CN111320591B - 一种合成手性γ-氨基醇的方法 - Google Patents

一种合成手性γ-氨基醇的方法 Download PDF

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CN111320591B
CN111320591B CN202010234438.1A CN202010234438A CN111320591B CN 111320591 B CN111320591 B CN 111320591B CN 202010234438 A CN202010234438 A CN 202010234438A CN 111320591 B CN111320591 B CN 111320591B
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王超
许瑞瑞
刘浩营
汤卫军
薛东
李超群
肖建良
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Abstract

本发明公开了一种合成手性γ‑氨基醇的方法，该方法以手性双膦双氮金属配合物为催化剂，以廉价易得的烯丙醇类化合物和胺类化合物为底物，磷酸钾或甲醇钠作为碱，在惰性气体氛围中实现了手性γ‑氨基醇的合成反应。此过程通过不对称借氢这一绿色、经济、有效的方法一锅法得到手性γ‑氨基醇。本发明反应体系简单、操作简便、经济效益高，不需要额外的氢源和其他辅助添加剂，是一种清洁、安全、高效的合成手性γ‑氨基醇的方法。此外，本发明目标产物收率较高、立体选择性好，弥补了传统的原料试剂昂贵、反应体系复杂、合成步骤冗长、立体选择性不高等不足，在抗抑郁性药物的合成等领域中有着非常好的应用前景。

Description

一种合成手性γ-氨基醇的方法
技术领域
本发明属于合成手性γ-氨基醇的技术领域，具体涉及到烯丙醇和胺类化合物在手性钌催化作用下直接通过不对称借氢过程合成手性γ-氨基醇的方法。
背景技术
手性氨基醇化合物是一类重要的具有手性特征的物质，可作为“手性源分子”。由于手性氨基醇可以合成许多其他手性大分子，在很多天然产物、药物分子、精细化工品、具有生物活性的化合物中都存在手性氨基醇的结构，且手性氨基醇中含有氮原子和羟基中的氧原子具有良好的配位能力，因此手性氨基醇可以与其他元素结合形成手性催化剂或配体。在不对称催化反应中，手性氨基醇是一类非常重要的手性配体，可用于催化多种不对称合成反应。例如：不对称催化环氧化、不对称催化Diels-Alders反应等。手性γ-氨基醇作为氨基醇类的一种，被广泛应用于临床医学上的抗抑郁性西汀类化合物，具有治疗精神病症和抑郁病症。随着抗抑郁西汀类药物的大量需求，科研工作者将其列为热门研究领域。
传统的化学合成方法是通过合成手性醇类衍生化合物，并对其进行修饰得到手性γ-氨基醇。除了传统的方法外，主要通过不对称催化氢化和不对称转移氢化两种方式。在反应过程中需要加入额外的高压氢气或者其他氢源，大大增加了实验的成本。同时我们知道对于不对称催化氢化反应原料一般通过Mannich反应得到氨基羰基化合物，但实验产物收率一般较低且反应条件较为苛刻。目前已报道合成手性γ-氨基醇的反应主要包含以下几大类：(1)不对称氢化反应，例如：张绪穆等课题组报道的一系列手性Ru、Rh等催化剂可用来对β-胺基酮、不饱和的仲氨基酮进行不对称氢化生成手性γ-氨基醇。(Angew.Chem.Int.Ed.,2005,117,1715-1717；Advanced Synthesis and Catalysis,2011,353,3039-3043)；张万斌等课题组报道的一系列手性Ru、Rh等催化剂可用来对β-胺基酮、被保护的的氨基酮进行不对称氢化生成手性γ-氨基醇。(Angew.Chem.Int.Ed.,2015,127,2288-2292；Advanced Synthesis and Catalysis,2015,357,3262-3272；Organic andBiomolecular Chemistry,2013,11,3855)；Adolfsson等利用N-Boc保护法不对称合成手性γ-氨基醇(ChemCatChem,2012,4,2082-2089.)。(2)不对称转移氢化反应，例如：刘国华课题组在2017年报道的以甲酸钠作为氢源，在手性Ru的催化下对芳基酮不对称转移氢化，结合Aza-Michael和不对称氢转移的各自优点，将烯酮类化合物一锅转化为手性γ-氨基醇(Org.Lett.,2017,19,3047-3050.)。综上所述，在反应过程中需要加入额外的高压氢气或者其他氢源，大大增加了实验的成本。同时对于不对称催化氢化反应原料一般通过Mannich反应得到氨基羰基化合物，但实验产物收率一般较低且反应条件较为苛刻。，因此，发展一种高效、绿色、简便、经济的方法来合成手性γ-氨基醇具有重要意义。
发明内容
本发明的目的是提供一种反应体系简单、操作简便、合成步骤短、立体选择性好、过程经济有效的合成手性γ-氨基醇的方法。
解决上述技术问题所采用的技术方案是：在惰性气体氛围下，将式I所示烯丙醇类化合物与式II或式IV或式VI或式VIII所示胺类化合物、手性双膦双氮金属配合物、碱加入有机溶剂中，在25～40℃下反应12～72小时，分离纯化产物得到式III或式V或式VII或式IX所示手性γ-氨基醇；
Figure BDA0002430505850000021
Figure BDA0002430505850000031
式中，R1、R2各自独立的代表C1～C6烷基、C4～C7环烷基、苯基、萘基、噻吩基、呋喃基、吡啶基、嘧啶基中任意一种，或者C1～C4烷基、C1～C4烷氧基、三氟甲基、卤素中任意一种或两种取代基取代的基团，所述基团指苯基、萘基、噻吩基、呋喃基、吡啶基、嘧啶基中任意一种；R3、R4各自独立的代表C1～C4烷基、苄基、苯基、C1～C4烷基取代苯基、C1～C4烷氧基取代苯基、三氟甲基取代苯基、卤代苯基、4-吡啶基亚甲基中任意一种，n＝0或1，X代表C、O或S，m＝1或2；
上述的手性双膦双氮金属配合物为下述式A～E中任意一种：
Figure BDA0002430505850000032
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式A～E中，Ar代表3,5-二甲基苯基。
上述的手性双膦双氮金属配合物优选式C所示手性双膦双氮金属配合物。
上述的合成手性γ-氨基醇的方法中，优选烯丙醇类化合物的用量为胺类化合物摩尔量的1.5～2.0倍，手性双膦双氮金属配合物的用量为胺类化合物摩尔量的0.01～0.02倍。其中，所述的烯丙醇类化合物根据文献“J.Am.Chem.Soc.2019,141,5125-5129”公开的方法合成。
