CN114106046A - 噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体及其制备方法和应用 - Google Patents
噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种噁唑啉5‑位取代的手性螺环噁唑啉‑胺基膦配及其体制备方法和应用。该手性螺环噁唑啉‑胺基膦配体是具有式I所示的化合物,或其消旋体或旋光异构体,或其催化可接受的盐,主要结构特征是具有手性螺二氢茚骨架和具有5‑位取代的噁唑啉基团。该手性螺环噁唑啉‑胺基膦配体可以由具有螺环骨架的7‑二芳/烷基膦基‑7′‑氨基‑1,1′‑螺二氢茚类化合物为手性起始原料合成。该手性螺环噁唑啉‑胺基膦配体与过渡金属(铱)盐形成配合物后,可用于催化α‑芳氧取代内酯化合物的不对称催化氢化反应。表现出很高的催化活性(TON达到1000)和对映选择性(高达98%ee),具有实用价值。
Description
技术领域
本发明属于有机合成技术领域,涉及一类噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体及其制备方法和应用,具体涉及一类具有螺环骨架的噁唑啉环5-位取代的手性螺环噁唑啉- 胺基膦配体及其制备方法和其在α-芳氧取代内酯化合物的不对称催化氢化反应方面的应用。
背景技术
酯的均相催化氢化制备醇是一种原子经济、环境友好、最为高效和简便的方法。正因如此,酯的均相催化氢化在最近十多年来得到了广泛的关注,已发展出了许多高效的催化剂及其催化体系,并已在药物分子和香料的规模化制备中得到了广泛的应用(Clarke,M.L.Catal. Sci.Technol.2012,2,2418-2423;Magano,J.;Dunetz,J.R.Org.ProcessRes.Dev.2012,16, 1156-1184)。然而,由于缺少高效、高对映选择性的手性催化剂,酯类化合物的不对称催化氢化合成手性醇成功的例子仍然稀少(Gu,X.-S.;et al.ActaChim.Sinica 2019,77,598-612)。如通过消旋内酯的不对称催化氢化合成光学活性的手性二醇,目前成功的例子仅限于手性螺环吡啶胺基膦配体的手性螺环铱络合物催化的消旋α-芳基/烷基以及芳胺基取代内酯的不对称氢化(Yang,X.-H.;et al.Chem.Sci.2017,8,1811-1814;Gu,X.-S.;et al.Org.Lett.2019,21, 4111-4115)。因此,发展新型高效的手性配体及其催化剂,实现在手性药物等方面有着重要用途的多样性手性二醇的高效、高对映选择性合成,仍然具有非常重要的意义和应用价值。
光学活性β-芳氧基取代手性二醇是一类重要的手性原料或中间体,在手性药物和具有重要生理活性的天然产物的不对称合成中有重要用途。如光学活性的β-芳氧基1,4-二醇可做为关键手性原料合成在手性药物和临床候选药物分子广泛存在的手性3-芳氧基取代的四氢呋喃及四氢吡咯结构单元,如可用于合成临床用于治疗非小细胞肺癌和晚期乳腺癌的抗癌药物阿法替尼(Afatinib)、治疗二型糖尿病新药恩格列净(Empaglifozin)等。但由于缺少绿色、高效、原子经济的不对称合成方法,目前文献报道的含有手性3-芳氧基取代的四氢呋喃和四氢吡咯结构单元的手性药物如阿法替尼等主要采用光学活性的3-羟基呋喃与酚经Mitsunobu反应或与氟代芳烃经亲核取代反应来制备(如:Widlicka,D.W.;etal.Org.Process Res.Dev.2016, 20,233-241;Wang,X.-J.;et al,Org.Lett.2014,16,4090-4093)。这些合成方法除了存在原子经济性差的不足以外,对芳氧基引入的原料也有一定的限制。因此,发展手性β-芳氧基1,4-二醇的不对称合成的绿色、高效、原子经济新方法,无疑会为这些手性药物分子的不对称合成提供了绿色、高效、实用的新方法。
我们在前期发现手性螺环吡啶胺基膦配体的铱催化剂(Xie,J.-H.;Zhou,Q.-L.;et al., Angew.Chem.Int.Ed.2011,50,7329-9332;周其林等CN102040625A)可以高效、高对映选择性地催化消旋α-芳基/烷基取代戊内酯(Yang,X.-H.;et al.Chem.Sci.2017,8,1811-1814)以及α-芳胺取代丁内酯和戊内酯(Gu,X.-S.;et al.Org.Lett.2019,21,4111-4115;谢建华等, CN201910366247)的不对称氢化合成相应的手性二醇的基础上,进一步针对光学活性手性β- 芳氧基取代二醇的不对称合成,设计发展了一类噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体,并采用其铱络合物实现了消旋α-芳氧取代内酯的高效、高对映选择性不对称催化氢化合成光学活性β-芳氧基取代1,4-和1,5-二醇。虽然已有噁唑啉环4-位取代的手性螺环噁唑啉- 胺基膦配体的文献报道(Zhang,F.-H.;etal.Adv.Synth.Catal.2019,361,2832-2835),但噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体的铱络合物在该酯的不对称催化氢化反应中给出了更加优秀的对映选择性。因此,噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体及其铱络合物为消旋α-芳氧取代内酯的高效、高对映选择性的不对称氢化合成光学活性β-芳氧基取代 1,4-和1,5-二醇提供了高效、高对映选择性的手性配体和催化剂,也为手性3-芳氧基取代的四氢呋喃及四氢吡咯等含氧、含氮杂环的不对称合成提供了重要的手性原料和方法。该合成方法具有绿色、原子经济、反应条件温和、操作简单、适于工业化生产的优点,具有非常好的应用前景和价值。
发明内容
本发明的目的在于提供一类噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体及其制备方法和应用。本发明通过在手性螺环胺基膦配体SpiroAP(Xie,J.-B.;et al,J.Am.Chem.Soc. 2010,132,4538-4539;周其林,谢建华,谢剑波,王立新CN CN101671365A)上引入5-位取代的噁唑啉环发展了一类新的手性螺环噁唑啉-胺基膦配体,该手性配体的铱络合物可高效催化消旋α-芳氧取代内酯的不对称催化氢化,取得了很好的收率(大于95%)和高达96%ee 对映选择性,从而为酯的不对称催化氢化提供了新的高效手性配体及其催化剂,也为光学活性β-芳氧基取代1,4-和1,5-二醇以及3-芳氧基取代四氢呋喃和四氢吡咯的不对称合成提供了一种绿色、高效、原子经济、操作简单的合成新方法。
本发明提供的噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体,是具有式I的化合物或所述化合物的对映体、消旋体,或其催化可接受的盐。
其中,R1选自C1~C10的烃基、苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基,所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5,杂芳基为呋喃基、噻吩基或吡啶基;
R2、R3分别选自H、C1~C10烷基、苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基,所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5,杂芳基为呋喃基、噻吩基或吡啶基;或C1~C10烷氧基;R2、R3可以相同也可以不同;
