消旋和手性3-(2,3-丁二烯基)氧化吲哚酮类化合物及制备方法及应用
阅读说明：本技术 消旋和手性3-(2,3-丁二烯基)氧化吲哚酮类化合物及制备方法及应用 (Racemic and chiral 3- (2, 3-butadienyl) oxindole compound, preparation method and application ) 是由 麻生明 林杰 贾敏强 程宝 陈勤 钱辉 于 2020-04-24 设计创作，主要内容包括：本发明公开了一种消旋和手性3-(2,3-丁二烯基)氧化吲哚酮类化合物及采用钯催化的偶联反应制备该化合物的方法及其应用。所述方法通过2,3-丁二烯基碳酸酯与氧化吲哚酮,使用钯催化剂,在有机溶剂中反应,一步直接构建消旋3-(2,3-丁二烯基)氧化吲哚酮类化合物；如果在体系中使用钯催化剂和手性膦配体,在有机溶剂中反应,可以一步直接构建手性3-(2,3-丁二烯基)氧化吲哚酮类化合物,并且这类化合物很容易转化成其他复杂分子。本发明方法操作方便,原料和试剂易得,底物普适性广,官能团兼容性好,反应具有好的转化率,高对映选择性和化学选择性。此外,本发明提供的3-(2,3-丁二烯基)氧化吲哚酮类化合物及其相关衍生物可以与SRAS-CoV-2主蛋白3CL水解酶结合,在治疗人类病毒感染方面有良好的应用前景。(The invention discloses a racemization and chirality 3- (2, 3-butadienyl) oxindole ketone oxide compound, a method for preparing the compound by adopting palladium-catalyzed coupling reaction and application thereof. According to the method, 2, 3-butadienyl carbonate and oxindole oxide react in an organic solvent by using a palladium catalyst, and a racemization 3- (2, 3-butadienyl) oxindole oxide compound is directly constructed in one step; if a palladium catalyst and a chiral phosphine ligand are used in the system and reacted in an organic solvent, the chiral 3- (2, 3-butadienyl) oxindole ketone oxide compound can be directly constructed in one step, and the compound can be easily converted into other complex molecules. The method has the advantages of convenient operation, easily obtained raw materials and reagents, wide substrate universality, good functional group compatibility, good reaction conversion rate, high enantioselectivity and chemical selectivity. In addition, the 3- (2, 3-butadienyl) oxindole compound and related derivatives thereof provided by the invention can be combined with SRAS-CoV-2 main protein 3CL hydrolase, and have good application prospects in the aspect of treating human virus infection.)
技术领域
本发明属于化学合成技术领域，具体涉及一种钯催化的偶联反应制备消旋和手性3-(2,3-丁二烯基)氧化吲哚酮类化合物的方法及其转化和抗病毒应用。
背景技术
联烯化合物，广泛应用于有机合成(Ref:Ye,J.；Ma,S.Acc.Chem.Res.2014,47,989)，药物研究(Ref：Hoffmann-A.；Krause,N.Angew.Chem.Int.Ed.2004,43,1196)以及材料应用中(Ref：Rivera-Fuentes,P.；Diederich,F.Angew.Chem.,Int.Ed.2012,51,2818)。如何简单高效的构建四取代光学活性的季碳中心，在过去十几年里被广泛的研究，并取得了不错的成果，然而在构建含联烯季碳手性中心化合物的合成依然存在较大的挑战，报道的方法仍十分有限，所以发展新型策略去高效的、高立体选择性的构筑这类分子引起了人们极大的兴趣和广泛的关注。(Ref：a)Yu,S.；Ma,S.Chem.Commun.2011,47,5384；b)Ye,J.；Ma,S.Org.Chem.Front.2014,1,1210；c)Huang,X.；S.Ma,Acc.Chem.Res.2019,52,1301)。使用外消的2,3-丁二烯醇衍生物衍生物与亲核试剂在过渡金属催化下不对称偶联反应是制备光学活性联烯一种高效、实用的方法。(Ref：a)Li,Q.；Fu,C.；Ma,S.Angew.Chem.Int.Ed.2012,51,11783；b)Li,Q.；Fu,C.；Ma,S.Angew.Chem.Int.Ed.2014,53,6511；c)Petrone,D.A.；Isomura,M.；Franzoni,I.；S.L.；Carreira,E.M.J.Am.Chem.Soc.2018,140,4697；d)Isomura,M.；Petrone,D.A.；Carreira,E.M.J.Am.Chem.Soc.2019,141,4738；e)Liu,H.-C.；Hu,Y.-Z.；Wang,Z.-F.；Tao,H.-Y.；Wang,C.-J.Chem.Eur.J.2019,25,8681)
