CN106008328B - 含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物及其衍生物的制备 - Google Patents

含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物及其衍生物的制备 Download PDF

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CN106008328B
CN106008328B CN201610390624.8A CN201610390624A CN106008328B CN 106008328 B CN106008328 B CN 106008328B CN 201610390624 A CN201610390624 A CN 201610390624A CN 106008328 B CN106008328 B CN 106008328B
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傅滨
麻红利
谢磊
张振华
李佳奇
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Abstract

本发明公开了属于有机合成技术领域的一种含全碳季碳手性中心和氮芳香杂环的α,α‑双取代‑β‑硝基酯类化合物及其衍生物的制备。有机溶剂中，在双噁唑啉手性配体‑镍催化剂或膦‑噁唑啉手性配体‑铜催化剂的催化下，2‑乙酰基氮杂芳香烃与α‑取代‑β‑硝基丙烯酸酯反应，合成式I所示含化合物；该化合物进一步转化为式II(1)所示γ‑丁内酯类化合物、式II(2)所示β2,2‑氨基酸酯类化合物、式II(3)所示琥珀酸酯类化合物或式II(4)所示γ‑内酰胺类化合物。所述制备反应条件温和，产率高，光学纯度高，为不对称合成含全碳季碳手性中心和含氮芳香杂环α,α‑双取代‑β‑硝基酯类化合物及其衍生物的提供了工具。

Description

含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯 类化合物及其衍生物的制备
技术领域
本发明属于有机合成技术领域，具体涉及一种含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物及其衍生物的制备。
背景技术
含氮芳香杂环结构(如吡啶环、喹啉环、噁唑环、噻唑环等)是众多天然产物和药物活性分子的基本结构骨架；同时由于氮原子的特殊性，使得含氮芳香杂环化合物在医药、农药和材料等方面具有广泛而重要的应用[D.Best and H.-W.,Lam,J.Org.Chem.2014,79,831.C.,Guo；D.-W.,Sun；Sh.,Yang；Sh.-J.,Mao；X.-H.,Xu；Sh.-F.,Zhu；and Q.-L.,ZhouJ.Am.Chem.Soc.2015,137,90.]。此外，α,α-双取代-β-硝基酯类化合物是一类合成β-氨基酸的关键中间体。目前合成具有三级手性中心的β-氨基酸的方法比较多，而合成具有全碳季碳手性中心的β2,2-氨基酸方法很少，这主要是因为全碳季碳手性中心周围有比较大的空间位阻而难于生成。因此高对映选择性地合成含全碳季碳手性中心的生物活性分子是有机合成领域最具挑战性的任务之一[Kyle W.Quasdorf and Larry E.Overman,Nature,2014,516,181.]。
鉴于含氮芳香杂环α,α-双取代-β-硝基酯类化合物具有广泛而优异的生物活性和基团可修饰多样性，所以探索此类化合物的制备新方法，特别是高产率高光学活性的合成，具有重要意义。
发明内容
本发明的目的在于提供一种含全碳季碳手性中心和氮芳香杂环的α,α-双取 代-β-硝基酯类化合物及其衍生物的制备方法，采取的技术方案如下：
