一种有机催化傅克反应合成手性胺基膦酸酯的方法与流程

本发明涉及一种应用手性磷酸的均相体系高度对映选择性催化亚胺膦酸酯与吲哚发生不对称傅克反应合成手性胺基膦酸酯的方法。

背景技术：

光学活性的胺基膦酸与氨基酸在结构上具有相似性，同样具备广泛的生理活性，可作为酶抑制剂，抗真菌剂，抗菌剂和抗癌剂等(参考文献一：(a)Senten,K.；L.；Van der Veken,P.；De Meester,I.；Lambeir,A.-M.；Scharpé,S.；Haemers,A.；Augustyns,K.J.Comb.Chem.2003,5,336.(b)Maier,L.；Diel,P.J.Phosphorous,Sulfur Silicon Relat.Elem.1994,90,259.(c)Grembecka,J.；Mucha,A.；Cierpicki,T.Kafarski,P.J.Med.Chem.2003,46,2641.(d)Yao,G.；Ye,M.；Huang,R.；Li,Y.；Pan,Y.；Xu,Q.；Liao,Z.；Wang,H.Bioorg.Med.Chem.Lett.2014,24,501.)。基于此，胺基膦酸及其衍生物的不对称合成受到了科研工作者的广泛关注，根据成键方式的不同，手性胺基膦酸及其衍生物的合成策略主要包括立体选择性的C-P键形成，C-C键形成，C-N键形成，C-H键形成(参考文献二：(a)M.；Rojas-Cabrera,H.；Cativiela,C.Tetrahedron 2009,65,17.(b)M.；Viveros-Ceballos,J.L.；Cativiela,C.；Sayago,F.J.Tetrahedron 2015,71,1745.)。

手性季碳中心的构建始终是一个充满挑战的课题。目前，已经发展了一些有效策略构建四级碳手性氨基膦酸酯化合物，如含碳或氮亲电试剂对膦酸酯底物的亲电进攻(参考文献三：(a)Studer,A.；Seebach,D.Heterocycles1995,40,357.(b)Kuwano,R.；Nishio,R.；Ito,Y.Org.Lett.1999,1,837.(c)Sawamura,M.；Hamashima,H.；Ito,Y.Bull.Chem.Soc.Jpn.2000,73,2559.(d)Kim,S.M.；Kim,H.R.；Kim,D.Y.Org.Lett.2005,7,2309.(e)Bernardi,L.；Zhuang,W.；K.A.J.Am.Chem.Soc.2005,127,5772.(f)Wilt,J.C.；Pink,M.；Johnston,J.N.；Chem.Commun.2008,4177.(g)Bera,K.；Namboothiri,I.N.N.Org.Lett.2012,14,980)，亚磷酸酯与酮亚胺底物的不对称加成反应(参考文献四：(a)Mikolajczyk,M.；P.；Drabowicz,J.Tetrahedron:Asymmetry 1997,8,3991.(b)Davis,F.A.；Lee,S.；Yan,H.；Titus,D.D.Org.Lett.2001,3,1757.(c)Chen,Q.；Li,J.；Yuan,C.Synthesis2008,2986.(d)Nakamura,S.；Hayashi,M.；Hiramatsu,Y.；Shibata,N.；Funahashi,Y.；Toru,T.J.Am.Chem.Soc.2009,131,18240.)，以及含碳亲核试剂对酮亚胺底物的不对称加成反应(参考文献五：(a)Rassukana,Y.V.；Yelenich,I.P.；Vlasenko,Y.G.；Onys’ko,P.P.Tetrahedron:Asymmetry 2014,25,1234.(b)Vicario,J.；Ezpeleta,J.M.；Palacios,F.Adv.Synth.Catal.2012,354,2641.(c)Vicario,J.；Ortiz,P.；Ezpeleta,J.M.；Palacios,F.J.Org.Chem.2015,80,156.(d)Yan,Z.；Wu,B.；Gao,X.；Zhou,Y.-G.Chem.Commun.2016,52,10882.)。值得一提的是，亲核加成策略中，亲核试剂仅局限于丙酮、乙酰氰、硝基甲烷和芳基硼酸等，为满足多样的季碳中心手性氨基膦酸酯的合成需求，亲核试剂仍有待进一步的丰富。手性磷酸催化吲哚对一系列亚胺底物的不对称加成反应已有一些报道(参考文献六：(a)Jia,Y.-X.；Zhong,J.；Zhu,S.-F.,Zhang,C.-M.；Zhou,Q.-L.Angew.Chem.2007,119,5661.(b)Rueping,M.；Raja,S.；A.Adv.Synth.Catal.2011,353,563.(c)Yin,Q.；You,S.-L.Chem.Sci.2011,2,1344.(d)Husmann,R.；Sugiono,E.；Mersmann,S.；Raabe,G.；Rueping,M.；Bolm,C.Org.Lett.2011,13,1044.(e)Qian,Y.；Jing,C.-C.；Zhai,C.-W.；Hu,W.-H.Adv.Synth.Catal.2012,354,301.(f)Feng,J.-C.；Yan,W.-J.；Wang,D.；Li,P.；Sun,Q.-T.；Wang,R.Chem.Commun.2012,48,8003.)，基于以上背景，我们设想能否采用相同的策略，利用手性磷酸催化吲哚与亚胺膦酸酯底物进行不对称加成反应来合成季碳中心手性氨基膦酸酯化合物。

