CN111499542B - 一种含α-氰基取代季碳中心的环烯酮化合物的制备方法 - Google Patents

一种含α-氰基取代季碳中心的环烯酮化合物的制备方法 Download PDF

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CN111499542B
CN111499542B CN202010250039.4A CN202010250039A CN111499542B CN 111499542 B CN111499542 B CN 111499542B CN 202010250039 A CN202010250039 A CN 202010250039A CN 111499542 B CN111499542 B CN 111499542B
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刘文博
陆志武
胡旭东
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Abstract

本发明公开了一种α‑氰基取代季碳中心的环烯酮化合物的制备方法。属于有机合成技术领域。所述制备方法是在镍络合物和配体催化下芳基或烯基硼试剂和炔基取代的二取代丙二腈类化合物发生炔烃插入和环化串联反应，得到α‑氰基取代季碳中心的环烯酮类化合物。本发明还提供了一种制备α‑氰基取代季碳中心的环烯胺的方法。本发明的方法操作简便安全，反应步骤少，反应效率高，反应条件温和，反应活性高，区域选择性和对映选择性好。所制备的环状含腈类化合物广泛地应用于药物化学、有机合成领域和材料化学。

Description

一种含α-氰基取代季碳中心的环烯酮化合物的制备方法
技术领域
本发明属于有机合成技术领域，具体涉及一种含α-氰基取代季碳中心的环烯酮化合物的制备方法。
背景技术
氰基基团(CN)作为重要的药效基团，在药物中起着重要的作用。氰基基团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，并改善分子的毒理学特征。在药物和临床候选药物中，越来越多地发现含有氰基基团。特别重要的是，那些包含氰基的全碳季碳立体中心的生物活性化合物，可防止化合物的α-碳氧化，导致有毒的氰化物释放。[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；b)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，可以轻松转化为多种官能团，例如羧酸，醛，胺，恶唑啉和哌啶等[a)F.F.Fleming,Nat.Prod.Rep.1999,16,597；b)K.Friedrich,K.Wallenfels,The Chemistry of the Cyano Group；Wiley-Interscience:NewYork.1970；c)Z.Zhang,X.Zhang,D.A.Nagib,Chem 2019,5,3127.]。因此在合成化学领域中受到科学家们的广泛关注。目前已经报道的合成这类含氰基手性季碳中心结构的方法主要包括：(1)α-氰基羰基亲电官能化[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.]。(b)乙烯酮亚胺亲电官能化[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]。(c)3-二羰基α-氰化[a)R.Chowdhury,J.
Figure BDA0002435160490000021
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.]。
由于前手性二取代丙二腈化合物容易获得且毒性较小，对其选择性去对称化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]。
鉴于以上挑战，目前仅有两例关于双取代丙二腈金属不对称去对称的例子。2006年，Tanaka课题组进行了铑催化的炔烃与氰基的[2+2+2]环加成反应，实现了75％的收率和33％ee的手性控制[K.Tanaka,N.Suzuki,G.Nishida,Eur.J.Org.Chem.2006,2006,3917；]。2010年，Ikariya基团报导了钌催化的水解反应，得到了54％的收率和30％ee的手性控制。[S.Kamezaki,S.Akiyama,Y.Kayaki,S.Kuwata,T.Ikariya,Tetrahedron:Asymmetry 2010,21,1169]。但是，在这两种情况下，不仅对映选择性差，而且为单一底物，并且产物结构单一。
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活性、高区域选择性、高对映选择性地合成手性含氰基季碳中心化合物的制备方法。
为达此目的，本发明采用以下技术方案：
第一方面，本发明提供一种含α-氰基取代季碳中心的环烯酮化合物的制备方法，包含如下步骤：(1)在镍络合物和配体催化下，原料I和II在溶剂中发生反应，并加入添加剂；(2)反应结束后，加入酸溶液搅拌后处理；(3)浓缩溶剂，分离提纯，生成III所示的α-氰基取代季碳中心的环烯酮化合物；其反应方程式如下：
Figure BDA0002435160490000031
其中[Ni]指镍络合物；Ligand指配体；solvent指有机溶剂；additive指添加剂；
其中R1、R2、R3是分别独立的取代基；其中R1任选自氢、烷基或芳基；R2任选自烷基、烯基或芳基；R3任选自芳基或者烯基；其中Z任选自亚甲基或R4取代的胺；其中m任取自0、1、或2；其中n任取自0、1、或2；其中R4任选自烷基、芳基、叔丁氧羰基、苄氧羰基、乙酰基、苯甲酰基或者磺酰基；其中[B]表示硼酸、硼酸酐、三氟硼酸盐、或者频那醇硼酸酯；*表示手性中心；
其中镍络合物为双-(1，5-环辛二烯)镍、双(环戊二烯)镍、卤化镍、乙酰丙酮酸镍、硫酸镍、硝酸镍、高氯酸镍、醋酸镍、碳酸镍、对甲苯磺酸镍、三氟甲烷磺酸镍、四氟硼酸镍或者这些物质的水合物、有机溶剂合物中的任意一种；
所述的配体具有式A-K所示结构或者其对映异构体，式A-K中Ar为芳基，Y任选自氧或R14取代的氮原子，所述的取代基R5、R6、R7、R8、R9、R10、R11、R12、R13、R14是独立的取代基；其中R5、R10任选自氢、氟、烷基、卤代烷基、卤代烷氧基、环烷基、杂环基、烷氨基、烷氧基、芳基或杂芳基；R6、R7、R8、R9、R13任选自氢、甲基、乙基、异丙基、叔丁基、环己基、芳基或芐基；R11、R12、R14任选自甲基、乙基、异丙基、叔丁基、环己基、芳基；
优选地，所述配体为具有如式A、式B、式C、式F或式I所示结构的配体；
Figure BDA0002435160490000041
所述催化剂为镍络合物中所含金属镍元素与配体的摩尔比为1:0.5～1:5；
优选地，镍络合物中所含金属镍元素与配体的摩尔比为1:1～1:1.2；
所述反应在有机溶剂中进行，所述有机溶剂为苯、甲苯、二甲苯、乙苯、氯苯、三氟甲苯、氯仿、二氯甲烷、乙腈、异丙醇、环己烷、正己烷、二甲基甲酰胺、乙二醇二甲醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环以及其中二种或二种以上混合溶剂；
优选地，所述反应在四氢呋喃或甲苯中进行；
所述添加剂是指三氟磺酸锌、三氟磺酸铁、六氟磷酸胺、水；
优选地，所述反应的添加剂为4当量的水；
所述金属催化剂中金属元素的物质量与原料I的物质量之比为0.01:1～0.2:1，优选0.25:1～0.1:1；
所述原料I和II的物质量之比为2:1～1:3；
所述添加剂和原料I的物质量之比为0.2:1～10:1；
所述反应的温度为60℃～120℃；
所述反应的时间为1～48小时；
上述制备方法步骤(2)所述酸溶液为盐酸、硫酸、磷酸、醋酸或硝酸中的任意一种，优选盐酸；
所述制备方法步骤(2)所述酸的量和原料I的物质量之比为1:1～100:1；
优选地，所述酸溶液的浓度为0.5～1.5M；
优选地，上述制备方法步骤(3)所述分离提纯方法为柱层析、薄层层析或重结晶。
优选地，所述柱层析使用的洗脱液为乙酸乙酯、二氯甲烷、或者石油醚和乙酸乙酯的混合液。
优选地，石油醚和乙酸乙酯的体积比为1:2～80:1。
第二方面，提供一种α-氰基取代季碳中心的环烯胺化合物IV的制备方法，具体步骤与上述α-氰基取代季碳中心的环烯酮的制备方法的步骤(1)相同，不需要上述α-氰基取代季碳中心的环烯酮制备方法中的步骤(2)酸后处理，直接将步骤(1)的产物进行分离提纯，获得α-氰基取代季碳中心的环烯胺化合物IV，具体方程式如下：
Figure BDA0002435160490000051
其中分离提纯方法与上述α-氰基取代季碳中心的环烯酮的分离方法一致；
其中R1、R2、R3、Z、m、n和[B]的范围和上述的α-氰基取代季碳中心的环烯酮的制备方法中的范围一致；[Ni]，ligand,solvent和additive也与α-氰基取代季碳中心的环烯酮的制备方法中的指代一致。
相对于现有技术，本发明具有以下有益效果：
(1)本发明的方法合成了一类全新的含氰基季碳手性中心的化合物结构。
(2)本发明的方法操作简便安全，反应步骤少，反应效率高，反应条件温和，反应活性高，区域选择性和对映选择性好。
(3)从容易获得的二取代丙二腈化合物出发，选择性去对称化是构建含氰基季碳中心化合物的非常直接有效的途径。
(4)使用非贵金属催化剂，成本低，可以有效减少所合成产物中的重金属残留以及反应本身对环境的污染。
具体实施方式
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，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)丙二腈和苯硼酸为标准底物，对镍催化α-腈基取代环烯酮合成的镍络合物的研究：
Figure BDA0002435160490000061
在100摄氏度下，1mL甲苯溶剂中反应14小时；其中[Ni]为镍络合物；配体结构如L1所示；mol％指的相对摩尔量，equiv代表当量；收率ee指α-腈基取代环烯酮化合物的手性控制的对映选择性，由高效液相测定。
实施例2：以2-苯基-2-(4-苯丁炔基)丙二腈和苯硼酸为标准底物，对镍催化α-腈基取代环烯酮合成的配体的研究：
Figure BDA0002435160490000062
Figure BDA0002435160490000071
Figure BDA0002435160490000081
