CN108976123B - 一种高光学活性轴手性联烯化合物及其构建方法 - Google Patents

一种高光学活性轴手性联烯化合物及其构建方法 Download PDF

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CN108976123B
CN108976123B CN201810887565.4A CN201810887565A CN108976123B CN 108976123 B CN108976123 B CN 108976123B CN 201810887565 A CN201810887565 A CN 201810887565A CN 108976123 B CN108976123 B CN 108976123B
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麻生明
宋世铧
周静
傅春玲
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Abstract

本发明是一种高光学活性轴手性联烯化合物及其构建方法，即通过钯催化剂、手性双膦配体和碱的作用下，2,3‑联烯基官能团化合物和亲核试剂在有机溶剂中反应，高立体选择性的直接构建具有轴手性联烯化合物的方法。本方法具有操作简单，原料和试剂易得等优点；底物普适性广；产物的立体选择性极其优秀(90‑96％ee)。本发明得到的高光学活性联烯产物被作为重要的中间体可以用于构筑手性的γ‑联烯酸酯、γ‑联烯酸、γ‑联烯醇和γ‑丁内酯化合物等化合物，并且首次高对映选择性的合成了γ‑丁内酯天然产物(R)‑traumatic lactone(98％ee)。

Description

一种高光学活性轴手性联烯化合物及其构建方法
技术领域
本发明涉及一种化合物及其化学合成方法，具体地说，是一种高光学活性轴手性联烯化合物及其构建方法。
背景技术
在过去的二十年，联烯化学取得了长足的发展，已经成为有机化学里一个非常重要的分支。与烯烃和炔烃不同，联烯化合物具有轴手性。1,3-二取代轴手性联烯结构单元存在于很多天然产物和药物分子中；同时1,3-二取代轴手性联烯也可以作为关键的中间体用于具有重要生物和化学活性的天然产物合成(Ref:(a)
Figure BDA0001756035950000011
A.；Krause,N.Angew.Chem.Int.Ed.2004,43,1196.(b)Ogasawara,M.；Nagano,T.；Hayashi,T.J.Org.Chem.2005,70,5764.(c)Crouch,I.T.；Neff,R.K.；Frantz,D.E.J.Am.Chem.Soc.2013,135,4970.(d)Tang,X.；Huang,X.；Cao,T.；Han,Y.；Jiang,X.；Lin,W.；Tang,Y.；Zhang,J.；Yu,Q.；Fu,C.；Ma,S.Org.Chem.Front.2015,2,688.(e)Jiang,X.；Xue,Y.；Ma,S.Org.Chem.Front.2017,4,951.(f)Yu,Q.,Ma,S.Eur.J.Org.Chem.2015,1596.(g)Zhou,J.；Fu,C.；Ma,S.Nat.Commun.2018,9,1654.)。
因此发展构建高光学活性轴手性联烯化合物的方法引起了广泛的研究兴趣。目前要获得高立体选择性的1,3-二取代联烯可以通过CuBr2催化的末端炔烃的不对称联烯基化反应(EATA)来实现。然而这种方法必须要加入至少当量的手性试剂如二苯基脯氨醇或二甲基脯氨醇(Ref:(a)Huang,X.；Cao,Tao.；Han,Y.；Jiang,X.；Lin,W.；Zhang,J.；Ma,S.Chem.Commun.2015,51,6956.(b)Ma,D.；Duan,X.；Fu,C.；Huang,X.；Ma,S.Synthesis2018,50,2533)。另外一种重要的方法是外消的2,3-联烯醇衍生物与亲核试剂的不对称联烯基化反应。文献中报道的利用外消的2,3-联烯醇衍生物与亲核试剂(如丙二酸酯、取代的丙二酸酯等)在不同的钯复合物和手性双膦配体的催化下反应，可以以中等到优秀的对映选择性得到了一系列光学活性的联烯化合物。然而，为了获得更好的对映选择性，必须在外消的2,3-联烯醇衍生物结构上装载一个大位阻的R基团或者在亲核试剂中引入一个大位阻的R基团。(Ref:(a)Imada,Y.；Ueno,K.；Kutsuwa,K.；Murahashi,S.-I.Chem.Lett.2002,140.(b)Imada,Y.；Nishida,M.；Kutsuwa,K.；Murahashi,S.-I.；Naota,T.；Org,Lett.2005,7,5837.(c)Imada,Y.；Nishida,M.；Naota,T.Tetrahedron Lett.2008,49,4915.(d)Trost,B.M.；Fandrick,D.R.；Dinh,D.C.J.Am.Chem.Soc.2005,127,14186.(e)Nemoto,T.；Kanematsu,M.；Tamura,S.；Hamada,Y.Adv.Synth.Catal.2009,351,1773)。大位阻的基团(如叔丁基等)是非常特殊的官能团，它们的存在会降低1,3-二取代轴手性联烯产物的应用可能性。因此，发展高效的、简单的、高立体选择性的构筑含有有价值的官能团的1,3-二取代轴手性联烯引起了科学工作者极大的兴趣，因为这些化合物可以被进一步衍生化来制备其他重要的化合物，尤其是天然产物。
发明内容
本发明的目的是提供一种高光学活性轴手性联烯化合物及其构建方法，即通过2,3-联烯基官能团化合物和亲核试剂，在钯催化剂、手性双膦配体和碱的作用下，在有机溶剂中反应，高光学活性构建轴手性联烯化合物的方法。
本发明是采用以下具体技术方案来实现的：
本发明公开了一种高光学活性轴手性联烯化合物，其结构如下(Ra)-3所示：
Figure BDA0001756035950000021
其中R1为烷基或者含有被杂原子官能团取代的烷基，R2为氢原子或非氢原子的基团，E为拉电子基团，为砜基、氰基、羧基、酯基或酮羰基中的一种。
本发明还公开了一种高光学活性轴手性联烯化合物的构建方法，在钯催化剂、手性双膦配体和碱的作用下，2,3-联烯基官能团化合物和亲核试剂在有机溶剂中反应，高立体选择性地构建轴手性联烯化合物，反应式如下：
Figure BDA0001756035950000031
其中所述的2,3-联烯基官能团化合物1中R1为烷基或者含有被杂原子官能团取代的烷基，LG为碳酸酯、醋酸酯、苯甲酸酯、特戊酸酯、磷酸酯或者卤素原子；
其中所述的亲核试剂2中R2为氢原子或非氢原子的官能团，E为拉电子基团，为砜基、氰基、羧基、酯基或酮羰基中的一种；
所述反应式(1)中2,3-联烯基官能团化合物1、亲核试剂2、钯催化剂、手性双膦配体和碱的摩尔比或质量比为1.0：1.0–3.0：0.005–0.05：0.01–0.20：1.0–6.0。
作为进一步地改进，具体操作步骤如下：
1)、在手套箱中，向一个干燥的反应管中依次投入手性双膦配体和碱，将反应管移出手套箱，在氮气保护下加入钯催化剂、亲核试剂2和一定体积的有机溶剂，将反应管置于室温搅拌反应30分钟；
2)、待步骤1)完成后，将反应管放入设定为反应温度的实验设备中，搅拌10分钟；
3)、待步骤2)完成后，在该温度和氮气保护下加入2,3-联烯基官能团化合物1和一定体积的有机溶剂，搅拌反应；
4)、待步骤3)反应完全后，将反应混合液用硅胶短柱过滤，并用有机溶剂淋洗，浓缩所得有机混合液，快速柱层析得最终产物。
作为进一步地改进，本发明所述的钯催化剂为二(肉桂基氯化钯)，二(烯丙基氯化钯)，四(三苯基膦)钯，三(二亚苄基丙酮)二钯，二(二亚苄基丙酮)一钯，氯化钯，醋酸钯，二(三苯基膦)氯化钯，二(乙腈)氯化钯中的任意一种。
作为进一步地改进，本发明所述的钯催化剂，优选地为二(肉桂基氯化钯)。
作为进一步地改进，本发明所述的手性双膦配体为具有以下结构及其对映异构体，其中Ar为苯基、芳基或杂环基，所述芳基是邻、间或对位有烃基或烃氧基取代的苯基；所述杂环基是呋喃、噻吩或吡啶；
Figure BDA0001756035950000041
作为进一步地改进，本发明所述的手性双膦配体，优选地为具有以下结构及其对映异构体，其中Ar为苯基、芳基或杂环基，所述芳基是邻、间或对位有烃基或烃氧基取代的苯基；所述杂环基是呋喃、噻吩或吡啶