本发明提供的所述的噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体选自如下化合物的对映体、消旋体或其催化可接受的盐:
本发明提供的噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体的制备方法,其特征是以具有手性螺二氢茚骨架的式II所示的消旋或光学活性的7-二芳/烷基膦基-7′-氨基-1,1′-螺二氢茚类化合物为起始原料经过下述反应式制备:
其中,式II、III、IV、V中R1、R2、R3的含义与上述一致。具有手性螺二氢茚骨架的式II所示的化合物是按文献方法制备(Jian-Bo Xie,Jian-Hua Xie,Xiao-Yan Liu,Wei-LingKong, Shen Li,Qi-Lin Zhou,J.Am.Chem.Soc.2010,132,4538;周其林,谢建华,谢剑波,王立新,CN 101671365A)。
噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体的制备方法描述如下:具有式II所示的化合物先与乙醛酸乙酯在有机溶剂和还原剂存在的条件下,在反应器中反应2~24小时制备得到式III所示的化合物;式III所示的化合物随后经碱水解得到式IV所示的化合物;在有机溶剂中,式IV所示的化合物与各种取代氨基醇在羧酸活化试剂作用下缩合得到式V所示的化合物;式V所示的化合物在甲基磺酰氯活化下关环得到式I所示的化合物。
在上述合成方法中,所述的有机溶剂可为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、甲苯、二甲苯、甲基叔丁基醚、***、二氧六环、N,N-二甲基甲酰胺、二甲亚砜、二氯甲烷、氯仿、1,2-二氯乙烷中的一种或其中几种的混合溶剂;所述的还原试剂可为氢化铝锂、硼氢化钠、三乙酰氧基硼氢化钠、腈基硼氢化钠;所述的碱包括有机碱和无机碱,其中有机碱可为吡啶、三乙胺、三丁胺、N-甲基***啉、N,N-二乙基异丙基胺;无机碱可为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾;所述的羧基活化试剂为氯甲酸乙酯、氯甲酸异丙酯、N,N′-二环己基碳二亚胺、羰基二咪唑。
本发明所述的噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体的应用,该配体与过渡金属(铱)金属盐原位形成络合物,铱络合物(可直接不脱溶或脱溶后制备成可存放的固体) 作为铱催化剂,用于催化α-芳氧取代内酯化合物的不对称催化氢化反应。
作为优先方案,首先使所述的噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体与过渡金属盐形成配合物,然后用于α-芳氧取代内酯化合物的不对称催化氢化反应。
作为优先方案,在惰性气体氛围下,将所述的手性螺环噁唑啉-胺基膦配体与过渡金属盐加入有机溶剂中,在25℃的反应条件下反应0.5~4小时;随后在0.1~20atm的氢气氛围中搅拌反应1~3小时制备得到手性螺环膦噁唑啉-胺基膦配体与过渡金属盐形成的配合物。作为更进一步的优先方案,所述的手性螺环噁唑啉-胺基膦配体与过渡金属盐的摩尔比为1∶1~2∶1,以1.2∶1~1.8∶1为最佳。
作为更优先方案,所述过渡金属盐为铱的金属盐。所述的铱金属盐为[Ir(COD)Cl]2(COD =环辛二烯)、[Ir(COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6或[Ir(COD)2]OTf。
本发明提供的所述的用于催化α-芳氧取代内酯的不对称催化氢化反应包括如下步骤:
作为进一步优先方案,向制备所得到的配合物溶液中加入α-芳氧取代内酯和碱,在 0.1~100atm的氢气氛围和0~80℃条件下进行氢化反应;所述的α-芳氧取代内酯与所述配合物的摩尔比为100∶1~50000∶1。底物浓度为0.001~10.0M,碱浓度为0.005M~1.0M;所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇钾、叔丁醇锂、三乙胺、三丁胺或N-甲基吗啉。
作为更进一步优先方案,所述有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、甲苯、甲基叔丁基醚、二氧六环、N,N-二甲基甲酰胺、二甲亚砜中的一种或其中几种的混合溶剂。
本发明提供的噁唑啉环5-位取代的手性螺环噁唑啉-胺基膦配体,主要结构特征是具有手性螺二氢茚骨架和具有噁唑啉基团,可作为手性配体用于铱催化的α-芳氧取代消旋γ-和δ-内酯的不对称催化氢化反应中给出了很好的收率和最高达96%ee的对映选择性。这是首例α- 芳氧取代消旋内酯的不对称催化氢化反应的报道。该不对称催化氢化反应也可以在0.1mol%的催化剂用量下以克级规模进行,并为手性α-芳氧基取代的四氢呋喃和四氢吡咯的不对称合成提供了新方法。
具体实施方式
下面结合实施例对本发明作进一步详细、完整的说明,列出的实施例将有助于理解本发明,但不能限制本发明的内容。
实施例1:
往接有冷凝回流管的250mL干燥的两口圆底烧瓶中加入II(1.5g,2.4mmol),置换成氩气氛围,加入60mL无水甲醇(不溶)。依次加入乙醛酸乙酯(1.2g,6mmol,50%w/w 甲苯溶液)和冰醋酸(345μL,6mmol)。40℃下反应6小时至固体全部溶解。一次性加入 NaBH3CN(495mg,7.8mmol)在40℃下继续反应6小时至原料消失。反应结束后冷却至室温,减压脱除溶剂,加入乙酸乙酯溶解,饱和碳酸氢钠溶液淬灭。用乙酸乙酯萃取(5mL×3),合并有机相,有机相用无水硫酸镁干燥,抽滤,减压脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=30∶1)得到1.4g白色固体III,收率为86%。熔点:157-159℃,(c 0.1,CHCl3)。1HNMR(400MHz,CDCl3)δ:7.36(d,J=7.2Hz,1H),7.32(s,1H),7.24-7.21(m, 2H),7.17-7.05(m,2H),6.93(d,J=8.0Hz,2H),6.74(d,J=7.2Hz,1H),6.68(d,J=7.2Hz,2H), 5.91(d,J=8.0Hz,1H),4.12-3.97(m,2H),3.65(d,J=5.0Hz,1H),3.39(dd,J=17.6,7.2Hz, 1H),3.16-3.04(m,2H),3.01-2.87(m,2H),2.81(dd,J=17.6,2.4Hz,1H),2.49-2.23(m,3H),2.20-2.12(m,1H),1.22(s,18H),1.16(s,18H).13C NMR(101MHz,CDCl3)δ:170.4,152.7,152.5,149.9,149.8,149.7,149.68,144.5,144.4,144.0,143.9,142.8,142.7,138.8,138.7,135.9,135.8,134.5,134.2,134.1(d),133.0,132.9,128.3,128.2,127.9,127.5,127.4,127.1,125.8,122.3, 121.1,114.2,108.1,61.5(d),60.7,45.0,39.2,39.1,35.7,34.7,34.6,31.4,31.3,31.2,30.8,14.0.31P NMR(162MHz,CDCl3)δ:-19.43.Calcd forC49H64NO2P[M+H]+:730.4747;Found:730.4752.
