CN110066294B - 一种合成手性γ-氨基膦酸酯的方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
- C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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Abstract
一种合成手性γ‑氨基膦酸酯的方法：从氮杂二烯和亚磷酸酯出发，在无机碱和有机催化剂的作用下反应可以得到含各种取代基的手性γ‑氨基膦酸酯。本发明操作简便实用，产率高，对映选择性高。
Description
技术领域
本发明涉及γ-氨基膦酸酯，具体地说是一种应用有机催化体系高度对映选择性合成手性γ-氨基膦酸酯的方法。
背景技术
γ-氨基丁酸(GABA)是一种四碳的非蛋白质氨基酸，是一种重要的游离氨基酸，广泛的存在于细菌、植物和脊椎动物中。具有抗高血压和抗抑郁的生物及药物活性。GABA的衍生物普瑞巴林对焦虑症具有很好的治疗效果。作为γ-氨基酸结构的类似物，γ-氨基膦酸衍生物也具有重要的生物活性，例如可以作为羊脑谷氨酰胺合成酶和大肠杆菌谷氨酰胺合成酶的抑制剂。
光学活性膦酸衍生物由于其在生物以及医学方面的重要应用，所以，催化不对称合成膦酸衍生物引起了化学家的广泛关注。在众多的合成之中，对映选择性加成是最有效的方法之一。利用相应的膦亲核试剂对α，β-不饱和羰基化合物的不对称加成反应取得了丰富的成果，例如α，β-不饱醛(文献一：X.Luo,Z.Zhou,X.Li,X.Liang and J.Ye,RSC Adv.,2011,1,698.)、α，β-不饱和酮(文献二：X.-Q.Hao,J.-J.Huang,T.Wang,J.Lv,J.-F.Gongand M.-P.Song,J.Org.Chem.,2014,79,9512.)、α，β-不饱和酯(文献三：M.Hatano,T.Horibe and K.Ishihara,Angew.Chem.Int.Ed.,2013,52,4549.)和α，β-不饱和酰胺(文献四：R.J.Chew,Y.Lu,Y.-X.Jia,B.-B.Li,E.H.Y.Wong,R.Goh,Y.Li,Y.Huang,S.A.Pullarkat and P.-H.Leung,Chem.Eur.J.,2014,20,14514.)。上述文献均是膦亲核试剂对α，β-不饱和羰基化合物的1,4-加成，而膦亲核试剂对α，β-不饱和亚胺的1,4-加成却未见报道。因此，发展一种膦亲核试剂对α，β-不饱和亚胺的1,4-加成反应来直接、简单和有效的合成光学活性的γ-氨基膦酸衍生物是非常必要的。
发明内容
本发明的目的是提供一类含各种取代基的手性γ-氨基膦酸酯的合成方法。
本发明的技术方案如下：
本发明提供的是一类具有不同立体和电子效应取代基的手性γ-氨基膦酸酯的合成方法，所述方法的反应式和条件如下：：
所述反应物和产物中取代基Ar为苯基、取代苯基或萘基，取代苯基上的取代基为C1-6烷基、卤素、甲氧基。R1为烷基、苯基、取代苯基或萘基，取代苯基上的取代基为C1-6烷基、卤素、甲氧基；R2为对甲苯磺酰基、对硝基苯磺酰基，甲磺酰基，2,4,6-三甲基苯磺酰基；R为苯基、苄基；X为氧、硫。
优选所述化合物1与碱摩尔比为1:0.3-1:5。
优选所述化合物1与有机催化剂的摩尔比为1:0.01-1:0.2。
优选所述化合物1与化合物2的摩尔为1:1-1:5。
优选化合物1于有机溶剂中的浓度为0.01-1.0mol/L。
上述方法包括以下步骤：
步骤一，在20-30℃下，将化合物1溶于有机溶剂中，得体系1；
步骤二，向体系1中加入碱，得体系2；
步骤三，向体系2中加入有机催化剂，得体系3；
步骤四，将体系3降温至-20℃，然后向体系3中加入化合物2，-20℃下反应1-8天，反应结束后加入水，用二氯甲烷萃取，合并二氯甲烷层后，无水硫酸钠干燥，过滤，减压去除溶剂，硅胶柱层析得到产品化合物3。
