CN112279743B - 一种手性α-氨基酸酯衍生物的合成方法 - Google Patents

一种手性α-氨基酸酯衍生物的合成方法 Download PDF

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CN112279743B
CN112279743B CN201910668946.8A CN201910668946A CN112279743B CN 112279743 B CN112279743 B CN 112279743B CN 201910668946 A CN201910668946 A CN 201910668946A CN 112279743 B CN112279743 B CN 112279743B
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胡向平
胡信虎
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Dalian Institute of Chemical Physics of CAS
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Abstract

本发明公开了一种手性α‑氨基酸酯衍生物的合成方法：以手性二茂铁骨架膦‑亚磷酰胺配体与金属铱前驱体反应原位制备配合物为催化剂，催化不对称氢化亚胺酸酯制备手性α‑氨基酸酯衍生物。为合成氨基酸提供了一条可行途径。与其它合成手性氨基酸酯方法相比，本方法用于氢化的手性二茂铁骨架膦‑亚磷酰胺配体合成简单、价格低廉、适宜公斤级生产，而且铱/手性二茂铁骨架膦‑亚磷酰胺体系催化活性高、对映选择性高，产物的对映体过量值(ee值)最高达96％以上，氢化反应操作简单、条件温和、原子经济性高，适合工业化生产，并且本发明对于苯甘氨酸乙酯合成具有较好的结果，达到92％收率，91％对映选择性，具有很好的工业实用性。

Description

一种手性α-氨基酸酯衍生物的合成方法
技术领域
本发明属于有机合成领域，具体涉及一种手性α-氨基酸酯衍生物的合成方法，适用于非天然氨基酸的生产。
背景技术
手性氨基酸及衍生物是化学品、制药、生物合成中重要的中间体，在蛋白质和多肽研究中起着至关重要的作用。最简洁、方便的合成手性氨基酸酯的方法包括脱氢氨基酸酯的不对称氢化和α-亚胺酸酯的不对称氢化。其中α-亚胺酸酯的不对称氢化是一种绿色、环保、高效的合成手性芳香氨基酸酯的方法。它是在手性催化剂及其他助剂的帮助下，使α-亚胺酸酯底物直接氢化生成手性芳香类氨基酸酯类化合物。近些年，关于有机小分子催化α-亚胺酸酯不对称转移氢化已有很大的进展，而关于金属催化不对称氢化α-亚胺酸酯的报道很少。
2001年，Amii团队(H.Abe,H.Amii,K.Uneyama.Org.Lett.2001,3,313-315；)利用(R) -(+)-1,1'-联萘-2,2'-双二苯膦配体与三氟醋酸钯成功催化不对称氢化α-亚胺酸酯合成手性氨基酸酯衍生物，取得了最高91％的对映选择性。但是该法只适应少量的底物。
2006年，张绪穆团队(G.Shang,Q.Yang,X.Zhang.Angew.Chem.2006,118,6508-6510； Angew.Chem.Int.Ed.2006,45,6360-6362)报道了芳香α-亚胺酸酯的不对称氢化，在Rh-(S,S,R,R)-tangPhos催化下可以得到手性α-芳基氨基酸酯产物，其产物产率大于93％，对映选择性最高达到95％。
因此，发展高活性、高立体选择性、底物适用广不对称还原α-亚胺酸酯的催化剂，具有十分重要的意义。
发明内容
本发明的目的是提供一种手性α-氨基酸酯衍生物的合成方法。
为实现上述目的，本发明的技术方案如下：
一种手性α-氨基酸酯衍生物的合成方法，该方法采用手性催化剂铱-L、α-亚胺酸酯不对称氢化制备手性氨基酸酯衍生物；所述手性催化剂铱-L由铱-环辛二烯络合物和手性二茂铁骨架膦-亚磷酰胺配体在溶剂中原位配位生成。
一种手性α-氨基酸酯衍生物的合成方法，该方法具体为：
在氮气保护下，将铱-环辛二烯络合物与手性二茂铁骨架膦-亚磷酰胺配体溶于溶剂，室温下搅拌10分钟，加入溶于溶剂的底物α-亚胺酸酯及添加剂(10mol％)，将其置于高压反应釜中，氢气置换3次，然后通入氢气至20-100bar，-20-50℃下反应1-24小时，慢慢释放氢气，除去溶剂后用硅胶柱(洗脱液：乙酸乙酯/石油醚＝1/10)分离得到产物手性α-氨基酸酯衍生物。
所述溶剂为四氢呋喃、二氧六环、二氯甲烷、1,2-二氯乙烷或甲苯；优选四氢呋喃、二氧六环。
