CN116199713A - 一种手性α-氨基膦酸的衍生物及其制备方法 - Google Patents
一种手性α-氨基膦酸的衍生物及其制备方法 Download PDFInfo
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- CN116199713A CN116199713A CN202111450124.6A CN202111450124A CN116199713A CN 116199713 A CN116199713 A CN 116199713A CN 202111450124 A CN202111450124 A CN 202111450124A CN 116199713 A CN116199713 A CN 116199713A
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- alpha
- nmr
- aminophosphonic acid
- chloroform
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- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
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- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3826—Acyclic unsaturated acids
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/40—Esters thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4015—Esters of acyclic unsaturated acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/28—Phosphorus compounds with one or more P—C bonds
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- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
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Abstract
本发明公开了一种手性α‑氨基膦酸及其衍生物的高效制备方法,所述的α‑氨基膦酸的衍生物具有如下式所示的结构。所述的方法通过α‑羰基膦酸酯和苄胺为原料缩合得到的亚胺中间体,再在金鸡纳碱骨架的甜菜碱(Betaine)催化剂作用下,发生高对映选择性的亚胺异构化反应,从而实现“一锅法”高效合成此类手性α‑氨基膦酸衍生物。本发明方法可以通过一步重结晶纯化,高收率和高对映选择性地得到手性α‑氨基膦酸,具有广阔的工业化生产应用前景。
Description
技术领域
本发明属于有机合成技术领域,具体地,本发明涉及一种手性α-氨基膦酸的衍生物及其制备方法。
背景技术
α-氨基膦酸及其衍生物是一类具有重要生物活性的天然α-氨基酸类似物,其不仅具有抗病毒、抗菌、抗真菌和抗癌等生物活性,还能抑制各种蛋白水解酶的活性,例如HIV蛋白酶、高血压蛋白原酶和PTPases等。因此,在新药开发、农药化工中起到日益重要的作用,并成为多年来有机磷化学发展的重要领域。α-氨基膦酸及其衍生物的绝对构型与其生物活性有着密切相关性。例如:(S,R)构型的阿拉法林(Alafosfalin)具有明显优于其他三个异构体的革兰氏阳性菌和阴性菌抑制率(Yager,K.M.;Taylor,C.M.;Smith,Ⅲ,A.B.J.Am.Chem.Soc.1994,116,9377–9378.)。因此,开发具有底物广谱性的不对称策略制备手性α-氨基膦酸衍生物具有重要意义。有机小分子催化具有催化剂合成容易、反应条件比较温和、环境友好、生物毒性小、底物兼容性和适应性强等特点,已经成为简单方便获得手性分子的高效方法之一,并且已经在工业生产中得到广泛应用。
目前合成手性α-氨基膦酸及其衍生物的主要策略是通过连接亚胺和膦酸酯构筑碳-磷键的Pudovik反应或者Kabachnik–Fields反应获得。近二十年来,不对称有机小分子催化被成功应用于这一碳-磷键构筑的策略,实现手性α-氨基膦酸衍生物的合成。例如氢键催化合成(Joly,G.D.;Jacobsen,E.N.J.Am.Chem.Soc.2004,126,4102–4103.),双功能催化合成(Nakamura,S.;Nakashima,H.;Yamamura,A.;Shibata,N.;Toru,T.Adv.Synth.Catal.2008,350,1209),酸催化合成;(Cheng,X.;Goddard,R.;Buth,G.;List,B.Angew.Chem.Int.Ed.2008,47,5079–5081.)以及手性碱催化合成(Fu,X.;Loh,W-T.;Zhang,Y.;Chen,T.;Ma,M.;Liu,H.;Wang,J.;Tan,C.-H.Angew.Chem.Int.Ed.2009,121,7523–7526.)等方法。亚胺的异构化反应制备功能性手性胺是一种具有良好应用潜力的替代方案。其中,有报道尝试使用金鸡纳碱衍生物催化的亚胺异构化来制备手性α-氨基膦酸衍生物(Kowalczyl,D.;Albrecht,/>Chem.Commun.,2015,51,3981–3984.)。但是,上述基于有机催化的策略通常催化效率低,催化剂用量高达5-20摩尔%,大大降低了其工业应用潜力。
鉴于α-氨基膦酸及其衍生物具有重要的应用价值和高效绿色的不对称合成方法的缺乏,本领域亟待开发一种高效率,高选择性,适合放大的α-氨基膦酸及其衍生物制备方法。
发明内容
本发明提供了一种手性α-氨基膦酸的衍生物及其制备方法。具体地,本发明通过α-羰基膦酸酯和苄胺为原料缩合得到的亚胺中间体,在金鸡纳碱骨架的甜菜碱(Betaine)催化剂作用下,发生高对映选择性的亚胺异构化反应,从而实现“一锅法”高效合成此类手性α-氨基膦酸衍生物。
本发明的第一方面,提供了一种催化合成手性α-氨基膦酸衍生物的方法,所述的α-氨基膦酸衍生物具有如下式所示的结构:
所述的方法包括步骤:
(a)在金鸡纳碱衍生物催化剂和无机碱存在下,用亚胺中间体II进行对映选择性异构化反应,制备得到具有光学活性的α-氨基膦酸前体II':和
用所述的α所氨基膦酸前体II'进行水解,得到手性α-氨基膦酸;
其中,*表示R构型或S构型;
R1选自取代或未取代的C1-C16烷基;
R2选自取代或未取代的C1-C16烷基;
Ar2为取代或未取代的C6-C10芳基,或5-12元杂芳基;其中,所述的5-12元杂芳基上任选地具有1-2个稠合的饱和5-7元环;
所述的金鸡纳碱衍生物催化剂选自下组:
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、C1-C4烷基、C2-C4烯基、C2-C4炔基、C2-C4酯基、硝基、3-8元环烷基、4-8元杂环基、或未取代或被选自下组的一个或多个取代基取代的C6-C10芳基或5-12元杂芳基:卤素、C1-C4烷氧基、C1-C4烷硫基、叔丁基二甲基硅基(TBS)、叔丁基二甲基硅氧(TBSO)、三异丙基硅基(TIPS)。
