CN110128471B - 氧杂螺环双膦配体的合成与应用 - Google Patents

氧杂螺环双膦配体的合成与应用 Download PDF

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CN110128471B
CN110128471B CN201810129226.XA CN201810129226A CN110128471B CN 110128471 B CN110128471 B CN 110128471B CN 201810129226 A CN201810129226 A CN 201810129226A CN 110128471 B CN110128471 B CN 110128471B
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张绪穆
陈根强
黄佳明
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Shenzhen Green Kate Pharmaceutical Technology Co ltd
Shenzhen Catalys Technology Co Ltd
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Abstract

本发明专利属于手性合成技术领域，具体提供了一类新型氧杂螺环双膦配体的合成与应用。该双膦配体从氧杂螺环二酚出发经过三氟甲磺酰化、钯催化二芳基氧膦偶联、三氯硅氢还原、再次钯催化二芳基氧膦偶联和再次的三氯硅氢还原制备得到。该氧杂螺环化合物具有中心手性，因此有左旋氧杂螺环双膦配体和右旋氧杂螺环双膦配体，消旋的螺环双膦配体可以通过消旋的氧杂螺环二酚为原料合成得到。本发明可以作为手性配体用于不饱和羧酸的不对称氢化中。其与钌的络合物在甲基‑肉桂酸的不对称氢化中可以得到大于99％的对映选择性。

Description

氧杂螺环双膦配体的合成与应用
技术领域
本发明涉及一种新型氧杂螺环双膦配体的合成。该化合物可以作为手性配体应用于不对称催化反应中，在不对称催化领域具有很高的潜在应用价值，属于不对称催化领域。
背景技术
在过去的几十年间，不对称催化得到了飞速的发展，各种各样的手性配体被合成出来，并应用到不对称催化领域当中。在众多的手性配体当中双膦配体是到目前为止研究的最多应用的最广的配体之一。它在不对称氢化、不对称氢甲酰化反应、不对称Pauson-Khand反应、不对称Heck反应、不对称环加成反应、不对称环异构化反应等反应中表现出优异的活性和对映选择性。
Kagan小组合成的DIOP、Noyori小组发展的BINAP以及Knowles小组发展的DIPAMP配体在双膦配体的发展历史中具有里程碑意义。它们在学术界和工业界得到了非常广泛的应用。随后各种各样的手性双膦配体被合成出来，例如SegePhos、DifluoPhos、SynPhos、Cn-TunePhos、TangPhos、DuanPhos、ZhangPhos、SKP、SDP、SFDP等。
尽管现在手性双膦配体不管在种类上还是在数目上都已经非常丰富，但是每一种配体都有它独特的性质，因此，开发新型的手性双膦配体具有非常重要的意义。
发明内容
鉴于现有技术需要改善的问题，本发明提供了一种氧杂螺环双磷配体，具有以下通式(I)的结构：
Figure GDA0002753023740000021
通式(I)中：
R1、R2独立为烷基、烷氧基、芳基、芳氧基或者氢原子，R1、R2、R3和R4可成环或不成环；R5、R6独立为烷基、芳基或者氢原子；R7、R8为烷基、苄基或者芳基。
上述术语烷基优选为甲基、乙基、丙基、丁基等；
烷氧基优选为甲氧基、乙氧基、丙氧基、丁氧基等；
芳基优选为被烷基或者烷氧基取代或者未取代的苯基等，烷基和烷氧基如上定义。
芳氧基优选为甲氧苯基、乙氧苯基等。
进一步的优选方案为R1、R2、R3、R4、R5和R6同时为氢。
所述氧杂螺环双磷配体是(±)-氧杂螺环双膦配体，(+)-氧杂螺环双膦配体，或(-)-氧杂螺环双膦配体。
进一步的优选方案为所述氧杂螺环双磷配体是下式化合物：
Figure GDA0002753023740000022
其中优选Ar为烷基、苄基或者芳基；最优选Ar为苯基、烷基或者烷氧基取代的苯基。
其中，烷基和烷氧基如上定义。
本发明另一目的在于提供一种合成前述化合物的方法，通过以下的路线合成得到：
Figure GDA0002753023740000031
本发明另一目的在于提供所述化合物在催化不对称反应中的应用，所述不对称反应包括：氢化反应，氢甲酰化反应，硅氢化反应，硼氢化反应，氢羟基化反应，氢氨化反应，氢氰基化反应，异构化甲酰基化反应，氢氨甲基化反应，转移氢化反应，烯丙基化反应，烯烃复分解反应，环异构化反应，Diels-Alder反应，不对称偶联反应，Aldol反应，Michael加成反应，不对称环氧化反应，动力学拆分和[m+n]环化反应。
该化合物制成的双膦醋酸钌络合物在有机溶剂中对不饱和羧酸的氢化具有很高的活性和对映选择性，大于99％。
所述双膦醋酸钌络合物是下式化合物：
Figure GDA0002753023740000032
其中，R＝烷基，氟代烷基或芳基；优选烷基和芳基如上定义。
具体的，优选的一种催化不对称反应，包括：使用前述的化合物作为催化剂，反应路线如下：
Figure GDA0002753023740000041
其中，R＝烷基，氟代烷基或芳基；优选烷基和芳基如上定义。
本发明另一目的提供了一种双膦醋酸钌络合物，在有机溶剂中对不饱和羧酸的氢化具有很高的活性和对映选择性，所述双膦醋酸钌络合物是下式化合物：
Figure GDA0002753023740000042
其中，R＝烷基，氟代烷基或芳基；优选烷基和芳基如上定义。