Figure BDA0001756035950000042
作为进一步地改进，本发明所述的碱为碳酸钾、碳酸氢钾、碳酸铯、磷酸钠、磷酸钾、磷酸二氢钠、氢氧化钾、氢氧化钠、叔丁醇钠、叔丁醇钾中的任意一种。
作为进一步地改进，本发明所述有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙腈、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、乙醚、二氯甲烷、三氯甲烷、甲苯、苯中的任意一种。
本发明还公开了一种高光学活性轴手性联烯化合物在制备γ-联烯酸酯、γ-联烯酸、γ-联烯醇和γ-丁内酯化合物的应用。
本发明具有以下优点：(1)原料简单易得，制备方便；(2)反应条件温和，操作简单；(3)底物普适性广，官能团兼容性好，产物的立体选择性极其优秀(90-96％ee)；(4)产物易分离纯化。
本发明的创新点在于先将钯复合物、手性配体、碱和亲核试剂2在一定体积的溶剂中搅拌反应一段时间，然后将反应混合物冷至反应温度，然后加入2,3-联烯基官能团化合物和一定体积的溶剂反应，通过该步骤能高效的、简单的、高立体选择性的构筑含有合成有用的基团的1,3-二取代轴手性联烯。此外，在1,3-二取代轴手性联烯结构上引入有价值的官能团，可以进一步被衍生化来制备手性的γ-联烯酸酯、γ-联烯酸、γ-联烯醇和γ-丁内酯化合物等化合物。为了展现该方法的实用价值，本发明得到的手性联烯产物被作为重要的中间体用于构筑γ-丁内酯天然产物(R)-traumatic lactone(98％ee)，这是首次高对映选择性的合成该化合物。
具体实施方式
下面通过具体实施例对本发明的具体技术方案作进一步地详细说明。
实施例1
Figure BDA0001756035950000051
其中，equiv表示当量，mol表示摩尔，THF表示四氢呋喃，ee表示对映异构体过量百分数。
在手套箱中，向一个干燥的Schlenk反应管中依次加入K2CO3(276.2mg,2mmol)和(R)-(-)-DTBM-SEGPHOS(70.5mg,0.06mmol)。将反应管移出手套箱，随后在氮气保护下加入[Pd(π-cinnamyl)Cl]2(13.2mg,0.025mmol)和2a(263.8mg,2mmol)/THF(3.5mL)。将反应管在25℃搅拌反应30分钟后，放入5℃的冰机中再搅拌反应10分钟。然后在氮气保护和搅拌下加入1a(226.2mg,1mmol)/THF(1.5mL)。将反应混合液在5℃下搅拌26小时后，薄层层析(TLC)监测反应完成。用硅胶短柱过滤，并用乙酸乙酯(10mL×3)淋洗。浓缩所得滤液，用硅胶柱快速柱层析(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝30/1)得油状手性联烯产物(Ra)-3aa(217.6mg,77％):90％ee(HPLC conditions:Chiralcel OD-H column,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝16.4min,tR(major)＝17.9min)；[α]D 20＝-54.2(c＝1.08,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.06(m,2H,CH＝C＝CH),3.74(s,6H,2×OCH3),3.51(t,J＝7.4Hz,1H,CH),2.61-2.54(m,2H,CH2),2.00-1.90(m,2H,CH2),1.43-1.19(m,10H,5×CH2),0.88(t,J＝6.8Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ204.0,169.4,169.3,93.0,87.3,52.5,51.3,31.8,29.12,29.10,29.08,28.8,28.0,22.6,14.1；IR(neat,cm-1)2955,2927,2855,1964,1761,1740,1436,1341,1266,1232,1154,1042；MS(EI,70eV)m/z(％)282(M+,3.91),138(100)；HRMS calcd.for C16H26O4[M+]:282.1831,found:282.1830.
实施例2
Figure BDA0001756035950000061
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.7mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(14.5mg,0.012mmol),K2CO3(55.5mg,0.4mmol),1b(28.5mg,0.2mmol)/THF(0.5mL)和2a(52.6mg,0.4mmol)/THF(1.5mL)反应得油状联烯产物(Ra)-3ba(30.7mg,77％)(淋洗剂:石油醚(60-90℃)/乙酸乙酯＝30/1):90％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝23.4min,tR(major)＝24.8min)；[α]D 20＝-40.9(c＝0.47,CHCl3)；1H NMR(300MHz,CDCl3)δ5.19-5.04(m,2H,CH＝C＝CH),3.750(s,3H,OCH3),3.745(s,3H,OCH3),3.52(t,J＝7.5Hz,1H,CH),2.62-2.53(m,2H,CH2),1.62(dd,J1＝6.8Hz,J2＝3.5Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ204.8169.4,169.3,87.6,86.8,52.5,51.1,27.8,14.3；IR(neat,cm-1)2987,2954,2919,2855,1966,1751,1739,1436,1341,1232,1152,1043；MS(EI,70eV)m/z(％)199(M++1,3.74),198(M+,27.55),98(100)；HRMS calcd.for C10H14O4[M+]:198.0892,found:198.0892.
实施例3
Figure BDA0001756035950000062
操作同实施例1。[Pd(π-cinnamyl)Cl]2(13.2mg,0.025mmol),(R)-(-)-DTBM-SEGPHOS(71.2mg,0.06mmol),K2CO3(276.6mg,2mmol),1c(169.5mg,1mmol)/THF(1.0mL)和2a(264.3mg,2mmol)/THF(4.0mL)反应得到油状联烯产物(Ra)-3ca(205.6mg,91％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝50/1):91％ee(HPLC conditions:Chiralcel AD-H column,n-hexane/i-PrOH＝100/1,0.7mL/min,λ＝214nm,tR(major)＝15.8min,tR(minor)＝16.7min)；[α]D 20＝-62.9(c＝1.00,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.06(m,2H,CH＝C＝CH),3.75(s,6H,2×OCH3),3.52(t,J＝7.5Hz,1H,CH),2.62-2.54(m,2H,CH2),1.98-1.88(m,2H,CH2),1.48-1.33(m,2H,CH2),0.92(t,J＝7.1Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ203.9,169.4,169.3,92.7,87.2,52.5,51.1,30.8,27.9,22.2,13.6；IR(neat,cm-1)2957,2933,2873,2847,1964,1755,1738,1436,1339,1269,1232,1154,1079,1040；MS(EI,70eV)m/z(％)226(M+,12.48),79(100)；HRMS calcd.for C12H18O4[M+]:226.1205,found:226.1206.