上述的合成手性γ-氨基醇的方法中，所述的碱为磷酸钾或甲醇钠，优选碱的用量为胺类化合物摩尔量的1.5～4倍。
上述的合成手性γ-氨基醇的方法中，所述的有机溶剂为甲苯或四氢呋喃。
本发明的有益效果如下：
本发明将烯丙醇类化合物与胺类化合物在手性双膦双氮金属配合物催化作用下，以及碱存在下，即可在近室温条件下一锅法得到手性γ-氨基醇，不需要加入额外氢源与其他辅助添加剂，且反应原料制备简单。本发明反应体系经济效益较高、原子利用率高、反应后处理简单。此外，产物手性γ-氨基醇的收率较好、立体选择性较高。本发明还克服了底物范围有限这一问题，减少了原料浪费，原子利用率高，与目前追求环保、经济、绿色的化学概念相符合，具有非常重要的应用前景。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围并不仅限于这些实施例。
实施例1
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000041
在氩气保护下，将50mg(0.375mmol)1-苯基烯丙醇、40.6mg(0.25mmol)N-苯基哌嗪、3mg(0.0025mmol)式C所示手性双膦双氮金属配合物、80mg(0.375mmol)磷酸钾、1mL甲苯加入厚壁耐压管中，30℃搅拌反应12小时，用二氯甲烷转移，减压蒸馏除二氯甲烷、甲苯，以石油醚、乙酸乙酯、甲醇体积比为10:2:0.5的混合液为淋洗剂，柱层析分离，得到白色固体产物，其产率为90％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.35-7.32(m,4H),7.28-7.22(m,3H),6.92(d,J＝7.6Hz,2H),6.87(t,J＝7.2Hz,1H),4.95(t,J＝5.6Hz,1H),3.24(t,J＝4.8Hz,4H),2.80-2.71(m,3H),2.67-2.59(m,3H),1.92-1.86(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):151.19,144.88,129.26,128.36,127.08,125.65,120.13,116.36,75.61,57.17,53.35,49.39,33.83；HRMS(ESI)m/zC19H24N2O[M+H]+:理论值297.1961,实测值297.1959。
实施例2
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000042
本实施例中，用等摩尔1-(4-甲基)苯基烯丙醇替换实施例1中的1-苯基烯丙用1mmol叔丁醇钾替换实施例1中的磷酸钾，反应时间延长至48小时，其他步骤与实施例1相同，得到白色固体产物，其产率为84％，高效液相色谱测得ee值为96％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.29-7.24(m,4H),7.16(d,J＝8Hz,2H),6.93(d,J＝8Hz,2H),6.87(t,J＝7.2Hz,1H),4.92(t,J＝5.6Hz,1H),3.24(t,J＝5.2Hz,4H),2.81-2.71(m,3H),2.67-2.59(m,3H),2.34(s,3H),1.91-1.87(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):151.21,141.95,136.63,129.27,129.05,125.58,120.11,116.36,75.53,57.24,53.38,49.40,33.91,21.22；HRMS(ESI)m/z C20H26N2O[M+H]+:理论值311.2118,实测值311.2118。
实施例3
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000051
本实施例中，用等摩尔1-(3-甲氧基)苯基烯丙醇替换实施例1中的1-苯基烯丙醇，反应时间延长至48小时，其他步骤与实施例1相同，得到白色固体产物，其产率为82％，高效液相色谱测得ee值为99％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.29-7.24(m,3H),6.98-6.92(m,4H),6.87(t,J＝7.2Hz,1H),6.79(d,J＝2Hz,1H),4.94(dd,J＝6.8,4Hz,1H),3.82(s,3H),3.25(t,J＝4.8Hz,4H),2.81-2.71(m,3H),2.68-2.60(m,3H),1.93-1.88(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):159.81,151.19,146.70,129.36,129.27,120.13,118.00,116.36,112.56,111.20,75.51,57.14,55.34,53.36,49.39,33.76；HRMS(ESI)m/zC20H26N2O2[M+H]+:理论值327.2067,实测值327.2055。
实施例4
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000052
本实施例中，用等摩尔1-(4-三氟甲基)苯基烯丙醇替换实施例1中的1-苯基烯丙醇，反应时间延长至72小时，其他步骤与实施例1相同，得到白色固体产物，其产率为97％，高效液相色谱测得ee值为99％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.61(d,J＝8.4Hz,2H),7.51(d,J＝8Hz,2H),7.30-7.26(m,2H),6.94(d,J＝8Hz,2H),6.89(t,J＝7.2Hz,1H),5.03(dd,J＝8,3.2Hz,1H),3.26(t,J＝4.8Hz,4H),2.83-2.76(m,3H),2.70-2.62(m,3H),1.97-1.83(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):151.16,148.99,129.33(q,2JC-F＝32.1Hz),129.32,125.95,124.42(q,1JC-F＝287Hz),125.35(q,3JC-F＝3.6Hz),120.27,116.43,75.26,57.22,53.39,49.44,33.65；HRMS(ESI)m/z C20H23F3N2O[M+H]+:理论值365.1835,实测值365.1846。
实施例5
