CN113248422A - 一种手性α-氮杂芳烃四级碳中心类化合物、其制备方法及应用 - Google Patents
一种手性α-氮杂芳烃四级碳中心类化合物、其制备方法及应用 Download PDFInfo
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- CN113248422A CN113248422A CN202010084754.5A CN202010084754A CN113248422A CN 113248422 A CN113248422 A CN 113248422A CN 202010084754 A CN202010084754 A CN 202010084754A CN 113248422 A CN113248422 A CN 113248422A
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- ONITWNIYPQSXDG-UHFFFAOYSA-N 2-(1-phenylethenyl)-1,3-benzothiazole Chemical group N=1C2=CC=CC=C2SC=1C(=C)C1=CC=CC=C1 ONITWNIYPQSXDG-UHFFFAOYSA-N 0.000 description 1
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- HNIXDYQCYLKTIT-UHFFFAOYSA-N 2-(1-phenylethenyl)quinoline Chemical group C=C(c1ccccc1)c1ccc2ccccc2n1 HNIXDYQCYLKTIT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开一种手性α‑氮杂芳烃四级碳中心类化合物、其制备方法及应用，属于有机合成领域。制备过程具体为：在保护气氛下，式I所示的N‑芳基取代环丙胺与式II所示的α‑芳基‑α‑（2‑氮杂芳基）取代末端烯烃在混合溶剂（乙醚：环戊基甲醚：苯=1:1:1）中以DPZ作为可见光氧化还原催化剂、BINOL衍生的双轴手性磷酰亚胺酸（BINOL‑IDPA，IV）作为手性催化剂，在可见光照射下于‑50~‑70℃反应完全，分离纯化得到目标手性α‑氮杂芳烃四级碳中心类化合物III，
Description
技术领域
本发明属于有机合成领域，具体涉及一种手性α-氮杂芳烃四级碳中心类化合物、其制备方法及应用。
背景技术
氮杂芳烃在很多天然和非天然活性物质、药物、配体和功能材料中广泛存在，例如，2012 年统计的世界销售额前200名药物中就有12种含有吡啶结构(http://www.pharmacytimes.com/publications/issue/2013/July2013/Top-200-Drugs-of-2012(accessedOct29,2014).)。氮杂芳烃手性衍生物的合成一直是合成化学领域的研究热点，因此发展一种绿色环保、高效合成手性α-氮杂芳烃四级碳中心类化合物的方法，在绿色有机合成化学研究中具有重要意义。
直接利用含嵌入亚胺(C＝N)基团氮杂芳烃本身的缺电子性质，实现前手性氮杂芳烃的催化不对称转化是一种直接、高效且简便的策略。在这些反应中，已建立很多高效的方法来实现诸如吡啶、喹啉等化合物不同位置的高立体选择性合成(Best,D.&Lam,H.W.J.Org. Chem.2014,79,831-845；Izquierdo,J.etal.J.Am.Chem.Soc.2016,138,3282-3285；Yu,S.,Sang, H.L.&Ge,S.Angew.Chem.,Int.Ed.2017,56,15896-15900；Proctor,R.S.J.,Davis,H.J.& Phipps,R.J.Science,2018,360,419-422；Yin,Y.etal.J.Am.Chem.Soc.2018,140,6083-6087； Bai,X.,Zeng,G.,Shao,T.&Jiang,Z.Angew.Chem.,Int.Ed.2017,56,3684-3688.)。而对于构建氮杂芳烃α-位四级碳中心，目前仅有一例报道(Izquierdo,J.etal.J.Am.Chem.Soc.2016,138, 3282-3285.)，该方法使用2-腈基氮杂芳烃氧化物作为亲核试剂，该底物含有强拉电子腈基且需事先将氮杂芳烃进行氧化，大大提高结构中C-H键的酸性才能导致有效的去质子化，因此无法广泛用于手性α-氮杂芳烃四级碳中心类化合物的合成。
近年来，可见光催化反应因其绿色、高效、温和在有机合成领域得到了广泛应用。由于反应条件无重金属残留，产物无需做重金属去除，通过可见光催化N-芳基取代环丙胺与α-芳基-α-(2-氮杂芳烃)取代末端烯烃两步自由基加成环化，合成手性α-氮杂芳烃四级碳中心类化合物也因此具有很大的应用前景。
发明内容
本发明目的在于克服现有技术缺陷，提供一种手性α-氮杂芳烃四级碳中心类化合物、其制备方法及应用。本发明制备方法反应底物简单，反应条件温和，无重金属参与，收率高且对映选择性高。