本发明相对于现有技术的有益效果包括：
(1)该氧杂螺环化合物具有中心手性，因此有左旋氧杂螺环双膦配体和右旋氧杂螺环双膦配体，消旋的螺环双膦配体可以通过消旋的氧杂螺环二酚为原料合成得到。
(2)本发明可以作为手性配体用于不饱和羧酸的不对称氢化中。其与钌的络合物在甲基-肉桂酸的不对称氢化中可以得到大于99％的对映选择性。
附图说明
图1，本发明多种不同手性化合物的制备示意图，以及对应的转化率和对映选择性ee值。
具体实施方式
下面通过实施例和附图对本发明加以说明，但本发明并不仅限于以下实施例。
实施例1：
(R)-2-氢,2'-氢-3,3'-螺二[苯并呋喃]-4,4'-二三氟甲磺酸酯2的合成：
Figure GDA0002753023740000051
N2氛围下，向一个250mL反应瓶中加入(S)-6(7.68g,30mmol)，然后加入150mL干燥的二氯甲烷。室温下搅拌体下加入吡啶(6.0mL,100mmol)。待反应体系澄清后，冷却至零度，然后逐滴加入Tf2O(12.0mL,70mmol)，滴加完毕后升至室温继续搅拌1h。加水淬灭反应。反应体系用稀盐酸洗涤，有机相在减压条件下出去溶剂，经过柱层析就可以得到产物(S)-7(15.6g,产率:99％)
白色固体.1H NMR(500MHz,CDCl3)δ4.70(d,J＝10.0Hz,2H,CH2),4.87-4.90(m,2H,CH2),6.91-6.93(m,4H,Ar),7.32(dd,J1＝8.5Hz,J2＝8.0Hz,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ162.3,145.8,131.9,119.8,118.1(q,J＝320.0Hz,CF3),113.1,110.4,82.5,54.9.19C{1H}NMR(126MHz,CDCl3)δ-74.23.HRMS(ESI)calcd.for C171H1F6O8S2[M+H]+:520.9800,Found:520.9794,[α]20 D＝+19.2(c＝0.5,丙酮).
实施例2：
(R)-4'-(二苯基膦氧基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯3a的合成：
Figure GDA0002753023740000052
N2氛围下，反应瓶中加入2(5.2g,10mmol)、dppb(213mg,0.05mmol)、Ph2POH(3.87g,15mmol)、Pd(PAc)2(112mg,0.05mmol)和DIPEA(6.5mL,40mmol)，最后加入50mL无水无氧的DMSO。100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物3a(5.15g,产率＝90％)。
白色固体.1H NMR(400MHz,CDCl3)δ4.64-4.68(m,2H,CH2),4.77(d,J＝9.6Hz,1H,CH2),5.15-5.18(m,1H,CH2),6.40(d,J＝8.0Hz,1H,Ar),6.58-6.60(m,1H,Ar),6.78-6.80(m,1H,Ar),6.88-6.90(m,1H,Ar),6.94-6.98(m,2H,Ar),7.05-7.13(m,3H,Ar),7.16-7.20(m,2H,Ar),7.24-7.28(m,4H,Ar).13C{1H}NMR(101MHz,CDCl3)δ162.6,160.3,145.4,136.6,134.5,133.4(m),132.3,132.0,131.2,130.0,128.4(m),122.6(m),120.7,112.3,110.9,109.4,84.5,82.9,56.3,26.9.31P{1H}NMR(202MHz,CDCl3)δ21.95(s).HRMS(ESI)calcd.forC18H21O6F3PS[M+H]+:573.0749,Found:573.0743,[α]20 D＝+237.2(c＝0.5,丙酮).
实施例3：
(R)-4'-(二苯基膦基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯4a的合成：
Figure GDA0002753023740000061
100mL封管中，加入3a(2.86g,5mmol)、DIPEA(6.6mL,40mmol)、20mL和三氯硅氢(2.0mL,20mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体4a(2.5g,产率＝90％)。
白色固体.1H NMR(400MHz,CDCl3)δ4.58-4.62(m,2H,CH2),4.69-4.72(m,1H,CH2),5.08-5.12(m,1H,CH2),6.32-6.34(m,1H,Ar),6.51-6.52(m,1H,Ar),6.72-6.74(m,1H,Ar),6.81-6.85(m,1H,Ar),6.88-6.91(m,2H,Ar),6.99-7.05(m,3H,Ar),7.10-7.13(m,2H,Ar),7.14-7.22(m,4H,Ar).13C{1H}NMR(126MHz,CDCl3)δ162.6,160.3,145.4,136.6,134.5(m),133.5(m),132.0,131.3,130.1,128.8(m),127.8,122.6,112.3,110.9,109.5,84.5,83.0,56.3.31P{1H}NMR(202MHz,CDCl3)δ-22.32(s).HRMS(ESI)calcd.for C18H21O5F3PS[M+H]+:557.0799,Found:557.0794,[α]20 D＝+56.0(c＝0.5,丙酮).