一种含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物及其衍生物，所述化合物的结构通式如式I所示，所述衍生物的结构通式如式II所示：
其中，式I和式II中的R1为甲基、苄基、异丙基或叔丁基；R2为芳基；Ar为吡啶-2-基、嘧啶-2-基、吡嗪-2-基、噻唑-2-基、噁唑-2-基、N-甲基咪唑-2-基、苯并噻唑-2-基、苯并噁唑-2-基、喹啉-2-基或喹喔啉-2-基。
所述含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物及其衍生物的制备方法的合成路线为：
具体步骤为：
在反应温度为-50℃～50℃的条件下，于有机溶剂中，在双噁唑啉手性配体-镍催化剂或膦-噁唑啉手性配体-铜催化剂的催化下，2-乙酰基氮杂芳香烃与α-取代-β-硝基丙烯酸酯反应，不对称合成(+)-2-硝基甲基-2-芳基-4-(氮杂芳香环-2-基)-4-丁酮酯，即式I所示含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物；
获得的含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物进一步转化为式II(1)所示γ-丁内酯类化合物、式II(2)所示β2,2-氨基酸酯类化合物、式II(3)所示琥珀酸酯类化合物或式II(4)所示γ-内酰胺类化合物。
所述的有机试剂为甲醇、乙醇、异丙醇、异丁醇、四氢呋喃、甲苯、二氯甲烷、三氯甲烷或乙醚。
所述的有机试剂为异丙醇。
所述双噁唑啉手性配体或膦-噁唑啉手性配体中的R为苯基、苄基、异丙基或叔丁基；镍催化剂为Ni(OAc)2.4H2O、Ni(OAc)2或Ni(acac)2；铜催化剂为Cu(OAc)2.H2O、Cu(OAc)2或Cu(OTf)2。
所述双噁唑啉手性配体中的R为苯基；所述膦-噁唑啉手性配体中的R为叔丁基；镍催化剂为Ni(acac)2；铜催化剂为Cu(OAc)2.H2O。
双噁唑啉手性配体与镍催化剂的摩尔当量比为(1.0-1.2):1；膦-噁唑啉手性配体与铜催化剂的摩尔当量比为(1.0-1.2):1。
双噁唑啉手性配体与镍催化剂的摩尔当量比为1.2:1；膦-噁唑啉手性配体与铜催化剂的摩尔当量比为1.2:1。
所述α-取代-β-硝基丙烯酸酯与2-乙酰基氮杂芳香烃的摩尔当量比为(1.0-1.5):1；所述双噁唑啉手性配体-镍催化剂和膦-噁唑啉手性配体-铜催化剂的摩尔当量均为2-乙酰基氮杂芳香烃摩尔当量的1％-10％。
所述α-取代-β-硝基丙烯酸酯与2-乙酰基氮杂芳香烃的摩尔当量比为1.5:1；所述双噁唑啉手性配体-镍催化剂和膦-噁唑啉手性配体-铜催化剂的摩尔当量均为2-乙酰基氮杂芳香烃摩尔当量的10％。
所述的反应温度为室温。
本发明的有益效果为：所述制备反应条件温和，产率高，光学纯度高，为不对称合成含全碳季碳手性中心和含氮芳香杂环α,α-双取代-β-硝基酯类化合物及其衍生物提供了制备工具。
具体实施方式
下面结合实施例对本发明做进一步说明，但本发明的保护范围不限于此。
实施例1：(+)-2-硝基甲基-2-芳基-4-(氮杂芳香环-2-基)-4-丁酮酯的合成
氮气气氛保护和室温条件下，在异丙醇中加入双噁唑啉手性配体(R为苯基)-Ni(acac)2或膦-噁唑啉手性配体(R为叔丁基)-Cu(OAc)2.H2O，然后加入2-乙酰基氮杂芳香烃，室温搅拌15分钟后，再加入α-取代-β-硝基丙烯酸酯，室温继续搅拌反应；反应完毕后除去溶剂，硅胶柱色谱纯化，制得(+)-2-硝基甲基-2-芳基-4-(氮杂芳香环-2-基)-4-丁酮酯，即含全碳季碳手性中心和氮芳香杂 环的α,α-双取代-β-硝基酯类化合物，反应的产率和光化学纯度见表1。从表1可知，所述反应的产率较高(85％～97％)，光学纯度高(92％～99％ee)。
表1：含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物的数据表
