CN105188926A - 用于不对称转化的金属有机催化 - Google Patents

用于不对称转化的金属有机催化 Download PDF

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CN105188926A
CN105188926A CN201480013940.2A CN201480013940A CN105188926A CN 105188926 A CN105188926 A CN 105188926A CN 201480013940 A CN201480013940 A CN 201480013940A CN 105188926 A CN105188926 A CN 105188926A
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CN105188926B (zh
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张绪穆
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Rutgers State University of New Jersey
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Abstract

本发明提供一种具有以下结构(I)的配体或其对映异构体：其中：Ra、Rb、Rc和Rd中的每一个选自烷基、环烷基和芳基；桥接基团选自CH2NH、*CH(CH3)NH(C*,R)；并且有机催化剂是共价结合至所述桥接基团的有机分子催化剂。此外，本发明提供具有以下结构(II)的催化剂或其对映异构体：其中：Ra、Rb、Rc和Rd中的每一个选自烷基、环烷基和芳基；桥接基团选自CH2NH、*CH(CH3)NH(C*,R)和*CH(CH3)NH(C*,S)；有机催化剂是共价结合至所述桥接基团的有机分子催化剂；并且M选自Rh、Pd、Cu、Ru、Ir、Ag、Au、Zn、Ni、Co和Fe。

Description

用于不对称转化的金属有机催化
相关申请的交叉引用
本申请根据35U.S.C.§119(e)要求2013年3月11日提交的美国临时申请序列号61/775,807的权益，其公开内容在此通过引用以其全文并入。
背景
已经开发了许多令人印象深刻的具有独特活化方式的催化剂用于过渡金属催化和有机催化中。但是，这些催化剂的利用受限于固有的缺点，如有限的反应范围和高的催化剂负载。为了改善这些局限性，最近几年出现了精梳(combing)过渡金属催化和有机催化的概念。已经建立了包括合作催化、协同催化以及顺序/中继催化在内的策略。然而，催化剂、底物、中间体和溶剂之间的不相容性是潜在的缺点。
概述
本文件描述一种具有以下结构的配体或其对映异构体：
其中：
Ra、Rb、Rc和Rd中的每一个选自烷基、环烷基和芳基；桥接基团选自CH2NH、*CH(CH3)NH(C*,R)和*CH(CH3)NH(C*,S)；并且有机催化剂是共价结合至桥接基团的有机分子催化剂。在一个实施方式中，Ra、Rb、Rc和Rd中的至少一个是选自苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基的芳基部分。在另一个实施方式中，Ra、Rb、Rc和Rd中的至少一个是选自叔丁基和异丙基的烷基部分。在另一实施方式中，Ra、Rb、Rc和Rd中的至少一个是选自环己基和环戊基的环烷基部分。
还提供具有以下结构或其对映异构体的催化剂：
其中：Ra、Rb、Rc和Rd中的每一个选自烷基、环烷基和芳基；桥接基团选自CH2NH、*CH(CH3)NH(C*,R)和*CH(CH3)NH(C*,S)；有机催化剂是共价结合至桥接基团的有机分子催化剂；并且M选自Rh、Pd、Cu、Ru、Ir、Ag、Au、Zn、Ni、Co和Fe。在一个实施方式中，Ra、Rb、Rc和Rd中的至少一个是选自苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基的芳基部分。在另一个实施方式中，Ra、Rb、Rc和Rd中的至少一个是选自叔丁基和异丙基的烷基部分。还在另一个实施方式中，Ra、Rb、Rc和Rd中的至少一个是选自环己基和环戊基的环烷基部分。
还提供了一种用于将烯烃不对称地氢化为相应的烷烃的方法，其包括将烯烃在适当的溶剂中与过量的氢气和催化有效量的根据本公开的催化剂在使该烯烃有效氢化的温度和压力下组合的步骤。在一个实施方式中，溶剂包含异丙醇。在另一个实施方式中，催化剂中的Ra、Rb、Rc和Rd中的至少一个是选自苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基的芳基部分。还在另一个实施方式中，催化剂中的Ra、Rb、Rc和Rd中的至少一个是选自叔丁基和异丙基的烷基部分。在进一步的实施方式中，催化剂中的Ra、Rb、Rc和Rd中的至少一个是选自环己基和环戊基的环烷基部分。
详细说明
本文描述配体和由其制备的催化剂，其通过使手性双膦与有机催化剂共价结合而提供与单独的金属催化剂和有机催化剂相比在转化率和选择性方面的意想不到的改善。与双膦络合的金属是一般的催化剂，且能够导致许多金属催化的反应具有高的逆转(turnover)。有机催化剂使底物活化并影响选择性。本文所用的术语“金属有机催化(metallorganocatalysis)”是指通过具有共价结合至有机催化剂部分的金属催化剂部分的化合物催化的反应和催化剂。源自金属部分的高活性和源自有机催化剂的高选择性提供用于不对称催化的有用方法。
如以上和在整个公开中所用，除非另有说明，否则下列术语应理解为具有以下含义：