在另一优选例中,所述的金鸡纳碱衍生物催化剂的用量为0.0001-0.5mol%,较佳地为0.01-0.05mol%(以式II化合物的用量为基础计)。
在另一优选例中,所述的无机碱选自下组:磷酸钾、碳酸钾、氢氧化钾、氢氧化锂、一水合氢氧化锂、碳酸氢钾、碳酸铯、磷酸氢钾、碳酸钠。
在另一优选例中,所述的无机碱的用量为10-40mol%,较佳地为15-30mol%(以式II化合物的用量为基础计)。
在另一优选例中,所述的步骤中,反应在选自下组的溶剂中进行:甲苯、氯仿、乙醚,或其组合。
在另一优选例中,所述的步骤中,反应在-40℃至40℃下进行,较佳地在-30℃至30℃下进行。
在另一优选例中,所述的α-氨基膦酸前体II'具有选自下组的结构:
在另一优选例中,Ar2为对硝基苯基。
在另一优选例中,所述的α-氨基膦酸前体II'具有选自下组的结构:
在另一优选例中,所述的金鸡纳碱衍生物催化剂选自下组:
Ar1选自下组:苯基、萘基、4-甲氧基苯基、3,5-二甲氧基苯基、3,4,5-三甲氧基苯基;R选自下组:叔丁基(tBu)、叔丁基二甲基硅基(TBS)、三异丙基硅基(TIPS)。
在另一优选例中,所述的金鸡纳碱衍生物催化剂选自下组:
在另一优选例中,所述的催化剂为Q-4。
在另一优选例中,所述的亚胺中间体II是通过以下方法制备的:
(a)用α-羰基膦酸酯I与苄胺进行反应,缩合得到亚胺中间体II。
在另一优选例中,所述的反应在氯仿中进行。
在另一优选例中,所述的方法还包括步骤:
(b)在酸存在下,对α-氨基膦酸前体II'进行水解,然后与氨水中和得到式III化合物:其中,式II'和式III的手性中心构型一致。
在另一优选例中,所述的酸为盐酸。
在另一优选例中,所述的反应在四氢呋喃中进行。
在另一优选例中,所述的方法还包括步骤:
(c)在酸存在下,用式III化合物进行水解反应,得到式IV化合物。
在另一优选例中,所述的酸为盐酸。
在另一优选例中,所述的方法还包括步骤:对产物进行重结晶,得到纯化后的产物IV。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,提供了一种手性α-氨基膦酸及其衍生物的制备方法。本发明通过α-羰基膦酸酯和苄胺为原料缩合得到的亚胺中间体,在金鸡纳碱骨架的甜菜碱(Betaine)催化剂作用下,发生高对映选择性的亚胺异构化反应,从而实现“一锅法”高效合成此类手性α-氨基膦酸衍生物。基于上述发现,发明人完成了本发明。
基于金鸡纳碱骨架的甜菜碱(Betaine)有机小分子催化剂
前期,我们课题组发展了一类基于金鸡纳碱骨架的甜菜碱(Betaine)有机小分子催化剂,此类催化剂在三氟甲基亚胺的异构化反应中展现优秀的催化活性和对映选择性。
在前期研究过程中,发明人发现该类催化剂的底物适用范围较窄,对于二氟甲基亚胺、烷基亚胺或芳基亚胺等与三氟甲基亚胺结构接近的底物都不具备催化活性:
然而,对于亚胺膦酸酯,该催化剂却可以高效率地催化完成手性异构化反应。因此,基于上述发现,发明人设计了“一锅法”高效合成此类手性α-氨基膦酸衍生物的方法。
本发明所述的金鸡纳碱衍生物催化剂具有如下结构式的光学活性化合物。
上式中:Ar为取代的芳烃基,所述的取代的芳烃基任意选自3,5-二芳基芳香基。
该反应中,催化剂优选为选自下组的催化剂:
最优选地,所述的催化剂为Q-4。
本发明所述制备α-氨基膦酸酯的对映体和消旋体反应式如下式所示:
上式中:R1选自为C1-C16的任何烷基取代基;
R2选自为C1-C16的任何烷基取代基;
R3为芳香取代基,具体为取代的苯基或杂环芳香基;
Ar2为芳香取代基,具体为取代的苯基或杂环芳香基。
优选的α-氨基膦酸酯II'为选自下组的化合物:
在另一优选例中,Ar2为对硝基苯基。
在另一优选例中,所述的α-氨基膦酸前体II'具有选自下组的结构:
“一锅法”合成性α-氨基膦酸的方法
本发明提供一种“一锅法”、十克规模级合成性α-氨基膦酸的方法。该方法最低只需要1ppm(0.0001摩尔%)的催化剂用量,而且只需要一步重结晶纯化过程。其步骤是以苄胺和α-羰基膦酸酯为原料,缩合得到亚胺中间体。再在金鸡纳碱衍生物催化剂和无机碱的参与下,发生对映选择性异构化反应,高效制备α-氨基膦酸酯。通过盐酸水解后,重结晶纯化得到高纯度手性α-氨基膦酸。
本发明方法的反应式如下式所示:
上式中:R1选自为C1-C16的任何烷基取代基;
R2选自为C1-C16的任何烷基取代基;
R3为芳香取代基,具体为取代的苯基或杂环芳香基;
Ar为芳香取代基。
上述方法中,各步骤之间可不经产物分离,于同一体系中完成。
与现有技术相比,本发明的主要优点包括:
本发明将催化剂用量从原来技术所用的20mol%降低至最低0.0001mol%,并且通过一锅法反应,进行一步重结晶即可得到高对映选择性的α-氨基磷酸,制备方法适合工业化,具有产业应用价值。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1:金鸡纳碱衍生物催化剂的合成:
反应式中,ArCH2Br表示苄溴,Ar可以是其他任意芳基取代基;CH3CN表示乙腈;R可以是叔丁基或者硅基保护基。
在20毫升的反应管中,将化合物A(0.5毫摩尔,287毫克)和化合物苄溴B(0.5毫摩尔)溶解于5毫升乙腈中。将反应在室温条件下搅拌24小时至反应完全。反应液在减压旋蒸浓缩后,粗产物通过硅胶柱层析分离(二氯甲烷/甲醇=20/1),得到产物C。部分催化剂表征如下:
结构式:
性状:白色固体
1H NMR(500MHz,Methanol-d4)δ8.64(d,J=4.6Hz,1H),8.06(d,J=9.2Hz,1H),7.84(d,J=2.5Hz,1H),7.71–7.44(m,11H),7.29(tt,J=7.4,1.2Hz,1H),7.12–7.02(m,2H),6.81(d,J=2.3Hz,4H),6.50(t,J=2.3Hz,2H),5.19–4.96(m,4H),4.75(d,J=12.5Hz,1H),4.24(t,J=9.6Hz,1H),4.02–3.92(m,1H),3.84(s,13H),3.52–3.43(m,1H),3.26(dt,J=11.9,9.1Hz,1H),3.07(ddd,J=12.1,9.0,2.7Hz,1H),2.57–2.39(m,2H),1.94–1.81(m,3H),1.55–1.46(m,1H),1.29(d,J=4.7Hz,1H),0.74(s,9H).13C NMR(126MHz,Methanol-d4)δ165.10,162.24,160.82,153.00,141.49,140.16,139.43,135.59,134.93,131.95,131.21,130.93,129.50,129.30,127.93,127.74,122.43,119.36,117.59,108.21,103.86,98.96,66.20,63.02,57.84,55.04,54.57,37.98,28.10,27.29,23.03,22.47.HRMS(ESI/[M-Br]+)Calcd for C62H62ClN4O7 +m/z 1009.4302,found 1009.4308.
