CN110724164A - 吡啶环上3-位取代手性螺环胺基膦配体制备方法及其应用 - Google Patents

吡啶环上3-位取代手性螺环胺基膦配体制备方法及其应用 Download PDF

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CN110724164A
CN110724164A CN201911043033.3A CN201911043033A CN110724164A CN 110724164 A CN110724164 A CN 110724164A CN 201911043033 A CN201911043033 A CN 201911043033A CN 110724164 A CN110724164 A CN 110724164A
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pyridine ring
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chiral spiro
aminophosphine ligand
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谢建华
赵乾坤
顾雪松
周其林
王立新
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Nankai University
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Abstract

本发明涉及一种吡啶环上3‑位取代手性螺环胺基膦配体制备方法和应用。该吡啶环上3‑位取代手性螺环胺基膦配体是具有式1所示的化合物，或其消旋体或旋光异构体，或其催化可接受的盐，主要结构特征是具有手性螺二氢茚骨架和具有吡啶基团。该吡啶环上3‑位取代手性螺环胺基膦配体可以由具有螺环骨架的7‑二芳/烷基膦基‑7′‑氨基‑1,1′‑螺二氢茚类化合物为手性起始原料合成。该吡啶环上3‑位取代手性螺环胺基膦配体与过渡金属(铱)盐形成配合物后，可用于催化α‑芳胺取代内酯化合物的不对称催化氢化反应。表现出很高的催化活性(TON达到19000)和对映选择性(高达99％ee)，具有实用价值。

Description

吡啶环上3-位取代手性螺环胺基膦配体制备方法及其应用
技术领域
本发明涉及一种吡啶环上3-位取代手性螺环胺基膦配体制备方法和应用，特别是一种具有螺环骨架的手性螺环胺基吡啶三齿配体的制备方法及其在β-芳基亚烷基丙二酸酯的不对称催化氢化反应方面的应用，属于有机合成技术领域。
背景技术
不对称催化氢化是合成手性化合物最绿色、原子经济的有效方法，在工业生产手性药物、农药、香料等方面已得到了实际应用。不对称催化氢化反应的效率和选择性取决于手性催化剂的活性、稳定性和效率。因此，发展新颖、高效的手性配体及其催化剂是实现高效、高对映选择性并具有工业应用价值的不对称催化氢化反应的关键，并受到学术界和工业界广泛关注。
β-位含有芳基烷基取代叔碳手性中心的丙二酸酯类手性化合物在手性药物和天然产物等的合成中有着重要的用途。如通过脱去一个酯基转化为相应的酯或羧酸就可以用于手性药物Tipranavir(Romero,A.G.；et al.J.Org.Chem.1999,64,4980)，(R)-RC-33(Pricl,S.；Collina,S.；et al.ChemMedChem 2013,8,1514)以及天然产物(-)-juvabione(Andersson,P.G.；et al.Org.Lett.2018,20,5676)的对映选择性合成。然而，目前仍未有直接通过β-芳基亚烷基丙二酸酯的不对称催化氢化来合成β-位含有芳基烷基取代叔碳手性中心的丙二酸酯类手性化合物的文献报道。此外，虽然有文献报道用α,β-不饱和羧酸及酯类衍生物的不对称催化氢化的方法来合成其脱酯产物(Hou,G.；etal.J.Org.Chem.2016,81,2070；Kitamura,M.；et al.Tetrahedron 2007,63,11399；Diéguez,M.；et al.Adv.Synth.Catal.2017,359,2801；Zhou,J.；et al.Org.Lett.2006,18,5344)，但底物的范围较窄，催化剂用量高(<1mol％)，反应条件也相对较苛刻(50-100atmH2)，且仅对单一构型的底物(Z或E)才能给出高的对映选择性。这些因素限制了α,β-不饱和羧酸及酯类衍生物的不对称催化氢化这种高原子经济性反应方法的应用。采用不含Z或E构型的β-芳基亚烷基丙二酸酯的不对称催化氢化无疑提供一种对映选择性合成β-位含有芳基烷基取代叔碳手性中心的手性羧酸及其衍生物的选择。