在100摄氏度下，1mL甲苯溶剂中反应14小时；其中ligand是指配体；三氟甲磺酸镍为镍络合物；配体结构如L1-L23所示；mol％指的相对摩尔量，equiv代表当量；收率ee指α-腈基取代环烯酮化合物的手性控制，由高效液相测定。
实施例3：以2-苯基-2-(4-苯丁炔基)丙二腈和苯硼酸为标准底物，对镍催化α-腈基取代环烯酮合成的溶剂的研究：
Figure BDA0002435160490000082
Figure BDA0002435160490000091
在100摄氏度下，1mL表格所示溶剂中反应14小时；其中三氟甲磺酸镍为镍络合物；配体结构如L1所示；solvent是指溶剂；mol％指的相对摩尔量，equiv代表当量；收率ee指α-腈基取代环烯酮化合物的手性控制，由高效液相测定。
实施例4：以2-苯基-2-(4-苯丁炔基)丙二腈和苯硼酸为标准底物，对镍催化α-腈基取代环烯酮合成的浓度、温度和添加剂的研究：
Figure BDA0002435160490000092
在表格所示摄氏度下和浓度下，在甲苯中反应14-16小时；其中temp是指温度；M表示浓度，指mol/L；配体结构如L1所示；mol％指的相对摩尔量，equiv代表当量；additive表示添加剂；ee指α-腈基取代环烯酮化合物的手性控制，由高效液相测定；[a]表示使用了2equiv的水；[b]表示使用了10equiv的水。
实施例5：以2-苯基-2-(4-苯丁炔基)丙二腈和苯硼酸为标准底物，对镍催化α-腈基取代环烯酮合成的催化剂用量，镍络合物和配体的比例的研究：
Figure BDA0002435160490000101
在表格所示催化剂用量下，在1mL甲苯中反应16-23小时；其中temp是指温度；配体结构如L1所示；mol％指的相对摩尔量；ee指α-腈基取代环烯酮化合物的手性控制，由高效液相测定。
实施例6：以2-苯基-2-(4-苯丁炔基)丙二腈对镍催化α-腈基取代环烯酮合成的R3[B]的硼试剂类型研究
Figure BDA0002435160490000102
实施例7-45
制备方法包括以下要素：取干燥的10mL装有磁力搅拌子的反应封管，于手套箱氩气氛围中加入10mol％三氟甲磺酸镍(7.2mg,0.0075mmol)和12mol％L1(9.3mg,0.024mmol)的1mL甲苯溶液中，室温下搅拌30分钟。接着加入反应物I(0.2mmol)和反应物II(0.4mmol,)，最后再补加1mL甲苯和H2O(15μL,0.8mmol)。80℃油浴条件下反应，至TLC监测原料反应完全(约24h)。体系恢复至室温，加入1M盐酸水溶液(1.0mL)进行后处理，并搅拌30分钟.混合体系用乙酸乙酯(10mL x 3)萃取，有机相饱和水萃取，无水硫酸钠干燥，过滤。旋转蒸发除去溶剂，选用200-300目的硅胶和石油醚与乙酸乙酯的混合溶剂作为洗脱液进行柱层析分离，得到目标产物III，产物的ee由配备手性分离柱的高相液相色谱测定。
实施例7
在本实施例中，制备(R)-4'-苄基-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4'-benzyl-3'-o xo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000111
白色固体(49.1mg,89％收率)，对映选择性ee为90％。比旋光度[α]D 25＝–116.88(c1.73,CHCl3)；Rf＝0.3(PE:EA＝10:1).
1H NMR(400MHz,CDCl3)δ7.40–7.32(m,5H),7.19–7.17(m,6H),7.05–7.02(m,2H),6.96–6.94(m,2H),3.54(d,J＝14.0Hz,1H),3.14–3.06(m,2H),2.93(dt,J＝19.6,4.6Hz,1H),2.39(dt,J＝13.7,4.6Hz,1H),2.24–2.17(m,1H).13C NMR(100MHz,CDCl3)δ190.2,158.5,139.5,135.8,134.8,134.5,130.9,130.7,128.8,128.7,128.24,128.20,127.9,127.8,127.5,118.7,47.7,39.7,30.2,29.8.HRMS(ESI+)m/z calc’d for C26H21NONa[M+Na]+:386.1515,found 386.1518.
实施例8
在本实施例中，制备制备(R)-4'-苄基-4-甲级-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-4-methyl-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000112
白色固体(53.3mg,71％收率)，对映选择性ee为90％。比旋光度[α]D 25＝–133.14(c2.1,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.38–7.35(m,5H),7.22–7.18(m,3H),6.99–6.92(m,6H),3.53(AB,J＝14.0Hz,1H),3.12–3.04(m,2H),2.92(dt,J＝19.5,4.6Hz,1H),2.38(dt,J＝13.7,4.6Hz,1H),2.26(s,3H),2.23–2.16(m,1H).13C NMR(100MHz,CDCl3)δ190.2,158.5,138.9,136.5,135.4,135.1,134.6,130.9,130.6,128.9,128.7,128.3,128.0,127.8,127.4,118.8,47.6,39.7,30.1,29.7,21.4.HRMS(ESI+)m/z calc’dfor C27H23NONa[M+Na]+:400.1672,found 400.1674.
实施例9
在本实施例中，制备(R)-4'-苄基-4-甲氧基-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-4-methoxy-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000121
白色固体(67.3mg,86％收率)，对映选择性ee为88％。比旋光度[α]D 25＝–118.89(c1.2,CHCl3).Rf＝0.2(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.40–7.31(m,5H),7.24–7.17(m,3H),7.00–6.96(m,4H),6.68(d,J＝8.8Hz,2H),3.74(s,3H),3.53(AB,J＝14.0Hz,1H),3.10(BA,J＝13.9Hz,1H),3.05(dd,J＝9.9,4.9Hz,1H),2.93(dt,J＝19.5,4.6Hz,1H),2.37(dt,J＝13.7,4.6Hz,1H),2.23–2.14(m,1H).13C NMR(100MHz,CDCl3)δ190.1,159.9,158.0,135.4,135.0,134.6,131.5,131.0,130.6,130.1,128.7,128.1,127.7,127.4,118.9,113.6,55.3,47.6,39.7,30.0,29.5.HRMS(ESI+)m/z calc’d for C27H23O2Na[M+Na]+:416.1621,found 416.1627.
实施例10
在本实施例中，制备(R)-4'-苄基-4-氟-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-4-fluoro-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000122
白色固体(60.9mg,80％收率)，对映选择性ee为90％。比旋光度[α]D 25＝–156.60(c1.5,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.40–7.30(m,5H),7.22–7.19(m,3H),7.05–6.99(m,2H),6.96–6.92(m,2H),6.89–6.83(m,2H),3.53(d,J＝14.0Hz,1H),3.12–3.04(m,2H),2.89(dt,J＝19.6,4.5Hz,1H),2.38(dt,J＝13.7,4.5Hz,1H),2.23–2.16(m,1H).13C NMR(100MHz,CDCl3)δ190.1,162.6(d,J＝249.9Hz),157.1,136.0,135.5(d,J＝3.1Hz),134.7,134.5,130.9,130.7,130.3(d,J＝8.1Hz),128.8,128.1,127.7(d,J＝18.4Hz),118.6,115.5,115.3,47.6,39.6,30.1,29.7.19F NMR(376MHz,CDCl3)δ–111.69.HRMS(ESI+)m/z calc’d for C26H20NOFNa[M+Na]+:404.1421,found 404.1423.
实施例11
在本实施例中，制备(R)-4'-苄基-4-氯-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-4-chloro-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000131
白色固体(65.0mg,82％收率)，对映选择性ee为83％。比旋光度[α]D 25＝–114.45(c1.5,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.40–7.31(m,5H),7.23–7.20(m,3H),7.15(d,J＝8.3Hz,2H),7.00–6.92(m,4H),3.53(d,J＝13.9Hz,1H),3.12–3.03(m,2H),2.88(dt,J＝19.5,4.4Hz,1H),2.39(dt,J＝13.8,4.4Hz,1H),2.23–2.16(m,1H).13CNMR(100MHz,CDCl3)δ190.1,156.8,137.9,136.1,134.7,134.5,134.4,130.8,130.7,129.7,128.8,128.6,128.2,127.8,127.7,118.6,47.6,39.6,30.1,29.6.HRMS(ESI+)m/zcalc’d for C26H20NOClNa[M+Na]+:420.1126,found 420.1126.