基于上述目的，本发明采取如下技术方案：
一种手性α-氮杂芳烃四级碳中心类化合物，结构通式如下：
上述手性α-氮杂芳烃四级碳中心类化合物的可见光不对称催化合成方法，
式I、式II、式III中，Ar、Ar1为苯基、
R1为Me、F、Br或OTf，Ar2不饱和氮杂环为
Ar3＝3-(3',5'-二甲基苯基)苯基。
具体制备步骤为：在保护气氛下，将式I所示的N-芳基取代环丙胺、式II所示的α-芳基 -α-(2-氮杂芳基)取代末端烯烃化合物、有机光催化剂DPZ和手性催化剂BINOL-IDPA溶于混合溶剂(体积比，乙醚：环戊基甲醚：苯＝1:1:1)中，在可见光照射下于-50～-70℃反应完全，分离纯化，即得到式III所示的手性α-氮杂芳烃四级碳中心类化合物，且在氮杂芳烃α- 位构建一个手性五元环戊烷结构，这类骨架在很多具有重要活性的药物分子中广泛存在，如除草剂(Herbicide)、组蛋白脱乙酰酶抑制剂(Histone deacetylase inhibitor)、蛋白质酪氨酸磷酸酶1B(PTP1B)抑制剂(PTP1B inhibitor)、脂肪酸结合蛋白抑制剂(Fattyacidbinding protein inhibitor)等。
氮杂芳烃α-位含手性五元环戊烷结构的重要药物分子结构如上所示。
上述的手性催化剂BINOL-IDPA和有机光催化剂DPZ的结构式如上所示。
具体的，化合物I和化合物II的摩尔比为1.5:1，所述有机光催化剂DPZ的加入量为化合物I摩尔量的0.5％，所述手性催化剂BINOL-IDPA的加入量为化合物II摩尔量的0.2倍。所述溶剂为混合溶剂(体积比，乙醚：环戊基甲醚：苯＝1:1:1)。所述可见光为波长450-455nm 的可见光，具体可见光来自于3W蓝灯照射。
和现有技术相比，本发明方法的有益效果：
本发明在反应中使用无金属的DPZ光催化剂，催化剂用量极少，催化效率高，且反应条件温和，稳定高效，操作简单，环境友好，产物转化率高，选择性好。与现有合成方法相比，本发明方法最大的特点是底物合成简单、范围广泛且不受取代基限制；使用无金属的DPZ光催化剂，催化剂用量少，反应条件温和，快速高效，产率高，对映选择性高，绿色环保，极具推广应用价值。
具体实施方式
以下结合实施例对本发明的技术方案作进一步地详细介绍，但本发明的保护范围并不局限于此。
下述实施例中，有机光催化剂DPZ可参照文献(Zhao Y.,
ZhangC.,
Chin K.F.,Pytela O., Wei G.,Liu H.,Bures F.*,Jiang Z.*RSC Adv.,2014,4,30062)制备获得。手性催化剂 BINOL-IDPA自行合成(
I,List B.Nature.,2012,483:315-319)，手性前体BINOL购自大赛璐。
实施例1
一种手性α-氮杂芳烃四级碳中心类化合物的可见光不对称催化合成方法，其反应式如下所示。N-((1R,2S)-2-苯基-2-(吡啶-2基)环戊基)苯胺的具体制备步骤如下：
将35.5μL(0.0005mmol,0.005equiv)的DPZ溶液(1.0mg的DPZ溶于200uL甲苯中制得)加到25mL Schlenk管中，真空除去溶剂。随后加入N-苯基环丙胺20.0mg(0.15mmol)、 2-(1-苯基乙烯基)吡啶18.1mg(0.1mmol)，手性催化剂BINOL-IDPA28.0mg(0.02mmol)，然后加入6mL混合溶剂(体积比，乙醚：环戊基甲醚：苯＝1:1:1)，依次经过抽真空、-80℃冷冻3-5min、恢复至室温、氩气保护(一般整个流程进行三次)，将反应瓶置于-60℃恒温箱中，在一个3W蓝色LED灯(LED灯距反应瓶为6cm；LED灯波长为450-455nm)照射条件下搅拌60h。待反应结束后，用旋转蒸发仪蒸去混合溶剂，直接通过柱层析分离(体积比，正己烷/乙酸乙酯80～5:1)即得到N-((1R,2S)-2-苯基-2-(吡啶-2基)环戊基)苯胺25.7mg淡黄色油状物，产率为82％，光学纯为91％ee，非对映选择性dr>19:1。核磁数据为：1H NMR (300MHz,CDCl3)δ8.57(d,J＝4.1Hz,1H),7.59(t,J＝7.5Hz,1H),7.36–7.25(m,6H),7.13 (dd,J＝15.7,7.9Hz,3H),6.71–6.58(m,3H),4.91(t,J＝5.4Hz,1H),3.59(br,1H),2.76(d,J＝ 21.4Hz,1H),2.60(ddd,J＝13.1,8.6,4.2Hz,1H),2.16(dt,J＝12.6,7.8Hz,1H),1.98–1.87(m,1H),1.70(dt,J＝16.4,8.2Hz,2H)；13C NMR(75MHz,CDCl3)δ165.7,148.6,147.6,143.2,136.3, 129.1,128.8,128.3,126.5,121.8,121.0,116.8,113.3,61.4,59.4,35.8,30.5,20.6；HRMS(ESI) m/z 315.1856(M+H+),calc.for C22H23N2315.1850.