性状:白色固体
1H NMR(500MHz,Methanol-d4)δ8.64(d,J=4.6Hz,1H),8.07(d,J=9.2Hz,1H),7.80–7.44(m,12H),7.33–7.26(m,1H),7.07(t,J=7.7Hz,2H),6.78(d,J=2.3Hz,4H),6.50(d,J=2.3Hz,2H),5.69(ddd,J=17.3,10.5,6.9Hz,1H),5.16–4.94(m,4H),4.16(t,J=9.1Hz,1H),3.83(s,12H),3.65–3.52(m,2H),3.18(td,J=11.5,5.2Hz,1H),2.65(d,J=9.0Hz,1H),2.35(dd,J=13.8,7.8Hz,1H),1.92(q,J=3.2Hz,1H),1.87–1.75(m,1H),1.54–1.42(m,1H),1.17–1.06(m,1H),0.73(s,9H).13C NMR(126MHz,Methanol-d4)δ160.79,146.08,141.50,140.13,139.53,136.91,134.95,131.91,131.20,131.07,129.79,128.91,128.89,127.95,127.75,122.69,122.32,119.25,119.15,116.46,108.24,103.43,98.94,83.70,71.06,67.18,63.90,61.02,54.56,50.69,37.49,28.11,26.39,23.80,22.16.HRMS(ESI/[M-Br]+)Calcd for C62H62ClN4O7 +m/z 1009.4302,found 1009.4311.
性状:白色固体
1H NMR(500MHz,Chloroform-d)δ10.43(s,1H),8.63(d,J=4.6Hz,1H),8.56(d,J=2.5Hz,1H),8.08(d,J=9.1Hz,1H),8.00–7.92(m,2H),7.76–7.46(m,7H),7.46–7.39(m,1H),7.28(t,J=7.8Hz,2H),7.15(d,J=4.5Hz,1H),7.01(s,4H),6.57(d,J=11.8Hz,1H),5.55(dd,J=7.5,3.6Hz,2H),5.03–4.90(m,1H),4.76(q,J=9.5,6.5Hz,2H),4.37(d,J=11.8Hz,1H),3.97(d,J=22.9Hz,18H),3.32(dd,J=13.1,10.5Hz,1H),3.20(td,J=11.5,6.1Hz,1H),3.16–3.01(m,1H),2.58(dt,J=8.1,3.9Hz,1H),2.07(q,J=3.1Hz,1H),1.98–1.84(m,1H),1.68–1.57(m,1H),1.57–1.45(m,2H),1.37–1.27(m,1H),0.76(s,9H).13C NMR(126MHz,Chloroform-d)δ164.86,163.15,157.77,153.20,152.90,145.85,143.52,140.00,137.67,136.52,135.38,134.88,134.24,132.09,131.57,131.30,129.56,129.50,129.15,128.62,128.14,124.65,123.68,121.38,118.27,117.69,107.49,104.30,84.15,72.51,65.19,62.12,60.95,59.85,56.41,50.13,37.15,29.00,25.95,24.90,23.17.HRMS(ESI/[M-Br]+)Calcd for C64H66ClN4O7 +m/z 1069.4513,found 1069.4503.
实施例2:部分金鸡纳碱衍生物催化剂和无机碱筛选结果
步骤1):在2毫升反应瓶中加入对硝基苄胺(0.2毫摩尔,30毫克)和400微升氯仿,零摄氏度冷却5分钟后,加入化合物I(0.2毫摩尔,42毫克),在该温度下继续搅拌10小时后,得到亚胺中间体II用于下一步转化。
步骤2):在另一4毫升反应瓶中加入催化剂和无机碱(20摩尔%)和1.6毫升甲苯。在指定温度下搅拌5分钟后,步骤1)中的亚胺中间体II直接全部一次加入到该4毫升反应瓶中并保持该温度下搅拌。反应过程中,用核磁检测反应的转化率,用高效液相色谱(HPLC)测量手性(ee)值。
a)转化率通过31P NMR测定;b)ee值通过HPLC测定;c)83%分离产率;d)转化数=17,000。
实施例3:不对称合成手性α-氨基膦酸衍生物
反应式1:
反应式1中:步骤1):在2毫升反应瓶中加入苄胺(0.2毫摩尔)和400微升氯仿,在零摄氏度冷却5分钟后,加入化合物I(0.2毫摩尔),在该温度下继续搅拌10小时得到亚胺中间体II以备用。步骤2):在另一4毫升反应瓶中加入催化剂Q-4(0.025摩尔%)和碳酸钾(20摩尔%)溶解于1.6毫升甲苯中。在-20摄氏度搅拌5分钟后,步骤1)中的混合物直接加入到该4毫升反应瓶中继续在-20摄氏度搅拌24小时。反应结束后,反应液直接通过去活化硅胶过滤除去碳酸钾,减压旋蒸除去溶剂,残留物经过去活化硅胶柱层析(石油醚/乙酸乙酯=90/10-70/30)分离获得目标产物II'。
下列为部分化合物II'的表征:
淡黄色油状物,83%产率(0.2毫摩尔规格,56毫克),99%ee[Daicel ChiralcelOD-3,Hexanes/IPA=95/5,1.0毫升/分钟,λ280nm,tmajor=7.75分钟,tminor=9.80分钟],TLC(PE/EA=1/1;Rf=0.3).1H NMR(600MHz,CDCl3)δ8.42(d,J=5.0Hz,1H),8.26(dt,J=8.7,2.1Hz,2H),7.92(dt,J=8.7,2.2Hz,2H),4.73(dpd,J=7.6,6.2,5.2Hz,2H),3.88(dq,J=13.7,6.9Hz,1H),1.56(dd,J=17.7,6.9Hz,3H),1.40–1.26(m,12H).13C NMR(151MHz,CDCl3)δ160.86(d,J=16.4Hz),149.20,141.36(d,J=3.2Hz),129.01,123.90,71.15(dd,J=28.9,7.0Hz),64.31(d,J=158.0Hz),24.08(ddd,J=24.2,11.7,4.1Hz),16.79(d,J=5.9Hz).31P NMR(203MHz,CDCl3)δ22.12.IR(薄膜):v 2980,1639,1600,1521,1344,1220,1104cm-1.HRMS(ESI/[M+H]+):Calcd.forC15H24N2O5P m/z 343.1423,found m/z 343.1457.