技术实现要素：

本发明的目的是提供一种有机催化傅克反应合成手性胺基膦酸酯的方法。本发明操作简便实用，对映选择性高，产率好，且反应具有原子经济性，环境友好等优点。

为实现上述目的，本发明的技术方案如下：

本发明以手性磷酸作催化剂，亚胺膦酸酯与吲哚发生不对称加成反应得到相应的手性胺基膦酸酯，反应式和条件如下：

式中：

温度：0-50℃；

溶剂：有机溶剂；

时间：24-48小时；

催化剂：手性磷酸

所述R为C1-C10的烷基，苯环上的取代基为F、Cl、Me、MeO、Et、CN中的一种或二种以上取代基，取代基个数为1-3；

反应步骤为：

反应步骤为：在反应瓶中投入亚胺膦酸酯底物，吲哚(式1中底物用量的2equiv–4equiv)和手性磷酸(式1中底物用量的5mol％-10mol％)，加入有机溶剂，0-50℃下反应24-48小时；除去溶剂后直接柱层析分离得到纯的产物。

所述催化剂为手性磷酸，均为市售且无需任何处理。

所述有机溶剂为二氯甲烷、乙醚、甲苯、均三甲苯中的一种或两种以上的混合。

本发明具有以下优点

1.反应活性和对映选择性高，反应完全，生成产物专一，核磁氢谱没有检测到副反应，使得能分离方便，能获得高的对映体过量纯品。

2.能得到季碳中心手性胺基膦酸酯。

3.催化剂制备方便，反应操作简便实用。

4.反应条件温和。

具体实施方式

下面通过实施例详述本发明，但本发明并不限于下述的实施例。

实施例1：条件的优化

空气中，依次向反应瓶中加入五元环亚胺膦酸酯2a(33mg,0.1mmol)，手性磷酸(式1中底物用量的10mol％)和有机溶剂(2mL)，室温下搅拌十分钟，随后加入吲哚3(35mg,0.3mmol)，30℃下反应，TLC监测反应进程。反应结束后，直接柱层析分离得到纯的产物，反应式和手性磷酸结构如下：

其产率为分离收率，产物的对映体过量用手性液相色谱测定，详见表1。

表1.亚胺膦酸酯2a与吲哚的不对称加成反应a

实施例2：手性磷酸催化傅克反应合成各种手性胺基膦酸酯4

空气中，依次向反应瓶中加入五元环亚胺膦酸酯2(0.1mmol)，手性磷酸(式1中底物用量的5mol％)和有机溶剂(2mL)，室温下搅拌十分钟，随后加入吲哚3(35mg,0.3mmol)，30℃下反应，TLC监测反应进程。反应结束后，直接柱层析分离得到纯的产物，反应式和手性磷酸结构如下：