实施例12
在本实施例中，制备(R)-4'-苄基-4-溴-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-4-bromo-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000132
白色固体(58.8mg,67％收率)，对映选择性ee为84％。比旋光度[α]D 25＝–109.30(c0.9,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.39–7.29(m,7H),7.23–7.19(m,3H),6.96–6.89(m,4H),3.52(d,J＝14.0Hz,1H),3.11–3.03(m,2H),2.87(dt,J＝19.6,4.5Hz,1H),2.38(dt,J＝13.8,4.5Hz,1H),2.23–2.15(m,1H).13C NMR(100MHz,CDCl3)δ190.1,156.8,138.4,136.1,134.5,134.4,131.5,130.8,130.7,129.9,128.8,128.2,127.9,127.8,123.0,118.6,47.6,39.6,30.1,29.6.HRMS(ESI+)m/z calc’d forC26H20NOBrNa[M+Na]+:464.0620,found 464.0624.
实施例13
在本实施例中，制备(R)-4'-苄基-3'-氧-4-三氟甲基-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-3'-oxo-4-(trifluoromethyl)-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000141
白色固体(68.9mg,80％收率)，对映选择性ee为78％。比旋光度[α]D 25＝–95.75(c2.1,CHCl3).Rf＝0.2(PE:EA＝15:1).1H NMR(400MHz,CDCl3)7.44(d,J＝8.1Hz,2H),7.40–7.32(m,5H),7.22–7.18(m,3H),7.15(d,J＝8.1Hz,2H),6.95–6.90(m,2H),3.54(d,J＝14.0Hz,1H),3.15–3.06(m,2H),2.88(dt,J＝19.6,4.4Hz,1H),2.41(dt,J＝13.8,4.5Hz,1H),2.26–2.19(m,1H).13C NMR(100MHz,CDCl3)δ190.1,156.4,143.2,136.7,134.3,134.1,130.7,130.6,130.4(q,J＝32.7Hz),128.8,128.5,128.2,127.91,127.87,125.3(q,J＝3.8Hz),123.8(q,J＝272.3Hz),118.5,47.6,39.6,30.2,29.6.19F NMR(376MHz,CDCl3)δ–62.82.HRMS(ESI+)m/z calc’d for C27H20F3NONa[M+Na]+:454.1389,found 454.1390.
实施例14
在本实施例中，制备(R)-4'-苄基-3'-氧-4-三氟甲氧基-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-3'-oxo-4-(trifluoromethoxy)-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000151
白色固体(50.2mg,56％收率)，对映选择性ee为81％。比旋光度[α]D 25＝–99.18(c2.1,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.40–7.32(m,5H),7.22–7.20(m,3H),7.07(d,J＝8.6Hz,2H),7.02(d,J＝8.5Hz,2H),6.95–6.93(m,2H),3.54(d,J＝14.0Hz,1H),3.13–3.05(m,2H),2.90(dt,J＝19.6,4.5Hz,1H),2.40(dt,J＝13.8,4.5Hz,1H),2.25–2.18(m,1H).13C NMR(100MHz,CDCl3)δ190.1,156.6,149.1,138.0,136.3,134.4,130.8,130.6,129.9,128.8,128.1,127.8,127.7,120.5,120.4(q,J＝256.3Hz),118.6,47.6,39.6,30.1,29.6.19F NMR(376MHz,CDCl3)δ–57.78.HRMS(ESI+)m/z calc’d forC27H20NO2F3Na[M+Na]+:470.1338,found 470.1329.
实施例15
在本实施例中，制备(R)-4'-苄基-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4,4'-二腈[(R)-4’-Benzy l-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4,4'-dicarbonitrile]，其结构式如下：
Figure BDA0002435160490000152
白色固体(62.0mg,80％收率)，对映选择性ee为85％。比旋光度[α]D 25＝–103.27(c1.0,CHCl3).Rf＝0.2(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ7.48–7.45(m,2H),7.40–7.31(m,5H),7.24–7.17(m,3H),7.16–7.12(m,2H),6.93–6.89(m,2H),3.53(AB,J＝14.0Hz,1H),3.14–3.05(m,2H),2.86(dt,J＝19.6,4.4Hz,1H),2.44–2.38(m,1H),2.25–2.18(m,1H).13CNMR(100MHz,CDCl3)δ189.9,155.7,144.2,137.0,134.2,133.8,132.1,130.7,130.6,128.9,128.8,128.3,128.1,127.9,118.3,112.3,47.6,39.5,30.2,29.4.HRMS(ESI+)m/zcalc’d for C27H20N2ONa[M+Na]+:411.1468,found 411.1457.
实施例16
在本实施例中，制备(R)-4'-苄基-4-甲酰基-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-碳腈[(R)-4’-Benzyl-4-formyl-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000161
白色固体(56.3mg,72％收率)，对映选择性ee为93％。比旋光度[α]D 25＝–122.02(c1.6,CHCl3).Rf＝0.2(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ9.91(s,1H),7.69(d,J＝8.3Hz,,2H),7.41–7.32(m,5H),7.21–7.15(m,5H),6.96–6.91(m,2H),3.54(AB,J＝14.0Hz,1H),3.16–3.07(m,2H),2.90(dt,J＝19.6,4.5Hz,1H),2.42(dt,J＝13.8,4.5Hz,1H),2.27–2.20(m,1H).13C NMR(100MHz,CDCl3)δ191.6,190.0,156.6,145.7,136.8,135.9,134.3,134.1,130.8,130.7,129.6,128.8,128.2,128.0,127.9,118.5,47.6,39.6,30.3,29.6.HRMS(ESI+)m/z calc’d for C27H21NO2Na[M+Na]+:414.1465,found 414.1468.
实施例17
在本实施例中，制备(R)-甲基-4'-苄基-4’-氰基-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4-酸酯[(R)-Methyl-4’-Benzyl-4'-cyano-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4-carboxylate]，其结构式如下：
Figure BDA0002435160490000162
白色固体(76.9mg,92％收率)，对映选择性ee为93％。比旋光度[α]D 25＝–118.40(c1.0,CHCl3).Rf＝0.2(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.1Hz,2H),7.40–7.31(m,5H),7.20–7.17(m,3H),7.11(d,J＝8.1Hz,2H),6.95–6.91(m,2H),3.87(s,3H),3.53(d,J＝14.0Hz,1H),3.14–3.06(m,2H),2.90(dt,J＝19.6,4.5Hz,1H),2.41(dt,J＝13.8,4.5Hz,1H),2.26–2.19(m,1H).13C NMR(100MHz,CDCl3)δ190.0,166.5,157.1,144.1,136.4,134.3,134.2,130.7,130.6,130.0,129.5,128.8,128.2,128.1,127.83,127.79,118.5,52.3,47.6,39.5,30.2,29.5.HRMS(ESI+)m/z calc’d for C28H23NO3Na[M+Na]+:444.1570,found 444.1558.
实施例18
在本实施例中，制备(R)-4'-苄基-4’-氰-N,N-二甲基-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4-酰胺[(R)-4’-Benzyl-4'-cyano-N,N-dimethyl-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4-carboxamide]，其结构式如下：
Figure BDA0002435160490000171
白色固体(45.2mg,63％收率)，对映选择性ee为94％。比旋光度[α]D 25＝–95.02(c1.7,CHCl3).Rf＝0.2(PE:EA＝1:1).1H NMR(400MHz,CDCl3)δ7.39–7.29(m,5H),7.22(d,J＝8.0Hz,2H),7.18–7.14(m,3H),7.06(d,J＝8.0Hz,2H),6.95–6.91(m,2H),3.52(AB,J＝13.9Hz,1H),3.12–2.87(m,9H),2.39(dt,J＝13.7,4.5Hz,1H),2.24–2.17(m,1H).13C NMR(100MHz,CDCl3)δ190.1,170.8,157.3,140.8,136.2,136.1,134.5,134.4,130.8,130.6,128.7,128.2,128.0,127.8,127.7,127.1,118.6,47.6,39.6,30.1,35.4(br),29.6.HRMS(ESI+)m/z calc’d for C29H26N2O2Na[M+Na]+:457.1886,found 457.1892.