术语“烷基”是指饱和的脂肪族基团，包括直链烷基和支链烷基。术语“环烷基”是指约3至7个碳原子的非芳香性的单环或多环的环体系。环烷基的实例包括环丙基、环丁基、环戊基和环己基等。
术语“芳基”是指从简单的芳香环衍生的任何官能团或取代基，其为苯基、噻吩基和吲哚基等。
在此公开是具有以下结构或其对映异构体的配体：
其中：
Ra、Rb、Rc和Rd中的每一个选自烷基、环烷基和芳基；桥接基团选自CH2NH、*CH(CH3)NH(C*,R)和*CH(CH3)NH(C*,S)；并且有机催化剂是共价结合至桥接基团的有机分子催化剂。
Ra、Rb、Rc和Rd中的每一个可以与任何其它R基团相同或不同。例如，在一个实施方式中，所有的Ra、Rb、Rc和Rd均为相同的芳基。在另一个实施方式中，Ra、Rb、Rc和Rd中的每一个均为不同的芳基。还在另一个实施方式中，Ra和Rb是不同的芳基，而Rc是烷基并且Rd是环烷基。
Ra、Rb、Rc和Rd的优选的芳基部分包括苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基。Ra、Rb、Rc和Rd的优选的环烷基部分(例如“Cy”)包括环己基和环戊基。Ra、Rb、Rc和Rd的优选的烷基部分包括叔丁基和异丙基。
本文所用的术语“有机催化剂”包括能够催化反应的有机分子。合适的有机催化剂含有能够共价结合至结构(I)的配体或结构(II)的催化剂中的桥接基团的至少一个部分。优选的有机催化剂包括能够共价结合至桥接基团的硫脲部分。示例性的有机催化剂包括但不限于以下指定为OC1至OC25的结构：
优选的配体由以下式表示：
可替代地，上述列出的任何配体中的PPh2基团可以是PRaRb或PRcRd，其中Ra、Rb、Rc和Rd中的至少一个选自烷基、环烷基和芳基。对于R优选的芳基部分包括苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基。对于R优选的环烷基部分包括环己基和环戊基。对于R优选的烷基部分包括叔丁基和异丙基。
Ra、Rb、Rc和Rd中的每一个可以与任何其它R基团相同或不同。例如，在一个实施方式中，所有的Ra、Rb、Rc和Rd均为相同的芳基。在另一个实施方式中，Ra、Rb、Rc和Rd中的每一个均为不同的芳基。还在另一个实施方式中，Ra和Rb是不同的芳基，而Rc是烷基并且Rd是环烷基。
本文还公开具有以下结构的催化剂或其对映异构体：
其中：Ra、Rb、Rc和Rd中的每一个选自烷基、环烷基和芳基；桥接基团选自CH2NH、*CH(CH3)NH(C*,R)和*CH(CH3)NH(C*,S)；并且有机催化剂是共价结合至桥接基团的有机分子催化剂。在一个实施方式中，桥接基团是有机催化剂分子的一部分，例如，用于双重氢键合的硫脲部分。
Ra、Rb、Rc和Rd中的每一个可以与任何其它R基团相同或不同。例如，在一个实施方式中，所有的Ra、Rb、Rc和Rd均为相同的芳基。在另一个实施方式中，Ra、Rb、Rc和Rd中的每一个均为不同的芳基。还在另一个实施方式中，Ra和Rb是不同的芳基，而Rc是烷基并且Rd是环烷基。
Ra、Rb、Rc和Rd的优选的芳基部分包括苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基。Ra、Rb、Rc和Rd的优选的环烷基部分包括环己基和环戊基。Ra、Rb、Rc和Rd的优选的烷基部分包括叔丁基和异丙基。
本文所用的术语“有机催化剂”包括能够催化反应的有机分子。合适的有机催化剂含有能够共价结合至结构(I)的配体或结构(II)的催化剂中的桥接基团的至少一个部分。优选的有机催化剂包括能够共价结合至桥接基团的硫脲部分。示例性的有机催化剂包括但不限于以上列出的那些。
当金属催化剂和有机催化剂通过共价键连接时，诸如以下相互作用方式的合作的相互作用给出高的活性和选择性。
在实施例部分讨论用于制备本文所述的配体和催化剂的方法。
本文所公开的催化剂可用于广泛的反应，包括但不限于不对称氢化、加氢甲酰化、羟醛反应、Diels-Alder反应、杂Diels-Alder反应、Mannich反应、Michael加成、烯丙基烷基化、烷基化、Friedel-Crafts、烯反应、Baylis-Hillman反应、氟化反应和Henry反应。在实施例中所描绘的一个实施方式中，提供了使烯烃、亚胺、酮或硫酮不对称地氢化为相应的烷烃、胺、醇或硫醇的方法，其包括在适当的溶剂中将烯烃、亚胺、酮或硫酮与过量的氢气和催化有效量的本文公开的催化剂在使该烯烃、亚胺、酮或硫酮有效氢化的温度和压力下组合。在一个实施方式中，β,β-二取代的硝基烯烃的不对称氢化提供高达>99％的转化率和99％的对映选择性。
合适的溶剂包括但不限于极性有机溶剂。示例性的极性有机溶剂包括但不限于异丙醇。催化剂的催化有效量可以由本领域技术人员容易地确定，并且包括使烯烃、亚胺或酮有效转化为相应的手性烷烃、胺或醇的量。
以下非限制性实施例用来进一步说明本发明。
实施例
材料和方法
处理空气或湿气敏感的化合物的所有反应均在氮气正压下的干燥反应容器中或充有氮气的手套箱中进行。除非另有说明，所有试剂和溶剂均购自商业供应商并且没有进一步纯化。无水溶剂购自Sigma-Aldrich并通过注射器转移。通过使用来自ACROS的硅胶(0.06至0.20mm)的色谱进行产物纯化，并且使用来自Merck的硅胶板(GF254)进行薄层色谱(TLC)分析。[Rh(COD)Cl]2、[Rh(COD)2]BF4和[Rh(COD)2]SbF6购自Heraeus。HPLC溶剂购自Alfa(正己烷)和Sigma-Aldrich(2-丙醇)。
使用CDCl3作为溶剂和四甲基硅烷(TMS)作为内标，在BrukerAvance(400MHz)光谱仪上记录1HNMR、13CNMR和31PNMR光谱。化学位移以相对于0.00ppm的TMS的低场的每百万份(ppm，δ标度)来报告并且参照7.26ppm(对于1HNMR)或77.0ppm(对于氘代氯仿)的CDCl3。数据被报告为：多重性(s＝单峰、d＝双峰、t＝三重峰、q＝四重峰、m＝多重峰)，以赫兹(Hz)表示的偶合常数和以自然数表示的信号面积积分。13CNMR和31PNMR分析在去耦合的情况下进行。
