 7.59(m,2H),7.50–7.47(m,1H),7.40–7.34(m,2H),7.27–7.16(m,6H),7.14–7.10(m,1H), 3.58(s,3H),2.02(s,3H)；13C NMR(100MHz,CDCl3)δ168.10,142.23,138.81,137.42,136.90,136.84,133.45,133.03,132.84,131.02,130.72,129.75,128.20,127.63,127.52,127.42,127.31, 126.95,126.92,126.77,126.04,125.56,51.90,21.00；HRMS(ESI-TOF):calc’dfor C25H20NaO2 [M+Na]+375.1356,found 375.1348；HPLC:Daicel chiralpak AD-Hcolumn,2％iPrOH in nhexane, 1mL/min,λ＝254nm,tR(major)＝5.92min,tR(minor)＝5.47min.
实施例26
化合物I-26的制备
Figure BDA0002561723400000112
操作步骤同实施例1，区别在于所使用的终止试剂为亚铁氰化钾(55.3mg,0.15mmol), 得化合物I-26(白色固体，48％产率，79％ee)。1H NMR(400MHz,CDCl3)δ8.28(d,J＝8.3 Hz,1H),8.11(d,J＝8.4Hz,1H),8.01–7.96(m,1H),7.73–7.70(m,1H),7.65–7.61(m,1H),7.54 (d,J＝7.6Hz,1H),7.48–7.44(m,1H),7.36(d,J＝8.4Hz,1H),3.60(s,3H),2.08(s,3H)；13C NMR(100MHz,CDCl3)δ167.02,146.00,139.46,137.54,134.54,132.68,132.56,131.90,129.75, 128.78,128.74,128.60,127.36,126.79,125.51,116.79,109.26,52.17,20.48；HRMS(ESI-TOF): calc’d for C20H15NNaO2[M+Na]+324.0995,found324.0988；HPLC:Daicel chiralpak OD-H column,10％iPrOH in nhexane,1mL/min,λ＝254nm,tR(major)＝6.40min,tR(minor)＝7.42min.
实施例27
化合物I-27的制备
Figure BDA0002561723400000121
操作步骤同实施例1，区别在于所使用的终止试剂为苯乙酮(18.1mg,0.15mmol)，所用的溶剂为乙二醇二甲醚，另外加入膦配体2-二叔丁基磷-2'-甲基联苯(7.5mg，0.022mmol)，得化合物I-27(无色油状液体，32％产率，95％ee)。1H NMR(400MHz,CDCl3)δ7.92–7.89 (m,1H),7.86–7.83(m,3H),7.72–7.69(m,2H),7.56–7.52(m,1H)7.50–7.44(m,2H),7.43– 7.39(m,1H),7.37(d,J＝7.5Hz,1H),7.32–7.28(m,1H),7.27–7.25(m,1H),4.51(d,J＝17.8 Hz,1H),4.38(d,J＝17.8Hz,1H),3.49(s,3H),2.00(s,3H)；13C NMR(100MHz,CDCl3)δ196.95, 168.24,141.37,138.46,137.08,133.76,133.20,133.17,132.90,131.35,129.03,128.88,128.69, 128.20,127.57,127.43,127.37,127.34,126.46,125.56,124.84,51.99,39.48,20.65；HRMS(ESI- TOF):calc’d for C27H22NaO3[M+Na]+417.1461,found 417.1459；HPLC:Daicel chiralpak OD-H column,10％iPrOH innhexane,1mL/min,λ＝254nm,tR(major)＝8.58min,tR(minor)＝7.80min.