实施例2：(+)-2-硝基甲基-2-苯基-4-(吡啶-2-基)-4-氧代丁酸叔丁酯的合成
向干燥的10mL圆底烧瓶中加入双噁唑啉手性配体(8.0mg，0.024mmol)，Ni(acac)2(5.1mg，0.020mmol)，氮气保护下加入异丙醇2mL，室温搅拌1.5h，再加入2-乙酰基吡啶(24.2mg,0.20mmol)，搅拌15min后加入3-硝基-2-苯基丙烯酸叔丁酯(75.1mg,0.30mmol)。加样完毕后，室温下反应过夜；TLC检测反应完毕，反应混合物减压脱溶后直接通过硅胶层析柱分离提纯(乙酸乙酯：石油醚＝1:10，体积比)，得到白色固体(+)-2-硝基甲基-2-苯基-4-(吡啶-2-基)-4-氧代丁酸叔丁酯。反应的产率为95％；(c＝1.0,CH2Cl2)，光学纯度为97％ee。
采用HPLC对白色固体进行分析鉴定，Daicel Chiralcel OD-H色谱柱，正己烷：异丙醇＝90:10，1.0mL/min，λ＝254nm；tR(minor)＝8.24min，t(major)＝12.69min。1H NMR(300MHz,CDCl3):δ8.72(d,J＝4.4Hz,1H),8.06(d,J＝7.8Hz,1H),7.85(dd,J＝10.9,4.5Hz,1H),7.49(d,J＝7.3Hz,3H),7.45–7.30(m,3H),5.40(ABd,J＝12.4Hz,1H),5.36(ABd,J＝12.4Hz,1H),4.58(d,J＝19.2Hz,1H),4.28(d,J＝19.2Hz,1H),1.38(s,9H).13CNMR(75MHz,CDCl3):δ198.73,170.07,152.79,148.94,137.48,136.78,128.76,128.00,127.43,125.74,121.48,82.52,79.61,51.27,40.12,27.37。
实施例3：(+)-2-硝基甲基-2-苯基-4-(喹啉-2-基)-4-氧代丁酸叔丁酯的合 成
向干燥的10mL圆底烧瓶中加入双噁唑啉手性配体(8.1mg，0.024mmol)，Ni(acac)2(5.1mg，0.020mmol)，氮气保护下加入异丙醇2mL，室温下搅拌1.5h，再加入2-乙酰基喹啉(34.2mg,0.2mmol)，搅拌15min后加入3-硝基-2-苯基丙烯酸叔丁酯(75.1mg,0.3mmol)，加样完毕后，室温下反应过夜；TLC检测反应完全，反应混合物减压脱溶后直接通过硅胶层析柱分离提纯(乙酸乙酯：石油醚＝1:10，体积比)，得到白色固体(+)-2-硝基甲基-2-苯基-4-(喹啉-2-基)-4-氧代丁酸叔丁酯。反应的产率为97％；(c＝0.55,CH2Cl2)，光化学纯度为98％ee。
采用HPLC对白色固体进行分析鉴定，Daicel Chiralcel OD-H色谱柱，正己烷：异丙醇＝90:10，1.0mL/min，λ＝254nm；tR(minor)＝6.86min，t(major)＝8.39min。1H NMR(300MHz,CDCl3)δ8.27(d,J＝8.4Hz,2H),8.12(d,J＝8.5Hz,1H),7.82(ddd,J＝11.8,9.8,4.7Hz,2H),7.71–7.60(m,1H),7.58–7.48(m,2H),7.38(ddd,J＝14.3,8.3,4.6Hz,3H),5.44(ABd,J＝12.4Hz,1H),5.41(ABd,J＝12.5Hz,1H),4.77(d,J＝19.2Hz,1H),4.41(d,J＝19.2Hz,1H),1.39(s,9H).13C NMR(75MHz,CDCl3)δ199.00,170.05,152.27,146.88,137.47,136.72,130.44,129.83,129.50,128.65,128.50,127.87,127.34,125.67,117.51,82.44,79.43,51.31,39.80,27.29.