同时，3,3-二取代氧化吲哚酮，基于其独特的结构，具有较高的生物活性以及药用价值(Ref：a)Cerchiaro，G.；Ferreira,A.M.C.；J.Braz.Chem.Soc.2006,17,1473；b)Peddibhotla,S.；Current Bioactive Compounds 2009,5,20；c)Santos,M.M.M.；Tetrahedron 2014,70,9735)。此外，它在天然产物的合成也扮演着着重要的角色(Ref:a)Sumpter,W.C.Chem.Rev.1945,37,443；b)Galliford,C.V.；Scheidt,K.A.Angew.Chem.Int.Ed.2007,46,8748)。目前，直接合成3，3-二取代的氧化吲哚酮的研究已取得不错的进展(Ref:a)Zhou,F.；Liu,Y.-L.；Zhou,J.Adv.Synth.Catal.2010,352,1381；b)Dalpozzo,R.；Bartoli,G.；Bencivenni,G.Chem.Soc.Rev.2012,41,7247；c)Singh,G.S.；Desta,Z.Y.Chem.Rev.2012,112,6104；d)Shen,K.；Liu,X.；Lin,L.；Feng,X.Chem.Sci.2012,3,327；e)Cao,Z.-Y.；Wang,Y.-H.；Zeng,X.-P.；Zhou,J.TetrahedronLett.2014,55,2571；f)Cheng,D.；Ishihara,Y.；Tan,B.；Barbas.III,C.F.ACSCatal.2014,4,743；g)Cao,Z.-Y.；Zhou,F.；Zhou,J.Acc.Chem.Res.2018,51,1443)。但是，氧化吲哚酮和2,3-丁二烯醇衍生物在过渡金属催化下的偶联反应，目前还没有被研究。这是因为氧化吲哚酮在烯醇互变后，形成的氧离子和2,3-丁二烯醇衍生物在过渡金属催化下，容易得到1,3-共轭二烯的产物。因此，进一步发展使用过渡金属催化下的偶联反应来制备3,3-二取代的氧化吲哚酮，就显得尤为重要。在此，我们发展了一种2,3-丁二烯基碳酸酯和氧化吲哚酮在钯催化的偶联反应制备消旋和手性3-(2,3-丁二烯基)氧化吲哚酮类化合物的方法。同时，我们还对合成的3-(2,3-丁二烯基)氧化吲哚酮类化合物作了进一步化学转化以及这些化合物在抗病毒中的应用。
发明内容
本发明的目的在于提供一种通过便宜易得的原料、简单高效的步骤直接制备3-(2,3-丁二烯基)氧化吲哚酮类化合物的方法及其转化和抗病毒应用。
本发明是采用以下具体技术方案来实现的：
本发明提供一种通过便宜易得的原料、简单高效的步骤直接制备3-(2,3-丁二烯基)氧化吲哚酮类化合物的方法，包括：在钯催化剂的作用下，带有不同取代基的氧化吲哚酮和2,3-丁二烯基碳酸酯，在有机溶剂中发生偶联反应一步生成消旋的3-(2,3-丁二烯基)氧化吲哚酮类化合物；或，在钯催化剂和手性膦配体的作用下，带有不同取代基的氧化吲哚酮和2,3-丁二烯基碳酸酯，在有机溶剂中发生不对称的偶联反应一步生成手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物，反应过程如下反应式(I)所示：
其中，
LG为离去基团；
R1、R2、R3和R4分别独立地为氢、烷基、烷基醚、卤素、氟代烷基；
R5为保护基；
R6为氢、烃基、末端带有官能团的烃基、苯基或者芳基，所述芳基是邻、间、对位有给电子或吸电子取代基的苯基。
优选地，
LG为碳酸甲酯、碳酸苄酯、碳酸叔丁酯；
R1为氢、氯；
R2为氢、甲基、甲氧基、氟、氯、溴；
R3为氢、氯、溴；
R4为氢、氯、三氟甲基；
R5为氢、甲基、碳酸叔丁酯、苄基；
R6为氢、烃基、末端带有官能团的烃基、苯基或者芳基；
其中，所述的末端带有官能团的烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、羧基；
所述芳基是邻、间、对位有给电子或吸电子取代基的苯基；
所述吸电子取代基包括卤素，所述给电子取代基包括烷基、苯基、烃氧基、羟基。
作为进一步改进，本发明的具体操作步骤如下：
联烯基化反应反应生成消旋的3-(2,3-丁二烯基)氧化吲哚酮类化合物的反应(消旋反应)：
1)Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入钯催化剂，氧化吲哚酮和2,3-丁二烯基碳酸酯，加入一定量的有机溶剂，将Schlenk反应管置于预置的油浴中，搅拌；
其中，所述有机溶剂的用量为1.0～10.0mL/mmol；优选地，所述有机溶剂的用量为5.0mL/mmol,以式(I)2,3-丁二烯基碳酸酯的用量为基准；
2)待步骤1)反应完全后，将Schlenk反应管提出油浴恢复至室温后，反应液用硅胶短柱过滤，并用一定体积的乙醚淋洗，浓缩，快速柱层析得消旋的3-(2,3-丁二烯基)氧化吲哚酮类化合物；
其中，所述乙酸乙酯的用量为1.0～60.0mL/mmol；优选地，所述乙酸乙酯的用量为60.0mL/mmol，所述一定体积的乙醚是指以式(I)2,3-丁二烯基碳酸酯的用量为基准。
不对称联烯基化反应反应生成手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物的反应(手性反应)：
i)Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入钯催化剂和手性膦配体，氧化吲哚酮，将Schlenk反应管置于乙醇-丙酮浴中冷却，加入2,3-丁二烯基碳酸酯，加入一定量的有机溶剂，抽换气3次，将Schlenk反应管置于水浴中解冻，解冻后立即放入预置的冷浴中，搅拌；
其中，所述有机溶剂的用量为1.0～10.0mL/mmol；优选地，所述有机溶剂的用量为5.0mL/mmol，以式(I)氧化吲哚酮的用量为基准。
ii)待步骤i)反应完全后，将Schlenk反应管提出冷浴，所得混合液用一定量的水和乙酸乙酯稀释后，用一定量的乙酸乙酯萃取后，合并有机相，用一定量的水洗涤后，用一定量的饱和食盐水洗涤后，用一定量的无水硫酸钠干燥，过滤，浓缩，快速柱层析得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物；
其中，所述用来稀释的水的用量为1.0～20.0mL/mmol，所述用来稀释的乙酸乙酯的用量为1.0～20.0mL/mmol；所述用来萃取的乙酸乙酯的用量为1.0～45.0mL/mmol，所述用来洗涤的水的用量为1.0～30.0mL/mmol，所述用来洗涤的饱和食盐水的用量为1.0～30.0mL/mmol；优选地，所述用来稀释的水的用量为15.0mL/mmol，所述用来稀释的乙酸乙酯的用量为15.0mL/mmol；所述用来萃取的乙酸乙酯的用量为15.0mL/mmol×3，所述用来洗涤的水的用量为10.0mL/mmol×3，所述用来洗涤的饱和食盐水的用量为10.0mL/mmol×3，以式(I)氧化吲哚酮的用量为基准。
本发明中，所述有机溶剂为甲苯、二氯甲烷、1,2-二氯乙烷、乙醚、乙酸乙酯、丙酮、环己烷、四氢呋喃、乙腈、二氧六环、1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮中的一种或多种；优选地，消旋反应为乙腈；优选地，手性反应为1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮。