在Agilent1200SeriesHPLC仪器或Agilent7980SeriesGC仪器上通过Daicel手性柱测定对映异构体过量值(“ee”)。新化合物通过具有电喷雾电离源的WatersQ-TOFUltima质谱仪上的高分辨率质谱(HRMS)(UniversityofIllinois,SCS,MassSpectrometryLab)进行进一步表征。在PERKINELMER旋光计343仪器上测量旋光度[α]D。
所有的(E)-β,β-二取代的硝基烯烃均是根据文献(Li,S.,etal.,Angew.Chem.Int.Ed.2012,51,8573-8576)制备的。所有的N-H亚胺均是根据文献(Hou,G.,etal.,J.Am.Chem.Soc.2009,131,9882-9883)制备的。产物的绝对构型通过将分析数据与文献(HPLC谱图，旋光)进行比较而确定。通过类推指定其它的绝对构型。
实施例1-配体的合成
根据文献(Hayashi,T.,etal.,Bull.Chem.Soc.Jpn.1980,53,1138-1151)合成配体L1-L3，轻微的修改在于：使用硅胶(对于L1为己烷/乙酸乙酯，对于L2为二氯甲烷/甲醇)代替氧化铝(对于L1为己烷/苯，对于L2为乙醚/乙酸乙酯)进行柱色谱法。所有的光谱数据与文献值一致。
在氩气氛下，向L2(1.0mmol)在干燥的DCM(1.0ml)中的溶液添加3,5-双(三氟甲基)苯基异硫氰酸酯(1.1mmol)。使反应混合物搅拌过夜之后，将反应混合物真空浓缩。将残余物通过硅胶上的快速柱色谱(洗脱剂为己烷/乙酸乙酯＝9/1)纯化，得到黄色固体形式的L8(640mg，74％)。L8的表征如下：
L8:
1HNMR(400MHz,CDCl3)δ7.69(s,3H),7.33–7.12(m,19H),7.11–7.01(m,3H),5.53(s,1H),4.47(d,J＝7.2Hz,2H),4.28(s,1H),4.18(t,J＝2.3Hz,1H),3.96(s,1H),3.56(s,1H),3.45(s,1H),1.42(d,J＝6.6Hz,1H)。
13CNMR(100MHz,CDCl3)δ178.37(s),139.18(s),138.94(d,J＝9.6Hz),138.82(d,J＝6.3Hz),138.04(d,J＝9.4Hz),135.55(d,J＝5.0Hz),134.68(d,J＝21.2Hz),133.71(d,J＝20.1Hz),133.01(d,J＝19.2Hz),132.20(d,J＝17.8Hz),129.58(s),128.97–127.94(m),124.48(s),124.31(s),121.60(s),119.16(s),95.36(d,J＝24.1Hz),77.63(d,J＝8.5Hz),75.34(d,J＝20.4Hz),74.16(d,J＝9.1Hz),73.84(d,J＝4.9Hz),73.37(d,J＝8.5Hz),73.10–72.50(m),71.97(d,J＝2.6Hz),50.87(s),21.86(s)。
31PNMR(162MHz,CDCl3)δ-17.81(s),-25.08(s)。
[α]D 25＝–237.3°(c＝0.30,CHCl3)
HRMS(ESI):[M+H+]计算为869.1406，发现为869.1401。
L4:
1HNMR(400MHz,CDCl3)δ7.54(s,2H),7.42–7.38(m,3H),7.34–7.14(m,18H),5.13(s,2H),5.13–5.07(m,1H),4.48(d,J＝1.7Hz,2H),4.37(d,J＝7.4Hz,2H),4.19(d,J＝8.1Hz,2H),4.14(t,J＝2.3Hz,1H),3.65(s,1H),3.57(s,1H),1.46(d,J＝6.7Hz,3H)。
13CNMR(100MHz,CDCl3)δ152.34(s),140.51(s),140.39(s),138.90(d,J＝9.7Hz),138.14(d,J＝9.4Hz),135.89(d,J＝8.1Hz),134.92(d,J＝21.2Hz),133.60(d,J＝20.0Hz),133.06(d,J＝19.2Hz),132.44(d,J＝18.8Hz),131.76(d,J＝33.2Hz),129.39(s),128.72(s),128.62–127.96(m),124.55(s),121.84(s),118.11(d,J＝3.1Hz),115.21(s),95.11(d,J＝23.6Hz),77.19(s),75.78(d,J＝10.3Hz),75.36(d,J＝19.6Hz),74.33(d,J＝3.0Hz),73.42–73.18(m),73.11(d,J＝4.5Hz),71.67(d,J＝2.2Hz),71.24(d,J＝1.9Hz),45.48(d,J＝7.1Hz),20.65(s)。
HRMS(ESI):[M+H+]计算为853.1635，发现为853.1644。
[α]D 25＝–262.1°(c＝0.33,CHCl3)。
L5:
1HNMR(400MHz,CDCl3)δ7.44(t,J＝7.2Hz,2H),7.40–7.11(m,24H),6.00(s,2H),5.46(s,1H),4.60(s,1H),4.57–3.52(m,4H),3.56(d,J＝10.8Hz,2H),1.35(d,J＝6.6Hz,3H),1.04(d,J＝6.2Hz,3H)。