实施例4：
(R)-(4'-(二苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]-4-二苯基膦氧5a的合成：
Figure GDA0002753023740000071
N2氛围下，反应瓶中加入4a(2.78g,5mmol)、dppb(107mg,0.025mmol)、Ph2POH(1.94g,7.5mmol)、Pd(PAc)2(56mg,0.0025mmol)和DIPEA(3.2mL,20mmol)，最后加入20mL无水无氧的DMSO。100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物5a(2.66g,产率＝87％)。
白色固体.1H NMR(500MHz,CDCl3)δ4.38(d,J＝9.5Hz,1H,CH2),4.43(d,J＝9.0Hz,1H,CH2),4.46(d,J＝9.5Hz,1H,CH2),5.19(d,J＝9.0Hz,1H,CH2),6.56-6.59(m,1H,Ar),6.74-6.84(m,4H,Ar),7.01-7.03(m,1H,Ar),7.07-7.12(m,3H,Ar),7.17-7.30(m,6H,Ar),7.32-7.36(m,5H,Ar),7.38-7.43(m,3H,Ar),7.48-7.55(m,3H,Ar).13C{1H}NMR(126MHz,CDCl3)δ162.9,160.4,138.1,137.9,137.4,134.9,134.4(m),134.1(m),133.3(m),132.5,132.1,131.7(m),129.8,128.9(m),128.4(m),128.1(m),126.7(m),113.4,110.2,85.2,84.0,58.2(m).31P{1H}NMR(162MHz,CDCl3)δ29.41(s),-20.96(s).HRMS(ESI)calcd.forC39H31O3P2[M+H]+:609.1748,Found:609.1743,[α]20 D＝+224.0(c＝0.5,丙酮).
实施例5：
(R)-4,4'-二(二苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]6a的合成：
Figure GDA0002753023740000072
100mL封管中，加入3a(1.216g,2mmol)、DIPEA(3.3mL,20mmol)、10mL甲苯和三氯硅氢(1.0mL,10mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体6a(1.15g,产率＝96％)。
白色固体.1H NMR(500MHz,CDCl3)4.38(d,J＝9.5Hz,2H,CH2),4.49(d,J＝9.5Hz,2H,CH2),6.67-6.68(m,2H,Ar),6.85-6.86(m,2H,Ar),6.92(s,4H,Ar),7.01-7.03(m,1H,Ar),7.11-7.23(m,12H,Ar),7.29-7.30(m,6H,Ar).13C{1H}NMR(126MHz,CDCl3)δ160.8(t,J＝7.5Hz),137.1,136.8,135.0,134.1,133.4,129.5,128.7128.4,128.0,127.3,110.4,83.6,58.0(m).31P{1H}NMR(162MHz,CDCl3)δ-20.99(s).HRMS(ESI)calcd.for C39H31O2P2[M+H]+:593.1799,Found:593.1782,[α]20 D＝+246(c＝0.5,丙酮).
实施例6：
(R)-4'-(二对甲基苯基膦氧基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯3b的合成：
Figure GDA0002753023740000081
N2氛围下，反应瓶中加入2(2.6g,5mmol)、dppb(107mg,0.025mmol)、Ar2POH(1.73g,7.5mmol)、Pd(PAc)2(56mg,0.025mmol)和DIPEA(3.2mL,20mmol)，最后加入30mL无水无氧的DMSO。100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物3b(2.60g,产率＝87％)。
白色固体.1H NMR(500MHz,CDCl3)δ2.36(s,3H,CH3),2.38(s,3H,CH3),4.60-4.62(m,1H,CH2),4.70-4.74(m,2H,CH2),5.69(d,J＝8.5Hz,1H,CH2),6.17(d,J＝8.0Hz,1H,Ar),6.66-6.70(m,1H,Ar),6.80-6.81(m,1H,Ar),7.03-7.07(m,2H,Ar),7.10-7.16(m,4H,Ar),7.18-7.21(m,3H,Ar),7.36-7.40(m,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ163.8,161.9,144.7,142.0(m),131.9(m),131.5(m),131.2(m),130.7(m),130.2,130.0,129.3,129.0(m),128.1,126.9,123.5,121.8,119.8,116.6,113.8,111.7,109.3,85.6,83.6,56.5,21.5.31P{1H}NMR(202MHz,CDCl3)δ29.86(s).HRMS(ESI)calcd.for C30H25O6F3PS[M+H]+:601.1062,Found:601.1056,[α]20 D＝+108.4(c＝0.5,丙酮).
