CN109096334B - 一种手性芳基膦氧化合物及其衍生物的制备方法 - Google Patents
一种手性芳基膦氧化合物及其衍生物的制备方法 Download PDFInfo
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Classifications
-
- 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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- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5333—Arylalkane phosphine oxides or thioxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种手性芳基膦氧化合物及其衍生物的制备方法。以膦氧基化合物、邻亚甲基苯醌化合物为原料，在手性方酰胺有机催化剂催化的条件下，邻亚甲基苯醌化合物与膦氧基化合物通过亲核加成进而得到手性芳基膦氧化合物。本发明采用手性方酰胺有机催化剂催化、一步直接构建C‑P键的路线，反应条件温和，操作简单，能快速简单的合成出一系列手性芳基膦氧化合物，提供多样性的化合物骨架，对新药筛选和制药工艺有很大的意义。
Description
技术领域
本发明涉及一种手性芳基膦氧化合物及其衍生物的制备方法，属于不对称催化领域。
背景技术
近期的研究发现，有机膦化合物表现出特别的生物活性和化学性质(Org.Lett.2006,8(23),5291-5293)，在有机合成、材料化学和药物化学上有广泛的应用。此外，芝麻酚骨架是治疗心力衰竭靶点G蛋白偶联受体激酶2(GRK2)的选择性抑制剂帕罗西汀的部分结构(ACS Chem.Biol.2012,7,1830-1839)。尽管现如今能够合成芳基和杂芳基有机膦化合物的方法多有报道，但是，手性芳基膦氧化合物及其衍生物的制备方法目前还是研究难点。
邻亚甲基苯醌化合物在合成化学中具有多样的反应性和巨大的潜在可能性(Chem.Eur.J.2012,18,9160–9173)，主要不对称研究于1,4-加成反应，[4+n]环加成反应等领域，而邻亚甲基苯醌化合物与杂原子化合物的不对称亲核加成的研究较少。李灿院士研究团队报道了邻亚甲基苯醌化合物与硫醇非对称共轭加成，构建碳-硫(C-S)键的反应(Angew.Chem.Int.Ed.2015,54,4522–4526)。孙建伟教授报道了邻亚甲基苯醌化合物与醇非对称亲核加成，构建碳-氧(C-O)键的反应(Org.Lett.2015,17,6058-6061)；近期，他们也报道了邻亚甲基苯醌化合物与磺酰胺不对称亲核加成，构建碳-氮(C-N)键的反应(ChineseJ.Chem.2018,36,587-593)。虽然邻亚甲基苯醌化合物与膦化合物的亲核加成，构建碳-磷(C-P)键的反应，已有报道(Org.Lett.2017,19,5988-5991；Org.Lett.,2018,20,477–480；Molecules,2018,23,1240-1249)，但是邻亚甲基苯醌化合物与膦化合物的不对称催化亲核加成反应还未有报道过。
发明内容
本发明的目的是公开一种原料价廉易得，操作简单，高收率的具有光学活性的芳基膦氧化合物及其衍生物。
为了实现上述目的，本发明采用了以下技术方案：
一种手性芳基膦氧化合物及其衍生物，所述化合物具有下列结构：
结构式一：
其中3k的结构式：
结构式二：
结构式三：
结构式四：
结构式五：
一种手性芳基膦氧化合物及其衍生物的制备方法，用邻亚甲基苯醌化合物和苯基膦氧基化合物在手性方酰胺催化剂催化的条件下，发生亲核加成反应生成C-P键，得到手性芳基膦氧化合物及其衍生物，具体步骤如下：
(1)先称取1.0当量的膦氧基化合物，将膦氧基化合物溶解于有机溶剂中，浓度控制为0.250～0.350mol/L，得到膦氧基化合物溶液；(2)在一个圆底烧瓶中加入1.0当量的邻醌甲基化物和10mol％的手性方酰胺催化剂，再加入有机溶剂，控制溶液中邻醌甲基化物的浓度为0.25～0.350mol/L；
(3)将膦氧基化合物溶液缓慢滴加入圆底烧瓶中，在0.5～1.0小时滴加结束，通过TLC监测反应进程，反应结束后浓缩得到粗产物；
(4)将粗产物用体积比为乙酸乙酯：石油醚＝1:1的溶液进行柱层析，或是将粗产物过滤并用正己烷冲洗得到所述具有光学活性的芳基膦氧化合物及其衍生物。
进一步的，所述手性方酰胺均为有机小分子酰胺，所述手性方酰胺包括1(-哌啶基)环己烷骨架手性方酰胺(4a)、甲氧基奎宁骨架手性方酰胺(4b，4c)、10,11-二氢-甲氧基奎宁骨架手性方酰胺(4d)；
结构式分别如下：
进一步的，所述有机溶剂为二氯甲烷。
进一步的，所述邻亚甲基苯醌化合物由相应的6-取代亚甲基苯酚经氧化银氧化制备得到。(请参阅J.Org.Chem.2017,82,1790.)。
进一步的，所述邻亚甲基苯醌化合物包括下列：3,4-二氧杂戊环-6-(4-甲氧基苯基)亚甲基-环己-2,4-二烯酮、3,4-二氧杂戊环-6-(4-乙氧基苯基)亚甲基-环己-2,4-二烯酮、3,4-二甲氧基-6-(4-甲氧基苯基)亚甲基-环己-2,4-二烯酮、3,4-二氧杂戊环-6-((4-甲氧基苯基)乙烯基)亚甲基-环己-2,4-二烯酮、3,4-二氧杂戊环-6-((3-甲氧基苯基)乙烯基)亚甲基-环己-2,4-二烯酮、3,4-二氧杂戊环-6-(苯乙烯基)亚甲基-环己-2,4-二烯酮、3,4-二氧杂戊环-6-((4-甲基苯基)乙烯基)亚甲基-环己-2,4-二烯酮、3,4-二氧杂戊环-6-((4-氯苯基)乙烯基)亚甲基-环己-2,4-二烯酮、3,4-二氧杂戊环-6-(2-噻吩乙烯基)亚甲基-环己-2,4-二烯酮和3,4-二氧杂戊环-6-(异丁烯)亚甲基-环己-2,4-二烯酮。
进一步的，所述膦氧基化合物包括下列：二苯基膦氧、二(4-甲基苯基)膦氧、二(4-叔丁基苯基)膦氧、二萘基膦氧、二(4-氟苯基)膦氧、二(4-氯苯基)膦氧、二(3-氟苯基)膦氧、二(4-三氟甲基苯基)膦氧、二(3-三氟甲基苯基)膦氧、二(3,5-双三氟甲基苯基)膦氧和杂菲膦。
本发明所用的有机溶剂和制备邻亚甲基苯醌化合物的原料以及催化剂都可在市场购得。
一种所述化合物3i的制备方法，具体步骤如下：
(1)称取0.8～1.2eq 6-(4-甲氧基苄基)芝麻酚和1.0～1.2eq氧化银于含有搅拌子的圆底烧瓶中，加入二氯甲烷，控制溶液中6-(4-甲氧基苄基)芝麻酚浓度为0.250～0.350mol/L，在25～35℃下搅拌12小时；
(2)再取2.5～3.0eq二(3-三氟甲基苯基)膦氧和8～10mol％手性方酰胺4d溶于二氯甲烷中，控制溶液中二(3-三氟甲基苯基)膦氧为0.250～0.350mol/L，得到混合溶液；
(3)混合溶液慢滴加入圆底烧瓶中，在0.5～1.0小时滴加结束，通过TLC监测反应进程，反应结束后浓缩得到粗产物；
