CN111646992B - 一种季碳中心的全取代吡啶化合物及其制备方法 - Google Patents

一种季碳中心的全取代吡啶化合物及其制备方法 Download PDF

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CN111646992B
CN111646992B CN202010507993.7A CN202010507993A CN111646992B CN 111646992 B CN111646992 B CN 111646992B CN 202010507993 A CN202010507993 A CN 202010507993A CN 111646992 B CN111646992 B CN 111646992B
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刘文博
蔡进辉
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Abstract

本发明提供了一种季碳中心的全取代吡啶化合物及其制备方法，在金属镍催化下炔烃和高炔丙基取代的二取代丙二腈类化合物发生[2+2+2]环加成反应。本发明的制备方法选用廉价镍金属催化剂，通过两组份反应一步构建吡啶环的同时对丙二腈衍生物进行去对称化构建手性，具有成本低，原料易得，反应条件温和，对映选择性好等特点。该方法还提供了一种C2对称的螺吡啶化合物V的制备方法。所制备的含有氰基取代的全取代吡啶化合物和C2对称的螺吡啶化合物广泛地应用于有机合成、药物化学和材料领域。

Description

一种季碳中心的全取代吡啶化合物及其制备方法
技术领域
本发明涉及有机合成技术领域，具体涉及一种季碳中心的全取代吡啶化合物及其制备方法。
背景技术
全取代吡啶衍生物是一类非常重要的杂环类化合物，不仅是许多天然产物、药物分子以及生物活性分子的基本核心骨架，而且在农药化学领域中起着非常重要的作用。由于这类全取代吡啶化合物具有重要的潜在应用价值，合成这类化合物有非常重要的意义。迄今为止，虽然已有很多文献报道了合成这些化合物的研究方法，而进一步发展其合成方法仍然是有机合成领域中的热点。
在有机合成方法学中，α位手性中心的吡啶衍生物的合成因吡啶化合物在反应过程中会毒化催化剂而具有一定的挑战，到目前为止，报道的方法较为稀少，而且大部分方法需要使用预先官能团化的吡啶化合物为原料。(1)2-酰基或亚胺基或烯基取代的吡啶经过1,2-加成反应，1,2-还原反应或α-质子化反应[a)V.Komanduri,M.J.Krische,J.Am.Chem.Soc.2006,128,16448；b)D.K.Friel,M.L.Snapper,A.H.Hoveyda,J.Am.Chem.Soc.2008,130,9942；c)V.Bizet,G.M.Borrajo-Calleja,C.Besnard,C.Mazet,ACS Catal.2016,6,7183；d)Y.Yin,Y.Dai,H.Jia,J.Li,L.Bu,B.Qiao,X.Zhao,Z.Jiang,J.Am.Chem.Soc.2018,140,6083；e)B.Qiao,C.Li,X.Zhao,Y.Yin,Z.Jiang,Chem.Commun.2019,55,7534.]。(2)2-卤代吡啶的芳基化反应或2-吡啶硼酸的烯丙基芳基化反应[a)S.Ge,J.F.Hartwig,J.Am.Chem.Soc.2011,133,16330.b)A.Ghosh,J.A.Walker,A.Ellern,L.M.Stanley,ACS Catal.2016,6,2673；c)P.
Figure BDA0002527237430000011
T.Palacin,M.Sidera,S.P.Fletcher,Nat.Commun.2017,8,15762.]。(3)2-烷基取代吡啶苄位的烯丙基化反应[B.M.Trost,D.A.Thaisrivongs,J.Am.Chem.Soc.2009,131,12056.]。(4)吡啶α位的Minisci加成反应或C-H烷基化反应[(a)R.S.J.Proctor,H.J.Davis,R.J.Phipps,Science2018,360,419；b)D.Zheng,A.Studer,Angew.Chem.Int.Ed.2019,58,15803.c)G.Song,W.W.N.O,Z.Hou,J.Am.Chem.Soc.2014,136,12209.]。(5)[2+2+2]环加成反应[a)A.Wada,K.Noguchi,M.Hirano,K.Tanaka,Org.Lett.2007,9,1295；b)G.Onodera,Y.Shimizu,J.Kimura,J.Kobayashi,Y.Ebihara,K.Kondo,K.Sakata,R.Takeuchi,J.Am.Chem.Soc.2012,134,10515.]。
氰基是一种重要的取代基，在药物中起着重要的作用，具有生物相容性和代谢稳定性，可以促进极性相互作用，增强氢键性质，改善分子的毒理学特征。近年来在药物和临床候选药物分子中，越来越多的药物分子都含有氰基取代基。含有氰基的全碳季碳立体中心的生物活性化合物，可以防止化合物氰基的α-碳氧化，从而不会释放有毒氰化物。[a)Y.Wang,Y.Du,N.Huang,Future Med.Chem.2018,10,2713；b)T.Sterling,J.J.Irwin,J.Chem.Inf.Model.2015,55,2324；c)F.F.Fleming,L.Yao,P.C.Ravikumar,L.Funk,B.C.Shook,J.Med.Chem.2010,53,7902；d)J.Michel,J.Tirado-Rives,W.L.Jorgensen,J.Am.Chem.Soc.2009,131,15403；e)H.Tanii,K.Hashimoto,Toxicol.Lett.1984,22,267；f)A.E.Ahmed,N.M.Trieff,Prog.Drug Metab.1983,7,229.]。此外，氰基基团是有机合成中最有用的官能团之一，可以转化为各种官能团，例如羧酸，酰胺，醛，胺，噁唑啉和吡啶等[a)F.F.Fleming,Nat.Prod.Rep.1999,16,597；b)K.Friedrich,K.Wallenfels,The Chemistryof the Cyano Group；Wiley-Interscience:New York.1970；c)Z.Zhang,X.Zhang,D.A.Nagib,Chem 2019,5,3127；d)Z.Jiao,K.W.Chee,J.Zhou,J.Am.Chem.Soc.2016,138,16240.]。因此在合成化学领域中合成含有氰基的化合物受到了科学家们的广泛关注。目前已经报道的合成这类含氰基季碳中心结构的方法主要包括：(1)α-氰基羰基化物的官能化反应[a)R.Kuwano,H.Miyazaki,Y.Ito,J.Organomet.Chem.2000,603,18；b)Y.Kawato,N.Takahashi,N.Kumagai,M.Shibasaki,Org.Lett.2010,12,1484；c)S.Mukhopadhyay,U.Nath,S.C.Pan,Adv.Synth.Catal.2017,359,3911；d)K.Nakashima,Y.Noda,S.-i.Hirashima,Y.Koseki,T.Miura,J.Org.Chem.2018,83,2402；e)K.Nagata,D.Sano,Y.Shimizu,M.Miyazaki,T.Kanemitsu,T.Itoh,Tetrahedron:Asymmetry 2009,20,2530；f)For a decarboxylative alkylation:L.Yin,M.Kanai,M.Shibasaki,J.Am.Chem.Soc.2009,131,9610.]。(2)烯酮亚胺的官能团化反应[a)A.H.Mermerian,G.C.Fu,Angew.Chem.Int.Ed.2005,44,949；b)S.E.Denmark,T.W.Wilson,M.T.Burk,J.R.Heemstra,Jr.J.Am.Chem.Soc.2007,129,14864；c)J.Zhao,X.Liu,W.Luo,M.Xie,L.Lin,X.Feng,Angew.Chem.Int.Ed.2013,52,3473；d)J.Zhao,B.Fang,W.Luo,X.Hao,X.Liu,L.Lin,X.Feng,Angew.Chem.Int.Ed.2015,54,241；e)B.W.H.Turnbull,P.A.Evans,J.Am.Chem.Soc.2015,137,6156；f)Z.Jiao,K.W.Chee,J.Zhou,J.Am.Chem.Soc.2016,138,16240；g)For a seminal report:A.Q.Mi,Z.Y.Wang,Y.Z.Jiang,Tetrahedron:Asymmetry,1993,4,1957]。(3)二羰基化合物的α-氰基化反应[a)R.Chowdhury,J.
Figure BDA0002527237430000022
J.Novacek,M.Waser,Tetrahedron Lett.2015,56,1911；b)M.Chen,Z.-T.Huang,Q.-Y.Zheng,Org Biomol.Chem.2015,13,8812；c)J.-S.Qiu,Y.-F.Wang,G.-R.Qi,P.G.Karmaker,H.-Q.Yin,F.-X.Chen,Chem.Eur.J.2017,23,1775.]。(4)烯烃的氢氰化反应[Y.Xing,R.Yu,X.Fang,Org.Lett.2020,22,1008.]。
基于这类前手性双取代丙二腈化合物的原料简单易得且毒性较小，对其进行选择性去对称化反应是构建含氰基季碳中心化合物一种直接有效的方法。但是由于氰基与过渡金属的配位亲和力[S.F.Rach,F.E.Kühn,Chem.Rev.2009,109,2061.]和氰基的微小空间尺寸[E.L.Eliel,S.H.Wilen,L.N.Mander,Stereochemistry of Organic Compounds,Wiley:New York,1994,pp 696.]，以及在过渡金属催化和有机金属试剂存在下，丙二腈会脱氰分解[a)L.R.Mills,J.M.Graham,P.Patel,S.A.L.Rousseaux,J.Am.Chem.Soc.2019,141,19257；b)J.T.Reeves,C.A.Malapit,F.G.Buono,K.P.Sidhu,M.A.Marsini,C.A.Sader,K.R.Fandrick,C.A.Busacca,C.H.Senanayake,J.Am.Chem.Soc.2015,137,9481；c)S.Alazet,M.S.West,P.Patel,S.A.L.Rousseaux,Angew.Chem.Int.Ed.2019,58,10300]。
发明内容
针对现有技术的局限和挑战，本发明的目的在于提供一种高效、高对映选择性不对称合成季碳中心的全取代吡啶化合物的方法。
本发明的技术方案可以通过以下技术措施来实现：
一种季碳中心的全取代吡啶化合物，具有如下式所示III或V所示的结构：
Figure BDA0002527237430000021
其中，其中R1、R3、R4是分别独立的取代基，任选自氢、硅基、烷基、芳基；R2任选自烷基、烯基或芳基；R9任选自氢、烷基、芳基；*表示手性中心。
本发明还提供一种含α-氰基季碳中心的全取代吡啶化合物的制备方法，包括以下步骤：(1)以双-(1,5-环辛二烯)镍和配体作为催化剂，原料I和II在有机溶剂中发生[2+2+2]环加成反应；(2)反应结束后分离提纯，生成III所示的含α-氰基季碳中心的全取代吡啶化合物，其反应方程式如下：
Figure BDA0002527237430000031
其中Ni(COD)2为双-(1,5-环辛二烯)镍；ligand指配体；additive指添加剂；solvent指有机溶剂；
其中R1、R3、R4是分别独立的取代基，任选自氢、硅基、烷基、芳基；R2任选自烷基、烯基或芳基；*表示手性中心；
所述反应的温度为40℃～100℃，反应的时间为1～72小时。
优选地，步骤(1)所述的配体为下式A-F所示结构或者其对映异构体：
Figure BDA0002527237430000032
其中Ar为芳基，取代基R5、R6、R7、R8是独立的取代基，R5、R6任选自甲基、叔丁基、环己基、芳基；R7任选自氢、烷基、卤素、烷氧基；R8任选自异丙基、芳基；n任选自1或者2。
优选地，步骤(1)所述催化剂中双-(1,5-环辛二烯)镍与配体的摩尔比为1:0.8～1:2，优选为1:1～1:1.5，更加优选1:1.5；所述催化剂中金属元素的物质的量与原料I的物质的量之比为0.01:1～0.5:1，优选为0.05:1～0.5:1，更加优选0.1:1；所述原料I和II的物质的量之比为1:1～1:50；所述的添加剂和原料I的物质的量之比为0.05:1～3:1。
优选地，步骤(1)所述的有机溶剂为甲苯、1,2-二氯乙烷、二氯甲烷、乙腈、乙二醇二甲醚，甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、乙醚、1,4-二氧六环、环戊基甲基醚、N,N’-二甲基甲酰胺中的任一种或多种的混合溶剂，优选为四氢呋喃，2-甲基四氢呋喃，或者1,4-二氧六环，更加优选2-甲基四氢呋喃。