淡黄色油状物,84%产率(0.2毫摩尔规格,70毫克),98%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=6.35分钟,tminor=9.27分钟],TLC(PE/EA=1/1;Rf=0.6),1H NMR(500MHz,Chloroform-d)δ8.36(d,J=5.1Hz,1H),8.33–8.17(m,2H),7.99–7.80(m,2H),4.86–4.61(m,2H),3.62(ddd,J=13.6,9.3,4.2Hz,1H),2.07–1.95(m,2H),1.37–1.20(m,19H),1.15(ht,J=5.9,4.0,3.1Hz,1H),0.84(t,J=6.9Hz,3H).13C NMR(126MHz,Chloroform-d)δ161.59(d,J=16.6Hz),149.31,141.43(d,J=3.5Hz),129.18(d,J=1.6Hz),124.05,71.23(dd,J=19.4,7.1Hz),70.09(d,J=156.5Hz),31.77,30.26(d,J=4.8Hz),28.89,27.01(d,J=14.8Hz),24.23(ddd,J=18.9,8.0,4.2Hz),22.71,14.18.31P NMR(203MHz,Chloroform-d)δ21.61.IR(薄膜):v 2928,2857,1638,1600,1523,1374,1344,2245,1105cm-1.HRMS(ESI/[M+H]+):Calcd.for C20H34N2O5P m/z 413.2200,found m/z 413.2203.
淡黄色油状物,72%产率(0.2毫摩尔规格,65毫克),97%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=14.13分钟,tminor=22.02分钟],TLC(PE/EA=1/1;Rf=0.5),1H NMR(600MHz,Chloroform-d)δ8.35(d,J=5.1Hz,1H),8.29–8.19(m,2H),7.95–7.84(m,2H),7.07(dd,J=5.1,1.2Hz,1H),6.87(dd,J=5.1,3.4Hz,1H),6.74(dt,J=3.5,1.1Hz,1H),4.70(dtt,J=12.3,7.8,6.1Hz,2H),3.66(ddd,J=13.8,9.6,4.0Hz,1H),2.84(tt,J=8.0,1.2Hz,2H),2.15–2.03(m,2H),1.71(dddd,J=18.5,9.8,7.5,5.8Hz,1H),1.65–1.51(m,1H),1.35–1.21(m,12H).13C NMR(151MHz,Chloroform-d)δ161.86(d,J=16.2Hz),149.29,144.79,141.26(d,J=3.3Hz),129.16,126.82,124.37,123.99,123.13,71.29(dd,J=27.1,7.1Hz),69.64(d,J=156.3Hz),29.86(d,J=4.7Hz),29.51,29.23(d,J=14.8Hz),24.16(ddd,J=24.2,11.8,4.1Hz).31P NMR(202MHz,Chloroform-d)δ21.10.IR(薄膜):v 2979,2932,1638,1600,1521,1344,1239,1105,978cm-1.HRMS(ESI/[M+H]+):Calcd.for C21H30N2O5PS m/z453.1613,found m/z 453.1611.
淡黄色油状物,73%产率(0.2毫摩尔规格,56毫克),97%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=7.46分钟,tminor=11.21分钟],TLC(PE/EA=1/1;Rf=0.5),1H NMR(500MHz,Chloroform-d)δ8.37(d,J=5.1Hz,1H),8.32–8.22(m,2H),7.97–7.86(m,2H),5.75(dddd,J=16.3,11.1,7.3,5.3Hz,1H),5.00(d,J=1.5Hz,1H),4.97(dt,J=7.7,1.7Hz,1H),4.71(dddd,J=16.0,12.3,7.5,6.1Hz,2H),3.69(ddd,J=13.2,10.1,3.0Hz,1H),2.12(ddddt,J=21.5,10.6,8.2,5.9,2.7Hz,3H),1.98–1.89(m,1H),1.39–1.23(m,12H).13C NMR(126MHz,Chloroform-d)δ162.16(d,J=16.1Hz),149.37,141.35(d,J=3.5Hz),137.35,129.18,124.07,115.83,71.32(dd,J=24.8,7.0Hz),68.94(d,J=156.5Hz),30.82(d,J=15.4Hz),29.27(d,J=4.4Hz),24.23(ddd,J=17.6,8.7,4.1Hz).31P NMR(203MHz,Chloroform-d)δ21.38.IR(薄膜):v 2979,2933,1639,1601,1522,1344,1240,1105,977cm-1.HRMS(ESI/[M+H]+):Calcd.for C18H28N2O5P m/z 383.1730,found m/z 383.1737.