本发明中，所述钯催化剂选自二(烯丙基氯化钯)，四(三苯基膦)钯，三(二亚苄基丙酮)二钯，二(肉桂基氯化钯)，二(二亚苄基丙酮)一钯，氯化钯，醋酸钯，二(三苯基膦)氯化钯，二(乙腈)氯化钯，三(二亚苄基丙酮)二钯氯仿配合物中的任意一种或多种；优选地，消旋反应为四(三苯基膦)钯；优选地，手性反应为二(二亚苄基丙酮)一钯。
本发明中，所述钯催化剂的用量为0.01～0.1mmol/mmol；优选地，消旋反应为0.05mmol/mmol，以式(I)2,3-丁二烯基碳酸酯的用量为基准；优选地，手性反应为0.029mmol/mmol，以式(I)氧化吲哚酮的用量为基准。
本发明中，所述的膦配体选自三苯基膦；优选地，消旋反应中不加入膦配体。
本发明中，所述的手性膦配体选自以下结构的(R)-L1～(R)-L7及其对映异构体(S)-L1～(S)-L7中的一种或多种；优选地，手性反应为(R)-L7及其对映异构体(S)-L7；其中，所述(R)-L1～(R)-L7的结构如下所示：
作为进一步地改进，本发明所述的手性膦配体选自(R)-L7～(R)-L12及其对映异构体(S)-L7～(S)-L12中的一种或几种；优选地，手性反应为(R)-L12及其对映异构体(S)-L12；其中，所述(R)-L7～(R)-L12的结构如下所示：
(R)-L7，Ar＝苯基
(R)-L8，Ar＝呋喃基
(R)-L9，Ar＝4-甲基苯基
(R)-L10，Ar＝3,5-二甲基苯基
(R)-L11，Ar＝3,5-二叔丁基苯基
(R)-L12，Ar＝3,5-二叔丁基-4-甲氧基苯基
本发明中，所述手性膦配体的用量为0.01～0.5mmol/mmol；优选地，手性反应为0.029mmol/mmol，以式(I)氧化吲哚酮的用量为基准。
本发明中，所述的消旋反应的温度为10～50℃；所述的手性反应的温度为-60～25℃；优选地，消旋反应的温度为20～30℃；优选地，手性反应的温度为-30～-25℃。
本发明中，所述的消旋反应的时间为5.5～18小时；所述的手性反应的时间为12～41小时；优选地，消旋反应的时间为12小时；优选地，手性反应的时间为36小时。
本发明所述反应优选在氩气保护下进行。
本发明还提出了一种消旋的3-(2,3-丁二烯基)氧化吲哚酮类化合物，其结构如式(3)所示：
其中，
LG为离去基团；
R1、R2、R3和R4分别独立地为氢、烷基、烷基醚、卤素、氟代烷基；
R5为保护基；
R6为氢、烃基、末端带有官能团的烃基、苯基或者芳基，所述芳基是邻、间、对位有给电子或吸电子取代基的苯基。
优选地，
LG为碳酸甲酯、碳酸苄酯、碳酸叔丁酯；
R1为氢、氯；
R2为氢、甲基、甲氧基、氟、氯、溴；
R3为氢、氯、溴；
R4为氢、氯、三氟甲基；
R5为氢、甲基、碳酸叔丁酯、苄基；
R6为氢、烃基、末端带有官能团的烃基、苯基或者芳基；其中，所述的末端带有官能团的烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、羧基；所述芳基是邻、间、对位有给电子或吸电子取代基的苯基；所述吸电子取代基包括卤素，所述给电子取代基包括烷基、苯基、烃氧基、羟基。
本发明还提出了一种手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物，其结构如式(R-3)所示：
其中，
LG为离去基团；
R1、R2、R3和R4分别独立地为氢、烷基、烷基醚、卤素、氟代烷基；
R5为保护基；
R6为氢、烃基、末端带有官能团的烃基、苯基或者芳基，所述芳基是邻、间、对位有给电子或吸电子取代基的苯基。
优选地，
LG为碳酸甲酯、碳酸苄酯、碳酸叔丁酯；
R1为氢、氯；
R2为氢、甲基、甲氧基、氟、氯、溴；
R3为氢、氯、溴；
R4为氢、氯、三氟甲基；
R5为氢、甲基、碳酸叔丁酯、苄基；
R6为氢、烃基、末端带有官能团的烃基、苯基或者芳基；其中，所述的末端带有官能团的烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、羧基；所述芳基是邻、间、对位有给电子或吸电子取代基的苯基；所述吸电子取代基包括卤素，所述给电子取代基包括烷基、苯基、烃氧基、羟基。
本发明还提供了消旋和手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物在脱保护反应(a)，偶联反应(c)，硼化反应(d)以及环化反应(b)等方面的应用，反应过程如反应式(II)所示。脱保护反应(a)：化合物(R)-3wb在三氟乙酸下脱去叔丁基碳酸酯保护基合成化合物(R)-4；环化反应(b)：化合物(R)-3wb在三氟乙酸下脱去叔丁基碳酸酯保护基，进一步与N-碘代丁二酰亚胺在硝基甲烷中反应生成并环化合物(R)-5；偶联反应(c)：化合物(R)-3wb钯催化下，与间硝基苯硼酸发生偶联反应生成化合物(R)-7；硼化反应(d)：化合物(R)-3wb在氯化亚铜催化下，与联硼酸频那醇酯反应生成1,1-二取代含硼烯烃(R)-8。
在一个
具体实施方式
中，所述消旋和手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物在脱保护反应(a)，偶联反应(c)，硼化反应(d)以及环化反应(b)等方面的应用，反应过程如反应式(II’)所示：
本发明对反应提出了以下可能的机理：首先，2,3-丁二烯基碳酸酯2b同钯和手性膦配体发生中间体I’,中间体I’快速转化为中间体I，然后中间体I同烯醇式的氧化吲哚发生配体交换，最后还原消除得到目标产物。当然中间体I’和中间体I也有可能在同烯醇式的氧化吲哚配位转化成中间体II，最后经过3,3-还原消除得到目标产物。具体机理如式(III)所示：
本发明同时保护所述的3-(2,3-丁二烯基)氧化吲哚酮类化合物及其相关衍生物在制备抗病毒感染药物中的应用。
所述病毒为SARS-CoV-2。
本发明还提出了所述的消旋或手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物及其相关衍生物在制备SARS-CoV-2主蛋白3CL水解酶抑制剂中的应用。
本发明中的3-(2,3-丁二烯基)氧化吲哚酮类化合物及其相关衍生物能够与SRAS-CoV-2主蛋白3CL水解酶结合。通过分子对接筛选了合成化合物对3CL水解酶的抑制活性，以化合物(R)-5和3CL水解酶为代表，模拟了(R)-5与3CL水解酶的结合模式，阐述了(R)-5结合和抑制3CL水解酶的作用机制，蛋白水平的实验也发现(R)-5在低浓度时对3CL水解酶具有抑制活性。且3CL水解酶的氨基酸序列在冠状病毒中十分保守，故3-(2,3-丁二烯基)氧化吲哚酮类化合物及其相关衍生物具有广谱的抗病毒活性。因此，此类3-(2,3-丁二烯基)氧化吲哚酮类化合物及其相关衍生物在治疗病毒感染等方面有良好的发展前景。