优选地，步骤(1)所述的添加剂是指ZnX2、BY3或者以上任意添加剂和分子筛的组合，其中X指卤素负离子、羧酸根离子或者磺酸根离子；B是指硼元素；Y是指氟负离子、烷基或者芳基；所述分子筛为
Figure BDA0002527237430000033
或者
Figure BDA0002527237430000034
所述添加剂优选为氯化锌、溴化锌、碘化锌、三苯基硼、三氟化硼或者溴化锌和
Figure BDA0002527237430000035
的组合，所述分子筛的量为50-200mg每0.1mmol原料I。
优选地，步骤(2)所述分离提纯方法为柱层析、薄层层析或重结晶，优选地，所述分离提纯方法为柱层析；所述柱层析使用的洗脱液为乙酸乙酯、二氯甲烷和石油醚的混合液。
本发明还提供一种C2对称的螺吡啶化合物的制备方法，包含如下步骤：(1)按照上述任意一项所述的制备方法，将其中的原料I替换成原料IV；(2)将步骤(1)的产物进行分离提纯，获得C2对称的螺吡啶化合物V，具体方程式如下：
Figure BDA0002527237430000041
其中R9任选自氢、烷基、芳基。
与现有技术相比，本发明具有如下有益效果：
(1)本方法合成了一类全新的含α-氰基季碳中心的全取代吡啶化合物结构。
(2)本方法操作简单，反应条件温和，对映选择性好，底物范围广，官能团容忍性好。
(3)从简单易得的二取代丙二腈化合物出发，选择性去对称化反应是构建含有氰基季碳中心化合物最直接的手段。
(4)使用廉价的金属催化剂，成本低，可以有效减少对环境的污染。
(5)本方法合成了一系列高对映选择性的C2对称的螺吡啶化合物。
具体实施方式
为使本发明更加容易理解，下面将进一步阐述本发明的具体实施例。
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，而不应视为对本发明的具体限制。
实施例1：以2-苯基-2-(4-苯丁炔基)丙二腈1a和6-十二炔为标准底物，对合成α-氰基季碳中心的全取代吡啶化合物反应中配体的研究：
Figure BDA0002527237430000042
Figure BDA0002527237430000051
entry ligand yield(％) ee(％)
1 L1 36 50
2 L2 70 50
3 L3 51 66
4 L4 57 40
5 L5 75 30
6 L6 51 60
7 L7 79 34
8 L8 57 48
9 L9 75 44
10 L10 36 44
11 L11 52 58
12 L12 55 30
13 L13 56 60
14 L14 21 50
15 L15 11 5
在65摄氏度下，1mL 1,4-二氧六环溶剂中反应24小时；其中双(1,5-环辛二烯)镍为镍络合物；配体结构如L1-L15所示；mol％指的相对摩尔量，equiv代表当量；yield指含α-氰基季碳中心的全取代吡啶化合物的总核磁收率，以均三甲氧基苯为内标物。ee指含α-氰基季碳中心的全取代吡啶化合物的对映选择性，由高效液相测定。
实施例2：以2-苯基-2-(4-苯丁炔基)丙二腈1a和6-十二炔为标准底物，对镍催化合成α-氰基季碳中心的全取代吡啶化合物反应中溶剂的研究：
Figure BDA0002527237430000061
Figure BDA0002527237430000062
在65摄氏度下，1mL表格所示溶剂中反应24小时；其中双(1,5-环辛二烯)镍为镍络合物；配体结构如L3所示；mol％指的相对摩尔量，equiv代表当量；yield指含α-氰基季碳手性中心的全取代吡啶化合物的总核磁收率，以均三甲氧基苯为内标物。ee指含α-氰基季碳手性中心的全取代吡啶化合物的对映选择性，由高效液相测定；其中1,4-dioxane是指1,4-二氧六环，THF是指四氢呋喃，2-MeTHF是指2-甲基四氢呋喃，MTBE是指甲基叔丁基醚，DME是指乙二醇二甲醚，Et2O是指乙醚，CPME是指环戊基甲基醚，toluene是指甲苯，DCM是指二氯甲烷，DCE是指1,2-二氯乙烷，MeCN是指乙腈，DMF是指N,N’-二甲基甲酰胺。
实施例3：以2-苯基-2-(4-苯丁炔基)丙二腈1a和6-十二炔为标准底物，对镍催化合成α-氰基季碳中心的全取代吡啶化合物反应中分子筛型号、浓度和温度、炔烃的物质的量的研究：
Figure BDA0002527237430000063
Figure BDA0002527237430000064
在65摄氏度下，1mL 2-甲基四氢呋喃溶剂中反应24小时；其中双(1,5-环辛二烯)镍为镍络合物；配体结构如L3所示；mol％指的相对摩尔量，equiv代表当量；yield指含α-氰基季碳中心的全取代吡啶化合物的总核磁收率，以均三甲氧基苯为内标物。ee指含α-氰基季碳中心的全取代吡啶化合物的对映选择性，由高效液相测定。a加入3当量6-十二炔。
实施例4：以2-苯基-2-(4-苯丁炔基)丙二腈1a和6-十二炔为标准底物，对镍催化合成α-氰基季碳中心的全取代吡啶化合物反应路易斯酸的研究：
Figure BDA0002527237430000071
Figure BDA0002527237430000072
在40摄氏度下，0.5mL 2-甲基四氢呋喃溶剂中反应36小时；其中双(1,5-环辛二烯)镍为镍络合物；配体结构如L3所示；mol％指的相对摩尔量，equiv代表当量；yield指含α-氰基季碳中心的全取代吡啶化合物的总核磁收率，以均三甲氧基苯为内标物。ee指含α-氰基季碳中心的全取代吡啶化合物的对映选择性，由高效液相测定。产率栏括号中的数字代表分离收率。
实施例5
在本实施例中，制备(R)-7-苄基-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)其结构式如下：
Figure BDA0002527237430000073
制备方法包括以下步骤：
在手套箱中，先称取Ni(COD)2(3.1mg,0.01mmol,10mol％)和(R)-L3(11.9mg,0.015mmol,15mol％)于带有磁子的10mL Schlenk管中，再用移液枪加入0.5mL 2-甲基四氢呋喃，然后在室温下搅拌5min后，再依次加入2-苄基-2-(4-苯基-3-丁炔基)丙二腈1a(29.0mg,0.1mmol,1.0equiv)，溴化锌(23.6mg,0.1mmol,1.0equiv)和
Figure BDA0002527237430000074
MS(100mg)，将其密封后，带出手套箱。在氩气保护下，加入6-十二炔(65μL,0.3mmol,3.0equiv)，最后将其密封，并在40℃下反应36h。反应完后的混合体系经过带硅胶的砂芯漏斗过滤，滤渣用20mL乙酸乙酯洗涤，所得滤液在减压下浓缩得到残留物，通过柱色谱纯化分离得到吡啶产物，选用200-300目的硅胶，流动相选用石油醚：乙酸乙酯。
所得目标产物为白色固体(28.6mg,64％yield)，对映选择性ee为94％。比旋光度[α]D 20＝–44.55(c 1.10,CHCl3)；Rf＝0.3(PE:EA＝10:1).
结构表征数据如下：
1H NMR(400MHz,CDCl3)δ7.44–7.31(m,3H),7.29–7.22(m,3H),7.17–7.09(m,3H),6.97(d,J＝6.8Hz,1H),3.53(AB,J＝13.5Hz,1H),3.13(BA,J＝13.5Hz,1H),2.95–2.82(m,2H),2.56–2.40(m,3H),2.39–2.30(m,1H),2.28–2.19(m,1H),2.18–2.07(m,1H),1.89–1.72(m,2H),1.50–1.37(m,4H),1.36–1.29(m,2H),1.20–1.07(m,4H),0.94(t,J＝6.8Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.2,156.7,147.3,138.1,135.7,133.5,132.8,130.3,128.6,128.5,128.4,128.1,128.0,127.7,127.3,122.9,48.8,43.2,35.3,34.3,32.2,32.1,30.6,30.0,29.0,27.4,22.8,22.1,14.3,14.0.
实施例6
在本实施例中，制备(R)-7-苄基-2,3-二戊基-4-(4-甲基苯基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dipentyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000081
白色固体(25.7mg,56％yield)，对映选择性ee为94％。比旋光度[α]D 20–53.46(c0.26,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.29–7.24(m,3H),7.20(t,J＝7.6Hz,2H),7.16–7.12(m,2H),7.01(d,J＝7.2Hz,1H),6.86(d,J＝7.6Hz,1H),3.54(AB,J＝13.5Hz,1H),3.14(BA,J＝13.5Hz,1H),2.96–2.81(m,2H),2.56–2.41(m,3H),2.39(s,3H),2.38–2.31(m,1H),2.28–2.10(m,2H),1.88–1.78(m,2H),1.50–1.38(m,4H),1.37–1.29(m,2H),1.22–1.09(m,4H),0.95(t,J＝7.2Hz,3H),0.79(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.1,156.6,147.5,137.4,135.8,135.1,133.8,133.0,130.3,129.3,129.2,128.4,128.0,127.9,127.3,122.8,48.8,43.2,35.2,34.4,32.2,32.1,30.6,30.0,29.0,27.5,22.8,22.2,21.4,14.3,14.0.
实施例7
在本实施例中，制备(R)-7-苄基-4-(4-甲氧基苯基)-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-(4-methoxyphenyl)-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000082
白色固体(25.7mg,53％yield)，对映选择性ee为93％。比旋光度[α]D 20＝–44.90(c0.51,CHCl3).Rf＝0.4(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.29–7.24(m,3H),7.18–7.12(m,2H),7.09–7.02(m,1H),6.97–6.85(m,3H),3.85(s,3H),3.53(AB,J＝13.5Hz,1H),3.13(BA,J＝13.5Hz,1H),2.93–2.80(m,2H),2.58–2.42(m,3H),2.40–2.31(m,1H),2.28–2.11(m,2H),1.88–1.78(m,2H),1.53–1.38(m,4H),1.37–1.28(m,2H),1.23–1.11(m,4H),0.95(t,J＝7.0Hz,3H),0.80(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.1,159.0,156.7,147.1,135.8,133.9,133.1,130.4,130.3,129.3,129.2,128.4,127.3,122.9,114.0,113.9,55.4,48.9,43.3,35.3,34.4,32.2,32.1,30.6,30.0,29.0,27.5,22.8,22.2,14.3,14.0.
实施例8
在本实施例中，制备(R)-7-苄基-4-(4-氟苯基)-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-(4-fluorophenyl)-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000083
无色液体(35.4mg,75％yield)，对映选择性ee为90％。比旋光度[α]D 20＝–43.06(c0.49,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.28–7.23(m,3H),7.17–7.04(m,5H),6.99–6.87(m,1H),3.53(AB,J＝13.5Hz,1H),3.15(BA,J＝13.5Hz,1H),2.93–2.78(m,2H),2.56–2.32(m,4H),2.31–2.19(m,1H),2.16–2.07(m,1H),1.90–1.77(m,2H),1.53–1.37(m,4H),1.36–1.28(m,2H),1.22–1.09(m,4H),0.95(t,J＝7.2Hz,3H),0.80(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ162.3(d,J＝245.0Hz),161.3,156.9,146.3,135.7,134.0(d,J＝3.6Hz),133.7,132.9,129.9(d,J＝7.7Hz),129.8(d,J＝8.0Hz),128.4,127.4,122.8,115.8(d,J＝8.9Hz),115.6(d,J＝9.0Hz),48.8,43.3,35.3,34.3,32.2,32.1,30.6,29.9,29.0,27.5,22.8,22.2,14.3,14.0.19F NMR(376MHz,CDCl3)δ–114.28.