产率为分离收率，产物的对映体过量用手性液相色谱测定，见表2。

表2.手性磷酸催化傅克反应合成各种手性胺基膦酸酯4^a

(R)-diisopropyl

(3-(1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phosphonate(4a):44mg,98％yield,96％ee,[α]²⁰_D＝+49.09(c 0.66,6.77(t,J＝7.3Hz,1H),4.85-4.60(m,1H),4.50-4.25(m,1H),1.40-1.05(m,9H),0.81(d,J＝5.8Hz,3H)；¹³C NMR(100MHz,DMSO)δ138.4(d,J_PC＝4.5Hz),137.6,136.8(d,J_PC＝5.2Hz),134.0,131.4,127.8,127.4(d,J_PC＝2.6Hz),126.1(d,J_PC＝11.5Hz),122.6,122.0,121.2,120.1,112.9,111.6(d,J_PC＝3.8Hz),73.6(d,J_PC＝8.2Hz),73.4(d,J_PC＝6.7Hz),64.7(d,J_PC＝166.3Hz),25.3,25.1(d,J_PC＝2.7Hz),24.8(d,J_PC＝5.4Hz),23.9(d,J_PC＝5.5Hz)；³¹P NMR(162MHz,DMSO)δ16.4.HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 14.9min and 18.3min(maj).HRMS Calculated for C₂₁H₂₆N₂O₅PS[M+H]⁺449.1295,found 449.1301.

(R)-diisopropyl

(3-(2-methyl-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4b):42mg,91％yield,59％ee,[α]²⁰_D＝+18.29

(m,1H),4.49-4.35(m,1H),2.19(s,3H),1.29(d,J＝6.2Hz,3H),1.26(d,J＝6.2Hz,3H),1.08(d,J＝6.2Hz,3H),0.79(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ139.0(d,J_PC＝5.2Hz),135.7(d,J_PC＝5.1Hz),135.2(d,J_PC＝8.1Hz),134.9,132.8(d,J_PC＝2.1Hz),130.1(d,J_PC＝2.1Hz),128.1(d,J_PC＝2.5Hz),127.1(d,J_PC＝6.4Hz),121.7,121.5,121.0,120.2,110.4,106.9(d,J_PC＝3.2Hz),74.2(d,J_PC＝8.1Hz),73.6(d,J_PC＝7.7Hz),65.8(d,J_PC＝165.9Hz),24.5(d,J_PC＝2.7Hz),24.4(d,J_PC＝3.3Hz),23.7(d,J_PC＝5.7Hz),23.0(d,J_PC＝5.9Hz),15.6；³¹P NMR(162MHz,CDCl₃)δ15.6.HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 10.8min(maj)and 16.8min.HRMS Calculated for C₂₂H₂₈N₂O₅PS[M+H]⁺463.1451,found 463.1460.

(R)-diisopropyl

(3-(4-methyl-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4c):42mg,91％yield,87％ee,[α]²⁰_D＝+9.64

7.02(t,J＝7.6Hz,1H),6.70(d,J＝7.1Hz,1H),5.40(d,J＝7.3Hz,1H),4.98-4.85(m,1H),4.40-4.28(m,1H),1.72(s,3H),1.35(d,J＝6.1Hz,6H),1.28(d,J＝6.1Hz,3H),0.74(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ140.4(d,J_PC＝4.8Hz),137.7,137.0(d,J_PC＝4.9Hz),133.1(d,J_PC＝2.9Hz),131.1,130.2(d,J_PC＝2.9Hz),129.7(d,J_PC＝5.3Hz),127.3(d,J_PC＝3.1Hz),124.2(d,J_PC＝12.6Hz),123.3,122.7,122.0(d,J_PC＝2.3Hz),109.7,74.3(d,J_PC＝1.7Hz),74.2(d,J_PC＝3.0Hz),65.9(d,J_PC＝159.1Hz),24.5(d,J_PC＝2.8Hz),24.3(d,J_PC＝4.2Hz),24.1(d,J_PC＝4.4Hz),22.8(d,J_PC＝5.9Hz),22.4；³¹P NMR(162MHz,CDCl₃)δ16.3.HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 33.9min and 37.1min(maj).HRMS Calculated for C₂₂H₂₈N₂O₅PS[M+H]⁺463.1451,found 463.1460.

