CN104817590A - 一种手性β-羟基膦酸酯的不对称化学合成方法 - Google Patents
一种手性β-羟基膦酸酯的不对称化学合成方法 Download PDFInfo
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Abstract
本发明涉及一种手性β-羟基膦酸酯的不对称化学合成方法。本发明采用硼酸酯与氨基茚醇原位生成1,3,2-噁唑硼烷作为催化剂,以氢硼烷为还原剂,进行β-羰基膦酸酯的不对称硼氢化还原,进而高选择性和高收率地合成手性β-羟基膦酸酯类目标化合物。本发明高效构建的手性β-羟基膦酸酯结构是许多药物、农药、生物活性分子和天然产物的重要骨架,本发明所述的合成方法为这类化合物的不对称合成提供了一个广泛适用的制备方法。
Description
技术领域
本发明涉及一种手性β-羟基膦酸酯类化合物的不对称化学合成方法。
背景技术
手性β-羟基膦酸酯是一类非常重要的化合物,近些年来在药物化学和有机合成研究领域受到了越来越广泛的关注,一方面是由于其与对应的羟基羧酸和氨基羧酸及衍生物具有很高的化学结构相似性,可作为两者的模拟物,用于某些抗菌药、酶抑制剂、多肽类似物等药物的化学结构改造;另一方面是因为作为一类化学中间体,可通过经典的官能转换反应,用来合成一些重要的化合物类型如氨基磷酸酯等。一些常见的β-羟基膦酸酯类化合物结构如下:
关于手性β-羟基膦酸酯的制备,目前主要有化学合成及生物合成两种策略方法。关于化学合成策略,目前报道较多也比较具有代表性的是,利用氢气还原相应的β-羰基膦酸酯制备手性β-羟基膦酸酯的方法(X.Tao,W.Li,X.Ma,X.Li,W.Fan,L.Zhu,X.Xie,Z.Zhang,J.Org.Chem.,2012,77,8401-8409),反应如下所示:
但该类方法需要使用高压氢气(10bar)以及昂贵复杂的过渡金属催化剂体系,反应操作较为复杂,实用性不够好。
关于生物合成策略,主要是利用一些生物酶催化动力学拆分的方法制备手性β-羟基膦酸 酯(Y.H.Zhang,C.F.Xu,J.F.Li,C.Y.Yuan,Chin.J.Chem.,2003,21,883-892.),反应如下所示:
但该类方法不可避免的要浪费掉50%的原料,而且酶的获取也不方便,化学实验室操作可行性不高。
总体来看,现有的方法普遍存在实用性不够好、试剂昂贵、反应时间较长等问题,化学实验操作性也不够理想。因此,寻找一种简单易行的手性β-羟基膦酸酯及其衍生物的不对称合成方法,仍然是目前极具应用价值和学术意义的研究领域。
发明内容
本发明要解决的技术问题是:提供一种条件温和、反应迅速、对映选择性高的手性β-羟基膦酸酯的不对称化学合成方法。
本发明合成方法的反应式如下:
其中,R为芳基、杂环芳基或烷基;催化剂为以1-氨基-2-茚醇与硼酸酯原位生成的1,3,2-噁唑硼烷;氢硼烷还原剂为BH3·THF或BH3·Me2S溶液;β-羰基膦酸酯、还原剂、催化剂的摩尔比为1∶1~1.2∶0.05~0.10。
本发明手性β-羟基膦酸酯的不对称化学合成方法反应步骤如下:在氮气保护下,将硼酸三甲酯加入氨基茚醇溶液中反应10~30min,再加入氢硼烷还原剂继续反应10~30min,然后加入β-羰基膦酸酯(1)的溶液,继续在10~30℃反应30~120min;加入饱和氯化铵溶液处理,乙酸乙酯提取、分液,有机相用无水硫酸镁干燥12h后,过滤、除溶剂、柱层析纯化,即得所述的目标化合物β-羟基膦酸酯(2)。
β-羰基膦酸酯为β-苯基-β-羰基膦酸二乙酯、β-对甲苯基-β-羰基膦酸二乙酯、β-对氟苯基-β-羰基膦酸二乙酯、β-对氯苯基-β-羰基膦酸二乙酯、β-对溴苯基-β-羰基膦酸二乙酯、β-(2-甲氧基)苯基-β-羰基膦酸二乙酯、β-(2-呋喃基)-β-羰基膦酸二乙酯、β-(3-甲基-2-呋喃基)-β-羰基膦酸二乙酯、β-(2-苯并噻吩基)-β-羰基膦酸二乙酯、或β-甲基-β-羰基膦酸二乙酯;溶剂为四氢呋喃THF或二氯甲烷DCM。
本发明的有益效果:
(1)所用还原剂为氢硼烷,所用催化剂为氨基茚醇,两者均为价廉易得的化工产品,无 需使用高压氢气和复杂的酶或化学催化剂。
(2)反应条件更加温和快速,仅需接近室温下反应2h以内即可完成。
(3)反应的对映选择性更高,最高达99.8%,反应收率也较高,最高达97.2%。
(4)底物适应性更好,不但是β-取代苯环,即使是β-杂环取代甚至是β-脂肪烷基取代的原料,均获得了良好的不对称还原反应选择性和收率。