实施例9
在本实施例中，制备(R)-7-苄基-2,3-二戊基-4-(4-三氟甲基苯基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dipentyl-4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000091
无色液体(46.3mg,89％yield)，对映选择性ee为89％。比旋光度[α]D 20–38.24(c0.51,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.68(t,J＝9.2Hz,2H),7.31–7.22(m,4H),7.16–7.07(m,3H),3.53(AB,J＝13.5Hz,1H),3.17(BA,J＝13.5Hz,1H),2.95–2.81(m,2H),2.52–2.33(m,4H),2.31–2.23(m,1H),2.14–2.01(m,1H),1.91–1.78(m,2H),1.51–1.38(m,4H),1.36–1.27(m,2H),1.21–1.08(m,4H),0.95(t,J＝7.2Hz,3H),0.78(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.5,157.0,145.8,141.9,135.5,133.2,132.5,130.3,130.1(q,J＝32.4Hz),128.7,128.5,128.4,127.4,125.7(q,J＝3.5Hz),125.5(q,J＝8.3Hz),124.1(q,J＝270.5Hz),122.7,48.8,43.3,35.2,34.3,32.2,32.0,30.5,29.9,29.0,27.4,22.8,22.1,14.3,13.9.
实施例10
在本实施例中，制备(R)-7-苄基-4-(4-甲酰基苯基)-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-(4-formylphenyl)-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000092
无色液体(42.9mg,90％yield)，对映选择性ee为85％。比旋光度[α]D 20–52.31(c0.65,CHCl3).Rf＝0.3(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ10.06(s,1H),7.93(t,J＝7.2Hz,2H),7.33(d,J＝7.6Hz,1H),7.28–7.21(m,3H),7.19–7.03(m,3H),3.53(AB,J＝13.5Hz,1H),3.17(BA,J＝13.5Hz,1H),2.97–2.83(m,2H),2.54–2.32(m,4H),2.31–2.22(m,1H),2.13–2.04(m,1H),1.90–1.76(m,2H),1.50–1.38(m,4H),1.37–1.28(m,2H),1.17–1.04(m,4H),0.95(t,J＝7.2Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ191.8,161.5,157.0,146.0,144.6,135.8,135.6,133.0,132.2,130.31,130.26,130.0,129.0,128.9,128.4,127.4,122.6,48.8,43.3,35.2,34.3,32.2,32.0,30.6,29.8,29.1,27.4,22.8,22.2,14.3,14.0.
实施例11
在本实施例中，制备(R)-4-(4-乙酰基苯基)-7-苄基-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-4-(4-acetylphenyl)-7-benzyl-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000101
无色液体(41.2mg,84％yield)，对映选择性ee为88％。比旋光度[α]D 20–57.71(c0.61,CHCl3).Rf＝0.3(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ8.00(t,J＝6.8Hz,2H),7.29–7.22(m,4H),7.16–7.03(m,3H),3.52(AB,J＝13.5Hz,1H),3.16(BA,J＝13.5Hz,1H),2.97–2.83(m,2H),2.64(s,3H),2.54–2.31(m,4H),2.30–2.20(m,1H),2.14–2.02(m,1H),1.89–1.78(m,2H),1.50–1.38(m,4H),1.37–1.27(m,2H),1.20–1.08(m,4H),0.94(t,J＝7.2Hz,3H),0.78(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ197.8,161.4,157.0,146.1,143.2,136.5,135.6,133.1,132.3,130.3,128.8,128.53,128.47,128.4,127.4,122.7,48.8,43.3,35.2,34.3,32.2,32.0,30.6,29.8,29.1,27.4,26.8,22.8,22.2,14.3,13.9.
实施例12
在本实施例中，制备(R)-甲基-4-(7-苄基-7-氰基-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-4-基)苯甲酸盐((R)-methyl-4-(7-benzyl-7-cyano-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)benzoate)，其结构式如下：
Figure BDA0002527237430000102
无色液体(42.3mg,83％yield)，对映选择性ee为89％。比旋光度[α]D 20–52.24(c0.76,CHCl3).Rf＝0.4(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ8.08(t,J＝8.0Hz,2H),7.29–7.21(m,4H),7.16–7.10(m,2H),7.06(d,J＝8.0Hz,1H),3.95(s,3H),3.54(AB,J＝13.5Hz,1H),3.17(BA,J＝13.5Hz,1H),2.96–2.80(m,2H),2.53–2.31(m,4H),2.30–2.19(m,1H),2.14–2.02(m,1H),1.90–1.74(m,2H),1.49–1.37(m,4H),1.35–1.28(m,2H),1.19–1.07(m,4H),0.95(t,J＝7.2Hz,3H),0.78(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ166.9,161.3,156.7,146.6,142.8,135.6,133.4,132.6,130.3,130.0,129.9,129.7,128.4,128.3,128.2,127.4,122.6,52.4,48.7,43.3,35.0,34.4,32.2,32.1,30.6,29.9,29.1,27.4,22.8,22.2,14.3,14.0.
实施例13
在本实施例中，制备(R)-7-苄基-2,3-二甲基-4-(3-甲基苯基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dimethyl-4-(m-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000103
无色液体(19.7mg,56％yield)，对映选择性ee为90％。比旋光度[α]D 20–49.23(c0.78,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.35–7.24(m,4H),7.22–7.15(m,3H),6.98–6.75(m,2H),3.58(AB,J＝13.6Hz,1H),3.09(BA,J＝13.6Hz,1H),2.64(s,3H),2.62–2.53(m,1H),2.38(s,3H),2.36–2.17(m,3H),2.09(s,3H).13C NMR(100MHz,CDCl3)δ157.7,156.7,147.4,138.4,137.8,135.7,132.9,130.3,129.3,128.8,128.62,128.58,128.5,127.4,125.3,122.7,48.9,43.1,34.5,27.5,23.5,21.6,16.4.
实施例14
在本实施例中，制备(R)-7-苄基-4-(3-甲氧基苯基)-2,3-二甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-(3-methoxyphenyl)-2,3-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000111
无色液体(29.2mg,79％yield)，对映选择性ee为90％。比旋光度[α]D 20–67.63(c0.38,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.32(t,J＝8.0Hz,1H),7.29–7.25(m,3H),7.21–7.12(m,2H),6.89(dd,J＝8.0,2.4Hz,1H),6.78–6.41(m,2H),3.80(s,3H),3.55(AB,J＝13.5Hz,1H),3.08(BA,J＝13.5Hz,1H),2.62(s,3H),2.61–2.52(m,1H),2.40–2.20(m,3H),2.08(s,3H).13C NMR(100MHz,CDCl3)δ159.8,157.7,156.7,147.1,139.2,135.7,132.8,130.3,129.8,129.3,128.5,127.4,122.7,120.5,113.9,113.3,55.4,48.9,43.2,34.5,27.5,23.5,16.4.
实施例15
在本实施例中，制备(R)-7-苄基-2,3-二甲基-4-(3-(三氟甲氧基)苯基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dimethyl-4-(3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000112
无色液体(25.0mg,59％yield)，对映选择性ee为85％。比旋光度[α]D 20–42.26(c0.53,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.45(t,J＝7.6Hz,1H),7.31–7.19(m,4H),7.18–7.11(m,2H),7.10–6.80(m,2H),3.55(AB,J＝13.5Hz,1H),3.11(BA,J＝13.5Hz,1H),2.64(s,3H),2.61–2.48(m,1H),2.42–2.13(m,3H),2.08(s,3H).13CNMR(100MHz,CDCl3)δ158.1,157.1,149.5,145.4,139.8,135.5,132.7,130.3,129.0,128.5,127.5,126.8,122.6,120.9,120.6(q,J＝255.0Hz),120.4,48.8,43.2,34.4,27.4,23.6,16.3.19F NMR(376MHz,CDCl3)δ–57.85.
实施例16
在本实施例中，制备(R)-7-苄基-4-(3-氟苯基)-2,3-二甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-(3-fluorophenyl)-2,3-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000113
无色液体(32.1mg,90％yield)，对映选择性ee为88％。比旋光度[α]D 20–51.85(c0.54,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.44–7.34(m,1H),7.31–7.22(m,3H),7.19–7.12(m,2H),7.06(td,J＝8.4,2.0Hz,1H),6.97–6.65(m,2H),3.55(AB,J＝13.5Hz,1H),3.09(BA,J＝13.6Hz,1H),2.63(s,3H),2.60–2.52(m,1H),2.41–2.17(m,3H),2.07(s,3H).13C NMR(100MHz,CDCl3)δ162.9(d,J＝246.0Hz),158.0,157.0,145.8,140.0(d,J＝7.7Hz),135.6,132.6,130.5(d,J＝8.0Hz),130.3,129.1,128.5,127.5,124.1,122.6,115.4(d,J＝22.0Hz),114.9(d,J＝21.0Hz),48.9,43.2,34.4,27.4,23.6,16.3.19F NMR(376MHz,CDCl3)δ–112.34.
实施例17
在本实施例中，制备(R)-7-苄基-2,3-二甲基-4-(3-(三氟甲基)苯基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dimethyl-4-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000121
无色液体(24.1mg,60％yield)，对映选择性ee为84％。比旋光度[α]D 20–42.55(c0.51,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.65(dd,J＝7.9,1.2Hz,1H),7.57(t,J＝7.6Hz,1H),7.48–7.20(m,5H),7.19–7.12(m,2H),3.55(AB,J＝13.5Hz,1H),3.12(BA,J＝13.5Hz,1H),2.65(s,3H),2.62–2.47(m,1H),2.45–2.13(m,3H),2.08(s,3H).13C NMR(100MHz,CDCl3)δ158.2,157.2,145.4,138.7,135.5,132.6,131.7,131.2(q,J＝31.2Hz),130.3,129.4,129.0,128.5,127.5,125.1(q,J＝3.3Hz),124.8(q,J＝3.7Hz),124.0(q,J＝270.9Hz),48.8,43.2,34.4,27.4,23.6,16.4.19F NMR(376MHz,CDCl3)δ–62.65.
实施例18
在本实施例中，制备(R)-7-苄基-4-(3-甲酰基苯基)-2,3-二甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-(3-formylphenyl)-2,3-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000123
无色液体(24.6mg,67％yield)，对映选择性ee为86％。比旋光度[α]D 20–54.82(c0.56,CHCl3).Rf＝0.2(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ10.04(s,1H),7.90(d,J＝7.6Hz,1H),7.73–7.49(m,2H),7.47–7.24(m,4H),7.21–7.14(m,2H),3.56(AB,J＝13.5Hz,1H),3.11(BA,J＝13.6Hz,1H),2.65(s,3H),2.60–2.51(m,1H),2.43–2.16(m,3H),2.08(s,3H).13C NMR(100MHz,CDCl3)δ191.9,158.1,157.1,145.5,138.9,136.8,135.5,134.3,132.6,130.3,129.6,129.0,128.5,127.5,122.5,48.9,43.2,34.4,27.4,23.6,16.4.