实施例7：
(R)-4'-(二对甲基苯基膦基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯4b的合成：
Figure GDA0002753023740000091
100mL封管中，加入3b(3.00g,5mmol)、DIPEA(3.2mL,20mmol)、20mL甲苯和三氯硅氢(2.0mL,20mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体4b(2.70g,产率＝92％)。
白色固体.1H NMR(400MHz,CDCl3)δ4.58-4.62(m,2H,CH2),4.69-4.72(m,1H,CH2),5.08-5.12(m,1H,CH2),6.43(d,J＝9.0Hz,1H,Ar),6.51-6.52(m,1H,Ar),6.72-6.74(m,1H,Ar),6.81-6.85(m,1H,Ar),6.88-6.91(m,2H,Ar),6.99-7.05(m,3H,Ar),7.10-7.13(m,2H,Ar),7.14-7.22(m,4H,Ar).13C{1H}NMR(101MHz,CDCl3)δ162.7,160.2,153.6,145.5,138.6,133.7,133.5,131.1,129.9,129.3,129.0,127.6,122.6,112.3,110.7,109.4,84.3,82.9,56.3,26.9,21.2.31P{1H}NMR(202MHz,CDCl3)δ-22.32(s).HRMS(ESI)calcd.forC30H25O5F3PS[M+H]+:585.1112,Found:585.1107,[α]20 D＝+111.4(c＝0.5,丙酮).
实施例8：
(R)-(4'-(二对甲基苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]-4-二苯基膦氧5b的合成：
Figure GDA0002753023740000101
N2氛围下，反应瓶中加入4b(0.584g,2mmol)、dppb(43mg,0.1mmol)、Ph2POH(0.69g,3mmol)、Pd(PAc)2(22.4mg,0.1mmol)和DIPEA(0.50mL,4mmol)，最后加入20mL无水无氧的DMSO。100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物5b(1.12g,产率＝85％)。
白色固体.1H NMR(500MHz,CDCl3)δ2.27(s,3H,CH3),2.31(s,6H,CH3),2.35(s,3H,CH3)4.36(d,J＝9.0Hz,1H,CH2),4.44(t,J＝9.5Hz,2H,CH2),5.25(d,J＝9.0Hz,1H,CH2),6.56-6.58(m,1H,Ar),6.67-6.70(m,2H,Ar),6.74-6.78(m,1H,Ar),6.79-6.80(m,1H,Ar),6.89-6.91(m,2H,Ar),6.97-7.00(m,3H,Ar),7.04-7.12(m,5H,Ar),7.18-7.26(m,5H,Ar),7.37-7.42(m,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ171.0,162.8,160.2,141.7,141.5,138.5,137.8,137.6,137.3,134.0(m),133.2,132.1,131.7,131.2,130.0,129.2(m),128.7(m),126.4,113.0,109.9,85.0,84.0,60.3,58.1(m),21.5,21.2.31P{1H}NMR(202MHz,CDCl3)δ29.37(s),-22.71(s).HRMS(ESI)calcd.for C43H39O3P2[M+H]+:665.2374,Found:665.2369,[α]20 D＝+211.2(c＝0.5,丙酮).
实施例9：
(R)-4,4'-二(二对甲基苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]6b的合成：
Figure GDA0002753023740000102
100mL封管中，加入5b(0.664g,1mmol)、DIPEA(3.3mL,20mmol)、10mL甲苯和三氯硅氢(1.0mL,10mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体6b(0.62g,产率＝95％)。
白色固体.1H NMR(500MHz,CDCl3)δ2.29(s,6H,CH3),2.33(s,6H,CH3),4.35(d,J＝9.5Hz,2H,CH2),4.44(d,J＝9.0Hz,2H,CH2),6.66-6.68(m,2H,Ar),6.81-6.84(m,6H,Ar),6.93-6.95(m,4H,Ar),7.10(s,8H,Ar),7.14-7.17(m,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ160.8(m),138.6,137.7,135.8,134.8(m),134.2(m),133.5(m),129.2(m),128.8(m),110.1,83.6(m),58.0(m),21.3.31P{1H}NMR(202MHz,CDCl3)δ-22.82(s).HRMS(ESI)calcd.for C43H39O2P2[M+H]+:649.2425,Found:649.2420,[α]20 D＝+231.2(c＝0.5,丙酮).
实施例10：
(R)-4'-(二对甲氧基苯基膦氧基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯3c的合成：
Figure GDA0002753023740000111
N2氛围下，反应瓶中加入2(5.2g,10mmol)、dppb(213mg,0.05mmol)、Ar2POH(3.93g,15mmol)、Pd(PAc)2(112mg,0.05mmol)和DIPEA(6.5mL,40mmol)，最后加入50mL无水无氧的DMSO。100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物3c(5.78g,产率＝91％)。
白色固体.1H NMR(500MHz,CDCl3)δ3.81(s,3H,CH3),3.84(s,3H,CH3),4.62(d,J＝9.5Hz,1H,CH2),4.70-4.75(m,2H,CH2),5.71(d,J＝8.5Hz,1H,CH2),6.23(d,J＝8.5Hz,1H,CH2),6.65-6.70(m,1H,Ar),6.80-6.82(m,3H,Ar),6.88-6.91(m,2H,Ar),7.03-7.07(m,2H,Ar),7.16-7.27(m,3H,Ar),7.39-7.43(m,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ163.8,162.2(m),144.7,133.7,133.0,131.4(m),130.3(m),129.3,126.9,125.9,125.0,122.8,121.7(m),119.1,116.6,113.8(m),111.5,109.2,85.6,83.6,56.5,55.2.31P{1H}NMR(202MHz,CDCl3)δ29.39(s).HRMS(ESI)calcd.for C30H25O8F3PS[M+H]+:633.0960,Found:633.0954,[α]20 D＝+62.4(c＝0.5,丙酮).