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000061
本实施例中，用等摩尔2-萘基烯丙醇替换实施例1中的1-苯基烯丙醇，反应时间延长至48小时，其他步骤与实施例1相同，得到白色固体产物，其产率为93％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.85-7.82(m,4H),7.49-7.43(m,3H),7.30-7.25(m,2H),6.96-6.87(m,3H),5.13(dd,J＝7.2,4.8Hz,1H),3.28(t,J＝5.2Hz,4H),2.84-2.76(m,3H),2.71-2.63(m,3H),2.04-1.97(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):151.14,142.29,133.50,132.84,129.28,128.06,128.05,127.75,126.09,125.65,124.19,124.09,120.18,116.39,75.56,57.13,53.33,49.33,33.72；HRMS(ESI)m/zC23H26N2O[M+H]+:理论值347.2118,实测值347.2114。
实施例6
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000062
本实施例中，用等摩尔1-呋喃基-3-烯丙醇替换实施例1中的1-苯基烯丙醇，反应时间延长至48小时，其他步骤与实施例1相同，得到淡黄色固体产物，其产率为83％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.41-7.39(m,2H),7.29-7.25(m,2H),6.93-6.86(m,2H),6.37(s,1H),4.92(dd,J＝7.6,3.6Hz,1H),3.23(t,J＝4.8Hz,4H),2.82-2.62(m,6H),2.02-1.86(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):151.15,143.23,138.87,129.40,129.26,120.14,116.35,108.62,69.05,57.17,53.36,49.35,32.33；HRMS(ESI)m/z C17H22N2O2[M+H]+:理论值287.1754,实测值287.1752。
实施例7
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000071
本实施例中，用等摩尔1-(4-甲氧基苯基)哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到白色固体产物，其产率为87％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.40-7.33(m,4H),7.27-7.26(m,1H),6.92-6.84(m,4H),4.97(t,J＝5.6Hz,1H),3.77(s,3H),3.15(t,J＝4.8Hz,4H),2.83-2.73(m,3H),2.69-2.62(m,3H),1.93-1.89(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):154.03,145.48,144.83,128.25,126.96,125.54,118.42,114.48,75.59,57.09,55.57,53.38,50.79,33.71；HRMS(ESI)m/z C19H24N2O[M+H]+:理论值327.2067,实测值327.2064。
实施例8
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000072
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔1-(3,4-二氯苯基)哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到白色固体产物，其核磁产率为89％，高效液相色谱测得ee值为99％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.46(d,J＝8.4Hz,2H),7.26(d,J＝9.2Hz,3H),6.95(d,J＝2.8Hz,1H),6.74-6.71(m,1H),4.90(dd,J＝7.2,4Hz,1H),3.20(t,J＝5.2Hz,4H),2.77-2.71(m,3H),2.63-2.58(m,3H),1.90-1.80(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):150.50,143.86,132.95,131.45,130.61,127.40,122.66,120.83,117.58,115.55,75.02,57.04,52.99,48.87,33.76；HRMS(ESI)m/z C19H21BrCl2N2O[M+Na]+:理论值465.0107,实测值465.0097。
实施例9
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000081
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔1-(2-嘧啶基)哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到白色固体产物，其产率为70％，高效液相色谱测得ee值为91％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):8.31(d,J＝4.4Hz,2H),6.51(t,J＝4.8Hz,1H),7.47(d,J＝8.4Hz,2H),7.27(d,J＝9.6Hz,2H),4.93(t,J＝5.6Hz,1H),3.88(s,4H),2.76-2.52(m,6H),1.89-1.84(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):161.64,157.86,143.95,131.44,127.44,120.80,110.24,75.16,57.33,53.25,43.72,33.69；HRMS(ESI)m/z C17H21BrN4O[M+Na]+:理论值399.0791,实测值399.0776。
实施例10