手性螺环吡啶胺基膦三齿配体的铱络合物Ir-SpiroPAP(Xie,J.-H.；Zhou,Q.-L.；et al.,Angew.Chem.Int.Ed.2011,50,7329-9332.周其林，谢建华，刘晓艳，谢剑波，王立新CN 102040625A)对酮和烯酮等羰基化合物的不对称催化氢化表现出优秀的催化活性和对映选择性(Xie,J.-H.；Zhou,Q.-L.et al.Acta Chimica Sinica 2014,72,778-797；Xie,J.-H.；Zhou,Q.-L.；et al.Org.Lett.2017,19,3231)。我们经过研究发现，吡啶环3-位含有立体效应显著取代基的手性螺环吡啶胺基膦三齿配体SpiroPAP配体的铱络合物，能够实现了β-芳基亚烷基丙二酸酯的高效和高对映选择性不对称催化氢化，氢化产物的对映选择性高达99％ee，转化数(氢化底物与催化剂的摩尔比)最高也可达到19000。这为光学活性β-芳基烷基取代丙二酸酯以及3-芳基脂肪酸或脂肪酸酯等的对映选择性合成提供了绿色、高效、实用的合成方法。该合成方法反应条件温和、操作简单、适于工业化生产，并具有非常好的应用前景和价值。
发明内容
本发明的目的在于提供一种吡啶环上3-位取代手性螺环胺基膦配体制备方法和应用，该手性螺环三齿配体是基于手性螺环吡啶胺基膦三齿配体的铱络合物Ir-SpiroPAP的基础上设计发展的吡啶环3-位含有立体效应更加显著取代基的新手性螺环膦-氨基-吡啶三齿配体。通过在吡啶环3-位引入立体效应更加显著的取代基从而更好控制催化氢化反应过程中的手性传递，从而显著地提高了催化剂对底物的手性控制，并在β-芳基亚烷基丙二酸酯的不对称催化氢化中获得了优秀的对映选择性(高达99％ee)和高转化数(高达19000的TON)，为光学活性3-芳基脂肪酸或脂肪酸酯的合成提供了绿色、高效、实用的合成方法。
本发明提供的一种吡啶环上3-位取代手性螺环胺基膦配体具有式1的化合物或其对映体、消旋体，或其催化可接受的盐。
Figure BDA0002253374570000021
其中，R1选自C1～C10的烃基、苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基；所述的苯基上的取代基为C1～C10的烃基、烷氧基，取代基数量为1～5；杂芳基为呋喃基、噻吩基或吡啶基；
R2、R3、R4分别独立选自H、C1～C10烷基、苯基、取代苯基、取代酯基；所述的苯基上的取代基为C1～C10的烃基、烷氧基，取代基数量为1～5；R2～R4可为C3～C7脂肪环、吡咯环、芳香环；R2、R3、R4相同或不同。
本发明提供的所述的吡啶环上3-位取代手性螺环胺基膦配体选自如下化合物的对映体、消旋体或其催化可接受的盐：
Figure BDA0002253374570000022
其中DTB为3，5-二叔丁基苯基；An为4-甲氧基苯基；iPr为异丙基；tBu为叔丁基。
本发明提供的所述的吡啶环上3-位取代手性螺环胺基膦配体的制备方法包括的步骤：以具有手性螺二氢茚骨架的式2所示的消旋或旋光活性的7-二芳/烷基膦基-7′-氨基-1,1′-螺二氢茚类化合物为起始原料，经过下述反应式：
Figure BDA0002253374570000031
具有手性螺二氢茚骨架的式2所示的化合物是按文献方法制备(Jian-Bo Xie,Jian-Hua Xie,Xiao-Yan Liu,Wei-Ling Kong,Shen Li,Qi-Lin Zhou,J.Am.Chem.S℃.2010,132,4538；周其林,谢建华,谢剑波,王立新,CN 101671365A)。
具体步骤如下：
在有机溶剂和还原剂存在的条件下，具有式2所示的化合物与醛、酸在反应器中反应2～24小时制备得到式1所示的化合物；
所述的有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、苯、苯甲醚、甲苯、二甲苯、甲基叔丁基醚、乙醚、二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、1,2-二氯乙烷、丙酮、石油醚、正己烷中的一种或其中几种的混合溶剂。
所述的还原试剂可为氢化铝锂、硼氢化钠、三乙酰氧基硼氢化钠、腈基硼氢化钠；述的酸包括有机酸和无机酸，可为盐酸、硫酸、硝酸、甲酸、乙酸、苯甲酸。