所述添加剂为碘、N-碘代丁二酰亚胺、N-溴代丁二酰亚胺、N-氯代丁二酰亚胺或四丁基碘化铵；优选碘、N-碘代丁二酰亚胺。
为实现上述目的，本发明的技术方案如下：
Figure BDA0002141026690000011
本发明所涉及的亚胺酸酯和制得的手性氨基酸酯具有以下结构：
Figure BDA0002141026690000021
式中：
R1为C1～C10烷基如CH3、CH3CH2等，C3～C12环烷基如环戊基、环己基等，或含有N、 S、O、P中一种或二种以上官能团的C1～C10烷基如甲氧甲基、乙氧甲基等，或含有N、S、 O、P中一种或二种以上官能团的C3～C10环烷基如2-四氢呋喃基、4-四氢呋喃基等；或芳基等C6-C30内的含或不含N、S、O、P等官能团的芳香基团如苯基、4-甲氧基苯基等
R2为芳基等C6-C30内的含或不含N、S、O、P等官能团的芳香基团如苯基、4-甲氧基苯基等；
R3为C1～C10烷基如CH3、CH3CH2等。
本发明所涉及的手性二茂铁骨架膦-亚磷酰胺配体具有以下结构：
Figure BDA0002141026690000022
式中:R1、R2为H；烷基和环烷基等C1～C40内的含或不含N、S、O、P等官能团的脂肪基团；苄基等C7-C60在内的含或不含N、S、O、P等官能团的芳香基团与脂肪基的组合基团；芳基等C6-C60内的含或不含N、S、O、P等官能团的芳香基团。
Ar为C6-C60内的含或不含N、S、O、P等官能团的芳香基团。
X基团为：手性或非手性的含或不含N、S、O、P等官能团的脂肪基团；含或不含N、S、O、P等官能团的芳香基团；手性或非手性的含或不含N、S、O、P等官能团的联苯、联萘或四氢联萘类芳香基团。
所述铱-环辛二烯络合物为：[Ir(COD)Cl]2、Ir(COD)2BF4或Ir(COD)2BARF。
所述反应体系中所述铱浓度为0.001-0.01mol/l，所述手性二茂铁骨架膦-亚磷酰胺配体与铱的摩尔比为1-5：1；优选铱浓度为0.002mol/l，配体与铱的摩尔比为1:1。
所述α-亚胺酸酯底物和手性催化剂铱-L的摩尔比为50-500：1；优选50-100:1。
本发明的有益效果是：与其它合成手性氨基酸酯方法相比，本方法用于氢化的手性二茂铁骨架膦-亚磷酰胺配体合成简单、价格低廉、适宜公斤级生产，而且铱/手性二茂铁骨架膦- 亚磷酰胺体系催化活性高、对映选择性高，产物的对映体过量值(ee值)最高达96％以上，氢化反应操作简单、条件温和、原子经济性高，适合工业化生产，并且本发明对于苯甘氨酸乙酯合成具有较好的结果，达到92％收率，91％对映选择性，具有很好的工业实用性。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1：实施例1制备的(4-甲氧基苯胺基)苯乙酸甲酯的核磁共振氢谱；
图2：实施例1制备的(4-甲氧基苯胺基)苯乙酸甲酯的核磁共振碳谱；
图3：实施例15制备的(4-甲基苯基)-(4-甲氧基苯胺基)乙酸甲酯核磁共振氢谱；
图4：实施例15制备的(4-甲基苯基)-(4-甲氧基苯胺基)乙酸甲酯核磁共振碳谱；
图5：实施例16制备的(4-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图6：实施例16制备的(4-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图7：实施例17制备的(3-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图8：实施例17制备的(3-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图9：实施例18制备的(2-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图10：实施例18制备的(2-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图11：实施例19制备的(4-氟苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图12：实施例19制备的(4-氟苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图13：实施例20制备的(4-氯苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图14：实施例20制备的(4-氯苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