实施例19
在本实施例中，制备(R)-甲基-4'-苄基-4’-氰-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-3-酸酯[(R)-Methyl-4’-Benzyl-4'-cyano-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-3-carboxylate]，其结构式如下：
Figure BDA0002435160490000172
白色固体(76.3mg,91％收率)，对映选择性ee为94％。比旋光度[α]D 25＝–127.94(c1.6,CHCl3).Rf＝0.2(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.87–7.83(m,2H),7.41–7.31(m,5H),7.21–7.16(m,4H),7.12(dt,J＝7.8,1.6Hz,1H),6.97–6.92(m,2H),3.88(s,3H),3.53(AB,J＝14.0Hz,1H),3.15–3.06(m,2H),2.95(dt,J＝19.7,4.6Hz,1H),2.41(dt,J＝13.7,4.6Hz,1H),2.26–2.19(m,1H).13C NMR(100MHz,CDCl3)δ190.1,166.5,157.1,139.8,136.4,134.4,134.3,132.9,130.8,130.6,130.3,129.7,129.0,128.8,128.4,128.1,127.8,127.7,118.6,52.4,47.6,39.6,30.1,29.6.HRMS(ESI+)m/z calc’d for C28H23NO3Na[M+Na]+:444.1570,found 444.1578.
实施例20
在本实施例中，制备(R)-4'-苄基-3'-氧-4-乙烯基-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-3'-oxo-4-vinyl-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000181
白色固体(30.2mg,39％收率)，对映选择性ee为92％。比旋光度[α]D 25＝–108.60(c0.6,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.42–7.30(m,5H),7.22–7.19(m,5H),7.02–6.94(m,4H),6.61(dd,J＝17.6,10.9Hz,1H),5.71(d,J＝17.6Hz,1H),5.25(d,J＝10.9Hz,1H),3.54(AB,J＝14.0Hz,1H),3.13–3.05(m,2H),2.92(dt,J＝19.5,4.4Hz,1H),2.39(dt,J＝13.7,4.5Hz,1H),2.24–2.17(m,1H).13C NMR(100MHz,CDCl3)δ190.2,157.9,138.8,137.9,136.1,135.6,134.9,134.5,130.9,130.6,128.8,128.6,128.0,127.8,127.5,126.0,118.7,115.2,47.7,39.7,30.2,29.5.HRMS(ESI+)m/z calc’d forC28H24NO[M+H]+:390.1852,found 390.1846.
实施例21
在本实施例中，制备(R)-3-苄基-6-(3-呋喃基)-2-氧-2,3,4,5-四氢-[1,1'-二苯基]-3-腈(R)-3-Benzyl-6-(furan-3-yl)-2-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-3-carbonitrile，其结构式如下：
Figure BDA0002435160490000182
白色固体(49.7mg,70％收率)，对映选择性ee为70％。比旋光度[α]D 25＝–62.63(c1.0,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.44–7.29(m,8H),7.19–7.16(m,2H),7.12–7.08(m,2H),5.66–5.65(m,1H),3.51(AB,J＝14.0Hz,1H),3.10–3.02(m,2H),2.92(dt,J＝18.8,4.7Hz,1H),2.36(dt,J＝13.7,4.7Hz,1H),2.19–2.12(m,1H).13C NMR(100MHz,CDCl3)δ189.8,147.7,144.5,143.2,136.1,134.6,134.0,130.6,129.9,128.9,128.7,128.3,127.7,124.7,118.8,110.0,47.5,39.6,29.8,27.0.HRMS(ESI+)m/z calc’dfor C24H19NO2Na[M+Na]+:376.1308,found 376.1309.
实施例22
在本实施例中，制备(R)-3-苄基-2-氧-6-(3-噻吩基)-2,3,4,5-四氢-[1,1'-二苯基]-3-腈[(R)-3-benzyl-2-oxo-6-(thiophen-3-yl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-3-carbonitrile]，其结构式如下：
Figure BDA0002435160490000191
白色固体(63.3mg,86％收率)，对映选择性ee为82％。比旋光度[α]D 25＝–89.42(c1.5,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.39–7.31(m,8H),7.13–7.03(m,4H),6.56(dd,J＝5.2,1.3Hz,1H),3.52(AB,J＝14.0Hz,1H),3.18–2.98(m,3H),2.38(dt,J＝13.7,4.6Hz,1H),2.21–2.14(m,1H).13C NMR(100MHz,CDCl3)δ190.3,150.9,139.7,135.9,134.6,130.6,130.4,128.8,128.6,128.1,128.0,127.8,127.7,125.2,118.8,47.5,39.7,29.9,28.7.HRMS(ESI+)m/z calc’d for C24H19NOSNa[M+Na]+:392.1080,found392.1083.
实施例23
在本实施例中，制备(R)-4'-苄基-4”-甲基-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-4”-methyl-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000192
白色固体(60.1mg,80％收率)，对映选择性ee为89％。比旋光度[α]D 25＝–145.67(c1.0,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.40–7.31(m,5H),7.21–7.16(m,3H),7.07–7.04(m,2H),6.99(AB,J＝7.8Hz,2H),6.84(BA,J＝7.7Hz,2H),3.53(AB,J＝13.9Hz,1H),3.13–3.04(m,2H),2.92(dt,J＝19.6,4.6Hz,1H),2.38(dt,J＝13.7,4.6Hz,1H),2.27(s,3H),2.23–2.16(m,1H).13C NMR(100MHz,CDCl3)δ190.4,158.0,139.7,137.2,135.6,134.6,131.7,130.7,130.6,128.74,128.71,128.6,128.23,128.22,127.8,118.8,47.6,39.6,30.1,29.8,21.4.HRMS(ESI+)m/z calc’d for C27H23NONa[M+Na]+:400.1672,found 400.1677.
实施例24
在本实施例中，制备(R)-4'-苄基-4”-甲氧基-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-4”-methoxy-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000201
白色固体(63.4mg,81％收率)，对映选择性ee为88％。比旋光度[α]D 25＝–157.10(c1.3,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.40–7.31(m,5H),7.20–7.18(m,3H),7.07–7.03(m,2H),6.86(d,J＝8.7Hz,2H),6.72(d,J＝8.6Hz,2H),3.75(s,3H),3.53(d,J＝14.0Hz,1H),3.13–3.03(m,2H),2.91(dt,J＝19.6,4.6Hz,1H),2.38(dt,J＝13.7,4.6Hz,1H),2.19(ddd,J＝14.1,9.6,5.0Hz,1H).13C NMR(100MHz,CDCl3)δ190.6,158.8,157.9,139.8,135.3,134.6,132.2,130.7,128.8,128.6,128.3,128.2,127.8,127.0,118.8,113.5,55.3,47.7,39.7,30.2,29.8.HRMS(ESI+)m/z calc’d for C27H23NO2Na[M+Na]+:416.1621,found 416.1618.
实施例25
在本实施例中，制备(R)-4'-苄基-4”-溴-3'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-4”-bromo-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000202
白色固体(55.9mg,63％收率)，对映选择性ee为94％。比旋光度[α]D 25＝–120.87(c1.0,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.40–7.30(m,7H),7.24–7.18(m,3H),7.03–7.01(m,2H),6.82(d,J＝8.5Hz,2H),3.52(d,J＝14.0Hz,1H),3.13–3.05(m,2H),2.92(dt,J＝19.7,4.5Hz,1H),2.39(dt,J＝13.8,4.6Hz,1H),2.20(ddd,J＝14.2,9.7,4.8Hz,1H).13C NMR(100MHz,CDCl3)δ190.0,159.2,139.2,134.6,134.4,133.7,132.6,131.2,130.6,129.0,128.8,128.5,128.1,127.9,121.8,118.6,47.6,39.6,30.1,29.8.HRMS(ESI+)m/z calc’d for C26H20BrNONa[M+Na]+:464.0620,found 464.0623.
实施例26
在本实施例中，制备(R)-4'-苄基-3'-氧-4”-三氟甲基-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(R)-4’-Benzyl-3'-oxo-4”-(trifluoromethyl)-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000211
白色固体(36.8mg,43％收率)，对映选择性ee为94％。比旋光度[α]D 25＝–127.63(c1.0,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.45(d,J＝8.1Hz,2H),7.41–7.33(m,5H),7.25–7.18(m,3H),7.08(d,J＝8.0Hz,2H),7.04–7.00(m,2H),3.54(AB,J＝14.0Hz,1H),3.17–3.09(m,2H),2.95(dt,J＝19.7,4.5Hz,1H),2.42(dt,J＝13.8,4.6Hz,1H),2.27–2.19(m,1H).13C NMR(100MHz,CDCl3)δ189.9,159.9,138.9,138.7,134.6,134.3,131.4,130.6,129.5(q,J＝32.7Hz),129.2,128.8,128.5,128.1,127.9,124.9(q,J＝3.7Hz),124.2(q,J＝272.5Hz),118.5,47.6,39.6,30.1,29.9.19F NMR(376MHz,CDCl3)δ–62.59.HRMS(ESI+)m/z calc’d for C27H20NOF3Na[M+Na]+:454.1389,found 454.1391.