实施例4：2-硝基甲基-2-苯基-4-(吡啶-2-基)-4-羟基丁酸叔丁酯的合成
向25mL圆底烧瓶中加入(+)-2-硝基甲基-2-苯基-4-(吡啶-2-基)-4-氧代丁酸叔丁酯(148mg,0.4mmol)和甲醇5mL，于0℃分批加入NaBH4(16mg,0.4mmol)，加毕，继续搅拌15min，反应转化完全后，加入水和乙酸乙酯，进行萃取，有机相经无水Na2SO4干燥后，减压脱溶后直接通过硅胶层析柱分离提纯(乙酸乙酯：石油醚＝1:5，体积比)，得到2-硝基甲基-2-苯基-4-(吡啶-2-基)-4-羟基丁酸叔丁酯。无色油，产物的收率为94％(d.r.＝1.4:1)，其中，主要旋光异构体的收率为54％。(c＝1.0,CH2Cl2).主要旋光异构体的氢谱、碳谱数据如下：)1H NMR(300MHz,CDCl3)δ8.44(d,J＝4.5Hz,1H),7.60(td,J＝7.7,1.2Hz,1H),7.46–7.26(m,5H),7.20–6.94(m,2H),5.82(d,J＝14.4Hz,1H),5.35(d,J＝14.4Hz,1H),4.65(s,1H),4.41(d,J＝10.4Hz,1H),2.64(d,J＝14.8Hz,1H),2.43(dd,J＝15.0,11.0Hz,1H),1.36(s,9H).13C NMR(75MHz,CDCl3)δ170.90,160.67,147.65,137.74,136.51,128.76,127.58,125.47,122.19,119.81,81.94,77.76,68.69,52.61,42.47,27.22.ESI-HRMS Calcd for C20H25N2O5[M+H]+:373.1758,Found:373.1754.
实施例5：(+)-2-硝基甲基-2-苯基-4-(吡啶-2-基)丁酸内酯的合成
向25mL圆底烧瓶中加入(-)-2-硝基甲基-2-苯基-4-(吡啶-2-基)-4-羟基丁酸叔丁酯(80mg,0.2mmol)，于室温加入二氯甲烷10mL和催化剂三氟乙酸2mL，加毕，将反应移至30℃油浴中反应24h后，减压脱溶后直接通过硅胶层 析柱分离提纯(乙酸乙酯：石油醚＝1:2，体积比)，得到环化产物γ-丁内酯：(+)-2-硝基甲基-2-苯基-4-(吡啶-2-基)丁酸内酯。无色油，81％收率；(c＝0.31,CH2Cl2).1H NMR(300MHz,CDCl3)δ8.45(d,J＝4.5Hz,1H),7.40(td,J＝7.8,1.6Hz,1H),7.26(dd,J＝6.7,3.0Hz,2H),7.16(dd,J＝9.6,5.7Hz,3H),7.11–7.00(m,2H),5.72(dd,J＝8.9,3.0Hz,1H),4.91(d,J＝14.2Hz,1H),4.76(d,J＝14.2Hz,1H),3.48(dd,J＝13.8,3.2Hz,1H),3.26(dd,J＝13.8,9.0Hz,1H).13C NMR(75MHz,CDCl3)δ175.04,157.53,148.84,136.17,134.20,128.67,128.22,126.08,122.37,119.51,80.39,77.67,50.32,36.69.ESI-HRMS Calcd for C16H15N2O4[M+H]+:299.1026,Found:299.1024.