所用的有机溶剂为四氢呋喃、二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、苯、氯苯、邻二甲苯、间二甲苯、对二甲苯、N,N-二甲基甲酰胺。
采用亚膦酸酯为反应物；采用碱作为反应促进剂；采用有机催化剂作为反应催化剂。
方法中所用的碱为碳酸钠、碳酸钾、碳酸铯、氢氧化钠、三乙胺中的一种或两种以上混合。
方法中所用的有机催化剂为奎宁，奎尼丁，辛可宁，辛可宁丁，硫脲，方酰胺中的一种。
反应温度为-2022
本发明从氮杂二烯1和亚磷酸酯出发，经过一步反应可以高产率、高高对映选择性地得到一系列含各种取代基的手性γ-氨基膦酸酯。
本发明从各种氮杂二烯1出发，与各种亚磷酸酯反应生成手性γ-氨基膦酸酯，该反应采用碱作为促进剂，有机催化剂作为催化剂，反应产率高，对映选择性高，底物范围广。本发明原料廉价易得，操作简便，体系简单，为后处理提供了便利，大大提高了反应效率，反应能容忍各种不同的取代基和官能团。
本发明具有以下优点：
1.原料简单易得。
2.反应活性高，原料转化完全，核磁氢谱检测到副产物含量较低或不存在，分离方便，能获得高纯度的产物。
3.反应底物范围广。
4.能高对映选择性地得到含各种取代基的手性γ-氨基膦酸酯。
5.操作简单。
具体实施方式
本发明将化合物1，在有机溶剂中和各种亚磷酸酯2反应，使用碱作为促进剂，有机催化剂作为催化剂，其合成路线如下：
其中：
取代基Ar为苯基、取代苯基或萘基，取代苯基上的取代基为C1-C6的烷基、卤素、甲氧基。R1为烷基、苯基、取代苯基或萘基，取代苯基上的取代基为C1-C6的烷基、卤素、甲氧基；R2为对甲苯磺酰基、对硝基苯磺酰基，甲磺酰基，2,4,6-三甲基苯磺酰基；R为苯基、苄基；X为氧、硫。
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1-13条件优化
在20-30℃下，向4mL反应瓶中加入氮杂二烯1a(56.3毫克,0.15毫摩尔)，碱(0.075毫摩尔),有机催化剂5a(0.0075毫摩尔)和溶剂(1.0-2.0毫升)，然后向该体系加入亚磷酸二苯酯2a(86.6微升，0.45毫摩尔)，30℃到-20℃下反应4小时到7天，反应结束后加入水，用二氯甲烷萃取，合并二氯甲烷层后，无水硫酸钠干燥，过滤，减压去除溶剂，硅胶柱层析得到产品化合物3aa。反应结构式如下：
产物的产率为分离收率，rr值为1,4-加成产物和1,2-加成产物之间的比例，ee值为1,4-加成产物的对映体过量百分率，见表1。
表1.合成手性γ-氨基膦酸酯3aa的条件优化a
a反应条件：氮杂二烯1a(56.3毫克,0.15毫摩尔),亚磷酸二苯酯2a(86.6微升，0.45毫摩尔),有机催化剂5a(0.0075毫摩尔),碱(0.075毫摩尔),溶剂(2.0mL),30℃,4h-7d.b区域选择性比例通过1H NMR确定.c分离收率.d通过手性HPLC确定.e 0℃反应2天(将1a,5a和碳酸钠的甲苯溶液先降温至0℃，然后再加入2a)；f-20℃反应7天(将1a,5a和碳酸钠的甲苯溶液先降温至-20℃，然后再加入2a)；g甲苯(1.0mL)，-20℃反应2天(将1a,5a和碳酸钠的甲苯溶液先降温至-20℃，然后再加入2a)。
实施例2：手性γ-氨基膦酸酯3的合成
在20-30℃下，向4mL反应瓶中加入氮杂二烯1(0.15毫摩尔)，碳酸钠(7.9毫克,0.075毫摩尔),有机催化剂5a(2.4毫克，0.0075毫摩尔)和1.0毫升甲苯，然后该体系降温至-20℃,然后向该体系加入亚磷酸酯2(0.45毫摩尔)，-20℃下反应1-8天，向反应体系中加入水，用二氯甲烷萃取，合并二氯甲烷层后，无水硫酸钠干燥，过滤，减压去除溶剂，硅胶柱层析得到产品化合物3。反应式如下：
产物的产率为分离收率，rr值为1,4-加成产物和1,2-加成产物之间的比例，ee值为1,4-加成产物的对映体过量百分率，见表2和表3。
表2.手性γ-氨基膦酸酯3的合成
表3.手性γ-氨基膦酸酯3pa在标准条件下的合成
各个化合物的实验数据如下：