实施例19
在本实施例中，制备(R)-4-(3-乙酰基苯基)-7-苄基-2,3-二甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-4-(3-acetylphenyl)-7-benzyl-2,3-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000122
无色液体(30.3mg,80％yield)，对映选择性ee为86％。比旋光度[α]D 20–57.43(c0.70,CHCl3).Rf＝0.2(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ7.96(d,J＝7.6Hz,1H),7.79–7.58(m,1H),7.54(t,J＝7.6Hz,1H),7.42–7.20(m,4H),7.19–7.12(m,2H),3.56(AB,J＝13.5Hz,1H),3.12(BA,J＝13.5Hz,1H),2.65(s,3H),2.61(s,3H),2.59–2.50(m,1H),2.43–2.14(m,3H),2.08(s,3H).13C NMR(100MHz,CDCl3)δ197.8,158.0,157.0,146.0,138.4,137.5,135.6,132.9,132.7,130.3,129.2,129.1,128.5,128.0,127.5,122.6,48.8,43.2,34.4,27.5,26.8,23.6,16.4.
实施例20
在本实施例中，制备(R)-甲基-3-(7-苄基-7-氰基-2,3-二甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-4-基)苯甲酸盐((R)-methyl-3-(7-benzyl-7-cyano-2,3-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)benzoate)，其结构式如下：
Figure BDA0002527237430000133
无色液体(27.9mg,70％yield)，对映选择性ee为90％。比旋光度[α]D 20–52.30(c0.61,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ8.05(d,J＝7.8Hz,1H),7.90–7.68(m,1H),7.52(t,J＝7.6Hz,1H),7.41–7.23(m,4H),7.21–7.11(m,2H),3.93(s,3H),3.56(AB,J＝13.6Hz,1H),3.10(BA,J＝13.6Hz,1H),2.64(s,3H),2.61–2.51(m,1H),2.43–2.16(m,3H),2.07(s,3H).13C NMR(100MHz,CDCl3)δ166.8,158.0,157.0,145.9,138.2,135.6,132.74,132.65,130.8,130.3,129.4,129.13,129.08,128.9,128.5,127.4,122.6,52.4,48.9,43.2,34.4,27.4,23.6,16.4.
实施例21
在本实施例中，制备(R)-7-苄基-4-(3,5-二甲基苯基)-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-(3,5-dimethylphenyl)-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000131
无色液体(28.1mg,59％yield)，对映选择性ee为90％。比旋光度[α]D 20–42.39(c0.46,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.30–7.23(m,3H),7.19–7.12(m,2H),6.98(s,1H),6.74(s,1H),6.58(s,1H),3.55(AB,J＝13.5Hz,1H),3.13(BA,J＝13.5Hz,1H),2.92–2.80(m,2H),2.59–2.49(m,1H),2.47–2.40(m,2H),2.39–2.34(m,1H),2.33(s,3H),2.32(s,3H),2.28–2.14(m,2H),1.88–1.77(m,2H),1.51–1.31(m,6H),1.20–1.12(m,4H),0.95(t,J＝7.2Hz,3H),0.79(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ161.0,156.6,147.8,138.1,138.0,137.9,135.8,133.6,132.7,130.3,129.2,128.4,127.3,125.8,125.7,122.9,48.8,43.2,35.2,34.4,32.2,32.1,30.6,30.0,29.1,27.5,22.8,22.2,21.5,14.3,14.0.
实施例22
在本实施例中，制备(R)-7-苄基-4-(2-氟苯基)-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-(2-fluorophenyl)-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000132
无色液体(21.5mg,46％yield)，对映选择性ee为84％。Rf＝0.4(PE:EA＝20:1).1HNMR(400MHz,CDCl3)δ7.41–7.33(m,1H),7.29–7.22(m,3H),7.21–7.08(m,5H),3.56(AB,J＝13.6Hz,1H),3.12(BA,J＝13.6Hz,1H),2.93–2.84(m,2H),2.58–2.45(m,2H),2.43–2.33(m,2H),2.32–2.18(m,2H),1.82–1.78(m,2H),1.50–1.28(m,6H),1.18–1.08(m,4H),0.95(t,J＝6.8Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.0,158.8(d,J＝244.0Hz),156.9,141.1,135.5,134.1,133.1(d,J＝3.4Hz),130.3,130.0,129.9(d,J＝7.8Hz),128.3,127.2,125.2,124.2(d,J＝3.5Hz),122.7,115.8(d,J＝21.7Hz),48.7,43.0,35.2,34.2,32.0,31.8,30.0,29.7,29.2,27.1,22.7,22.0,14.1,13.8.19F NMR(376MHz,CDCl3)δ–114.37.
实施例23
在本实施例中，制备(R)-7-苄基-2,3-二甲基-4-(2-萘基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dimethyl-4-(naphthalen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000143
无色液体(29.3mg,75％yield)，对映选择性ee为90％。比旋光度[α]D 20–64.54(c0.66,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.95–7.87(m 2H),7.86–7.79(m,1H),7.67–7.45(m,3H),7.34–7.27(m,3H),7.24–7.08(m,3H),3.61(AB,J＝13.5Hz,1H),3.13(BA,J＝13.6Hz,1H),2.67(s,3H),2.66–2.53(m,1H),2.45–2.20(m,3H),2.13(s,3H).13C NMR(100MHz,CDCl3)δ157.8,156.8,147.1,135.7,135.3,133.3,133.1,132.8,130.3,129.5,128.5,128.1,128.0,127.4,127.3,126.7,126.6,126.2,122.7,48.9,43.2,34.5,27.6,23.6,16.5.
实施例24
在本实施例中，制备(R)-7-苄基-2,3-二戊基-4-(2-噻吩基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dipentyl-4-(thiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000142
白色固体(16.6mg,36％yield)，对映选择性ee为94％。比旋光度[α]D 20–37.98(c0.84,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.39(dd,J＝4.8,1.2Hz,1H),7.29–7.24(m,3H),7.18–7.13(m,2H),7.08(dd,J＝5.2,3.6Hz,1H),6.83(dd,J＝3.6,1.2Hz,1H),3.53(AB,J＝13.6Hz,1H),3.11(BA,J＝13.6Hz,1H),2.96–2.82(m,2H),2.76–2.62(m,1H),2.61–2.51(m,2H),2.39–2.16(m,3H),1.88–1.73(m,2H),1.52–1.37(m,6H),1.24(m,4H),0.95(t,J＝7.2Hz,3H),0.85(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ161.3,156.9,140.2,137.7,135.7,135.2,134.2,130.3,128.5,127.4,127.2,127.0,126.2,122.7,48.9,43.2,35.3,34.3,32.19,32.17,31.2,30.0,29.5,27.8,22.8,22.3,14.3,14.1.
实施例25
在本实施例中，制备(R)-7-苄基-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000141
1H NMR(400MHz,CDCl3)δ7.27–7.15(m,6H),3.53(AB,J＝13.6Hz,1H),3.34(BA,J＝13.6Hz,1H),3.19–3.11(m,2H),2.67–2.48(m,4H),2.43–2.30(m,1H),2.18–2.06(m,1H),1.70–1.50(m,4H),1.42–1.26(m,8H),0.91(t,J＝7.2Hz,3H),0.71(t,J＝6.8Hz,3H).
实施例26
在本实施例中，制备(R)-7-苄基-4-甲基-2,3-二戊基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-methyl-2,3-dipentyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000151
1H NMR(400MHz,CDCl3)δ7.31–7.08(m,5H),3.73(AB,J＝13.6Hz,1H),3.34(BA,J＝13.6Hz,1H),3.08–2.99(m,2H),2.68–2.48(m,4H),2.43–2.31(m,1H),2.29(s,3H),2.18–2.05(m,1H),1.70–1.50(m,4H),1.41–1.27(m,8H),0.89(t,J＝7.2Hz,3H),0.69(t,J＝6.8Hz,3H).
实施例27
在本实施例中，制备(R)-7-苄基-2,3-二戊基-4-(三甲基硅基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dipentyl-4-(trimethylsilyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000152
1H NMR(400MHz,CDCl3)δ7.33–7.09(m,5H),3.72(AB,J＝13.6Hz,1H),3.34(BA,J＝13.6Hz,1H),3.02–2.95(m,2H),2.67–2.45(m,4H),2.41–2.29(m,1H),2.16–2.01(m,1H),1.68–1.46(m,4H),1.43–1.25(m,8H),0.90(t,J＝7.2Hz,3H),0.72(t,J＝6.8Hz,3H),0.33(s,9H).
实施例28
在本实施例中，制备(R)-7-苄基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000153
1H NMR(400MHz,CDCl3)δ8.81(d,J＝7.6Hz,1H),8.16(d,J＝7.2Hz,1H),7.52–7.34(m,5H),7.29–7.19(m,5H),3.46(AB,J＝13.6Hz,1H),3.40(BA,J＝13.6Hz,1H),3.32–3.26(m,2H),2.43–2.31(m,1H),2.18–2.06(m,1H).
实施例29
在本实施例中，制备(R)-7-苄基-4-苯基-2,3-双(三甲基硅基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-phenyl-2,3-bis(trimethylsilyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000155
1H NMR(400MHz,CDCl3)δ7.55–7.36(m,5H),7.27–7.14(m,5H),3.51(AB,J＝13.6Hz,1H),3.35(BA,J＝13.6Hz,1H),3.11–3.02(m,2H),2.44–2.29(m,1H),2.19–2.05(m,1H),–0.29(s,9H),–0.33(s,9H).
实施例30
在本实施例中，制备(R)-7-(4-甲基苄基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(4-methylbenzyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000154
无色液体(24.2mg,52％yield)，对映选择性ee为90％。比旋光度[α]D 20–39.22(c0.64,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.44–7.32(m,3H),7.14(d,J＝7.2Hz,1H),7.10–7.02(m,4H),6.99(d,J＝6.8Hz,1H),3.50(AB,J＝13.6Hz,1H),3.09(BA,J＝13.6Hz,1H),2.94–2.82(m,2H),2.60–2.40(m,3H),2.40–2.29(m,4H),2.28–2.12(m,2H),1.89–1.75(m,2H),1.48–1.30(m,6H),1.22–1.06(m,4H),0.95(t,J＝7.2Hz,3H),0.78(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.1,156.9,147.3,138.2,136.9,133.4,132.70,132.68,130.2,129.1,128.6,128.5,128.2,128.0,127.7,122.9,48.9,42.8,35.3,34.3,32.2,32.1,30.6,30.0,29.0,27.4,22.8,22.1,21.2,14.3,14.0.
实施例31
在本实施例中，制备(R)-7-(4-溴苄基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(4-bromobenzyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000161
无色液体(32.8mg,62％yield)，对映选择性ee为90％。比旋光度[α]D 20–32.67(c0.86,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.45–7.33(m,5H),7.13(d,J＝7.2Hz,1H),7.07–7.02(m,2H),7.00(d,J＝6.8Hz,1H),3.49(AB,J＝13.6Hz,1H),3.10(BA,J＝13.6Hz,1H),2.93–2.80(m,2H),2.61–2.50(m,1H),2.48–2.41(m,2H),2.40–2.31(m,1H),2.27–2.12(m,2H),1.87–1.76(m,2H),1.49–1.31(m,6H),1.20–1.08(m,4H),0.95(t,J＝7.2Hz,3H),0.78(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.3,156.4,147.5,138.0,134.8,133.7,132.7,132.0,131.6,128.64,128.56,128.1,128.0,127.8,122.6,121.5,48.7,42.6,35.3,34.5,32.2,32.1,30.6,29.9,29.0,27.5,22.8,22.1,14.3,14.0.