实施例27
在本实施例中，制备(R)-甲基-5'-苄基-5’-氰基-6'-氧-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4-酸酯[(R)-Methyl-5'-benzyl-5'-cyano-6'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4-carboxylate]，其结构式如下：
Figure BDA0002435160490000212
白色固体(67.3mg,80％收率)，对映选择性ee为92％。比旋光度[α]D 25＝–138.37(c1.0,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.3Hz,2H),7.40–7.31(m,5H),7.23–7.13(m,3H),7.04–6.99(m,4H),3.87(s,3H),3.53(d,J＝13.9Hz,1H),3.16–3.07(m,2H),2.94(dt,J＝19.7,4.5Hz,1H),2.40(dt,J＝13.8,4.6Hz,1H),2.25–2.18(m,1H).13C NMR(100MHz,CDCl3)δ189.8,166.9,159.6,139.9,139.0,135.0,134.4,131.1,130.6,129.2,129.1,129.0,128.8,128.4,128.1,127.9,118.5,52.2,47.6,39.6,30.1,29.9.HRMS(ESI+)m/z calc’d for C28H23NO3Na[M+Na]+:444.1570,found 444.1571.
实施例28
在本实施例中，制备(R)-4-苄基-6-(2-萘基)-5-氧-2,3,4,5-四氢-[1,1'-二苯基]-4-腈[(R)-4-Benzyl-6-(naphthalen-2-yl)-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carbonitrile]，其结构式如下：
Figure BDA0002435160490000221
白色固体(58.0mg,80％收率)，对映选择性ee为88％。比旋光度[α]D 25＝–133.45(c0.85,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.76–7.73(m,1H),7.68–7.64(m,2H),7.47–7.46(m,1H),7.45–7.32(m,7H),7.15–7.03(m,6H),3.57(AB,J＝14.0Hz,1H),3.19–3.11(m,2H),2.98(dt,J＝19.7,4.6Hz,1H),2.43(dt,J＝13.7,4.6Hz,1H),2.28–2.13(m,1H).13C NMR(100MHz,CDCl3)δ190.4,158.8,139.5,135.6,134.6,133.1,132.6,132.4,130.7,130.4,128.8,128.7,128.6,128.4,128.3,128.2,127.8,127.7,127.4,126.2,126.0,118.8,47.8,39.7,30.2,29.9.HRMS(ESI+)m/z calc’d for C30H23NONa[M+Na]+:436.1672,found 436.1675.
实施例29
在本实施例中，制备(R)-4-苄基-5-氧-6-(2-噻吩基)-2,3,4,5-四氢-[1,1'-二苯基]-4-腈[(R)-4-Benzyl-5-oxo-6-(thiophen-2-yl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carbonitrile]，其结构式如下：
Figure BDA0002435160490000222
白色固体(59.7mg,81％收率)，对映选择性ee为76％。比旋光度[α]D 25＝–85.12(c1.4,CHCl3).Rf＝0.4(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.41–7.32(m,5H),7.30–7.26(m,3H),7.24(dd,J＝5.1,1.2Hz,1H),7.18–7.13(m,2H),6.84(dd,J＝5.1,3.6Hz,1H),6.68(dd,J＝3.6,1.2Hz,1H),3.56(AB,J＝14.0Hz,1H),3.13–3.05(m,2H),2.94(dt,J＝20.0,4.7Hz,1H),2.39(dt,J＝13.8,4.7Hz,1H),2.24–2.17(m,1H).13C NMR(100MHz,CDCl3)δ189.6,159.6,139.9,134.8,134.4,130.6,130.1,129.1,128.9,128.8,128.6,127.9,127.8,127.1,126.3,118.6,47.9,39.8,30.4,30.0.HRMS(ESI+)m/z calc’d forC24H19NOSNa[M+Na]+:392.1080,found 392.1081.
实施例30
在本实施例中，制备(R)-4-苄基-6-(2-甲基-1-丙烯基)-5-氧-2,3,4,5-四氢-[1,1'-二苯基]-4-腈[(R)-4-Benzyl-6-(2-methylprop-1-en-1-yl)-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carbonitrile]，其结构式如下：
Figure BDA0002435160490000231
白色固体(42.9mg,63％收率)，对映选择性ee为82％。比旋光度[α]D 25＝–113.06(c1.0,CHCl3).Rf＝0.4(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.41–7.30(m,8H),7.28–7.26(m,2H),5.64(s,1H),3.49(d,J＝14.0Hz,1H),3.05–2.94(m,2H),2.82(dtd,J＝19.6,4.6,1.6Hz,1H),2.30(dt,J＝13.7,4.6Hz,1H),2.11–2.04(m,1H),1.66(d,J＝1.5Hz,3H),1.21(d,J＝1.3Hz,3H).
13C NMR(100MHz,CDCl3)δ190.9,157.6,140.2,138.8,134.6,132.3,130.6,128.8,128.7,128.2,127.9,127.7,118.8,118.2,47.6,39.6,30.3,29.2,25.5,20.1.HRMS(ESI+)m/z calc’d for C24H23NONa[M+Na]+:364.1672,found 364.1679.
实施例31
在本实施例中，制备(R)-4-苄基-6-甲基-5-氧-2,3,4,5-四氢-[1,1'-二苯基]-4-腈[(R)-4-benzyl-6-methyl-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carbonitrile]，其结构式如下：
Figure BDA0002435160490000232
白色固体(6.8mg,23％收率)，对映选择性ee为83％。比旋光度[α]D 25＝–64.45(c0.4,CHCl3).Rf＝0.3(PE:EA＝15:1).1H NMR(400MHz,CDCl3)δ7.44–7.28(m,8H),7.23–7.19(m,2H),3.48(AB,J＝13.9Hz,1H),3.03(BA,J＝13.9Hz,1H),2.94–2.85(m,1H),2.74–2.65(m,1H),2.28(dt,J＝13.6,4.8Hz,1H),2.07(ddd,J＝13.9,9.3,4.8Hz,1H),1.80(t,J＝1.9Hz,3H).13C NMR(100MHz,CDCl3)δ191.4,157.3,140.1,134.6,130.6,130.3,128.8,128.7,128.6,127.8,127.1,119.0,47.4,39.8,30.4,29.7,13.9.HRMS(ESI+)m/z calc’dfor C21H19NONa[M+Na]+:324.1359,found 324.1359.
实施例32
在本实施例中，制备(R)-4’-(4-溴苄基)-3’-氧-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(R)-4'-(4-Bromobenzyl)-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000241
白色固体(68.3mg,77％收率)，对映选择性ee为94％。比旋光[α]D 25＝–59.91(c0.5,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.50(d,J＝8.3Hz,2H),7.23(d,J＝8.4Hz,2H),7.20–7.15(m,6H),7.06–7.02(m,2H),6.97–6.92(m,2H),3.48(d,J＝14.0Hz,1H),3.16–3.06(m,2H),2.93(dt,J＝19.7,4.4Hz,1H),2.37(dt,J＝13.6,4.4Hz,1H),2.19(ddd,J＝14.1,10.1,4.8Hz,1H).13C NMR(100MHz,CDCl3)δ189.9,158.6,139.4,135.7,134.7,133.5,132.3,131.9,130.9,128.7,128.3,128.2,128.0,127.5,122.0,118.4,47.4,39.1,30.2,29.8.
实施例33
在本实施例中，制备(R)-4’-(1-萘甲基)-3’-氧-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(R)-4'-(Naphthalen-1-ylmethyl)-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000242
白色固体(40.5mg,98％收率)，对映选择性ee为94％。比旋光度[α]D 25＝–136.29(c1.2,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.2Hz,1H),7.91(dd,J＝8.0,1.6Hz,1H),7.86(d,J＝8.2Hz,1H),7.62(d,J＝7.0Hz,1H),7.60–7.48(m,3H),7.23–7.14(m,6H),7.05–6.95(m,4H),4.09(AB,J＝14.8Hz,1H),3.64(BA,J＝14.7Hz,1H)ABBA,3.06(dt,J＝19.7,7.7Hz,1H),2.85(dt,J＝19.7,4.1Hz,1H),2.29(dd,J＝7.7,4.1Hz,2H).13C NMR(100MHz,CDCl3)δ190.4,158.7,139.5,135.8,134.9,134.1,132.9,131.1,130.9,129.3,129.1,128.7,128.5,128.21,128.19,127.9,127.5,126.4,125.9,125.6,124.0,118.7,48.1,34.8,30.9,30.0.HRMS(ESI+)m/z calc’d for C30H23NONa[M+Na]+:436.1672,found 436.1674.