所述的碱包括有机碱和无机碱，可为吡啶、三乙胺、三丁胺、N-甲基吗啡啉、N,N-二乙基异丙基胺、二异丙基氨基锂、氢化锂、氢化钾、氢化钠、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾。
本发明提供的所述的吡啶环上3-位取代手性螺环胺基膦配体的应用是：该配体与过渡金属(铱)金属盐原位形成配合物，铱配合物(可直接不脱溶或脱溶后制备成可存放的固体)作为铱催化剂，用于催化β-芳基亚烷基丙二酸酯化合物的不对称催化氢化反应：
Figure BDA0002253374570000032
所述的铱配合物原位制备包括如下步骤：在有机溶剂和25～120℃的反应条件下，吡啶环上3-位取代手性螺环胺基膦配体首先与铱催化剂前体反应0.5～4小时，然后再在0.1～50atm的氢气氛围中搅拌反应0.1～3小时，便可得到氢化反应所需的吡啶环上3-位取代手性螺环胺基膦配体铱催化剂；
所述的手性螺环胺基膦配体与铱催化剂前体的摩尔比为1：1～2：1；
作为优先方案，在惰性气体氛围下，将所述的吡啶环上3-位取代手性螺环胺基膦配体与铱催化剂前体加入有机溶剂中，在25℃的反应条件下反应0.5～4小时；随后在0.1～20atm的氢气氛围中搅拌反应1～3小时制备得到吡啶环上3-位取代手性螺环胺基膦配体与铱催化剂前体形成的配合物。
作为更进一步的优先方案，所述的吡啶环上3-位取代手性螺环胺基膦配体与过渡金属盐的摩尔比为1.2：1～1.8：1。
所述的铱催化剂前体为[Ir(COD)Cl]2(COD＝环辛二烯)、[Ir(COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6或[Ir(COD)2]OTf。
本发明提供的所述的用于催化β-芳基亚烷基丙二酸酯化合物的不对称催化氢化反应包括如下步骤：
在氮气保护下，于氢化反应器的有机溶剂中加入吡啶环上3-位取代手性螺环胺基膦配体铱催化剂，并加入β-芳基亚烷基丙二酸酯和碱，并在0.1～100atm的氢气氛围中搅拌反应0.1～80小时，旋转蒸发仪脱除溶剂和催化剂，用薄层层析或者核磁共振分析反应的转化率和收率。
所述的β-芳基亚烷基丙二酸酯底物与催化剂的摩尔比为500:1～20000:1，即催化剂用量为0.2～0.005mol％；底物浓度为0.5～1.3M；
所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇钾、叔丁醇锂、三乙胺、三丁胺或N-甲基吗啉；碱浓度为0.02-0.2M；反应温度为0～80℃。
所述的有机溶剂为甲醇、乙醇、正丙醇、异丙醇、丁醇、四氢呋喃、甲苯、甲基叔丁基醚、二氧六环、N,N-二甲基甲酰胺、二甲亚砜中的一种或其中几种的混合溶剂。
本发明提供了一种吡啶环上3-位取代手性螺环胺基膦配体制备方法和应用，该手性螺环三齿配体是基于手性螺环吡啶胺基膦三齿配体的铱络合物Ir-SpiroPAP的基础上设计发展的吡啶环3-位含有立体效应更加显著取代基的新手性螺环膦-氨基-吡啶三齿配体。通过在吡啶环3-位引入立体效应更加显著的取代基从而更好控制催化氢化反应过程中的手性传递，从而显著地提高了催化剂对底物的手性控制，并在β-芳基亚烷基丙二酸酯化合物的不对称催化氢化中获得了优秀的对映选择性(高达99％ee)和高转化数(高达19000的TON)，为光学活性3-芳基脂肪酸或脂肪酸酯的合成提供了绿色、高效、实用的合成方法。
总之，本发明提供的新的吡啶环上3-位取代手性螺环胺基膦配体，合成方法简单，条件温和。其具有手性螺二氢茚骨架，可作为手性配体用于铱催化的β-芳基亚烷基丙二酸酯化合物的不对称催化氢化反应中，具有很高的催化活性和手性诱导效果，对映选择性(高达99％ee)，而且具有很强的调节能力。
具体实施方式
下面结合实施例对本发明作进一步详细、完整的说明，列出的实施例将有助于理解本发明。实施例中未注明具体条件的实验方法，通常按照常规条件以及手册中所述的条件，或按照制造厂商所建议的条件；所用的设备、材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1：
Figure BDA0002253374570000041