实施例2
合成N-((1R,2S)-2-(2-氟苯基)-2-(吡啶-2-基)环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(1-(2-氟苯)乙烯基)吡啶替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-(2-氟苯基)-2-(吡啶-2-基)环戊基)苯胺21.9mg，为淡黄色油状物，产率66％，光学纯为96％ee，非对映选择性dr>19:1。核磁数据为：1H NMR (300MHz,CD2Cl2)δ8.55(d,J＝4.6Hz,1H),7.68(t,J＝7.8Hz,1H),7.46(t,J＝7.7Hz,1H), 7.30(d,J＝8.0Hz,1H),7.24–7.00(m,5H),6.87(dd,J＝11.6,8.1Hz,1H),6.60(t,J＝8.6Hz, 3H),4.75(s,1H),4.31(dd,J＝10.7,6.7Hz,1H),3.20–2.96(m,1H),2.56–2.22(m,1H),2.17–1.95(m,2H),1.87(dd,J＝21.0,7.7Hz,1H),1.42–1.15(m,1H)；13C NMR(75MHz,CD2Cl2)δ 162.5,160.7(d,J＝246.8Hz),148.1,147.1,135.9,134.6(d,J＝13.0Hz),128.8,127.7(d,J＝8.6 Hz),127.3(d,J＝5.0Hz),123.5(d,J＝3.3Hz),122.0,121.0,116.0,115.2(d,J＝22.6Hz),112.1, 59.1,55.1(d,J＝1.0Hz),34.8,34.8,28.7,19.1；高分辨数据为：HRMS(ESI)m/z 333.1762.1534 (M+H+),calc.for C22H22FN2333.1757.
实施例3
合成N-((1R,2S)-2-(2-甲基苯基)-2-(吡啶-2-基)环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(1-(4-甲基苯基)乙烯基)吡啶替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-(2-甲基苯基)-2-(吡啶-2-基)环戊基)苯胺 27.6mg，为黄色油状物，产率84％，光学纯为81％ee，非对映选择性dr>19:1。核磁数据为：1H NMR(300MHz,CDCl3)δ8.53(d,J＝3.9Hz,1H),7.52(td,J＝7.9,1.7Hz,1H),7.35–7.20 (m,1H),7.20–6.99(m,7H),6.63(dd,J＝19.7,7.6Hz,3H),4.89(t,J＝5.3Hz,1H),3.34(br,1H), 2.80–2.45(m,2H),2.29(s,3H),2.14(ddd,J＝16.7,11.5,6.6Hz,1H),2.00–1.82(m,1H),1.78– 1.54(m,2H)；13C NMR(75MHz,CDCl3)δ165.9,148.5,147.7,140.1,136.2,136.0,129.0,129.0, 128.6,121.7,120.9,116.8,113.3,61.0,59.3,35.9,30.4,20.9,20.5；高分辨数据为：HRMS(ESI) m/z 329.2012(M+H+),calc.for C23H25N2329.2009.