本发明的创新点在于，本发明通过以廉价易得的官能团化氧化吲哚酮和2,3-丁二烯基碳酸酯为起始原料，在钯催化剂，实现了一步制备消旋的3-(2,3-丁二烯基)氧化吲哚酮类化合物。同时也实现了通过以廉价易得的官能团化氧化吲哚酮和2,3-丁二烯基碳酸酯为起始原料，在钯催化剂和手性膦配体，实现了一步制备手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物。本发明得到的3-(2,3-丁二烯基)氧化吲哚酮类化合物可以作为重要的合成中间体，可用于多种反应。本发明具有：原料和试剂简单易得，制备简单；底物普适性广；官能团兼容性好；可一步构建3-(2,3-丁二烯基)氧化吲哚酮类化合物；产物具有较高对映选择性、较好的化学选择性和较高的转化率；产物易分离纯化等特点。本发明提供的3-(2,3-丁二烯基)氧化吲哚酮类化合物及其相关衍生物可以与SRAS-CoV-2主蛋白3CL水解酶结合，在治疗人类病毒感染方面有良好的应用前景。
附图说明
图1为化合物(R)-5与SRAS-CoV-2主蛋白3CL水解酶的结合模式图。
具体实施方式
结合以下具体实施例，进一步对本发明作详细解释，但本发明保护不仅仅局限于以下实施例。实施本发明的过程、条件、试剂、仪器、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明并无特定限制内容。以下实施例有助于理解本发明，但不限制本发明保护范围。
注：以下实施例反应式中的equiv表示当量；mol表示摩尔；Pd(PPh3)4表示四(三苯基膦)钯；Pd(dba)2表示二(二亚苄基丙酮)钯；[Pd(π-cinnamyl)Cl]2表示二(肉桂基氯化钯)；(R)-DTBM-Biphep表示(R)-L12；(R)-DTBM-Segphos表示(R)-L13；MeCN表示乙腈；THF表示四氢呋喃，Et2O表示乙醚；DMPU表示1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮；hexane表示正己烷；i-PrOH表示异丙醇；H2O表示水；Ar表示氩气；min表示分钟；h表示小时；石油醚沸程为60-90℃；核磁产率由1H NMR确定，内标为二溴甲烷；硅胶目数为300-400；ee表示对映异构体过量百分数。所有实施例中所涉及的手性膦配体的具体结构式和对应编号如下所示：
(R)-L12，Ar＝3,5-二叔丁基-4-甲氧基苯基
(R)-L13，Ar＝3,5-二叔丁基-4-甲氧基苯基
实施例1
表1
操作步骤：Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入[Pd](0.01mmol),1a(0.24mmol)，2a(0.2mmol)，有机溶剂(1.0mL)，放入预置的25℃冷浴中，搅拌12小时；将Schlenk反应管提出冷浴，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用50mL的乙醚淋洗，浓缩，加入17.5μL的二溴甲烷，0.8mL氘代氯仿，核磁氢谱分析，得消旋的3-(2,3-丁二烯基)氧化吲哚酮类化合物3aa核磁收率。
实施例2
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入Pd(PPh3)4(57.5mg,0.05mmol),1a(266.5mg,1.2mmol),和2a(203.8mg,1.0mmol)/MeCN(5.0mL)，将Schlenk反应管置于预置的25℃油浴中，搅拌5.5小时(通过薄层层析色谱检测(TLC)),将Schlenk反应管提出油浴恢复至室温后，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用60mL的乙醚淋洗，浓缩，快速柱层析[淋洗剂:石油醚/乙酸乙酯＝15/1]得消旋的3-(2,3-丁二烯基)氧化吲哚酮类化合物3aa(246.7mg,90％)，油状液体，1H NMR(400MHz,CDCl3)δ＝7.37(d,J＝7.6Hz,2H,ArH),7.36-7.18(m,5H,ArH),7.10(t,J＝7.4Hz,1H,ArH),6.87(d,J＝7.6Hz,1H,ArH),4.80-4.70(quintet,J＝7.0Hz,1H,＝CH),4.56-4.48(m,1H,one proton of＝CH2),4.44-4.36(m,1H,one proton of＝CH2),3.18(s,3H,CH3),3.03-2.90(m,2H,CH2)；13C NMR(100MHz,CDCl3)δ＝210.0,177.7,143.9,139.2,131.4,128.4,128.3,127.3,127.0,125.2,122.4,108.2,84.3,74.4,56.3,37.0,26.3；IR(neat,cm-1):3056,2930,1954,1707,1608,1491,1468,1369,1344,1252,1182,1158,1128,1086,1019；MS(70eV,EI)m/z(％):275[M+,46.27],222(100)；HRMS Calcd for C19H17NO[M+]:275.1310；Found:275.1308.
实施例3
操作同实施例2。Pd(PPh3)4(57.5mg,0.05mmol),1b(372.0mg,1.2mmol),2a(205.0mg,1.0mmol)，MeCN(5.0mL)反应10.7小时得3ba(318.1mg,88％)，油状液体，[第一次柱层析，淋洗剂:石油醚/乙酸乙酯＝30/1，收集所有的产物第二次柱层析,淋洗剂:石油醚/乙醚/二氯甲烷＝20/1/1]，1H NMR(400MHz,CDCl3)δ＝7.94(d,J＝8.0Hz,1H,ArH),7.40-7.15(m,8H,ArH),4.82-4.73(quintet,J＝7.4Hz,1H,＝CH),4.58-4.50(m,1H,one protonof＝CH),4.50-4.40(m,1H,one proton of＝CH),3.14-3.05(m,1H,one proton of CH2),3.00-2.88(m,1H,one proton of CH2),1.61(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.1,149.3,140.1,139.1,130.2,128.61,128.56,127.7,127.3,125.2,124.3,115.2,84.3,84.1,74.7,56.8,37.7,28.1；IR(neat,cm-1):2999,2981,2930,2907,1945,1768,1724,1605,1477,1461,1418,1392,1369,1342,1284,1249,1214,1144,1101,1076,1045,1033,1000；MS(70eV,EI)m/z(％):361[M+,2.77],208(100)；HRMS Calcd forC23H23NO3[M+]:361.1678；Found:361.1680.