实施例2:
在装有磁力搅拌子的100mL带支口封管中加入手性螺环甘氨酸乙酯III(900mg,1.3 mmol)和氢氧化锂一水合物(259mg,6.5mmol),四氢呋喃和水各7mL。脱气四次,放入 80℃的油浴中反应12个小时。反应结束后,冷却至室温,使用4N稀盐酸将反应体系酸化至pH值为2.0到3.0。用乙酸乙酯萃取(5mL×3),合并有机相,有机相用无水硫酸镁干燥,抽滤,减压脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得到780mg白色固体IV,收率为90%,熔点为111-113℃,(c 0.1,CHCl3)。1H NMR(400MHz,CDCl3) δ:7.40-7.28(m,2H),7.25-7.16(m,2H),7.16-7.05(m,2H),6.96(d,J=8.0Hz,2H),6.75(d,J= 7.2Hz,1H),6.68(d,J=7.6Hz,2H),5.97(d,J=8.0Hz,1H),3.23(d,J=18.0Hz,1H),3.18-2.75(m,5H),2.26-2.15(m,4H),1.19(d,J=23.5Hz,36H).13C NMR(101MHz,CDCl3)δ:174.4,152.3,152.0,150.2(d),149.8(d),144.8(d),144.0(d),142.5(d),138.1(d),135.4(d),134.5(d), 134.0,133.1(d),128.4(d),128.1,127.6(d),127.2,125.9,122.6,121.4,115.2,108.5,61.5(d),45.4, 38.8(d),36.2,34.7(d),31.36,31.3.31P NMR(162MHz,CDCl3)δ:-18.35.HRMS(MALDI) Calcd for C47H60NO2P[M+H]+:702.4435;Found:702.4439.
实施例3:
在装有磁力搅拌子的100mL干燥的Schlenk瓶中依次加入IV(200mg,0.3mmol)、(S)- 苯甘氨醇(148mg,0.9mmol)、HOBt(193mg,1.5mmol)、EDCI-HCl(274mg,1.5mmol),置换成氩气氛围,注射器加入25mL无水二氯甲烷和三乙胺(396μL,3.0mmol)。室温搅拌反应12小时。减压除去溶剂,残余物经硅胶柱层析(石油醚∶乙酸乙酯=10∶1)得到216mg 白色固体Va,收率为88%,熔点为96-98℃,(c 0.1,CHCl3).1H NMR(400MHz, CDCl)δ:7.42-7.36(m,1H),7.35-7.30(m,2H),7.25-7.18(m,4H),7.17-7.10(m,2H),7.09-7.03 (m,2H),6.87(d,J=7.6Hz,2H),6.77-6.66(m,3H),6.04(d,J=8.0Hz,1H),4.60-4.54(m,1H),3.77-3.70(m,1H),3.42-3.25(m,2H),3.17(d,J=3.6Hz,1H),3.13-2.96(m,4H),2.91-2.81(m, 1H),2.66-2.58(m,1H),2.28-2.16(m,1H),2.15-2.03(m,2H),2.01-1.91(m,1H),1.19(s,18H), 1.15(s,18H).13C NMR(101MHz,CDCl3)δ:170.8,150.6,150.3,149.2,149.1,148.9(d),143.8(d), 142.8,142.7,141.8(d),140.1,135.3,135.2,134.0,133.9,132.8,132.6,132.0,130.8(d),127.1, 126.9,126.8,126.6,126.5,126.3,126.1,126.0,124.9,124.3,121.3,120.7,114.4,107.1,72.3, 60.3(d),46.4,46.2,36.8,36.7,34.9,33.5,33.4,30.1,30.0,29.5,29.3.31P NMR(162MHz,CDCl3) δ:-16.67.HRMS(ESI)Calcd forC50H70N2O2P([M+H]+):821.5169;Found:821.5174.
实施例4:
操作过程同实施例3.Vb:白色固体,216mg,收率为88%,熔点为96-98℃, (c 0.1,CHCl3).。1H NMR(400MHz,CDCl3)δ:7.58-7.51(m,1H),7.39-7.30(m,3H),7.30-7.24 (m,3H),7.21-7.11(m,4H),6.92(d,J=8.0Hz,2H),6.78(dd,J=17.6,8.0Hz,3H),6.07(d,J= 8.0Hz,1H),4.72-4.65(m,1H),3.86-3.79(m,1H),3.53-3.44(m,1H),3.37(dd,J=17.8,6.4Hz, 1H),3.29-3.21(m,1H),3.16-3.13(m,1H),3.12-3.00(m,2H),2.94-2.83(m,2H),2.68-2.58(m, 1H),2.30-2.18(m,1H),2.15-2.04(m,2H),1.97-1.85(m,1H),1.24(s,18H),1.21(s,18H).13C NMR(101MHz,CDCl3)δ:170.9,150.8,150.6,149.4(d),149.2,149.1,144.1,143.1,143.0, 142.1(d),140.5,135.4,135.3,134.4,134.3,133.2,133.0,132.2,130.9(d),127.4(d),127.2(d),126.7, 126.5,126.4,126.3,125.1,124.7,121.5,121.0,114.6,107.2,72.3,60.7,60.6,46.7,46.3,36.9,35.2, 33.8,33.7,30.4,30.3,29.8,29.6.31P NMR(162MHz,CDCl3)δ:-16.35.HRMS(ESI)Calcd forC50H70N2O2P([M+H]+):821.5169;Found:821.5174.
实施例5:
操作过程同实施例3.Vc:白色固体,186mg,收率:82%,熔点:101-102℃, (c 0.1,CHCl3).1H NMR(400MHz,CDCl3)δ:7.60-7.51(m,1H),7.35-7.29(m,2H),7.22-7.08 (m,3H),6.88(dd,J=7.8,1.8Hz,2H),6.76(dd,J=8.4,2.0Hz,2H),6.70(d,J=7.4Hz,1H),6.11 (d,J=8.0Hz,1H),3.88-3.79(m,1H),3.77-3.68(m,1H),3.45-3.32(m,2H),3.20-3.11(m,1H),3.09-2.94(m,2H),2.88-2.70(m,2H),2.60-2.42(m,2H),2.34-2.21(m,1H),2.13-1.99(m,2H), 1.89-1.77(m,1H),1.20(s,18H),1.17(s,18H),,0.96(d,J=6.3Hz,3H).13C NMR(101MHz, CDCl3)δ:171.9,151.7,151.5,150.4,150.4,150.2,150.1,145.1(d),144.1,144.0,143.1(d),136.1, 136.0,135.3,135.2,134.1,133.9,133.1,131.6(d),128.5,128.4,128.3,127.7,127.5,127.3,126.1, 122.4,122.2,115.6,108.3,67.3,61.7,61.6,47.7,46.7,37.7(d),36.2,34.8,34.7,31.4,31.3,30.7,30.5,20.3.31PNMR(162MHz,CDCl3)δ:-15.9.HRMS(ESI)Calcd for C50H68N2O2P([M+H]+): 759.5013;Found:759.5022.