实施例4
合成3-((1S,2R)-2’-(苯胺)-1’-(吡啶)环戊基)苯基三氟甲磺酸酯的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用3-(1’-(吡啶)乙烯基)苯基三氟甲磺酸酯替换，其它步骤与实施例1相同，得到3-((1S,2R)-2’-(苯胺)-1’-(吡啶)环戊基)苯基三氟甲磺酸酯37.0mg，为黄色油状物，产率80％，光学纯为90％ee，非对映选择性dr>19:1。核磁数据为：1H NMR(300MHz,CD2Cl2)δ8.54(d,J＝3.7Hz,1H),7.58(t,J＝6.8Hz,1H),7.34(s, 2H),7.24(d,J＝9.3Hz,2H),7.19–6.99(m,4H),6.61(t,J＝9.6Hz,3H),5.02(t,J＝5.4Hz,1H), 4.72(s,1H),2.80–2.41(m,2H),2.14(ddd,J＝16.3,13.3,8.0Hz,1H),2.04–1.80(m,1H),1.65 (qdd,J＝11.7,7.4,4.2Hz,2H)；13C NMR(75MHz,CD2Cl2)δ164.1,149.1,148.4,147.1,146.5, 136.2,129.3,128.6,128.6,121.6,121.2,121.1,118.7,118.4(q,J＝320.7Hz),116.7,112.9,60.9, 59.2,35.2,30.2,19.8；高分辨数据为：HRMS(ESI)m/z 463.1298(M+H+),calc.for C23H22F3N2O3S 463.1292.
实施例5
合成N-((1R,2S)-2-(4’-甲基苯基)-2-(4’-溴吡啶)环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(1-苯基乙烯基)-4-溴吡啶替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-(4’-甲基苯基)-2-(4’-溴吡啶)环戊基)苯胺37.2mg，为黄色油状物，产率95％，光学纯为90％ee，非对映选择性dr＝14:1。核磁数据为：1H NMR (300MHz,CD2Cl2)δ8.35(d,J＝5.2Hz,1H),7.42(d,J＝1.3Hz,1H),7.34–7.17(m,6H),7.09(t, J＝7.9Hz,2H),6.68–6.50(m,3H),4.94(t,J＝5.1Hz,1H),2.75–2.46(m,2H),2.09(tt,J＝12.9, 6.4Hz,1H),1.99–1.82(m,1H),1.76–1.57(m,2H)；13C NMR(75MHz,CD2Cl2)δ167.0,148.9, 147.3,142.3,132.5,128.6,128.4,127.9,126.3,124.9,124.1,116.5,112.8,61.2,58.9,35.2,30.0, 20.0；高分辨数据为：HRMS(ESI)m/z393.0961(M+H+),calc.for C22H22N2393.0953.
实施例6
合成N-((1R,2S)-2-苯基-2-吡啶环戊基)-3-氟苯胺的反应式如下所示。
本实施例中，将实施例1中的N-苯基环丙胺用N-3-氟苯基环丙胺替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-苯基-2-吡啶环戊基)-3-氟苯胺18.3mg，为黄色油状物，产率55％，光学纯为91％ee，非对映选择性dr＝12:1。核磁数据为：1HNMR(300MHz,CDCl3)δ8.54(d, J＝4.1Hz,1H),7.53(td,J＝8.0,1.5Hz,1H),7.31–7.19(m,6H),7.09–6.97(m,2H),6.36–6.24 (m,3H),4.95(t,J＝5.3Hz,1H),3.48(br,1H),2.68–2.52(m,2H),2.16(ddd,J＝12.7,9.5,6.2Hz, 1H),1.90(ddd,J＝13.8,8.7,4.7Hz,1H),1.74–1.59(m,2H)；13CNMR(75MHz,CDCl3)δ165.4, 164.1(d,J＝242.2Hz),149.4(d,J＝10.9Hz),148.4,143.0,136.4,130.0(d,J＝10.3Hz),128.8, 128.3,126.7,121.9,121.2,109.2(d,J＝2.2Hz),103.2(d,J＝21.6Hz),99.8(d,J＝25.4Hz),61.4, 59.3,35.9,30.6,20.6；高分辨数据为：HRMS(ESI)m/z333.1759(M+H+),calc.forC22H22FN2 333.1762.