实施例4
Figure BDA0001756035950000071
操作同实施例1。[Pd(π-cinnamyl)Cl]2(13.4mg,0.025mmol),(R)-(-)-DTBM-SEGPHOS(71.3mg,0.06mmol),K2CO3(276.0mg,2mmol),1d(184.5mg,1mmol)/THF(1.0mL)和2a(264.7mg,2mmol)/THF(9.0mL)反应得到油状联烯产物(Ra)-3da(206.7mg,86％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝30/1):91％ee(HPLC conditions:Chiralcel OD-H column,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝20.3min,tR(major)＝21.9min)；[α]D 20＝-62.2(c＝1.03,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.06(m,2H,CH＝C＝CH),3.74(s,6H,2×OCH3),3.51(t,J＝7.5Hz,1H,CH),2.62-2.54(m,2H,CH2),2.01-1.90(m,2H,CH2),1.42-1.25(m,4H,2×CH2),0.90(t,J＝7.1Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ203.9,169.4,169.3,92.9,87.3,52.5,51.2,31.1,28.4,28.0,22.1,13.8；IR(neat,cm-1)2956,2931,2873,2859,1964,1756,1739,1436,1342,1264,1232,1154,1080,1043；MS(EI,70eV)m/z(％)240(M+,8.64),79(100)；HRMS calcd.for C13H20O4[M+]:240.1362,found:240.1370.
实施例5
Figure BDA0001756035950000081
操作同实施例1。[Pd(π-cinnamyl)Cl]2(13.0mg,0.025mmol),(R)-(-)-DTBM-SEGPHOS(71.3mg,0.06mmol),K2CO3(276.6mg,2mmol),1e(198.5mg,1mmol)/THF(1.0mL)和2a(264.1mg,2mmol)/THF(9.0mL)反应得到油状联烯产物(Ra)-3ea(216.2mg,85％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝30/1):91％ee(HPLC conditions:Chiralcel OD-H column,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝18.0min,tR(major)＝19.7min)；[α]D 20＝-62.8(c＝1.00,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.06(m,2H,CH＝C＝CH),3.74(s,6H,2×OCH3),3.51(t,J＝7.5Hz,1H,CH),2.62-2.53(m,2H,CH2),2.00-1.90(m,2H,CH2),1.44-1.22(m,6H,3×CH2),0.89(t,J＝6.8Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ203.9,169.4,169.3,93.0,87.3,52.5,51.2,31.3,28.73,28.69,28.0,22.4,14.0；IR(neat,cm-1)2955,2926,2871,2857,1961,1757,1739,1436,1342,1263,1232,1154,1040；MS(EI,70eV)m/z(％)254(M+,3.98),79(100)；HRMS calcd.for C14H22O4[M+]:254.1518,found:254.1523.
实施例6
Figure BDA0001756035950000082
操作同实施例1。[Pd(π-cinnamyl)Cl]2(13.1mg,0.025mmol),(R)-(-)-DTBM-SEGPHOS(71.2mg,0.06mmol),K2CO3(275.9mg,2mmol),1f(211.9mg,1mmol)/THF(1.0mL)和2a(264.8mg,2mmol)/THF(9.0mL)反应得到油状联烯产物(Ra)-3fa(228.2mg,85％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝30/1):91％ee(HPLC conditions:Chiralcel OD-H column,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝17.0min,tR(major)＝18.3min)；[α]D 20＝-65.8(c＝1.12,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.06(m,2H,CH＝C＝CH),3.74(s,6H,2×OCH3),3.51(t,J＝7.5Hz,1H,CH),2.61-2.52(m,2H,CH2),2.00-1.89(m,2H,CH2),1.44-1.23(m,8H,4×CH2),0.88(t,J＝6.8Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ203.9,169.34,169.27,93.0,87.3,52.4,51.2,31.6,29.0,28.7,28.0,22.6,14.0；IR(neat,cm-1)2955,2928,2856,1964,1755,1739,1436,1342,1266,1232,1154,1080,1042；MS(EI,70eV)m/z(％)268(M+,5.07),138(100)；HRMS calcd.for C15H24O4[M+]:268.1675,found:268.1678.
实施例7
Figure BDA0001756035950000091
操作同实施例1。[Pd(π-cinnamyl)Cl]2(13.2mg,0.025mmol),(R)-(-)-DTBM-SEGPHOS(71.0mg,0.06mmol),K2CO3(276.6mg,2mmol),1g(239.8mg,1mmol)/THF(1.0mL)和2a(264.3mg,2mmol)/THF(4.0mL)反应得到油状联烯产物(Ra)-3ga(242.5mg,82％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝35/1):92％ee(HPLC conditions:Chiralcel OD-H column,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝16.2min,tR(major)＝17.7min)；[α]D 20＝-64.6(c＝0.91,CHCl3)(reported value:94％ee；[α]D 29.5＝-61.8(c＝1.02,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.05(m,2H,CH＝C＝CH),3.74(s,6H,2×OCH3),3.51(t,J＝7.4Hz,1H,CH),2.62-2.53(m,2H,CH2),2.00-1.89(m,2H,CH2),1.44-1.20(m,12H,6×CH2),0.88(t,J＝6.6Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ203.9,169.4,169.3,93.0,87.3,52.5,51.2,31.8,29.4,29.2,29.1,29.0,28.8,28.0,22.6,14.1；IR(neat,cm-1)2954,2926,2855,1963,1757,1740,1436,1342,1260,1232,1153,1042；MS(EI,70eV)m/z(％)296(M+,1.87),79(100).
实施例8
Figure BDA0001756035950000101
操作同实施例1。[Pd(π-cinnamyl)Cl]2(13.1mg,0.025mmol),(R)-(-)-DTBM-SEGPHOS(71.0mg,0.06mmol),K2CO3(275.8mg,2mmol),1h(254.5mg,1mmol)/THF(1.0mL)和2a(264.2mg,2mmol)/THF(9.0mL)反应得到油状联烯产物(Ra)-3ha(266.7mg,86％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝30/1):90％ee(HPLC conditions:Chiralcel OD-H column,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝15.3min,tR(major)＝16.7min)；[α]D 20＝-61.5(c＝1.13,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.06(m,2H,CH＝C＝CH),3.74(s,6H,2×OCH3),3.51(t,J＝7.5Hz,1H,CH),2.62-2.53(m,2H,CH2),2.00-1.90(m,2H,CH2),1.46-1.22(m,14H,7×CH2),0.88(t,J＝6.6Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ203.9,169.4,169.3,93.0,87.3,52.5,51.2,31.9,29.6,29.4,29.3,29.12,29.06,28.8,28.0,22.7,14.1；IR(neat,cm-1)2954,2925,2854,1965,1757,1740,1458,1436,1340,1264,1232,1154,1043；MS(EI,70eV)m/z(％)310(M+,5.42),138(100)；HRMS calcd.for C18H30O4[M+]:310.2144,found:310.2145.
实施例9
Figure BDA0001756035950000102
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.7mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(16.7mg,0.014mmol),K2CO3(55.1mg,0.4mmol),1i(56.4mg,0.2mmol)/THF(0.5mL)和2a(53.3mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3ia(54.3mg,80％)(淋洗剂:石油醚(60-90℃)/乙酸乙酯＝30/1):91％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝16.4min,tR(major)＝18.2min)；[α]D 20＝-47.6(c＝0.62,CHCl3))(reported value:94％ee；[α]D 26＝-49.9(c＝1.00,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.06(m,2H,CH＝C＝CH),3.74(s,6H,2×OCH3),3.51(t,J＝7.5Hz,1H,CH),2.61-2.53(m,2H,CH2),2.00-1.89(m,2H,CH2),1.44-1.21(m,18H,9×CH2),0.88(t,J＝6.8Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ203.9,169.35,169.28,93.0,87.3,52.4,51.2,31.9,29.61,29.58,29.4,29.3,29.1,29.0,28.8,28.0,22.6,14.1；IR(neat,cm-1)2954,2925,2854,1964,1757,1741,1459,1436,1341,1262,1231,1153,1043；MS(EI,70eV)m/z(％)339(M++1,1.46),338(M+,5.66),138(100).