实施例6:
操作过程同实施例3.Vd:白色固体,175mg,收率:74%,熔点:94-96℃。(c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.65-7.57(m,1H),7.34-7.28(m,3H),7.24-7.12(m,3H),6.86-6.75(m,4H),6.70(d,J=7.4Hz,1H),6.13(d,J=8.0Hz,1H),3.91-3.84(m,1H), 3.46(dd,J=18.0,6.0Hz,1H),3.42-3.35(m,1H),3.26(dd,J=18.0,5.0Hz,1H),3.19-3.14(m, 1H),3.10-2.93(m,2H),2.85-2.73(m,2H),2.55-2.41(m,2H),2.31-2.20(m,1H),2.11-1.94(m, 2H),1.77-1.66(m,1H),1.56-1.47(m,1H),1.18(d,J=3.8Hz,36H),0.82(d,J=6.8Hz,3H), 0.63(d,J=6.8Hz,3H).13C NMR(101MHz,CDCl3)δ:172.2(d),151.8,151.5,150.5,150.4(d), 150.3,145.3,145.2,144.2,144.1,143.3(d),135.9,135.8,135.6,135.5,134.2,134.0,132.9, 131.3(d),128.8,128.6,128.4,127.6,127.4(d),126.3,122.5,122.3,115.6,108.4,76.4,61.8(d),47.8, 43.4,37.7,37.6,36.3,34.9,34.8,31.6,31.5,31.4,30.8,30.6,18.8,18.0.31P NMR(162MHz, CDCl3)δ:-15.07.HRMS(ESI)Calcd for C52H72N2O2P([M+H]+):787.5326;Found:787.5328
实施例7:
操作过程同实施例3.Ve:白色固体,199mg,收率:78%,熔点:100-102℃, (c 0.1,CHCl3).1H NMR(400MHz,CDCl3)δ:7.50-7.43(m,1H),7.36-7.26(m,3H),7.24-7.19 (m,1H),7.17-7.08(m,2H),7.07-7.02(m,2H),6.91-6.85(m,2H),6.79-6.70(m,5H),6.02(d,J= 8.0Hz,1H),4.65-4.55(m,1H),3.81-3.71(m,4H),3.43-3.35(m,1H),3.30(dd,J=17.8,6.8Hz, 1H),3.11-2.92(m,4H),2.91-2.79(m,2H),2.61(dd,J=16.0,9.2Hz,1H),2.26-2.15(m,1H), 2.11-2.00(m,2H),1.98-1.87(m,1H),1.20(s,18H),1.16(s,18H).13C NMR(101MHz,CDCl3)δ: 171.7,158.9,151.9,151.6,150.4,150.6,150.2,150.1,145.1,145.1,144.1,144.0,143.1,143.0,136.5,136.4,135.3,135.2,134.2,134.0,133.7,133.3,132.0(d),128.4,128.3,128.1,127.6(d), 127.3,127.0,126.2,122.5,122.0,115.6,113.6,108.2,72.8,61.6,55.2,47.7,47.2,38.0,37.9,36.1, 34.8,34.7,31.4,31.3,30.8,30.6.31P NMR(162MHz,CDCl3)δ:-16.71.HRMS(ESI)Calcd for C56H72N2O3P([M+H]+):851.5275;Found:851.5270.
实施例8:
操作过程同实施例3.Vf:白色固体,240mg,收率:90%,熔点:110-111℃, (c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.72-7.60(m,1H),7.46(d,J=8.0Hz,2H), 7.35-7.28(m,3H),7.24-7.13(m,3H),7.11-7.05(m,1H),6.87(d,J=7.6Hz,2H),6.79(d,J=8.4 Hz,2H),6.71(d,J=7.6Hz,1H),6.01(d,J=8.0Hz,1H),4.70(d,J=7.8Hz,1H),3.96-3.81(m, 1H),3.61(s,1H),3.48-3.33(m,2H),3.19(dd,J=18.0,4.4Hz,1H),3.08-2.92(m,2H),2.88-2.71 (m,2H),2.58-2.48(m,1H),2.23-2.11(m,1H),2.08-1.97(m,2H),1.84-1.75(m,1H),1.18(s, 36H).13C NMR(101MHz,CDCl3)δ:172.2,151.7,151.5,150.5,150.5,150.4,150.3,145.6,145.4, 144.1,144.1,143.0,143.0,135.9,135.8,135.5,135.4,134.0,133.8,133.0,131.6,131.6,129.7, 129.4,128.6,128.4,127.6,127.4,126.2,126.1,125.5,125.2,125.1,122.8,122.4,122.3,115.8, 107.9,72.7,61.7(d),47.6,47.3,37.7,36.2,34.9,34.8,31.4,31.3,30.8,30.5.31P NMR(162MHz, CDCl3)δ:-15.36.HRMS(ESI)Calcd for C58H69F3N2O2P([M+H]+):889.5043;Found:889.5046.
实施例9:
操作过程同实施例3.Vg:白色固体,200mg,收率:78%,熔点:99-100℃,(c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.45(s,1H),7.35-7.29(m,2H),7.24-7.18(m,1H), 7.15-7.08(m,2H),6.89(d,J=8.0Hz,2H),6.86-6.79(m,3H),6.75(dd,J=14.4,7.8Hz,3H), 6.06(d,J=8.0Hz,1H),4.60(d,J=8.6Hz,1H),3.81-3.74(m,1H),3.51-3.43(m,1H),3.31(dd, J=17.8,6.8Hz,1H),3.12-2.78(m,6H),2.68-2.50(m,2H),2.22(s,6H),2.12-2.04(m,2H),1.99-1.90(m,1H),1.19(s,18H),1.16(s,18H).13C NMR(101MHz,CDCl3)δ:171.8,151.9, 151.7,150.5,150.4,150.2(d),145.2,145.1,144.1,144.0,143.2(d),141.5,137.8,136.6(d),135.3, 135.2,134.4,134.2,133.4,132.2(d),129.1,128.4,128.3,128.1,127.9,127.7,127.4,126.2,123.5, 122.6,122.0,115.7,108.3,73.3,61.7(d),47.9,47.3,46.2,38.0,38.0,36.2,34.9,34.8,31.4,31.3, 30.9,30.6,21.3.31P NMR(162MHz,CDCl3)δ:-17.02.HRMS(ESI)Calcd for C57H74N2O2P ([M+H]+):849.5482;Found:849.5479.