13CNMR(100MHz,CDCl3)δ178.66(s),141.83(s),139.05(d,J＝2.9Hz),138.97(s),138.23(d,J＝9.6Hz),136.13(d,J＝7.2Hz),134.71(d,J＝21.0Hz),133.62(d,J＝20.1Hz),132.98(d,J＝19.2Hz),132.55(d,J＝18.6Hz),129.29(s),128.98–127.45(m),125.65(s),95.44(d,J＝23.6Hz),77.17(d,J＝8.1Hz),75.25(d,J＝19.9Hz),74.80(d,J＝10.3Hz),74.08(d,J＝4.5Hz),73.25(d,J＝9.0Hz),73.13(s),72.72(d,J＝4.3Hz),72.41(s),71.50(d,J＝2.6Hz),52.79(s),50.51(s),23.82(s),21.45(s)。
31PNMR(162MHz,CDCl3)δ-17.66(s),-25.81(s)。
HRMS(ESI):[M+H+]计算为761.1972，发现为761.1972。
[α]D 25＝–343.5°(c＝0.21,CHCl3)。
L6:
1HNMR(400MHz,CDCl3)δ8.21(t,J＝9.1Hz,1H),7.59(s,1H),7.25–6.92(m,23H),5.51–5.41(m,1H),4.43–4.38(m,2H),4.29(s,1H),4.17(s,1H),3.70(s,1H),3.40(s,1H),3.09(s,1H),2.42(s,6H),1.24(d,J＝6.9Hz,3H)。
13CNMR(100MHz,CDCl3)δ178.51(s),140.22(s),139.32(d,J＝9.9Hz),138.56(d,J＝5.4Hz),138.03(d,J＝9.7Hz),135.93(s),134.64(d,J＝21.2Hz),133.84(d,J＝20.4Hz),132.76(d,J＝18.9Hz),132.08(d,J＝17.5Hz),129.27(d,J＝17.7Hz),128.67(s),128.29–127.92(m),96.88(d,J＝24.1Hz),75.39(d,J＝22.6Hz),73.95(d,J＝5.3Hz),73.65(d,J＝5.6Hz),72.98(d,J＝6.8Hz),72.81(s),72.56(d,J＝3.7Hz),72.16(d,J＝3.6Hz),51.84(s),24.43(s),21.48(s)。
31PNMR(162MHz,CDCl3)δ-17.61(s),-25.96(s)。
HRMS(ESI):[M+H+]计算为761.1972，发现为761.1964。
[α]D 25＝–219.9°(c＝0.22,CHCl3)
L7:
1HNMR(400MHz,CDCl3)δ8.22(s,1H),7.73(d,J＝8.4Hz,2H),7.71–7.64(m,1H),7.35–7.13(m,18H),7.08–7.02(m,4H),5.56–5.46(m,1H),4.45(s,1H),4.32(s,1H),4.25(s,1H),4.17(t,J＝2.4Hz,1H),3.72(s,1H),3.50(s,1H),3.26(s,1H),1.33(d,J＝6.8Hz,1H)。
13CNMR(100MHz,CDCl3)δ178.11(s),139.79(s),139.14(d,J＝9.8Hz),138.63(d,J＝5.5Hz),137.96(d,J＝9.4Hz),135.58(d,J＝4.5Hz),134.68(d,J＝21.2Hz),133.81(d,J＝20.3Hz),132.83(d,J＝18.9Hz),132.22(s),130.27–129.77(m),128.78(s),128.66–128.01(m),127.27(d,J＝3.4Hz),125.01(s),95.87(d,J＝24.2Hz),77.59(d,J＝8.6Hz),75.42(d,J＝22.0Hz),73.63(d,J＝5.2Hz),73.14(d,J＝7.2Hz),72.83(s),72.08(d,J＝3.0Hz),51.60(s),23.10(s)。
31PNMR(162MHz,CDCl3)δ-17.85(s),-26.34(s)。
HRMS(ESI):[M+H+]计算为801.1532，发现为801.1538。
[α]D 25＝–239.5°(c＝0.30,CHCl3)
根据文献(Zhao,Q.,etal.,Org.Lett.2013,15,4014-4017)制备配体L9-L14。
如下合成配体L15-L17。
根据文献(Zhao,Q.,etal.,Org.Lett.2013,15,4014-4017)制备SI2。根据文献(Gotov,B.,etal.,NewJ.Chem.2000,24,597-602)制备SI3。在氮气气氛下，向SI3(1.0mmol)在干燥的DCM(1.0ml)中的溶液添加3,5-双(三氟甲基)苯基异硫氰酸酯(1.1mmol)。将反应混合物搅拌过夜后，将反应混合物真空浓缩。将残余物通过硅胶上的快速柱色谱(洗脱剂为己烷/乙酸乙酯＝9/1)纯化，得到黄色固体形式的L15。
L15:1HNMR(400MHz,CDCl3)δ7.65(s,2H),7.54(s,1H),7.49–7.40(m,3H),7.35–7.07(m,18H),6.44(s,1H),4.53(d,J＝6.0Hz,2H),4.21(d,J＝15.6Hz,3H),3.71(s,2H),2.50(s,3H),1.50(d,J＝6.7Hz,3H)。