(S)-(-)-Diphenyl((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)phosphonate(3aa):89mg,97％yield,91％ee,[α]20 D＝-50.00(c 0.89,CHCl3),new compound,white solid,m.p.＝
13C NMR(101MHz,CDCl3)δ153.6(d,J＝1.0Hz),150.2(d,J＝9.9Hz),150.1(d,J＝9.4Hz),146.4(d,J＝11.9Hz),143.7,136.7,131.3(d,J＝6.8Hz),130.3(d,J＝7.1Hz),129.7,129.6,129.6,128.6(d,J＝1.8Hz),128.1(d,J＝2.5Hz),127.4,125.7(d,J＝2.6Hz),125.4,125.3,124.9,123.3,120.5(d,J＝4.4Hz),120.3(d,J＝4.3Hz),119.9,116.1(d,J＝10.1Hz),111.5,43.1(d,J＝139.4Hz),21.5；13C DEPT-45o NMR(101MHz,CDCl3)δ130.3(d,J＝7.1Hz),129.7,129.6,129.6,128.6(d,J＝1.8Hz),128.2(d,J＝2.6Hz),127.4,125.4,125.3,124.9,123.3,120.5(d,J＝4.4Hz),120.3(d,J＝4.3Hz),119.9,111.5,43.1(d,J＝139.4Hz),21.5；31P NMR(162MHz,CDCl3)δ14.2.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 14.3min and 15.5min(maj).HRMS Calculated for C34H29NO6PS[M+H]+610.1448,found610.1449.
(Z)-Diphenyl(2-benzylidene-3-((4-methylphenyl)sulfonamido)-2,3-dihydrobenzofuran-3-yl)phosp honate(4aa):new compound,white solid,m.p.＝190-191℃,Rf＝0.25(hexanes/ethyl acetate＝3/1).1H
(d,J＝2.0Hz),143.8(s),138.0(d,J＝1.8Hz),133.7(d,J＝4.7Hz),131.4(d,J＝2.9Hz),129.8(d,J＝0.6Hz),129.6,129.3,128.9(d,J＝1.8Hz),128.2(d,J＝3.5Hz),128.1,127.5,127.0(d,J＝0.9Hz),125.7(d,J＝0.8Hz),125.6(d,J＝0.9Hz),122.4(d,J＝2.9Hz),120.5(d,J＝4.1Hz),120.3(d,J＝4.2Hz),120.0(d,J＝8.7Hz),110.3(d,J＝2.0Hz),108.2(d,J＝8.6Hz),65.9(d,J＝171.5Hz),21.4；13CDEPT-45o NMR(101MHz,CDCl3)δ131.4(d,J＝2.9Hz),129.8(d,J＝0.8Hz),129.6(d,J＝0.5Hz),129.3,128.9(d,J＝1.8Hz),128.2(d,J＝3.5Hz),128.1,127.5,127.0(d,J＝0.9Hz),125.7(d,J＝0.9Hz),125.6(d,J＝0.8Hz),122.4(d,J＝2.9Hz),120.5(d,J＝4.1Hz),120.3(d,J＝4.2Hz),110.3(d,J＝2.0Hz),108.2(d,J＝8.6Hz),21.4；31P NMR(162MHz,CDCl3)δ6.2.HRMS CalculatedforC34H32N2O6PS[M+NH4]+627.1713,found 627.1711.