实施例10:
操作过程同实施例3.Vh:白色固体,140mg,收率:52%,熔点:114-115℃,(c 0.1,CHCl3).1H NMR(400MHz,CDCl3)δ:7.44-7.32(m,2H),7.31-7.26(m,1H),7.25-7.16(m, 5H),7.16-7.01(m,6H),7.00-6.88(m,6H),6.83(d,J=7.2Hz,1H),6.61(d,J=7.2Hz,2H),5.89 (d,J=8.0Hz,1H),5.02(dd,J=8.0,4.8Hz,1H),4.74(d,J=4.8Hz,1H),3.51-3.41(m,1H), 3.18-2.92(m,4H),2.80(dd,J=17.6,7.2Hz,1H),2.62(dd,J=17.6,3.6Hz,1H),2.41-2.27(m, 3H),2.23-2.12(m,1H),1.2(s,18H),1.1(s,18H).13C NMR(101MHz,CDCl3)δ:171.0,152.6, 152.4,150.5(d),150.0,149.9,144.6(d),144.1,144.0,142.7(d),140.3,139.2,138.5,138.4,135.0, 134.9,134.7,134.5,134.4(d),133.9,133.8,128.6,128.4,128.3(d),128.0,127.6,127.5,127.4(d), 127.3,127.2,126.3,123.2,121.3,116.1,109.5,77.2,61.8,61.7,59.2,47.6,39.1(d),36.1,34.9, 34.7,31.5,31.3,31.2,30.9.31P NMR(162MHz,CDCl3)δ:-20.15.HRMS(ESI)Calcd for C61H74N2O2P([M+H]+):897.5482 Found:897.5492
实施例11:
操作过程同实施例3.Vi:白色固体,165mg,收率:66%,熔点:117-118℃, (c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.40(s,1H),7.29-7.26(m,1H),7.21-7.05(m,7H),6.96(d,J=8.2Hz,2H),6.84(d,J=7.2Hz,1H),6.78(d,J=7.4Hz,1H),6.62(d,J=7.6Hz,2H),6.08(d,J=7.6Hz,1H),5.28-5.17(m,1H),4.58-4.47(m,1H),3.60-3.49(m,1H),3.16-2.83(m, 7H),2.81-2.68(m,1H),2.35-2.12(m,3H),2.07-1.97(m,1H),1.76(d,J=5.2Hz,1H),1.25(s, 18H),1.13(s,18H).13C NMR(101MHz,CDCl3)δ:170.5,151.5,151.2,149.5,149.4,148.9(d), 143.6(d),143.1,143.0,141.8(d),139.3,138.6,137.4,137.2,134.1,134.0,133.7,133.4,133.3(d), 132.7(d),127.3(d),127.1,127.0,126.5,126.3,126.2,126.1,125.1,124.1,123.2,122.0,120.3, 114.9,108.2,72.7,60.6(d),56.4,46.9,38.7,37.8(d),35.0,33.9,33.7,30.5,30.3,30.0,29.7.31P NMR(162MHz,CDCl3)δ:-20.11.HRMS(ESI)Calcd for C56H70N2O2P([M+H]+):833.5169; Found:833.5178
实施例12:
在装有磁力搅拌子的50mL干燥的Schlenk管中加入Va(164mg,0.2mmol)和DMAP(6.0mg,0.04mmol),置换成氩气氛围,注射器加入三乙胺(260μL,1.6mmol)和10mL 无水二氯甲烷。冰盐浴冷至在0℃以下,缓慢滴加MsCl(20μL,0.22mmol)至反应体系中。室温搅拌反应12小时。反应结束后,体系用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=30∶1)得到128mg白色固体Ia,收率:80%,熔点:77-78℃, (c 0.1,CHCl3)。1H NMR(400MHz,CDCl)δ:7.51-7.27(m,5H),7.20-7.15(m,1H),7.14-6.99(m, 5H),6.98-6.93(m,2H),6.89(d,J=7.2Hz,1H),6.73(d,J=7.2Hz,1H),6.66(dd,J=7.4,2.0Hz, 2H),6.12(d,J=8.0Hz,1H),5.25(dd,J=10.2,7.2Hz,1H),4.23-4.02(m,1H),3.75-3.58(m,2H),3.54-3.43(m,1H),3.04-2.74(m,5H),2.41-2.14(m,3H),2.08-1.97(m,1H),1.21(s,18H), 1.13(s,18H).13C NMR(101MHz,CDCl3)δ:165.0,152.8,152.5,150.1,150.0,149.9,149.8, 144.5,144.4,144.0,143.9,143.4(d),141.1,138.9,138.8,136.0,135.9,134.6,134.4,134.2,134.2, 133.5(d),128.7,128.5,128.4,128.2(d),127.7,127.5,126.9,125.9,125.6,122.6,121.3,114.6, 108.9,80.7,62.7,61.6(d),41.0,39.3(d),35.8,34.9,34.8,31.5,31.4,31.3,30.9.31P NMR(162 MHz,CDCl3)δ:-19.79.HRMS(ESI)Calcdfor C55H68N2OP([M+H]+):803.5064;Found: 803.5053.
实施例13:
操作过程同实施例12.Ib:白色固体,107mg,收率为80%,熔点为77-78℃, (c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.34-7.26(m,4H),7.24-7.18(m,2H),7.16-7.06 (m,5H),6.95(dd,J=8.2,1.8Hz,2H),6.77-6.64(m,3H),6.14(d,J=8.0Hz,1H),5.38-5.25(m, 1H),4.15-4.02(m,1H),3.73-3.59(m,2H),3.32(dd,J=16.4,6.0Hz,1H),3.15-2.85(m,5H),2.47-2.34(m,1H),2.29-2.19(m,2H),2.16-2.06(m,1H),1.22(s,18H),1.14(s,18H).13C NMR (101MHz,CDCl3)δ:165.2,152.8,152.5,150.1,150.0,149.9,149.8,144.5,144.5,144.1(d), 143.5(d),140.8,138.9138.7,136.1,136.0,134.7,134.5,134.2(d),133.0,133.0,128.8,128.4,128.3, 128.2,127.8,127.6,127.0,125.9,125.8,122.5,121.3,114.4,108.6,81.1,62.5,61.6,61.6,41.0, 39.3(d),36.1,34.9,34.8,31.6,31.4,31.3,30.9,29.8,29.8.31P NMR(162MHz,CDCl3)δ:-19.46. HRMS(ESI)Calcd for C55H68N2OP([M+H]+):803.5064;Found:803.5068.