实施例7
合成N-((1R,2S)-2-(1-甲基-1H-苯并咪唑-2-基)-2-苯基环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(1-苯基乙烯基)-1-甲基-1H-苯并咪唑替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-(1-甲基-1H-苯并咪唑-2-基)-2-苯基环戊基)苯胺31.9mg，为黄色油状物，产率87％，光学纯为93％ee，非对映选择性dr>19:1。核磁数据为：1HNMR(300MHz,CDCl3)δ7.87(d,J＝4.7Hz,1H),7.30(dt,J＝18.7,7.0Hz,8H), 7.13(t,J＝7.4Hz,2H),6.67(t,J＝8.2Hz,3H),5.39(t,J＝5.6Hz,1H),3.28(s,3H),3.24–3.00 (m,1H),2.92(dt,J＝13.3,8.5Hz,1H),2.70–2.50(m,1H),2.48–2.29(m,1H),2.05(td,J＝16.2, 12.2Hz,1H),1.89–1.64(m,2H)；13CNMR(75MHz,CDCl3)δ158.4,147.5,141.7,140.4,137.0, 128.8,128.6,128.0,127.3,122.2,121.6,119.8,117.0,113.9,108.7,61.1,56.2,34.8,32.0,31.0, 21.7；高分辨数据为：HRMS(ESI)m/z368.2121(M+H+),calc.forC20H20N2Na368.2117.
实施例8
合成N-((1R,2S)-2-苯基-2-喹啉环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(1-苯基乙烯基)喹啉替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-苯基-2-喹啉环戊基)苯胺28.0mg，为黄色油状物，产率77％，光学纯为87％ee，非对映选择性dr>19:1。1H NMR(300MHz,CDCl3)δ8.03(d,J＝ 8.3Hz,1H),7.85(d,J＝8.7Hz,1H),7.68–7.52(m,2H),7.50–7.32(m,1H),7.33–6.97(m,8H), 6.58(t,J＝7.9Hz,3H),5.25(t,J＝5.2Hz,1H),3.26(s,1H),2.84–2.44(m,2H),2.36–2.11(m, 1H),1.93–1.79(m,1H),1.71(ddd,J＝13.7,10.2,5.3Hz,1H),1.62–1.43(m,1H)；13C NMR(75 MHz,CDCl3)δ165.0,147.9,146.9,143.0,135.9,129.7,129.1,129.0,128.3,127.2,126.7,126.5, 126.0,120.8,116.7,113.5,62.6,59.1,35.8,31.3,21.0；高分辨数据为：HRMS(ESI)m/z 365.2012 (M+H+),calc.for C26H25N2365.2006.
实施例9
合成N-((1R,2S)-2-苯基-1-异喹啉环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用1-(1-苯基乙烯基)异喹啉替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-苯基-1-异喹啉环戊基)苯胺26.8mg，为黄色油状物，产率73％，光学纯为91％ee，非对映选择性dr>19:1。核磁数据为：1HNMR(300MHz,CD2Cl2) δ8.45(d,J＝5.6Hz,1H),7.76(d,J＝8.2Hz,1H),7.63(d,J＝8.9Hz,1H),7.56(d,J＝5.7Hz, 1H),7.48(t,J＝7.4Hz,1H),7.33–7.14(m,6H),7.07(t,J＝7.9Hz,2H),6.68–6.42(m,3H), 5.37(t,J＝7.4Hz,1H),3.24–2.95(m,1H),2.32(dt,J＝20.1,9.2Hz,2H),2.13–1.90(m,1H), 1.62(dt,J＝18.4,10.0Hz,2H)；13C NMR(75MHz,CDCl3)δ164.5,148.1,144.2,140.5,137.5, 128.8,128.7,128.2,127.5,126.6,126.3,125.8,119.9,116.5,113.8,61.2,59.9,37.0,30.9,21.3；高分辨数据为：HRMS(ESI)m/z 365.2012(M+H+),calc.for C26H25N2365.2010.