实施例28～40
化合物I-28～I-40的制备
操作步骤同实施例1，区别在于所使用的芳基碘化物的芳环(或杂芳环)上的取代基不同。得到具有不同取代基的轴手性联芳基产物，结果见表2。
表2实施例28～40所得轴手性联芳基化合物结果
Figure BDA0002561723400000131
实施例41～49
化合物I-41～I-49的制备
操作步骤同实施例1，区别在于所使用的芳基碘化物的芳环上的取代基不同，所用的烯烃为苯乙烯。得到具有不同取代基的轴手性联芳基产物，结果见表3。
表3实施例41～49所得轴手性联芳基化合物结果
Figure BDA0002561723400000132
实施例50～64
化合物I-50～I-64的制备
操作步骤同实施例1，区别在于所使用的芳基溴化物的芳环上的取代基不同，所用的烯烃为苯乙烯。得到具有不同取代基的轴手性联芳基产物，结果见表4。
表4实施例50～64所得轴手性联芳基化合物结果
Figure BDA0002561723400000141
实施例65
化合物II-1的制备
Figure BDA0002561723400000142
在氩气保护下，向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg，0.01mmol)、三(2-呋喃基)膦(5.1mg，0.022mmol)、碳酸钾(34.6mg,0.25mmol)和干燥的乙腈(1.0 mL)，然后加入(1S,4R)-2-降冰片烯-2-甲酸乙酯(8.3mg，0.05mmol)、1-碘萘(38.1mg，0.15 mmol)和1-(2-溴-3-甲基苯基)乙酮(21.3mg，0.1mmol)。所得混合物于120℃在氩气保护氛围下反应24小时。反应结束后冷却至室温，混合物用硅藻土过滤，乙酸乙酯洗涤，减压蒸馏除去溶剂，柱层析分离纯化得化合物II-1(白色固体，95％产率，99％ee)。1H NMR(400MHz,CDCl3):δ8.51(d,J＝8.4Hz,1H),7.98(dd,J＝8.5,1.4Hz,1H),7.92–7.87(m,2H),7.60– 7.55(m,1H),7.51–7.47(m,2H),7.25–7.22(m,1H),7.16(d,J＝7.5Hz,1H),2.73(s,3H),2.06 (s,1H),1.88(s,3H)；13C NMR(100MHz,CDCl3):δ152.21,144.25,137.24,136.81,133.39,132.88, 131.48,129.72,129.46,128.97,127.51,126.57,125.57,124.77,121.52,120.38,81.15,27.04,21.05； HRMS(ESI-TOF):calc’d for C19H15[M-OH]+243.2268,found 243.1166；HPLC:Daicel chiralpak AD-H column,5％iPrOH in nhexane,1mL/min,λ＝254nm,tR(major)＝16.38min,tR(minor)＝ 18.67min.
实施例66
化合物II-2的制备
Figure BDA0002561723400000151
操作步骤同实施例65，区别在于所使用的芳基溴化物为1-(2-溴-3-甲基苯基)-1-丙酮(22.7 mg),得化合物II-2(白色固体，73％产率，99％ee)。1H NMR(400MHz,CDCl3):δ8.48(d, J＝8.4Hz,1H),7.97(d,J＝8.6Hz,1H),7.92–7.86(m,2H),7.58–7.53(m,1H),7.51–7.47(m, 1H),7.40(d,J＝7.4Hz,1H),7.24–7.21(m,1H),7.15(d,J＝7.5Hz,1H),2.72(s,3H),2.59–2.49 (m,1H),2.44–2.35(m,1H),2.24(s,1H),0.25(t,J＝7.5Hz,3H)；13C NMR(100MHz,CDCl3):δ 150.30,142.63,138.48,138.00,133.25,132.50,131.46,129.67,129.65,128.92,127.31,126.46, 125.52,124.54,121.28,120.50,84.86,32.82,21.01,8.44；HRMS(ESI-TOF):calc’d for C20H17[M- OH]+257.1325,found 257.1329；HPLC:Daicelchiralpak IG column,5％iPrOH in nhexane,1 mL/min,λ＝254nm,tR(major)＝13.38min,tR(minor)＝12.36min.
实施例67
化合物II-3的制备
Figure BDA0002561723400000161
操作步骤同实施例65，区别在于所使用的芳基溴化物为1-(2-溴-3-甲基苯基)-2,2-二甲基-1- 丙酮(25.5mg),得化合物II-3(白色固体，64％产率，99％ee)。1H NMR(400MHz,CDCl3): δ8.73(d,J＝8.6Hz,1H),7.95(d,J＝8.5Hz,1H),7.84–7.81(m,2H),7.47–7.38(m,3H),7.14– 7.09(m,2H),2.70(s,3H),2.19(s,1H),0.94(s,9H)；13C NMR(100MHz,CDCl3):δ151.07,145.15, 139.70,138.55,132.77,131.93,131.25,130.97,129.58,128.37,127.32,125.51,125.20,125.13, 122.06,121.00,91.24,39.83,27.05,21.28；HRMS(ESI-TOF):calc’d for C22H21[M-OH]+285.1638, found 285.1634；HPLC:Daicel chiralpak AD-H column,5％iPrOH in nhexane,1mL/min,λ＝254 nm,tR(major)＝7.92min,tR(minor)＝9.06min.