图15：实施例21制备的(3-氯苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图16：实施例21制备的(3-氯苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图17：实施例22制备的(4-溴苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图18：实施例22制备的(4-溴苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图19：实施例23制备的(4-三氟甲基苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图20：实施例23制备的(4-三氟甲基苯基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图21：实施例24制备的(2-萘基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图22：实施例24制备的(2-萘基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图23：实施例25制备的(2-噻吩基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图24：实施例25制备的(2-噻吩基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图25：实施例26制备的(环己基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图26：实施例26制备的(环己基)-(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱；
图27：实施例27制备的苯(4-甲氧基苯胺基)乙酸乙酯的核磁共振氢谱；
图28：实施例27制备的苯(4-甲氧基苯胺基)乙酸乙酯的核磁共振碳谱；
图29：实施例28制备的苯(4-甲氧基苯胺基)乙酸异丙酯的核磁共振氢谱；
图30：实施例28制备的苯(4-甲氧基苯胺基)乙酸异丙酯的核磁共振碳谱；
图31：实施例29制备的苯(4-甲氧基苯胺基)乙酸甲酯的核磁共振氢谱；
图32：实施例29制备的苯(4-甲氧基苯胺基)乙酸甲酯的核磁共振碳谱。
具体实施方式
下面的实施例将对本发明予以进一步的说明，但并不因此而限制本发明。核磁共振是通过Bruker核磁共振仪测定，高效液相色谱(HPLC)是通过Agilent 1100系列高效液相色谱测定。
实施例1
Figure BDA0002141026690000031
氮气保护下，将[Ir(COD)Cl]2(0.002mmol,0.5mol％)，手性二茂铁骨架膦-亚磷酰胺配体 (0.0048mmol,1.1mol％)溶于四氢呋喃(1.0mL)，室温下搅拌10分钟，加入底物(4-甲氧基苯亚胺基)苯乙酸甲酯(0.4mmol)的四氢呋喃(1.0mL)溶液及5.1mg碘，将其置于高压反应釜中，氢气置换3次，然后通入氢气至50个大气压，25℃下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 96％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).92％ee wasdetermined by chiral HPLC(Chiralcel OJ-H, n-hexane/i-PrOH＝70/30,0.8ml/min,254nm,40℃):tR(minor)＝26.8min,tR(major)＝29.0min. [α]25 D＝100(c 0.88,CH2Cl2).1HNMR(400MHz,CDCl3)δ7.52–7.44(m,2H),7.39–7.26(m, 3H),6.79–6.65(m,2H),6.60–6.45(m,2H),5.01(s,1H),4.67(s,1H),3.71(s,3H),3.69(s,3H). 13C NMR(101MHz,CDCl3)δ172.58(s),152.54(s),140.21(s),137.81(s),128.88(s),128.30(s), 127.30(s),114.83(d,J＝8.3Hz),77.39(s),77.07(s),76.76(s),61.67(s),55.70(s),52.74(s).