(dichloromethane/methanol 80/1).¹H NMR(400MHz,CDCl₃)δ8.85(s,1H),7.90(d,J＝7.7Hz,1H),7.74(s,1H),7.65-7.51(m,3H),7.23(d,J＝8.3Hz,1H),7.02(s,1H),6.96(d,J＝8.2Hz,1H),5.33(d,J＝4.8Hz,1H),4.95-4.80(m,1H),4.52-4.34(m,1H),2.27(s,3H),1.39-1.17(m,9H),0.77(d,J＝6.1Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ137.8(d,J_PC＝3.8Hz),135.5(d,J_PC＝5.2Hz),135.0,133.3(d,J_PC＝2.3Hz),130.1(d,J_PC＝2.5Hz),129.8,127.3(d,J_PC＝2.6Hz),126.1(d,J_PC＝4.3Hz),125.0(d,J_PC＝10.5Hz),124.4,121.5(d,J_PC＝1.7Hz),119.9,111.4,110.5,74.0(d,J_PC＝8.4Hz),73.7(d,J_PC＝7.7Hz),64.8(d,J_PC＝165.4Hz),24.5,24.3(d,J_PC＝3.7Hz),24.0(d,J_PC＝5.1Hz),22.9(d,J_PC＝5.9Hz),21.8；³¹P NMR(162MHz,CDCl₃)δ15.4(d,J＝5.9Hz).HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 20.3min(maj)and 23.0min.HRMS Calculated for C₂₂H₂₈N₂O₅PS[M+H]⁺463.1451,found463.1458.

(R)-diisopropyl

(3-(6-methyl-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4e):43mg,93％yield,94％ee,[α]²⁰_D＝

4.95-4.81(m,1H),4.52-4.36(m,1H),2.35(s,3H),1.33(d,J＝6.1Hz,3H),1.31-1.21(m,6H),0.79(d,J＝6.1Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ137.8(d,J_PC＝4.0Hz),137.2,135.5(d,J_PC＝5.0Hz),133.3(d,J_PC＝2.5Hz),132.6,130.2(d,J_PC＝2.5Hz),127.2(d,J_PC＝2.7Hz),125.6(d,J_PC＝4.0Hz),122.6(d,J_PC＝11.0Hz),122.3,121.5(d,J_PC＝1.9Hz),119.8,111.7,110.8(d,J_PC＝3.6Hz),74.0(d,J_PC＝8.3Hz),73.7(d,J_PC＝7.7Hz),64.7(d,J_PC＝166.0Hz),24.5(d,J_PC＝2.7Hz),24.3(d,J_PC＝3.6Hz),24.0(d,J_PC＝5.2Hz),23.0(d,J_PC＝5.8Hz),21.7；³¹P NMR(162MHz,CDCl₃)δ15.3(d,J＝5.4Hz).HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 20.5min(maj)and 24.5min.HRMS Calculated for C₂₂H₂₈N₂O₅PS[M+H]⁺463.1451,found 463.1461.

(R)-diisopropyl

(3-(7-methyl-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4f):44mg,96％yield,95％ee,[α]²⁰_D＝+60.11(c 0.88,THF),

4.49-4.35(m,1H),2.46(s,3H),1.35(d,J＝6.1Hz,3H),1.32-1.25(m,6H),0.79(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ137.8(d,J_PC＝3.8Hz),136.3,135.6(d,J_PC＝5.0Hz),133.3(d,J_PC＝2.5Hz),130.2(d,J_PC＝2.5Hz),127.2(d,J_PC＝2.7Hz),126.2(d,J_PC＝3.9Hz),124.3(d,J_PC＝11.5Hz),123.3,121.5(d,J_PC＝2.0Hz),121.0,120.8,117.7,111.2(d,J_PC＝4.1Hz),74.1(d,J_PC＝8.4Hz),73.8(d,J_PC＝7.8Hz),64.8(d,J_PC＝165.4Hz),24.5(d,J_PC＝2.8Hz),24.3(d,J_PC＝3.8Hz),24.1(d,J_PC＝5.0Hz),22.9(d,J_PC＝5.8Hz),16.7；³¹P NMR(162MHz,CDCl₃)δ15.2.HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 18.5min and 21.4min(maj).HRMS Calculated for