实施例10
Figure BDA0001756035950000111
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.5mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(16.4mg,0.014mmol),K2CO3(55.4mg,0.4mmol),1j(64.1mg,0.2mmol)/THF(0.5mL)和2a(53.1mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3ja(62.8mg,84％)(淋洗剂:石油醚(60-90℃)/乙酸乙酯/二氯甲烷＝30/1/1):91％ee(HPLC conditions:Chiralcel OD-H column,n-hexane/i-PrOH＝90/10,0.7mL/min,λ＝214nm,tR(minor)＝11.7min,tR(major)＝12.9min)；[α]D 20＝-43.0(c＝0.56,CHCl3)；1H NMR(300MHz,CDCl3)δ7.39-7.24(m,5H,Ar-H),5.20-5.06(m,2H,CH＝C＝CH),4.50(s,2H,OCH2),3.73(s,6H,2×OCH3),3.56-3.42(m,3H,OCH2+CH),2.62-2.53(m,2H,CH2),2.00-1.89(m,2H,CH2),1.67-1.55(m,2H,CH2),1.45-1.24(m,6H,3×CH2)；13C NMR(75MHz,CDCl3)δ203.9,169.34,169.29,138.6,128.3,127.5,127.4,92.9,87.4,72.8,70.4,52.5,51.2,29.7,28.92,28.90,28.7,28.0,26.0；IR(neat,cm-1)2932,2855,1963,1755,1738,1496,1454,1436,1342,1265,1232,1153,1101,1028；MS(EI,70eV)m/z(％)374(M+,2.26),91(100)；HRMS calcd.for C22H30O5[M+]:374.2093,found:374.2094.
实施例11
Figure BDA0001756035950000121
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.7mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(16.7mg,0.014mmol),K2CO3(55.5mg,0.4mmol),1k(73.4mg,0.2mmol)/THF(0.5mL)和2a(52.8mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3ka(74.7mg,88％)(淋洗剂:石油醚(60-90℃)/乙酸乙酯/二氯甲烷＝15/1/1):91％ee(HPLC conditions:Chiralcel As-H column,n-hexane/i-PrOH＝100/1,1.5mL/min,λ＝214nm,tR(major)＝8.3min,tR(minor)＝9.2min)；[α]D 20＝-42.9(c＝0.65,CHCl3)；1H NMR(300MHz,CDCl3)δ8.14-8.07(m,1H,ArH),7.88-7.77(m,2H,ArH),7.56-7.38(m,4H,ArH),5.17-5.05(m,2H,CH＝C＝CH),4.93(s,2H,ArCH2O),3.71(s,6H,2×OCH3),3.54(t,J＝6.5Hz,2H,OCH2),3.50(t,J＝6.9Hz,1H,CH),2.60-2.52(m,2H,CH2),1.98-1.86(m,2H,CH2),1.70-1.57(m,2H,CH2),1.42-1.22(m,6H,3×CH2)；13C NMR(75MHz,CDCl3)δ204.0,169.4,169.3,134.1,133.8,131.8,128.50,128.47,126.3,126.1,125.7,125.2,124.1,93.0,87.4,71.4,70.5,52.5,51.3,29.8,29.0,28.9,28.8,28.1,26.1；IR(neat,cm-1)2932,2855,1963,1739,1598,1511,1436,1339,1265,1232,1154,1098；MS(EI,70eV)m/z(％)424(M+,1.64),141(100)；HRMScalcd.for C26H32O5[M+]:424.2250,found:424.2251.
实施例12
Figure BDA0001756035950000122
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.7mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(14.8mg,0.012mmol),K2CO3(55.0mg,0.4mmol),1l(69.0mg,0.2mmol)/THF(0.5mL)和2a(53.3mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3la(66.8mg,84％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝40/1):92％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝16.4min,tR(major)＝17.3min)；[α]D 20＝-46.5(c＝0.64,CHCl3)；1H NMR(300MHz,CDCl3)δ5.35-5.21(m,2H,CH＝C＝CH),3.89(s,6H,2×OCH3),3.75(t,J＝6.5Hz,2H,OCH2),3.66(t,J＝7.7Hz,1H,CH),2.77-2.68(m,2H,CH2),2.15-2.05(m,2H,CH2),1.71-1.60(m,2H,CH2),1.59-1.42(m,6H,3×CH2),1.04(s,9H,t-Bu),0.20(s,6H,2×CH3)；13C NMR(75MHz,CDCl3)δ203.9,169.32,169.26,92.9,87.3,63.2,52.4,51.2,32.8,29.0,28.9,28.7,28.0,25.9,25.6,18.3,-5.4；IR(neat,cm-1)2949,2930,2857,1964,1757,1742,1472,1463,1436,1388,1340,1256,1233,1153,1100,1042,1006；MS(EI,70eV)m/z(％)399(M++1,1.01),398(M+,3.18),309(100)；HRMS calcd.for C21H38O5Si[M+]:398.2489,found:398.2485.
实施例13
Figure BDA0001756035950000131
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.6mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(14.5mg,0.012mmol),K2CO3(55.6mg,0.4mmol),1m(42.9mg,0.2mmol)/THF(0.5mL)和2a(53.5mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3la(44.3mg,83％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝50/1):93％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝21.1min,tR(major)＝23.6min)；1H NMR(300MHz,CDCl3)δ5.20-5.10(m,2H,CH＝C＝CH),3.75(s,3H,OCH3),3.74(s,3H,OCH3),3.51(t,J＝7.5Hz,1H,CH),2.63-2.54(m,2H,CH2),2.00-1.85(m,1H,oneprotonofCy),1.79-1.57(m,5H,protonsofCy),1.35-0.96(m,5H,protonsofCy)；13C NMR(75MHz,CDCl3)δ202.6,169.4,169.3,99.0,88.2,52.49,52.46,51.1,37.1,32.83,32.78,28.0,26.0,25.9；IR(neat,cm-1)2925,2851,1962,1752,1735,1437,1342,1263,1232,1153,1035；MS(EI,70eV)m/z(％)266(M+,9.93),134(100).
实施例14
Figure BDA0001756035950000141
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.7mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(14.5mg,0.012mmol),K2CO3(55.7mg,0.4mmol),1f(42.9mg,0.2mmol)/THF(0.5mL)和2b(69.1mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3fb(50.1mg,81％)(淋洗剂:石油醚(60-90℃)/乙酸乙酯＝40/1):94％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝12.4min,tR(major)＝12.8min)；[α]D 20＝-50.8(c＝0.51,CHCl3)；1H NMR(300MHz,CDCl3)δ5.74-5.57(m,1H,CH＝),5.16-5.03(m,3H,CH2＝and one proton of CH＝C＝CH),4.94-4.83(m,1H,oneproton of CH＝C＝CH),3.72(s,6H,2×OCH3),2.69(d,J＝7.5Hz,2H,CH2),2.59(dd,J1＝7.8Hz,J2＝2.4Hz,2H,CH2),1.96(qd,J1＝7.0Hz,J2＝2.8Hz,2H,CH2),1.42-1.20(m,8H,4×CH2),0.88(t,J＝6.7Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ205.8,171.1,132.3,119.2,91.1,84.5,57.9,52.39,52.36,36.7,32.6,31.7,29.2,28.81,28.78,22.6,14.1；IR(neat,cm-1)3080,2954,2929,2856,1963,1739,1641,1438,1325,1289,1214,1141,1077；MS(EI,70eV)m/z(％)309(M++1,5.99),308(M+,1.19),163(100)；HRMS calcd.for C18H28O4[M+]:308.1988,found:308.1988.