在氮气氛围中，将含有(R)-DTB-SpiroAP(283mg，0.44mmol)和3-异丙基-2-吡啶甲醛(131mg,0.88mmol)的1,2-二氯乙烷(10mL)混合物在45℃搅拌反应14h。当亚胺中间体的生成量不再增加时(由TLC监测)，将NaBH(OAc)3(148mg，0.70mmol)加入到体系中，并将得到的反应混合物在相同温度下搅拌反应12h(由TLC监测)。用饱和NaHCO3溶液淬灭后，将混合物用乙酸乙酯萃取，合并有机相，有机相用无水硫酸镁干燥，抽滤除去干燥剂，滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚:乙酸乙酯＝20:1)进行纯化，得到相应的无色糖浆状物0.22g,收率为97％；
Figure BDA0002253374570000055
–265(c＝0.5,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.75(dd,J＝4.7,1.5Hz,1H),7.35(dd,J＝7.8,1.5Hz,1H),7.28(d,J＝7.2Hz,1H),7.19–7.08(m,3H),7.04–6.97(m,2H),6.90(dd,J＝7.7,4.7Hz,1H),6.74(dd,J＝7.7,1.8Hz,2H),6.62(dd,J＝7.6,1.8Hz,2H),6.58(d,J＝7.4Hz,1H),6.24(d,J＝7.8Hz,1H),5.50(d,J＝5.4Hz,1H),4.19(dd,J＝15.6,6.4Hz,1H),3.04–2.80(m,4H),2.65(dd,J＝15.6,9.2Hz,1H),2.42–2.31(m,1H),2.09–1.86(m,3H),1.09(s,18H),1.08(s,3H),0.87(s,18H)；31P NMR(162MHz,CDCl3)δ–22.47(s)；13C NMR(100MHz,CDCl3)δ157.6,152.2,151.9,147.6,143.4,143.3,142.3,138.5,138.4,135.4,135.3,135.2,133.4(d,J＝2.6Hz),133.0,132.8,132.2,132.0,131.9,127.2(d,J＝4Hz),127.0(d,J＝5.7Hz),126.9,126.8,126.6,126.3,125.0.120.4,119.6,112.7,107.3,64.8,60.6(d,J＝3.2Hz),47.1,38.5(d,J＝5.1Hz),35.0,30.3,29.9.HRMS(ESI)calcd for C35H31N2P[M+H]+:511.2298；Found:511.2296.
实施例2：
Figure BDA0002253374570000051
操作过程同实施例1a。白色固体,熔点为74-75℃,0.35g,94％产率。
Figure BDA0002253374570000052
1H NMR(400MHz,CDCl3)δ:7.83(dd,J＝4.6,1.4Hz,1H),7.75(dd,J＝8.0,1.4Hz,1H),7.2–7.21(m,5H),7.18–7.07(m,5H),7.07–6.99(m,2H),6.83(dd,J＝7.9,1.8Hz,2H),6.68(dd,J＝7.4,1.8Hz,2H),6.55(d,J＝7.4Hz,1H),5.74(d,J＝7.8Hz,1H),5.24(d,J＝7.4Hz,1H),3.81–3.58(m,2H),2.97–2.86(m,2H),2.84–2.74(m,1H),2.56–2.50(m,1H),2.36–2.28(m,1H),1.96–1.88(m,2H),1.72–1.66(m,1H),1.60(s,6H),1.16(s,18H),0.97(s,18H)；31P NMR(162MHz,CDCl3)δ:-16.26(s)；13C NMR(101MHz,CDCl3)δ:156.0,152.1,151.9,149.9,149.8,149.4,149.3,149.2,146.0,145.2(2),144.2(2),144.0(2),141.6,137.5,137.4,137.2,137.1,135.2,135.0,133.2,133.0,131.7(2),129.0,128.8,128.6,128.3,128.0,127.8,126.3,126.2,125.7,125.2,121.7,121.1,120.9,112.7,107.4,71.4,61.6,46.8,42.6,42.3,37.6,35.6,34.8,34.6,31.4,31.3(2),31.1,30.8,30.6(2),27.0.HRMS(ESI)calcd for C60H74N2P[M+H]+:853.5584；Found:853.5588.