(S)-(-)-Diphenyl((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(o-tolyl)methyl)phosphonate(3ba):89mg,95％yield,92％ee,[α]20 D＝-11.98(c 0.86,CHCl3),new compound,white solid,m.p.＝
(101MHz,CDCl3)δ153.5,150.4(d,J＝9.8Hz),150.3(d,J＝9.7Hz),147.3(d,J＝11.6Hz),143.8,137.3(d,J＝8.8Hz),137.1,130.8(d,J＝1.7Hz),130.6(d,J＝4.7Hz),130.3(d,J＝6.4Hz),129.7,129.7,129.6,128.2(d,J＝2.7Hz),127.5,126.4(d,J＝2.7Hz),125.5(d,J＝2.0Hz),125.4,125.2,124.9,123.2,120.6(d,J＝4.4Hz),120.4(d,J＝4.3Hz),119.8,116.1(d,J＝10.2Hz),111.6,38.9(d,J＝141.0 Hz),21.6,20.0；31P NMR(162 MHz,CDCl3)δ15.0.HPLC:Chiralcel IC column,220 nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 9.8 min and 13.6 min(maj).HRMS Calculated forC35H31NO6PS[M+H]+624.1604,found 624.1605.
(S)-(-)-Diphenyl((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(m-tolyl)methyl)phosphonate(3ca):93 mg,99％yield,92％ee,[α]20 D＝-62.74(c 0.91,CHCl3),new compound,white solid,m.p.＝139-140℃,Rf＝0.35(hexanes/ethyl acetate＝3/1).1H NMR(400MHz,
150.2(d,J＝9.1Hz),146.3(d,J＝11.6Hz),143.7,138.3(d,J＝1.8Hz),137.0,131.1(d,J＝7.6Hz),131.0(d,J＝6.8Hz),129.8,129.7,129.6,129.1(d,J＝2.6Hz),128.6(d,J＝1.8Hz),127.5,127.5(d,J＝7.4Hz),125.9(d,J＝2.7Hz),125.4,125.3,125.0,123.4,120.6(d,J＝4.4Hz),120.3(d,J＝4.3Hz),120.0,116.1(d,J＝10.0Hz),111.6,43.2(d,J＝138.9Hz),21.6,21.6；31P NMR(162MHz,CDCl3)δ14.4.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 13.6 min and15.2min(maj).HRMS Calculated for C35H31NO6PS[M+H]+624.1604,found 624.1602.
(S)-(-)-Diphenyl((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(p-tolyl)methyl)phosphonate(3da):90mg,96％yield,91％ee,[α]20 D＝-56.58(c 0.85,CHCl3),new compound,white solid,m.p.＝20 171-172℃,Rf＝0.35(hexanes/ethylacetate＝3/1).1H NMR(400MHz,CDCl3)
Hz),129.8,129.7,129.4(d,J＝1.7Hz),128.0(d,J＝6.9Hz),127.5,125.9(d,J＝2.7Hz),125.5,125.4,124.9,123.4,120.6(d,J＝4.4Hz),120.4(d,J＝4.3Hz),120.0,116.0(d,J＝10.0Hz),111.6,42.9(d,J＝139.4Hz),21.6,21.3；31P NMR(162MHz,CDCl3)δ14.6.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 15.0min and 16.7min(maj).HRMSCalculated for C35H31NO6PS[M+H]+624.1604,found 624.1603.
(S)-Diphenyl([1,1'-biphenyl]-4-yl(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)phosp honate(3ea):102 mg,99％yield,91％ee,[α]20 D＝-29.10(c 1.00,CHCl3),new compound,white solid,
(d,J＝2.4Hz),125.5,125.4,125.0,123.5,120.5(d,J＝4.3Hz),120.4(d,J＝4.3Hz),119.9,116.2(d,J＝10.0Hz),111.6,42.9(d,J＝139.4Hz),21.6；31P NMR(162MHz,CDCl3)δ14.1.HPLC:Chiralcel ICcolumn,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 16.6min and18.5min(maj).HRMS Calculated forC40H33NO6PS[M+H]+686.1761,found 686.1760.