(4)将粗产物用体积比为乙酸乙酯：石油醚＝0.8～1.2:1的溶液进行柱层析，得到化合物3i。
在具体生产中，6-(4-甲氧基苄基)芝麻酚可以称取0.8eq、0.9eq、1.0eq、1.1eq或1.2eq；
氧化银可以称取0.8eq、0.9eq、1.0eq、1.1eq或1.2eq；
控制溶液中6-(4-甲氧基苄基)芝麻酚浓度为0.250mol/L、0.280mol/L、0.300mol/L、0.320mol/L或0.350mol/L；
二(3-三氟甲基苯基)膦氧可以取2.5eq、2.6eq、2.7eq、2.8eq、2.9eq或3.0eq；
手性方酰胺4d可以取8mol％、8.5mol％、9mol％、9.5mol％或10mol％；
控制溶液中二(3-三氟甲基苯基)膦氧为0.250mol/L、0.280mol/L、0.300mol/L、0.320mol/L或0.350mol/L；
一种所述化合物3i的制备方法，具体步骤如下：
(1)称取0.8～1.2eq 6-(羟基(4-甲氧基苯基)甲基)芝麻酚和8～10mol％手性方酰胺4d于含有搅拌子的圆底烧瓶中，加入二氯甲烷，控制溶液中6-(羟基(4-甲氧基苯基)甲基)芝麻酚浓度为0.250～0.350mol/L，在25～35℃下搅拌12小时；
(2)再取0.8～1.2eq二(3-三氟甲基苯基)膦氧溶于二氯甲烷，控制溶液中为0.250～0.350mol/L，得到二(3-三氟甲基苯基)膦氧化合物溶液；
(3)将二(3-三氟甲基苯基)膦氧化合物溶液缓慢滴加入圆底烧瓶中，在0.5～1.0小时滴加结束，通过TLC监测反应进程，反应结束后浓缩得到粗产物；
(4)将粗产物用体积比为乙酸乙酯：石油醚＝0.8～1.2:1的溶液进行柱层析，得到化合物3i。
在具体生产中，6-(羟基(4-甲氧基苯基)甲基)芝麻酚可以称取0.8eq、0.9eq、1.0eq、1.1eq或1.2eq；
手性方酰胺4d可以取8mol％、8.5mol％、9mol％、9.5mol％或10mol％；
控制溶液中6-(羟基(4-甲氧基苯基)甲基)芝麻酚浓度为0.250mol/L、0.280mol/L、0.300mol/L、0.320mol/L或0.350mol/L；
二(3-三氟甲基苯基)膦氧可以称取0.8eq、0.9eq、1.0eq、1.1eq或1.2eq；
控制溶液中二(3-三氟甲基苯基)膦氧为0.250mol/L、0.280mol/L、0.300mol/L、0.320mol/L或0.350mol/L。
一种所述化合物4的制备方法，具体步骤如下：
(1)称取0.8～1.2eq 2-(羟基(苯基)甲基)萘酚和8～10mol％手性方酰胺4d于含有搅拌子的圆底烧瓶中，加入二氯甲烷，控制溶液中2-(羟基(苯基)甲基)萘酚浓度为0.250～0.350mol/L，在25～35℃下搅拌12小时；
(2)再取0.8～1.2eq二苯基膦氧溶于二氯甲烷，控制溶液中为0.250～0.350mol/L，得到二苯基膦氧化合物溶液；
(3)将二苯基膦氧化合物溶液缓慢滴加入圆底烧瓶中，在0.5～1.0小时滴加结束，通过TLC监测反应进程，反应结束后浓缩得到粗产物；
(4)将粗产物用体积比为乙酸乙酯：石油醚＝0.8～1.2:1的溶液进行柱层析，得到化合物4。
在具体生产中，2-(羟基(苯基)甲基)萘酚可以称取0.8eq、0.9eq、1.0eq、1.1eq或1.2eq；
手性方酰胺4d可以取8mol％、8.5mol％、9mol％、9.5mol％或10mol％；
控制溶液中2-(羟基(苯基)甲基)萘酚浓度为0.250mol/L、0.280mol/L、0.300mol/L、0.320mol/L或0.350mol/L；
二苯基膦氧可以称取0.8eq、0.9eq、1.0eq、1.1eq或1.2eq；
控制溶液中二苯基膦氧为0.250mol/L、0.280mol/L、0.300mol/L、0.320mol/L或0.350mol/L。
以上制备方法中，柱层析使用的体积比为乙酸乙酯：石油醚＝0.8:1、乙酸乙酯：石油醚＝1:1或者乙酸乙酯：石油醚＝1.2:1。
与现有技术相比较，本发明具备的有益效果：
本发明公开了一种通过邻亚甲基苯醌化合物以及膦氧基化合物作为反应底物，合成一系列手性芳基膦氧化合物及其衍生物的新型合成策略。在这个反应中，膦氧化合物对邻亚甲基苯醌化合物的亚甲基碳原子进行亲核加成。这个方法的特色就是提供一种手性方酰胺催化剂催化，一步直接构建C-P键的路线。该反应具有操作简易，反应条件温和且能实现放大反应。
本发明所用的原料，邻亚甲基苯醌化合物、膦氢化合物和有机溶剂廉价易得，因此本发明合成手性芳基膦氧化合物及其衍生物成本合理。
本发明合成路线简单，一步构建目标产物。
本发明具有高选择性，较好收率，环境友好等优点，符合绿色化学的要求。
本发明能快速简单的合成出一系列手性芳基膦氧化合物及其衍生物，提供多样性的化合物骨架，对新药筛选和制药工艺有很大的意义。
具体实施方式
下面通过实施例对本发明的技术方案作进一步阐述。
实施例中用到的邻亚甲基苯醌化合物1和膦氧基化合物2具体名称和对应的代号见于下表：
实施例1
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；
再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3a。收率91％，对映体过量92％。
1H NMR(600MHz,DMSO-d6)δ9.56(s,1H),7.77–7.71(m,2H),7.67–7.61(m,2H),7.46(s,1H),7.44–7.36(m,4H),7.35–7.28(m,4H),6.70–6.65(m,2H),6.28(s,1H),5.78(dd,J＝27.7,1.0Hz,2H),5.42(d,J＝9.7Hz,1H),3.58(s,3H)；13C NMR(151MHz,DMSO-d6)δ158.23(d,J＝0.7Hz),149.70(d,J＝8.1Hz),146.56,139.99,133.80(d,J＝95.9Hz),133.65(d,J＝96.7Hz),131.90(d,J＝1.3Hz),131.77(d,J＝1.6Hz),131.11(d,J＝8.7Hz),131.08(d,J＝6.1Hz),130.85(d,J＝8.6Hz),129.86(d,J＝3.9Hz),128.90(d,J＝12.9Hz),128.83(d,J＝12.9Hz),116.66(d,J＝2.7Hz),113.99,109.63(d,J＝5.3Hz),101.10,98.01,55.35,41.85(d,J＝72.1Hz)；31P NMR(243MHz,DMSO-d6)δ31.98；[α]D 25＝-122.0(c＝0.5inCHCl3)；HRMS(ESI)Calcd.for C27H24O5P(M+H)+459.1361,Found:459.1364；HPLC(ChiralIC,λ＝254nm,hexane/2-propanol/MeOH＝80/10:10,Flow rate＝0.9mL/min),tR＝8.057min,8.857min.