实施例68
化合物II-4的制备
Figure BDA0002561723400000162
操作步骤同实施例65，区别在于所使用的芳基溴化物为(2-溴-3-甲基苯基)(环丙基)甲酮(23.9mg),得化合物II-4(白色固体，80％产率，99％ee)。1H NMR(400MHz,CDCl3): δ8.66(d,J＝8.5Hz,1H),7.98(d,J＝8.5Hz,1H),7.91–7.87(m,1H),7.59–7.54(m,1H),7.50–7.46(m,1H),7.44(dd,J＝7.1,1.4Hz,1H),7.2–7.18(m,1H),7.17–7.14(m,1H),2.74(s,3H), 2.16(s,1H),1.53–1.46(m,1H),0.97–0.89(m,1H),0.63–0.56(m,1H),0.37–0.25(m,2H)；13C NMR(100MHz,CDCl3):δ150.16,144.94,137.65,137.50,133.39,132.71,131.62,129.75,129.62, 128.84,126.86,126.33,125.54,125.49,121.44,121.37,83.06,21.14,20.23,3.13,1.77；HRMS(ESI- TOF):calc’d for C21H17[M-OH]+269.1325,found 269.1319；HPLC:Daicel chiralpak AD-H column, 10％iPrOH in nhexane,1mL/min,λ＝254nm,tR(major)＝11.10min,tR(minor)＝11.68min.
实施例69
化合物II-5的制备
Figure BDA0002561723400000171
操作步骤同实施例65，区别在于所使用的芳基溴化物为(2-溴-3-甲基苯基)(环己基)甲酮 (28.1mg),得化合物II-5(白色固体，91％产率，99％ee)。1H NMR(400MHz,CDCl3):δ8.61(d,J＝8.4Hz,1H),7.94(d,J＝8.5Hz,1H),7.90(d,J＝8.1Hz,1H),7.85(d,J＝8.5Hz,1H), 7.57–7.53(m,1H),7.50–7.48(m,1H),7.45(d,J＝7.5Hz,1H),7.20–7.16(m,1H),7.13(d,J＝ 7.4Hz,1H),2.71(s,3H),2.59–2.52(m,2H),2.14(s,1H),1.86(dt,J＝14.3,3.1Hz,1H),1.54– 1.51(m,1H),1.43–1.35(m,1H),1.35–1.25(m,2H),0.99–0.83(m,2H),0.69(dt,J＝12.7,3.2 Hz,1H),0.31–0.21(m,1H)；13C NMR(100MHz,CDCl3):δ149.45,144.50,138.33,133.27,132.42, 131.30,129.42,129.39,128.89,126.29,126.21,125.45,124.91,122.29,121.06,87.03,47.31,27.49, 27.26,26.86,26.47,26.45,21.17；HRMS(ESI-TOF):calc’d for C24H23[M-OH]+311.1794,found 311.1790；HPLC:Daicel chiralpakIG column,5％iPrOH in nhexane,1mL/min,λ＝254nm,tR (major)＝12.98min,tR(minor)＝9.92min.
实施例70
化合物II-6的制备
Figure BDA0002561723400000181
操作步骤同实施例65，区别在于所使用的芳基溴化物为(2-溴-3-甲基苯基)(苯基)甲酮 (27.5mg),得化合物II-6(白色固体，68％产率，>99％ee)。1H NMR(400MHz,CDCl3):δ8.05(d,J＝8.6Hz,1H),7.94(d,J＝8.5Hz,1H),7.87–7.84(m,2H),7.40–7.36(m,3H),7.34– 7.30(m,1H),7.24–7.14(m,4H),7.11–7.09(m,2H),2.77(s,3H),2.46(s,1H)；13C NMR(100 MHz,CDCl3):δ152.68,144.63,143.29,139.13,137.24,133.61,132.92,131.53,130.37,129.29, 128.69,128.47,127.92,127.09,126.75,125.70,125.10,125.04,121.95,121.33,84.01,21.04； HRMS(ESI-TOF):calc’d for C24H17[M-OH]+305.1325,found305.1317；HPLC:Daicel chiralpak IG column,5％iPrOH in nhexane,1mL/min,λ＝254nm,tR(major)＝15.31min,tR(minor)＝14.48 min.