(S)-Diphenyl((4-isopropylphenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)phos phonate(3fa):94mg,96％yield,93％ee,[α]20 D＝-38.48(c 0.92,CHCl3),new compound,white solid,
Hz),129.8,129.72(s),129.6,128.2(d,J＝6.9Hz),127.5,126.8(d,J＝1.0Hz),125.9(d,J＝2.4Hz),125.4,125.3,124.9,123.4,120.6(d,J＝4.2Hz),120.3(d,J＝4.2Hz),119.9,116.0(d,J＝10.0Hz),111.6,42.9(d,J＝139.3Hz),33.9,24.1,21.6；31P NMR(162 MHz,CDCl3)δ14.5.HPLC:Chiralcel IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝1.0mL/min,retention time 24.1min and45.6min(maj).HRMS Calculated forC37H35NO6PS[M+H]+652.1917,found 652.1917.
(S)-Diphenyl((4-(tert-butyl)phenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)pho sphonate(3ga):99 mg,99％yield,93％ee,[α]20 D＝-35.77(c 0.97,CHCl3),new compound,white solid,
146.5(d,J＝11.4Hz),143.9,137.0,130.2(d,J＝7.2Hz),129.8,129.8,129.6,127.8(d,J＝6.9Hz),127.5,125.9(d,J＝2.7Hz),125.7(d,J＝1.7Hz),125.5,125.3,125.0,123.5,120.6(d,J＝4.4Hz),120.3(d,J＝4.3Hz),119.9,115.9(d,J＝10.1Hz),111.7,42.9(d,J＝139.3Hz),34.7,31.4,21.7；31P NMR(162MHz,CDCl3)δ14.4.HPLC:Chiralcel IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝1.0mL/min,retention time 17.5 minand 35.8min(maj).HRMS Calculated for C38H37NO6PS[M+H]+666.2074,found 666.2073.
(S)-Diphenyl((4-methoxyphenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)phosp honate(3ha):95mg,99％yield,92％ee,[α]20 D＝-45.00(c 0.94,CHCl3),new compound,white solid,
143.8,136.9,131.6(d,J＝7.3Hz),129.8,129.7,127.5,125.9(d,J＝2.8Hz),125.5,125.4,124.9,123.4,123.1(d,J＝6.8Hz),120.6(d,J＝4.4Hz),120.4(d,J＝4.3Hz),119.9,115.9(d,J＝9.9Hz),114.1(d,J＝1.5Hz),111.6,55.4,42.4(d,J＝139.8Hz),21.6；31P NMR(162MHz,CDCl3)δ14.6.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 17.8min and20.1min(maj).HRMSCalculated for C35H31NO7PS[M+H]+640.1553,found 640.1551.
(S)-Diphenyl((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(naphthalen-2-yl)methyl)phosph onate(3ia):97mg,98％yield,90％ee,[α]20 D＝-48.92(c 0.93,CHCl3),new compound,white solid,m.p.
6H),5.02(d,J＝26.9Hz,1H),2.17(s,3H)；13C NMR(101MHz,CDCl3)δ153.7(d,J＝0.9Hz),150.2(d,J＝9.9Hz),150.1(d,J＝9.4Hz),146.2(d,J＝11.9Hz),143.7,136.6,133.2(d,J＝2.0Hz),132.8(d,J＝1.8Hz),129.6,129.6,129.5,129.5(d,J＝9.4Hz),128.9(d,J＝7.0Hz),128.2(d,J＝1.1Hz),128.1,127.7,127.6(d,J＝7.4Hz),127.4,126.5,126.4,125.8(d,J＝2.5Hz),125.4,125.3,125.0,123.4,120.4(d,J＝4.4Hz),120.3(d,J＝4.3Hz),120.1,116.4(d,J＝10.0Hz),111.5,43.2(d,J＝139.2Hz),21.4；31P NMR(162MHz,CDCl3)δ14.2.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 15.9min and 18.0 min(maj).HRMS Calculated forC38H31NO6PS[M+H]+660.1604,found 660.1608.