¹H NMR(400MHz,CDCl₃)δ9.35(s,1H),7.98(s,1H),7.90(d,J＝7.5Hz,1H),7.66-7.42(m,3H),7.05-6.83(m,3H),5.26(d,J＝4.6Hz,1H),5.01-4.83(m,1H),4.53-4.29(m,1H),3.00-2.70(m,2H),1.45-1.15(m,12H),0.78(d,J＝5.8Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ137.8(d,J_PC＝3.9Hz),135.6,135.6(d,J_PC＝5.3Hz),133.3(d,J_PC＝2.2Hz),130.2(d,J_PC＝2.5Hz),127.3(d,J_PC＝2.6Hz),127.2,126.1(d,J_PC＝3.6Hz),124.5(d,J_PC＝11.5Hz),121.5(d,J_PC＝2.0Hz),121.3,120.9,117.7,111.2(d,J_PC＝4.2Hz),74.1(d,J_PC＝8.4Hz),73.9(d,J_PC＝7.6Hz),64.8(d,J_PC＝165.4Hz),24.5(d,J_PC＝2.6Hz),24.3(d,J_PC＝3.8Hz),24.2(d,J_PC＝5.0Hz),24.0,22.9(d,J_PC＝5.9Hz),14.0；³¹P NMR(162MHz,CDCl₃)δ15.2(d,J＝5.8Hz).HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 16.1min and 20.4min(maj).HRMS Calculated for C₂₃H₃₀N₂O₅PS[M+H]⁺477.1608,found 477.1613.

(R)-diisopropyl

(3-(5-methoxy-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4h):47mg,98％yield,94％ee,[α]²⁰_D＝(d,J＝1.7Hz,1H),4.78-4.64(m,1H),4.41-4.25(m,1H),3.46(s,3H),1.25(d,J＝6.1Hz,3H),1.21-1.12(m,6H),0.78(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,DMSO)δ154.1,138.4(d,J_PC＝4.8Hz),136.9(d,J_PC＝4.9Hz),134.0(d,J_PC＝1.6Hz),132.6,131.3(d,J_PC＝2.0Hz),127.8(d,J_PC＝2.4Hz),127.7(d,J_PC＝3.5Hz),126.5(d,J_PC＝11.4Hz),121.9,113.4,112.7,111.3(d,J_PC＝5.3Hz),103.2,73.6(d,J_PC＝8.0Hz),73.3(d,J_PC＝7.5Hz),64.8(d,J_PC＝165.8Hz),56.2,25.3(d,J_PC＝2.7Hz),25.1(d,J_PC＝3.3Hz),24.8(d,J_PC＝5.5Hz),23.9(d,J_PC＝5.6Hz)；³¹P NMR(162MHz,DMSO)δ16.5.HPLC:Chiralcel OD-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 10.0min and 12.5min(maj).HRMS Calculated for C₂₂H₂₈N₂O₆PS[M+H]⁺479.1400,found 479.1408.

(R)-diisopropyl

(3-(5-fluoro-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4i):44mg,94％yield,94％ee,[α]²⁰_D＝+25.79