实施例15
Figure BDA0001756035950000142
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.8mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(14.0mg,0.012mmol),K2CO3(55.8mg,0.4mmol),1f(42.3mg,0.2mmol)/THF(0.5mL)和E-2c(100.0mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra,E)-3fc(63.4mg,82％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝40/1):93％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝19.3min,tR(major)＝20.7min)；[α]D 20＝-54.9(c＝0.53,CHCl3)；1H NMR(300MHz,CDCl3)δ7.35-7.16(m,5H,Ar-H),6.44(d,J＝15.9Hz,1H,CH＝),6.03(dt,J1＝15.5Hz,J2＝7.6Hz,1H,CH＝),5.14-5.06(m,1H,＝CH),4.98-4.86(m,1H,＝CH),3.73(s,6H,2×OCH3),2.85(d,J＝7.5Hz,2H,CH2),2.64(dd,J1＝7.8Hz,J2＝2.1Hz,2H,CH2),2.05-1.92(m,2H,CH2),1.44-1.18(m,8H,4×CH2),0.87(t,J＝6.8Hz,3H,CH3)；13CNMR(75MHz,CDCl3)δ205.8,171.1,137.1,134.0,128.4,127.3,126.1,123.8,91.1,84.6,58.1,52.43,52.40,36.0,32.8,31.6,29.2,28.8,28.7,22.6,14.0；IR(neat,cm-1)3027,2953,2927,2855,1963,1737,1496,1436,1323,1291,1273,1241,1203,1177,1092,1076；MS(EI,70eV)m/z(％)385(M++1,1.40),384(M+,5.05),91(100)；HRMS calcd.for C24H32O4[M+]:384.2301,found:384.2301.
实施例16
Figure BDA0001756035950000151
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.5mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(16.6mg,0.014mmol),K2CO3(55.6mg,0.4mmol),1f(42.0mg,0.2mmol)/THF(0.5mL)和2d(68.1mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3fd(50.8mg,83％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝30/1):94％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝19.0min,tR(major)＝20.2min)；[α]D 20＝-50.1(c＝0.64,CHCl3)；1H NMR(300MHz,CDCl3)δ5.14-5.04(m,1H,＝CH),δ4.93-4.83(m,1H,＝CH),3.742(s,3H,OCH3),3.739(s,3H,OCH3),2.86(d,J＝2.4Hz,2H,CH2C≡),2.75(dd,J1＝8.0Hz,J2＝2.3Hz,2H,CH2),2.01(t,J＝2.6,1H,HC≡),1.97(dq,J1＝7.0Hz,J2＝2.8Hz,CH2),1.45-1.20(m,8H,4×CH2),0.88(t,J＝6.8Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ205.9,170.0,91.1,84.0,78.7,71.3,57.1,52.7,52.6,32.3,31.6,29.0,28.70,28.68,22.5,14.0；IR(neat,cm-1)3295,2955,2928,2856,1963,1741,1437,1324,1292,1245,1210,1183,1079,1059；MS(EI,70eV)m/z(％)306(M+,6.36),117(100)；HRMScalcd.for C18H26O4[M+]:306.1831,found:306.1832.
实施例17
Figure BDA0001756035950000161
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.5mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(16.6mg,0.014mmol),K2CO3(55.6mg,0.4mmol),1n(34.0mg,0.2mmol)/THF(0.5mL)和2d(69.0mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3nd(33.3mg,63％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝40/1):96％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝21.6min,tR(major)＝22.7min)；[α]D 20＝-45.6(c＝0.47,CHCl3))；1H NMR(300MHz,CDCl3)δ5.15-5.07(m,1H,＝CH),4.98-4.87(m,1H,＝CH),3.75(s,6H,2×OCH3),2.87(d,J＝2.4Hz,2H,CH2C≡),2.77(d,J＝6.9Hz,2H,CH2),2.33-2.20(m,1H,CH),2.02(t,J＝2.6Hz,1H,HC≡),1.00(d,J＝6.9Hz,6H,2×CH3)；13C NMR(75MHz,CDCl3)δ204.4,170.1,98.6,85.3,78.8,71.4,57.1,52.8,52.7,32.5,27.9,22.6,22.39,22.37；IR(neat,cm-1)3295,2956,2928,2855,1962,1739,1438,1323,1291,1211,1177,1079,1057；MS(EI,70eV)m/z(％)264(M+,2.66),145(100)；HRMS calcd.for C15H20O4[M+]:264.1362,found:264.1359.
实施例18
Figure BDA0001756035950000162
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.4mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(16.5mg,0.014mmol),K2CO3(55.6mg,0.4mmol),1o(55.3mg,0.2mmol)/THF(0.5mL)和2d(68.5mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3od(61.5mg,85％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝40/1):92％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝19.8min,tR(major)＝21.0min)；[α]D 20＝-43.3(c＝0.495,CHCl3))；1H NMR(300MHz,CDCl3)δ5.88-5.73(m,1H,CH＝),5.15-4.83(m,4H,2×＝CH+＝CH2),3.74(s,6H,2×OCH3),2.87(d,J＝3.0Hz,2H,CH2C≡),2.75(dd,J1＝7.8Hz,J2＝2.1Hz,2H,CH2),2.10-1.90(m,5H,HC≡and2×CH2),1.45-1.22(m,12H,6×CH2)；13C NMR(75MHz,CDCl3)δ205.9,170.0,139.1,114.0,91.2,84.0,78.7,71.3,57.0,52.71,52.67,33.7,32.3,29.4,29.3,29.1,29.04,29.00,28.8,28.7,22.5；IR(neat,cm-1)3297,3076,2926,2854,1963,1740,1640,1437,1324,1292,1210,1180,1079,1057；MS(EI,70eV)m/z(％)360(M+,5.37),117(100)；HRMS calcd.for C22H32O4[M+]:360.2301,found:360.2302.
实施例19
Figure BDA0001756035950000171
操作同实施例1。[Pd(π-cinnamyl)Cl]2(2.6mg,0.005mmol),(R)-(-)-DTBM-SEGPHOS(16.8mg,0.014mmol),K2CO3(55.8mg,0.4mmol),1f(42.3mg,0.2mmol)/THF(0.5mL)和2e(98.1mg,0.4mmol)/THF(1.5mL)反应得到油状联烯产物(Ra)-3fe(63.1mg,82％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝50/1):95％ee(HPLC conditions:Chiralcel OD-Hcolumn,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝20.4min,tR(major)＝21.5min)；[α]D 20＝-52.3(c＝0.61,CHCl3)；1H NMR(300MHz,CDCl3)δ7.40-7.32(m,2H,Ar-H),7.31-7.23(m,3H,Ar-H),5.15-5.05(m,1H,＝CH),4.99-4.88(m,1H,＝CH),3.76(s,6H,2×OCH3),3.09(s,2H,CH2),2.82(dd,J1＝7.8Hz,J2＝2.4Hz,2H,CH2),1.97(qd,J1＝7.1Hz,J2＝2.7Hz,2H,CH2),1.43-1.17(m,8H,4×CH2),0.87(t,J＝6.6Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ205.9,170.2,131.6,128.1,127.9,123.2,91.2,84.22,84.20,83.5,57.4,52.73,52.69,32.6,31.6,29.1,28.8,28.7,23.5,22.5,14.0；IR(neat,cm-1)2954,2928,2856,1963,1739,1598,1491,1436,1326,1293,1209,1183,1079,1030；MS(EI,70eV)m/z(％)383(M++1,11.60),382(M+,40.22),91(100)；HRMS calcd.fo rC24H30O4[M+]:382.2144,found:382.2148.