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000082
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔N-乙基哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到黄色油状产物，其产率为90％，高效液相色谱测得ee值>99％，波谱数据为：1HNMR(400MHz,CDCl3)δ(ppm):7.45(d,J＝8.4Hz,2H),7.27-7.24(m,2H),4.88(dd,J＝7.2,4Hz,1H),2.73-2.40(m,12H),1.86-1.74(m,2H),1.09(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ(ppm):144.14,131.37,127.42,120.68,75.14,57.08,53.28,52.86,52.31,33.64,12.07；HRMS(ESI)m/z C15H23BrN2O[M+Na]+:理论值349.0886,实测值349.0883。
实施例11
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000091
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔N-异丙基哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到黄色油状产物，其产率为87％，高效液相色谱测得ee值为97％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.45(d,J＝8.4Hz,2H),7.26-7.24(m,2H),4.89(dd,J＝7.2,4Hz,1H),2.73-2.53(m,10H),1.85-1.73(m,2H),1.25(s,1H),1.05(d,J＝6.4Hz,6H)；13CNMR(100MHz,CDCl3)δ(ppm):144.18,131.40,127.44,120.71,75.24,57.13,54.59,53.56,48.79,33.61,18.71；HRMS(ESI)m/z C16H25BrN2O[M+Na]+:理论值363.1042,实测值363.1037。
实施例12
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000092
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔N-环戊基哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到黄色油状产物，其产率为56％，高效液相色谱测得ee值为95％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.46(d,J＝8Hz,2H),7.25(d,J＝9.2Hz,2H),4.89(t,J＝4Hz,1H),2.73-2.48(m,10H),1.86-1.81(m,4H),1.70-1.26(m,7H).13C NMR(100MHz,CDCl3)δ(ppm):144.16,131.42,127.45,120.74,75.20,67.59,57.11,52.37,33.66,30.50,24.26；HRMS(ESI)m/z C18H27BrN2O[M+Na]+:理论值367.1680,实测值367.1685。
实施例13
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000101
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本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔N-(4-溴)苯基哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到淡黄色固体产物，其产率为87％，高效液相色谱测得ee值为99％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.47-7.45(m,2H),7.35-7.33(m,4H),7.26-7.24(m,2H),6.79-6.77(m,2H),4.91(dd,J＝7.2,4Hz,1H),3.20(t,J＝4.8Hz,4H),2.79-2.71(m,3H),2.65-2.58(m,3H),1.87-1.82(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):150.19,143.94,132.07,131.46,127.43,120.83,117.95,112.36,75.12,57.14,53.18,49.24,33.75；HRMS(ESI)m/z C19H22Br2N2O[M+H]+:理论值453.0172,实测值453.0164。
实施例14
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000102
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔N-(4-三氟甲基)苯基哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到白色固体产物，其产率为70％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.49-7.45(m,4H),7.24(d,J＝2.4Hz,2H),6.91(d,J＝8.8Hz,2H),4.91(dd,J＝7.2,4.4Hz,1H),3.31(t,J＝4.8Hz,4H),2.79-2.71(m,3H),2.65-2.58(m,3H),1.88-1.83(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):153.18,143.88,131.48,127.43,126.57(q,3JC-F＝3.6Hz),124.81(q,1JC-F＝269Hz),120.87(q,3JC-F＝2.2Hz),114.88,75.08,57.13,53.05,48.22,33.78；HRMS(ESI)m/z C20H22BrF3N2O[M+Na]+:理论值465.0760,实测值465.0749。
实施例15