实施例32
在本实施例中，制备(R)-2,3-二戊基-4-苯基-7-(4-(三氟甲基)苄基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-2,3-dipentyl-4-phenyl-7-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000162
无色液体(25.7mg,50％yield)，对映选择性ee为90％。比旋光度[α]D 20–31.54(c0.52,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.0Hz,2H),7.46–7.33(m,3H),7.30(d,J＝8.0Hz,2H),7.13(d,J＝7.2Hz,1H),6.97(d,J＝6.4Hz,1H),3.60(AB,J＝13.5Hz,1H),3.20(BA,J＝13.5Hz,1H),2.93–2.80(m,2H),2.62–2.50(m,1H),2.49–2.31(m,3H),2.27–2.13(m,2H),1.89–1.74(m,2H),1.50–1.31(m,6H),1.22–1.08(m,4H),0.95(t,J＝7.2Hz,3H),0.78(t,J＝7.2Hz,3H).13CNMR(100MHz,CDCl3)δ161.4,156.2,147.5,139.9,137.9,133.8,132.6,130.7,129.7(q,J＝33.0Hz),128.7,128.5,128.1,127.9,127.8,125.3(q,J＝3.6Hz),124.3(q,J＝270.2Hz),122.4,48.7,42.9,35.3,34.6,32.2,32.1,30.6,29.9,29.0,27.4,22.8,22.1,14.3,14.0.19F NMR(376MHz,CDCl3)δ–62.54.
实施例33
在本实施例中，制备(R)-7-(3-甲基苄基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(3-methylbenzyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000163
无色液体(25.6mg,55％yield)，对映选择性ee为90％。比旋光度[α]D 20–37.89(c0.52,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.46–7.30(m,3H),7.18–7.11(m,2H),7.07(dd,J＝7.6,1.2Hz,1H),6.97(t,J＝7.6Hz,2H),6.91(s,1H),3.48(AB,J＝13.5Hz,1H),3.12(BA,J＝13.5Hz,1H),2.93–2.84(m,2H),2.55–2.32(m,4H),2.29(s,3H),2.27–2.21(m,1H),2.18–2.08(m,1H),1.88–1.78(m,2H),1.51–1.30(m,6H),1.20–1.09(m,4H),0.95(t,J＝7.2Hz,3H),0.78(t,J＝6.8Hz,3H).13CNMR(100MHz,CDCl3)δ161.2,156.9,147.3,138.2,137.9,135.6,133.4,132.8,131.1,128.6,128.5,128.3,128.2,128.03,127.99,127.7,127.4,123.0,48.8,43.2,35.3,34.3,32.2,32.1,30.6,30.0,29.0,27.5,22.8,22.1,21.5,14.3,14.0.
实施例34
在本实施例中，制备(R)-2,3-二戊基-4-苯基-7-(3,4,5-三甲氧基苄基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-2,3-dipentyl-4-phenyl-7-(3,4,5-trimethoxybenzyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000171
白色固体(32.5mg,60％yield)，对映选择性ee为84％。比旋光度[α]D 20–51.46(c0.55,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.45–7.31(m,3H),7.13(d,J＝7.2Hz,1H),6.94(d,J＝6.4Hz,1H),6.28(s,2H),3.82(s,3H),3.74(s,6H),3.42(AB,J＝13.5Hz,1H),3.17(BA,J＝13.5Hz,1H),2.92–2.80(m,2H),2.55–2.34(m,4H),2.30–2.20(m,1H),2.12–2.02(m,1H),1.89–1.76(m,2H),1.50–1.38(m,4H),1.37–1.26(m,2H),1.18–1.06(m,4H),0.94(t,J＝7.2Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.2,156.7,153.0,147.5,138.0,137.3,133.5,133.1,131.2,128.63,128.58,128.0,127.9,127.8,123.1,107.2,61.0,56.1,48.7,43.7,35.4,34.1,32.2,32.1,30.6,30.1,29.0,27.6,22.8,22.1,14.3,13.9.
实施例35
在本实施例中，制备(R)-7-(1-萘基甲基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(naphthalen-1-ylmethyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000172
黄色固体(36.8mg,69％yield)，对映选择性ee为90％。比旋光度[α]D 20–63.33(c0.90,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.84(t,J＝7.6Hz,2H),7.78(dd,J＝7.2,1.6Hz,1H),7.46–7.27(m,7H),7.08(d,J＝7.2Hz,1H),6.69(d,J＝4.0Hz,1H),3.98(AB,J＝14.1Hz,1H),3.79(BA,J＝14.1Hz,1H),2.98–2.72(m,2H),2.49–2.07(m,5H),1.95–1.72(m,3H),1.54–1.39(m,4H),1.36–1.27(m,2H),1.20–1.06(m,4H),0.97(t,J＝7.2Hz,3H),0.78(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.0,156.6,147.5,138.0,133.8,133.7,132.8,132.0,129.0,128.8,128.5,128.4,128.2,127.9,127.7,125.9,125.6,125.3,123.9,123.1,48.9,38.8,35.2,34.8,32.3,32.1,30.6,29.9,28.9,27.6,22.8,22.1,14.3,14.0.
实施例36
在本实施例中，制备(R)-7-(2-萘基甲基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(naphthalen-2-ylmethyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000181
黄色固体(26.8mg,53％yield)，对映选择性ee为90％。比旋光度[α]D 20–49.83(c0.57,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.87–7.78(m,1H),7.77–7.67(m,2H),7.54(s,1H),7.49–7.43(m,2H),7.38(t,J＝7.2Hz,1H),7.35–7.27(m,3H),7.11(d,J＝7.2Hz,1H),6.77(d,J＝7.2Hz,1H),3.69(AB,J＝13.5Hz,1H),3.36(BA,J＝13.5Hz,1H),3.00–2.82(m,2H),2.56–2.24(m,5H),2.12–2.01(m,1H),1.95–1.80(m,2H),1.54–1.40(m,4H),1.39–1.30(m,2H),1.21–1.09(m,4H),0.97(t,J＝7.1Hz,3H),0.79(t,J＝6.9Hz,3H).13C NMR(100MHz,CDCl3)δ161.2,156.7,147.4,138.1,133.6,113.34,133.25,132.8,132.7,129.2,128.5,128.43,128.38,128.1,127.93,127.91,127.8,127.7,127.6,126.2,126.0,123.0,48.8,43.4,35.4,34.3,32.3,32.1,30.6,30.0,29.0,27.5,22.8,22.2,14.3,14.0.
实施例37
在本实施例中，制备(R)-7-(2-呋喃基甲基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(furan-2-ylmethyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000183
无色液体(29.4mg,67％yield)，对映选择性ee为88％。比旋光度[α]D 20–27.55(c0.94,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.47–7.31(m,4H),7.15(d,J＝7.2Hz,1H),7.07(d,J＝6.8Hz,1H),6.31(t,J＝2.0Hz,1H),6.12(d,J＝3.2Hz,1H),3.64(AB,J＝14.9Hz,1H),3.14(BA,J＝14.9Hz,1H),2.92–2.78(m,2H),2.70–2.57(m,1H),2.56–2.27(m,5H),1.88–1.73(m,2H),1.48–1.38(m,4H),1.36–1.30(m,2H),1.21–1.05(m,4H),0.94(t,J＝6.8Hz,3H),0.77(t,J＝6.8Hz,3H).13CNMR(100MHz,CDCl3)δ161.2,156.3,150.5,147.4,142.2,138.1,133.6,132.6,128.7,128.5,128.2,128.0,127.8,122.4,110.7,108.7,48.1,35.9,35.2,35.1,32.2,32.1,30.5,29.8,29.0,27.4,22.8,22.1,14.3,14.0.
实施例38
在本实施例中，制备(R)-2,3-二戊基-4-苯基-7-(2-噻吩基甲基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-2,3-dipentyl-4-phenyl-7-(thiophen-2-ylmethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000182
无色液体(34.8mg,76％yield)，对映选择性ee为88％。比旋光度[α]D 20–36.34(c0.71,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.45–7.32(m,3H),7.18–7.12(m,2H),7.03(d,J＝7.2Hz,1H),6.94(dd,J＝5.2,3.6Hz,1H),6.87(dd,J＝3.2,1.2Hz,1H),3.77(AB,J＝14.7Hz,1H),3.43(BA,J＝14.7Hz,1H),2.93–2.84(m,2H),2.69–2.54(m,1H),2.52–2.40(m,3H),2.35–2.21(m,2H),1.89–1.75(m,2H),1.53–1.37(m,4H),1.37–1.27(m,2H),1.22–1.07(m,4H),0.94(t,J＝7.2Hz,3H),0.77(t,J＝8.4Hz,3H).13C NMR(100MHz,CDCl3)δ161.3,156.0,147.5,138.1,137.1,133.8,133.0,128.6,128.5,128.2,128.0,127.9,127.8,127.0,125.2,122.6,48.8,37.5,35.3,34.5,32.2,32.1,30.6,29.9,29.0,27.6,22.8,22.1,14.3,14.0.
实施例39
在本实施例中，制备(R)-7-((1-甲基-1H-3-吲哚基)甲基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-((1-methyl-1H-indol-3-yl)methyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000191
黄色固体(31.0mg,61％yield)，对映选择性ee为87％。比旋光度[α]D 20–38.92(c0.74,CHCl3).Rf＝0.3(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.44–7.31(m,3H),7.28(d,J＝8.4Hz,2H),7.19(td,J＝7.6,1.2Hz,1H),7.12(d,J＝7.2Hz,1H),7.05–6.98(m,2H),6.86–6.77(m,1H),3.76(s,3H),3.63(AB,J＝14.5Hz,1H),3.37(BA,J＝14.5Hz,1H),2.95–2.83(m,2H),2.54–2.34(m,4H),2.33–2.25(m,1H),2.23–2.12(m,1H),1.91–1.78(m,2H),1.53–1.40(m,4H),1.38–1.28(m,2H),1.20–1.08(m,4H),0.96(t,J＝7.2Hz,3H),0.79(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.0,157.3,147.4,138.2,136.7,133.4,132.7,128.8,128.7,128.5,128.4,128.1,128.0,127.6,123.6,121.6,119.2,118.7,109.3,108.7,49.6,35.4,34.7,33.0,32.9,32.3,32.1,30.6,30.0,29.0,27.6,22.8,22.1,14.3,14.0.
实施例40
在本实施例中，制备(S)-7-甲基-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((S)-7-methyl-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000193
无色液体(30.1mg,80％yield)，对映选择性ee为72％。比旋光[α]D 2010.91(c0.55,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.48–7.33(m,3H),7.15(t,J＝8.4Hz,2H),2.86–2.78(m,2H),2.76–2.49(m,3H),2.50–2.36(m,2H),2.13–2.01(m,1H),1.83–1.75(m,2H),1.74(s,3H),1.45–1.28(m,6H),1.16–1.08(m,4H),0.93(t,J＝7.2Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.1,157.7,147.4,138.2,133.3,131.7,128.7,128.5,128.3,128.0,127.7,123.7,43.2,38.1,35.3,32.2,32.1,30.5,29.8,29.0,27.4,24.4,22.8,22.1,14.3,14.0.
实施例41
在本实施例中，制备(S)-2,3-二戊基-4-苯基-7-丙基-6,7-二氢-5H-环戊二烯基并[b]吡啶-7-腈((S)-2,3-dipentyl-4-phenyl-7-propyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000192
无色液体(26.9mg,67％yield)，对映选择性ee为92％。比旋光度[α]D 2010.57(c0.53,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.49–7.33(m,3H),7.15(t,J＝8.4Hz,2H),2.87–2.77(m,2H),2.76–2.62(m,1H),2.60–2.49(m,2H),2.47–2.37(m,2H),2.24(td,J＝12.0,3.6Hz,1H),2.16–2.04(m,1H),1.86–1.62(m,4H),1.61–1.46(m,1H),1.45–1.29(m,6H),1.21–1.07(m,4H),1.00(t,J＝7.2Hz,3H),0.93(t,J＝7.2Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ160.9,157.5,147.3,138.3,133.2,132.0,128.7,128.5,128.3,128.1,127.7,123.0,48.0,39.8,35.8,35.3,32.2,32.1,30.5,29.8,29.0,27.6,22.8,22.1,18.9,14.25,14.24,14.0.