实施例20
Figure BDA0001756035950000181
操作同实施例1。[Pd(π-cinnamyl)Cl]2(13.1mg,0.025mmol),(R)-(-)-DTBM-SEGPHOS(71.0mg,0.06mmol),K2CO3(276.7mg,2mmol),1f(212.0mg,1mmol)/THF(1.0mL)和2f(368.1mg,2mmol)/THF(9.0mL)反应得到油状联烯产物(Ra)-3ff(264.9mg,83％)(淋洗剂:石油醚(30-60℃)/乙酸乙酯＝50/1):95％ee(HPLC conditions:Chiralcel OD-H column,n-hexane/i-PrOH＝200/1,0.5mL/min,λ＝214nm,tR(minor)＝13.1min,tR(major)＝14.7min)；[α]D 20＝-57.1(c＝1.01,CHCl3)；1H NMR(300MHz,CDCl3)δ5.12-5.03(m,1H,CH＝),δ5.01-4.73(m,2H,CH＝C＝CH),δ4.68-4.63(dt,J1＝6.6Hz,J2＝2.4Hz,2H,＝CH2),3.72(s,6H,2×OCH3),2.70-2.58(m,4H,2×OCH2),1.96(qd,J1＝7.1Hz,J2＝2.8Hz,2H,CH2),1.44-1.23(m,8H,4×CH2),0.88(t,J＝6.9Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ209.9,205.7,170.9,91.0,84.4,84.0,74.4,57.8,52.31,52.28,32.4,31.63,31.57,29.1,28.7,22.5,14.0；IR(neat,cm-1)2954,2928,2856,1957,1738,1732,1435,1378,1280,1243,1205,1180,1081；MS(EI,70eV)m/z(％)320(M+,24.04),131(100)；HRMS calcd.for C19H28O4[M+]:320.1988,found:320.1985.
为证明本发明的实用性，以下实施例为本发明所得1,3-二取代联烯产物的应用。
实施例21
Figure BDA0001756035950000182
向一个Schlenk反应管中依次加入(±)-3la,甲醇(12mL),水(8mL)和NaOH(320.4mg,8.0mmol)。将反应管放入100℃的油浴中搅拌反应3小时，TLC监测反应结束。将反应混合液冷至室温，用1M的稀盐酸调节pH至1。用乙醚(20mL×4)萃取反应混合液，合并有机相用无水硫酸钠干燥。过滤，浓缩，所得粗产品直接用于下一步反应。
将所得的上述粗产物溶解于乙酸(8.0mL)中，并加入另一个Schlenk管中。将反应管放入120℃的油浴中反应41小时,TLC监测反应结束。将反应混合液冷至室温，浓缩，所得粗产品经快速柱层析纯化(淋洗剂:石油醚(60-90℃)/乙酸乙酯/二氯甲烷＝3/1/1)。
将所得的上述产物(50.3mg,0.2mmol)转移至另一个Schlenk管中，依次加入甲醇(1.5mL),水(0.5mL)和氢氧化钠(23.7mg,0.6mmol)。室温搅拌反应2.5小时，TLC监测反应结束。用1M的稀盐酸调节pH至1。用乙酸乙酯(15mL×4)萃取反应混合液，合并有机相用无水硫酸钠干燥。过滤，浓缩，所得粗产品经快速柱层析(淋洗剂:乙酸乙酯/二氯甲烷＝1/1)得到油状化合物(±)-4la(39.8mg,78％):1H NMR(300MHz,CDCl3)δ6.33(brs,2H,COOHandOH),5.19-5.08(m,2H,CH＝C＝CH)3.63(t,J＝6.6Hz,2H,OCH2),2.49-2.40(m,2H,CH2),2.34-2.23(m,2H,CH2),2.02-1.89(m,2H,CH2),1.62-1.50(m,2H,CH2),1.48-1.24(m,6H,3×CH2)；13C NMR(75MHz,CDCl3)δ203.6,177.8,92.5,89.4,62.6,33.1,32.1,28.7,28.6,28.5,25.3,23.5；IR(neat,m-1)3500-2200(COOH),2931,2856,1963,1717,1436,1409,1338,1251,1207,1166,1053；MS(70ev,EI)m/z(％)213(M++1,1.51),212(M+,2.60),67(100)；HRMScalcd for C12H20O3[M+]:212.1412,Found:212.1411.
实施例22
Figure BDA0001756035950000191
在手套箱中，向一干燥的Schlenk管中加入AgOTs(2.8mg,0.01mmol)。移出手套箱，在氮气保护下依次加入AuCl(LB-Phos)(5.9mg,0.01mmol)和CHCl3(1mL)。先将反应混合液在25℃搅拌反应15分钟,然后在-20℃搅拌10分钟。在氮气保护和搅拌下，加入(±)-4la(42.7mg,0.2mmol)和CHCl3(1mL)。将反应混合液在-20℃下搅拌反应11.5小时,TLC监测反应结束。滤短柱，用乙酸乙酯(10mL×3)淋洗。浓缩，所得粗产品是(E)-(±)-5la和(Z)-(±)-5la的混合物(E/Z＝96/4,通过粗产品的1H NMR分析确定)。所得粗产品经快速柱层析(淋洗剂:乙醚/二氯甲烷＝1/2)得油状产物(±)-5la(39.1mg,92％,通过分析产物氢谱确认E/Z＝96/4)；(E)-(±)-5la:1H NMR(300MHz,CDCl3)δ5.81(dt,J1＝14.7Hz,J2＝7.2Hz,1H,＝CH),5.49(dd,J1＝15.3Hz,J2＝6.9Hz,1H,＝CH),4.90(q,J＝7.1Hz,1H,OCH),3.63(t,J＝6.5Hz,2H,OCH2),2.61-2.46(m,2H,CH2),2.46-2.29(m,1H,one proton from CH2),2.13-1.88(m,3H,CH2and one proton from CH2),1.66(s,1H,OH),1.61-1.48(m,2H,CH2),1.47-1.21(m,6H,3×CH2)；13C NMR(75MHz,CDCl3)δ177.3,135.5,127.4,81.2,62.7,32.6,32.0,28.82,28.78,28.72,28.66,25.5；IR(neat,cm-1)3429,2930,2856,1771,1672,1460,1421,1329,1219,1180,1124,1056,1007；MS(70ev,EI)m/z(％)213(M++1,2.57),212(M+,1.14),41(100)；HRMS calcd forC12H20O3[M+]:212.1412,Found:212.1412.
下列信号属于(Z)-(±)-5la:1H NMR(300MHz,CDCl3)δ5.70-5.63(m,1H,＝CH),5.25(q,J＝7.3Hz,1H,OCH).