实施例6：(+)-2-胺甲基-2-苯基-4-(吡啶-2-基)-4-羟基丁酸叔丁酯的合成
向25mL圆底烧瓶中加入(-)-2-硝基甲基-2-苯基-4-(吡啶-2-基)-4-羟基丁酸叔丁酯(80mg,0.2mmol)，甲醇6mL，镍催化剂(50mg)；室温条件下，在氢气气氛中搅拌24h后，过滤除去镍催化剂，加水和乙酸乙酯，萃取，有机相经无水Na2SO4干燥后，减压脱溶后的得到β2,2-氨基酯(+)-2-胺甲基-2-苯基-4-(吡啶-2-基)-4-羟基丁酸叔丁酯。无色油，88％收率。(c＝0.42,CH2Cl2).1H NMR(300MHz,CDCl3)δ8.52(d,J＝4.4Hz,1H),7.65(t,J＝7.1Hz,1H),7.48–7.23(m,6H),7.18–7.11(m,1H),4.81(d,J＝9.3Hz,1H),3.58(br s,5H),2.71(d,J＝14.9Hz,1H),2.46(dd,J＝14.8,10.0Hz,1H),1.38(s,9H).ESI-HRMS Calcdfor C20H27N2O3[M+H]+:343.2016,Found:343.2013.
实施例7：(+)-2-硝基甲基-2-苯基丁二酸酯的合成
向25mL圆底烧瓶中加入合成(+)-2-硝基甲基-2-苯基-4-(1-甲基咪唑-2-基)-4-氧代丁酸叔丁酯(93mg,0.25mmol)，30mg分子筛，无水乙腈2mL；室温条件下，在氮气气氛中搅拌，加入三氟甲磺酸甲酯(CF3SO2Me,45mg,0.275mmol)，加毕，继续搅拌12h；然后加入无水甲醇1mL和DBU 0.1mL，并于室温继续搅拌1h，反应转化完全，加水和二氯甲烷，萃取，有机相经无水Na2SO4干燥后，减压脱溶后直接通过硅胶层析柱分离提纯(乙酸乙酯：石油醚＝1:10，体积比)，得到琥珀酸酯：(+)-2-硝基甲基-2-苯基丁二酸酯。白色固体的熔点为：80-81℃，92％收率；(c＝0.50,CH2Cl2).光化学纯度为：99.5％ee。
采用HPLC对白色固体进行分析鉴定，Daicel Chiralcel OD-H色谱柱，正己烷：异丙醇＝90:10，1.0mL/min，λ＝254nm；tR(minor)＝6.31min，t(major)＝7.45min。1H NMR(300MHz,CDCl3)δ7.43–7.28(m,5H),5.36(q,J＝13.1Hz,2H),3.71(s,3H),3.47(ABd,J＝17.2Hz,1H),3.32(ABd,J＝17.3Hz,1H),1.43(s,9H).13C NMR(75MHz,CDCl3)δ170.93,169.35,136.65,128.70,127.98,125.24,82.79,78.52,51.54,51.15,36.62,27.22.ESI-HRMS Calcd for C16H22NO6[M+H]+:322.1296,Found:322.1297.
实施例8：(-)-3-苯基-3-甲酸叔丁酯丁内酰胺的合成
向25mL圆底烧瓶中加入(+)-2-硝基甲基-2-苯基丁二酸酯(40mg,0.12mmol)，NiCl2.6H2O(43mg,0.18mmol)，无水乙醇2mL，于0℃在不断搅拌下分批加入NaBH4(68mg,1.8mmol)，加毕，恢复到室温搅拌9h，反应转化完全， 加入饱和氯化铵水溶液和二氯甲烷，萃取，有机相经无水Na2SO4干燥后，减压脱溶后直接通过硅胶层析柱分离提纯(乙酸乙酯：石油醚＝1:1，体积比)，得到γ-内酰胺：(-)-3-苯基-3-甲酸叔丁酯丁内酰胺。白色固体的熔点为：122-124℃，89％收率；(c＝0.62,CH2Cl2)，光化学纯度为99.2％ee。