实施例2
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；
再取二(4-甲基苯基)膦氧(46.0mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3b。收率93％，对映体过量80％。
1H NMR(600MHz,DMSO-d6)δ9.59(s,1H),7.62(dd,J＝10.6,7.9Hz,2H),7.51(dd,J＝10.7,7.9Hz,2H),7.46(s,1H),7.35–7.31(m,2H),7.19(dd,J＝8.1,2.4Hz,2H),7.15(dd,J＝8.2,2.4Hz,2H),6.73–6.67(m,2H),6.29(s,1H),5.82(d,J＝1.1Hz,1H),5.77(d,J＝1.0Hz,1H),5.38(d,J＝9.7Hz,1H),3.61(s,3H),2.24(s,3H),2.22(s,3H)；13C NMR(151MHz,DMSO)δ158.18,149.70(d,J＝7.9Hz),146.50,141.70(d,J＝2.6Hz),141.56(d,J＝1.4Hz),139.96,131.09(d,J＝8.9Hz),131.06(d,J＝6.0Hz),130.82(d,J＝98.27Hz),130.80(d,J＝9.0Hz),130.64(d,J＝98.98Hz),130.17(d,J＝3.4Hz),129.49(d,J＝14.3Hz),129.41(d),J＝14.4Hz),116.95(d,J＝2.8Hz),113.98,109.69(d,J＝5.5Hz),101.07,98.06,55.35,21.43,21.41；31P NMR(243MHz,DMSO)δ32.27；[α]D 25＝-68.0(c＝0.5in CHCl3)；HRMS(ESI)Calcd.for C29H28O5P(M+H)+487.1674,Found:487.1674.HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝20/10,Flow rate＝0.8mL/min),tR＝23.967min,28.217min.
实施例3
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；
再取二(4-叔丁基基苯基)膦氧(62.8mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3c。收率54％，对映体过量87％。
1H NMR(600MHz,Chloroform-d)δ7.60(dd,J＝10.8,8.4Hz,2H),7.44(dd,J＝11.1,8.4Hz,2H),7.39(dd,J＝8.4,2.7Hz,2H),7.35(dd,J＝8.4,2.7Hz,2H),7.22(dd,J＝8.7,1.5Hz,2H),6.67(d,J＝8.7Hz,2H),6.51(s,1H),6.48(s,1H),5.80(dd,J＝7.9,1.5Hz,2H),4.65(d,J＝13.7Hz,1H),3.71(s,3H),1.28(s,9H),1.28(s,9H)；13C NMR(151MHz,CDCl3)δ158.55(d,J＝1.0Hz),155.61(d,J＝2.6Hz),155.47(d,J＝2.6Hz),151.23(d,J＝4.7Hz),147.74(d,J＝1.3Hz),140.96,131.31(d,J＝27.6Hz),131.25(d,J＝27.1Hz),130.86(d,J＝6.1Hz),128.13(d,J＝3.3Hz),127.43(d,J＝100.8Hz),127.25(d,J＝101.6Hz),125.55(d,J＝28.0Hz),125.47(d,J＝28.3Hz),115.71(d,J＝4.5Hz),113.81,110.46(d,J＝8.7Hz),101.50(d,J＝0.8Hz),101.02,55.17,52.23(d,J＝66.1Hz),34.99,31.05,31.04；31P NMR(243MHz,CDCl3)δ39.38；[α]D 25＝-80.0(c＝0.5in CHCl3)；HRMS(ESI)Calcd.for C35H40O5P(M+H)+571.2613,Found:571.2601；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝20/10,Flow rate＝0.8mL/min),tR＝9.598min,10.965min.
实施例4
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；
再取二萘基膦氧(60.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3d。收率85％，对映体过量84％。
1H NMR(600MHz,DMSO-d6)δ9.63(s,1H),8.44(d,J＝12.5Hz,1H),8.36(d,J＝12.7Hz,1H),7.97–7.92(m,2H),7.91–7.80(m,6H),7.56(s,1H),7.54–7.45(m,4H),7.44–7.40(m,2H),6.68–6.63(m,2H),6.28(s,1H),5.77–5.72(m,3H),3.52(s,3H)；13C NMR(151MHz,DMSO)δ158.25,149.81(d,J＝8.0Hz),149.73(d,J＝8.1Hz),146.60(d,J＝6.0Hz),140.01(d,J＝3.5Hz),134.29(d,J＝16.8Hz),133.81(d,J＝95.6Hz),133.66(d,J＝96.4Hz),132.83(d,J＝7.7Hz),132.55-132.37(m),131.83(d,J＝20.3Hz),131.56(d,J＝38.5Hz),131.14,131.10(d,J＝4.0Hz),130.86(d,J＝8.8Hz),130.01(d,J＝3.6Hz),129.87(d,J＝3.8Hz),129.16,128.91(d,J＝11.1Hz),128.81(d,J＝11.1Hz),128.54,128.46,128.09(d,J＝5.1Hz),127.36(d,J＝7.5Hz),126.30(d,J＝9.6Hz),126.11(d,J＝9.6Hz),116.76(d,J＝3.0Hz),116.57(d,J＝2.9Hz),114.07,113.99,109.77(d,J＝5.4Hz),109.65(d,5.3Hz),101.10,98.03,98.00,55.34,55.30,41.86(d,J＝71.3Hz),41.66(d,J＝72.1Hz)；31P NMR(243MHz,DMSO)δ32.03；[α]D 25＝-35.0(c＝1.0in CHCl3)；HRMS(ESI)Calcd.for C35H28O5P(M+H)+559.1674,Found:559.1672；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝20/10,Flow rate＝0.8mL/min),tR＝46.815min,65.523min.
实施例5
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；
再取二(4-氟苯基)膦氧(47.6mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3e。收率80％，对映体过量91％。
1H NMR(600MHz,Chloroform-d)δ9.77(s,2H),7.73–7.66(m,2H),7.56–7.49(m,2H),7.25(d,J＝7.6Hz,2H),7.10–7.01(m,4H),6.72(s,1H),6.70(d,J＝8.5Hz,2H),6.45(s,1H),5.83–5.79(m,2H),4.79(d,J＝12.8Hz,1H),3.72(s,3H)；13C NMR(151MHz,CDCl3)δ165.07(dd,J＝254.42,3.14Hz),165.05(dd,J＝254.63,3.13Hz),158.78,150.41(d,J＝5.9Hz),147.81,141.22,133.84(dd,J＝9.6,3.1Hz),133.83(dd,J＝22.5,10.1Hz),130.85(d,J＝6.4Hz),127.52(d,J＝3.1Hz),126.65(dd,J＝102.0,3.1Hz),126.55(dd,J＝101.6,3.0Hz),116.11(dd,J＝21.1,12.8Hz),,115.99(dd,J＝21.2,13.0Hz),115.04(d,J＝4.0Hz),114.03,110.53(d,J＝7.9Hz),101.13,100.83,55.17,50.15(d,J＝72.2Hz)；31PNMR(243MHz,Chloroform-d)δ36.95；19F NMR(565MHz,Chloroform-d)δ-105.79,-105.86；[α]D 25＝-74.0(c＝0.5in CHCl3)；HRMS(ESI)Calcd.for C27H22F2O5P(M+H)+495.1173,Found:495.1176；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝20/10,Flow rate＝0.8mL/min),tR＝15.673min,20.807min.