实施例14:
操作过程同实施例12.Ic:白色固体,107mg,收率:72%,熔点:83-84℃,(c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.35-7.26(m,2H),7.20-7.05(m,4H),6.95-6.87(m,2H),6.75-6.64(m,3H),6.07(d,J=8.0Hz,1H),4.55-4.37(m,1H),3.80-3.69(m,1H),3.66-3.57(m,1H),3.33-3.18(m,2H),3.09-2.82(m,5H),2.45-2.34(m,1H),2.29-2.17(m,2H), 2.15-2.07(m,1H),1.23-1.10(m,39H).13C NMR(101MHz,CDCl3)δ:163.8,151.6,151.3,148.9, 148.8,148.7(d),143.3(d),143.0(d),142.4(d),137.6,137.5,134.9,134.8,133.6,133.4,133.0,132.9, 131.7(d),127.3,127.2,127.0,126.7,126.5,125.8,124.7,121.3,120.2,113.1,107.3,75.1,60.5, 60.4,59.9,39.9,38.0(d),34.9,33.7,33.6,30.4,30.3,30.2,29.8,28.7,19.9.31P NMR(162MHz, CDCl3)δ:-19.18.HRMS(ESI)Calcd for C50H66N2OP([M+H]+):741.4907;Found:741.4916.
实施例15:
操作过程同实施例12.Id:白色固体,100mg,收率:65%,熔点:78-79℃,(c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.33-7.24(m,2H),7.20-7.13(m,2H),7.12-7.04(m,2H),6.93(d,J=8.1Hz,2H),6.72-6.64(m,3H),6.07(d,J=8.0Hz,1H),4.13-4.03(m,1H), 3.70-3.54(m,2H),3.43-3.31(m,1H),3.24-3.16(m,1H),3.10-2.82(m,5H),2.47-2.34(m,1H),2.30-2.18(m,2H),2.15-2.06(m,1H),1.70-1.59(m,1H),1.21(s,18H),1.14(s,18H),0.81(dd,J =14.4,6.4Hz,6H).13C NMR(101MHz,CDCl3)δ:165.3,152.7,152.5,150.0,149.9,149.8,149.7, 144.4(d),144.0(d),143.5(d),138.7,138.6,136.0,135.9,134.7,134.4,134.1,134.0,132.8(d),128.3, 128.0,127.7,127.5,126.9,125.8,122.3,121.2,114.2,108.5,85.0,61.5(d),57.1,40.9,39.2,39.1, 35.9,34.8,34.7,32.5,31.4,31.3,31.2,30.9,17.9,17.5.31P NMR(162MHz,CDCl3)δ:-19.34. HRMS(ESI)Calcd forC52H70N2OP([M+H]+):769.5220;Found:769.5226
实施例16:
操作过程同实施例12.Ie:白色固体,199mg,收率:20%,熔点:78-79℃,(c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.33-7.28(m,1H),7.25-7.17(m,2H),7.15-7.03(m,5H),6.94(dd,J=8.0,2.0Hz,2H),6.88-6.81(m,2H),6.74-6.63(m,3H),6.12(d,J=8.0Hz, 1H),5.37-5.18(m,1H),4.04(dd,J=14.4,10.0Hz,1H),3.79(s,3H),3.68-3.59(m,2H),3.29(dd, J=16.2,6.0Hz,1H),3.13-2.84(m,5H),2.45-2.34(m,1H),2.31-2.19(m,2H),2.15-2.08(m,1H), 1.21(s,18H),1.13(s,18H).13C NMR(101MHz,CDCl3)δ:163.2,157.7,150.7,150.5,148.0(d), 147.9,147.8,142.5(d),142.1,142.0,141.5(d),136.8,136.7,134.1,134.0,132.7,132.5,132.1, 132.1,131.0,130.9,130.7,126.3,126.3,126.1,125.8,125.6(d),125.0,123.9,120.4,119.3,112.3, 112.1,106.6,79.1,60.1,59.6,59.6,53.4,38.95,38.0,37.2,34.0,32.9,32.8,29.5,29.4,29.5,28.9. 31P NMR(162MHz,CDCl3)δ:-19.45.HRMS(ESI)Calcd for C56H70N2O2P([M+H]+):833.5169; Found:833.5176.
实施例17:
具操作过程同实施例12.If:白色固体,110mg,收率:66%,熔点:90-91℃, (c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.57(d,J=8.1Hz,2H),7.38-7.32(m,1H), 7.26-7.21(m,3H),7.19-7.08(m,3H),6.99(dd,J=8.0,1.6Hz,2H),6.79-6.68(m,3H),6.18(d,J =8.0 Hz,1H),5.38(dd,J=10.0,8.0 Hz,1H),4.21-4.10(m,1H),3.74-3.59(m,2H),3.38(dd,J= 16.4,6.4Hz,1H),3.19(dd,.J=16.4,4.8Hz,1H),3.11-2.85(m,4H),2.46-2.34(m,1H),2.30-2.20 (m,2H),2.18-2.11(m,1H),1.24(s,18H),1.17(s,18H).13C NMR(101MHz,CDCl3)δ:163.9, 151.4,151.1,148.8,148.7,148.6(d),143.5,143.3(d),142.9,142.8,142.2,142.1,137.3,137.2, 134.9,134.8,133.5,133.2,132.9,132.8,131.8(d),129.2,128.9,127.1,126.9,126.8,126.5,126.3, 125.7,124.6,124.5(d),124.4(d),124.1121.4,121.2,120.1,113.3,107.3,78.8,61.2,60.4,60.3, 39.7,37.9,37.8,34.8,33.6,33.5,30.2,30.1,30.0,29.6.31P NMR(162MHz,CDCl3)δ:-19.52. HRMS(ESI)Calcd for C58H67F3N2OP([M+H]+):871.4938;Found:871.4944.
实施例18:
具操作过程同实施例12.Ig:白色固体,91mg,收率:55%,熔点:179-180℃, (c 0.1,CHCl3)。1H NMR(400MHz CDCl3)δ:7.31(s,1H),7.26-7.17(m,2H),7.15-7.06(m,3H), 6.98-6.90(m,3H),6.78(s,2H),6.73-6.66(m,3H),6.14(d,J=8.0 Hz,1H),5.24(t,J=8.8Hz, 1H),4.08-3.97(m,1H),3.69-3.59(m,2H),3.28(dd,J=16.4,6.0Hz,1H),3.13-2.89(m,5H), 2.46-2.34(m,1H),2.31-2.20(m,8H),2.16-2.08(m,1H),1.22(s,18H),1.14(s,18H).13C NMR (101MHz,CDCl3)δ:164.1,151.7,151.4,148.9(d),148.7(d),143.4,143.3,143.0,142.9,142.3(d), 139.6,137.7,137.6,137.3,135.0,134.9,133.6,133.4,133.1,133.0,131.9,131.8,128.8,127.2, 127.0,126.6,126.4,125.9,124.8,122.5,121.3,120.1,113.2,107.5,80.2,61.3,60.5(d),39.8, 38.2(d),34.9,33.8,33.7,30.4,30.3,30.2,29.8,25.9,20.2.31P NMR(162MHz,CDCl3)δ:-19.62. HRMS(ESI)Calcdfor C57H72N2OP([M+H]+):831.5377;Found:831.5381.