实施例42
在本实施例中，制备(S)-2,3-二戊基-4-苯基-7-(3-苯丙基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((S)-2,3-dipentyl-4-phenyl-7-(3-phenylpropyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000201
无色液体(28.3mg,59％yield)，对映选择性ee为88％。比旋光度[α]D 20–1.51(c0.53,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.46–7.34(m,3H),7.32–7.25(m,2H),7.22–7.10(m,5H),2.86–2.79(m,2H),2.79–2.61(m,3H),2.59–2.47(m,2H),2.46–2.36(m,2H),2.34–2.24(m,1H),2.20–2.01(m,2H),1.91–1.72(m,4H),1.47–1.28(m,6H),1.19–1.06(m,4H),0.93(t,J＝7.2Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.0,157.2,147.3,141.8,138.2,133.3,132.1,128.6,128.53,128.51,128.3,128.0,127.7,126.0,122.8,47.8,37.2,35.9,35.8,35.2,32.2,32.1,30.5,29.8,29.0,27.5,27.2,22.8,22.1,14.3,14.0.
实施例43
在本实施例中，制备(R)-7-(环丙基甲基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(cyclopropylmethyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000202
无色液体(26.1mg,63％yield)，对映选择性ee为87％。比旋光度[α]D 2012.88(c0.49,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.49–7.34(m,3H),7.15(dd,J＝16.8,7.2Hz,2H),2.85–2.77(m,2H),2.76–2.67(m,1H),2.66–2.51(m,2H),2.47–2.36(m,2H),2.33–2.26(m,1H),2.25–2.18(m,1H),1.81–1.61(m,4H),1.45–1.36(m,4H),1.35–1.28(m,2H),1.17–1.07(m,4H),0.92(t,J＝7.2Hz,3H),0.76(t,J＝7.2Hz,3H),0.64–0.44(m,2H),0.35–0.27(m,1H),0.17–0.10(m,1H).13C NMR(100MHz,CDCl3)δ160.9,157.4,147.3,138.3,133.2,132.2,128.7,128.5,128.3,128.1,127.7,123.2,48.3,42.1,35.6,35.3,32.2,32.1,30.5,29.8,29.0,27.7,22.8,22.1,14.3,14.0,7.3,4.6,4.5.
实施例44
在本实施例中，制备(R)-7-(环己基甲基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(cyclohexylmethyl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000203
无色液体(37.2mg,81％yield)。对映选择性ee为94％。比旋光度[α]D 2013.79(c0.58,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.47–7.34(m,3H),7.15(t,J＝7.6Hz,2H),2.81(t,J＝8.0Hz,2H),2.77–2.65(m,1H),2.64–2.47(m,2H),2.46–2.35(m,2H),2.28(dd,J＝14.0,5.6Hz,1H),2.19–2.09(m,1H),1.98–1.84(m,2H),1.83–1.66(m,6H),1.56(dd,J＝14.4,7.2Hz,1H),1.47–1.37(m,4H),1.36–1.27(m,4H),1.23–0.99(m,7H),0.94(t,J＝7.6Hz,3H),0.76(t,J＝7.2Hz,3H).13CNMR(100MHz,CDCl3)δ160.9,157.9,147.4,138.3,133.2,131.9,128.7,128.5,128.3,128.1,127.7,123.3,46.9,44.7,37.0,35.5,35.2,34.3,34.2,32.2,32.1,30.5,29.0,27.6,26.39,26.34,22.8,22.1,14.3,14.0.
实施例45
在本实施例中，制备(R)-(7-氰基-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-基)甲基对甲苯磺酸酯((R)-(7-cyano-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)methyl4-methylbenzenesulfonate)，其结构式如下：
Figure BDA0002527237430000211
无色液体(28.1mg,52％yield)，对映选择性ee为80％。比旋光度[α]D 2045.26(c0.57,CHCl3).Rf＝0.3(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.0Hz,2H),7.51–7.30(m,5H),7.13(t,J＝6.8Hz,2H),4.53(AB,J＝9.6Hz,1H),4.27(BA,J＝9.6Hz,1H),2.82–2.66(m,3H),2.65–2.51(m,2H),2.47(s,3H),2.45–2.35(m,3H),1.75–1.61(m,2H),1.42–1.22(m,6H),1.19–1.06(m,4H),0.92(t,J＝6.8Hz,3H),0.76(t,J＝6.8Hz,3H).13CNMR(100MHz,CDCl3)δ161.5,152.7,147.8,145.4,137.7,134.5,133.3,132.4,130.2,128.72,128.66,128.2,128.1,128.0,119.8,71.3,47.9,35.1,33.1,32.11,32.07,30.4,29.5,29.0,27.5,22.7,22.1,21.9,14.2,13.9.
实施例46
在本实施例中，制备(R)-7-烯丙基-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-allyl-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000212
无色液体(30.5mg,76％yield)，对映选择性ee为81％。比旋光[α]D 201.48(c 0.88,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.50–7.33(m,3H),7.15(t,J＝8.0Hz,2H),5.99–5.86(m,1H),5.28–5.17(m,2H),3.02(dd,J＝14.0,6.8Hz,1H),2.92–2.77(m,2H),2.76–2.64(m,1H),2.64–2.35(m,5H),2.24–2.12(m,1H),1.86–1.71(m,2H),1.50–1.28(m,6H),1.21–1.05(m,4H),0.93(t,J＝7.2Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.1,156.7,147.4,138.2,133.4,132.6,132.2,128.7,128.5,128.3,128.1,127.8,122.6,119.8,47.6,41.8,35.2,34.8,32.2,32.1,30.5,29.8,29.0,27.5,22.8,22.1,14.3,14.0.
实施例47
在本实施例中，制备(R)-7-(3-甲基-2-丁烯-1-基)-2,3-二戊基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(3-methylbut-2-en-1-yl)-2,3-dipentyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下：
Figure BDA0002527237430000213
无色液体(26.7mg,62％yield)，对映选择性ee为80％。比旋光[α]D 20–1.71(c0.70,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.48–7.33(m,3H),7.15(dd,J＝12.0,7.6Hz,2H),5.34–5.25(m,1H),2.91(dd,J＝14.8,6.8Hz,1H),2.87–2.78(m,2H),2.72–2.61(m,1H),2.58–2.39(m,5H),2.19–2.08(m,1H),1.84–1.76(m,2H),1.75(s,3H),1.62(s,3H),1.48–1.27(m,6H),1.19–1.09(m,4H),0.93(t,J＝7.2Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.0,157.2,147.3,138.3,136.5,133.2,132.2,128.6,128.5,128.3,128.1,127.7,123.1,118.2,48.1,36.1,35.2,34.8,32.2,32.1,30.5,29.8,29.0,27.5,26.1,22.8,22.1,18.2,14.3,14.0.
实施例48
在本实施例中，制备(S)-2,3-二戊基-4-苯基-7-(4-苯基-3-丁炔-1-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((S)-2,3-dipentyl-4-phenyl-7-(4-phenylbut-3-yn-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000221
无色液体(16.6mg,34％yield)，对映选择性ee为91％。比旋光度[α]D 206.75(c1.2,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.48–7.34(m,5H),7.29–7.26(m,3H),7.15(dd,J＝12.0,7.6Hz,2H),3.00–2.88(m,1H),2.87–2.68(m,4H),2.67–2.48(m,3H),2.46–2.38(m,2H),2.31–2.24(m,1H),2.19–2.09(m,1H),1.83–1.73(m,2H),1.47–1.36(m,4H),1.33–1.28(m,2H),1.18–1.08(m,4H),0.93(t,J＝7.2Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.0,156.8,147.5,138.1,133.6,132.1,131.7,128.7,128.6,128.4,128.2,128.1,127.9,127.8,123.8,122.2,88.8,81.4,47.5,36.7,36.1,35.2,32.2,32.1,30.5,29.6,29.0,27.6,22.8,22.1,16.2,14.3,14.0.
实施例49
在本实施例中，制备(R)-2,3-二戊基-4,7-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-2,3-dipentyl-4,7-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000223
1H NMR(400MHz,CDCl3)δ7.54–7.34(m,5H),7.31–7.14(m,5H),3.13–3.06(m,2H),2.77–2.38(m,6H),1.70–1.49(m,4H),1.41–1.26(m,8H),1.00(t,J＝7.2Hz,3H),0.73(t,J＝7.2Hz,3H).
实施例50
在本实施例中，制备(R)-7-苄基-2,3-二丁基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-2,3-dibutyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000222
无色液体(21.8mg,55％yield)，对映选择性ee为90％。比旋光[α]D 20–41.40(c0.50,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.44–7.30(m,3H),7.29–7.21(m,3H),7.17–7.09(m,3H),6.97(d,J＝6.8Hz,1H),3.53(AB,J＝13.5Hz,1H),3.14(BA,J＝13.5Hz,1H),2.97–2.77(m,2H),2.56–2.29(m,4H),2.28–2.19(m,1H),2.18–2.07(m,1H),1.87–1.74(m,2H),1.55–1.42(m,2H),1.37–1.26(m,2H),1.23–1.09(m,2H),1.00(t,J＝7.2Hz,3H),0.74(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ161.2,156.7,147.4,138.1,135.7,133.5,132.8,130.3,128.6,128.5,128.4,128.1,128.0,127.7,127.3,122.9,48.8,43.3,35.0,34.3,33.1,32.4,28.7,27.5,23.1,23.0,14.3,13.7.
实施例51
在本实施例中，制备(R)-7-苄基-4-苯基-2,3-二丙基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-benzyl-4-phenyl-2,3-dipropyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000224
无色液体(22.7mg,54％yield)，对映选择性ee为90％。比旋光[α]D 20–44.91(c0.53,CHCl3).Rf＝0.4(PE:EA＝20:1).1H NMR(400MHz,CDCl3)δ7.45–7.32(m,3H),7.29–7.23(m,3H),7.18–7.08(m,3H),6.97(d,J＝6.8Hz,1H),3.53(AB,J＝13.5Hz,1H),3.15(BA,J＝13.5Hz,1H),2.94–2.75(m,2H),2.58–2.30(m,4H),2.29–2.20(m,1H),2.18–2.07(m,1H),1.95–1.82(m,2H),1.43–1.31(m,2H),1.08(t,J＝7.2Hz,3H),0.78(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ161.0,156.8,147.4,138.2,135.7,133.4,132.8,130.3,128.6,128.5,128.4,128.1,128.0,127.7,127.3,122.9,48.8,43.3,37.3,34.3,31.2,27.5,24.3,23.4,14.6,14.5.
实施例52
在本实施例中，制备(R)-7-(环己基甲基)-2,3-二甲基-4-苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-7-(cyclohexylmethyl)-2,3-dimethyl-4-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000231
无色液体(19.6mg,57％yield)，对映选择性ee为94％。比旋光[α]D 201.19(c 0.42,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.48–7.35(m,3H),7.15(d,J＝7.2Hz,2H),2.85–2.72(m,1H),2.66–2.58(m,2H),2.57(s,3H),2.34(dd,J＝14.2,6.0Hz,1H),2.22–2.10(m,1H),2.06(s,3H),2.03–1.95(m,1H),1.87–1.79(m,1H),1.78–1.62(m,3H),1.52(dd,J＝14.2,6.8Hz,1H),1.37–1.24(m,3H),1.22–0.97(m,3H).13C NMR(100MHz,CDCl3)δ158.0,157.6,147.0,138.0,132.0,128.9,128.7,128.4,127.9,123.2,47.0,44.6,36.9,35.6,34.4,34.1,27.7,26.3,23.6,16.4.