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000111
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔N-(3-甲基)苯基哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到白色固体产物，其产率为89％，高效液相色谱测得ee值>99％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.48(d,J＝8Hz,2H),7.27(d,J＝8.8Hz,2H),7.17(t,J＝8Hz,1H),6.76-6.71(m,3H),4.92(dd,J＝6.8,4.8Hz,1H),3.24(t,J＝4.4Hz,4H),2.81-2.73(m,3H),2.67-2.61(m,3H),2.33(s,3H),1.88-1.86(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):151.19,143.98,138.95,131.40,129.10,127.42,121.10,120.74,117.25,113.50,75.11,57.14,53.36,49.46,33.68,21.88；HRMS(ESI)m/z C20H25BrN2O[M+Na]+:理论值411.1042,实测值411.1048。
实施例16
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000112
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔N-(2-甲氧基)苯基哌嗪替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，其他步骤与实施例1相同，得到黄色油状产物，其产率为83％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.46(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),7.04-6.99(m,1H),6.95-6.86(m,3H),4.92(dd,J＝6.8,4.4Hz,1H),3.86(s,3H),3.13(s,4H),2.83-2.62(m,6H),1.89-1.79(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):152.44,144.16,141.13,131.44,127.47,123.32,121.23,120.75,118.48,111.44,75.25,57.27,53.63,50.82,33.67；HRMS(ESI)m/z C20H25BrN2O2[M+Na]+:理论值427.0992,实测值427.0972。
实施例17
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000121
在氩气保护下，将67.1mg(0.5mmol)1-苯基烯丙醇、30.3mg(0.25mmol)N-甲基苄胺、6mg(0.005mmol)式C所示手性双膦双氮金属配合物、80mg(0.375mmol)磷酸钾、1mL甲苯加入厚壁耐压管中，30℃搅拌反应72小时，用二氯甲烷转移，减压蒸馏除二氯甲烷、甲苯，以二氯甲烷、甲醇体积比为10:0.5混合液为淋洗剂，柱层析分离，得到黄色油状液体产物，其产率为74％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.27-7.13(m,10H),4.83(dd,J＝7.6,3.6Hz,1H),3.57(d,J＝12.8Hz,1H),3.39(d,J＝12.8Hz,1H),2.77-2.70(m,1H),2.54-2.48(m,1H),2.18(s,3H),1.87-1.74(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):144.99,137.76,129.25,128.54,128.20,127.44,126.88,125.56,75.81,62.84,56.55,41.81,34.51；HRMS(ESI)m/z C17H21BrNO[M+Na]+:理论值256.1696,实测值256.1695。
实施例18
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000122
本实施例中，用等摩尔2-噻吩烯丙醇替换实施例17中的1-苯基烯丙醇，其他步骤与实施例17相同，得到黄色油状液体产物，其产率为69％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.36-7.25(m,5H),7.20(d,J＝4.8Hz,1H),6.96-6.89(m,2H),5.15(dd,J＝7.2,3.6Hz,1H),3.63(d,J＝12.8Hz,1H),3.47(d,J＝12.8Hz,1H),2.84-2.78(m,1H),2.68-2.63(m,1H),2.25(s,3H),2.08-1.95(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):149.58,137.63,129.24,128.54,127.46,126.59,123.70,122.28,72.23,62.88,56.25,41.68,34.60；HRMS(ESI)m/z C17H21BrNO[M+Na]+:理论值262.1260,实测值262.1260。
实施例19
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000131
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例17中的1-苯基烯丙醇，用等摩尔N-甲基-N-(4-吡啶甲基)胺替换实施例17中的N-甲基苄胺，其他步骤与实施例17相同，得到黄色油状产物，其产率为83％，高效液相色谱测得ee值为95％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):8.58(d,J＝4.4Hz,2H),7.44(d,J＝8.4Hz,2H),7.27-7.22(m,4H),4.87(dd,J＝7.6,4.4Hz,1H),3.64(d,J＝13.6Hz,1H),3.47(d,J＝13.6Hz,1H),2.83-2.76(m,1H),2.63-2.57(m,1H),2.28(s,3H),1.91-1.80(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):150.19,146.89,143.82,131.45,127.39,124.06,120.86,75.07,61.78,56.74,42.17,34.64；HRMS(ESI)m/z C16H19BrN2O[M+Na]+:理论值357.0573,实测值357.0560。