实施例3：
Figure BDA0002253374570000054
操作过程同实施例1a。白色固体,熔点为86-87℃,0.33g,83％产率。
Figure BDA0002253374570000061
Figure BDA0002253374570000062
1H NMR(400MHz,CDCl3)δ:7.85(d,J＝4.8Hz,1H),7.27–7.22(m,2H),7.19–7.10(m,7H),7.08–7.01(m,3H),6.98–6.92(m,3H),6.90–6.84(m,3H),6.78(dd,J＝7.8,1.6Hz,2H),6.62(dd,J＝7.8,1.6Hz,2H),6.54(d,J＝8.0Hz,1H),6.15(d,J＝8.0Hz,1H),5.51(s,1H),5.25(d,J＝7.6Hz,1H),4.00(dd,J＝15.6,6.0Hz,1H),3.66(d,J＝15.2Hz,1H),3.00–2.85(m,2H),2.84–2.74(m,1H),2.58–2.52(m,1H),2.41–2.27(m,1H),1.98–1.93(m,2H),1.85–1.72(m,1H),1.10(s,18H),0.90(s,18H)；31P NMR(162MHz,CDCl3)δ:-16.33(s)；13C NMR(101MHz,CDCl3)δ:155.1,152.2,151.9,149.9(2),149.5,149.4,146.2,144.7(2),144.3,144.2(2),142.0,141.7,137.6,137.5,137.1,137.0,136.5,135.1,134.9,133.1,132.2(2),129.4,129.2,128.8,128.6,128.3,127.9,127.7,126.8(2),126.5,125.3,121.7,121.2,121.1,113.2,107.7,100.0,71.4,61.7,51.7,45.6,42.6,38.0,36.1,34.8,34.6,31.4,31.3,31.2,30.8.HRMS(ESI)calcd for C64H74N2P[M+H]+:901.5584；Found:901.5588.
实施例4：
Figure BDA0002253374570000063
操作过程同实施例1a。无色糖浆状物,0.80g,90％产率。
Figure BDA0002253374570000064
1H NMR(400MHz,CDCl3)δ:7.79(dd,J＝4.5,1.3Hz,1H),7.25(dd,J＝8.0,1.3Hz,1H),7.20–7.16(m,3H),7.16–7.03(m,8H),7.02–6.94(m,5H),6.92–6.83(m,4H),6.81(dd,J＝8.0,1.7Hz,2H),6.65(d,J＝8.9Hz,2H),6.59(dd,J＝7.2,1.7Hz,2H),6.42(d,J＝7.4Hz,1H),5.46(d,J＝7.8Hz,1H),5.13(d,J＝8.2Hz,1H),3.75–3.69(m,1H),3.68(s,3H),2.97–2.87(m,1H),2.82(dd,J＝15.4,8.6Hz,1H),2.73–2.61(m,1H),2.55(d,J＝14.4Hz,1H),2.36(dt,J＝15.4,10.7Hz,2H),1.90–1.75(m,2H),1.10(s,18H),0.89(s,18H)；31P NMR(162MHz,CDCl3)δ:-15.08(s)；13C NMR(101MHz,CDCl3)δ:158.8,157.7,151.9,151.7,150.0,149.9,149.3(2),146.6,145.7,145.6,145.1,145.0,144.1(2),143.8(2),139.8,137.5,137.3,136.9,136.8,136.7,135.3,135.1,132.5,132.1,131.3,131.3,131.0(2),129.5,129.3,128.2,127.9,127.7,127.6,126.4,126.2,125.1,122.0,120.8,120.7,112.9,112.7,107.2,100.0,62.8,61.7(2),55.1,48.3,36.9,35.6,31.5,31.4,31.3,31.1,30.9,30.6,29.7,26.9.HRMS(ESI)calcd for C71H80N2OP[M+H]+:1007.6003；Found:1007.6006.