实施例53
在本实施例中，制备(R)-4-(4-乙酰基苯基)-7-苄基-2,3-二苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-4-(4-acetylphenyl)-7-benzyl-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000232
棕色固体(31.7mg,63％yield)，对映选择性ee为84％。比旋光[α]D 20–51.27(c0.55,CHCl3).Rf＝0.4(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.4Hz,2H),7.39–7.27(m,7H),7.24–7.18(m,3H),7.09–6.98(m,5H),6.84(d,J＝6.4Hz,2H),3.74(AB,J＝13.6Hz,1H),3.23(BA,J＝13.6Hz,1H),2.85–2.72(m,1H),2.55(s,3H),2.53–2.45(m,2H),2.44–2.35(m,1H).13C NMR(100MHz,CDCl3)δ197.7,159.8,158.4,146.4,142.4,140.1,137.3,136.0,135.6,134.6,133.8,131.3,130.4,130.2,129.4,128.6,128.1,128.0,127.9,127.8,127.6,127.1,122.1,49.2,43.0,34.9,27.9,26.7.
实施例54
在本实施例中，制备(R)-4-(4-乙酰基苯基)-7-苄基-2,3-二对甲基苯基-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-4-(4-acetylphenyl)-7-benzyl-2,3-di-p-tolyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000241
黄色固体(36.2mg,68％yield)，对映选择性ee为86％。比旋光[α]D 20–48.70(c0.46,CHCl3).Rf＝0.4(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.8Hz,2H),7.36–7.22(m,7H),7.02(dd,J＝8.0,3.6Hz,4H),6.84(d,J＝8.0Hz,2H),6.72(d,J＝7.6Hz,2H),3.72(AB,J＝13.6Hz,1H),3.21(BA,J＝13.6Hz,1H),2.83–2.68(m,1H),2.56(s,3H),2.52–2.43(m,2H),2.42–2.32(m,1H),2.30(s,3H),2.22(s,3H).13C NMR(100MHz,CDCl3)δ197.8,159.53,158.49,146.3,142.7,137.6,137.5,136.6,135.9,135.7,134.4,134.3,133.4,131.1,130.4,130.1,129.4,128.7,128.61,128.56,128.1,127.5,122.2,49.2,43.0,34.9,27.9,26.7,21.4,21.3.
实施例55
在本实施例中，制备(R)-4-(4-乙酰基苯基)-7-苄基-2,3-双(4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-腈((R)-4-(4-acetylphenyl)-7-benzyl-2,3-bis(4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile)，其结构式如下
Figure BDA0002527237430000243
黄色固体(41.4mg,73％yield)，对映选择性ee为88％。比旋光[α]D 20–25.89(c0.73,CHCl3).Rf＝0.2(PE:EA＝3:1).1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.38–7.26(m,7H),7.01(d,J＝8.4Hz,2H),6.79–6.69(m,4H),6.59(d,J＝8.4Hz,2H),3.78(s,3H),3.71(s,3H),3.72(AB,J＝13.2Hz,1H),3.20(BA,J＝13.6Hz,1H),2.80–2.69(m,1H),2.56(s,3H),2.52–2.42(m,2H),2.41–2.29(m,1H).13C NMR(100MHz,CDCl3)δ197.8,159.5,159.3,158.5,158.2,146.5,142.8,135.9,135.7,133.8,133.1,132.9,132.4,131.6,130.4,129.7,129.4,128.6,128.2,127.6,122.3,113.6,113.3,55.4,55.2,49.2,43.0,34.9,27.9,26.7.
实施例56
在本实施例中，制备(R)-2,2',3,3'-四戊基-4,4'-二苯基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3'-tetrapentyl-4,4'-diphenyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine]),其结构式如下
Figure BDA0002527237430000244
制备方法包括以下步骤：
在手套箱中，先称取Ni(COD)2(6.2mg,0.02mmol,20mol％)和手性配体(R)-L3(25.0mg,0.03mmol,30mol％)于带有磁子的10mL Schlenk管中，再加入1.0mL 2-甲基四氢呋喃溶剂，使其在室温下搅拌5min后，依次加入原料2,2-双(4-苯基-3-丁炔基)丙二腈(33.0mg,0.1mmol,1.0equiv)，溴化锌(24.6mg,0.1mmol,1.0equiv)和
Figure BDA0002527237430000245
MS(106.2mg)，待其密封后，拿出手套箱，并在氩气保护下加入6-十二炔(130μL,0.6mmol,6.0equiv)，并在40℃下反应72h。最后，把所得混合物过滤，滤渣用乙酸乙酯冲洗，所得滤液浓缩后再经柱色谱纯化分离得到螺吡啶产物，选用200-300目的硅胶，流动相选用石油醚：乙酸乙酯。
白色固体(28.1mg,43％yield)，对映选择性为>99％，比旋光[α]D 20–45.00(c0.50,CHCl3).Rf＝0.3(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.48–7.33(m,6H),7.29(d,J＝6.8Hz,2H),7.20(d,J＝7.2Hz,2H),2.85–2.68(m,6H),2.63–2.51(m,2H),2.50–2.34(m,6H),2.19–2.10(m,2H),1.74–1.62(m,4H),1.40–1.27(m,12H),1.20–1.06(m,8H),0.88(t,J＝6.8Hz,6H),0.77(t,J＝6.8Hz,6H).13CNMR(100MHz,CDCl3)δ165.1,159.5,146.2,139.4,133.2,130.9,128.6,128.4,128.3,128.2,127.2,61.3,37.4,35.2,32.23,32.15,30.7,30.1,29.1,28.2,22.8,22.2,14.2,14.0.
实施例57
在本实施例中，制备(R)-2,2',3,3'-四戊基-4,4'-二对甲苯基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3'-tetrapentyl-4,4'-di-p-tolyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000251
白色固体(29.5mg,43％yield)，对映选择性>99％，比旋光[α]D 20–52.71(c 0.59,CHCl3).Rf＝0.3(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.26–7.19(m,4H),7.16(d,J＝6.4Hz,2H),7.08(d,J＝6.4Hz,2H),2.84–2.68(m,6H),2.64–2.52(m,2H),2.48–2.35(m,12H),2.18–2.08(m,2H),1.73–1.59(m,4H),1.39–1.28(m,12H),1.21–1.06(m,8H),0.87(t,J＝6.8Hz,6H),0.78(t,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3)δ165.0,159.5,146.3,136.7,136.4,133.4,131.0,129.01,128.95,128.5,128.3,61.3,37.4,35.2,32.3,32.2,30.8,30.1,29.1,28.3,22.8,22.2,21.4,14.3,14.0.
实施例58
在本实施例中，制备(R)-4,4'-双(4-甲氧基苯基)-2,2',3,3'-四戊基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-4,4'-bis(4-methoxyphenyl)-2,2',3,3'-tetrapentyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000252
白色固体(18.3mg,26％yield)，对映选择性>99％，比旋光[α]D 20–53.46(c 1.53,CHCl3).Rf＝0.2(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.25–7.05(m,4H),7.01–6.87(m,4H),3.87(s,6H),2.83–2.68(m,6H),2.64–2.53(m,2H),2.47–2.34(m,6H),2.18–2.09(m,2H),1.75–1.56(m,4H),1.44–1.27(m,12H),1.21–1.08(m,8H),0.87(t,J＝6.8Hz,6H),0.78(t,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3)δ165.0,159.5,158.7,146.0,133.7,131.6,131.3,129.8,129.6,113.7,61.3,55.4,37.4,35.2,32.3,32.2,30.8,30.2,29.1,28.3,22.8,22.3,14.3,14.0.
实施例59
在本实施例中，制备(R)-4,4'-双(4-氟苯基)-2,2',3,3'-四戊基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-4,4'-bis(4-fluorophenyl)-2,2',3,3'-tetrapentyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000261
白色固体(34.3mg,49％yield)，对映选择性>99％，比旋光[α]D 20–42.17(c 0.69,CHCl3).Rf＝0.2(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.26–7.22(m,2H),7.20–7.05(m,6H),2.82–2.68(m,4H),2.61–2.51(m,2H),2.48–2.33(m,6H),2.19–2.09(m,2H),1.72–1.60(m,4H),1.38–1.25(m,14H),1.20–1.08(m,8H),0.86(t,J＝6.8Hz,6H),0.78(t,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3)δ165.1,162.1(d,J＝244.0Hz),159.6,145.3,135.2(d,J＝3.4Hz),133.4,131.1,130.2(d,J＝24.7Hz),130.1(d,J＝24.1Hz),115.4(d,J＝20.4Hz),115.3(d,J＝20.6Hz),61.3,37.4,35.1,32.2,32.1,30.7,30.1,29.0,28.2,22.8,22.2,14.2,14.0.19F NMR(376MHz,CDCl3)δ–115.34.
实施例60
在本实施例中，制备(R)-4,4'-双(4-氟苯基)-2,2',3,3'-四丙基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-4,4'-bis(4-fluorophenyl)-2,2',3,3'-tetrapropyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine]),其结构式如下
Figure BDA0002527237430000262
白色固体(20.9mg,36％yield)，对映选择性为>99％，比旋光[α]D 20–38.46(c1.37,CHCl3).Rf＝0.2(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.26–7.21(m,2H),7.20–7.06(m,6H),2.83–2.66(m,5H),2.63–2.52(m,2H),2.48–2.31(m,5H),2.20–2.10(m,2H),1.76–1.60(m,4H),1.40–1.24(m,6H),0.95(t,J＝7.2Hz,6H),0.77(t,J＝7.2Hz,6H).13CNMR(100MHz,CDCl3)δ165.2,162.1(d,J＝244.0Hz),159.5,145.3,135.2(d,J＝3.6Hz),133.4,131.0,130.18(d,J＝14.7Hz),130.10(d,J＝13.0Hz),115.5(d,J＝20.5Hz),115.4(d,J＝20.1Hz),61.3,37.3,37.2,31.3,28.3,24.4,23.5,14.7,14.4.19F NMR(376MHz,CDCl3)δ–115.33.
实施例61
在本实施例中，制备(R)-2,2',3,3'-四乙基-4,4'-双(4-氟苯基)-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3'-tetraethyl-4,4'-bis(4-fluorophenyl)-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000263
白色固体(24.5mg,47％yield)，对映选择性为97％，比旋光[α]D 20–45.33(c 1.22,CHCl3).Rf＝0.2(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.30–7.22(m,2H),7.21–7.08(m,6H),2.87–2.68(m,6H),2.64–2.53(m,2H),2.51–2.36(m,6H),2.20–2.11(m,2H),1.24(t,J＝7.2Hz,6H),0.96(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3)δ165.3,162.2(d,J＝244.0Hz),160.6,145.2,135.1(d,J＝3.5Hz),133.6,132.0,130.12(d,J＝14.7Hz),130.06(d,J＝13.0Hz),115.5(d,J＝20.5Hz),115.4(d,J＝20.1Hz),61.4,37.3,28.3,28.2,22.1,15.5,14.8.19F NMR(376MHz,CDCl3)δ–115.31.
实施例62
在本实施例中，制备(R)-2,2',3,3'-四戊基-4,4'-双(4-(三氟甲基)苯基)-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3'-tetrapentyl-4,4'-bis(4-(trifluoromethyl)phenyl)-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000271
白色固体(39.9mg,50％yield)，对映选择性为>99％，比旋光[α]D 20–53.24(c0.71,CHCl3).Rf＝0.2(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.75–7.66(m,4H),7.41(d,J＝7.6Hz,2H),7.34(d,J＝7.6Hz,2H),2.85–2.68(m,6H),2.63–2.42(m,4H),2.41–2.32(m,4H),2.26–2.11(m,2H),1.74–1.59(m,4H),1.40–1.25(m,12H),1.18–1.03(m,8H),0.87(t,J＝6.8Hz,6H),0.76(t,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3)δ165.3,159.8,144.8,143.2,132.8,130.6,129.6(q,J＝32.0Hz),129.1,128.9,125.4,124.4(q,J＝271.0Hz),61.2,37.4,35.1,32.12,32.08,30.7,29.9,29.0,28.2,22.8,22.1,14.2,13.9.19F NMR(376MHz,CDCl3)δ–62.44.