实施例4
操作同实施例2,Pd(PPh3)4(57.7mg,0.05mmol),1c(359.5mg,1.2mmol),2a(204.1mg,1.0mmol)，MeCN(5.0mL)反应10.7小时得3ca(280.4mg,80％)，固体，[淋洗剂:石油醚/乙酸乙酯＝20/1]，m.p.＝79.7-80.9℃(石油醚/二氯甲烷)；1H NMR(400MHz,CDCl3)δ＝7.40(d,J＝7.6Hz,2H,ArH),7.36-7.13(m,10H,ArH),7.08-7.00(m,1H,ArH),6.74(d,J＝8.0Hz,1H,ArH),4.97(d,J＝15.6Hz,1H,one proton of CH2),4.88-4.69(m,2H,＝CH andone proton of CH2),4.58-4.47(m,1H,one proton of＝CH2),4.45-4.38(m,1H,oneproton of＝CH2),3.13-2.96(m,2H,CH2)；13C NMR(100MHz,CDCl3)δ＝210.0,177.8,143.0,139.4,135.8,131.4,128.6,128.5,128.1,127.4,127.3,127.1,127.0,125.1,122.4,109.2,84.3,74.4,56.4,43.8,37.0；IR(neat,cm-1):2935,2849,1953,1702,1610,1486,1465,1442,1377,1361,1341,1299,1208,1165,1153,1111,1077,1025,1002；MS(70eV,EI)m/z(％):351[M+,45.42],91(100)；Anal.Calcd for C25H21NO:C 85.44,H 6.02；Found:C85.42,H 6.15.
实施例5
操作同实施例2,Pd(PPh3)4(57.6mg,0.05mmol),1d(251.5mg,1.2mmol),2a(203.8mg,1.0mmol)，MeCN(5.0mL)反应8小时得3da(212.5mg,81％)，固体，[淋洗剂:石油醚/乙酸乙酯＝15/1]，m.p.＝120.7-121.9℃(石油醚/二氯甲烷)；1H NMR(400MHz,CDCl3)δ＝9.23-8.80(br,1H,NH),7.42-7.34(m,2H,ArH),7.34-7.18(m,5H,ArH),7.07(t,J＝7.4Hz,1H,ArH),6.95(d,J＝7.6Hz,1H,ArH),4.85-4.75(quintet,J＝7.4Hz,1H,＝CH),4.57-4.47(m,1H,one proton of＝CH2),4.47-4.38(m,1H,one proton of＝CH2),3.10-2.92(m,2H,CH2)；13C NMR(100MHz,CDCl3)δ＝210.1,181.0,141.4,139.1,132.3,128.5,128.2,127.4,127.0,125.1,122.3,110.4,84.1,74.5,57.2,36.6；IR(neat,cm-1):3174,3080,1954,1695,1612,1497,1467,1434,1403,1320,1297,1251,1220,1165,1104,1084,1018；MS(70eV,EI)m/z(％):261[M+,51.74],208(100)；Anal.Calcd for C18H15NO:C 82.73,H 5.79；Found:C 82.85,H 5.72.
实施例6
操作同实施例2,Pd(PPh3)4(58.2mg,0.05mmol),1e(304.0mg,1.2mmol),2b(170.8mg,1.0mmol)，MeCN(5.0mL)反应13小时得3eb(274.2mg,89％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝10/1]，1H NMR(400MHz,CDCl3)δ＝7.45-7.20(m,4H,ArH),7.09(t,J＝7.6Hz,1H,ArH),6.86(d,J＝8.0Hz,1H,ArH),6.81(d,J＝8.8Hz,2H,ArH),4.80-4.70(quintet,J＝7.2Hz,1H,＝CH),4.60-4.45(m,1H,one proton of＝CH2),4.45-4.36(m,1H,one proton of＝CH2),3.71(s,3H,CH3),3.17(s,3H,CH3),3.00-2.86(m,2H,CH2)；13C NMR(100MHz,CDCl3)δ＝209.8,177.8,158.7,143.8,131.4,131.1,128.1,128.0,125.0,122.2,113.7,108.0,84.2,74.3,55.5,55.0,37.0,26.1；IR(neat,cm-1):3054,2932,2835,1954,1706,1608,1510,1492,1467,1371,1344,1293,1248,1182,1128,1088,1031；MS(70eV,EI)m/z(％):305[M+,22.54],252(100)；HRMS Calcd for C20H19NO2[M+]:305.1416；Found:305.1412.
实施例7
操作同实施例2,Pd(PPh3)4(57.9mg,0.05mmol),1f(292.0mg,1.2mmol),2a(204.6mg,1.0mmol)，MeCN(5.0mL)反应14小时得3fa(256.6mg,87％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝16/1]，1H NMR(400MHz,CDCl3)δ＝7.43-7.30(m,3H,ArH),7.27(d,J＝7.2Hz,1H,ArH),7.12(t,J＝7.4Hz,1H,ArH),6.96(t,J＝8.8Hz,2H,ArH),6.89(d,J＝7.6Hz,1H,ArH),4.78-4.68(quintet,J＝7.2Hz,1H,＝CH),4.57-4.46(m,1H,one protonof＝CH2),4.45-4.36(m,1H,one proton of＝CH2),3.19(s,3H,CH3),2.95-2.88(m,2H,CH2)；13C NMR(100MHz,CDCl3)δ＝209.9,177.5,161.9(d,J＝244.9Hz),143.8,134.8(d,J＝3.2Hz),131.0,128.8(d,J＝7.9Hz),128.4,125.1,122.4,115.1(d,J＝21.3Hz),108.3,84.0,74.4,55.7,37.3,26.2；19F NMR(376MHz,CDCl3)δ＝-115.9；IR(neat,cm-1):3056,2931,1954,1707,1609,1506,1493,1469,1371,1345,1307,1230,1162,1128,1088,1016；MS(70eV,EI)m/z(％):293[M+,36.30],240(100)；HRMS Calcd for C19H16FNO[M+]:293.1216；Found:293.1220.