实施例11：
(R)-4'-(二对甲氧基苯基膦基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯4c的合成：
Figure GDA0002753023740000121
100mL封管中，加入3c(2.86g,5mmol)、DIPEA(6.6mL,40mmol)、20mL和三氯硅氢(2.0mL,20mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体4c(2.81g,产率＝91％)。
白色固体.1H NMR(400MHz,CDCl3)δ4.58-4.62(m,2H,CH2),4.69-4.72(m,1H,CH2),5.08-5.12(m,1H,CH2),6.43(d,J＝9.0Hz,1H,Ar),6.51-6.52(m,1H,Ar),6.72-6.74(m,1H,Ar),6.81-6.85(m,1H,Ar),6.88-6.91(m,2H,Ar),6.99-7.05(m,3H,Ar),7.10-7.13(m,2H,Ar),7.14-7.22(m,4H,Ar).13C{1H}NMR(101MHz,CDCl3)δ162.7,160.2,153.6,145.5,138.6,133.7,133.5,131.1,129.9,129.3,129.0,127.6,122.6,112.3,110.7,109.4,84.3,82.9,56.3,26.9,21.2.31P{1H}NMR(202MHz,CDCl3)δ-22.32(s).HRMS(ESI)calcd.forC30H25O5F3PS[M+H]+:585.1112,Found:585.1107,[α]20 D＝+111.4(c＝0.5,丙酮).
实施例12：
(R)-(4'-(二对甲氧基苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]-4-二苯基膦氧5c的合成：
Figure GDA0002753023740000131
N2氛围下，反应瓶中加入4c(1.232g,2mmol)、dppb(43mg,0.1mmol)、Ph2POH(0.79g,3mmol)、Pd(PAc)2(22.4mg,0.1mmol)和DIPEA(1.6mL,5mmol)，最后加入20mL无水无氧的DMSO，100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物5c(1.27g,产率＝87％)。
白色固体.1H NMR(500MHz,CDCl3)δ3.73(s,3H,CH3),3.74(s,3H,CH3),3.77(s,6H,CH3),3.80(s,3H,CH3)4.37(d,J＝9.0Hz,1H,CH2),4.45-4.47(m,2H,CH2),5.28(d,J＝9.0Hz,1H,CH2),6.55-6.57(m,1H,Ar),6.64-6.71(m,6H,Ar),6.75-6.83(m,4H,Ar),6.89-6.91(m,2H,Ar),6.98-7.00(m,1H,Ar),7.06-7.11(m,1H,Ar),7.13-7.14(m,2H,Ar),7.20-7.26(m,3H,Ar),7.42-7.45(m,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ171.0,162.8(m),161.9(m),160.3(m),137.5,135.4,134.8,134.0(m),133.5,130.6,129.9,128.5(m),128.1,126.6(m),126.0(m),124.7,123.8,113.9(m),112.9,109.8,85.0,84.2,60.3,58.1(m),55.0(m).31P{1H}NMR(202MHz,CDCl3)δ28.75(s),-24.27(s).HRMS(ESI)calcd.forC43H39O7P2[M+H]+:729.2171,Found:729.2166,[α]20 D＝+173.2(c＝0.5,丙酮).
实施例13：
(R)-4,4'-二(二对甲基苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]6c的合成：
Figure GDA0002753023740000132
100mL封管中，加入5c(0.728g,1mmol)、DIPEA(1.65mL,10mmol)、10mL甲苯和三氯硅氢(1.0mL,10mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体6c(0.64g,产率＝90％)。
白色固体.1H NMR(500MHz,CDCl3)δ3.75(s,6H,CH3),3.79(s,6H,CH3),4.36(d,J＝9.0Hz,2H,CH2),4.46(d,J＝9.5Hz,2H,CH2),6.64-6.70(m,6H,Ar),6.82-6.85(m,10H,Ar),7.12-7.18(m,6H,Ar).13C{1H}NMR(126MHz,CDCl3)δ160.8(m),160.1(m),136.2(m),135.5(m),134.5(m),129.3,128.3(m),126.8,114.0(m),110.0,83.6(m),57.9(m),55.1(m).31P{1H}NMR(202MHz,CDCl3)δ-24.20(s).HRMS(ESI)calcd.for C43H39O2P2[M+H]+:649.2425,Found:649.2420,[α]20 D＝+133.6(c＝0.5,丙酮).