实施例63
在本实施例中，制备(R)-2,2',3,3'-四丁基-4,4'-双(4-(三氟甲基)苯基)-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3'-tetrabutyl-4,4'-bis(4-(trifluoromethyl)phenyl)-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000272
白色固体(32.4mg,44％yield)，对映选择性为>99％，比旋光[α]D 20–35.42(c0.83,CHCl3).Rf＝0.2(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.75–7.67(m,4H),7.41(d,J＝7.6Hz,2H),7.34(d,J＝7.6Hz,2H),2.86–2.68(m,4H),2.61–2.50(m,2H),2.49–2.32(m,6H),2.21–2.11(m,2H),1.70–1.59(m,4H),1.44–1.25(m,10H),1.22–1.11(m,4H),0.91(t,J＝7.2Hz,6H),0.73(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3)δ165.2,159.8,144.9,143.1,132.9,130.6,129.6(q,J＝32.0Hz),129.1,128.9,125.4,124.4(q,J＝270.0Hz),61.2,37.3,34.8,33.2,32.5,28.7,28.2,23.0,22.9,14.3,13.7.19F NMR(376MHz,CDCl3)δ–62.43.
实施例64
在本实施例中，制备(R)-2,2',3,3'-四丙基-4,4'-双(4-(三氟甲基)苯基)-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3'-tetrapropyl-4,4'-bis(4-(trifluoromethyl)phenyl)-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000281
白色固体(31.7mg,48％yield)，对映选择性>99％，比旋光[α]D 20–50.76(c 1.19,CHCl3).Rf＝0.2(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.76–7.67(m,4H),7.42(d,J＝7.2Hz,2H),7.33(d,J＝7.6Hz,2H),2.83–2.67(m,5H),2.62–2.50(m,2H),2.49–2.32(m,6H),2.21–2.11(m,2H),1.76–1.63(m,4H),1.42–1.28(m,5H),0.95(t,J＝7.2Hz,6H),0.77(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3)δ165.3,159.7,144.9,143.2,132.9,130.6,129.6(q,J＝33.0Hz),129.1,128.9,125.4,124.4(q,J＝270.0Hz),61.2,37.3,37.0,31.3,28.2,24.5,23.5,14.6,14.4.19F NMR(376MHz,CDCl3)δ–62.42.
实施例65
在本实施例中，制备(R)-2,2',3,3'-四乙基-4,4'-双(4-(三氟甲基)苯基)-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3'-tetraethyl-4,4'-bis(4-(trifluoromethyl)phenyl)-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000282
无色液体(42.4mg,68％yield)，对映选择性>99％，比旋光[α]D 20–45.49(c 0.82,CHCl3).Rf＝0.2(PE:EA＝50:1).1H NMR(400MHz,CDCl3)δ7.77–7.67(m,4H),7.44(d,J＝6.4Hz,2H),7.35(d,J＝7.6Hz,2H),2.92–2.69(m,6H),2.65–2.52(m,2H),2.51–2.38(m,6H),2.23–2.13(m,2H),1.25(t,J＝7.2Hz,6H),0.97(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3)δ165.4,160.8,144.9,143.1,133.1,131.6,129.7(q,J＝32.0Hz),129.0,128.8,125.5,124.4(q,J＝270.0Hz),61.3,37.4,28.2,22.2,15.5,14.7.19F NMR(376MHz,CDCl3)δ–62.44.
实施例66
在本实施例中，制备(R)-2,2',3,3'-四戊基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3'-tetrapentyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000283
1H NMR(400MHz,CDCl3)δ7.21(s,2H),3.22(t,J＝13.6Hz,4H),2.67–2.57(m,4H),2.56–2.46(m,4H),2.39–2.26(m,2H),2.13–2.01(m,2H),1.71–1.48(m,8H),1.41–1.25(m,16H),1.21(t,J＝7.2Hz,6H),0.92(t,J＝7.2Hz,6H).
实施例67
在本实施例中，制备(R)-4,4'-二甲基-2,2',3,3'-四戊基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-4,4'-dimethyl-2,2',3,3'-tetrapentyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000291
1H NMR(400MHz,CDCl3)δ3.15(t,J＝13.6Hz,4H),2.64–2.54(m,4H),2.53–2.42(m,4H),2.37–2.29(m,2H),2.28(s,6H),2.14–1.99(m,2H),1.73–1.46(m,8H),1.40–1.20(m,16H),1.19(t,J＝7.2Hz,6H),0.89(t,J＝7.2Hz,6H).
实施例68
在本实施例中，制备(R)-4,4'-二苯基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-4,4'-diphenyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000292
1H NMR(400MHz,CDCl3)δ8.81(d,J＝7.5Hz,2H),8.16(d,J＝7.5Hz,2H),7.46(t,J＝7.2Hz,4H),7.44–7.34(m,6H),3.38(t,J＝6.8Hz,4H),2.37–2.26(m,2H),2.12–2.04(m,2H).
实施例69
在本实施例中，制备(R)-4,4'-二苯基-2,2',3,3'-四(三甲基硅基)-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-4,4'-diphenyl-2,2',3,3'-tetrakis(trimethylsilyl)-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000293
1H NMR(400MHz,CDCl3)δ7.48–7.30(m,5H),7.29–7.18(m,5H),3.36(t,J＝6.8Hz,4H),2.38–2.23(m,2H),2.10–2.01(m,2H),–0.24(s,18H),–0.34(s,18H).
实施例70
在本实施例中，制备(R)-2,2',3,3',4,4'-六苯基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-2,2',3,3',4,4'-hexaphenyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000294
1H NMR(400MHz,CDCl3)δ8.22–8.13(m,4H),7.70–7.59(m,4H),7.54–7.34(m,22H),3.46(t,J＝13.6Hz,4H),2.39–2.27(m,2H),2.14–2.00(m,2H).
实施例71
在本实施例中，制备(R)-4-甲基-2,2',3,3'-四戊基-4'-苯基-5,5',6,6'-四氢-7,7'-螺双[环戊二烯并[b]吡啶]((R)-4-methyl-2,2',3,3'-tetrapentyl-4'-phenyl-5,5',6,6'-tetrahydro-7,7'-spirobi[cyclopenta[b]pyridine])，其结构式如下
Figure BDA0002527237430000301
1H NMR(400MHz,CDCl3)δ7.59–7.33(m,5H),3.28–3.20(m,4H),2.63(t,J＝15.3Hz,4H),2.53(t,J＝15.7Hz,4H),2.40–2.30(m,2H),2.29(s,3H),2.14–2.01(m,2H),1.70–1.50(m,8H),1.41–1.27(m,16H),1.16(t,J＝7.2Hz,6H),0.85(t,J＝7.2Hz,6H).
申请人声明，本发明通过上述实施例来说明本发明的详细方法及具体产品，但本发明并不局限于上述详细方法和具体产品，即不意味着本发明必须依赖上述详细方法才能实施和局限于已报道所得产品。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，以及基于本发明中已报到产品骨架的修饰改造，均落在本发明的保护范围和公开范围之内。
本发明的实施例是将作为例证进行说明，但并不限于本发明所描述的内容，还可以是在本发明范围内所作的修改或在权利要求中所添加的等同内容。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

Claims (5)

1.一种含α-氰基季碳中心的全取代吡啶化合物的制备方法，其特征在于：包括以下步骤：(1)以双-(1,5-环辛二烯)镍和配体作为催化剂，原料I和II在有机溶剂中发生[2+2+2]环加成反应；(2)反应结束后分离提纯，生成III所示的含α-氰基季碳中心的全取代吡啶化合物，其反应方程式如下：
Figure FDA0003075816670000011
其中Ni(COD)2为双-(1,5-环辛二烯)镍；ligand指配体；additive指添加剂；solvent指有机溶剂；
其中R1、R3、R4是分别独立的取代基，任选自氢、硅基、烷基、芳基；R2任选自烷基、烯基或芳基；*表示手性中心；
所述反应的温度为40℃～100℃，反应的时间为1～72小时；
其中，步骤(1)所述的配体为下式A-F所示结构或者其对映异构体：
Figure FDA0003075816670000012
其中Ar为芳基，取代基R5、R6、R7、R8是独立的取代基，R5、R6任选自甲基、叔丁基、环己基、芳基；R7任选自氢、烷基、卤素、烷氧基；R8任选自异丙基、芳基；n任选自1或者2；
所述的添加剂是指ZnX2、BY3或者以上任意添加剂和分子筛的组合，其中X指卤素负离子、羧酸根离子或者磺酸根离子；B是指硼元素；Y是指氟负离子、烷基或者芳基。
2.根据权利要求1所述的制备方法，其特征在于，步骤(1)所述催化剂中双-(1,5-环辛二烯)镍与配体的摩尔比为1:0.8～1:2；所述催化剂中金属元素的物质的量与原料I的物质的量之比为0.01:1～0.5:1；所述原料I和II的物质的量之比为1:1～1:50；所述的添加剂和原料I的物质的量之比为0.05:1～3:1。
3.根据权利要求1所述的制备方法，其特征在于，步骤(1)所述的有机溶剂为甲苯、1,2-二氯乙烷、二氯甲烷、乙腈、乙二醇二甲醚，甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、乙醚、1,4-二氧六环、环戊基甲基醚、N,N’-二甲基甲酰胺中的任一种或多种的混合溶剂。
4.根据权利要求1所述的制备方法，其特征在于，步骤(2)所述分离提纯方法为柱层析、薄层层析或重结晶；所述柱层析使用的洗脱液为乙酸乙酯、二氯甲烷和石油醚的混合液。
5.一种C2对称的螺吡啶化合物的制备方法，其特征在于，包含如下步骤：(1)按照权利要求1～4任意一项所述的制备方法，将其中的原料I替换成原料IV；(2)将步骤(1)的产物进行分离提纯，获得C2对称的螺吡啶化合物V，具体方程式如下：
Figure FDA0003075816670000021
其中R9任选自氢、烷基、芳基。
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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Edward C. Taylor et al..Intramolecular Diels-Alder Reactions of 1,2,4-Triazines: Exploitation of the Thorpe-Ingold Effect for the Synthesis of 2,3-Cyclopentenopyridines and 5,6,7,8-Tetrahydroquinolines.《Tetrahedron Letters》.1986,第27卷(第19期),第2107-2110页. *
Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis;Zhiwu Lu et al.;《J. Am. Chem. Soc.》;20200407;第142卷;第7328-7333页 *
Intramolecular Diels-Alder Reactions of 1,2,4-Triazines: Exploitation of the Thorpe-Ingold Effect for the Synthesis of 2,3-Cyclopentenopyridines and 5,6,7,8-Tetrahydroquinolines;Edward C. Taylor et al.;《Tetrahedron Letters》;19861231;第27卷(第19期);第2107-2110页 *
Jesús A. Varela et al..One-Step Synthesis of Spiropyridines, a Novel Class of C2-Symmetric Chiral Ligands, by Cobalt(I)-Catalyzed [2 + 2 + 2] Cycloadditions between Bis-Alkynenitriles and Alkynes.《Org.Lett.》.1999,第1卷(第13期),第2141-2143页. *
One-Step Synthesis of Spiropyridines, a Novel Class of C2-Symmetric Chiral Ligands, by Cobalt(I)-Catalyzed [2 + 2 + 2] Cycloadditions between Bis-Alkynenitriles and Alkynes;Jesús A. Varela et al.;《Org.Lett.》;19991209;第1卷(第13期);第2141-2143页 *

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