淡黄色油状物,72%产率(0.2毫摩尔规格,60毫克),93%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=7.45分钟,tminor=9.72分钟],TLC(PE/EA=1/1;Rf=0.3),1H NMR(600MHz,Chloroform-d)δ8.40(d,J=5.1Hz,1H),8.28–8.22(m,2H),7.94–7.87(m,2H),4.71(dddd,J=26.0,12.3,7.4,6.1Hz,2H),3.79–3.70(m,1H),3.62(s,3H),2.41(ddd,J=12.7,6.3,1.5Hz,1H),2.38–2.27(m,3H),1.37–1.24(m,12H).13C NMR(151MHz,Chloroform-d)δ173.37,162.70(d,J=15.6Hz),149.44,141.20(d,J=3.7Hz),129.24,124.07,71.56(dd,J=43.7,7.0Hz),68.42(d,J=156.0Hz),51.79,31.11(d,J=14.3Hz),26.14(d,J=4.0Hz),24.21(ddd,J=25.1,12.7,4.2Hz).31P NMR(202MHz,Chloroform-d)δ20.50.IR(薄膜):v2980,1735,1638,1600,1522,1345,1239,1105,978cm-1.HRMS(ESI/[M+H]+):Calcd.forC18H28N2O7P m/z 415.1634,found m/z 415.1631.
淡黄色油状物,59%产率(0.2毫摩尔规格,48毫克),90%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=11.63分钟,tminor=19.01分钟],TLC(PE/EA=1/1;Rf=0.3),1H NMR(500MHz,Chloroform-d)δ8.40(d,J=5.2Hz,1H),8.26(d,J=8.7Hz,2H),7.91(d,J=8.5Hz,2H),4.71(ddt,J=10.7,7.6,6.3Hz,2H),3.67(ddd,J=14.1,9.2,4.3Hz,1H),3.54(t,J=6.6Hz,2H),2.16(tdd,J=14.4,7.7,4.3Hz,2H),1.83(ddq,J=15.7,9.3,6.3Hz,1H),1.72(ddq,J=13.5,9.7,6.7Hz,1H),1.39–1.23(m,12H).13C NMR(126MHz,Chloroform-d)δ162.08(d,J=15.7Hz),149.27,141.03(d,J=3.6Hz),129.08(d,J=1.7Hz),123.94,71.36(dd,J=27.2,7.1Hz),68.96(d,J=156.0Hz),44.38,29.96(d,J=14.7Hz),28.01(d,J=4.5Hz),24.07(ddd,J=18.9,10.4,4.2Hz).31P NMR(203MHz,Chloroform-d)δ20.65.IR(薄膜):v 2980,1707,1638,1601,1522,1344,1237,1104,980cm-1.HRMS(ESI/[M+H]+):Calcd.for C17H27ClN2O5P m/z 405.1341,found m/z 405.1349.
淡黄色油状物,64%产率(0.2毫摩尔规格,38毫克),96%ee[Daicel ChiralcelOD-3,Hexanes/IPA=95/5,1.0毫升/分钟,λ254nm,tmajor=8.11分钟,tminor=10.47分钟],TLC(EA;Rf=0.4),1H NMR(500MHz,Chloroform-d)δ8.78–8.59(m,2H),8.32(d,J=5.0Hz,1H),7.67–7.52(m,2H),4.72(dpd,J=7.6,6.0,4.0Hz,2H),3.86(dq,J=13.8,6.9Hz,1H),1.54(dd,J=17.7,6.9Hz,3H),1.37–1.25(m,12H).13C NMR(126MHz,Chloroform-d)δ161.43(d,J=16.6Hz),150.60,142.77(d,J=3.1Hz),122.18,71.30(dd,J=22.3,7.1Hz),64.41(d,J=158.1Hz),24.22(ddd,J=21.7,10.3,4.1Hz),16.89(d,J=6.0Hz).31P NMR(202MHz,Chloroform-d)δ22.10.IR(薄膜):v3443,2979,2935,1640,1598,1558,1227,1105,986cm-1.HRMS(ESI/[M+H]+):Calcd.forC14H24N2O3P m/z 299.1519,found m/z 299.1514./>
0.05摩尔%催化剂,室温反应12小时。淡黄色油状物,70%产率(0.2毫摩尔规格,46毫克),99%ee[Daicel Chiralcel OD-3,Hexanes/IPA=98/2,1.0毫升/分钟,λ254nm,tmajor=6.48分钟,tminor=8.01分钟],TLC(PE/EA=1/1;Rf=0.6),1H NMR(500MHz,Chloroform-d)δ8.30(d,J=4.8Hz,1H),7.68(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),4.73(ddtd,J=12.5,8.0,6.2,1.8Hz,2H),3.80(dq,J=13.7,6.9Hz,1H),1.53(dd,J=17.9,6.9Hz,3H),1.37–1.25(m,12H).13C NMR(126MHz,Chloroform-d)δ161.96(d,J=16.6Hz),137.07(d,J=1.3Hz),134.69(d,J=3.1Hz),129.72(d,J=1.5Hz),129.06,71.13(dd,J=13.3,7.1Hz),64.20(d,J=158.5Hz),24.25(ddd,J=22.7,7.8,4.2Hz),17.06(d,J=5.7Hz).31P NMR(203MHz,Chloroform-d)δ22.88.IR(薄膜):v 2978,2934,1638,1595,1490,1374,1221,1105,978cm-1.HRMS(ESI/[M+H]+):Calcd.for C15H24ClNO3P m/z 332.1177,found m/z 332.1179.