(S)-Diphenyl((3-chlorophenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)phospho nate(3ja):95mg,98％yield,88％ee,[α]20 D＝-45.50(c 0.89,CHCl3),new compound,white solid,m.p.
(d,J＝8.9Hz),145.6(d,J＝12.8Hz),143.9,136.6,134.3,133.4(d,J＝6.7Hz),130.3(d,J＝7.4Hz),129.9(d,J＝1.5Hz),129.8,129.7,128.5(d,J＝7.0Hz),128.4(d,J＝2.2Hz),127.4,125.6(d,J＝4.4Hz),125.6,125.5,125.2,123.5,120.4(d,J＝4.4Hz),120.3(d,J＝4.2Hz),120.1,116.6(d,J＝10.0Hz),111.6,42.7(d,J＝139.4Hz),21.6；31P NMR(162MHz,CDCl3)δ13.3.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 11.6 min and 14.2min(maj).HRMS Calculated forC34H28ClNO6PS[M+H]+644.1058,found 644.1059.
(S)-Diphenyl((4-chlorophenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)phospho nate(3ka):94 mg,97％yield,87％ee,[α]20 D＝-22.89(c 0.90,CHCl3),new compound,white solid,m.p.
131.6(d,J＝6.9Hz),130.3(d,J＝6.7Hz),129.8,129.7,129.6,128.8(d,J＝1.6Hz),127.5,125.5,125.4,125.1,123.4,120.4(d,J＝4.7Hz),120.4(d,J＝4.6Hz),119.9,116.4(d,J＝10.1Hz),111.6,42.4(d,J＝139.9Hz),21.6；31P NMR(162MHz,CDCl3)δ13.4.HPLC:Chiralcel IA column,220nm,30℃,n-hexane/i-propanol＝60/40,flow＝1.0mL/min,retention time 51.1min and 95.9min(maj).HRMS Calculated for C34H28ClNO6PS[M+H]+644.1058,found 644.1058.
(S)-Diphenyl((3-bromophenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)phosph onate(3la):93 mg,90％yield,89％ee,[α]20 D＝-46.20(c 0.87,CHCl3),new compound,white solid,m.p.
40 150.0(d,J＝9.1Hz),145.4(d,J＝12.1Hz),144.0,136.8,133.4(d,J＝6.7Hz),133.2(d,J＝7.9Hz),131.4(d,J＝2.6Hz),130.2(d,J＝2.0Hz),129.9,129.8,129.8,129.0(d,J＝6.5Hz),127.5,125.8(d,J＝2.7Hz),125.7,125.5,125.2,123.6,122.5(d,J＝1.8Hz),120.5(d,J＝4.4Hz),120.3(d,J＝4.4Hz),120.1,116.5(d,J＝9.9Hz),111.6,42.7(d,J＝139.0Hz),21.8；31P NMR(162MHz,CDCl3)δ13.4.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 11.8min and 14.9min(maj).HRMS Calculated for C34H28BrNO6PS[M+H]+688.0553,found 688.0550.
(S)-(-)-Diphenyl((4-(tert-butyl)phenyl)(6-methyl-3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)phosphonate(3ma):83mg,81％yield,94％ee,[α]20 D＝-44.02(c 0.72,CHCl3),new
Hz),151.1(d,J＝2.9Hz),150.3(d,J＝10.0Hz),150.2(d,J＝9.5Hz),145.8(d,J＝11.8Hz),143.7,136.9,135.2(d,J＝1.0Hz),130.0(d,J＝7.1Hz),129.7,129.7,129.6,128.1(d,J＝6.7Hz),127.5,125.6(d,J＝1.6Hz),125.3,125.2,124.8,123.3(d,J＝2.5Hz),120.6(d,J＝4.3Hz),120.4(d,J＝4.3Hz),119.4,115.9(d,J＝10.2Hz),111.8,42.7(d,J＝139.7Hz),34.6,31.4,21.7,21.6；31P NMR(162MHz,CDCl3)δ14.5.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 12.4min(maj)and 14.8min.HRMS Calculated for C39H39NO6PS[M+H]+680.2230,found 680.2234.