13CNMR(100MHz,CDCl3)δ180.28(s),141.45(s),138.82(d,J＝9.8Hz),138.30(d,J＝9.8Hz),135.78(d,J＝7.7Hz),134.88(d,J＝21.3Hz),133.42(dd,J＝33.4,19.7Hz),132.53(d,J＝19.5Hz),131.28(q,J＝33.4Hz),129.43(s),129.01–128.44(m),128.28(d,J＝6.8Hz),128.16(s),124.61(s),123.89(s),121.90(s),117.57(s),93.41(d,J＝26.4Hz),75.47(d,J＝18.1Hz),74.42(s),73.56(d,J＝5.1Hz),73.40(d,J＝4.6Hz),72.18(s),71.75(s),54.83(d,J＝7.7Hz),31.93(s),15.64(s)。
31PNMR(162MHz,CDCl3)δ-18.09(s),-26.79(s)。
HRMS(ESI):[M+H+]计算为883.1485，发现为883.1583。
根据文献(Zhao,Q.,etal.,Org.Lett.2013,15,4014-4017)制备SI4。在氮气气氛下，向SI4(1.0mmol)在干燥的DCM(1.0ml)中的溶液添加3,5-双(三氟甲基)苯基异硫氰酸酯(1.1mmol)。将反应混合物搅拌过夜后，将反应混合物真空浓缩。将残余物通过硅胶上的快速柱色谱(洗脱剂为己烷/乙酸乙酯＝9/1)纯化，得到黄色固体形式的L16。
L16:1HNMR(400MHz,CDCl3)δ8.07(s,1H),7.75(d,J＝10.5Hz,3H),6.29(s,1H),5.30(s,1H),4.26–4.15(m,3H),4.08(s,2H),4.03(s,4H),1.60(d,J＝6.5Hz,3H)。
13CNMR(100MHz,CDCl3)δ179.16(s),138.72(s),133.43(d,J＝33.7Hz),124.42(s),124.07(s),121.36(s),119.84(s),90.06(s),68.59(d,J＝3.6Hz),68.27(s),67.41(s),65.57(s),50.14(s),19.99(s)。
HRMS(ESI):[M+]计算为500.0444，发现为500.0452。
根据文献(Zhao,Q.,etal.,Org.Lett.2013,15,4014-4017和Hayashi,T.,etal.,Bull.Chem.Soc.Jpn.1980,53,1138-1151)制备SI5。在氮气气氛下，向SI5(1.0mmol)在干燥的DCM(1.0ml)中的溶液添加3,5-双(三氟甲基)苯基异硫氰酸酯(1.1mmol)。将反应混合物搅拌过夜后，将反应混合物真空浓缩。将残余物通过硅胶上的快速柱色谱(洗脱剂为己烷/乙酸乙酯＝9/1)纯化，得到黄色固体形式的L17。
L17:1HNMR(400MHz,CDCl3)δ7.74(s,3H),7.51(s,2H),7.40–7.28(m,5H),7.22(s,3H),7.15–7.05(m,2H),5.59(s,1H),4.51(s,1H),4.32(s,1H),3.96(s,5H),3.79(s,1H),1.46(d,J＝4.7Hz,3H)。
13CNMR(100MHz,CDCl3)δ177.42(s),138.02(s),137.86(d,J＝6.0Hz),134.85(d,J＝4.5Hz),133.73(d,J＝20.8Hz),131.89(d,J＝33.9Hz),131.25(d,J＝17.8Hz),128.51(s),127.43–127.02(m),126.10–125.89(m),123.82(s),123.27(s),120.56(s),118.42(s),118.01–117.76(m),93.98(d,J＝24.2Hz),72.16(s),71.07(d,J＝4.0Hz),70.22(s),68.83(s),68.66(s),50.33(s),21.26(s)。
31PNMR(162MHz,CDCl3)δ-24.67(s)。
HRMS(ESI):[M+H+]计算为685.0964，发现为685.0950。
实施例2-硝基烯烃的不对称氢化
在填充有氮的手套箱中，将L(2.2当量)和[Rh(COD)Cl]2(3.0mg，0.006mmol)在3.0mL的无水异丙醇(i-PrOH)中的溶液在室温下搅拌30分钟。将规定量的所得溶液(0.25mL)通过注射器转移至装有1a(0.1mmol)的小瓶中。将小瓶转移至高压釜，然后在其中充入5atm的H2，并在35℃下搅拌24小时。缓慢释放氢气，并将溶液浓缩并使其通过硅胶短柱以除去金属络合物。用NMR光谱分析产物(2a)的转化率并用手性HPLC分析其ee值。
(R)-2a:1HNMR(400MHz,CDCl3)δδ7.38–7.31(m,2H),7.30–7.20(m,3H),4.58–4.46(m,1H),3.85–3.16(m,1H),1.38(d,J＝7.0Hz,1H)。
13CNMR(100MHz,CDCl3)δ140.93(s),128.98(s),127.57(s),126.90(s),81.87(s),38.65(s),18.73(s)。
HPLC:OD,215nm,正己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝19.4min,tR(次要)＝27.4min。
[α]D 25＝+41.4°(c＝0.67,CHCl3)。
表1对压力、浓度和温度的影响的研究a
[a]除非另外说明，以1a(0.1mmol)和1a/Rh/L比率为1/1.1/1.1进行反应。[b]通过粗反应混合物的1HNMR光谱和HPLC分析而测定转化率。[c]通过手性固定相上的HPLC分析而测定。