实施例14：
(R)-4'-(二3,5-二甲基苯基膦氧基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯3d的合成：
Figure GDA0002753023740000141
N2氛围下，反应瓶中加入2(5.20g,10mmol)、dppb(213mg,0.05mmol)、Ar2POH(3.87g,15mmol)、Pd(PAc)2(112mg,0.05mmol)和DIPEA(6.5mL,40mmol)，最后加入50mL无水无氧的DMSO，100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物3d(5.15g,产率＝82％)。
白色固体.1H NMR(500MHz,CDCl3)δ2.15(s,6H,CH3),2.17(s,6H,CH3),4.54(d,J＝9.5Hz,1H,CH2),4.62-4.64(m,2H,CH2),5.69(d,J＝8.5Hz,1H,CH2),6.07(d,J＝8.0Hz,1H,Ar),6.63-6.67(m,1H,Ar),6.72-6.78(m,3H,Ar),6.93-6.98(m,2H,Ar),7.00-7.05(m,4H,Ar),7.12-7.18(m,1H,Ar).13C{1H}NMR(126MHz,CDCl3)δ163.9,161.7,144.7,137.8(m),133.9,133.3(m),131.5,130.7,130.0(m),129.4(m),128.7,126.9,121.6,119.1,116.5,113.6,111.3,109.1,85.7,83.6,56.3,21.2.31P{1H}NMR(202MHz,CDCl3)δ29.59(s).HRMS(ESI)calcd.for C32H29O6F3PS[M+H]+:629.1375,Found:629.1369,[α]20 D＝+196.4(c＝0.5,丙酮).
实施例15：
(R)-4'-(二3,5-二甲基苯基膦基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯4d的合成：
Figure GDA0002753023740000151
100mL封管中，加入3d(3.14g,5mmol)、DIPEA(6.6mL,40mmol)、20mL和三氯硅氢(2.0mL,20mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体4d(2.88g,产率＝94％)。
白色固体.1H NMR(400MHz,CDCl3)δ2.16(s,6H,CH3),2.19(s,6H,CH3),4.44(d,J＝9.0Hz,1H,CH2),4.63-4.67(m,2H,CH2),5.15-5.18(m,1H,CH2),6.36-6.40(m,1H,Ar),6.51-6.53(m,3H,Ar),6.65-6.68(m,1H,Ar),6.73-6.79(m,3H,Ar),6.83-6.87(m,3H,Ar),6.99-7.01(m,1H,Ar),7.11-7.15(m,1H,Ar).13C{1H}NMR(101MHz,CDCl3)δ162.6,160.2,145.3,137.7(m),136.3,135.2,134.0,131.8(m),130.5(m),129.9,127.7,122.8,119.3,116.7,112.1,110.6,109.4,84.4,83.0,56.2,21.3.31P{1H}NMR(162MHz,CDCl3)δ-21.56(s).HRMS(ESI)calcd.for C32H29O5F3PS[M+H]+:613.1425,Found:613.1420,[α]20 D＝+60.0(c＝0.5,丙酮).
实施例16：
(R)-(4'-(二3,5-二甲基苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]-4-二苯基膦氧5b的合成：
Figure GDA0002753023740000161
N2氛围下，反应瓶中加入4d(1.22g,2mmol)、dppb(107mg,0.1mmol)、Ph2POH(0.77g,3mmol)、Pd(PAc)2(22.4mg,0.1mmol)和DIPEA(0.8mL,5mmol)，最后加入10mL无水无氧的DMSO，100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物5d(1.22g,产率＝86％)。
白色固体.1H NMR(500MHz,CDCl3)δ2.04(s,6H,CH3),2.06(s,6H,CH3),2.24(s,6H,CH3),2.29(s,6H,CH3),4.14(d,J＝9.5Hz,1H,CH2),4.41(d,J＝9.5Hz,2H,CH2),5.15(d,J＝8.5Hz,1H,CH2),6.49(d,J＝7.5Hz,1H,Ar),6.70-6.73(m,1H,Ar),6.75-6.78(m,2H,Ar),6.86-6.90(m,3H,Ar),6.95-6.98(m,3H,Ar),7.03-7.06(m,2H,Ar),7.07(s,1H,Ar),7.09(s,1H,Ar),7.19(s,1H,Ar),7.21(s,1H,Ar),7.24-7.25(m,1H,Ar).13C{1H}NMR(126MHz,CDCl3)δ162.8(m),159.8(m),137.7(m),136.8(m),135.0,134.2,134.0.133.2(m),132.8,132.4(m),130.8(m),130.0(m),129.4(m),128.5(m),126.7,126.4,112.9,109.9,84.1,83.3,58.3(m),21.3(m).31P{1H}NMR(202MHz,CDCl3)δ-19.53(s),29.83(s).HRMS(ESI)calcd.for C47H47O3P2[M+H]+:721.3000,Found:721.2995,[α]20 D＝+137.2(c＝0.5,丙酮).
实施例17：
(R)-4,4'-二(二3,5-二苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]6d的合成：
Figure GDA0002753023740000162
100mL封管中，加入5d(0.72g,1mmol)、DIPEA(3.3mL,20mmol)、10mL甲苯和三氯硅氢(1.0mL,10mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体6d(0.65g,产率＝93％)。
白色固体.1H NMR(500MHz,CDCl3)δ2.07(s,6H,CH3),2.09(s,6H,CH3),2.24(s,6H,CH3),2.26(s,6H,CH3),4.19-4.20(m,2H,CH2),4.31-4.34(m,2H,CH2),6.65-6.66(m,4H,Ar),6.81-6.84(m,6H,Ar),6.85-6.88(m,4H,Ar),6.95-6.96(m,2H,Ar),7.18-7.22(m,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ160.9(m),137.7(m),137.2(m),136.1,133.8(m),132.3(m),131.0(m),129.6(m),127.1,110.1,82.9,58.3(m),21.3(m).31P{1H}NMR(202MHz,CDCl3)δ-19.92(s).HRMS(ESI)calcd.for C47H47O2P2[M+H]+:705.3051,Found:705.3046,[α]20 D＝+138.0(c＝0.5,丙酮).