实施例10
合成N-((1R,2S)-2-(1-甲基-1H-咪唑-2-基)-2-苯基环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(1-苯基乙烯基)-1-甲基-1H-咪唑替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-(1-甲基-1H-咪唑-2-基)-2-苯基环戊基)苯胺25.4mg，为黄色油状物，产率80％，光学纯为91％ee，非对映选择性dr>19:1。核磁数据为：1H NMR(300MHz,CDCl3)δ7.32(dd,J＝12.6,6.8Hz,3H),7.19(d,J＝7.5Hz,2H),7.08(dd, J＝14.6,7.0Hz,3H),6.80(s,1H),6.62(m,3H),5.09(t,J＝5.6Hz,1H),3.12(s,3H),2.77(m, 1H),2.53(dd,J＝16.0,12.3Hz,1H),2.29(m,1H),1.99(d,J＝4.3Hz,1H),1.72(m,2H)；13C NMR(75MHz,CDCl3)δ151.4,147.5,140.8,128.9,128.6,128.0,127.2,126.0,122.4,117.0, 113.8,60.9,55.7,34.3,34.0,31.7,21.7；高分辨数据为：HRMS(ESI)m/z 318.1965(M+H+),calc. for C21H24N3318.1962.
实施例11
合成N-((1R,2S)-2-(1-甲基-1H-咪唑-2-基)-2-(4-溴苯基)环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(4-溴苯基)乙烯基)-1-甲基-1H- 咪唑替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-(1-甲基-1H-咪唑-2-基)-2-(4-溴苯基) 环戊基)苯胺32.4mg，为黄色固体，熔点为：60.1-61.9℃，产率82％，光学纯为90％ee，非对映选择性dr＝12:1。核磁数据为：1HNMR(300MHz,CDCl3)δ7.40(d,J＝8.4Hz,2H),7.11– 6.95(m,5H),6.76(s,1H),6.60(dd,J＝17.1,7.7Hz,3H),5.10(t,J＝5.8Hz,1H),3.09(s,3H), 3.07–2.75(m,1H),2.65(dt,J＝13.1,8.5Hz,1H),2.46(dt,J＝12.0,8.2Hz,1H),2.28–2.18(m, 1H),1.92(td,J＝7.5,4.0Hz,1H),1.70–1.55(m,2H)；13CNMR(75MHz,CDCl3)δ150.9,147.3, 140.2,131.5,129.7,128.9,126.3,122.5,121.1,117.2,113.9,61.1,55.3,34.4,34.0,32.0,21.6；高分辨数据为：HRMS(ESI)m/z 396.1070(M+H+),calc.for C21H23BrN3396.1065.
实施例12
合成N-((1R,2S)-2-苯基-2-噻唑环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(1-苯基乙烯基)-噻唑替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-苯基-2-噻唑环戊基)苯胺22.4mg，为黄色油状物，产率70％，光学纯为92％ee，非对映选择性dr>19:1。1HNMR(300MHz,CD2Cl2)δ7.65(d,J＝3.2Hz,1H),7.38(d,J＝7.2Hz,2H),7.26(dt,J＝6.7,5.3Hz,4H),7.09(t,J＝7.8Hz,2H),6.64(t, J＝7.3Hz,1H),6.55(d,J＝8.0Hz,2H),4.99–4.80(m,1H),2.69(dt,J＝26.2,10.5Hz,2H),2.13 (dd,J＝18.1,11.6Hz,1H),1.97(dt,J＝15.9,11.5Hz,1H),1.87–1.66(m,2H)；13C NMR(75 MHz,CD2Cl2)δ177.1,146.8,141.6,141.3,128.7,128.1,128.0,126.7,118.7,117.0,113.0,61.5, 60.2,36.2,30.2,20.4；高分辨数据为：HRMS(ESI)m/z321.1420(M+H+),calc.for C20H21N2S 321.1414.
实施例13
合成N-((1R,2S)-2-苯基-2-苯并噻唑环戊基)苯胺的反应式如下所示。
本实施例中，将实施例1中的2-(1-苯基乙烯基)吡啶用2-(1-苯基乙烯基)-苯并噻唑替换，其它步骤与实施例1相同，得到N-((1R,2S)-2-苯基-2-苯并噻唑环戊基)苯胺26.8mg，为黄色油状物，产率82％，光学纯为94％ee，非对映选择性dr>19:1。1H NMR(300MHz,CD2Cl2)δ7.96 (d,J＝8.1Hz,1H),7.79(d,J＝7.9Hz,1H),7.42(t,J＝5.6Hz,3H),7.38–7.18(m,4H),7.11(t,J ＝7.8Hz,2H),6.63(dd,J＝19.1,7.6Hz,3H),5.00(dd,J＝5.5,3.4Hz,1H),2.98–2.57(m,2H), 2.39–2.12(m,1H),2.13–1.92(m,1H),1.89–1.70(m,2H)；13C NMR(75MHz,CD2Cl2)δ177.5, 152.4,146.9,140.9,135.2,128.6,128.2,128.0,126.9,125.4,124.4,122.5,121.1,116.8,112.9, 61.1,60.8,36.0,30.4,20.4；高分辨数据为：HRMS(ESI)m/z 371.1576(M+H+),calc.for C24H23N2S 371.1569.