使用不同的硝基烯烃和如上所述的一般步骤制备β,β-二取代的硝基烷烃。可以容忍在苯环具有各种取代基的硝基烯烃。间位和对位取代导致优异的结果，而无论其是否为吸电子基团或给电子基团。邻甲氧基导致更低的转化率和对映异构选择性。该催化体系还提供具有良好的转化率和优异的对映异构选择性的对映异构的β-乙基硝基烷烃。如下表征硝基烷烃：
(R)-2b:1HNMR(400MHz,CDCl3)δ7.39–6.86(m,5H),4.47–4.36(m,2H),3.47–3.49(m,1H),2.25(s,3H),1.28(d,J＝7.0Hz,3H)。
13CNMR(100MHz,CDCl3)δ137.87(s),137.21(s),129.61(s),126.73(s),81.98(s),38.27(s),20.98(s),18.75(s)。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝14.1min,tR(次要)＝23.0min。
[α]D 25＝+42.9°(c＝0.51,CHCl3)
(R)-2c:1HNMR(400MHz,CDCl3)δ7.19–7.11(m,2H),6.96–6.84(m,2H),4.52–4.42(m,2H),3.79(s,3H),3.66–3.54(m,1H),1.35(d,J＝7.0Hz,3H)。
13CNMR(100MHz,CDCl3)δ158.94(s),132.86(s),127.89(s),114.34(s),82.12(s),55.26(s),37.92(s),18.79(s)。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝22.1min,tR(次要)＝40.6min。
[α]D 25＝+35.8°(c＝0.51,CHCl3)
(R)-2d:1HNMR(400MHz,CDCl3)δ7.37–7.27(m,2H),7.21–7.12(m,2H),4.63–4.42(m,2H),3.75–3.48(m,1H),1.37(d,J＝7.0Hz,3H)。
13CNMR(100MHz,CDCl3)δ139.35(s),133.43(s),129.15(s),128.27(s),81.56(s),38.07(s),18.71(s)。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝18.8min,tR(次要)＝27.1min。
[α]D 25＝+39.5°(c＝0.48,CHCl3)
(R)-2e:1HNMR(400MHz,CDCl3)δ7.18–7.13(m,4H),4.56–4.43(m,2H),3.70–3.48(m,1H),2.63(q,J＝7.6Hz,2H),1.36(d,J＝7.0Hz,3H),1.22(t,J＝7.6Hz,3H)。
13CNMR(100MHz,CDCl3)δ143.58(s),138.10(s),128.43(s),126.83(s),82.01(s),38.30(s),28.42(s),18.75(s),15.42(s)。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝11.8min,tR(次要)＝19.9min。
[α]D 25＝+54.3°(c＝0.44,CHCl3)。
(R)-2f:1HNMR(400MHz,CDCl3)δ7.37–7.32(m,2H),7.18–7.12(m,2H),4.56–4.43(m,2H),3.69–3.51(m,1H),1.37(d,J＝7.0Hz,3H),1.30(s,3H)。
13CNMR(100MHz,CDCl3)δ150.47(s),137.79(s),126.55(s),125.84(s),81.97(s),38.13(s),34.47(s),31.29(s),18.67(s)。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝9.7min,tR(次要)＝18.4min。
[α]D 25＝+41.8°(c＝1.0,CHCl3)
(R)-2g:1HNMR(400MHz,CDCl3)δ7.30–7.22(m,1H),7.16(dd,J＝7.6,1.6Hz,1H),6.96–6.88(m,2H),4.68(dd,J＝11.9,6.0Hz,1H),4.46(dd,J＝11.9,8.8Hz,1H),3.97–3.90(m,1H),3.88(s,3H),1.38(d,J＝7.0Hz,3H)。
13CNMR(100MHz,CDCl3)δ157.06(s),128.82(s),128.51(s),127.71(s),120.86(s),110.83(s),80.45(s),55.34(s),33.48(s),17.05(s)。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝14.4min,tR(次要)＝17.0min。
[α]D 25＝+6.9(c＝0.2,CHCl3).
(R)-2h:1HNMR(400MHz,CDCl3)δ7.35–7.27(m,1H),7.05–6.87(m,3H),4.57–4.45(m,2H),3.69–3.62(m,1H),1.38(d,J＝7.0Hz,3H)。
13CNMR(100MHz,CDCl3)δ164.33(s),161.88(s),143.46(d,J＝7.0Hz),130.57(d,J＝8.3Hz),122.65(d,J＝2.9Hz),114.59(d,J＝21.0Hz),113.96(d,J＝21.8Hz),81.51(s),38.37(d,J＝1.6Hz),18.67(s)。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝20.0min,tR(次要)＝28.4min。
[α]D 25＝+33.3°(c＝0.72,CHCl3).