采用HPLC对白色固体进行分析鉴定，Daicel Chiralcel OD-H色谱柱，正己烷：异丙醇＝80:20，1.0mL/min，λ＝210nm；tR(minor)＝6.82min，t(major)＝8.30min。1H NMR(300MHz,CDCl3)δ7.40-7.22(m,5H),6.33(s,1H),4.32(d,J＝9.8Hz,1H),3.61(d,J＝9.8Hz,1H),3.27(d,J＝16.7Hz,1H),2.75(d,J＝16.7Hz,1H),1.36(s,9H).ESI-HRMS Calcdfor C15H20NO3[M+H]+:262.1438,Found:262.1436。

Claims (9)

1.一种含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物及其衍生物的制备方法，所述化合物的结构通式如式I所示，所述衍生物的结构通式如式II所示：
其中，式I和式II中的R1为甲基、苄基、异丙基或叔丁基；R2为芳基；Ar为吡啶-2-基、嘧啶-2-基、吡嗪-2-基、噻唑-2-基、噁唑-2-基、N-甲基咪唑-2-基、苯并噻唑-2-基、苯并噁唑-2-基、喹啉-2-基或喹喔啉-2-基；
其特征在于，合成路线为：
具体步骤为：
在反应温度为-50℃～50℃的条件下，于有机溶剂中，在双噁唑啉手性配体-镍催化剂或膦-噁唑啉手性配体-铜催化剂的催化下，2-乙酰基氮杂芳香烃与α-取代-β-硝基丙烯酸酯反应，不对称合成(+)-2-硝基甲基-2-芳基-4-(氮杂芳香环-2-基)-4-丁酮酯，即式I所示含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物；
获得的含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物进一步转化为式II(1)所示γ-丁内酯类化合物、式II(2)所示β2,2-氨基酸酯类化合物、式II(3)所示琥珀酸酯类化合物或式II(4)所示γ-内酰胺类化合物；
所述双噁唑啉手性配体或膦-噁唑啉手性配体中的R为苯基、苄基、异丙基或叔丁基；镍催化剂为Ni(OAc)2.4H2O、Ni(OAc)2或Ni(acac)2；铜催化剂为Cu(OAc)2.H2O、Cu(OAc)2或Cu(OTf)2。
2.根据权利要求1所述的制备方法，其特征在于，所述的有机溶剂为甲醇、乙醇、异丙醇、异丁醇、四氢呋喃、甲苯、二氯甲烷、三氯甲烷或乙醚。
3.根据权利要求2所述的制备方法，其特征在于，所述的有机溶剂为异丙醇。
4.根据权利要求1所述的制备方法，其特征在于，所述双噁唑啉手性配体中的R为苯基；所述膦-噁唑啉手性配体中的R为叔丁基；镍催化剂为Ni(acac)2；铜催化剂为Cu(OAc)2.H2O。
5.根据权利要求1所述的制备方法，其特征在于，双噁唑啉手性配体与镍催化剂的摩尔当量比为1.0-1.2比1，膦-噁唑啉手性配体与铜催化剂的摩尔当量比为1.0-1.2比1。
6.根据权利要求5所述的制备方法，其特征在于，双噁唑啉手性配体与镍催化剂的摩尔当量比为1.2:1，膦-噁唑啉手性配体与铜催化剂的摩尔当量比为1.2:1。
7.根据权利要求1所述的制备方法，其特征在于，所述α-取代-β-硝基丙烯酸酯与2-乙酰基氮杂芳香烃的摩尔当量比为1.0-1.5比1；所述双噁唑啉手性配体-镍催化剂和膦-噁唑啉手性配体-铜催化剂的摩尔当量均为2-乙酰基氮杂芳香烃摩尔当量的1％-10％。
8.根据权利要求7所述的制备方法，其特征在于，所述α-取代-β-硝基丙烯酸酯与2-乙酰基氮杂芳香烃的摩尔当量比为1.5:1；所述双噁唑啉手性配体-镍催化剂和膦-噁唑啉手性配体-铜催化剂的摩尔当量均为2-乙酰基氮杂芳香烃摩尔当量的10％。
9.根据权利要求1所述的制备方法，其特征在于，所述的反应温度为室温。
CN201610390624.8A 2016-06-02 2016-06-02 含全碳季碳手性中心和氮芳香杂环的α,α-双取代-β-硝基酯类化合物及其衍生物的制备 Active CN106008328B (zh)

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