(S)-(-)-Diphenyl((3-(methylsulfonamido)benzofuran-2-yl)(phenyl)methyl)phosphonate(3na):78
5.47(d,J＝26.6Hz,1H),2.80(s,3H)；13C NMR(101MHz,CDCl3)δ153.8(d,J＝1.0Hz),150.4(d,J＝9.9Hz),150.2(d,J＝9.6Hz),147.7(d,J＝10.9Hz),132.1(d,J＝5.9Hz),130.3(d,J＝7.3Hz),129.8,129.8,129.1(d,J＝1.5Hz),128.5(d,J＝2.3Hz),125.5,125.4(d,J＝2.5Hz),123.9,120.5(d,J＝4.4Hz),120.4(d,J＝4.4Hz),119.5,115.9(d,J＝9.9Hz),112.1,43.4(d,J＝141.1Hz),40.1.；31P NMR(162MHz,CDCl3)δ13.7.HPLC:Chiralcel ICcolumn,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.7mL/min,retention time21.9min(maj)and 24.2min.HRMS Calculated for C28H25NO6PS[M+H]+534.1135,found534.1136.
(S)-(-)-Diphenyl((3-((4-nitrophenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)phosphonate(3oa):90 mg,94％yield,87％ee,[α]20 D＝-0.62(c 0.80,CHCl3),new compound,white solid,m.p.＝
(d,J＝6.0Hz),128.6(d,J＝2.2Hz),128.5,128.3(d,J＝2.9Hz),125.8,125.6,125.6,124.9(d,J＝1.3Hz),123.8,123.5,120.7(d,J＝4.2Hz),120.5(d,J＝4.3Hz),120.4,116.5(d,J＝10.5Hz),111.4,42.7(d,J＝139.2Hz).；31P NMR(162MHz,CDCl3)δ14.3.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 12.6min and 28.6min(maj).HRMSCalculated for C33H26N2O8PS[M+H]+641.1142,found 641.1143.
(S)-N-(2-((diphenylphosphoryl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ab):69mg,80％yield,66％ee,[α]20 D＝+9.36(c 0.63,CHCl3),new compound,white solid,m.p.＝
210-212℃,Rf＝0.40(hexanes/ethyl acetate＝1/1).1H NMR(400MHz,DMSO)δ9.79(s,1H),7.86-7.69(m,4H),7.57-7.33(m,7H),7.27(d,J＝8.2Hz,2H),7.25-7.07(m,7H),7.04-6.99(m,3H),5.69(d,J＝11.6Hz,1H),2.18(s,3H)；13C NMR(101MHz,DMSO)δ153.2,148.3(d,J＝9.6Hz),143.6,136.4,133.7(d,J＝4.9Hz),132.8(d,J＝36.6Hz),132.4(d,J＝2.4Hz),132.2(d,J＝2.5Hz),131.8(d,J＝36.5Hz),131.5(d,J＝8.8Hz),131.0(d,J＝9.2Hz),130.2(d,J＝4.8Hz),129.8,129.0(d,J＝11.5Hz),128.7(d,J＝11.6Hz),128.4,127.4(d,J＝1.2Hz),127.0,125.1,124.8,123.1,120.3,116.3(d,J＝7.1Hz),111.6,44.5(d,J＝61.9Hz),21.4；31P NMR(162MHz,DMSO)δ28.1.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 18.1min and27.1min(maj).HRMSCalculated for C34H29NO4PS[M+H]+578.1549,found 578.1550.