生物活性评价
将化合物分别溶解于DMSO中配置成10mM母液，用无血清培养基分别稀释成100μM、75μM、50μM、25μM、10μM、5μM工作液备用。在细胞水平对制备的化合物进行生物活性评价：乳腺癌MCF-7、肝癌HβG2、宫颈癌Hela、结肠癌HCT-116四株细胞株，将处于对数生长期的细胞株制成浓度为1×10-5个/mL的细胞悬液，每孔加入90μL细胞悬液，接种于96孔细胞培养板中，接种4-6h细胞贴壁后，分别加入10μL不同浓度的化合物溶液，孵育48h，每孔加入10μLCCK-8溶液，继续在培养箱中培养2-4h后，用酶标仪测定450nm 处的吸光度。
细胞活力率＝[1-(对照组-实验组)/(对照组-空白组)]×100％。其中对照组为含有细胞的培养基、CCK-8、无待测化合物、空白组是仅含CCK-8。4000-6000个细胞的标准接种于96孔细胞培养板中，孵育24小时后，分别加入不同浓度的化合物，继续培养48h，向每孔加入10μL CCK-8溶液，将细胞培养板放入二氧化碳培养箱中孵育3h，最后使用全波长酶标仪在450nm 处测量其OD值。计算得到细胞抑制率，统计如表1所示：
表1不同手性α-氮杂芳烃四级碳中心类化合物对不同癌细胞的抑制率
由表1可知，本发明实施例1至13制备得到的化合物对结肠癌HCT-116、HT-29、肝癌HβG2、宫颈癌Hela、乳腺癌MCF-7五类癌细胞表现出一定的活性，有望应用于抗癌药物的制备。因此，按照药物开发的一般途径(先进行常规的抗肿瘤体外筛选，然后进行针对性的研究)，本发明化合物可以通过与人体可接受的酸成盐或与药用载体混合制备新的抗肿瘤药物。
最后所应说明的是：上述实施例仅用于说明而非限制本发明的技术方案，任何对本发明进行的等同替换及不脱离本发明精神和范围的修改或局部替换，其均应涵盖在本发明权利要求保护的范围之内。
Claims (7)
1.一种手性α-氮杂芳烃四级碳中心类化合物，其特征在于，结构通式如下：
2.权利要求1所述手性α-氮杂芳烃四级碳中心类化合物的可见光不对称催化合成方法，其特征在于，具体制备步骤为：在保护气氛下，将式I所示的N-芳基取代环丙胺与式II所示的α-芳基-α-(2-氮杂芳基)取代末端烯烃在有机溶剂中以DPZ作为可见光氧化还原催化剂、BINOL-IDPA作为手性催化剂，在可见光照射下于-50～-70℃反应完全，分离纯化得到目标手性氮杂芳烃化合物III，
Ar、Ar1为苯基、
R1为Me、F、Br或OTf，Ar2不饱和氮杂环为
Ar3＝3-(3',5'-二甲基苯基)苯基。
3.根据权利要求2所述手性α-氮杂芳烃四级碳中心类化合物的可见光不对称催化合成方法，其特征在于，化合物I和化合物II的摩尔比为1.5:1，所述有机光催化剂DPZ的加入量为化合物I摩尔量的0.5％，所述手性催化剂BINOL-IDPA的加入量为化合物II摩尔量的0.2倍。
4.根据权利要求2所述手性α-氮杂芳烃四级碳中心类化合物的可见光不对称催化合成方法，其特征在于，所述的有机溶剂为混合溶剂，以体积比计，具体为乙醚：环戊基甲醚：苯＝1:1:1。
5.根据权利要求2所述手性α-氮杂芳烃四级碳中心类化合物的可见光不对称催化合成方法，其特征在于，所述可见光波长为450nm―455nm。
6.权利要求1所述手性α-氮杂芳烃四级碳中心类化合物在制备抗肿瘤药物中的应用。
7.根据权利要求6所述得应用，其特征在于，所述抗肿瘤药物是指治疗乳腺癌、肝癌、宫颈癌或结肠癌的药物。
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