实施例34
在本实施例中，制备(R)-4’-(2-呋喃基)-3’-氧-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(R)-4'-(Furan-2-ylmethyl)-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000251
白色固体(44.6mg,66％收率)，对映选择性ee为87％。比旋光[α]D 25＝–115.35(c1.0,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.42(s,1H),7.19–7.15(m,6H),7.06–7.04(m,2H),6.96–6.94(m,2H),6.39–6.35(m,2H),3.53(AB,J＝15.2Hz,1H),3.27(BA,J＝15.2Hz,1H),3.15(ddd,J＝19.7,9.7,4.8Hz,1H),2.97(dt,J＝19.7,4.7Hz,1H),2.53(dt,J＝13.9,4.6Hz,1H),2.26(ddd,J＝14.2,9.7,4.8Hz,1H).13C NMR(100MHz,CDCl3)δ189.7,158.7,149.1,142.6,139.5,135.6,134.7,130.9,128.7,128.2,128.1,127.9,127.5,118.5,110.9,109.8,47.2,32.5,30.5,29.7.HRMS(ESI+)m/z calc’d forC24H20NO2[M+H]+:354.1489,found 354.1482.
实施例35
在本实施例中，制备(R)-4’-(3-甲基-2-丁烯基)-3’-氧-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(R)-4'-(3-Methylbut-2-en-1-yl)-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000252
黄色油状液体(29.7mg,87％收率)，对映选择性ee为86％。比旋光度[α]D 25＝–110.47(c 0.6,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.19–7.15(m,6H),7.05–7.03(m,2H),6.94–6.92(m,2H),5.30(t,J＝7.5Hz,1H),3.13(ddd,J＝19.6,8.9,4.9Hz,1H),2.96–2.88(m,2H),2.59–2.53(m,2H),2.29(ddd,J＝13.8,9.0,4.9Hz,1H),1.80(s,3H),1.72(s,3H).13C NMR(100MHz,CDCl3)δ190.7,158.0,139.6,137.9,135.7,134.8,130.9,128.6,128.23,128.19,127.9,127.4,119.2,116.9,47.2,32.5,30.4,29.7,26.2,18.4.HRMS(ESI+)m/z calc’d for C24H23NONa[M+Na]+:364.1672,found 364.1678；
实施例36
在本实施例中，制备(R)-4’-烯丙基-3’-氧-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(R)-4'-Allyl-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000261
黄色油状液体(29.7mg,87％收率)，对映选择性ee为87％。比旋光[α]D 25＝–123.89(c 1.0,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.20–7.15(m,6H),7.07–7.03(m,2H),6.96–6.91(m,2H),5.99–5.89(m,1H),5.33–5.28(m,2H),3.15(ddd,J＝19.7,9.1,5.0Hz,1H),2.98–2.91(m,2H),2.62–2.53(m,2H),2.29(ddd,J＝13.9,9.1,4.9Hz,1H).13C NMR(100MHz,CDCl3)δ190.3,158.2,139.6,135.7,134.8,131.4,130.9,128.7,128.3,128.2,127.9,127.5,121.1,118.7,46.6,38.3,30.5,29.7.HRMS(ESI+)m/z calc’d forC22H19NONa[M+Na]+:336.1359,found 336.1363.
实施例37
在本实施例中，制备(R)-3’-氧-4’-(3-氧代丁基)-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(R)-3'-Oxo-4'-(3-oxobutyl)-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000262
浅色油状液体(28.0mg,41％收率)，对映选择性ee为83％。比旋光度[α]D 25＝–60.65(c 0.4,CHCl3).Rf＝0.2(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ7.20–7.14(m,6H),7.06–7.02(m,2H),6.94–6.90(m,2H),3.11(ddd,J＝19.7,7.5,5.2Hz,1H),3.03–2.96(m,1H),2.96–2.88(m,1H),2.79(ddd,J＝18.3,9.5,5.4Hz,1H),2.61(ddd,J＝13.8,6.4,5.1Hz,1H),2.45(ddd,J＝14.4,9.6,5.7Hz,1H),2.35(ddd,J＝13.7,7.5,5.0Hz,1H),2.21(s,3H),2.12(ddd,J＝14.4,9.7,5.5Hz,1H).13C NMR(100MHz,CDCl3)δ206.9,190.9,157.9,139.4,135.5,134.6,130.9,128.7,128.3,128.2,127.9,127.5,118.9,46.7,39.4,32.0,30.2,29.4,27.8.HRMS(ESI+)m/z calc’d for C23H21NO2Na[M+Na]+:366.1465,found366.1469.
实施例38
在本实施例中，制备(R)-4’-(环己基甲基)-3’-氧-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(R)-4'-(Cyclohexylmethyl)-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000271
白色固体(44.7mg,61％收率)，对映选择性ee为88％。比旋光度[α]D 25＝–46.82(c1.6,CHCl3).Rf＝0.4(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.20–7.13(m,6H),7.06–7.01(m,2H),6.94–6.91(m,2H),3.11(ddd,J＝19.6,7.6,5.0Hz,1H),2.93(ddd,J＝19.6,6.4,4.9Hz,1H),2.63(ddd,J＝13.7,6.4,5.0Hz,1H),2.36(ddd,J＝13.7,7.6,4.9Hz,1H),2.08(dd,J＝14.4,6.5Hz,1H),1.99–1.90(m,1H),1.87–1.81(m,1H),1.80–1.58(m,5H),1.37–1.25(m,2H),1.19(tt,J＝12.5,3.1Hz,1H),1.15–1.04(m,2H).13C NMR(100MHz,CDCl3)δ191.4,157.3,139.6,135.4,134.9,130.9,128.6,128.22,128.19,127.9,127.4,119.8,46.5,40.6,34.8,34.1,31.3,29.4,26.3,26.23,26.16.HRMS(ESI+)m/z calc’d forC26H27NONa[M+Na]+:392.1985,found 392.1992.
实施例39
在本实施例中，制备(S)-4’-甲基-3’-氧-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(S)-4'-Methyl-3'-oxo-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000272
无色油状液体(21.0mg,73％收率)，对映选择性ee为83％。比旋光[α]D 25＝–168.90(c 0.9,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.20–7.15(m,6H),7.07–7.04(m,2H),6.95-6.92(m,2H),3.21(ddd,J＝19.6,9.8,4.9Hz,1H),2.95(dt,J＝19.6,4.5Hz,1H),2.57(dt,J＝13.7,4.6Hz,1H),2.30(ddd,J＝14.2,9.8,4.8Hz,1H),1.67(s,3H).13C NMR(100MHz,CDCl3)δ190.9,158.2,139.6,135.4,134.8,130.9,128.6,128.24,128.21,127.9,127.4,119.8,42.3,33.6,29.9,21.3.
实施例40
在本实施例中，制备(R)-3’-氧-4’-苯基)-3’,4’,5’,6’-四氢-[1,1':2',1”-三苯基]-4’-腈[(R)-3'-Oxo-4'-phenyl-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000281
白色固体(21.6mg,62％收率)，对映选择性ee为72％。比旋光度[α]D 25＝49.83(c1.4,CHCl3).Rf＝0.3(PE:EA＝5:1).1H NMR(400MHz,CDCl3)δ7.51–7.36(m,5H),7.22–7.13(m,6H),7.04–6.96(m,4H),3.14–3.02(m,1H),2.98–2.81(m,3H).13C NMR(100MHz,CDCl3)δ189.8,158.3,139.5,136.3,134.6,134.4,131.0,129.3,129.0,128.7,128.2,128.1,127.9,127.5,127.1,119.1,52.5,33.9,29.6.HRMS(ESI+)m/z calc’d for C25H19NONa[M+Na]+:372.1359,found 372.1363.
实施例41
在本实施例中，制备(S)-1-苄基-2-氧-3,4-二苯基环戊-3-烯基-1-腈[(S)-1-Benzyl-2-oxo-3,4-diphenylcyclopent-3-ene-1-carbonitrile]，其结构式如下：
Figure BDA0002435160490000282
白色固体(21.6mg,52％收率)，对映选择性ee为73％。比旋光[α]D 25＝56.33(c1.2,CHCl3).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.39–7.26(m,11H),7.17–7.14(m,2H),7.13–7.10(m,2H),3.46–3.40(m,2H),3.32–3.27(m,2H).13C NMR(100MHz,CDCl3)δ198.7,166.2,137.4,134.0,133.8,130.9,130.8,130.2,129.4,128.9,128.8,128.7,128.1,128.1,119.9,46.7,42.1,39.8.HRMS(ESI+)m/z calc’d for C25H19NONa[M+Na]+:372.1359,found 372.1361.
实施例42
在本实施例中，制备(R)-4-苄基-5-氧-2,3,4,5-四氢-[1,1'-二苯基]-4-腈[(R)-4-benzyl-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carbonitrile]，其结构式如下：
Figure BDA0002435160490000291
白色固体(16.1mg,56％收率)，对映选择性ee为28％。1H NMR(400MHz,CDCl3)δ7.60–7.55(m,2H),7.50–7.42(m,3H),7.40–7.30(m,5H),6.55(s,J＝1.4Hz,1H),3.46(d,J＝13.9Hz,1H),3.07–2.98(m,2H),2.91(dt,J＝18.9,5.0,1H),2.35(dt,J＝13.8,5.0Hz,1H),2.10(ddd,J＝13.8,8.9,4.8Hz,1H).13C NMR(100MHz,CDCl3)δ190.6,160.4,137.3,134.4,131.1,130.5,129.2,128.8,127.8,126.4,122.7,118.7,47.4,39.2,30.7,25.4.