实施例5：
操作过程同实施例1a。白色固体,熔点为91-92℃,0.39g,93％产率。
Figure BDA0002253374570000072
Figure BDA0002253374570000073
1H NMR(400MHz,CDCl3)δ:8.05(dd,J＝4.7,1.4Hz,1H),7.45–7.43(m,1H),7.36–7.32(m,2H),7.29–7.23(m,2H),7.23–7.16(m,2H),7.06–7.02(m,1H),6.97(dd,J＝7.8,1.7Hz,3H),6.91(s,1H),6.83(dd,J＝7.5,1.7Hz,2H),6.74–6.72(m,3H),6.66(s,2H),6.39(d,J＝7.9Hz,1H),5.52(s,1H),5.43–5.33(m,1H),4.11(dd,J＝16.0,5.6Hz,1H),3.92(d,J＝14.6Hz,1H),3.20–3.05(m,2H),3.02–2.94(m,1H),2.80–2.74(m,1H),2.58–2.46(m,1H),2.35(s,6H),2.31(s,6H),2.19–2.12(m,2H),2.06–1.98(m,1H),1.29(s,18H),1.09(s,18H)；31P NMR(162MHz,CDCl3)δ:-16.50(s)；13C NMR(101MHz,CDCl3)δ:155.1,152.3,152.0,150.0,149.9,149.5,149.4,146.0,144.7(2),144.3,144.2,142.1,141.6,137.9,137.8,137.7,137.6,137.2,137.0(2),136.6,135.1,134.9,133.2,132.2,132.2,128.8,128.6,128.5,128.4,128.3,127.9,127.7,127.4,127.0,126.6,125.3,121.7,121.2,121.1,113.1,107.9,71.4,61.7,51.6,45.8,42.6,38.1,36.1,34.8,34.6,31.4(2),31.3,31.2,30.8,30.3.HRMS(ESI)calcd for C68H82N2P[M+H]+:957.6210；Found:957.6212.
实施例6：
Figure BDA0002253374570000074
操作过程同实施例1a。无色糖浆状物,0.42g,90％产率。
Figure BDA0002253374570000075
1H NMR(400MHz,CDCl3)δ:7.86(d,J＝4.4Hz,1H),7.26–7.24(m,1H),7.17–7.12(m,2H),7.06(s,1H),7.04–6.95(m,3H),6.86–7.84(m,2H),6.80–7.78(m,3H),6.70–6.63(m,2H),6.63(s,2H),6.57(s,2H),6.54–6.50(m,1H),6.15(d,J＝7.9Hz,1H),5.34(s,1H),5.24–5.20(m,1H),3.91(dd,J＝16.0,5.4Hz,1H),3.76(d,J＝15.8Hz,1H),3.00–2.87(m,2H),2.84–2.59(m,6H),2.37–2.29(m,1H),2.01–1.92(m,2H),1.90–1.84(m,1H),1.12(s,6H),1.10(s,18H),1.06(d,J＝6.7Hz,18H),0.91(s,18H)；31P NMR(162MHz,CDCl3)δ:-16.73(s)；13C NMR(101MHz,CDCl3)δ:154.1,151.3,151.1,148.8(2),148.4,148.3,147.8,147.7,144.7,143.6,143.5,143.1(2),143.07,140.8,140.4,136.7,136.6,136.3,136.2,136.1,135.1,134.0,133.8,132.2(2),131.3,131.2,127.7,127.5,127.2,126.8,126.6,125.5,124.2(2),123.9,121.6(2),120.6,120.0(2),111.8,106.8,98.9,70.3,60.6,51.2,44.7,41.5,37.3,35.1,33.7,33.5,33.0(2),30.6,30.3,30.2(2),29.8,23.2,23.1,22.9,22.8,21.6,13.1.HRMS(ESI)calcd for C76H98N2P[M+H]+:1069.7462；Found:1069.7468.