0.5摩尔%催化剂,20摩尔%氢氧化钾,室温反应64小时。淡黄色油状物,68%产率(0.2毫摩尔规格,42毫克),96%ee[Daicel Chiralcel OD-3,Hexanes/IPA=98/2,1.0毫升/分钟,λ254nm,tminor=8.37分钟,tmajor=10.50分钟], TLC(PE/EA=1/1;Rf=0.6),1H NMR(600MHz,Chloroform-d)δ8.30(d,J=4.7Hz,1H),7.64(d,J=7.9Hz,2H),7.20(d,J=7.8Hz,2H),4.74(dp,J=7.4,6.1Hz,2H),3.78(dq,J=13.7,6.9Hz,1H),2.38(s,3H),1.53(dd,J=17.9,6.9Hz,3H),1.37–1.25(m,12H).13C NMR(126MHz,Chloroform-d)δ163.20(d,J=16.5Hz),141.38,133.68(d,J=3.1Hz),129.46,128.54,71.05(dd,J=7.0,3.7Hz),64.22(d,J=158.5Hz),25.14–23.75(m),21.71,17.16(d,J=5.5Hz).31P NMR(202MHz,Chloroform-d)δ23.36.IR(薄膜):v2920,2850,1658,1632,1468cm-1.HRMS(ESI/[M+H]+):Calcd.for C16H27NO3P m/z 312.1723,found m/z 312.1742./>
室温反应48小时。淡黄色油状物,71%产率(0.2毫摩尔规格,43毫克),98%ee[Daicel Chiralcel OD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=8.28分钟,tminor=10.84分钟],TLC(EA;Rf=0.4),1H NMR(500MHz,Chloroform-d)δ8.06(d,J=4.6Hz,1H),6.81–6.51(m,1H),6.07(d,J=3.3Hz,1H),4.73(dpd,J=7.5,6.2,4.6Hz,2H),3.71(dq,J=14.0,6.9Hz,1H),2.35(s,3H),1.55(dd,J=18.0,7.0Hz,3H),1.32(ddd,J=17.3,9.6,6.1Hz,12H).13C NMR(126MHz,Chloroform-d)δ156.08,151.88(d,J=15.3Hz),150.30(d,J=3.7Hz),116.93,108.40,71.11(dd,J=10.5,7.1Hz),63.80(d,J=156.2Hz),25.26–23.52(m),17.07(d,J=5.3Hz),14.15.31P NMR(203MHz,Chloroform-d)δ23.16.IR(薄膜):v 3448,2978,2931,1638,1531,1221,1105,978cm-1.HRMS(ESI/[M+H]+):Calcd.for C14H25NO4P m/z 302.1516,found m/z302.1521.
反应式2:
反应式2中,步骤1):在2毫升反应瓶中加入苄胺(0.2毫摩尔)和400微升氯仿,在0摄氏度冷却5分钟后,加入化合物I(0.2毫摩尔),在该温度下继续搅拌10小时得到亚胺中间体II以备用。步骤2):在另一4毫升反应瓶中加入催化剂Q-4(0.05摩尔%)和碳酸钾(20摩尔%)溶解于1.6毫升甲苯中。在-20摄氏度搅拌5分钟后,步骤1)中的混合物直接加入到该4毫升反应瓶中继续在-20摄氏度搅拌12小时,升温至室温另外反应12小时。反应结束后,反应液直接通过去活化硅胶过滤除去碳酸钾,减压旋蒸除去溶剂,残留物经过去活化硅胶柱层析(石油醚/乙酸乙酯=90/10-70/30)分离获得目标产物II'。
下列为挑选的产物II'的表征:
淡黄色油状物,63%产率(0.2毫摩尔规格,52毫克),94%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=13.20分钟,tminor=18.00分钟],TLC(PE/EA=1/1;Rf=0.5),1H NMR(500MHz,Chloroform-d)δ8.26–8.18(m,2H),7.88(d,J=4.8Hz,1H),7.83–7.75(m,2H),7.22–7.16(m,2H),7.16–7.12(m,1H),7.11–7.05(m,2H),4.79(dh,J=7.6,6.1Hz,2H),3.81(ddd,J=12.1,10.8,2.5Hz,1H),3.38(ddd,J=13.8,7.6,2.5Hz,1H),3.23(ddd,J=13.8,10.9,7.1Hz,1H),1.42–1.28(m,12H).13C NMR(126MHz,Chloroform-d)δ162.11(d,J=17.5Hz),149.32,141.27(d,J=3.1Hz),138.26(d,J=16.5Hz),129.73,129.06(d,J=1.4Hz),128.49,126.69,124.02,71.56(d,J=157.8Hz),71.54(dd,J=16.7,7.0Hz),37.15(d,J=4.1Hz),24.29(ddd,J=19.9,8.2,4.3Hz).31P NMR(203MHz,Chloroform-d)δ20.76.IR(薄膜):v 2979,2932,1638,1600,1521,1343,1247,1104,979cm-1.HRMS(ESI/[M+H]+):Calcd.for C21H28N2O5P m/z 419.1730,found m/z 419.1729.
淡黄色油状物,79%产率(0.2毫摩尔规格,69毫克),92%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=10.68分钟,tminor=15.46分钟],TLC(PE/EA=1/1;Rf=0.4),1H NMR(500MHz,Chloroform-d)δ8.23(d,J=8.7Hz,2H),7.91(d,J=4.8Hz,1H),7.81(d,J=8.6Hz,2H),7.10–6.99(m,2H),6.94–6.81(m,2H),4.78(ddq,J=12.2,7.2,6.1Hz,2H),3.76(ddd,J=12.3,10.8,2.6Hz,1H),3.34(ddd,J=14.0,7.6,2.7Hz,1H),3.21(ddd,J=13.9,10.8,7.4Hz,1H),1.41–1.26(m,12H).13C NMR(126MHz,Chloroform-d)δ162.07(d,J=17.3Hz),161.60(d,J=244.9Hz),149.22,140.95(d,J=3.1Hz),133.76(dd,J=16.6,3.2Hz),130.98(d,J=7.9Hz),128.92(d,J=1.4Hz),123.90,115.14(d,J=21.2Hz),71.43(d,J=157.6Hz),71.43(dd,J=14.9,7.1Hz),36.22(d,J=4.1Hz),26.83–21.05(m).31P NMR(203MHz,Chloroform-d)δ20.46.19F NMR(565MHz,Chloroform-d)δ-116.38.IR(薄膜):v2980,2934,1369,1600,1521,1509,1375,1344,1219,1104,981cm-1.HRMS(ESI/[M+H]+):Calcd.for C21H27FN2O5P m/z 437.1636,found m/z 437.1653.
淡黄色油状物,68%产率(0.2毫摩尔规格,58毫克),88%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=16.05分钟,tminor=20.66分钟],TLC(PE/EA=1/1;Rf=0.5),1H NMR(500MHz,Chloroform-d)δ8.29–8.16(m,2H),7.87(d,J=4.8Hz,1H),7.84–7.74(m,2H),7.05–6.92(m,2H),6.79–6.65(m,2H),4.78(dtd,J=7.5,6.2,5.1Hz,2H),3.80–3.73(m,1H),3.72(s,3H),3.31(ddd,J=14.0,7.3,2.5Hz,1H),3.16(ddd,J=14.0,10.9,6.8Hz,1H),1.43–1.26(m,12H).13C NMR(126MHz,Chloroform-d)δ162.04(d,J=17.7Hz),158.35,149.28,141.28(d,J=3.1Hz),130.69,130.21(d,J=16.9Hz),129.07,124.00,113.83,71.80(d,J=157.4Hz),71.46(dd,J=14.5,7.1Hz),55.33,36.22(d,J=4.0Hz),24.27(ddd,J=19.3,7.3,4.2Hz).31P NMR(202MHz,Chloroform-d)δ20.91.IR(薄膜):v 2979,2934,1639,1600,1512,1344,1245,1177,1105,978cm-1.HRMS(ESI/[M+H]+):Calcd.for C22H30N2O6P m/z449.1836,found m/z 449.1854.