实施例43
在本实施例中，制备(R)-1-苄基-2-氧-3,4-二苯基环庚-3-烯基-1-腈[(R)-1-Benzyl-2-oxo-3,4-diphenylcyclohept-3-ene-1-carbonitrile]，其结构式如下：
Figure BDA0002435160490000292
白色固体(16.1mg,78％收率)，对映选择性ee为98％。比旋光[α]D 25＝–221.77(c1.0,CHCl3).Rf＝0.4(PE:EA＝10:1).1H NMR(400MHz,CDCl3)δ7.30–7.27(m,5H),7.19–7.12(m,3H),7.11–7.01(m,5H),6.88–6.80(m,2H),3.37(AB,J＝13.6Hz,1H),3.02(BA,J＝13.6Hz,1H),2.97–2.75(m,2H),2.30–2.12(m,3H),2.12–2.00(m,1H).13C NMR(100MHz,CDCl3)δ201.2,145.7,141.2,138.6,136.5,134.6,130.8,129.8,128.6,128.5,128.3,128.2,127.7,127.7,127.4,120.4,55.5,41.9,36.6,35.7,23.4.HRMS(ESI+)m/z calc’dfor C27H23NNaO+[M+Na]+:400.1672,found 400.1664；
实施例44
在本实施例中，制备(S)-3-苄基–4-氧-5,6-二苯基-1-对甲苯磺酰基-2,3,4,7-四氢-1氢-氮杂卓-3-腈[(S)-3-benzyl-4-oxo-5,6-diphenyl-1-tosyl-2,3,4,7-tetrahydro-1H-azepine-3-carbonitrile]，其结构式如下：
Figure BDA0002435160490000301
白色固体(26.6mg,50％收率)，对映选择性ee为87％。1H NMR(400MHz,CD3CN)δ7.23(d,J＝8.3Hz,2H),7.10–7.02(m,8H),6.82–6.76(m,7H),6.60–6.51(m,2H),4.01(d,J＝5.3Hz,1H),3.81(d,J＝7.1Hz,1H),3.58(s,2H),3.28(d,J＝13.7Hz,1H),3.09(d,J＝13.7Hz,1H),2.25(s,3H).
实施例45
在本实施例中，制备(R,E)-3-苄基-2-氧-6-苯乙烯基-2,3,4,5-四氢-[1,1’-二苯基]-3-腈[(R,E)-3-benzyl-2-oxo-6-styryl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-3-carbonitrile]，其结构式如下：
Figure BDA0002435160490000302
油状液体(6.2mg,16％yield)，对映选择性ee为55％。1H NMR(400MHz,CDCl3)δ7.53–7.51(m,2H),7.39–7.29(m,5H),7.26–7.09(m,8H),6.65–6.53(m,2H),3.34(d,J＝13.4Hz,1H),3.01–2.82(m,3H),2.61–2.49(m,1H),2.43–2.33(m,1H).
实施例46-52
制备方法包括以下要素：取干燥的10mL装有磁力搅拌子的反应封管，于氩气氛围中加入10mol％三氟甲磺酸镍(7.2mg,0.0075mmol)和12mol％L1(9.3mg,0.024mmol)到1mL甲苯溶液中，室温下搅拌30分钟。接着加入反应物I(0.2mmol)和反应物II(0.4mmol,)，最后再补加1mL甲苯和H2O(15uL,0.8mmol)。80℃油浴条件下反应，至TLC监测原料反应完全(约24h)。体系恢复至室温，旋转蒸发除去溶剂后直接进行柱层析分离，选用200-300目的硅胶，洗脱液选用石油醚和乙酸乙酯的混合溶剂或者使用乙酸乙酯或者二氯甲烷。对映选择性ee由配备手性分离柱的高效液相色谱测定。
实施例46
在本实施例中，制备(S)-1-苄基–2-亚胺基-3,4-二苯基环庚-3-烯基-1-腈[(S)-1-benzyl-2-imino-3,4-diphenylcyclohept-3-ene-1-carbonitrile]，其结构式如下：
Figure BDA0002435160490000311
白色固体(54.1mg,72％收率)，对映选择性ee为98％。比旋光度[α]D 25＝–128.00(c1.0,CH3CN).；Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,C6D6)δ9.73(s,1H),7.62–7.40(m,2H),7.23–7.09(m,3H),7.08–7.02(m,2H),6.94–6.73(m,8H),3.64(AB,J＝13.5Hz,1H),3.09(BA,J＝13.5Hz,1H),2.65–2.44(m,1H),2.44–2.28(m,1H),1.98–1.80(m,1H),1.78–1.64(m,2H),1.54–1.34(m,1H).13C NMR(100MHz,C6D6)δ180.5,142.6,141.9,139.3,138.4,136.4,131.7,130.7,129.2,128.50,128.46,128.1,127.9,127.5,127.4,121.9,51.3,43.2,39.1,36.2,22.8.HRMS(ESI+)m/z calc’d for C27H24N2Na[M+Na]+:399.1832,found399.1824.
实施例47
在本实施例中，制备(S)-1-苄基–2-亚胺基-3-苯基-4-对甲基苯基-环庚-3-烯基-1-腈[(S)-1-Benzyl-2-imino-3-phenyl-4-(p-tolyl)cyclohept-3-ene-1-carbonitrile]，其结构式如下：
Figure BDA0002435160490000312
黄色固体(53.1mg,68％收率)，对映选择性ee为98％。比旋光[α]D 25＝–77.20(c1.0,CH3CN).Rf＝0.2(PE:EA＝10:1).1H NMR(400MHz,CD3COCD3)δ10.21(s,1H),7.51–7.37(m,2H),7.36–7.28(m,3H),7.11–7.00(m,5H),7.01–6.96(m,2H),6.95–6.82(m,2H),3.55(AB,J＝13.5Hz,1H),3.22(BA,J＝13.4Hz,1H),2.78–2.65(m,2H),2.29–2.16(m,5H),2.03–1.87(m,2H).13C NMR(100MHz,CD3COCD3)δ181.0,142.0,140.0,139.9,138.2,137.5,137.0,131.9,131.1,129.6,129.5,128.9,128.7,128.0,127.7,122.2,51.6,43.7,38.3,36.3,22.9,21.1.HRMS(ESI+)m/z calc’d for C28H27N2[M+H]+:391.2169,found 391.2174.
实施例48
在本实施例中，制备(S)-1-苄基–2-亚胺基-4-对甲氧基苯基-3-苯基环庚-3-烯基-1-腈[(S)-1-Benzyl-2-imino-4-(4-methoxyphenyl)-3-phenylcyclohept-3-ene-1-carbonitrile]，其结构式如下：
Figure BDA0002435160490000321
黄色固体(56.2mg,70％收率)，对映选择性ee为98％。比旋光[α]D 25＝–81.27(c1.0,CH3CN).Rf＝0.2(PE:EA＝10:1).1H NMR(400MHz,CD3CN)δ9.97(br s,1H),7.45–7.26(m,5H),7.12–7.07(m,3H),7.04(d,J＝8.8Hz,2H),6.94–6.82(m,2H),6.75–6.66(m,2H),3.70(s,3H),3.49(AB,J＝13.7Hz,1H),3.16(BA,J＝13.6Hz,1H),2.75–2.60(m,2H),2.29–2.12(m,2H),1.96–1.86(m,2H).13C NMR(100MHz,CD3CN)δ181.4,159.7,142.2,140.1,137.5,137.1,135.0,131.9,131.2,131.1,129.0,128.9,128.2,127.9,122.6,114.3,55.8,51.7,43.7,37.9,36.2,22.8.HRMS(ESI+)m/z calc’d for C28H27N2O[M+H]+:407.2118,found 407.2116.