实施例7：
Figure BDA0002253374570000081
操作过程同实施例1a。无色糖浆状物,0.42g,85％产率。
Figure BDA0002253374570000082
1H NMR(400MHz,CDCl3)δ:7.95(dd,J＝4.7,1.4Hz,1H),7.34–7.32(m,1H),7.28–7.26(m,1H),7.25–7.23(m,1H),7.22–7.18(m,2H),7.14–7.04(m,4H),6.96–6.92(m,1H),6.89–6.88(m,3H),6.87(d,J＝1.8Hz,1H),6.83(d,J＝1.6Hz,2H),6.76(dd,J＝7.5,1.7Hz,2H),6.60(d,J＝7.4Hz,1H),6.17(d,J＝7.9Hz,1H),5.40(s,1H),5.35–5.33(m,1H),3.97(dd,J＝16.1,5.2Hz,1H),3.88(dd,J＝16.1,2.4Hz,1H),3.08–2.96(m,2H),2.92–2.84(m,1H),2.77–2.71(m,1H),2.42–2.32(m,1H),2.12–1.98(m,3H),1.24(s,18H),1.21(s,18H),1.17(s,18H),0.99(s,18H)；31P NMR(162MHz,CDCl3)δ:-17.09(s)；13CNMR(101MHz,CDCl3)δ:155.2,152.6,152.3,150.6(2),149.9,149.8,149.4(2),145.8,144.6(2),144.2(2),144.1(2),140.8,137.9,137.8,137.6,137.4,137.3,135.9,135.0,134.8,133.4,132.6,132.5,128.7,128.5,128.3,127.8,127.6,126.6,125.2,124.0,123.6(2),121.0,120.4,112.7,108.0,71.4,61.7,53.0,45.8,42.6,38.7,36.2,34.9,34.8,34.6,31.6,31.5,31.4,31.3,30.9,30.3,30.2,29.8.HRMS(ESI)calcd for C80H106N2P[M+H]+:1125.8088；Found:1125.8090.
实施例8：
吡啶环上3-位取代手性螺环胺基膦配体用于铱催化的β-芳基亚烷基丙二酸酯化合物的不对称催化氢化反应中的应用。
Figure BDA0002253374570000083
在手套箱中称取配体(R)-1(6.4μmol)和[Ir(COD)Cl]2(2.0mg,3.0μmol)于装有磁力搅拌子的干燥洁净的10mL Schlenk管中，密封备用。取出后加入2mL无水乙醇，室温下搅拌0.5小时。在氮气保护下，用注射器将该溶液加入到装有玻璃内管和磁力搅拌子的氢化反应釜中，用氢气快速置换反应釜中的气体三次，调节氢气压力为10atm，室温下搅拌反应0.5小时后，缓慢释放出反应釜中的氢气。在氮气保护下，用注射器取出1mL加入装有1.0～20mmol底物和0.4～2mmol叔丁醇钾的乙醇溶液(1mL(0.5mmol/mL)～15mL(1.3mmol/mL))的应釜中中。用氢气快速置换反应釜中的气体三次，最后调节氢气压力为30～80atm，室温下搅拌反应至氢气压力不再降低为止。缓慢释放出反应釜中的氢气，旋转蒸发仪脱除溶剂后得粗产物。经短硅胶柱过滤除去催化剂后，用薄层层析或者核磁共振分析反应的转化率和收率，高效液相色谱分析产物的光学纯度，所得氢化实验结果见表1。
表1.β-芳基亚烷基丙二酸酯化合物的不对称催化氢化。
Figure BDA0002253374570000091
Figure BDA0002253374570000101
Figure BDA0002253374570000111

Claims (10)

1.一种吡啶环上3-位取代手性螺环胺基膦配体，其特征在于它是具有式1的化合物或其对映体、消旋体，或其催化可接受的盐。
Figure FDA0002253374560000011
其中，R1选自C1～C10的烃基、苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基；所述的苯基上的取代基为C1～C10的烃基、烷氧基，取代基数量为1～5；杂芳基为呋喃基、噻吩基或吡啶基；