无色油状物,56%产率(0.2毫摩尔规格,5毫克),84%ee[Daicel Chiralcel OD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=6.80分钟,tminor=8.22分钟],TLC(PE/EA=1/1;Rf=0.6),1H NMR(500MHz,Chloroform-d)δ8.21(d,J=8.7Hz,2H),7.82(d,J=4.6Hz,1H),7.78(d,J=8.7Hz,2H),6.91(d,J=8.5Hz,2H),6.66(d,J=8.4Hz,2H),4.79(dpd,J=7.6,6.2,3.0Hz,2H),3.74(td,J=11.1,2.6Hz,1H),3.30(ddd,J=13.9,7.2,2.6Hz,1H),3.13(ddd,J=13.9,11.0,7.0Hz,1H),1.42–1.25(m,12H),0.92(s,9H),0.10(s,6H).13C NMR(126MHz,Chloroform-d)δ161.96(d,J=18.0Hz),154.36,149.28,141.27(d,J=2.8Hz),130.88(d,J=16.8Hz),130.68,129.04,123.97,120.09,71.83(d,J=158.5Hz),71.43(dd,J=12.9,6.9Hz),36.31(d,J=4.0Hz),25.80,24.47–24.11(m),18.35,-4.32.31P NMR(203MHz,Chloroform-d)δ20.93.IR(薄膜):v 2930,2958,1640,1601,1523,1509,1344,1250,1104,981cm-1.HRMS(ESI/[M+H]+):Calcd.for C27H42N2O6PSi m/z 549.2544,found m/z 549.2544.
淡黄色油状物,71%产率(0.2毫摩尔规格,69毫克),87%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=12.83分钟,tminor=12.76分钟],TLC(PE/EA=1/1;Rf=0.5),1H NMR(500MHz,Chloroform-d)δ8.27–8.20(m,2H),8.02(d,J=4.9Hz,1H),7.87–7.79(m,2H),7.25(d,J=8.5Hz,1H),7.22(d,J=2.1Hz,1H),6.94(dd,J=8.2,2.1Hz,1H),4.83–4.67(m,2H),3.77(ddd,J=13.4,10.6,2.9Hz,1H),3.30(ddd,J=14.0,7.8,2.9Hz,1H),3.22(ddd,J=13.9,10.5,7.8Hz,1H),1.39–1.26(m,12H).13C NMR(126MHz,Chloroform-d)δ162.61(d,J=16.2Hz),149.45,140.91(d,J=3.2Hz),138.59(d,J=16.5Hz),132.37,131.58,130.77,130.34,129.15,129.14,124.09,71.73(dd,J=20.6,7.1Hz),70.91(d,J=156.5Hz),36.44(d,J=4.0Hz),24.24(ddd,J=15.0,9.4,4.2Hz).31P NMR(203MHz,Chloroform-d)δ19.83.IR(薄膜):v 2979,2934,1639,1600,1522,1469,1344,1248,1101,979cm-1.HRMS(ESI/[M+H]+):Calcd.for C21H26Cl2N2O5P m/z 487.0951,found m/z 487.0953.
淡黄色油状物,75%产率(0.2毫摩尔规格,69毫克),90%ee[Daicel ChiralcelOD-3,Hexanes/IPA=97/3,1.0毫升/分钟,λ280nm,tmajor=17.33分钟,tminor=23.05分钟],TLC(PE/EA=1/1;Rf=0.5),1H NMR(500MHz,Chloroform-d)δ8.31–8.12(m,2H),7.95(d,J=4.9Hz,1H),7.88–7.75(m,2H),6.62(d,J=7.9Hz,1H),6.59(d,J=1.8Hz,1H),6.52(dd,J=8.0,1.7Hz,1H),5.85(dd,J=8.4,1.5Hz,2H),4.77(dh,J=7.7,6.1Hz,2H),3.75(ddd,J=12.5,10.9,2.5Hz,1H),3.28(ddd,J=13.9,7.5,2.5Hz,1H),3.14(ddd,J=14.0,10.8,6.9Hz,1H),1.40–1.26(m,12H).13C NMR(126MHz,Chloroform-d)δ162.10(d,J=17.2Hz),149.31,147.67,146.25,141.23(d,J=3.2Hz),131.97(d,J=16.9Hz),129.07(d,J=1.4Hz),124.02,122.70,109.85,108.21,100.99,71.68(d,J=157.0Hz),71.50(dd,J=16.2,7.1Hz),36.87(d,J=3.9Hz),25.77–23.03(m).31P NMR(203MHz,Chloroform-d)δ20.64.IR(薄膜):v 2979,2933,1638,1601,1522,1489,1443,1344,1244,1103,1037,978cm-1.HRMS(ESI/[M+H]+):Calcd.forC22H28N2O7P m/z 463.1629,found m/z 463.1632.