本发明高效构建的手性β-羟基膦酸酯结构,是许多药物、农药、生物活性分子和天然产物的重要骨架,本发明所述的合成方法为这类化合物的不对称合成提供了一个广泛适用的制备方法。
具体实施方式
实施例1
以β-苯基-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-苯基-β-羟基膦酸二乙酯(2a):
将硼酸三甲酯(4.2mg,0.04mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的THF(4ml)溶液中,氮气保护下室温反应10min,加入BH3·THF(4.4ml,4.4mmol)溶液,室温反应10min,加入β-苯基-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,室温60min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2a(0.974g,89%),无色油状液体。+27.3(c 1.1,CHCl3)[lit.,+29.8(c2.8,CH3OH)];νmax(ATR)/cm-1:3333,2982,17161455,1392,1215,1020,956;1H NMR(400MHz;CDCl3)δH 1.28(m,6H,OCH2CH3),2.19(m,2H,CH2P),4.06(m,4H,OCH2CH3),4.20(s,1H,OH),5.08(m,1H,CHOH),7.32(m,5H,PhH);13C NMR(101MHz,CDCl3):δC 143.8,143.7,128.5,127.6,125.6,68.8,68.8,62.0,62.0,61.9,61.8,36.6,35.3,16.4,16.4,16.3;31P NMR(101MHz,CDCl3)δP 28.94,28.97;HRMS(ES+)Calculated for C12H20O4P 259.1099,found 259.1111(MH+);手性HPLC:Chiralpak AS,10%iPrOH in hexane;1mL/min;保留时间为10.6min/11.6min.
实施例2
以β-对甲苯基-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-对甲苯基-β-羟基膦酸二乙酯(2b):
将硼酸三甲酯(4.2mg,0.04mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的THF(4ml)溶液中,氮气保护下室温反应20min,加入BH3.THF(4.4ml,4.4mmol)溶液,室温反应10min,加入β-对甲苯基-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,10℃反应30min后,加入饱和NH4Cl(10mi)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2b(1.051g,97%),浅灰色油状液体。+30(c1.5,CHCl3);νmax(ATR)/cm-1:3347,2982,29091515,1443,1392,1217,1020,957;1H NMR(400MHz;CDCl3)δH 1.34(m,6H,OCH2CH3),2.21(m,3H,CH2P),2.36(s,3H,CH3Ar),3.86(s,1H,COH),4.06(m,4H,OCH2CH3),5.10(tt,1H,J 10.1and 2.6,CHOH),7.18(d,2H,J 8.0,PhCH),7.30(d,2H,J 8.0,PhCH);13C NMR(101MHz,CDCl3):δC 140.8,140.6,137.5,129.3,125.6,68.8,68.8,62.2,62.1,62.1,62.0,36.7,35.4,21.2,16.6,16.5,16.5;31P NMR(101MHz,CDCl3)δP 29.18;HRMS(ES+)Calculated for C13H22O4P273.1256,found 273.1263(MH+);手性HPLC:Chiralpak AS,10%iPrOH in hexane;1mL/min;保留时间为10.0min/10.7min.