经检测，产物为：(4-甲氧基苯胺基)苯乙酸甲酯。
实施例2
将实施例1中的反应条件H2压力改为100个大气压，其余同实施例1，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率98％，对映选择性为92％ee。
实施例3
将实施例1中的反应条件H2压力改为20个大气压，其余同实施例1，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率76％，对映选择性为90％ee。
实施例4
将实施例1中的反应条件温度改为25℃，其余同实施例1，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率93％，对映选择性为91％ee。
实施例5
将实施例1中的反应条件温度改为50℃，其余同实施例1，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率95％，对映选择性为80％ee。
实施例6
将实施例4中的反应条件添加剂改为N-碘代丁二酰亚胺，其余同实施例4，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率95％，对映选择性为83％ee。
实施例7
将实施例4中的反应条件添加剂改为N-溴代丁二酰亚胺，其余同实施例4，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率53％，对映选择性为67％ee。
实施例8
将实施例6中的反应条件溶剂改为二氯甲烷，其余同实施例6，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率93％，对映选择性为69％ee。
实施例9
将实施例6中的反应条件溶剂改为二氯乙烷，其余同实施例6，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率93％，对映选择性为67％ee。
实施例10
将实施例6中的反应条件溶剂改为甲苯，其余同实施例6，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率94％，对映选择性为77％ee。
实施例11
Figure BDA0002141026690000051
将实施例6中的反应条件配体改为3，3’-二氢取代的二茂铁膦-亚磷酰胺酯，其余同实施例6，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率94％，对映选择性为63％ee。
实施例12
Figure BDA0002141026690000052
将实施例6中的反应条件配体改为3，3’-甲基取代的二茂铁膦-亚磷酰胺酯，其余同实施例6，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率95％，对映选择性为74％ee。
实施例13
Figure BDA0002141026690000053
将实施例6中的反应条件配体改为3，3’-苯基取代的二茂铁膦-亚磷酰胺酯，其余同实施例6，反应得产物，经检测，产物为(4-甲氧基苯胺基)苯乙酸甲酯，收率43％，对映选择性为51％ee。
实施例14
将实施例1中的底物与催化剂比例改为S/C＝1000，即：[Ir(COD)Cl]2(0.00025mmol,0.05 mol％)，手性膦-亚膦酰胺配体(0.00055mmol,0.11mol％)，反应得产物，经检测，产物为(4- 甲氧基苯胺基)苯乙酸甲酯，对映选择性为80％ee。
实施例15
将实施例1中的底物改为(4-甲基苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 96％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee wasdetermined by chiral HPLC(Chiralcel OJ-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):tR(major)＝33.8min,tR(minor)＝37.2min. [α]25 D＝100(c 1.02,CH2Cl2).1HNMR(400MHz,CDCl3)δ7.36(d,J＝8.0Hz,2H),7.15(d,J＝ 8.0Hz,2H),6.75–6.66(m,2H),6.58–6.46(m,2H),4.98(s,1H),4.62(s,1H),3.70(s,3H),3.69 (s,3H),2.32(s,3H).13CNMR(101MHz,CDCl3)δ172.75(s),152.49(s),140.29(s),138.08(s), 134.80(s),129.58(s),127.19(s),114.82(d,J＝9.7Hz),77.39(s),77.08(s),76.76(s),61.38(s), 55.70(s),52.69(s),21.16(s).
经检测，产物为：(4-甲基苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例16
将实施例1中的底物改为(4-甲氧基苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow solid was obtained in 97％yield after purification with columnchromatography on silica gel(hexanes/ethyl acetate,10/1).95％ee wasdetermined by chiral HPLC(Chiralcel OJ-H, n-hexane/i-PrOH＝70/30,0.8ml/min,254nm,40℃):tR(minor)＝31.9min,tR(major)＝36.8min. [α]25 D＝82.4(c 0.93,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.39(d,J＝8.7Hz,2H),6.87(d,J＝ 8.7Hz,2H),6.72(d,J＝8.9Hz,2H),6.53(d,J＝8.9Hz,2H),4.96(s,1H),4.61(s,1H),3.78(s, 3H),3.71(s,3H),3.70(s,3H).13C NMR(101MHz,CDCl3)δ172.83(s),159.56(s),152.50(s), 140.26(s),129.74(s),128.43(s),114.82(d,J＝7.7Hz),114.26(s),77.37(s),77.05(s),76.74(s),61.02(s),55.70(s),55.28(s),52.67(s),29.72(s).