实施例20
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000132
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例17中的1-苯基烯丙醇，用等摩尔二甲胺替换实施例17中的N-甲基苄胺，其他步骤与实施例17相同，得到黄色油状产物，其产率为82％，高效液相色谱测得ee值>99％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.47-7.45(m,2H),7.27-7.25(m,2H),4.90(dd,J＝8.4,3.6Hz,1H),2.72-2.66(m,1H),2.54-2.48(m,1H),2.33(s,6H),1.87-1.72(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):144.33,131.38,127.49,120.67,75.31,58.48,45.39,34.50；HRMS(ESI)m/z C11H16BrNO[M+H]+:理论值258.0488,实测值258.0481。
实施例21
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000141
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例17中的1-苯基烯丙醇，用等摩尔二乙胺替换实施例17中的N-甲基苄胺，其他步骤与实施例17相同，得到黄色油状产物，其产率为56％，高效液相色谱测得ee值>99％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.44(d,J＝8.4Hz,2H),7.27-7.25(m,2H),4.88(t,J＝6Hz,1H),2.89-2.72(m,4H),2.67-2.59(m,2H),1.87-1.83(m,2H),1.14(t,J＝7.2Hz,6H)；13C NMR(100MHz,CDCl3)δ(ppm):144.50,131.33,127.51,120.59,75.26,52.65,46.80,34.50,11.60；HRMS(ESI)m/zC13H20BrNO[M+H]+:理论值286.0801,实测值286.0794。
实施例22
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000142
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例17中的1-苯基烯丙醇，用等摩尔二苄胺替换实施例17中的N-甲基苄胺，以石油醚、乙酸乙酯体积比为20:1的混合液为淋洗剂，其他步骤与实施例17相同，得到白色固体产物，其产率为70％，高效液相色谱测得ee值为97％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.37-7.31(m,12H),7.07(d,J＝8.4Hz,2H),6.59(s,1H),4.68(dd,J＝7.2,3.6Hz,1H),3.80(d,J＝13.2Hz,2H),3.41(d,J＝12.8Hz,2H),2.85-2.79(m,1H),2.65-2.61(m,1H),1.88-1.80(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):143.95,137.81,131.27,129.55,128.72,127.63,127.41,120.55,74.81,58.76,52.23,34.64；HRMS(ESI)m/z C23H24BrNO[M+Na]+:理论值432.0933,实测值432.0943。
实施例23
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000151
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例17中的1-苯基烯丙醇，用等摩尔N-甲基苄胺替换实施例17中的N-甲基苄胺，其他步骤与实施例17相同，得到黄色油状产物，其产率为89％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.43(d,J＝8Hz,2H),7.38-7.26(m,5H),7.22(d,J＝8.4Hz,2H),4.86(t,J＝5.6Hz,1H),3.63(d,J＝12.8Hz,1H),3.48(d,J＝12.8Hz,1H),2.84-2.77(m,1H),2.61-2.56(m,1H),2.27(s,3H),1.86-1.82(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):144.18,137.72,131.34,129.37,128.67,127.61,127.45,120.64,75.29,62.95,56.39,41.94,34.47；HRMS(ESI)m/z C17H21BrNO[M+Na]+:理论值356.0620,实测值356.0615。
实施例24
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000152
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例17中的1-苯基烯丙醇，用等摩尔N-甲基-N-(4-三氟甲基)苄基胺替换实施例17中的N-甲基苄胺，其他步骤与实施例17相同，得到黄色油状产物，其产率为75％，高效液相色谱测得ee值>99％，波谱数据为：1HNMR(400MHz,CDCl3)δ(ppm):7.61(d,J＝8Hz,2H),7.46-7.42(m,4H),7.21(d,J＝8Hz,2H),4.86(t,J＝6Hz,1H),3.67(d,J＝13.2Hz,1H),3.52(d,J＝12.8Hz,1H),2.83-2.77(m,1H),2.62-2.57(m,1H),2.27(s,3H),1.87-1.83(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):143.91,141.89,131.43,129.98(q,2JC-F＝32.4Hz),129.55,127.41,125.66(q,3JC-F＝3.7Hz),124.26(q,1JC-F＝270.1Hz),120.81,75.22,62.44,56.60,42.05,34.51；HRMS(ESI)m/zC18H19BrF3NO[M+Na]+:理论值424.0494,实测值424.0486。