实施例18：
(R)-4'-(二3,5-二叔丁基基苯基膦氧基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯3e的合成：
Figure GDA0002753023740000171
N2氛围下，反应瓶中加入2(5.2g,10mmol)、dppb(213mg,0.05mmol)、Ar2POH(6.39g,15mmol)、Pd(PAc)2(112mg,0.05mmol)和DIPEA(6.5mL,40mmol)，最后加入50mL无水无氧的DMSO。100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物3e(7.43g,产率＝93％)。
白色固体.1H NMR(500MHz,CDCl3)δ1.18(s,9H,CH3),1.19(s,9H,CH3),1.20(s,9H,CH3),1.21(s,9H,CH3),4.54-4.56(m,1H,CH2),4.62-4.64(m,1H,CH2),4.80-4.82(m,2H,CH2),6.63-6.68(m,2H,Ar),6.82-6.88(m,6H,Ar),6.90-6.94(m,2H,Ar),7.15-7.21(m,1H,Ar),7.26-7.34(m,1H,Ar).13C{1H}NMR(126MHz,CDCl3)δ162.9,160.1,150.5,150.2,145.7,136.0(m),135.5,134.4,131.2,129.6,128.4,127.5,122.4(m),112.5,110.5,109.6,83.5,82.3,56.4(m),34.8(m),31.3(m).31P{1H}NMR(202MHz,CDCl3)δ-19.74(s).HRMS(ESI)calcd.for C44H53O6F3PS[M+H]+:797.3253,Found:797.3247,[α]20 D＝+109.6(c＝0.5,丙酮).
实施例19：
(R)-4'-(二3,5-二叔丁基苯基膦基)-2氢,2'氢-3,3'-螺二[苯并呋喃]-4-三氟甲磺酸酯4e的合成：
Figure GDA0002753023740000181
100mL封管中，加入3e(3.98g,5mmol)、DIPEA(6.6mL,40mmol)、20mL和三氯硅氢(2.0mL,20mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体4e(3.51g,产率＝90％)。
白色固体.1H NMR(500MHz,CDCl3)δ1.17(s,9H,CH3),1.19(s,9H,CH3),1.20(s,9H,CH3),1.21(s,9H,CH3),4.52-4.55(m,1H,CH2),4.60-4.63(m,1H,CH2),4.77-4.82(m,2H,CH2),6.61-6.69(m,2H,Ar),6.80-6.94(m,6H,Ar),7.14-7.22(m,2H,Ar),7.28-7.34(m,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ162.9,160.1(m),150.5(m),145.8,136.1(m),135.5(m),134.4,131.9(m),131.2,129.6,128.4(m),127.5,122.4(m),116.9,112.6,110.6,109.6,83.5,82.4,56.4(m),34.8(m),31.3(m).31P{1H}NMR(202MHz,CDCl3)δ-19.73(s).HRMS(ESI)calcd.for C32H29O5F3PS[M+H]+:781.3303,Found:781.3298,[α]20 D＝+78.8(c＝0.5,丙酮).
实施例20：
(R)-(4'-(二3,5-二叔丁基苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]-4-二苯基膦氧5e的合成：
Figure GDA0002753023740000191
N2氛围下，反应瓶中加入4e(1.56g,2mmol)、dppb(43mg,0.1mmol)、Ph2POH(1.28g,3mmol)、Pd(PAc)2(22.4mg,0.1mmol)和DIPEA(1.6mL,10mmol)，最后加入10mL无水无氧的DMSO，100℃下反应6h。冷却至室温后，加入水淬灭反应，用乙酸乙酯萃取反应体系，有机相用无水硫酸钠干燥后减压条件下除去溶剂，经过简单的柱层析后就可以拿到产物5e(1.85g,产率＝92％)。
白色固体.1H NMR(500MHz,CDCl3)δ1.95(s,18H,CH3),1.02(s,18H,CH3),1.27(s,18H,CH3),1.30(s,18H,CH3),3.78(d,J＝8.8Hz,1H,CH2),4.36(d,J＝9.6Hz,1H,CH2),4.45(d,J＝8.4Hz,1H,CH2),4.91(d,J＝8.4Hz,1H,CH2),6.67(d,J＝6.8Hz,2H,Ar),6.76-6.78(m,1H,Ar),6.86-6.90(m,2H,Ar),6.97-7.01(m,1H,Ar),7.06-7.10(m,2H,Ar),7.16-7.20(m,1H,Ar),7.22-7.24(m,2H,Ar),7.39(s,2H,Ar),7.41(s,2H,Ar),7.49(s,2H,Ar),7.61(d,J＝8.0Hz,2H,Ar),7.65(d,J＝9.6Hz,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ162.3,159.0,150.4(m),149.5(m),137.7,137.3(m),135.5(m),134.7,133.9(m),132.9,132.4(m),129.6(m),128.0(m),127.5,126.5(m),122.9,120.7,112.2,109.9,81.4,81.3,59.1,34.8(m),31.2(m).31P{1H}NMR(202MHz,CDCl3)δ30.86(s),-16.07(s).HRMS(ESI)calcd.forC71H95O3P2[M+H]+:1057.6756,Found:1057.6751,[α]20 D＝+152.4(c＝0.5,丙酮).