实施例4:十克级规格,一步重结晶纯化制备高纯度手性α-氨基膦酸
反应式1:1.0ppm(0.0001摩尔%)催化剂负载,十克级规格制备手性α-氨基膦酸
步骤1):在250毫升干燥史莱克管中加入对硝基苄胺(50毫摩尔,7.61克)和50毫升干燥氯仿,在-20摄氏度冷却5分钟后,缓慢滴加化合物I(51毫摩尔,10.6克溶解于30毫升干燥氯仿中)。加料结束后,缓慢升温至0摄氏度,并在该温度下继续搅拌24小时。NMR检测转化率98%,纯度93%。不经后处理,直接用于下一步。
步骤2):在1000毫升反应瓶中加入催化剂Q-4(0.0001摩尔%,0.05毫克),碳酸钾(30摩尔%,2.1克)和4毫升去离子水溶解于400毫升甲苯中。在-20摄氏度搅拌10分钟后,步骤1)中的混合物直接加入到该1000毫升反应瓶中继续在-20摄氏度搅拌10天(转化率92%,ee=93%)。反应结束后,反应液直接通过去活化硅胶过滤除去碳酸钾,减压除去溶剂得到淡黄色油状物,用于下一步反应。
步骤3):将步骤2)所得油状物与四氢呋喃(100毫升)混合后,加入3N稀盐酸(约30毫升)将pH调至2。室温下搅拌过夜,TLC检测反应完全后。减压旋蒸除去四氢呋喃,水相用乙醚洗涤三次。后加入氨水将pH调至12,再用二氯甲烷萃取。有机相浓缩后得到淡黄色油状物。将得到的油状物和6N稀盐酸(50毫升,300毫摩尔,6当量)混合,100摄氏度加热回流过夜,核磁检测至反应完全。将水旋蒸除去,得到半固体产物。向其中加入乙醇(15毫升)加热至完全溶解,再滴加甲基环氧乙烷(7.5毫升)。然后将其置于室温下搅拌30分钟,抽滤后滤饼用乙醇/甲基环氧乙烷(15毫升,V/V=2:1)洗涤,得到产物IV,呈白色固体4.5克,总产率72%。
反应式2:对氯苄胺出发,室温下十克规格制备α-氨基膦酸
步骤1):在250毫升干燥史莱克管中加入对氯苄胺(50毫摩尔,7.08克)和80毫升干燥氯仿,在-20摄氏度冷却5分钟后,缓慢滴加化合物I(51毫摩尔,10.62克溶解于20毫升干燥氯仿中)。加料结束后,缓慢升温至0摄氏度,并在该温度下继续搅拌24小时,NMR检测转化率98%,纯度88%。不经后处理,直接用于下一步。
步骤2):在1000毫升反应瓶中加入催化剂Q-4(0.05摩尔%,28.8毫克),膦酸钾(30摩尔%,3.18克)和4毫升去离子水溶解于400毫升甲苯中。在室温搅拌10分钟后,步骤1)中的混合物直接加入到该1000毫升反应瓶中继续在室温搅拌24小时(转化率>97%,ee=99%)。反应结束后,反应液直接通过去活化硅胶过滤除去膦酸钾,减压除去溶剂得到淡黄色油状物,用于下一步反应。
步骤3):将步骤2)所得油状物与四氢呋喃(100毫升)混合后,加入3N稀盐酸(约30毫升)将pH调至2。室温下搅拌过夜,TLC检测反应完全后。减压旋蒸除去四氢呋喃,水相用乙醚洗涤三次。后加入氨水将pH调至12,再用二氯甲烷萃取。有机相浓缩后得到淡黄色油状物。。将得到的油状物和6N稀盐酸(50毫升,300毫摩尔,6当量)混合,100摄氏度加热回流过夜,核磁检测至反应完全。将水旋蒸除去,得到半固体产物。向其中加入乙醇(15毫升)加热至完全溶解,再滴加甲基环氧乙烷(7.5毫升)。然后将其置于室温下搅拌30分钟,抽滤后滤饼用乙醇/甲基环氧乙烷(15毫升,V/V=2:1)洗涤。得到产物IV,呈白色固体4.0克,总产率64%。
产物α-氨基膦酸表征:
白色固体, 1H NMR(500MHz,Deuterium Oxide)δ3.40–3.21(m,1H),1.29(dd,J=15.5,7.3Hz,3H).13C NMR(126MHz,Deuterium Oxide)δ44.08(d,J=148.5Hz),13.15(d,J=2.7Hz).31P NMR(203MHz,Deuterium Oxide)δ15.76.
实施例5:消旋α氨基膦酸衍生物制备
步骤1):在2毫升反应瓶中加入苄胺(0.2毫摩尔)和400微升氯仿,在0摄氏度冷却5分钟后,加入化合物I(0.2毫摩尔),在0摄氏度继续搅拌10小时以备用。
步骤2):在另一4毫升反应瓶中加入四丁基溴化铵(20摩尔%)和氢氧化钾(1.0当量)溶解于1.6毫升甲苯中。在室温搅拌5分钟后,步骤1)中的混合物直接加入到该4毫升反应瓶中继续搅拌1小时。反应结束后,反应液直接通过去活化硅胶过滤,减压旋蒸除去溶剂,残留物经过柱层析(石油醚/乙酸乙酯=90/10-70/30)分离获得目标消旋产物II'。核磁表征和手性化合物相同,可参见实施例3数据。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种催化合成手性α-氨基膦酸衍生物的方法,所述的α-氨基膦酸衍生物具有如下式所示的结构:
其特征在于,所述的方法包括步骤:
(a)在金鸡纳碱衍生物催化剂和无机碱存在下,用亚胺中间体II进行对映选择性异构化反应,制备得到具有光学活性的α-氨基膦酸前体II':和
用所述的α所氨基膦酸前体II'进行水解,得到手性α-氨基膦酸;
其中,*表示R构型或S构型;
R1选自取代或未取代的C1-C16烷基;
R2选自取代或未取代的C1-C16烷基;
Ar2为取代或未取代的C6-C10芳基,或5-12元杂芳基;其中,所述的5-12元杂芳基上任选地具有1-2个稠合的饱和5-7元环;
所述的金鸡纳碱衍生物催化剂选自下组:
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、C1-C4烷基、C2-C4烯基、C2-C4炔基、C2-C4酯基、硝基、3-8元环烷基、4-8元杂环基、或未取代或被选自下组的一个或多个取代基取代的C6-C10芳基或5-12元杂芳基:卤素、C1-C4烷氧基、C1-C4烷硫基、叔丁基二甲基硅基(TBS)、叔丁基二甲基硅氧(TBSO)、三异丙基硅基(TIPS)。
2.如权利要求1所述的方法,其特征在于,所述的金鸡纳碱衍生物催化剂的用量为0.0001-0.5mol%,较佳地为0.01-0.05mol%(以式II化合物的用量为基础计)。
10.如权利要求9所述的方法,其特征在于,所述的方法还包括步骤:对产物进行重结晶,得到纯化后的产物IV。
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