实施例19:
具操作过程同实施例12.Ih:白色固体,96.7mg,收率:55%,熔点:82-84℃, (c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.33(s,1H),7.21-7.12(m,2H),7.10-6.92(m,12H),6.78-6.67(m,7H),6.21(d,J=8.0Hz,1H),5.67(d,J=10.0Hz,1H),5.35(d,J=10.1Hz,1H), 3.92-3.85(m,1H),3.56(dd,J=16.0,6.4Hz,1H),3.28-3.20(m,1H),3.09-2.90(m,4H), 2.53-2.43(m,1H),2.39-2.31(m,1H),2.28-2.22(m,1H),2.17-2.09(m,1H),1.24(s,19H),1.14 (s,19H).13C NMR(101MHz,CDCl3)δ:166.3,152.7,152.4,149.9,149.8,149.8,149.7,144.5, 144.4,144.0,143.9,143.4(d),138.8,138.7(d),136.3,136.2,136.0,134.5,134.3,134.2,134.2, 133.4,133.4,128.3,128.1,127.7,127.7,127.6,127.5,127.4,127.3,127.0,126.7,126.5,125.9, 122.4,121.2,114.3,108.6,85.6,73.4,61.6(d),40.9,39.4(d),36.1,34.9,34.7,31.5,31.3,30.9,29.7. 31P NMR(162MHz,CDCl3)δ:-19.51.HRMS(ESI)Calcd for C61H72N2OP([M+H]+):879.5377 Found:879.5379.
实施例20:
具操作过程同实施例12.Ii:白色固体,81mg,收率:50%,熔点:99-100℃, (c 0.1,CHCl3)。1H NMR(400MHz,CDCl3)δ:7.40-7.29(m,2H),7.26(s,1H),7.23-7.14(m,5H), 7.08-7.00(m,2H),6.85(dd,J=8.4,1.6Hz,2H),6.71-6.61(m,3H),5.90(d,J=7.6Hz,1H),5.38 (d,J=8.0Hz,1H),5.17-5.08(m,1H),3.55(dd,J=7.4,3.2Hz,1H),3.37-3.26(m,2H), 3.14-2.86(m,5H),2.84-2.77(m,1H),2.43-2.28(m,2H),2.26-2.19(m,1H),2.14-2.05(m,1H), 1.15-1.10(m,36H).13C NMR(101MHz,CDCl3)δ:164.9,152.8,152.5,149.8,149.7,149.7, 144.3(d),144.0(d),143.2(d),141.7,139.5,138.8,138.7,135.7,135.5,134.7,134.4,134.1(d),133.0, 133.0,128.3(d),128.1,127.9,127.6,127.4,127.2,126.9,125.7,125.6,125.1,122.4,121.1,114.0, 108.2,83.1,76.3,61.5,61.4,40.5,39.5,39.3(d),35.9,34.7,31.3(d),30.9.31P NMR(162MHz, CDCl3)δ:-19.43.HRMS(ESI)Calcd for C56H68N2OP([M+H]+):815.5064;Found:815.5072.
实施例21:
手性螺环噁唑啉-胺基膦配体铱催化对α-苯氧取代丁内酯化合物的不对称催化氢化反应
在手套箱中称取配体(Sa,S)-I(3.2μmol)和[Ir(COD)Cl]2(1.0mg,1.5μmol)于装有磁力搅拌子的干燥洁净的10mL Schlenk管中,密封备用。取出后加入6mL无水正丙醇,室温下搅拌0.5小时。在氮气保护下,用注射器将该溶液加入到装有玻璃内管和磁力搅拌子的氢化反应釜中,用氢气快速置换反应釜中的气体三次,调节氢气压力为10atm,室温下搅拌反应 0.5小时后,缓慢释放出反应釜中的氢气。在氮气保护下,用注射器取出4mL加入装有1.0~10 mmol底物和0.05~25mmol叔丁醇钾的正丙醇溶液(0.5mL(0.1mmol/mL)~25mL(1mmol/mL))的应釜中。用氢气快速置换反应釜中的气体三次,最后调节氢气压力为8~30atm,室温下搅拌反应至氢气压力不再降低为止。缓慢释放出反应釜中的氢气,旋转蒸发仪脱除溶剂后得粗产物。经短硅胶柱过滤除去催化剂后,用薄层层析或者核磁共振分析反应的转化率和收率,高效液相色谱分析产物的光学纯度,所得氢化实验结果见表1。
表1.手性螺环噁唑啉-胺基膦配体铱催化对α-苯氧取代丁内酯化合物的不对称催化氢化
序号 | I | S/C | 反应时间(h) | 收率(%) | ee(%) |
1 | (S<sub>a</sub>,S)-Ia | 500 | 20 | 43 | 68 |
2 | (S<sub>a</sub>,S)-Ib | 500 | 6 | 94 | 91 |
3 | (S<sub>a</sub>,S)-Ic | 500 | 20 | 66 | 90 |
4 | (S<sub>a</sub>,S)-Id | 500 | 20 | 66 | 90 |
5 | (S<sub>a</sub>,S)-Ie | 500 | 20 | 93 | 86 |
6 | (S<sub>a</sub>,S)-If | 500 | 20 | 93 | 86 |
7 | (S<sub>a</sub>,S)-Ig | 500 | 20 | 92 | 90 |
8 | (S<sub>a</sub>,R,S)-Ih | 500 | 20 | 94 | 89 |
9 | (S<sub>a</sub>,S,S)-Ii | 500 | 20 | 95 | 64 |
实施例22:
手性螺环噁唑啉-胺基膦配体铱催化在α-芳氧取代内酯化合物的不对称催化氢化反应中的应用。
具操作过程同实施例21。经短硅胶柱过滤除去催化剂后,用薄层层析或者核磁共振分析反应的收率,高效液相色谱分析产物的光学纯度,所得氢化实验结果见表2。
表2.消旋α-芳氧基取代内酯的不对称催化氢化
实施案例23:
α-芳氧取代内酯不对称催化氢化的动态动力学拆分高转化数实验(S/C=1000)
在氩气保护下,向氢化反应内管中依次加入10mmolα-苯氧基-γ-丁内酯,0.1mol%手性螺环噁唑啉催化剂、2mmol叔丁醇钾、20mL正丙醇。密封反应釜,用氢气快速置换反应釜中的气体三次,调节氢气压力为10atm,室温下搅拌反应12小时后。反应结束后,缓慢释放出反应釜中的氢气,旋转蒸发仪脱除溶剂后得粗产物。柱层析得到1.6g氢化产物,88%的收率和94%ee。
实施案例24:
往10mL带支口的封管中依次加入(S)-2-苯氧基-1,4-丁二醇(182mg,1.0mmol),无水对甲苯磺酸(86mg,0.5mmol)。氩气保护下加入干燥的甲苯(2mL),拧紧封管。于110℃下反应24h。冷却至室温,加入水,乙酸乙酯萃取三次(2mL×3)。无水硫酸镁干燥,抽滤,减压脱除溶剂得到粗品。粗品经硅胶柱层析分离提纯(石油醚∶乙酸乙酯=5∶1)得到黄色液体156mg,产率95%。(c 0.5,CHCl3)。1H NMR(400MHz,CDCl3)δ7.33-7.24(m,2H),6.98-6.92(m,1H),6.88-6.82(m,2H),4.96-4.84(m,1H),4.03-3.93(m,3H),3.92-3.85(m,1H), 2.23-2.09(m,2H).13C NMR(101MHz,CDCl3)δ157.40,129.57,120.95,115.37,77.19,73.15, 67.23,33.05.