(R)-2i:1HNMR(400MHz,CDCl3)δ7.31–7.21(m,3H),7.12–7.10(m,1H),4.56–4.45(m,2H),3.70–3.55(m,1H),1.37(d,J＝7.0Hz,3H)。
13CNMR(100MHz,CDCl3)δ142.94(s),134.83(s),130.26(s),127.84(s),127.17(s),125.18(s),81.41(s),38.33(s),18.65(s)。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝19.8min,tR(次要)＝30.5min。
[α]D 25＝+37.1°(c＝0.58,CHCl3)
(R)-2j:1HNMR(400MHz,CDCl3)δ7.26(t,J＝7.9Hz,1H),6.96–6.68(m,3H),4.57–4.44(m,2H),3.80(s,3H),3.66–3.54(m,1H),1.37(d,J＝7.0Hz,3H)。
13CNMR(100MHz,CDCl3)δ160.00(s),142.54(s),130.01(s),119.11(s),113.10(s),112.55(s),81.79(s),77.34(s),77.03(s),76.71(s),55.23(s),38.66(s),18.70(s)。
HPLC:OD,215nm,己烷/2-丙醇＝95:5,流速0.9mL/min,tR(主要)＝29.3min,tR(次要)＝52.2min。
[α]D 25＝+40.6°(c＝0.73,CHCl3)
(R)-2k:1HNMR(400MHz,CDCl3)δ8.08–7.70(m,3H),7.67(d,J＝1.0Hz,1H),7.56–7.40(m,2H),7.35(dd,J＝8.5,1.8Hz,1H),4.67–4.54(m,2H),4.02–3.55(m,1H),1.47(d,J＝7.0Hz,2H)。
13CNMR(100MHz,CDCl3)δ138.29,133.52,132.78,128.85,127.76,127.69,126.44,126.08,125.78,124.81,81.80,38.80,18.79。
HPLC:OD,215nm,己烷/2-丙醇＝80:20,流速0.9mL/min,tR(主要)＝19.8min,tR(次要)＝53.5min。
[α]D 25＝+36.8°(c＝0.9,CHCl3)
(R)-2l:1HNMR(400MHz,CDCl3)δ7.39–7.23(m,3H),7.21–7.10(m,2H),4.59–4.51(m,2H),3.54–3.11(m,1H),1.79–1.66(m,2H),0.84(t,J＝7.4Hz,3H)。
13CNMR(100MHz,CDCl3)δ139.33,128.89,127.56,80.76,46.00,26.18,11.49。
HPLC:OD,215nm,己烷/2-丙醇＝98:2,流速0.9mL/min,tR(主要)＝16.0min,tR(次要)＝27.7min。
[α]D 25＝+35.5°(c＝0.54,CHCl3)
(S)-2m:1HNMR(400MHz,CDCl3)δ6.26–6.23(m,1H),6.05(d,J＝3.1Hz,1H),4.59(dd,J＝12.2,6.6Hz,1H),4.36(dd,J＝12.2,8.0Hz,1H),3.72–3.60(m,1H),1.31(d,J＝7.0Hz,3H)。
13CNMR(100MHz,CDCl3)δ152.85(s),141.08(s),109.27(s),104.92(s),78.49(s),31.41(s),15.12(s)。
HPLC:OD,215nm,己烷/2-丙醇＝99.5:0.5,流速0.9mL/min,tR(主要)＝27.5min,tR(次要)＝30.7min。
实施例3：N-H亚胺的不对称氢化
根据文献(Hou,G.,etal.,J.Am.Chem.Soc.2009,131,9882-9883.)制备所有的N-H亚胺。所有的光谱数据与文献值一致。
1HNMR(400MHz,CDCl3)δ11.46(s,2H),8.20–7.91(m,2H),7.78(t,J＝7.5Hz,1H),7.61(dd,J＝17.7,9.6Hz,2H),2.94(d,J＝5.2Hz,3H)。
13CNMR(100MHz,CDCl3)δ186.36(s),136.95(s),129.92(s),129.35(s),129.33(s),21.73(s)。
通用操作：
在填充有氮气的手套箱中，将L14(2.2当量)和[Rh(COD)Cl]2(3.0mg,0.006mmol)在6.0mL无水异丙醇中的溶液在室温下搅拌30min。
将规定量的所得溶液(1mL)通过注射器转移至装有1a(0.1mmol)的小瓶中。将小瓶转移至高压釜，然后在其中充入10atm的H2，并在25℃下搅拌24小时。将所得混合物真空浓缩并溶于饱和的NaHCO3水溶液(5mL)中。搅拌10min后，用CH2Cl2(3×2mL)萃取混合物并用Na2SO4干燥。向所得溶液添加Ac2O(300μL)并搅拌30min。然后直接用GC分析所得溶液的转化率和ee值。产物在硅胶柱上用二氯甲烷/甲醇(90:10)通过色谱法纯化。所有光谱数据与文献值(Hou,G.,etal.,J.Am.Chem.Soc.2009,131,9882-9883)一致。
表2.对金属盐的研究
[a]除非另外说明，以1a(0.1mmol)和金属/L14比率为1/1.1进行反应。[b]通过GC分析相应的乙酰胺而测定。ND＝未测得。
表3对压力和温度的研究
[a]除非另外说明，以1a(0.1mmol)和[Rh(COD)Cl]2/L14比率为1/1.1进行反应。[b]通过GC分析相应的乙酰胺而测定。