实施例6
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二(4-氯苯基)膦氧(54.2mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3f。收率77％，对映体过量93％。
1H NMR(600MHz,Chloroform-d)δ7.65–7.59(m,2H),7.48–7.43(m,2H),7.38–7.31(m,4H),7.26(dd,J＝8.6,1.5Hz,2H),6.75–6.69(m,3H),6.44(s,1H),5.83–5.80(m,2H),4.79(d,J＝12.8Hz,1H),3.72(s,3H)；13C NMR(151MHz,CDCl3)δ158.83(d,J＝1.1Hz),150.28(d,J＝5.8Hz),147.87(d,J＝1.2Hz),141.30,138.91(d,J＝2.8Hz),132.68(d,J＝11.8Hz),132.61(d,J＝11.5Hz),130.84(d,J＝6.5Hz),129.12(d,J＝99.9Hz),129.05(d,J＝17.0Hz),129.04(d,J＝99.8Hz),128.97(d,J＝17.2Hz),127.30(d,J＝3.5Hz),114.86(d,J＝4.3Hz),114.09,110.03(d,J＝7.8Hz),101.17,100.79,55.18,49.68(d,J＝67.2Hz)；31P NMR(243MHz,CDCl3)δ36.95；[α]D 25＝-66.0(c＝0.5in CHCl3)；HRMS(ESI)Calcd.for C27H22Cl2O5P(M+H)+527.0582,Found:527.0579；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝20/10,Flow rate＝0.8mL/min),tR＝20.232min,29.323min.
实施例7
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二(3-氯苯基)膦氧(54.2mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3g。收率50％，对映体过量92％。
1H NMR(600MHz,DMSO-d6)δ9.58(s,1H),7.81–7.67(m,4H),7.57–7.49(m,2H),7.49–7.40(m,3H),7.37–7.34(m,2H),6.78–6.71(m,2H),6.33(s,1H),5.85(d,J＝1.0Hz,1H),5.80(d,J＝1.1Hz,1H),5.55(d,J＝9.8Hz,1H),3.63(s,3H)；13C NMR(151MHz,DMSO)δ158.44,149.79(d,J＝8.3Hz),146.80,140.05,136.06(d,J＝14.8Hz),135.44(d,J＝15.3Hz),134.04(d,J＝14.8Hz),133.98(d,J＝14.8Hz),132.18(d,J＝26.3Hz),131.17(d,J＝9.9Hz),131.09(d,J＝7.3Hz),130.68(d,J＝9.4Hz),130.13(d,J＝84.7Hz),130.07(d,J＝83.5Hz),129.70(d,J＝30.0Hz),129.24(d,J＝3.9Hz),115.55(d,J＝3.1Hz),114.18,109.49(d,J＝5.1Hz),101.20,97.93,55.40,41.35(d,J＝69.4Hz)；31P NMR(243MHz,DMSO)δ30.23；[α]D 25＝-24.0(c＝1.5in CHCl3)；HRMS(ESI)Calcd.for C27H22Cl2O5P(M+H)+527.0582,Found:527.0577；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝20/10,Flowrate＝0.8mL/min),tR＝10.165min,11.532min.
实施例8
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二(4-三氟甲基苯基)膦氧(67.6mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3h。收率77％，对映体过量93％。
1H NMR(600MHz,DMSO-d6)δ9.61(s,1H),8.08–7.99(m,4H),7.83–7.73(m,4H),7.48(d,J＝1.1Hz,1H),7.44–7.38(m,2H),6.78–6.72(m,2H),6.34(s,1H),5.85(d,J＝1.1Hz,1H),5.80(d,J＝1.1Hz,1H),5.67(d,J＝9.5Hz,1H),3.62(s,3H)；13C NMR(151MHz,DMSO)δ158.48,149.69(d,J＝8.3Hz),146.87,140.13,138.01(d,J＝92.9Hz),137.63(d,J＝93.3Hz),132.27(d,J＝9.1Hz),131.95(d,J＝9.2Hz),131.11(d,J＝6.7Hz),129.14(d,J＝3.6Hz),125.79(m),124.09(q,J＝272.9Hz)124.06(q,J＝272.9Hz),115.39(d,J＝3.0Hz),114.25,109.44(d,J＝4.9Hz),101.22,97.93,55.34,41.17(d,J＝70.0Hz)；31P NMR(243MHz,DMSO)δ30.19；19F NMR(565MHz,DMSO)δ-61.73,-61.77；[α]D 25＝-16.8(c＝2.5inCHCl3)；HRMS(ESI)Calcd.for C29H20F6O5P(M-H)-593.0953,Found:593.0956；HPLC(ChiralIA,λ＝254nm,hexane/2-propanol＝20/10,Flow rate＝0.8mL/min),tR＝12.398min,13.507min.
实施例9
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二(3-三氟甲基苯基)膦氧(67.6mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3i。收率77％，对映体过量97％。
1H NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.12(dd,J＝16.9,9.7Hz,2H),8.08–8.02(m,1H),7.94(d,J＝10.7Hz,1H),7.88(d,J＝7.8Hz,1H),7.82(d,J＝7.8Hz,1H),7.74–7.68(m,1H),7.67–7.62(m,1H),7.46(s,1H),7.38–7.35(m,2H),6.75(d,J＝8.7Hz,2H),6.34(s,1H),5.84(d,J＝1.1Hz,1H),5.81(d,J＝1.1Hz,1H),5.64(d,J＝9.7Hz,1H),3.63(s,3H)；13CNMR(151MHz,DMSO)δ158.56,149.83(d,J＝8.5Hz),146.89,140.08,135.20(d,J＝8.8Hz),134.72(d,J＝4.7Hz),134.08(d,J＝4.5Hz),131.10(d,J＝6.6Hz),130.32,130.31(d,J＝23.1Hz),129.10(m),128.90(d,J＝3.9Hz),127.97(m),127.55(m),125.06(d,J＝9.3Hz),123.25(d,J＝9.4Hz),115.09(d,J＝3.6Hz),114.20,109.45(d,J＝4.7Hz),101.21,97.82,55.41,41.46(d,J＝70.0Hz)；31P NMR(243MHz,DMSO)δ30.69；19F NMR(565MHz,DMSO)δ-61.32,-61.41；[α]D 25＝-25.0(c＝1.0in CHCl3)；HRMS(ESI)Calcd.for C29H20F6O5P(M-H)-593.0953,Found:593.0955；HPLC(Chiral OD-H,λ＝254nm,hexane/2-propanol/MeOH＝40/1:1,Flow rate＝0.8mL/min),tR＝26.115min,29.390min.
实施例10
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二(3,5-二三氟甲基苯基)膦氧(94.8mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3j。收率94％，对映体过量96％。
1H NMR(600MHz,DMSO-d6)δ9.51(s,1H),8.55(d,J＝10.4Hz,2H),8.39(d,J＝10.4Hz,2H),8.26(d,J＝5.8Hz,1H),8.15(d,J＝6.7Hz,1H),7.45–7.33(m,3H),6.73(d,J＝8.2Hz,2H),6.32(s,1H),6.01(d,J＝9.8Hz,1H),5.80(d,J＝17.6Hz,2H),3.59(s,3H)；13CNMR(151MHz,DMSO)δ158.72,150.15(d,J＝8.6Hz),147.10,140.07,135.69(d,J＝95.0Hz),135.61(d,J＝93.8Hz),132.46(d,J＝26.5Hz),131.17(d,J＝7.0Hz),131.02(d,J＝11.4Hz),130.82(d,J＝4.8Hz),130.74(d,J＝4.9Hz),130.54(d,J＝11.5Hz),128.50(d,J＝4.0Hz),126.56,126.11,123.35(q,J＝273.3Hz),123.28(q,J＝273.4Hz),114.25,113.91(d,J＝3.4Hz),109.69(d,J＝4.6Hz),101.26,97.67,55.41,55.39,41.14(d,J＝70.1Hz)；31P NMR(243MHz,DMSO)δ29.91；19F NMR(565MHz,DMSO)δ-61.35,-61.37,-61.42,-61.43；[α]D 25＝-58.0(c＝1.5in CHCl3)；HRMS(ESI)Calcd.for C31H20F12O5P(M+H)+731.0857,Found:731.0864；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝20/1,Flowrate＝0.8mL/min),tR＝5.032min,7.140min.