(c 0.88,THF),unknown compound,white solid,m.p.＝233-234℃,R_f＝0.20(dichloromethane/methanol 80/1).¹H NMR(400MHz,DMSO)δ11.36(d,J＝2.0Hz,1H),8.83(s,1H),7.98-7.90(m,1H),7.76(d,J＝2.5Hz,1H),7.73-7.65(m,2H),7.57-7.50(m,1H),7.37(dd,J＝8.8,4.8Hz,1H),6.94-6.79(m,2H),4.77-4.63(m,1H),4.40-4.26(m,1H),1.25(d,J＝6.2Hz,3H),1.19(d,J＝6.1Hz,3H),1.13(d,J＝6.2Hz,3H),0.78(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,DMSO)δ157.8(d,J_FC＝231.1Hz),138.0(d,J_PC＝4.7Hz),136.7(d,J_PC＝5.0Hz),134.3,134.1(d,J_PC＝2.4Hz),131.5(d,J_PC＝1.5Hz),129.1(d,J_PC＝4.3Hz),127.7(d,J_PC＝2.4Hz),126.2(d,J_PC＝10.4Hz),122.1,113.9(d,J_FC＝10.2Hz),112.1,110.9(d,J_FC＝26.0Hz),106.2(d,J_FC＝24.6Hz),73.7(d,J_PC＝8.0Hz),73.5(d,J_PC＝7.4Hz),64.5(d,J_PC＝166.1Hz),25.3(d,J_PC＝2.8Hz),25.1(d,J_PC＝3.3Hz),24.7(d,J_PC＝5.6Hz),23.9(d,J_PC＝5.7Hz)；¹⁹F NMR(376MHz,DMSO)δ-124.2；³¹P NMR(162MHz,DMSO)δ16.3(t,J＝6.5Hz).HPLC:Chiralcel AS-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 12.0min(maj)and 23.4min.HRMS Calculated for C₂₁H₂₅FN₂O₅PS[M+H]⁺467.1200,found 467.1205.

(dichloromethane/methanol 40/1).¹H NMR(400MHz,CDCl₃)δ8.82(s,1H),7.90(d,J＝7.8Hz,1H),7.75(d,J＝1.8Hz,1H),7.67-7.53(m,3H),7.22(dd,J＝8.9,5.2Hz,1H),7.00(dd,J＝9.2,2.0Hz,1H),6.78-6.67(m,1H),5.33(d,J＝5.5Hz,1H),4.92-4.79(m,1H),4.50-4.34(m,1H),1.34(d,J＝6.2Hz,3H),1.28(d,J＝6.1Hz,3H),1.23(d,J＝6.2Hz,3H),0.78(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ160.2(d,J_FC＝239.6Hz),137.5(d,J_PC＝4.2Hz),136.8(d,J_FC＝12.3Hz),135.4(d,J_PC＝5.0Hz),133.4(d,J_PC＝2.5Hz),130.4(d,J_PC＝2.4Hz),127.1(d,J_PC＝2.7Hz),126.3,121.6(d,J_PC＝1.8Hz),121.5(d,J_FC＝9.9Hz),110.2,109.5(d,J_FC＝24.2Hz),97.9(d,J_FC＝25.8Hz),74.1(d,J_PC＝8.2Hz),73.9(d,J_PC＝7.6Hz),64.4(d,J_PC＝164.2Hz),24.5(d,J_PC＝2.7Hz),24.3(d,J_PC＝3.6Hz),24.0(d,J_PC＝5.2Hz),23.0(d,J_PC＝5.9Hz)；¹⁹F NMR(376MHz,CDCl₃)δ-120.1；³¹P NMR(162MHz,CDCl₃)δ15.3.HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 22.5min(maj)and 28.6min.HRMS Calculated for C₂₁H₂₅FN₂O₅PS[M+H]⁺467.1200,found 467.1207.

(R)-diisopropyl

(3-(5-chloro-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4k):47mg,98％yield,95％ee,[α]²⁰_D＝-5.11

1H),7.71-7.51(m,4H),7.30(s,1H),7.17(d,J＝8.7Hz,1H),7.03(d,J＝8.7Hz,1H),5.56(d,J＝5.4Hz,1H),4.90-4.75(m,1H),4.49-4.32(m,1H),1.33(d,J＝6.1Hz,3H),1.27(d,J＝6.1Hz,3H),1.19(d,J＝6.1Hz,3H),0.75(d,J＝6.1Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ137.2(d,J_PC＝4.3Hz),135.5(d,J_PC＝5.2Hz),135.1,133.4(d,J_PC＝2.3Hz),130.4(d,J_PC＝2.2Hz),127.1(d,J_PC＝4.9Hz),127.1(d,J_PC＝2.9Hz),126.2,125.9(d,J_PC＝9.1Hz),123.1,121.8(d,J_PC＝1.5Hz),120.1,112.7,111.1(d,J_PC＝3.5Hz),74.2(d,J_PC＝8.2Hz),74.0(d,J_PC＝7.7Hz),64.2(d,J_PC＝165.2Hz),24.5(d,J_PC＝2.7Hz),24.3(d,J_PC＝3.6Hz),23.9(d,J_PC＝5.3Hz),23.0(d,J_PC＝5.9Hz)；³¹P NMR(162MHz,CDCl₃)δ15.3(d,J＝5.9Hz).HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 21.3min and 22.9min(maj).HRMS Calculated for C₂₁H₂₅ClN₂O₅PS[M+H]⁺483.0905,found 483.0910.