(S)-Dibenzyl((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)phosphonate(3ac):77mg,80％yield,80％ee,[α]20 D＝-34.32(c 0.74,CHCl3),newcompound,white solid,m.p.＝
143.7,136.9,135.8(d,J＝5.7Hz),135.8(d,J＝5.9Hz),131.8(d,J＝6.4Hz),130.2(d,J＝6.8Hz),129.7,128.6,128.6,128.5,128.5,127.9,127.9,127.5,125.9(d,J＝2.6Hz),124.8,123.4,120.2,115.8(d,J＝9.6Hz),111.6,68.9(d,J＝7.1Hz),68.6(d,J＝7.1Hz),43.3(d,J＝137.7Hz),21.6；31P NMR(162MHz,CDCl3)δ22.6.HPLC:Chiralcel IA column,220nm,30℃,n-hexane/i-propanol＝60/40,flow＝1.0mL/min,retention time 22.2minand 60.6min(maj).HRMS Calculated for C36H33NO6PS[M+H]+638.1761,found 638.1763.
(S)-Diphenyl((3-((4-methylphenyl)sulfonamido)benzo[b]thiophen-2-yl)(phenyl)methyl)phosphon ate(3pa):88 mg,94％yield,87％ee,[α]20 D＝-153.11(c0.77,CHCl3),new compound,pale yellow solid,
10.4Hz),149.8(d,J＝8.4Hz),143.8,138.05(s),137.2(d,J＝3.5Hz),136.8(d,J＝1.9Hz),134.1(d,J＝9.6Hz),133.4(d,J＝6.3Hz),129.9,129.8(d,J＝8.3Hz),129.8,129.7,129.0,128.7(d,J＝1.4Hz),127.4,126.5(d,J＝9.6Hz),125.7,125.5,125.2(d,J＝1.0Hz),124.7,123.4,121.9(d,J＝1.1Hz),120.7(d,J＝4.3Hz),120.2(d,J＝4.3Hz),44.2(d,J＝138.8Hz),21.5；31P NMR(162MHz,CDCl3)δ17.1.HPLC:Chiralcel IC column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 13.7min and18.5min(maj).HRMS Calculated for C34H29NO5PS2[M+H]+626.1219,found 626.1216.
Claims (7)
1.一种合成手性γ-氨基膦酸酯的方法，所述方法的反应式和条件如下：
式中，Ar为苯基、萘基或任选地被至少一个选自C1-6烷基、卤素和甲氧基的基团取代的苯基；
R1为烷基、苯基、萘基、或任选地被至少一个选自C1-6烷基、卤素和甲氧基的基团取代的苯基；R2为对甲苯磺酰基、对硝基苯磺酰基，，甲磺酰基或2,4,6-三甲基苯磺酰基；
R为苯基或苄基；
X为氧或硫；
所述的有机催化剂为奎宁，奎尼丁，辛可宁，辛可宁丁，硫脲，方酰胺中的一种；
所述方酰胺、硫脲的结构为5c、5d所示：
所述的碱为碳酸钠、碳酸钾、碳酸铯、氢氧化钠、三乙胺中的一种或两种以上混合。
2.如权利要求1所述的方法，其特征在于：
所述化合物1与碱摩尔比为1:0.3-1:5。
3.如权利要求1所述的方法，其特征在于：
所述化合物1与有机催化剂的摩尔比为1:0.01-1:0.2。
4.如权利要求1所述的方法，其特征在于：
所述化合物1与化合物2的摩尔为1:1-1:5。
5.如权利要求1所述的方法，其特征在于：所述方法包括以下步骤：
步骤一，在20-30℃下，将化合物1溶于有机溶剂中，得体系1；
步骤二，向体系1中加入碱，得体系2；
步骤三，向体系2中加入有机催化剂，得体系3；
步骤四，将体系3降温至-20℃，然后向体系3中加入化合物2，-20℃下反应1-8天，反应结束后加入水，用二氯甲烷萃取，合并二氯甲烷层后，无水硫酸钠干燥，过滤，减压去除溶剂，硅胶柱层析得到产品化合物3。
6.如权利要求1所述的方法，其特征在于：
化合物1于有机溶剂中的浓度为0.01-1.0mol/L。
7.如权利要求5所述的方法，其特征在于：
所述的有机溶剂为四氢呋喃、二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、苯、氯苯、邻二甲苯、间二甲苯、对二甲苯、N,N-二甲基甲酰胺中的至少一种。
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