实施例21：
(R)-4,4'-二(二3,5-二叔丁基苯基膦基)-2H,2'H-3,3'-螺二[苯并呋喃]6e的合成：
Figure GDA0002753023740000192
100mL封管中，加入5e(1.01g,1mmol)、DIPEA(1.65mL,10mmol)、10mL甲苯和三氯硅氢(1.0mL,10mmol)。反应在120℃条件下搅拌过夜。反应体系用过量的碳酸氢钠饱和溶液淬灭，加入100mL乙酸乙酯，硅藻土过滤，有机相用无水硫酸钠干燥。减压下除去溶剂，然后柱层析得到白色固体6e(0.82g,产率＝79％)。
白色固体.1H NMR(500MHz,CDCl3)δ0.99(s,36H,CH3),1.25(s,36H,CH3),3.85(d,J＝9.0Hz,2H,CH2),4.25(d,J＝8.5Hz,2H,CH2),6.80(d,J＝8.0Hz,2H,Ar),6.91-6.93(m,2H,Ar),7.01-7.02(m,4H,Ar),7.09-7.10(m,2H,Ar),7.15-7.18(m,2H,Ar),7.25-7.36(m,4H,Ar),7.37(s,2H,Ar).13C{1H}NMR(126MHz,CDCl3)δ160.5(m),150.4(m),149.2(m),139.0,137.4,135.5(m),131.4(m),129.6(m),126.9(m),123.0,120.9,110.0,80.4,59.1(m),34.8(m),31.4(m).31P{1H}NMR(202MHz,CDCl3)δ-15.41(s).HRMS(ESI)calcd.for C71H95O2P2[M+H]+:1041.6807,Found:1041.6802,[α]20 D＝+140.4(c＝0.5,丙酮).
实施例22：
催化剂Ru(6a)OAc2的制备：
在N2氛围下，向一个10mL单口瓶中加入[RuPhCl2]2(25mg,0.05mmol)、配体6a(61mg,0.103mmol),然后加入2mLDMF。100℃条件下反应3h。冷却至室温，然后加入1.5mL无水醋酸钠(0.111g,1.3mmol)的甲醇溶液。20Min后加入脱氧的去离子水。有灰色固体从反应体系中析出，过滤，减压除去溶剂和水就可以得到催化剂Ru(6a)OAc2(57mg,产率＝71％)。
实施例23：
催化剂Ru(6a)(CF3CO)2的制备：
在N2氛围下，向一个10mL单口瓶中加入双-(2-甲基烯丙基)环辛-1,5-二烯钌(32mg,0.05mmol)、配体6a(61mg,0.103mmol),然后加入2mL丙酮。40℃条件下反应0.5h。然后加入三氟乙酸(33mg,0.3mmol),40℃条件下搅拌过夜，减压除去溶剂，然后加入1mL石油醚，过滤得到目标产物Ru(6a)(CF3CO)2(81mg,产率＝88％)。
实施例24：
配体6a在2-甲基肉桂酸的不对称氢化中的应用：
在N2氛围下，向氢化小瓶中加入2-甲基肉桂酸(162mg,1mmol)、催化剂Ru(6a)OAc2(0.8mg,0.001mmol)以及1mL的甲醇。在10atm的氢气氛围下进行12h后，原料全部转化为产物。将产物和苯胺进行缩合生成酰胺，来测量产物的对映选择性(ee>99％)。HPLC条件：Daicel ADH,进样量2μL(c＝1mg/mL),IPA/hexane＝90/10,1.0mL/Min,210nm,tR(major)＝26.8Min,tR(minor)＝29.7Min。
采用6a应用于多种物质的转化率参见图1所示。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (6)

1.一种氧杂螺环双膦配体化合物，其特征在于，具有以下通式(I)的结构，
Figure FDA0002753023730000011
选自以下化合物：
Figure FDA0002753023730000012
2.一种合成权利要求1所述的化合物的方法，其特征在于，通过以下的路线合成得到：
Figure FDA0002753023730000013
取代基Ar如权利要求1所述。
3.权利要求1所述的化合物在催化不对称反应中的应用，其特征在于，所述不对称反应为不饱和羧酸的氢化。
4.根据权利要求3所述的应用，其特征在于，该化合物制成的双膦醋酸钌络合物，应用在有机溶剂中对不饱和羧酸的氢化。
5.根据权利要求4所述的应用，其特征在于，所述双膦醋酸钌络合物为
Ru(6a)(CF3CO)2，结构如下：
Figure FDA0002753023730000021
6.一种催化剂，其特征在于，所述催化剂为Ru(6a)(CF3CO)2，结构如
下：
Figure FDA0002753023730000022
或者Ru(6a)OAc2，结构如下：
Figure FDA0002753023730000023
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