实施例3
以β-(2-甲氧基)苯基-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-(2-甲氧基)苯基-β-羟基膦酸二乙酯(2c):
将硼酸三甲酯(4.2mg,0.04mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的THF(4ml)溶液中,氮气保护下室温反应20min,加入BH3.THF(4.4ml,4.4mmol)溶液,30℃反应10min,加入β-(2-甲氧基)苯基-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,10℃反应90min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2c(1.051g,92%),白色固体;+39(c 1.0,CHCl3);νmax(ATR)/cm-1:3315,2982,2907,2838,1602,1490,1233,1218,1019,956;1H NMR(400MHz;CDCl3)δH 1.29(t,3H,J 7.0,OCH2CH3),1.38(t,3H,J 7.0,OCH2CH3),2.23(td,1H,J 15.2and 9.3,CHHP)2.40(td,1H,J 15.2 and 3.0,CHHP),3.87(s,3H,OCH3),3.96(d,1H,J 4.4,OH),4.11(m,4H,OCH2CH3),5.35(m,1H,CHOH),6.88(dd,1H,J 8.3and 0.7,PhH),7.01(td,1H,J 7.5and 0.7,PhH),7.26(m,1H,PhH),7.53(dd,1H,J 7.5and 1.2,PhH);13C NMR(101MHz,CDCl3):δC 155.64,131.5,131.3,128.4,126.2,120.8,110.1,76.6,64.6,64.6,61.9,61.8,61.7,55.2,34.4,33.0,16.4,16.3,16.3,16.2;31P NMR(101MHz,CDCl3)δP 29.80;HRMS(ES+)Calculated for C13H22O5P 289.1205,found289.1209(MH+);手性HPLC:Chiralpak AS,10%iPrOH in hexane;1mL/min;保留时间为15.9min/22.7min.
实施例4
以β-对氟苯基-β-羰基膦酸二乙酯为原料,以BH3·DMS为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-对氟苯基-β-羟基膦酸二乙酯(2d):
将硼酸三甲酯(4.2mg,0.04mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的DCM(4ml)溶液中,氮气保护下室温反应20min,加入BH3.DMS(4.4ml,4.4mmol)溶液,30℃反应20min,加入β-对氟苯基-β-羰基膦酸二乙酯(4.0mmol)的DCM(4ml)溶液,10℃反应60min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2d(0.812g,74%),无色油状液体;+30(c1.5,CHCl3)[lit.,+30.3(c1.5,CHCl3)];νmax(ATR)/cm-1:3332,2984,2909,2838,1604,1508,1393,1217,1020,957;1H NMR(400MHz;CDCl3)δH 1.33(tt,6H,J19.1and 7.1,OCH2CH3),2.17(m,2H,CH2P),3.97(s,1H,OH),4.13(m,4H,OCH2CH3),5.09(m,1H,CHOH),7.04(m,2H,PhH),7.36(m,2H,PhH);13C NMR(101MHz,CDCl3):δC 163.6,161.2,139.4,127.4,127.3,115.6,115.4,68.4,68.4,62.3,62.3,62.2,62.2,36.8,35.5,16.6,16.6,16.5,14.4;31P NMR(101MHz,CDCl3)δP 28.83;19F NMR(101MHz,CDCl3)δF114.82,114.83,114.84;HRMS(ES+)Calculated for C12H19O4PF 277.1005,found 277.0996(MH+);手性HPLC:Chiralpak AS,10%iPrOH in hexane;1mL/min;保留时间为10.1min/11.2min.
实施例5
以β-(2-呋喃基)-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-(2-呋喃基)-β-羟基膦酸二乙酯 (2e):
将硼酸三甲酯(4.2mg,0.04mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的THF(4ml)溶液中,氮气保护下室温反应20min,加入BH3.THF(4.0ml,4.0mmol)溶液,25℃反应20min,加入β-(2-呋喃基)-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,25℃反应60min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2e(0.985g,85%),无色油状液体。+18(c1.0,CHCl3);νmax(ATR)/cm-1:3326,2983,2909,1444,1393,1218,1017,958;1H NMR(400MHz;CDCl3)δH 1.32(m,6H,OCH2CH3),2.33(m,2H,CH2P),3.83(m,1H,OH),4.11(m,4H,OCH2CH3),5.11(m,1H,CHOH),6.31(m,2H,ArH),7.36(m,1H,ArH);13C NMR(101MHz,CDCl3):δC 155.2,155.0,142.1,110.2,106.1,76.6,63.0,63.0,62.1,62.1,61.9,32.9,31.5,16.4,16.3,16.3;31P NMR(101MHz,CDCl3)δP 28.63;HRMS(ES+)Calculated for C10H18O5P 249.0892,found 249.0898(MH+);手性HPLC:Chiralpak AS,10%iPrOH in hexane;1mL/min;保留时间为10.1min/11.2min.