(R)-diisopropyl

(3-(5-bromo-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4l):52mg,98％yield,96％ee,[α]²⁰_D＝

4.47-4.33(m,1H),1.32(d,J＝6.1Hz,3H),1.26(d,J＝6.1Hz,3H),1.18(d,J＝6.2Hz,3H),0.74(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ137.2(d,J_PC＝4.3Hz),135.5(d,J_PC＝5.3Hz),135.4,133.3(d,J_PC＝2.2Hz),130.4(d,J_PC＝2.1Hz),127.1(d,J_PC＝2.6Hz),127.0(d,J_PC＝4.8Hz),126.5(d,J_PC＝8.9Hz),125.6,123.2,121.7(d,J_PC＝1.6Hz),113.7,113.2,110.9,74.3(d,J_PC＝8.3Hz),74.0(d,J_PC＝7.8Hz),64.2(d,J_PC＝165.7Hz),24.5(d,J_PC＝2.7Hz),24.3(d,J_PC＝3.6Hz),23.9(d,J_PC＝5.3Hz),23.0(d,J_PC＝5.9Hz)；³¹P NMR(162MHz,CDCl₃)δ15.3(d,J＝5.8Hz).HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 21.9min and 27.1min(maj).HRMS Calculated for C₂₁H₂₅BrN₂O₅PS[M+H]⁺527.0400,found 527.0409.

(dichloromethane/methanol 40/1).¹H NMR(400MHz,CDCl₃)δ9.64(s,1H),7.90(d,J＝7.0Hz,1H),7.77-7.51(m,5H),7.24-7.12(m,2H),6.05(d,J＝3.3Hz,1H),4.88-4.70(m,1H),4.54-4.34(m,1H),1.31(d,J＝6.1Hz,3H),1.26(d,J＝6.1Hz,3H),1.15(d,J＝6.1Hz,3H),0.79(d,J＝6.1Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ138.4,136.9(d,J_PC＝5.2Hz),135.4(d,J_PC＝5.2Hz),133.5(d,J_PC＝1.6Hz),130.7,128.1(d,J_PC＝4.9Hz),126.9(d,J_PC＝2.4Hz),126.4,125.3,124.6(d,J_PC＝8.7Hz),121.9,120.6,112.8,112.3,103.4,74.5(d,J_PC＝8.0Hz),74.2(d,J_PC＝7.7Hz),63.8(d,J_PC＝165.5Hz),24.4(d,J_PC＝2.7Hz),24.3(d,J_PC＝3.4Hz),23.8(d,J_PC＝5.5Hz),23.1(d,J_PC＝5.8Hz)；³¹P NMR(162MHz,CDCl₃)δ15.2(d,J＝5.7Hz).HPLC:Chiralcel AS-H column,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time9.2min(maj)and 13.9min.HRMS Calculated for C₂₂H₂₅N₃O₅PS[M+H]⁺474.1247,found 474.1255.

(R)-diisopropyl

(3-(1H-indol-3-yl)-5-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phos-phonate(4n):40mg,87％yield,96％ee,[α]²⁰_D＝