实施例23
Figure BDA0001756035950000201
向一反应瓶中依次加入Pd/C(10％on C,dry,10.8mg,0.01mmol),(±)-5la(43.0mg,0.2mmol)和乙酸乙酯(2mL)。将反应管放入高压釜中，调节H2压力为25atm。室温搅拌反应11小时，TLC监测反应结束。滤短柱，用乙酸乙酯(10mL×3)淋洗，浓缩得到粗产品(±)-6，未经纯化直接投下一步反应。
向一Schlenk管中依次加入Fe(NO3)3·9H2O(8.2mg,0.02mmol),KCl(1.6mg,0.02mmol),TEMPO(4.9mg,0.03mmol),和1,2-二氯乙烷(0.5mL)。给反应管装上氧气球，并加入上述制备的(±)-6和1,2-二氯乙烷(1.5mL)。室温搅拌反应19小时，TLC监测反应结束。滤短柱，乙酸乙酯(10mL×4)洗涤，将所得滤液浓缩,所得粗产品经快速柱层析(淋洗剂:石油醚(60-90℃)/乙酸乙酯/二氯甲烷＝1/1/1)得固状的外消天然产物(±)-traumaticlactone(36.1mg,两步总收率79％):熔点53.5-55.0℃(二氯甲烷/正己烷)(文献值：48.5-50℃(异丙醚/正己烷))；1H NMR(300MHz,CDCl3)δ8.56(bs,1H,COOH),4.49(q,J＝6.8Hz,1H,OCH),2.54(dd,J1＝9.5Hz,J2＝7.1Hz,2H,CH2),2.40-2.26(m,3H,CH2 and one protonfrom CH2),1.94-1.23(m,13H,6×CH2 and one proton from CH2)；13C NMR(75MHz,CDCl3)δ179.8,177.5,81.1,35.5,34.0,29.1,29.02,28.88,28.87,28.0,25.2,24.6；IR(neat,cm-1)3716-2218(COOH),2933,2858,2672,1771,1711,1461,1420,1356,1284,1186,1017；MS(70ev,EI)m/z(％)229(M++1,19.74),228(M+,1.81),211(100),85(100).
实施例24
Figure BDA0001756035950000211
向一Schlenk管中依次加入(Ra)-3ja(374.6mg,1.0mmol)/甲醇(3mL)和氢氧化钠(2mL,2M,4mmol,160.0mg)。在100℃下搅拌反应2.5小时，TLC监测反应结束。将反应混合液冷至室温，用1M的稀盐酸调节pH至1。向混合液中加入20mL饱和食盐水，用乙醚(20mL×3)萃取。合并有机相用无水硫酸钠干。经过滤，将滤液浓缩得粗产品(346.2mg)，未经纯化直接投下一步反应。
将上述得到的粗产品(242.0mg)溶于乙酸(4.2mL)中，在氮气保护下转移至另一干燥的Schlenk中。将反应管置于120℃的油浴中搅拌反应8小时，TLC监测反应结束。将反应混合液冷至室温，浓缩，所得粗产品经快速柱层析(淋洗剂:石油醚(60-90℃)/乙酸乙酯/二氯甲烷＝3/1/1)得到油状产物(Ra)-4ja(192.5mg,91％):1H NMR(300MHz,CDCl3)δ10.19(brs,1H,COOH),7.40-7.23(m,5H,ArH),5.19-5.09(m,2H,＝CH×2),4.50(s,2H,CH2),3.46(t,J＝6.6Hz,2H,CH2),2.50-2.40(m,2H,CH2),2.34-2.23(m,2H,CH2),2.02-1.90(m,2H,CH2),1.68-1.55(m,2H,CH2),1.45-1.25(m,6H,CH2×3)；13CNMR(75MHz,CDCl3)δ203.6,179.0,138.5,128.3,127.6,127.4,92.7,89.3,72.8,70.3,33.1,29.6,28.9,28.8,28.7,25.9,23.5；IR(neat,cm-1)3699-2268(COOH),1963,1710,1496,1454,1363,1250,1207,1160,1101,1028；MS(70ev,EI)m/z(％)303(M++1,10.72),302(M+,2.49),91(100)；HRMS calcdfor C19H26O3[M+]:302.1882,Found:302.1885.
实施例25
Figure BDA0001756035950000221
在手套箱中，向一干燥的Schlenk管中加入AgOTs(2.7mg,0.01mmol)。将反应管移出手套箱，在氮气保护下加入Au(LB-Phos)Cl(5.8mg,0.01mmol)和CHCl3(1mL)。先将反应混合液在室温搅拌反应15分钟，然后在-20℃搅拌10分钟，再加入(Ra)-4ja(60.3mg,0.2mmol)和CHCl3(1mL)。反应混合液在-20℃搅拌反应12小时后，TLC监测反应结束。滤短柱，用乙酸乙酯(10mL×3)淋洗，将所得的滤液浓缩后得到粗产品为(S,E)-5ja和(R,Z)-5ja的混合物：通过分析粗产品1H NMR确定(S,E)/(R,Z)＝98/2。快速柱层析(淋洗剂:石油醚(60-90℃)/乙醚＝2/1)得到油状产物(S,E)-5ja(57.1mg,95％,通过产物的1H NMR分析确定(S,E)/(R,Z)＝98/2):91％ee(HPLC conditions:Chiralcel PA-2 column,n-hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(major)＝44.0min,tR(minor)＝65.5min；[α]D 20＝+20.4(c＝0.62,CHCl3)；1H NMR(300MHz,CDCl3)δ7.36-7.21(m,5H,ArH),5.84-5.72(m,1H,＝CH),5.46(ddt,J1＝15.3Hz,J2＝7.2Hz,J3＝1.4Hz,1H,＝CH),4.86(q,J＝7.2Hz,1H,OCH),4.49(s,2H,ArCH2),3.46(t,J＝6.8Hz,2H,OCH2),2.55-2.46(m,2H,CH2),2.42-2.26(m,1H,oneproton fromCH2),2.05(q,J＝6.6Hz,2H,CH2),1.99-1.86(m,1H,one proton fromCH2),1.67-1.53(m,2H,CH2),1.45-1.24(m,6H,3×CH2)；13C NMR(75MHz,CDCl3)δ177.1,138.7,135.6,128.3,127.6,127.5,81.1,72.9,70.4,32.0,29.7,28.9,28.8,28.75,28.72,26.0；IR(neat,cm-1)3087,3062,3030,2929,2853,2791,1774,1671,1496,1453,1364,1327,1175,1101；GC-MS(70ev,EI)m/z(％)for(S,E)-5ja:tR(major)＝9.30min:302(M+,0.15),193((M+-C7H9O,7.81),91(100)；for(R,Z)-5ja:tR(minor)＝9.11min:193(M+-C7H9O,7.33),91(100)；Anal.Calcd for C19H26O3:C75.46,H 8.67.Found:C75.19,H8.53.