实施例8
操作同实施例2,Pd(PPh3)4(58.0mg,0.05mmol),1g(283.1mg,1.1mmol),2a(200.5mg,1.0mmol)，MeCN(5.0mL)反应13小时得3ga(301.2mg,99％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝20/1]，1H NMR(400MHz,CDCl3)δ＝7.40-7.28(m,3H,ArH),7.28-7.17(m,3H,ArH),7.11(t,J＝7.2Hz,1H,ArH),6.88(d,J＝7.6Hz,1H,ArH),4.80-4.70(quintet,J＝7.2Hz,1H,CH),4.57-4.48(m,1H,one proton of＝CH2),4.46-4.38(m,1H,one proton of＝CH2),3.18(s,3H,CH3),2.98-2.85(m,2H,CH2)；13C NMR(100MHz,CDCl3)δ＝210.1,177.4,143.9,137.7,133.4,130.9,128.62,128.60,128.56,125.2,122.6,108.4,84.1,74.6,55.9,37.2,26.4；IR(neat,cm-1):3055,2932,1954,1707,1609,1490,1469,1400,1370,1344,1309,1254,1184,1128,1089,1013；MS(70eV,EI)m/z(％):311[(M(37Cl))+,13.39],309[(M(35Cl))+,44.31],256(100)；HRMS Calcd for C19H16 35ClNO[M+]:309.0920；Found:309.0922.
实施例9
操作同实施例2,Pd(PPh3)4(57.8mg,0.05mmol),1h(388.3mg,1.2mmol),2b(170.2mg,1.0mmol)，MeCN(5.0mL)反应12小时得3hb(368.6mg,98％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.86(d,J＝8.0Hz,1H,ArH),7.62(d,J＝8.0Hz,1H,ArH),7.40-7.24(m,2H,ArH),7.20(t,J＝7.4Hz,1H,ArH),7.13-7.00(m,2H,ArH),6.83(d,J＝7.2Hz,1H,ArH),4.82-4.68(quintet,J＝7.2Hz,1H,＝CH),4.62-4.50(m,1H,one proton of＝CH2),4.54-4.36(m,1H,one proton of＝CH2),3.12-3.00(m,1H,one proton of CH2),3.00-2.91(m,1H,one proton of CH2),1.73(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.5,149.3,139.9,137.5,137.1,132.1,131.2,128.2,127.8,127.3,125.9,124.7,123.4,114.6,84.2,82.8,74.4,56.6,38.7,28.1,19.9；IR(neat,cm-1):2981,1956,1791,1764,1739,1605,1478,1462,1394,1369,1344,1290,1249,1145,1092,1045,1001；MS(70eV,EI)m/z(％):375[M+,8],57(100)；HRMSCalcd for C24H25NO3[M+]:375.1829；Found:375.1836.
实施例10
操作同实施例2,Pd(PPh3)4(28.9mg,0.025mmol),1i(202.5mg,0.6mmol),2b(85.3mg,0.5mmol)，MeCN(2.5mL)反应13小时得3ib(163.5mg,84％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.87(d,J＝8.0Hz,1H,ArH),7.64-7.58(m,1H,ArH),7.34-7.25(m,3H,ArH),7.18-7.10(m,1H,ArH),7.07(t,J＝7.4Hz,1H,ArH),6.84-6.80(m,1H,ArH),4.80-4.67(quintet,J＝7.6Hz,1H,＝CH),4.60-4.51(m,1H,one proton of＝CH2),4.42-4.36(m,1H,one proton of＝CH2),3.10-3.03(m,1H,oneproton of CH2),2.98-2.79(m,1H,one proton of CH2),2.20-2.08(m,1H,one proton ofCH2),1.94-1.84(m,1H,one proton of CH2),1.65(s,9H,CH3×3),0.799(t,J＝7.4Hz,3H,CH3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.8,149.4,143.0,139.6,136.8,132.4,129.9,128.2,128.0,127.4,125.7,124.6,123.6,114.8,84.1,82.9,74.4,56.4,39.3,28.1,25.0,14.1；IR(neat,cm-1):2973,2933,2878,1955,1764,1723,1605,1462,1393,1369,1346,1288,1250,1145,1089,1045,1021；MS(70eV,EI)m/z(％):389[M+,3.58],57(100)；HRMSCalcd for C20H19NO[(M-Boc+H)+]:289.1461；Found:289.1464.
实施例11
操作同实施例2,Pd(PPh3)4(29.0mg,0.025mmol),1j(203.6mg,0.6mmol),2b(85.1mg,0.5mmol)，MeCN(2.5mL)反应15小时得3jb(153.2mg,78％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝30/1,1.4L]，1H NMR(400MHz,CDCl3)δ＝7.83(d,J＝8.0Hz,1H,ArH),7.54(d,J＝7.6Hz,1H,ArH),7.30-7.19(m,2H,ArH),7.08-6.97(m,2H,ArH),6.84-6.72(m,2H,ArH),4.83-4.70(quintet,J＝7.2Hz,1H,＝CH),4.62-4.48(m,1H,one proton of＝CH2),4.42-4.39(m,1H,one proton of＝CH2),3.45(s,3H,CH3),3.02-2.87(m,2H,CH2),1.66(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.1,177.3,156.7,149.7,140.2,131.8,129.6,128.9,127.6,127.1,123.9,122.7,120.8,114.2,112.3,83.5,82.8,74.3,55.6,53.9,36.6,28.1；IR(neat,cm-1):2978,1956,1768,1717,1604,1492,1479,1466,1438,1391,1368,1350,1292,1251,1145,1092,1077,1050,1022；MS(70eV,EI)m/z(％):391[M+,13.56],57(100)；HRMS Calcd for C19H17NO2[(M-Boc+H)+]:291.1254；Found:291.1250.