1H),4.78-4.62(m,1H),4.43-4.27(m,1H),2.32(s,3H),1.26(d,J＝6.1Hz,3H),1.19(d,J＝6.1Hz,3H),1.15(d,J＝6.2Hz,3H),0.83(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,DMSO)δ144.1(d,J_PC＝2.4Hz),138.8(d,J_PC＝4.3Hz),137.6,134.4(d,J_PC＝5.0Hz),132.2(d,J_PC＝2.4Hz),127.6(d,J_PC＝2.6Hz),127.4(d,J_PC＝3.4Hz),126.1(d,J_PC＝11.8Hz),122.6,121.8(d,J_PC＝1.7Hz),121.2,120.1,112.9,111.7(d,J_PC＝5.0Hz),73.6(d,J_PC＝8.1Hz),73.3(d,J_PC＝7.4Hz),64.6(d,J_PC＝165.2Hz),25.3(d,J_PC＝2.9Hz),25.2(d,J_PC＝3.2Hz),24.8(d,J_PC＝5.5Hz),24.0(d,J_PC＝5.4Hz),22.5；³¹P NMR(162MHz,DMSO)δ16.5.HPLC:Chiralcel AD-H column,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 13.7min and 17.2min(maj).HRMS Calculated for C₂₂H₂₈N₂O₅PS[M+H]⁺463.1451,found 463.1456.

(R)-diisopropyl

(5-methyl-3-(5-methyl-1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phosphonate(4o):42mg,88％yield,96％ee,

1H),7.23(d,J＝8.3Hz,1H),6.91(s,1H),6.84(d,J＝8.2Hz,1H),4.77-4.63(m,1H),4.39-4.26(m,1H),2.33(s,3H),2.15(s,3H),1.26(d,J＝6.1Hz,3H),1.18(d,J＝6.1Hz,3H),1.15(d,J＝6.2Hz,3H),0.80(d,J＝6.2Hz,3H)；¹³C NMR(100MHz,DMSO)δ144.0(d,J_PC＝2.4Hz),138.8(d,J_PC＝4.5Hz),135.9,134.4(d,J_PC＝5.0Hz),132.1(d,J_PC＝2.2Hz),128.3,127.7(d,J_PC＝2.3Hz),127.2(d,J_PC＝3.8Hz),126.4(d,J_PC＝11.1Hz),124.1,121.8,121.2,112.5,111.2(d,J_PC＝4.8Hz),73.6(d,J_PC＝8.0Hz),73.3(d,J_PC＝7.6Hz),64.7(d,J_PC＝165.6Hz),25.3(d,J_PC＝2.8Hz),25.2(d,J_PC＝3.3Hz),24.8(d,J_PC＝5.5Hz),23.9(d,J_PC＝5.5Hz),22.7,22.5；³¹P NMR(162MHz,DMSO)δ16.6.HPLC:Chiralcel AS-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 8.9min(maj)and 12.9min.HRMS Calculated for C₂₃H₃₀N₂O₅PS[M+H]⁺477.1608,found 477.1613.

(R)-diethyl

(3-(1H-indol-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)phosphon

1H),7.12(t,J＝7.5Hz,1H),6.98(d,J＝8.0Hz,1H),6.90(t,J＝7.5Hz,1H),5.50(s,1H),4.42-4.22(m,2H),4.04-3.88(m,1H),3.87-3.67(m,1H),1.30(t,J＝7.0Hz,3H),1.12(t,J＝7.0Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ137.6(d,J_PC＝3.9Hz),136.7,135.5(d,J_PC＝4.7Hz),133.4(d,J_PC＝2.4Hz),130.4(d,J_PC＝2.5Hz),127.4(d,J_PC＝2.7Hz),126.4(d,J_PC＝3.9Hz),124.6(d,J_PC＝11.7Hz),122.9,121.5(d,J_PC＝2.1Hz),120.7,119.9,111.8,110.7(d,J_PC＝4.3Hz),65.6(d,J_PC＝7.6Hz),64.5(d,J_PC＝165.8Hz),64.2(d,J_PC＝7.5Hz),16.7(d,J_PC＝5.3Hz),16.3(d,J_PC＝5.6Hz)；³¹P NMR(162MHz,CDCl₃)δ17.2.HPLC:Chiralcel AS-H column,230nm,30℃，n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time 23.3min(maj)and 30.9min.HRMS Calculated for C₁₉H₂₂N₂O₅PS[M+H]⁺421.0982,found 421.0987.

本发明涉及一种应用手性磷酸的均相体系高度对映选择性催化亚胺膦酸酯与吲哚发生不对称傅克反应合成季碳中心手性胺基膦酸酯的方法，其产率可达98％，对映体过量可达到98％。本发明操作简便易行，原料及催化剂均简单易得，反应条件温和。