实施例26
Figure BDA0001756035950000231
向一反应管中依次加入(S,E)-5ja((S,E)/(R,Z)＝98/2)(127.2mg,0.42mmol),乙酸乙酯(4.2mL)和Pd/C(10％on C,dry,22.4mg,0.021mmol)。将反应管放入高压釜中，调节H2压力为25atm。室温搅拌反应12小时，TLC监测反应结束。滤短柱，用乙酸乙酯(10mL×3)淋洗，浓缩得到粗产品(R)-6，未经纯化直接投下一步反应。
向一Schlenk管中依次加入Fe(NO3)3·9H2O(17.2mg,0.042mmol)，KCl(3.2mg,0.042mmol),TEMPO(10.0mg,0.063mmol)和1,2-二氯乙烷DCE(1mL)。给反应管装上氧气球，并加入上述制备的(R)-6和1,2-二氯乙烷(3.2mL)。室温搅拌反应20小时，TLC监测反应结束。滤短柱，乙酸乙酯(15mL×4)淋洗。浓缩,所得粗产品经快速柱层析(淋洗剂:石油醚(60-90℃)/乙酸乙酯/二氯甲烷＝1/1/1)得固状的手性天然产物(R)-traumatic lactone(86.2mg,90％,两步总收率90％):87％ee(determined by Esterification)；[α]D 20＝+26.8(c＝0.47,CHCl3)；熔点60.3-62.2℃(乙醚/正己烷)；1H NMR(300MHz,CDCl3)δ9.98(bs,1H,COOH),4.57-4.42(m,1H,CH),2.54(dd,J1＝9.6Hz,J2＝6.9Hz,2H,CH2),2.40-2.26(m,3H,CH2 and one proton from CH2),1.93-1.22(m,13H,6×CH2 and one proton fromCH2)；13C NMR(75MHz,CDCl3)δ179.8,177.5,81.0,35.4,33.9,29.0,28.9,28.80,28.77,27.9,25.1,24.5；IR(neat,cm-1)3728-2284(COOH),1770,1708,1462,1420,1356,1185,1017；MS(70ev,EI)m/z(％)229(M++1,13.81),228(M+,0.63),221(M+-OH,88.79),85(100)；Anal.Calcd for C12H20O4:C 63.14,H 8.83.Found:C 63.07,H 8.64.
实施例27
Figure BDA0001756035950000241
向一Schlenk管中依次加入K2CO3(41.5mg,0.3mmol),(R)-traumatic lactone(22.2mg,0.1mmol),BnBr(21.0mg,0.12mmol)和DMF(2mL)。将反应混合液在室温下搅拌反应4小时，TLC监测反应结束。用20mL乙酸乙酯稀释反应混合液，并将反应混合液转移至分液漏斗中，用饱和食盐水(20mL×3)洗涤。合并水相，用20mL乙酸乙酯萃取。合并有机相用无水硫酸钠干燥。过滤，浓缩滤液得粗产品。粗产品经快速柱层析(淋洗剂:石油醚(60-90℃)/乙酸乙酯/二氯甲烷＝5/1/1)得到油状产物(R)-7(29.0mg,91％):87％ee(HPLC conditions:Chiralcel AS-H column,n-hexane/i-PrOH＝90/10,2.0mL/min,λ＝214nm,tR(minor)＝20.4min,tR(major)＝25.1min)；[α]D 20＝+19.6(c＝0.53,CHCl3)；1H NMR(300MHz,CDCl3)δ7.41-7.29(m,5H,ArH),5.11(s,2H,ArCH2),4.52-4.41(m,1H,OCH),2.53(dd,J1＝9.6Hz,J2＝6.9Hz,2H,CH2),2.40-2.24(m,3H,CH2 and one proton from CH2),1.91-1.23(m,13H,6×CH2 and one proton from CH2)；13C NMR(75MHz,CDCl3)δ177.2,173.5,136.0,128.5,128.1,80.9,66.0,35.5,34.2,29.0,28.97,28.86,28.8,27.9,25.1,24.8；IR(neat,cm-1)3087,3061,3033,2929,2856,1771,1732,1498,1456,1419,1383,1351,1260,1195,1180,1143,1132,1076,1021；MS(70ev,EI)m/z(％)319(M++1,22.16),318(M+,1.53),211(100)；HRMS calcd for C19H26O4[M+]:318.1831,found:318.1836.
实施例28
Figure BDA0001756035950000242
向一圆底瓶中加入(R)-traumatic lactone(64.0mg),再加入乙醚(10mL)将其完全溶解,最后加入正己烷(10mL)。将所得混合液室温静置结晶得到(R)-traumatic lactone(47.4mg,74％):98％ee(determined by Esterification)；[α]D 20＝+32.0(c＝0.48,CHCl3).
操作同实施例27。K2CO3(41.4mg,0.3mmol),(R)-traumatic lactone(22.9mg,0.1mmol)和BnBr(20.8mg,0.12mmol)/DMF反应得到油状产物(R)-7(30.5mg,96％)(淋洗剂:石油醚(60-90℃)/乙酸乙酯/二氯甲烷＝5/1/1)as an oil:98％ee(HPLC conditions:Chiralcel AS-H column,n-hexane/i-PrOH＝90/10,2.0mL/min,λ＝214nm,tR(minor)＝19.0min),tR(major)＝22.9min；[α]D 20＝+22.3(c＝0.52,CHCl3)；1H NMR(300MHz,CDCl3)δ7.40-7.28(m,5H,ArH),5.11(s,2H,ArCH2),4.52-4.41(m,1H,CH),2.56-2.47(m,2H,CH2),2.38-2.24(m,3H,CH2+one proton fromCH2),1.91-1.24(m,13H,6×CH2+one protonfromCH2)；13C NMR(75MHz,CDCl3)δ177.2,173.5,136.0,128.5,128.1,80.9,66.0,35.5,34.2,29.04,28.98,28.88,28.8,27.9,25.1,24.8.
最后，还需要注意的是，以上列举的仅是本发明的具体实施例子。显然，本发明不限于以上实施例子，还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形，均应认为是本发明的保护范围。

Claims (1)

1.一种高光学活性轴手性联烯化合物的构建方法，其特征在于，在钯催化剂、手性双膦配体和碱的作用下，2,3-联烯基官能团化合物和亲核试剂在有机溶剂中反应，高立体选择性地构建轴手性联烯化合物，反应式如下：
Figure FDA0003376773800000011
其中，所述的2,3-联烯基官能团化合物1中R1为烷基或者含有被杂原子官能团取代的烷基，LG为碳酸酯、醋酸酯、苯甲酸酯、特戊酸酯、磷酸酯或者卤素原子；
其中，所述的亲核试剂2中R2为氢原子或非氢原子的官能团，E为拉电子基团，为砜基、氰基、羧基、酯基或酮羰基中的一种；
所述的化合物(Ra)-3中，R1为烷基或者含有被杂原子官能团取代的烷基，R2为氢原子或非氢原子的基团，E为拉电子基团，为砜基、氰基、羧基、酯基或酮羰基中的一种；
所述反应式(1)中2,3-联烯基官能团化合物1、亲核试剂2、钯催化剂、手性双膦配体和碱的摩尔比或质量比为1.0：1.0–3.0：0.005–0.05：0.01–0.20：1.0–6.0；
所述的构建方法的具体操作步骤如下：
1)、在手套箱中，向一个干燥的反应管中依次投入手性双膦配体和碱，将反应管移出手套箱，在氮气保护下加入钯催化剂、亲核试剂2和一定体积的有机溶剂，将反应管置于室温搅拌反应30分钟，所述有机溶剂为四氢呋喃；
2)、待步骤1)完成后，将反应管放入设定为反应温度的实验设备中，搅拌10分钟；
3)、待步骤2)完成后，在该温度和氮气保护下加入2,3-联烯基官能团化合物1和一定体积的有机溶剂，搅拌反应；
4)、待步骤3)反应完全后，将反应混合液用硅胶短柱过滤，并用有机溶剂淋洗，浓缩所得有机混合液，快速柱层析得最终产物；
所述钯催化剂为二(肉桂基氯化钯)；
所述手性双膦配体为(R)-(-)-DTBM-SEGPHOS；
所述碱为碳酸钾。
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