实施例11
称取1a(51.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取9,10-二氢-9-氧杂-10-磷杂菲-10-氧化物(43.2mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3k。收率50％，非对映体58：42，对映体过量分别88％，89％。
1H NMR(600MHz,DMSO-d6)δ9.13(s,1H),8.15–8.10(m,2H),7.74–7.68(m,1H),7.49–7.42(m,3H),7.40(d,J＝1.3Hz,1H),7.36–7.30(m,1H),7.22–7.18(m,2H),7.03(dd,J＝8.1,1.2Hz,1H),6.88–6.83(m,2H),6.23–6.20(m,1H),5.96(d,J＝1.0Hz,1H),5.87(d,J＝1.0Hz,1H),4.76(d,J＝15.4Hz,1H),3.71(s,3H)；13C NMR(151MHz,DMSO)δ158.73,150.15(d,J＝10.1Hz),149.34(d,J＝8.0Hz),147.01,140.15,135.84(d,J＝7.2Hz),134.05,131.41,131.41(d,J＝8.3Hz),130.83(d,J＝6.6Hz),128.74(d,J＝12.2Hz),127.93(d,J＝7.2Hz),126.39,125.44,125.20,124.98(d,J＝93.0Hz),124.74,124.58(d,J＝19.6Hz),122.99(d,J＝10.1Hz),120.52(d,J＝6.2Hz),114.32,113.44,109.28(d,J＝5.0Hz),101.30,97.91,55.53,41.48(d,J＝91.1Hz)；31P NMR(243MHz,DMSO)δ33.48；mixture[α]D 25＝-37.3(c＝1.5in CHCl3)；HRMS(ESI)Calcd.for C27H22O6P(M+H)+473.1154,Found:473.1161；HPLC(Chiral AD-H,λ＝254nm,hexane/2-propanol＝2/1,Flow rate＝0.7mL/min),tR(major)＝54.073min,65.190min；tR(minor)＝24.023min,27.640min.
实施例12
称取1b(54.0mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3l。收率86％，对映体过量86％。
1H NMR(600MHz,DMSO-d6)δ9.57(s,1H),7.78–7.72(m,2H),7.67–7.62(m,2H),7.47(s,1H),7.46–7.32(m,6H),7.32–7.27(m,2H),6.70–6.65(m,2H),6.29(s,1H),5.81(d,J＝1.1Hz,1H),5.77(d,J＝1.1Hz,1H),5.43(d,J＝9.7Hz,1H),3.90–3.80(m,2H),1.21(t,J＝7.0Hz,3H)；13C NMR(151MHz,DMSO)δ157.52,149.70(d,J＝7.9Hz),146.55,139.98,133.80(d,J＝95.6Hz),133.66(d,J＝96.6Hz),131.82(d,J＝21.5Hz),131.11(d,J＝8.7Hz),131.08(d,J＝5.9Hz),130.86(d,J＝8.7Hz),129.68(d,J＝4.0Hz),128.89(d,J＝15.7Hz),128.82(d,J＝15.9Hz),116.67(d,J＝3.2Hz),114.43,109.63(d,J＝5.5Hz),101.09,98.01,63.25,41.86(d,J＝73.8Hz),15.06；31P NMR(243MHz,DMSO)δ31.91；[α]D 25＝-48.0(c＝1.5in CHCl3)；HRMS(ESI)Calcd.for C28H24O5P(M-H)-471.1361,Found:471.1367；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝2/1,Flow rate＝0.8mL/min),tR＝11.090min,17.232min.
实施例13
称取1c(54.4mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3m。收率74％，对映体过量77％。
1H NMR(600MHz,DMSO-d6)δ9.51(s,1H),7.85–7.77(m,2H),7.75–7.68(m,2H),7.58(s,1H),7.46-7.38(m,6H),7.37–7.31(m,2H),6.75–6.69(m,2H),6.33(s,1H),5.45(d,J＝9.9Hz,1H),3.63(s,3H),3.62(s,3H),3.60(s,3H)；13C NMR(151MHz,DMSO)δ158.19,149.37(d,J＝8.4Hz),148.81,141.77,131.83,131.16(d,J＝2.0Hz),131.11,130.89(d,J＝8.6Hz),129.74(d,J＝3.7Hz),128.88(d,J＝11.0Hz),128.83(d,J＝11.1Hz),115.81(d,J＝2.9Hz),115.68(d,J＝5.6Hz),113.89,101.23,56.89,55.59,55.35；31P NMR(243MHz,DMSO)δ32.19；[α]D 25＝-58.0(c＝0.5in CHCl3)；HRMS(ESI)Calcd.for C28H28O5P(M+H)+475.1674,Found:475.1670；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝2/1,Flowrate＝0.8mL/min),tR＝6.840min,9.923min.
实施例14
称取1d(56.4mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3n。收率66％，对映体过量94％。
1H NMR(600MHz,DMSO-d6)δ9.66(s,1H),7.84–7.79(m,2H),7.75–7.69(m,2H),7.50–7.41(m,4H),7.40–7.36(m,2H),7.14(s,1H),7.12–7.07(m,2H),6.80–6.72(m,2H),6.32(s,1H),6.20–6.15(m,1H),5.83–5.80(m,2H),5.72(s,1H),5.04(dd,J＝9.3,7.7Hz,1H),3.67(s,3H)；13C NMR(151MHz,DMSO)δ159.26,149.79(d,J＝7.4Hz),146.79,140.25,133.30(d,J＝11.2Hz),132.73,132.62,132.05,131.32(d,J＝8.7Hz),130.90(d,J＝8.8Hz),129.76,129.44(d,J＝1.7Hz),128.95(d,J＝27.6Hz),128.88(d,J＝27.6Hz),127.68,122.11(d,J＝5.5Hz),114.45,109.71(d,J＝4.2Hz),101.15,98.50,55.53,55.37；31P NMR(243MHz,DMSO)δ33.47；[α]D 25＝-40.0(c＝1.0in CHCl3)；HRMS(ESI)Calcd.forC29H26O5P(M+H)+485.1518,Found:485.1519；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝2/1,Flow rate＝0.8mL/min),tR＝15.582min,24.348min.