实施例71
化合物II-7的制备
Figure BDA0002561723400000182
操作步骤同实施例65，区别在于所使用的芳基溴化物为1-(2-溴-3-氯苯基)-1-乙酮(23.3 mg),得化合物II-7(白色固体，71％产率，99％ee)。1H NMR(400MHz,CDCl3):δ8.52–8.47(m,2H),7.94–7.90(m,1H),7.62–7.58(m,1H),7.55–7.51(m,2H),7.37(d,J＝7.9Hz,1H), 7.30–7.26(m,1H),2.17(s,1H),1.89(s,3H)；13C NMR(100MHz,CDCl3):δ154.24,144.28, 135.55,134.96,133.95,130.51,129.86,129.11,129.09,128.63,128.52,126.70,126.01,124.66, 121.63,121.13,81.30,26.90；HRMS(ESI-TOF):calc’d forC18H12Cl[M-OH]+263.0622,found 263.0624；HPLC:Daicel chiralpak AD-H column,15％iPrOH in nhexane,1mL/min,λ＝254nm,tR (major)＝7.32min,tR(minor)＝9.87min.
实施例72
化合物II-8的制备
Figure BDA0002561723400000191
操作步骤同实施例65，区别在于所使用的芳基溴化物为1-(1-溴-2-萘基)-1-乙酮(24.9mg), 得化合物II-8(白色固体，95％产率，99％ee)。1H NMR(400MHz,CDCl3):δ8.74(d,J＝8.5 Hz,1H),8.48(d,J＝8.5Hz,1H),8.38(dd,J＝8.6,1.5Hz,1H),7.92(q,J＝8.2Hz,3H),7.84(d,J ＝8.2Hz,1H),7.74–7.71(m,1H),7.65–7.61(m,1H),7.58–7.46(m,3H),2.13(s,1H),1.89(s, 3H)；13C NMR(100MHz,CDCl3):δ150.28,144.97,137.20,134.74,133.26,133.10,129.77,129.49, 129.32,129.21,128.90,128.82,126.91,126.62,125.67,125.58,124.65,124.09,121.49,120.55, 81.14,26.50；HRMS(ESI-TOF):calc’d forC22H15[M-OH]+279.1168,found 279.1162；HPLC: Daicel chiralpak AD-H column,15％iPrOH in nhexane,1mL/min,λ＝254nm,tR(major)＝14.86 min,tR(minor)＝16.65min.
实施例73
化合物II-9的制备
Figure BDA0002561723400000201
操作步骤同实施例65，区别在于所使用的芳基溴化物为1-(1-溴-2-萘基)-1-乙酮(24.9mg), 所使用的芳基碘化物为1-碘芘(49.2mg)，得化合物II-9(白色固体，71％产率，>99％ee)。1H NMR(400MHz,CDCl3):δ8.76(d,J＝8.4Hz,1H),8.69(s,1H),8.56(d,J＝9.2Hz,1H),8.06 –8.03(m,3H),7.96(dd,J＝9.0,7.1Hz,2H),7.90–7.86(m,2H),7.79(d,J＝8.2Hz,1H),7.68(d, J＝8.2Hz,1H),7.63–7.59(m,1H),7.52–7.48(m,1H),2.16(brs,1H),1.89(s,3H)；13C NMR (100MHz,CDCl3):δ150.35,142.66,137.52,134.72,132.81,132.11,131.15,130.60,129.52,129.45, 127.99,127.54,127.06,126.65,125.86,125.74,125.40,125.37,124.95,124.17,124.13,123.64, 120.60,119.56,81.01,27.00；HRMS(ESI-TOF):calc’d for C28H17[M-OH]+353.1325,found 353.1312；HPLC:Daicel chiralpakIE column,10％iPrOH in nhexane,1mL/min,λ＝330nm,tR (major)＝14.20min.
实施例74
化合物II-10的制备
Figure BDA0002561723400000202
操作步骤同实施例65，区别在于所使用的芳基碘化物为2-甲氧基-3-碘吡啶(23.5mg)，得化合物II-10(白色固体，68％产率，>99％ee)。1H NMR(400MHz,CDCl3):δ8.16(d,J＝ 5.4Hz,1H),7.46(d,J＝7.5Hz,1H),7.35–7.29(m,2H),7.17(d,J＝7.5Hz,1H),4.08(s,3H),2.64 (s,3H),2.62(brs,1H),1.81(s,3H)；13C NMR(100MHz,CDCl3):δ160.56,150.89,150.29,147.82, 135.08,134.58,131.28,129.82,128.94,120.93,112.56,79.27,53.55,24.88,20.55；HRMS(ESI- TOF):calc’d for C15H16NO2[M+H]+242.1176,found242.1172；HPLC:Daicel chiralpak AD-H column,10％iPrOH in nhexane,1mL/min,λ＝254nm,tR(major)＝10.62min.