实施例25
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000161
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例17中的1-苯基烯丙醇，用等摩尔N-甲基-N-(4-甲基)苄基胺替换实施例17中的N-甲基苄胺，其他步骤与实施例17相同，得到黄色油状产物，其产率为74％，高效液相色谱测得ee值为92％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.43(d,J＝8.4Hz,2H),7.22(d,J＝8Hz,4H),7.16(d,J＝8Hz,2H),4.85(t,J＝5.6Hz,1H),3.59(d,J＝12.4Hz,1H),3.44(d,J＝12.4Hz,1H),2.82-2.76(m,1H),2.59-2.54(m,1H),2.36(s,3H),2.26(s,3H),1.85-1.81(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):144.21,137.26,134.63,131.32,129.33,127.45,120.60,75.34,62.63,56.26,41.90,34.40,21.27；HRMS(ESI)m/z C18H22BrNO[M+Na]+:理论值370.0777,实测值370.0769。
实施例26
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000162
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例17中的1-苯基烯丙醇，用等摩尔N-甲基苯胺替换实施例17中的N-甲基苄胺，以石油醚、乙酸乙酯体积比为5:1的混合液为淋洗剂，其他步骤与实施例17相同，得到黄色油状产物，其产率为40％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.48-7.44(m,2H),7.27-7.22(m,4H),6.80-6.75(m,3H),4.78(dd,J＝7.2,5.6Hz,1H),3.50-3.39(m,2H),2.91(s,3H),2.82(s,1H),2.00-1.93(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):149.93,143.70,131.71,129.36,127.59,121.40,117.69,113.88,72.73,50.84,38.90,35.85；HRMS(ESI)m/zC16H18BrNO[M+Na]+:理论值342.0464,实测值342.0463。
实施例27
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000171
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔吗啉替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，以二氯甲烷、甲醇体积比为10:0.5的混合液为淋洗剂，其他步骤与实施例1相同，得到浅黄色油状产物，其产率为87％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.46(d,J＝7.6Hz,2H),7.25(d,J＝8.4Hz,2H),4.90(t,J＝5.2Hz,1H),3.75(s,4H),2.72-2.50(m,6H),1.85-1.82(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):143.79,131.33,127.27,120.69,75.03,66.91,57.55,53.66,33.26；HRMS(ESI)m/z C13H18BrNO2[M+Na]+:理论值322.0413,实测值322.0402。
实施例28
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000172
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔硫代吗啉替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，以二氯甲烷、甲醇体积比为10:0.5的混合液为淋洗剂，其他步骤与实施例1相同，得到浅黄色油状产物，其产率为91％，高效液相色谱测得ee值为99％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.46(d,J＝8Hz,2H),7.24(d,J＝8Hz,2H),4.88(dd,J＝6.8,4.4Hz,1H),2.88-2.85(m,2H),2.74-2.73(m,6H),2.69-2.56(m,2H),1.85-1.74(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):143.93,131.41,127.37,120.76,75.01,57.92,55.29,33.52,28.13；HRMS(ESI)m/zC13H18BrNOS[M+Na]+:理论值338.0185,实测值338.0174。
实施例29
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000173