实施例15
称取1e(56.4mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3o。收率70％，对映体过量88％。
1H NMR(600MHz,DMSO-d6)δ9.75(s,1H),7.92–7.84(m,2H),7.83–7.76(m,2H),7.56–7.39(m,6H),7.25–7.14(m,3H),6.92–6.87(m,1H),6.87–6.80(m,1H),6.53(dd,J＝15.9,3.7Hz,1H),6.42–6.33(m,2H),5.85(dd,J＝4.7,1.1Hz,2H),5.15–5.11(m,1H),3.67(s,3H).13C NMR(151MHz,DMSO)δ156.44,149.92(d,J＝6.6Hz),146.86,140.29,132.94(d,J＝94.9Hz),132.84(d,J＝95.4Hz),132.06,131.32(d,J＝8.6Hz),130.93(d,J＝8.8Hz),129.25,129.00(d,J＝11.3Hz),128.86(d,J＝11.3Hz),128.69(d,J＝11.3Hz),126.68,125.38(d,J＝2.2Hz),124.90,120.99,114.47(d,J＝5.4Hz),111.80,109.74(d,J＝4.4Hz),101.17,98.69,55.81；31P NMR(243MHz,DMSO)δ33.72；[α]D 25＝-63.0(c＝1.0inCHCl3)；HRMS(ESI)Calcd.for C29H24O5P(M-H)-483.1361,Found:483.1368；HPLC(ChiralIA,λ＝254nm,hexane/2-propanol＝2/1,Flow rate＝0.8mL/min),tR＝12.323min,14.007min.
实施例16
称取1f(50.4mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3p。收率74％，对映体过量92％。
1H NMR(600MHz,Chloroform-d)δ7.84–7.78(m,2H),7.77–7.72(m,2H),7.56–7.51(m,1H),7.51–7.45(m,3H),7.44–7.39(m,2H),7.24–7.20(m,2H),7.20–7.15(m,3H),6.68–6.61(m,1H),6.54(s,1H),6.34(s,1H),6.23(dd,J＝15.7,3.9Hz,1H),5.81(s,2H),4.31–4.26(m,1H)；13C NMR(151MHz,Chloroform-d)δ151.38(d,J＝4.4Hz),147.90(d,J＝2.1Hz),141.28,136.50(d,J＝2.4Hz),135.11(d,J＝11.2Hz),132.41(d,J＝2.6Hz),132.28(d,J＝2.6Hz),131.58(d,J＝9.0Hz),131.22(d,J＝8.9Hz),130.11(d,J＝97.7Hz),129.57(d,J＝97.4Hz),128.71(d,J＝1.6Hz),128.63(d,J＝1.5Hz),128.43,127.75,126.43(d,J＝0.7Hz),121.03(d,J＝6.2Hz),113.83(d,J＝6.6Hz),109.75(d,J＝7.1Hz),101.91(d,J＝2.0Hz),101.11,51.61(d,J＝65.4Hz)；31P NMR(243MHz,CDCl3)δ39.67；[α]D 25＝-48.7(c＝1.5in CHCl3)；HRMS(ESI)Calcd.for C28H24O4P(M+H)+455.1412,Found:455.1407；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝2/1,Flow rate＝0.8mL/min),tR＝11.015min,15.699min.
实施例17
称取1g(53.2mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3q。收率82％，对映体过量90％。
1H NMR(600MHz,Chloroform-d)δ10.19(s,1H),7.81–7.77(m,2H),7.76–7.72(m,2H),7.56–7.52(m,1H),7.51–7.45(m,3H),7.45–7.40(m,2H),7.08(d,J＝8.0Hz,2H),7.04(d,J＝7.9Hz,2H),6.61–6.55(m,1H),6.54(s,1H),6.32(s,1H),6.20(dd,J＝15.7,3.9Hz,1H),5.82(s,2H),4.27(dd,J＝12.0,9.1Hz,1H),2.29(s,3H)；13C NMR(151MHz,CDCl3)δ151.35(d,J＝4.6Hz),147.83,141.25,137.65,135.04(d,J＝11.2Hz),133.72(d,J＝2.2Hz),132.37(d,J＝2.7Hz),132.25(d,J＝2.8Hz),131.60(d,J＝9.0Hz),131.24(d,J＝8.8Hz),130.17(d,J＝90.3Hz),129.52(d,J＝90.7Hz),129.13,128.64(d,J＝11.7Hz),126.33,119.85(d,J＝6.2Hz),114.00(d,J＝6.8Hz),109.70(d,J＝7.2Hz),101.90(d,J＝2.4Hz),101.10,51.57(d,J＝65.4Hz),21.18；31P NMR(243MHz,CDCl3)δ39.71；[α]D 25＝-56.0(c＝1.0in CHCl3)；HRMS(ESI)Calcd.for C29H26O4P(M+H)+469.1569,Found:469.1579；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝2/1,Flow rate＝0.8mL/min),tR＝12.548min,17.582min.
实施例18
称取1h(57.3mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3r。收率92％，对映体过量90％。
1H NMR(600MHz,Chloroform-d)δ10.18(s,1H),7.84–7.78(m,2H),7.77–7.70(m,2H),7.57–7.53(m,1H),7.52–7.45(m,3H),7.44–7.38(m,2H),7.20–7.17(m,2H),7.10–7.07(m,2H),6.65–6.59(m,1H),6.53(s,1H),6.35(s,1H),6.16(dd,J＝15.7,4.0Hz,1H),5.82(s,2H),4.25(dd,J＝11.6,8.9Hz,1H)；13C NMR(151MHz,Chloroform-d)δ151.40(d,J＝4.6Hz),148.02(d,J＝2.4Hz),141.32,134.95(d,J＝2.6Hz),133.77(d,J＝11.1Hz),133.42,132.46(d,J＝2.8Hz),132.35(d,J＝2.7Hz),131.51(d,J＝8.9Hz),131.16(d,J＝8.9Hz),129.94(d,J＝97.9Hz),129.54(d,J＝97.6Hz),128.75(d,J＝1.4Hz),128.67(d,J＝1.1Hz),128.61,127.61(d,J＝1.3Hz),121.69(d,J＝6.5Hz),113.43(d,J＝6.4Hz),109.80(d,J＝7.4Hz),101.99(d,J＝2.5Hz),101.16,51.88(d,J＝65.2Hz)；31P NMR(243MHz,CDCl3)δ39.63；[α]D 25＝-112.0(c＝0.5in CHCl3)；HRMS(ESI)Calcd.forC28H21ClO4P(M-H)-487.0866,Found:487.0868；HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝2/1,Flow rate＝0.8mL/min),tR＝15.523min,19.248min.
实施例19
称取1i(51.6mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3s。收率59％，对映体过量82％。
1H NMR(600MHz,Chloroform-d)δ10.13(s,1H),7.82–7.77(m,2H),7.77–7.71(m,2H),7.60–7.53(m,1H),7.53–7.46(m,3H),7.45–7.39(m,2H),7.10(d,J＝5.0Hz,1H),6.87(dd,J＝5.1,3.5Hz,1H),6.78(d,J＝3.5Hz,1H),6.54(s,1H),6.45–6.34(m,2H),6.31(s,1H),5.85–5.80(m,2H),4.26(dd,J＝12.7,7.7Hz,1H)；13C NMR(151MHz,CDCl3)δ151.39(d,J＝4.4Hz),147.93(d,J＝2.1Hz),141.36(d,J＝3.0Hz),141.28,132.47(d,J＝2.8Hz),132.31(d,J＝2.8Hz),131.58(d,J＝9.0Hz),131.24(d,J＝8.8Hz),130.02(d,J＝98.0Hz),129.45(d,J＝97.2Hz),128.73(d,J＝11.8Hz),128.67(d,J＝11.6Hz),128.05(d,J＝11.6Hz),127.26,125.82(d,J＝2.1Hz),124.62,120.39(d,J＝6.1Hz),113.50(d,J＝6.3Hz),109.71(d,J＝7.1Hz),101.88(d,J＝2.3Hz),101.13,51.16(d,J＝65.7Hz)；31P NMR(243MHz,CDCl3)δ39.28；[α]D 25＝-57.0(c＝1.0in CHCl3)；HRMS(ESI)Calcd.for C26H22O4PS(M+H)+461.0976,Found:461.0983.HPLC(Chiral IA,λ＝254nm,hexane/2-propanol＝2/1,Flow rate＝0.8mL/min),tR＝13.032min,18.107min.