实施例75～87
化合物II-11～II-23的制备
操作步骤同实施例65，区别在于所使用的芳基碘化物的芳环上的取代基不同。得到具有不同取代基的手性芴醇产物，结果见表5。
表5实施例76～88所得手性芴醇化合物结果
Figure BDA0002561723400000211
以上所述，仅为本发明较佳的具体实施方式，但本发明保护的范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内所做的任何修改，等同替换和改进等，均应包含在发明的保护范围之内。

Claims (10)

1.一种轴手性联芳基化合物的制备方法，其特征在于，包括以下步骤：
在氩气保护下，以芳基碘化物A、芳基溴化物B和终止试剂C为起始原料，在钯催化剂D、手性降冰片烯衍生物E、碱F的作用下，于有机溶剂G中搅拌反应直至反应结束，将反应混合物过滤、浓缩、柱层析纯化即得到如式I的轴手性联芳基化合物，
所述反应式如下：
Figure FDA0002561723390000011
其中：
R1-R5选自氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、烯基、炔基或卤素；
m表示R4的个数，0≤m≤3；当m≥2时，两个基团可以相同也可以不同；
n表示R5的个数，0≤n≤3；当n≥2时，两个基团可以相同也可以不同；
T表示终止试剂，包括烯烃、炔烃、硼酸、硼酸酯、氰化物、醇类；
Ar1和Ar2为芳烃及杂环芳烃。
2.一种手性芴醇化合物的制备方法，其特征在于，包括以下步骤：
在氩气保护下，以芳基碘化物A和芳基溴化物B为起始原料，在钯催化剂D、配体H、手性降冰片烯衍生物E、碱F的作用下，于有机溶剂G中搅拌反应至反应结束，将反应混合物过滤、浓缩、柱层析纯化即得到如式II的手性芴醇化合物；
反应式如下：
Figure FDA0002561723390000012
其中：
R1-R5为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、烯基、炔基、卤素中的一种或几种；
m表示R4的个数，0≤m≤3，当m≥2时，两个基团可以相同也可以不同；
n表示R5的个数，0≤n≤3，当n≥2时，两个基团可以相同也可以不同；
Ar1和Ar2为芳烃及杂环芳烃。
3.根据权利要求1所述的轴手性联芳基化合物的制备方法，其特征在于：所述终止试剂C选自烯烃、炔烃、芳基硼酸或硼酸酯、烷基硼酸或硼酸酯、氰化物、腈类化合物、酮类化合物。
4.根据权利要求1或2所述的轴手性联芳基化合物及手性芴醇化合物的制备方法，其特征在于，所述钯催化剂D选自Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、PdI2、[Pd(allyl)Cl]2中的任意一种或几种。
5.根据权利要求1或2所述的轴手性联芳基化合物及手性芴醇化合物的制备方法，其特征在于，所述手性降冰片烯衍生物E的结构式为：
Figure FDA0002561723390000021
其中：
i)R6为左边五元环上的取代基，p代表取代基个数，0≤p≤8；R7为双键上的取代基，q代表取代基个数，0≤q≤2；
ii)R6，R7选自芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、烯基、炔基或卤素中的任意一种或几种；
iii)左边五元环上取代基数目为2个及2个以上时，可以相同，也可以不相同；双键上的取代基数目为2个时，可以相同，也可以不相同；
iv)R6和R7取代基的种类可以相同，也可以不相同。
6.根据权利要求1或2所述的轴手性联芳基化合物及手性芴醇化合物的制备方法，其特征在于，所述碱F选自碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠中的任意一种或几种。
7.根据权利要求1或2所述的轴手性联芳基化合物及手性芴醇化合物的制备方法，其特征在于，所述溶剂G选自甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、乙醚、二甲基乙二醚、甲基叔丁基醚、1,4-二氧六烷、1,3-二氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的任意一种或几种。
8.根据权利要求1所述的轴手性联芳基化合物的制备方法，其特征在于：所述膦配体H选自三芳基膦、三烷基膦、二环己基(2',4',6'-三异丙基-[1,1'-二苯基]-2-基)膦、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-二苯基]-2-基)膦、二环己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦、2'-(二环己基膦基)-N,N-二甲基-[1,1'-二苯基]-2-胺、二环己基(2',6'-二异丙氧基-[1,1'-二苯基]-2-基)膦、三(2-呋喃基)膦、(3S,5S,7S)-金刚烷-1-基((1R,5S)-金刚烷-2-基)(丁基)膦中的任意一种或几种。
9.一种轴手性联芳基化合物，其特征在于：采用权利要求1所述的方法制备。
10.一种手性芴醇化合物，其特征在于：采用权利要求2所述的方法制备。
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