实施例6
以β-对氯苯基-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-对氯苯基-β-羟基膦酸二乙酯(2f):
将硼酸三甲酯(4.2mg,0.04mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的THF(4ml)溶液中,氮气保护下室温反应20min,加入BH3.THF(4.8ml,4.8mmol)溶液,25℃反应20min,加入β-对氯苯基-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,25℃反应60min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2f(0.989g,85%)无色油状液体。+30(c 1.5,CHCl3);νmax(ATR)/cm-1:3326,2983,2907,1490,1393,1215,1022,958;1H NMR(400MHz;CDCl3)δH 1.33(tt,3H,J 20.5and 7.5,OCH2CH3),2.16(m,2H,CH2P),4.06(m,1H,OH),4.11(m,4H,OCH2CH3),5.08(m,1H,CHOH),7.33(s,4H,PhH);13C NMR(101MHz,CDCl3):δC 142.0,133.3,128.6,126.9,76.2,68.2,68.1, 62.2,62.0,62.0,36.5,35.2,16.4,16.4,16.3,16.3;31P NMR(101MHz,CDCl3)δP 28.71;HRMS(ES+)Calculated for C12H19O4PCl 293.0710,found 293.0720(MH+);手性HPLC:Chiralpak AS,10%iPrOH in hexane;1mL/min;保留时间为9.7min/11.1min.
实施例7
以β-对溴苯基-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-对溴苯基-β-羟基膦酸二乙酯(2g):
将硼酸三甲酯(4.2mg,0.04mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的THF(4ml)溶液中,氮气保护下室温反应20min,加入BH3.THF(4.8ml,4.8mmol)溶液,25℃反应20min,加入β-对溴苯基-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,25℃反应60min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2g(1.134g,85%),浅黄色油状液体。+22.9(c 0.35,CHCl3))[lit.,+25(c 0.9,CHCl3)];νmax(ATR)/cm-1:3325,2981,2906,1483,1393,1215,1022,958;1H NMR(400MHz;CDCl3)δH 1.32(t,3H,J 7.1,OCH2CH3),1.37(dt,3H,J 7.1and 0.6,OCH2CH3),2.18(m,2H,CH2P),4.13(m,5H,OCH2CH3and OH),5.09(m,1H,CHOH),7.29(d,2H,J 7.8,PhH),7.49(d,2H,J 8.4,PhH); 13C NMR(101MHz,CDCl3):δC 142.5,142.4,131.5,127.2,121.4,68.2,68.1,62.2,62.1,62.0,62.0,36.5,35.1,16.4,16.3,16.3,16.3;31P NMR(101MHz,CDCl3)δP 28.65;HRMS(ES+)Calculated for C12H19O4PCl 337.0204,found 337.0211(MH+);手性HPLC:Chiralpak AS,10%iPrOH in hexane;1mL/min;保留时间为10.7min/11.4min.
实施例8
以β-苯并噻吩基-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-苯并噻吩基-β-羟基膦酸二乙酯(2h):
将硼酸三甲酯(2.1mg,0.02mmol)缓慢加入(1S,2R)-氨基茚醇(3.0mg,0.02mmol)的THF (4ml)溶液中,氮气保护下室温反应20min,加入BH3.THF(4.4ml,4.4mmol)溶液,25℃反应20min,加入β-苯并噻吩基-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,25℃反应60min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2h(1.124g,90%),白色固体。+13.4(c 0.37,CHCl3);νmax(ATR)/cm-1:3336,2982,2905,1388,1218,1020,959;1H NMR(400MHz;CDCl3)δH 1.29(t,3H,J 7.1,OCH2CH3),1.35(dd,1H,J 7.1,CH2CH3),2.36(m,2H,CH2P),4.13(m,5H,OCH2CH3and OH),5.43(m,1H,CHOH),7.31(m,3H,ArH),7.71(dd,1H,J 8.5and 1.5,ArH),7.81(dd,1H,J 8.5and 1.0,ArH); 13C NMR(101MHz,CDCl3):δC 147.9,147.8,139.3,139.3,124.3,124.3,123.5,122.4,119.9,76.6,65.8,65.8,62.3,62.1,62.0,36.4,35.0,16.4,16.4,16.3;31P NMR(101MHz,CDCl3)δP 28.11;HRMS(ES+)Calculated for C12H19O4PCl 315.0820,found 315.0820(MH+);手性HPLC:Chiralpak AS,10%iPrOH in hexane;1mL/min;保留时间为11.3min/13.6min.