实施案例25:(S)-3-芳氧基四氢吡咯化合物的合成
往25mL Schleck管中加入氢化底物(S)-2-苯氧基-1,4-丁二醇(236.6mg,1.3mmol),置换氩气。冷至0℃以下,加入干燥的三乙胺(525.2mg,5.2mmol),缓慢滴加甲磺酰氯(592.8mg, 5.2mmol)。反应2小时后,直接减压除去溶剂,加入乙腈(2mL)溶解,甲胺的甲醇溶液(2M, 4.0mL)回流24小时。反应结束后,冷至室温,减压除去溶液得到粗品。粗品经硅胶柱层析分离提纯(石油醚∶乙酸乙酯=5∶1)得到黄色液体138mg,产率60%。(c0.5,EtOH)1H NMR(400MHz,CDCl3)δ7.31-7.23(m,2H),6.96-6.90(m,1H),6.87-6.82(m,2H),4.87-4.79 (m,1H),2.91-2.78(m,3H),2.55-2.47(m,1H),2.41(s,3H),2.36-2.25(m,1H),2.06-1.95(m,1H). 13C NMR(101MHz,CDCl3)δ157.63,129.46,120.61,115.27,76.78,62.36,55.13,42.15,32.86. HRMS(ESI)Calcd for C11H16NO([M+H]+):178.1226;Found:178.1227。
Claims (10)
3.权利要求1所述的手性螺环噁唑啉-胺基膦配体的制备方法,其特征是以具有手性螺二氢茚骨架的式II所示的消旋或光学活性的7-二芳/烷基膦基-7′-氨基-1,1′-螺二氢茚类化合物为起始原料经过下述反应式制备:
具体步骤为:
在有机溶剂和还原剂存在的条件下,具有式II所示的化合物先与乙醛酸乙酯在有机溶剂和还原剂存在的条件下,在反应器中反应2~24小时制备得到式III所示的化合物;式III所示的化合物随后经碱水解得到式IV所示的化合物;在有机溶剂中,式IV所示的化合物与各种取代氨基醇在羧酸活化试剂作用下缩合得到式V所示的化合物;式V所示的化合物在甲基磺酰氯活化下关环得到式I所示的化合物;
所述的有机溶剂可为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、甲苯、二甲苯、甲基叔丁基醚、***、二氧六环、N,N-二甲基甲酰胺、二甲亚砜、二氯甲烷、氯仿、1,2-二氯乙烷中的一种或其中几种的混合溶剂;
所述的还原试剂可为氢化铝锂、硼氢化钠、三乙酰氧基硼氢化钠、腈基硼氢化钠;所述的碱包括有机碱和无机碱,其中有机碱可为吡啶、三乙胺、三丁胺、N-甲基***啉、N,N-二乙基异丙基胺;无机碱可为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾;
所述的羧基活化试剂为氯甲酸乙酯、氯甲酸异丙酯、N,N′-二环己基碳二亚胺、羰基二咪唑。
4.根据权利要求1或2中所述的手性螺环噁唑啉胺基膦配体的应用,其特征在于该配体与铱金属盐原位形成铱配合物作为铱催化剂,用于催化α-芳氧取代内酯化合物的不对称催化氢化反应。
5.根据权利要求4所述的应用,其特征在于铱配合物原位制备方法包括如下步骤:
在有机溶剂和25~120℃的反应条件下,手性螺环噁唑啉-胺基膦配体首先与铱催化剂前体反应0.5~4小时,然后再在0.1~50atm的氢气氛围中搅拌反应0.1~3小时,便可得到氢化反应所需的手性螺环噁唑啉-胺基膦配体铱催化剂;
所述的手性螺环噁唑啉-胺基膦配体与铱催化剂前体的摩尔比为1∶1~2∶1;
所述的铱催化剂前体为[Ir(COD)Cl]2(COD=环辛二烯)、[Ir(COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6或[Ir(COD)2]OTf。
6.根据权利要求4中所述的应用,其特征在于铱配合物原位制备是在惰性气体氛围下,将所述的手性螺环噁唑啉-胺基膦配体与铱催化剂前体加入有机溶剂中,在25℃的反应条件下反应0.5~4小时;随后在0.1~20atm的氢气氛围中搅拌反应1~3小时制备得到手性螺环噁唑啉-胺基膦配体与铱催化剂前体形成的配合物;
所述的手性螺环噁唑啉-胺基膦配体与过渡金属盐的摩尔比为1.2∶1~1.8∶1。
7.根据权利要求4中所述的应用,其特征在于所述的用于催化α-芳氧取代内酯化合物的不对称催化氢化反应包括如下步骤:
在氮气保护下,于氢化反应器的有机溶剂中加入手性螺环噁唑啉-胺基膦配体铱催化剂,并加入α-芳氧取代内酯化合物和碱,并在0.1~100atm的氢气氛围中搅拌反应0.1~80小时,旋转蒸发仪脱除溶剂和催化剂,用薄层层析或者核磁共振分析反应的转化率和收率。
8.根据权利要求7中所述的应用,其特征在于所述的α-芳氧取代内酯底物与催化剂的摩尔比为10∶1~5000∶1,即催化剂用量为0.1~0.02mol%;底物浓度为0.001~10.0M。
9.根据权利要求7中所述的应用,其特征在于所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇钾、叔丁醇锂、三乙胺、三丁胺或N-甲基吗啉;碱浓度为0.005M~1.0M;反应温度为0~80℃。
10.根据权利要求7中所述的应用,其特征在于所述的有机溶剂为甲醇、乙醇、正丙醇、异丙醇、丁醇、四氢呋喃、甲苯、甲基叔丁基醚、二氧六环、N,N-二甲基甲酰胺、二甲亚砜中的一种或其中几种的混合溶剂。
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