经检测，产物为：(4-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例17
将实施例1中的底物改为(3-甲氧基苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 95％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).87％ee wasdetermined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝70/30,0.8ml/min,254nm,40℃):tR(minor)＝29.7min,tR(major)＝34.0min. [α]25 D＝83.7(c 1.05,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.26(dd,J＝9.9,5.9Hz,1H),7.05 (dd,J＝14.5,4.9Hz,2H),6.84(dd,J＝8.2,2.4Hz,1H),6.76–6.66(m,2H),6.57–6.47(m,2H), 4.98(s,1H),4.65(s,1H),3.79(s,3H),3.72(s,3H),3.70(s,3H).13C NMR(101MHz,CDCl3)δ 172.47(s),160.00(s),152.54(s),140.21(s),139.42(s),129.86(s),119.64(s),114.82(d,J＝8.7 Hz),113.74(s),112.84(s),77.36(s),77.04(s),76.73(s),61.66(s),55.70(s),55.27(s),52.77(s).
经检测，产物为：(3-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例18
将实施例1中的底物改为(2-甲氧基苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 93％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).77％ee wasdetermined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝70/30,0.8ml/min,254nm,40℃):tR(minor)＝30.2min,tR(major)＝35.9min. [α]25 D＝82.1(c 1.0,CH2Cl2).1HNMR(400MHz,CDCl3)δ7.34(dd,J＝7.4,1.3Hz,1H),7.30–7.21(m,1H),6.92(t,J＝7.9Hz,2H),6.75–6.66(m,2H),6.67–6.53(m,2H),5.44(s,1H),4.59 (s,1H),3.89(s,3H),3.69(s,3H),3.68(s,3H).13C NMR(101MHz,CDCl3)δ173.09(s),157.14 (s),152.58(s),140.65(s),129.43(s),128.18(s),126.53(s),121.05(s),115.09(s),114.79(s), 111.20(s),77.41(s),77.10(s),76.78(s),55.97–55.58(m),52.54(s).
经检测，产物为：(2-甲氧基苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例19
将实施例1中的底物改为(4-氟苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例 1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 92％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee wasdetermined by chiral HPLC(Chiralpak AD-H, n-hexane/i-PrOH＝80/20,0.8ml/min,254nm,40℃):tR(major)＝11.2min,tR(minor)＝12.6min. [α]25 D＝88.0(c 0.74,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.51–7.41(m,2H),7.09–6.97(m, 2H),6.77–6.66(m,2H),6.55–6.44(m,2H),4.99(s,1H),4.68(s,1H),3.72(s,3H),3.70(s,3H). 13C NMR(101MHz,CDCl3)δ172.33(s),163.86(s),161.40(s),152.62(s),139.94(s),133.57(d, J＝3.1Hz),128.94(d,J＝8.2Hz),115.90(s),115.68(s),114.84(d,J＝8.2Hz),99.99(s),77.36 (s),77.05(s),76.73(s),60.93(s),55.69(s),52.83(s).
经检测，产物为：(4-氟苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例20
将实施例1中的底物改为(4-氯苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例 1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 98％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee wasdetermined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):tR(major)＝32.2min,tR(minor)＝35.7min. [α]25 D＝112.7(c 0.93,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.43(d,J＝8.5Hz,2H),7.37–7.28 (m,2H),6.81–6.64(m,2H),6.59–6.37(m,2H),4.98(s,1H),4.70(s,1H),3.72(s,3H),3.70(s, 3H).13C NMR(101MHz,CDCl3)δ172.05(s),152.65(s),139.82(s),136.42(s),134.11(s), 129.04(s),128.65(s),114.84(d,J＝9.4Hz),77.37(s),77.05(s),76.73(s),60.99(s),55.69(s),52.90(s).
经检测，产物为：(4-氯苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例21
将实施例1中的底物改为(3-氯苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例 1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 95％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).86％ee wasdetermined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):tR(minor)＝36.1min,tR(major)＝38.3min. [α]25 D＝85.0(c 0.84,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.50(s,1H),7.38(td,J＝4.6,1.6Hz, 1H),7.32–7.22(m,2H),6.78–6.64(m,2H),6.59–6.39(m,2H),4.97(s,1H),4.72(s,1H),3.73 (s,3H),3.70(s,3H).13C NMR(101MHz,CDCl3)δ171.88(s),152.68(s),140.05(s),139.81(s), 134.78(s),130.10(s),128.52(s),127.46(s),125.47(s),114.85(d,J＝12.2Hz),77.37(s),77.05(s),76.73(s),61.19(s),55.70(s),52.96(s).