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔哌啶替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，以二氯甲烷、甲醇体积比为10:0.5的混合液为淋洗剂，其他步骤与实施例1相同，得到黄色油状产物，其产率为77％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.46-7.43(m,2H),7.25(d,J＝8.4Hz,2H),4.88(dd,J＝7.6,3.6Hz,1H),2.66-2.42(m,6H),1.83-1.75(m,2H),1.74-1.59(m,4H),1.46(s,2H)；13C NMR(100MHz,CDCl3)δ(ppm):144.40,131.34,127.48,120.59,75.19,57.79,54.73,33.67,26.13,24.29；HRMS(ESI)m/z C14H20BrNO[M+Na]+:理论值320.0620,实测值320.0607。
实施例30
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000181
本实施例中，用等摩尔4-溴-1-苯基烯丙醇替换实施例1中的1-苯基烯丙醇，用等摩尔四氢吡咯替换实施例1中的N-苯基哌嗪，反应时间延长至72小时，以二氯甲烷、甲醇体积比为10:0.5的混合液为淋洗剂，其他步骤与实施例1相同，得到黄色油状产物，其产率为76％，高效液相色谱测得ee值为95％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.44(d,J＝8.4Hz,2H),7.25(d,J＝8Hz,2H),4.90(dd,J＝8.8,3.2Hz,1H),2.96-2.90(m,1H),2.74-2.60(m,5H),1.91-1.74(m,6H)；13C NMR(100MHz,CDCl3)δ(ppm):144.25,131.38,127.49,120.68,74.86,54.68,54.16,35.62,23.57；HRMS(ESI)m/z C13H18BrNO[M+Na]+:理论值306.0464,实测值306.0457。
实施例31
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000182
在氩气保护下，将80mg(0.375mmol)4-溴-1-苯基烯丙醇、33.3mg(0.25mmol)四氢异喹啉、6mg(0.005mmol)式C所示手性双膦双氮金属配合物、80mg(0.375mmol)磷酸钾、1mL甲苯加入厚壁耐压管中，30℃搅拌反应72小时，用二氯甲烷转移，减压蒸馏除二氯甲烷、甲苯，以二氯甲烷、甲醇体积比为20:0.5的混合液为淋洗剂，柱层析分离，得到黄色固体产物，其产率为82％，高效液相色谱测得ee值为98％，波谱数据为：1H NMR(400MHz,CDCl3)δ(ppm):7.45(d,J＝8.4Hz,2H),7.26-7.24(m,2H),7.15-7.09(m,3H),7.02(t,J＝5.6Hz,1H),4.92(dd,J＝7.6,3.6Hz,1H),3.76(d,J＝14.8Hz,1H),3.66(d,J＝14.8Hz,1H),2.96-2.69(m,6H),2.00-1.83(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):144.18,134.03,133.94,131.39,128.78,127.47,126.67,126.57,125.97,120.70,75.05,56.79,56.31,50.78,34.03,29.01；HRMS(ESI)m/z C18H20BrNO[M+Na]+:理论值368.0620,实测值368.0606。
实施例32
合成结构式如下的手性γ-氨基醇
Figure BDA0002430505850000191
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本实施例中，用等摩尔异吲哚啉替换实施例31中的四氢异喹啉，其他步骤与实施例31相同，得到黄色固体产物，其产率为81％，高效液相色谱测得ee值为99％，波谱数据为：1HNMR(400MHz,CDCl3)δ(ppm):7.48-7.46(m,2H),7.29-7.22(m,6H),4.96(dd,J＝8.4,3.2Hz,1H),4.09(d,J＝11.2Hz,2H),4.00(d,J＝11.6Hz,2H),3.13-3.07(m,1H),3.00-2.94(m,1H),2.01-1.82(m,2H)；13C NMR(100MHz,CDCl3)δ(ppm):144.18,139.39,131.43,127.51,127.16,122.44,120.76,75.27,59.38,55.00,35.83；HRMS(ESI)m/z C17H18BrNO[M+Na]+:理论值354.0464,实测值354.0452。

Claims (7)

1.一种合成手性γ-氨基醇的方法，其特征在于：在惰性气体氛围下，将式I所示烯丙醇类化合物与式II或式IV或式VI或式VIII所示胺类化合物、手性双膦双氮金属配合物、碱加入有机溶剂中，在25～40 oC下反应12～72小时，分离纯化产物得到式III或式V或式VII或式IX所示手性γ-氨基醇；
Figure 591621DEST_PATH_IMAGE002
式中，R1、R2各自独立的代表C1～C6烷基、C4～C7环烷基、苯基、萘基、噻吩基、呋喃基、吡啶基、嘧啶基中任意一种，或者C1～C4烷基、C1～C4烷氧基、三氟甲基、卤素中任意一种或两种取代基取代的基团，所述基团指苯基、萘基、噻吩基、呋喃基、吡啶基、嘧啶基中任意一种；R3、R4各自独立的代表C1～C4烷基、苄基、苯基、C1～C4烷基取代苯基、C1～C4烷氧基取代苯基、三氟甲基取代苯基、卤代苯基、4-吡啶基亚甲基中任意一种，n=0或1，X代表C、O或S，m=1或2；
所述的手性双膦双氮金属配合物为下述式A～E中任意一种：
Figure 233342DEST_PATH_IMAGE003
式A～E中，Ar代表3,5-二甲基苯基。
2.根据权利要求1所述的合成手性γ-氨基醇的方法，其特征在于：所述的手性双膦双氮金属配合物为式C所示手性双膦双氮金属配合物。
3.根据权利要求1所述的合成手性γ-氨基醇的方法，其特征在于：所述烯丙醇类化合物的用量为胺类化合物摩尔量的1.5～2.0倍。
4.根据权利要求1所述的合成手性γ-氨基醇的方法，其特征在于：所述手性双膦双氮金属配合物的用量为胺类化合物摩尔量的0.01～0.02倍。
5.根据权利要求1所述的合成手性γ-氨基醇的方法，其特征在于：所述的碱为磷酸钾或甲醇钠。
6.根据权利要求5所述的合成手性γ-氨基醇的方法，其特征在于：所述碱的用量为胺类化合物摩尔量的1.5～4倍。
7.根据权利要求1所述的合成手性γ-氨基醇的方法，其特征在于：所述的有机溶剂为甲苯或四氢呋喃。
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