表4.对添加剂的研究
[a]除非另外说明，以1a(0.1mmol)和[Rh(COD)Cl]2/L14比率为1/2.2进行反应。[b]通过GC分析相应的乙酰胺而测定。
表5.对溶剂的研究
测试了多种N-H亚胺。大多数在苯环上具有间位和对位取代基的底物给出高的产率和对映异构选择性(96-99％的产率和90-94％的ee值)。
然而，氯基团和甲氧基导致产率的明显下降(2d、2e和2g)。在苯环上的邻位甲氧基导致34％的产率和84％的ee值(2h)。分别以92％的ee值和93％ee值获得具有1-和2-萘基的产物。R2基团的改变对结果有显著效果。当R2为乙基时，观察到更低的转化率和对映异构选择性两者(2k)。随着R2基团变为丁基，观察到转化率和对映异构选择性的进一步损失(70％的产率和75％的ee值，2l)。
为深入研究该催化体系，制备了一系列的手性配体并进行了对照实验。
表6.配体研究
无(硫)脲的Rh-双膦络合物(L9)显示出非常低的活性和对映异构选择性(表6，条目1)。脲L10提供22％的转化率和66％的ee值，这与酸性更强的硫脲L14形成鲜明对比(表6，条目2对比条目6)1a。3,5-(三氟甲基)苯基部分上的CF3基团在催化体系中仍然重要(表6，条目3-5)。此外，制备和筛选了几种改性的配体。L14的N-甲基化导致转化率和对映异构选择性的显著降低(表6，条目7)。这一发现表明，NH参与亚铵盐的活化和氢化的立体选择性。此外，用单齿磷配体得到的低的转化率和对映异构选择性意味着双膦部分是必要的(表6，条目9)。重要的是，既不是手性膦与3,5-双三氟甲基苯基硫脲的组合也不是手性硫脲与简单的膦的组合改善了此反应(表6，条目1对比条目11，条目8对比条目10)，其指出了共价连接基对于高的活性和对映异构选择性的重要性。
还研究了不同的抗衡离子和添加剂。当用三氟甲磺酸盐代替la中的氯抗衡离子时，仅观察到20％的转化率和53％的ee值(表7，条目1)。添加氯抗衡离子提高转化率和对映异构选择性(条目2和3)。然而，添加溴和碘抗衡离子降低转化率和对映异构选择性(条目4-6)。
表3.底物研究和对照实验a
1a：Y＝Cl，1m：Y＝CF3SO3
通过1HNMR研究由配体和TBAC产生的混合物获得反应的进一步信息。向CDCl3中的L14添加不同量的TBAC导致NH质子信号移向低场。在1.0当量TBAC时，NH的信号出现在9.73ppm，但是当添加3.0当量的TBAC时，NH信号出现在10.16ppm。采用一系列不同的配体和TBAC的类似实验给出相似的结果。该发现与催化剂的硫脲和氯离子之间的氢键相互作用一致。此观察(加上最佳的产率和ee值均涉及氯离子的事实)使我们提出，催化的氯结合的中间体参与了该机制。
已经具体参考优选的实施方式描述了本发明。应当理解，前述说明和实施例仅说明本发明。本领域的技术人员可以设计各种替代和修改形式而不脱离本发明的精神和范围。因此，本发明旨在包括所有这样的落入所附权利要求范围内的替换、修改和变化。

Claims (16)

1.一种具有以下结构的配体或其对映异构体：
其中：
Ra、Rb、Rc和Rd中的每一个选自烷基、环烷基和芳基；
所述桥接基团选自CH2NH、*CH(CH3)NH(C*,R)和*CH(CH3)NH(C*,S)；并且
所述有机催化剂是共价结合至所述桥接基团的有机分子催化剂。
2.如权利要求1所述的配体，其中Ra、Rb、Rc和Rd中的至少一个是选自苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基的芳基部分。
3.如权利要求1所述的配体，其中Ra、Rb、Rc和Rd中的至少一个是选自叔丁基和异丙基的烷基部分。
4.如权利要求1所述的配体，其中Ra、Rb、Rc和Rd中的至少一个是选自环己基和环戊基的环烷基部分。
5.如权利要求1所述的配体，其中所述配体选自由下式表示的化合物：
6.如权利要求1所述的配体，其中所述配体选自由下式表示的化合物：
7.如权利要求1所述的配体，其中所述配体选自由下式表示的化合物：
8.一种具有以下结构的催化剂或其对映异构体：
其中：
Ra、Rb、Rc和Rd中的每一个选自烷基、环烷基和芳基；
所述桥接基团选自CH2NH、*CH(CH3)NH(C*,R)和*CH(CH3)NH(C*,S)；
所述有机催化剂是共价结合至所述桥接基团的有机分子催化剂；并且
M选自Rh、Pd、Cu、Ru、Ir、Ag、Au、Zn、Ni、Co和Fe。
9.如权利要求8所述的催化剂，其中Ra、Rb、Rc和Rd中的至少一个是选自苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基的芳基部分。
10.如权利要求8所述的催化剂，其中Ra、Rb、Rc和Rd中的至少一个是选自叔丁基和异丙基的烷基部分。
11.如权利要求8所述的催化剂，其中Ra、Rb、Rc和Rd中的至少一个是选自环己基和环戊基的环烷基部分。
12.一种用于将烯烃不对称地氢化为相应的烷烃的方法，包括使烯烃在适当的溶剂中与过量的氢气和催化有效量的权利要求8的催化剂在使所述烯烃有效氢化的温度和压力下组合。
13.如权利要求12所述的方法，其中所述溶剂包含异丙醇。
14.如权利要求12所述的方法，其中所述催化剂中的Ra、Rb、Rc和Rd中的至少一个是选自苯基、P-CH3苯基、3,5-二-CH3苯基、3,5-二-叔丁基苯基、3,5-二-CF3苯基、2-CH3苯基、C6F5、2-萘基和1-萘基的芳基部分。
15.如权利要求12所述的方法，其中所述催化剂中的Ra、Rb、Rc和Rd中的至少一个是选自叔丁基和异丙基的烷基部分。
16.如权利要求12所述的方法，其中所述催化剂中的Ra、Rb、Rc和Rd中的至少一个是选自环己基和环戊基的环烷基部分。
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