实施例12
操作同实施例2,Pd(PPh3)4(28.9mg,0.025mmol),1k(210.1mg,0.54mmol,91％纯度),2b(85.2mg,0.5mmol)，MeCN(2.5mL)反应17小时得3kb(149.3mg,74％)，固体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，m.p.＝92.6-93.5℃(石油醚/二氯甲烷)；1H NMR(400MHz,CDCl3)δ＝7.86(d,J＝8.4Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.34-7.25(m,2H,ArH),7.23-7.21(m,2H,ArH),7.05(t,J＝7.2Hz,1H,ArH),6.83(d,J＝7.2Hz,1H,ArH),4.82-5.74(quintet,J＝7.4Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.43-4.36(m,1H,one proton of＝CH2),3.08-2.98(m,1H,one proton of CH2),2.95-2.87(m,1H,oneproton of CH2),2.22-2.15(quintet,J＝6.6Hz,1H,CH),1.64(s,9H,CH3×3),1.03(d,J＝6.8Hz,3H,CH3),0.54(d,J＝6.4Hz,3H,CH3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.7,149.5,148.2,139.2,135.9,133.1,128.2,128.1,127.4,127.3,125.7,124.5,123.5,114.8,84.0,83.0,74.4,56.2,39.3,29.6,28.1,23.3,23.1；IR(neat,cm-1):2976,2931,2870,1956,1765,1728,1604,1472,1391,1368,1343,1291,1248,1144,1090,1041,1017；MS(70eV,EI)m/z(％):403[M+,6.08],57(100)；Anal.Calcd for C26H29NO3:C 77.39,H 7.24；Found:C 77.13,H 7.33.
实施例13
操作同实施例2,Pd(PPh3)4(28.9mg,0.025mmol),1l(202.5mg,0.6mmol),2b(85.2mg,0.5mmol)，MeCN(2.5mL)反应14小时得3lb(133.8mg,69％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.85(d,J＝8.0Hz,1H,ArH),7.50(d,J＝8.0Hz,1H,ArH),7.32-7.26(m,1H,ArH),7.12-7.00(m,2H,ArH),6.90-6.80(m,2H,ArH),4.80-4.68(quintet,J＝7.6Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.44-4.35(m,1H,one proton of＝CH2),3.09-3.00(m,1H,one proton of CH2),2.98-2.88(m,1H,one proton of CH2),2.28(s,3H,CH3),1.69(s,3H,CH3),1.64(s,9H,CH3×3)；13CNMR(100MHz,CDCl3)δ＝210.2,176.7,149.3,139.9,137.4,136.8,134.6,133.0,131.5,128.1,127.3,126.5,124.6,123.4,114.6,84.1,82.9,74.4,56.3,38.7,28.1,20.7,19.8；IR(neat,cm-1):2981,2929,2869,1956,1765,1728,1606,1477,1463,1369,1344,1289,1249,1145,1090,1044,1019；MS(70eV,EI)m/z(％):389[M+,3.81],57(100)；HRMS Calcdfor C20H19NO[(M-Boc+H)+]:289.1461；Found:289.1461.
实施例14
操作同实施例2，(28.8mg,0.025mmol),1m(202.5mg,0.6mmol),2b(85.2mg,0.5mmol)，MeCN(2.5mL)反应13小时得3mb(155.7mg,77％,96％纯度)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.85(d,J＝8.0Hz,1H,ArH),7.42(s,1H,ArH),7.33-7.25(m,1H,ArH),7.11-7.04(m,1H,ArH),7.01(d,J＝7.6Hz,1H,ArH),6.93(d,J＝7.6Hz,1H,ArH),6.85(d,J＝7.6Hz,1H,ArH),4.80-4.69(quintet,J＝7.4Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.44-4.38(m,1H,one protonof＝CH2),3.10-3.02(m,1H,one proton of CH2),3.00-2.91(m,1H,one proton of CH2),2.38(s,3H,CH3),1.67(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.6,149.3,139.9,137.2,135.2,133.9,132.0,131.4,128.4,128.2,128.1,124.6,123.5,114.6,84.1,82.9,74.4,56.5,38.7,28.1,21.3,19.4；IR(neat,cm-1):2981,2930,1956,1764,1729,1606,1477,1463,1369,1344,1289,1249,1145,1092,1045；MS(70eV,EI)m/z(％):389[M+,4.28],57(100)；HRMS Calcd for C20H19NO[(M-Boc+H)+]:289.1461；Found:289.1463.
实施例15
操作同实施例2,Pd(PPh3)4(28.9mg,0.025mmol),1n(212.0mg,0.6mmol),2b(85.2mg,0.5mmol),MeCN(2.5mL)反应16小时得3nb(172.1mg,80％,94％纯度)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.85(d,J＝8.0Hz,1H,ArH),7.53(d,J＝8.8Hz,1H,ArH),7.34-7.27(m,1H,ArH),7.11-7.04(m,1H,ArH),6.86-6.76(m,2H,ArH),6.63-6.57(m,1H,ArH),4.79-4.62(quintet,J＝7.4Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.45-4.37(m,1H,one proton of＝CH2),3.77(s,3H,OCH3),3.06-2.96(m,1H,one proton of CH2),2.95-2.87(m,1H,one proton of CH2),1.70(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.8,158.8,149.3,139.8,138.6,131.6,129.8,128.5,128.1,124.6,123.4,117.9,114.6,110.5,84.1,82.9,74.4,56.0,55.1,38.9,28.1,20.1；IR(neat,cm-1):2980,1956,1791,1764,1728,1607,1576,1501,1477,1463,1369,1345,1290,1247,1213,1144,1121,1091,1047,1002；MS(70eV,EI)m/z(％):405[M+,4.62],57(100)；HRMS Calcd for C20H19NO2[(M-Boc+H)+]:305.1410；Found:305.1408.
实施例16
操作同实施例2,Pd(PPh3)4(29.0mg,0.025mmol),1o(214.8mg,0.6mmol),2b(85.2mg,0.5mmol)，MeCN(2.5mL)反应13小时得3ob(196.6mg,96％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.86(d,J＝8.0Hz,1H,ArH),7.54(d,J＝8.4Hz,1H,ArH),7.32(t,J＝8.0Hz,1H,ArH),7.29-7.23(m,1H,ArH),7.12-7.03(m,2H,ArH),6.82(d,J＝7.2Hz,1H,ArH),4.80-4.68(quintet,J＝7.3Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.45-4.37(m,1H,one proton of＝CH2),3.07-2.96(m,1H,one proton of CH2),2.95-2.86(m,1H,one proton of CH2),1.71(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.1,149.2,139.9,139.2,136.2,133.6,131.9,130.7,128.8,128.4,125.9,124.8,123.4,114.7,84.4,82.6,74.6,56.2,38.8,28.1,19.7；IR(neat,cm-1):2980,1956,1765,1729,1601,1535,1473,1343,1292,1251,1147,1093,1033,1009；MS(70eV,EI)m/z(％):411[(M(37Cl))+,0.72],409[(M(35Cl))+,1.93],57(100)；HRMS Calcd for C19H16 35ClNO[(M-Boc+H)+]:309.0915；Found:309.0913.