经检测，产物为：(3-氯苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例22
将实施例1中的底物改为(4-溴苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例 1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 97％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee wasdetermined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):tR(major)＝33.6min,tR(minor)＝37.6min. [α]25 D＝94.1(c 1.06,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.52–7.42(m,2H),7.37(d,J＝8.5 Hz,2H),6.78–6.64(m,2H),6.56–6.41(m,2H),4.97(s,1H),4.71(s,1H),3.72(s,3H),3.70(s, 3H).13C NMR(101MHz,CDCl3)δ171.96(s),152.65(s),139.79(s),136.97(s),131.99(s), 129.00(s),122.26(s),114.85(d,J＝9.7Hz),77.38(s),77.07(s),76.75(s),61.05(s),55.69(s), 52.92(s).
经检测，产物为：(4-溴苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例23
将实施例1中的底物改为(4-三氟甲基苯基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同
实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 97％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).92％ee wasdetermined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):tR(minor)＝11.3min,tR(major)＝15.3min. [α]25 D＝74.5(c 0.86,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.77–7.50(m,4H),6.80–6.63(m, 2H),6.58–6.36(m,2H),5.07(s,1H),4.78(s,1H),3.74(s,3H),3.70(s,3H).13C NMR(101MHz, CDCl3)δ171.66(s),152.73(s),142.01(s),139.65(s),130.66(s),127.69(s),125.82(d,J＝3.7Hz), 114.85(d,J＝14.5Hz),77.35(s),77.03(s),76.71(s),61.27(s),55.67(s),53.03(s).
经检测，产物为：(4-三氟甲基苯基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例24
将实施例1中的底物改为(2-萘基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 94％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).80％ee wasdetermined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):tR(major)＝24.1min,tR(minor)＝37.5min. [α]25 D＝84.0(c 0.97,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.87–7.76(m,3H), 7.59(dd,J＝8.5,1.6Hz,1H),7.53–7.38(m,2H),6.75–6.63(m,2H),6.65–6.49(m,2H),5.17 (s,1H),4.81(s,1H),3.70(s,3H),3.67(s,3H).13C NMR(101MHz,CDCl3)δ172.54(s),152.58 (s),140.22(s),135.36(s),133.35(d,J＝11.1Hz),128.77(s),128.09(s),127.74(s),126.62– 126.19(m),125.00(s),114.89(d,J＝3.7Hz),77.41(s),77.09(s),76.78(s),61.85(s),55.70(s),52.82(s).
经检测，产物为：(2-萘基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例25
将实施例1中的底物改为(2-噻吩基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例 1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 90％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).53％ee wasdetermined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):tR(major)＝17.7min,tR(minor)＝21.5min. [α]25 D＝31.8(c 1.02,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.26–7.20(m,1H),7.12(d,J＝3.5 Hz,1H),6.97(dd,J＝5.0,3.6Hz,1H),6.78–6.70(m,2H),6.65–6.54(m,2H),5.28(s,1H),4.64 (s,1H),3.77(s,3H),3.71(s,3H).13C NMR(101MHz,CDCl3)δ171.69(s),153.01(s),141.49(s), 139.95(s),127.10(s),125.58(d,J＝11.2Hz),115.27(s),114.87(s),77.40(s),77.08(s),76.76(s),57.83(s),55.67(s),52.95(s).