实施例20
称取1j(40.8mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，至于0℃冰浴中；再取二苯基膦氧(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应，待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3t。收率75％，对映体过量95％。
1H NMR(600MHz,Chloroform-d)δ10.20(s,1H),7.79–7.74(m,2H),7.72–7.67(m,2H),7.55–7.48(m,2H),7.47–7.41(m,4H),6.51(s,1H),6.32(s,1H),5.86–5.82(m,1H),5.81(s,2H),4.37(dd,J＝12.7,10.5Hz,1H),1.66–1.63(m,3H),1.29–1.28(m,3H)；13C NMR(151MHz,Chloroform-d)δ151.31(d,J＝4.4Hz),147.44(d,J＝2.1Hz),141.10,137.18(d,J＝11.8Hz),132.18,131.55(d,J＝27.2Hz),131.49(d,J＝26.9Hz),130.22(d,J＝96.8Hz),129.99(d,J＝97.2Hz),128.55(d,J＝11.5Hz),128.35(d,J＝11.7Hz),115.79(d,J＝4.7Hz),115.19(d,J＝6.4Hz),109.41(d,J＝7.0Hz),101.89(d,J＝2.2Hz),101.01,46.19(d,J＝67.5Hz),25.85(d,J＝1.4Hz),17.93(d,J＝1.4Hz)；31P NMR(243MHz,CDCl3)δ40.44；[α]D 25＝-54.5(c＝2.0in CHCl3)；HRMS(ESI)Calcd.for C24H24O4P(M+H)+407.1412,Found:407.1416；HPLC(Chiral IC,λ＝254nm,hexane/2-propanol＝8/1,Flow rate＝0.8mL/min),tR＝13.907min,16.107min.
实施例1～20中，手性芳基膦氧化合物的反应方程式是：
实施例21
称取6-(4-甲氧基苄基)芝麻酚5(51.6mg,0.2mmol)和氧化银(Ag2O,55.6mg,0.24mml)于含有搅拌子的圆底烧瓶中，加入2.0mL二氯甲烷，30℃下搅拌12小时；
再取二(3-三氟甲基苯基)膦氧2i(202.8mg,0.6mmol)和手性方酰胺4d(12.6mg,0.02mmol)溶于1.0mL二氯甲烷中，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应；
待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3i。收率57％，对映体过量90％。
1H NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.12(dd,J＝16.9,9.7Hz,2H),8.08–8.02(m,1H),7.94(d,J＝10.7Hz,1H),7.88(d,J＝7.8Hz,1H),7.82(d,J＝7.8Hz,1H),7.74–7.68(m,1H),7.67–7.62(m,1H),7.46(s,1H),7.38–7.35(m,2H),6.75(d,J＝8.7Hz,2H),6.34(s,1H),5.84(d,J＝1.1Hz,1H),5.81(d,J＝1.1Hz,1H),5.64(d,J＝9.7Hz,1H),3.63(s,3H)；13CNMR(151MHz,DMSO)δ158.56,149.83(d,J＝8.5Hz),146.89,140.08,135.20(d,J＝8.8Hz),134.72(d,J＝4.7Hz),134.08(d,J＝4.5Hz),131.10(d,J＝6.6Hz),130.32,130.31(d,J＝23.1Hz),129.10(m),128.90(d,J＝3.9Hz),127.97(m),127.55(m),125.06(d,J＝9.3Hz),123.25(d,J＝9.4Hz),115.09(d,J＝3.6Hz),114.20,109.45(d,J＝4.7Hz),101.21,97.82,55.41,41.46(d,J＝70.0Hz)；31P NMR(243MHz,DMSO)δ30.69；19F NMR(565MHz,DMSO)δ-61.32,-61.41；[α]D 25＝-25.0(c＝1.0in CHCl3)；HRMS(ESI)Calcd.for C29H20F6O5P(M-H)-593.0953,Found:593.0955；HPLC(Chiral OD-H,λ＝254nm,hexane/2-propanol/MeOH＝40/1:1,Flow rate＝0.8mL/min),tR＝26.115min,29.390min.
实施例21中，手性芳基膦氧化合物(3i)的反应方程式是：
实施例22
称取6-(羟基(4-甲氧基苯基)甲基)芝麻酚6(54.8mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，30℃下搅拌12小时；
再取二(3-三氟甲基苯基)膦氧2i(67.6mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应；
待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物3i。收率77％，对映体过量97％。
1H NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.12(dd,J＝16.9,9.7Hz,2H),8.08–8.02(m,1H),7.94(d,J＝10.7Hz,1H),7.88(d,J＝7.8Hz,1H),7.82(d,J＝7.8Hz,1H),7.74–7.68(m,1H),7.67–7.62(m,1H),7.46(s,1H),7.38–7.35(m,2H),6.75(d,J＝8.7Hz,2H),6.34(s,1H),5.84(d,J＝1.1Hz,1H),5.81(d,J＝1.1Hz,1H),5.64(d,J＝9.7Hz,1H),3.63(s,3H)；13CNMR(151MHz,DMSO)δ158.56,149.83(d,J＝8.5Hz),146.89,140.08,135.20(d,J＝8.8Hz),134.72(d,J＝4.7Hz),134.08(d,J＝4.5Hz),131.10(d,J＝6.6Hz),130.32,130.31(d,J＝23.1Hz),129.10(m),128.90(d,J＝3.9Hz),127.97(m),127.55(m),125.06(d,J＝9.3Hz),123.25(d,J＝9.4Hz),115.09(d,J＝3.6Hz),114.20,109.45(d,J＝4.7Hz),101.21,97.82,55.41,41.46(d,J＝70.0Hz)；31P NMR(243MHz,DMSO)δ30.69；19F NMR(565MHz,DMSO)δ-61.32,-61.41；[α]D 25＝-25.0(c＝1.0in CHCl3)；HRMS(ESI)Calcd.for C29H20F6O5P(M-H)-593.0953,Found:593.0955；HPLC(Chiral OD-H,λ＝254nm,hexane/2-propanol/MeOH＝40/1:1,Flow rate＝0.8mL/min),tR＝26.115min,29.390min.