R2、R3、R4分别独立选自H、C1～C10烷基、苯基、取代苯基、取代酯基；所述的苯基上的取代基为C1～C10的烃基、烷氧基，取代基数量为1～5；R2～R4可为C3～C7脂肪环、吡咯环、芳香环；R2、R3、R4相同或不同。
2.根据权利要求1所述的吡啶环上3-位取代手性螺环胺基膦配体，其特征在于它选自如下化合物的对映体、消旋体或其催化可接受的盐：
Figure FDA0002253374560000012
3.权利要求1所述的吡啶环上3-位取代手性螺环胺基膦配体的制备方法，其特征在于：以具有手性螺二氢茚骨架的式2所示的消旋或旋光活性的7-二芳/烷基膦基-7′-氨基-1,1′-螺二氢茚类化合物为起始原料，经过下述反应式：
Figure FDA0002253374560000021
具体步骤如下：
在有机溶剂和还原剂存在的条件下，具有式2所示的化合物与醛、酸在反应器中反应2～24小时制备得到式1所示的化合物；
所述的有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、苯、苯甲醚、甲苯、二甲苯、甲基叔丁基醚、乙醚、二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、1,2-二氯乙烷、丙酮、石油醚、正己烷中的一种或其中几种的混合溶剂；
所述的还原试剂可为氢化铝锂、硼氢化钠、三乙酰氧基硼氢化钠、腈基硼氢化钠；述的酸包括有机酸和无机酸，可为盐酸、硫酸、硝酸、甲酸、乙酸、苯甲酸；
所述的碱包括有机碱和无机碱，可为吡啶、三乙胺、三丁胺、N-甲基吗啡啉、N,N-二乙基异丙基胺、二异丙基氨基锂、氢化锂、氢化钾、氢化钠、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾。
4.权利要求1或2中所述的吡啶环上3-位取代手性螺环胺基膦配体的应用，其特征在于该配体与铱金属盐原位形成铱配合物作为铱催化剂，用于催化β-芳基亚烷基丙二酸酯化合物的不对称催化氢化反应。
5.根据权利要求4所述的应用，其特征在于铱配合物原位制备方法包括如下步骤：
在有机溶剂和25～120℃的反应条件下，吡啶环上3-位取代手性螺环胺基膦配体首先与铱催化剂前体反应0.5～4小时，然后再在0.1～50atm的氢气氛围中搅拌反应0.1～3小时，便可得到氢化反应所需的吡啶环上3-位取代手性螺环胺基膦配体铱催化剂；
所述的手性螺环胺基膦配体与铱催化剂前体的摩尔比为1：1～2：1；
所述的铱催化剂前体为[Ir(COD)Cl]2(COD＝环辛二烯)、[Ir(COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6或[Ir(COD)2]OTf。
6.根据权利要求4所述的应用，其特征在于铱配合物原位制备是在惰性气体氛围下，将所述的吡啶环上3-位取代手性螺环胺基膦配体与铱催化剂前体加入有机溶剂中，在25℃的反应条件下反应0.5～4小时；随后在0.1～20atm的氢气氛围中搅拌反应1～3小时制备得到吡啶环上3-位取代手性螺环胺基膦配体与铱催化剂前体形成的配合物；
所述的吡啶环上3-位取代手性螺环胺基膦配体与过渡金属盐的摩尔比为1.2：1～1.8：1。
7.根据权利要求4所述的应用，其特征在于所述的用于催化β-芳基亚烷基丙二酸酯化合物的不对称催化氢化反应包括如下步骤：
在氮气保护下，于氢化反应器的有机溶剂中加入吡啶环上3-位取代手性螺环胺基膦配体铱催化剂，并加入β-芳基亚烷基丙二酸酯化合物和碱，并在0.1～100atm的氢气氛围中搅拌反应0.1～80小时，旋转蒸发仪脱除溶剂和催化剂，用薄层层析或者核磁共振分析反应的转化率和收率。
8.根据权利要求7所述的应用，其特征在于所述的β-芳基亚烷基丙二酸酯底物与催化剂的摩尔比为500:1～20000:1，即催化剂用量为0.2～0.005mol％；底物浓度为0.5～1.3M。
9.根据权利要求7所述的应用，其特征在于所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇钾、叔丁醇锂、三乙胺、三丁胺或N-甲基吗啉；碱浓度为0.02-0.2M；反应温度为0～80℃。
10.根据权利要求7所述的应用，其特征在于所述的有机溶剂为甲醇、乙醇、正丙醇、异丙醇、丁醇、四氢呋喃、甲苯、甲基叔丁基醚、二氧六环、N,N-二甲基甲酰胺、二甲亚砜中的一种或其中几种的混合溶剂。
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