经检测，产物为：(2-噻吩基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例26
将实施例1中的底物改为(环己基)-(4-甲氧基苯亚胺基)乙酸甲酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 91％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).73％ee wasdetermined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):tR(minor)＝7.0min,tR(major)＝7.9min. [α]25 D＝-45.2(c 0.88,CH2Cl2).1HNMR(400MHz,CDCl3)δ6.81–6.70(m,2H),6.66–6.51(m, 2H),3.86(d,J＝2.5Hz,1H),3.78(d,J＝6.2Hz,1H),3.73(s,3H),3.68(s,3H),1.86(d,J＝12.5 Hz,1H),1.82–1.59(m,6H),1.34–1.07(m,5H).13C NMR(101MHz,CDCl3)δ174.59(s), 152.66(s),141.58(s),115.14(s),114.89(s),77.37(s),77.05(s),76.73(s),63.39(s),55.73(s), 51.75(s),41.33(s),29.72(s),29.25(s),26.14(d,J＝10.9Hz).
经检测，产物为：(环己基)-(4-甲氧基苯胺基)乙酸甲酯。
实施例27
将实施例1中的底物改为苯基(4-甲氧基苯亚胺基)乙酸乙酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 94％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee wasdetermined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):tR(major)＝11.0min,tR(minor)＝12.3min. [α]25 D＝71.7(c 0.96,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.48(d,J＝7.2Hz,2H),7.41–7.19 (m,3H),6.79–6.64(m,2H),6.63–6.38(m,2H),5.00(s,1H),4.76–4.44(m,1H),4.33–4.04(m, 2H),3.69(s,3H),1.20(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ172.06(s),152.48(s), 140.27(s),137.92(s),128.80(s),128.19(s),127.25(s),114.81(d,J＝8.7Hz),77.38(s),77.06(s), 76.74(s),61.72(s),55.70(s),14.06(s).
经检测，产物为：苯(4-甲氧基苯胺基)乙酸乙酯。
实施例28
将实施例1中的底物改为苯基(4-甲氧基苯亚胺基)乙酸异丙酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 96％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).96％ee wasdetermined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):tR(major)＝8.5min,tR(minor)＝9.5min. [α]25 D＝65.9(c 0.94,CH2Cl2).1HNMR(400MHz,CDCl3)δ7.40(d,J＝7.3Hz,2H),7.22(ddd,J ＝15.7,13.9,6.5Hz,3H),6.64(dd,J＝9.6,2.7Hz,2H),6.46(t,J＝6.2Hz,2H),4.94(dt,J＝12.5, 6.3Hz,1H),4.89(s,1H),4.59(s,1H),3.62(s,3H),1.18(d,J＝6.3Hz,3H),0.99(d,J＝6.2Hz, 3H).13C NMR(101MHz,CDCl3)δ171.57(s),152.43(s),140.34(s),137.97(s),128.72(s), 128.09(s),127.17(s),114.80(d,J＝9.7Hz),77.38(s),77.06(s),76.74(s),69.35(s),61.80(s),55.71(s),21.78(s),21.39(s).
经检测，产物为：苯(4-甲氧基苯胺基)乙酸异丙酯。
实施例29
将实施例1中的底物改为苯基(4-苯亚胺基)乙酸甲酯，其余同实施例1，反应得产物。
对产物进行检测分析，NMR和HPLC数据如下所示：
Yellow oil was obtained in 95％yield after purification with columnchromatography on silica gel (hexanes/ethyl acetate,10/1).90％ee wasdetermined by chiral HPLC(Chiralcel OD-H, n-hexane/i-PrOH＝99/1,0.8ml/min,254nm,40℃):tR(major)＝32.9min,tR(minor)＝41.2min. [α]D 23＝93.7(c 0.94,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.52–7.45(m,2H),7.39–7.26(m, 3H),7.11(t,J＝7.9Hz,2H),6.69(t,J＝7.3Hz,1H),6.55(d,J＝7.9Hz,2H),5.08(d,J＝5.8Hz, 1H),4.95(d,J＝5.5Hz,1H),3.72(s,3H).13C NMR(101MHz,CDCl3)δ172.36(s),145.96(s), 137.63(s),129.26(s),128.91(s),128.34(s),127.27(s),118.14(s),113.42(s),77.38(s),77.06(s), 76.74(s),60.76(s),52.83(s).