实施例22中，手性芳基膦氧化合物(3i)的反应方程式是：
实施例23
称取2-(羟基(苯基)甲基)萘酚7(50.0mg,0.2mmol)和手性方酰胺4d(12.6mg,0.02mmol)于含有搅拌子的圆底烧瓶中，加入0.4mL二氯甲烷，30℃下搅拌12小时；
再取二苯基膦氧2a(40.4mg,0.2mmol)溶于0.4mL二氯甲烷，并通过蠕动泵30分钟注入圆底烧瓶的反应体系中，注入完毕后，TLC监测反应；
待反应完全后，将反应液浓缩再通过柱层析(石油醚：乙酸乙酯＝1:1)分离得到产物4。收率87％，对映体过量51％。
1H NMR(600MHz,Chloroform-d)δ11.80(s,1H),8.47–8.41(m,1H),7.81–7.74(m,2H),7.65(dd,J＝7.1,2.1Hz,1H),7.61–7.53(m,2H),7.50–7.32(m,10H),7.20(d,J＝8.4Hz,1H),7.16–7.07(m,4H),4.85(d,J＝12.7Hz,1H)；13C NMR(151MHz,CDCl3)δ152.20(d,J＝5.0Hz),135.88(d,J＝3.9Hz),134.18,132.23(d,J＝5.7Hz),132.23,131.48(d,J＝9.3Hz),131.21(d,J＝8.9Hz),130.46(d,J＝100.0Hz),130.20(d,J＝9.3Hz),130.11(d,J＝100.2Hz),129.69(d,J＝5.9Hz),128.74,128.66,128.48(d,J＝5.5Hz),128.44(d,J＝6.5Hz),127.45,127.21(d,J＝1.8Hz),126.86,126.42,125.06,123.66,119.70,116.15(d,J＝4.8Hz),54.56(d,J＝64.5Hz)；31P NMR(243MHz,CDCl3)δ39.50；[α]D 25＝-41.0(c＝2.0inCHCl3)；HRMS(ESI)Calcd.for C29H24O2P(M+H)+435.1514,Found:435.1518；HPLC(ChiralAD-H,λ＝254nm,hexane/2-propanol/MeOH＝10/1:1,Flow rate＝0.7mL/min),tR＝18.198min,23.823min.
实施例23中，手性芳基膦氧化合物(4)的反应方程式是：
Claims (5)
1.一种手性芳基膦氧化合物的制备方法，其特征在于，
用邻亚甲基苯醌化合物和膦氧基化合物在手性方酰胺有机催化剂催化的条件下，发生亲核加成反应，得到手性芳基膦氧化合物；
具体步骤如下：
(1)先称取0.8～1.2eq膦氧基化合物，将膦氧基化合物溶解于有机溶剂中，浓度控制为0.250～0.350mol/L，得到膦氧基化合物溶液；
(2)在一个圆底烧瓶中加入0.8～1.2eq的邻亚甲基苯醌化合物与10～12mol％手性方酰胺有机催化剂，加入有机溶剂，控制溶液中邻亚甲基苯醌化合物的浓度为0.250～0.350mol/L；
(3)将膦氧基化合物溶液缓慢滴加入圆底烧瓶中，在0.5～1.0小时滴加结束，通过TLC监测反应进程，反应结束后浓缩得到粗产物；
(4)将粗产物用体积比为乙酸乙酯：石油醚＝0.8～1.2:1的溶液进行柱层析，得到所述手性芳基膦氧化合物；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3a；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二(4-甲基苯基)膦氧反应时，得到产物3b；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二(4-叔丁基苯基)膦氧反应时，得到产物3c；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二萘基膦氧反应时，得到产物3d；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二(4-氟苯基)膦氧反应时，得到产物3e；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二(4-氯苯基)膦氧反应时，得到产物3f；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二(3-氯苯基)膦氧反应时，得到产物3g；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二(4-三氟甲基苯基)膦氧反应时，得到产物3h；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二(3-三氟甲基苯基)膦氧反应时，得到产物3i；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物二(3,5-二三氟甲基苯基)膦氧反应时，得到产物3j；
当邻亚甲基苯醌化合物1a在手性方酰胺催化下与膦氧基化合物9,10-二氢-9-氧杂-10-磷杂菲-10-氧化物反应时，得到产物3k；
当邻亚甲基苯醌化合物1b在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3l；
当邻亚甲基苯醌化合物1c在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3m；
当邻亚甲基苯醌化合物1d在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3n；
当邻亚甲基苯醌化合物1e在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3o；
当邻亚甲基苯醌化合物1f在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3p；
当邻亚甲基苯醌化合物1g在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3q；
当邻亚甲基苯醌化合物1h在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3r；
当邻亚甲基苯醌化合物1i在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3s；
当邻亚甲基苯醌化合物1j在手性方酰胺催化下与膦氧基化合物二苯基膦氧反应时，得到产物3t；
邻亚甲基苯醌化合物1a～1j的具体名称和对应的代号见于下表：
所述手性方酰胺为结构式4a～4d中的一种：
所述手性芳基膦氧化合物结构如下：
结构式一：
结构式二：
结构式三：
结构式四：
3k的结构式：
2.如权利要求1所述的手性芳基膦氧化合物的制备方法，其特征在于，所述有机溶剂为二氯甲烷。
3.一种化合物3i的制备方法，其特征在于，具体步骤如下：
(1)称取0.8～1.2eq 6-(4-甲氧基苄基)芝麻酚和1.0～1.2eq氧化银于含有搅拌子的圆底烧瓶中，加入二氯甲烷，控制溶液中6-(4-甲氧基苄基)芝麻酚浓度为0.250～0.350mol/L，在25～35℃下搅拌12小时；
(2)再取2.5～3.0eq二(3-三氟甲基苯基)膦氧和8～10mol％手性方酰胺4d溶于二氯甲烷中，控制溶液中二(3-三氟甲基苯基)膦氧为0.250～0.350mol/L，得到混合溶液；
(3)混合溶液慢滴加入圆底烧瓶中，在0.5～1.0小时滴加结束，通过TLC监测反应进程，反应结束后浓缩得到粗产物；
(4)将粗产物用体积比为乙酸乙酯：石油醚＝0.8～1.2:1的溶液进行柱层析，得到化合物3i；化合物3i的结构式为
所述手性方酰胺4d的结构式如下：
4.一种化合物3i的制备方法，其特征在于，具体步骤如下：
(1)称取0.8～1.2eq 6-(羟基(4-甲氧基苯基)甲基)芝麻酚和8～10mol％手性方酰胺4d于含有搅拌子的圆底烧瓶中，加入二氯甲烷，控制溶液中6-(羟基(4-甲氧基苯基)甲基)芝麻酚浓度为0.250～0.350mol/L，在25～35℃下搅拌12小时；
(2)再取0.8～1.2eq二(3-三氟甲基苯基)膦氧溶于二氯甲烷，控制溶液中为0.250～0.350mol/L，得到二(3-三氟甲基苯基)膦氧化合物溶液；
(3)将二(3-三氟甲基苯基)膦氧化合物溶液缓慢滴加入圆底烧瓶中，在0.5～1.0小时滴加结束，通过TLC监测反应进程，反应结束后浓缩得到粗产物；
(4)将粗产物用体积比为乙酸乙酯：石油醚＝0.8～1.2:1的溶液进行柱层析，得到化合物3i；化合物3i的结构式为
所述手性方酰胺4d的结构式如下：
5.一种化合物4的制备方法，其特征在于，具体步骤如下：
(1)称取0.8～1.2eq 2-(羟基(苯基)甲基)萘酚和8～10mol％手性方酰胺4d于含有搅拌子的圆底烧瓶中，加入二氯甲烷，控制溶液中2-(羟基(苯基)甲基)萘酚浓度为0.250～0.350mol/L，在25～35℃下搅拌12小时；
(2)再取0.8～1.2eq二苯基膦氧溶于二氯甲烷，控制溶液中为0.250～0.350mol/L，得到二苯基膦氧化合物溶液；
(3)将二苯基膦氧化合物溶液缓慢滴加入圆底烧瓶中，在0.5～1.0小时滴加结束，通过TLC监测反应进程，反应结束后浓缩得到粗产物；
(4)将粗产物用体积比为乙酸乙酯：石油醚＝0.8～1.2:1的溶液进行柱层析，得到化合物4；化合物4的结构式为
所述手性方酰胺4d的结构式如下：
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