实施例9
以β-(3-甲基-2-呋喃基)-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-(3-甲基-2-呋喃基)-β-羟基膦酸二乙酯(2i):
将硼酸三甲酯(4.2mg,0.04mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的THF(4ml)溶液中,氮气保护下室温反应20min,加入BH3.THF(4.4ml,4.4mmol)溶液,25℃反应20min,加入β-(3-甲基-2-呋喃基)-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,25℃反应60min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2i(0.921g,89%),橘黄色油状液体。+5.0(c 1.0,CHCl3);νmax(ATR)/cm-1:3340,2982,2916,1713,1444,1393,1217,1018,956;1H NMR(400MHz;CDCl3)δH 1.31(dt,6H,J 7.1and 2.5,OCH2CH3),2.06(s,3H,ArCH3),2.22(dd,1H,J 18.5,15.4and 4.0,CHHP),2.51(td,1H,J 15.4and 9.4,CHHP),3.46(m,1H,OH),4.09(m,4H,CH2CH3),5.13(td,1H,J 9.7,CHOH),6.18(d,1H,J 1.8,ArH),7.27(d,1H,J 1.8,ArH);13C NMR(101MHz,CDCl3):δC 149.2,149.1,141.2,116.6,113.1,76.6,62.1,62.0,61.8,60.9,60.9,32.8,32.4,16.4,16.3,16.3,16.3,9.6;31P NMR(101MHz,CDCl3)δP 28.71;HRMS(ES+)Calculated for C11H19O4NaP 285.0868,found 285.0868(MNa+);手性HPLC:Chiralpak AS,5%iPrOH in hexane;1mL/min;保留时间为16.9min/41.2min.
实施例10
以β-甲基-β-羰基膦酸二乙酯为原料,以BH3·THF为还原剂,以(1S,2R)-1-氨基-2-茚醇与硼酸三甲酯原位生成的1,3,2-噁唑硼烷为催化剂,合成β-甲基-β-羟基膦酸二乙酯(2j):
将硼酸三甲酯(42mg,0.4mmol)缓慢加入(1S,2R)-氨基茚醇(6.0mg,0.04mmol)的THF(4ml)溶液中,氮气保护下室温反应20min,加入BH3.THF(4.4ml,4.4mmol)溶液,20℃反应20min,加入β-甲基-β-羰基膦酸二乙酯(4.0mmol)的THF(4ml)溶液,25℃反应60min后,加入饱和NH4Cl(10ml)水溶液,搅拌10min,EtOAc(3x 5ml)提取,合成有机相,无水MgSO4干燥12h,过滤,除溶剂后,柱层析(展开剂为:乙酸乙酯/石油醚,2∶1)纯化得到产物2j(0.718g,92%),无色油状液体。νmax(ATR)/cm-1:3376,2985,2909,1275,1260,1018,937;1H NMR(400MHz;CDCl3)δH 1.27(dd,3H,J 6.2and 2.3,OCH2CH3),1.32(t,6H,J 17.1,OCH2CH3),1.89(m,2H,CH2P),3.51(s,1H,OH),4.11(m,4H,OCH2CH3);13C NMR(101MHz,CDCl3):δC 76.6,62.8,61.8,61.8,35.8,34.4,24.3,24.1,16.4,16.4,16.3,16.3;31P NMR(101MHz,CDCl3)δP 30.09;HRMS(ES+)Calculated for C12H18O4P 197.0943,found 197.0943(MH+).。
Claims (1)
1.一种手性β-羟基膦酸酯的不对称化学合成方法,其特征在于该合成方法的反应式如下:
其中,R为芳基、杂环芳基或烷基;催化剂为以氨基茚醇与硼酸酯原位生成的1,3,2-噁唑硼烷;还原剂为氢硼烷BH3·THF或BH3·Me2S溶液;
合成方法的反应步骤如下:在氮气保护下,将硼酸三甲酯加入氨基茚醇溶液中反应10~30min,再加入氢硼烷还原剂继续反应10~30min,然后加入β-羰基膦酸酯(1)的溶液,继续在10~30℃反应30~120min;加入饱和氯化铵溶液处理,乙酸乙酯提取、分液,有机相用无水硫酸镁干燥12h后,过滤、除溶剂、柱层析纯化,即得目标化合物β-羟基膦酸酯(2);β-羰基膦酸酯、还原剂、催化剂的摩尔比为1∶1~1.2∶0.05~0.10;
β-羰基膦酸酯为β-苯基-β-羰基膦酸二乙酯、β-对甲苯基-β-羰基膦酸二乙酯、β-对氟苯基-β-羰基膦酸二乙酯、β-对氯苯基-β-羰基膦酸二乙酯、β-对溴苯基-β-羰基膦酸二乙酯、β-(2-甲氧基)苯基-β-羰基膦酸二乙酯、β-(2-呋喃基)-β-羰基膦酸二乙酯、β-(3-甲基-2-呋喃基)-β-羰基膦酸二乙酯、β-(2-苯并噻吩基)-β-羰基膦酸二乙酯、或β-甲基-β-羰基膦酸二乙酯;
所用溶剂为四氢呋喃THF或二氯甲烷DCM。
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