经检测，产物为：苯(4-甲氧基苯胺基)乙酸甲酯。
Table.Asymmetric hydrogenation ofα-imino estersa)
Figure BDA0002141026690000101
Figure BDA0002141026690000102
Figure BDA0002141026690000111
a)Conditions:5(0.2mmol),[Ir(COD)Cl]2(2μmol),ligand 2d(4.8μmol),H2(50bar),THF (2.0ml),I2(10mol％),24h,0℃.b)Isolated yields.c)Determined bychiral HPLC。

Claims (4)

1.一种手性α-氨基酸酯衍生物的合成方法，其特征在于：该方法以α-亚胺酸酯化合物为原料，铱/手性二茂铁骨架膦-亚磷酰胺酯配体为催化剂，制备手性α-氨基酸酯衍生物，其反应方程式如下：
Figure 877590DEST_PATH_IMAGE001
式中：
R1为C1～C10烷基，C3～C12环烷基，或含有N、S、O、P中一种或二种以上官能团的C1～C10烷基，或含有N、S、O、P中一种或二种以上官能团的C3～C10环烷基；或C6-C30内的含或不含N、S、O、P官能团的芳香基团；
R2为C6-C30内的含或不含N、S、O、P官能团的芳香基团；
R3为C1～C10烷基；
所述手性二茂铁骨架膦-亚磷酰胺配体L通式为：
Figure 60310DEST_PATH_IMAGE003
；其中R1、R2为甲基，Ar为苯基，X为手性联萘类芳香基团；
该方法具体为：
在氮气保护下，将铱-环辛二烯络合物与手性二茂铁骨架膦-亚磷酰胺配体溶于溶剂，室温下搅拌10分钟，加入溶于溶剂的底物α-亚胺酸酯及添加剂，将其置于高压反应釜中，氢气置换3次，然后通入氢气至20-100bar，-20-50 ℃下反应1-24小时，慢慢释放氢气，除去溶剂后用硅胶柱分离，采用乙酸乙酯/石油醚=1/10的洗脱液洗脱，得到产物手性α-氨基酸酯衍生物；
所述添加剂的摩尔百分比为10mol%；
所述溶剂为四氢呋喃、二氧六环、二氯甲烷、1,2-二氯乙烷或甲苯；
所述添加剂为碘、N-碘代丁二酰亚胺、N-溴代丁二酰亚胺、N-氯代丁二酰亚胺或四丁基碘化铵。
2.根据权利要求1所述的一种手性α-氨基酸酯衍生物的合成方法，其特征在于：所述铱-环辛二烯络合物为：[Ir(COD)Cl]2、Ir(COD)2BF4或Ir(COD)2BARF。
3.根据权利要求1所述的一种手性α-氨基酸酯衍生物的合成方法，其特征在于：所述铱浓度为0.001-0.01mol / L，所述手性二茂铁骨架膦-亚磷酰胺配体与铱的摩尔比为1-5：1。
4.根据权利要求1所述的一种手性α-氨基酸酯衍生物的合成方法，其特征在于：所述α-亚胺酸酯底物和手性催化剂铱-L的摩尔比为50-500：1。
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EP2361919A1 (de) * 2010-02-15 2011-08-31 AIKAA-Chemicals GmbH Imidazo[1,5-b]pyridazin-Amino-Phosphor-Liganden und deren Komplexverbindungen

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EP2361919A1 (de) * 2010-02-15 2011-08-31 AIKAA-Chemicals GmbH Imidazo[1,5-b]pyridazin-Amino-Phosphor-Liganden und deren Komplexverbindungen

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Highly Enantioselective Hydrogenation of Acyclic Imines Catalyzed by Ir ± f-Binaphane Complexes;Denming Xiao等;《Angewndte Chemie International Edition》;20010914;第40卷(第18期);第3427页Experimental Section部分，表2 Entry 2 *
Rh-Catalyzed Asymmetric Hydrogenation of a-Aryl Imino Esters: An Efficient Enantioselective Synthesis of Aryl Glycine Derivatives;Gao Shang等;《Angewndte Chemie International Edition》;20060828;第45卷;第6361页Experimental Section部分、表2 Entry 1 *

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