实施例49
在本实施例中，制备(S)-1-苄基–4-对氯苯基-2-亚胺基-3苯基环庚-3-烯基-1-腈[(S)-1-Benzyl-4-(4-chlorophenyl)-2-imino-3-phenylcyclohept-3-ene-1-carbonitrile]，其结构式如下：
Figure BDA0002435160490000322
黄色固体(50.8mg,62％收率)，对映选择性ee为98％。比旋光[α]D 25＝–117.27(c1.0,CH3CN).Rf＝0.4(PE:EA＝5:1).1H NMR(400MHz,CD3CN)δ10.04(s,1H),7.44–7.26(m,5H),7.19–7.14(m,2H),7.14–7.05(m,5H),6.96–6.79(m,2H),3.50(AB,J＝13.6Hz,1H),3.17(BA,J＝13.6Hz,1H),2.73–2.60(m,2H),2.22–2.13(m,2H),2.00–1.87(m,2H).13C NMR(100MHz,CD3CN)δ180.6,141.9,141.5,139.5,138.8,137.0,133.2,131.9,131.4,131.1,129.02,129.00,128.95,128.2,122.6,52.0,43.4,38.4,36.2,22.9.HRMS(ESI+)m/z calc’d for C27H24N2Cl+[M+H]+:411.1623,found 411.1633；
实施例50
在本实施例中，制备(S)-1-苄基–4-对溴苯基-2-亚胺基-3-苯基环庚-3-烯基-1-腈[(S)-1-Benzyl-4-(4-bromophenyl)-2-imino-3-phenylcyclohept-3-ene-1-carbonitrile]，其结构式如下：
Figure BDA0002435160490000331
白色固体(56.2mg,61％收率)，对映选择性ee为98％。比旋光[α]D 25＝–118.27(c1.0,CH3CN).Rf＝0.3(PE:EA＝10:1).1H NMR(400MHz,CD3CN)δ10.04(s,1H),7.45–7.24(m,7H),7.17–7.06(m,3H),7.02(d,J＝8.5Hz,2H),6.96–6.80(m,2H),3.50(AB,J＝13.5Hz,1H),3.16(BA,J＝13.6Hz,1H),2.73–2.61(m,2H),2.27–2.12(m,2H),2.01–1.88(m,2H).13CNMR(100MHz,CD3CN)δ180.6,142.4,141.5,139.4,138.8,137.0,132.0,131.9,131.7,131.1,129.03,128.97,128.2,128.2,122.6,121.4,52.0,43.5,38.4,36.2,23.0.HRMS(ESI+)m/z calc’d for C27H24N2Br[M+H]+:455.1118,found 455.1106.
实施例51
在本实施例中，制备(S)-1-苄基–4-亚胺基-5,6-二苯基-1-对甲苯磺酰基-2,3,4,7-四氢-1氢-氮杂卓-3-腈[(R)-3-benzyl-4-imino-5,6-diphenyl-1-tosyl-2,3,4,7-tetrahydro-1H-azepine-3-carbonitrile]，其结构式如下：
Figure BDA0002435160490000332
白色固体(29.8mg,68％收率)，对映选择性ee为86％。1H NMR(400MHz,CD3CN)δ9.73(s,1H),7.43(d,J＝8.3Hz,2H),7.19–7.10(m,8H),6.95–6.89(m,7H),6.69–6.66(m,2H),4.09(d,J＝5.3Hz,1H),3.84(d,J＝7.1Hz,1H),3.64(s,2H),3.32(d,J＝13.7Hz,1H),3.07(d,J＝13.7Hz,1H),2.17(s,3H).
实施例52
在本实施例中，制备(S)-4'-苄基-3'-亚氨基-3',4',5',6'-四氢-[1,1':2',1”-三苯基]-4'-腈[(S)-4'-benzyl-3'-imino-3',4',5',6'-tetrahydro-[1,1':2',1”-terphenyl]-4'-carbonitrile]，其结构式如下：
Figure BDA0002435160490000341
白色固体(48.2mg,88％收率)，对映选择性ee为91％。1H NMR(400MHz,CDCl3)δ9.92(s,1H),7.62–7.52(m,5H),7.149–7.37(m,6H),7.25–7.22(m,2H),7.16–7.14(m,2H),3.64(d,J＝14.0Hz,1H),3.24–3.16(m,2H),2.83(dt,J＝19.6,4.6Hz,1H),2.29(dt,J＝13.7,4.6Hz,1H),2.12–2.01(m,1H).
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。

Claims (9)

1.一种含α-氰基取代季碳中心的环烯酮化合物的制备方法，其特征在于，包含如下步骤：(1)在镍络合物和配体催化下，原料I和II在有机溶剂中发生反应，并加入添加剂；(2)反应结束后，加入酸溶液搅拌后处理；(3)浓缩溶剂，分离提纯，生成III所示的α-氰基取代季碳中心的环烯酮化合物，其反应方程式如下：
Figure FDA0003028536920000011
其中[Ni]指镍络合物；Ligand指配体；solvent指有机溶剂；additive指添加剂；
其中R1、R2、R3是分别独立的取代基；其中R1任选自氢、烷基或芳基；R2任选自烷基、烯基或芳基；R3任选自芳基或者烯基；其中Z任选自亚甲基或R4取代的胺；其中m任取自0、1、或2；其中n任取自0、1、或2；其中R4任选自烷基、芳基、叔丁氧羰基、苄氧羰基、乙酰基、苯甲酰基或者磺酰基；其中R3[B]表示R3取代的硼酸、R3取代的硼酸酐、R3取代的三氟硼酸盐、或者R3取代的频哪醇硼酸酯；*表示手性中心；
其中镍络合物为双-(1，5-环辛二烯)镍、双(环戊二烯)镍、卤化镍、乙酰丙酮酸镍、硫酸镍、硝酸镍、高氯酸镍、醋酸镍、碳酸镍、对甲苯磺酸镍、三氟甲烷磺酸镍、四氟硼酸镍或者这些物质的水合物、有机溶剂合物中的任意一种；所述的配体具有式A-K所示结构或者其对映异构体，
Figure FDA0003028536920000021
式A-K中Ar为芳基，Y任选自氧或R14取代的氮原子，所述的取代基R5、R6、R7、R8、R9、R10、R11、R12、R13、R14是独立的取代基；其中R5、R10任选自氢、氟、烷基、卤代烷基、卤代烷氧基、环烷基、杂环基、烷氨基、烷氧基、芳基或杂芳基；R6、R7、R8、R9、R13任选自氢、甲基、乙基、异丙基、叔丁基、环己基、芳基或芐基；R11、R12、R14任选自甲基、乙基、异丙基、叔丁基、环己基、芳基；
所述催化剂镍络合物中所含金属镍元素与配体的摩尔比为1:0.5～1:5；
所述有机溶剂为苯、甲苯、二甲苯、乙苯、氯苯，三氟甲苯、氯仿、二氯甲烷、乙腈、异丙醇、环己烷、正己烷、二甲基甲酰胺、乙二醇二甲醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环以及其中二种或二种以上混合溶剂；
所述添加剂是指三氟磺酸锌、三氟磺酸铁、六氟磷酸胺、水；
所述原料I和II的物质量之比为2:1～1:3；
所述添加剂和原料I的物质量之比为0.2:1～10:1；
所述步骤(2)酸溶液为盐酸、硫酸、磷酸、醋酸或硝酸中的任意一种；
所述步骤(2)后处理加入酸的量和原料I的物质量之比为1:1～100:1；
所述反应的温度为60℃～120℃；
所述反应的时间为1～48小时。
2.根据权利要求1所述的制备方法，其特征在于，步骤(1)所述配体为具有如式A、式B、式C、式F或式I所示结构的配体。
3.根据权利要求1所述的制备方法，其特征在于，步骤(1)所述镍络合物中所含金属镍元素与配体的摩尔比为1:1～1:1.2。
4.根据权利要求1所述的制备方法，其特征在于，步骤(1)所述有机溶剂为四氢呋喃或甲苯。
5.根据权利要求1所述的制备方法，其特征在于，步骤(1)所述反应的添加剂为4当量的水。
6.根据权利要求1所述的制备方法，其特征在于，步骤(2)所述酸溶液为盐酸。
7.根据权利要求1所述的制备方法，其特征在于，步骤(3)所述分离提纯方法为柱层析、薄层层析或重结晶。
8.根据权利要求7所述的制备方法，其特征在于，所述柱层析使用的洗脱液为乙酸乙酯、二氯甲烷、或者石油醚和乙酸乙酯的混合液，其中石油醚和乙酸乙酯的体积比为1:2～80:1。
9.一种α-氰基取代季碳中心的环烯胺化合物IV的制备方法，其特征在于，包含如下步骤：(1)与权利要求1-8任意一项所述的制备方法的步骤(1)相同；(2)将步骤(1)的产物进行分离提纯，获得α-氰基取代季碳中心的环烯胺化合物IV，具体方程式如下：
Figure FDA0003028536920000031
其中分离提纯方法与权利要求1中的步骤(3)分离方法一致；
其中R1、R2、R3、Z、m、n和[B]的范围和权利要求1所述的α-氰基取代季碳中心的环烯酮的制备方法中的范围一致；[Ni]，ligand,solvent和additive也与权利要求1所述的α-氰基取代季碳中心的环烯酮的制备方法中的指代一致。
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Catalytic Asymmetric Conjugate Addition of -Cyanoketonesfor the Construction of a Quaternary Stereogenic Center;Yuji Kawato等;《Org.Lett.》;20100304;1484-1487 *
Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis;Zhiwu Lu等;《J.Am.Chem.Soc.》;20200407;7328-7333 *
Enantioselective Nickel-Catalyzed Intramolecular Allylic Alkenylations Enabled by Reversible Alkenylnickel E/Z Isomerization;Connor Yap 等;《Angew.Chem.》;20171231;8328-8332 *

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