实施例17
操作同实施例2,Pd(PPh3)4(58.2mg,0.05mmol),1p(405.8mg,1.2mmol),2b(167.1mg,1.0mmol)，MeCN(5.0mL)反应8.5小时得3pb(306.6mg,80％)，固体，[第一次柱层析，淋洗剂:石油醚/乙酸乙酯＝40/1(0.8L)得253.3mg纯净物3pb和一些不纯的3pb。不纯的产物第二次柱层析(淋洗剂:石油醚/乙酸乙酯＝20/1(0.04L))得到53.3mg纯净物3pb]，m.p.＝109.2-110.6℃(石油醚/二氯甲烷)；1H NMR(400MHz,CDCl3)δ＝7.73(d,J＝8.4Hz,1H,ArH),7.61(d,J＝8.0Hz,1H,ArH),7.28(t,J＝8.4Hz,1H,ArH),7.21(t,J＝7.2Hz,1H,ArH),7.12-7.04(m,2H,ArH),6.63(s,1H,ArH),4.80-4.72(quintet,J＝7.2Hz,1H,＝CH),4.65-4.50(m,1H,one proton of＝CH2),4.50-4.40(m,1H,one proton of＝CH2),3.10-3.00(m,1H,one proton of CH2),3.00-2.92(m,1H,one proton of CH2),2.24(s,3H,CH3),1.75(s,3H,CH3),1.60(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.6,137.7,137.6,137.2,134.4,132.1,131.1,128.7,127.8,127.3,125.9,123.9,114.4,84.0,82.9,74.4,56.6,38.7,28.1,21.0,19.9；IR(neat,cm-1):2984,2933,1955,1765,1722,1596,1485,1457,1393,1369,1336,1298,1280,1249,1229,1158,1108,1069,1038；MS(70eV,EI)m/z(％):389[M+,11.51],57(100)；Anal.Calcd for C25H27NO3:C 77.09,H 6.99；Found:C77.17,H 6.87.
实施例18
操作同实施例2,Pd(PPh3)4(29.0mg,0.025mmol),1q(212.1mg,0.56mmol,94％纯度),2b(85.2mg,0.5mmol)，MeCN(2.5mL)反应13小时得3qb(117.4mg,58％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,1.2L]，1H NMR(400MHz,CDCl3)δ＝7.79(d,J＝8.8Hz,1H,ArH),7.60(d,J＝7.6Hz,1H,ArH),7.30-7.24(m,1H,ArH),7.23-7.17(m,1H,ArH),7.06(d,J＝7.2Hz,1H,ArH),6.83(dd,J1＝8.8Hz,J2＝2.8Hz,1H,ArH),6.39(d,J＝2.8Hz,1H,ArH),4.80-4.70(quintet,J＝7.6Hz,1H,＝CH),4.62-4.54(m,1H,one proton of＝CH2),4.48-4.40(m,1H,one proton of＝CH2),3.70(s,3H,CH3),3.10-3.01(m,1H,one proton ofCH2),2.98-2.80(m,1H,one proton of CH2),1.76(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.5,157.2,149.4,137.5,137.2,133.4,132.6,132.1,127.8,127.3,125.9,115.6,113.0,109.6,84.0,82.9,74.5,56.9,55.6,38.7,28.1,19.9；IR(neat,cm-1):2980,2936,2956,1763,1725,1599,1485,1434,1393,1369,1337,1297,1276,1249,1149,1106,1073,1032；MS(70eV,EI)m/z(％):405[M+,12.12],57(100)；HRMS Calcdfor C20H19NO2[(M-Boc+H)+]:305.1410；Found:305.1407.
实施例19
操作同实施例2,Pd(PPh3)4(29.0mg,0.025mmol),1r(170.7mg,0.5mmol),2b(102.2mg,0.6mmol)，MeCN(2.5mL)反应12小时得3rb(186.4mg,95％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.90-7.84(m,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.32-7.26(m,1H,ArH),7.22(t,J＝7.4Hz,1H,ArH),7.08(d,J＝7.2Hz,1H,ArH),7.04-6.98(dt,J1＝9.0Hz,J2＝2.8Hz,1H,ArH),6.57(dd,J1＝7.6Hz,J2＝2.8Hz,1H,ArH),4.80-4.70(quintet,J＝7.2Hz,1H,＝CH),4.62-4.55(m,1H,one proton of＝CH2),4.45-4.38(m,1H,one proton of＝CH2),3.12-3.04(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.75(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.1,160.2(d,J＝242.5Hz),149.3,137.0,136.9,135.9(d,J＝3.2Hz),133.2(d,J＝8.7Hz),132.2,128.1,127.2,126.1,116.0(d,J＝7.9Hz),114.7(d,J＝22.9Hz),111.0(d,J＝24.4Hz),84.4,82.5,74.6,56.8 38.7,28.1,19.9；19F NMR(376MHz,CDCl3)δ＝-117.9；IR(neat,cm-1):2980,2932,1956,1768,1728,1609,1478,1342,1298,1258,1146,1100,1034；MS(70eV,EI)m/z(％):393[M+,3.91],57(100)；HRMS Calcdfor C24H24FNO3[M+]:393.1735；Found:393.1731.
实施例20
操作同实施例2，Pd(PPh3)4(57.7mg,0.05mmol),1s(429.5mg,1.2mmol),2b(170.5mg,1.0mmol)，MeCN(5.0mL)反应18小时得3sb(385.4mg,94％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.84(d,J＝8.8Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.36-7.18(m,3H,ArH),7.08(d,J＝7.2Hz,1H,ArH),6.82(s,1H,ArH),4.80-4.70(quintet,J＝7.2Hz,1H,＝CH),4.63-4.55(m,1H,one proton of＝CH2),4.50-4.38(m,1H,one proton of＝CH2),3.12-3.00(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.75(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,175.8,149.1,138.5,137.0,136.8,133.1,132.2,130.2,128.2,128.1,127.2,126.1,123.7,115.9,84.5,82.5,74.7,56.6,38.7,28.1,20.0；IR(neat,cm-1):2980,1956,1768,1729,1469,1332,1288,1254,1150,1107,1035；MS(70eV,EI)m/z(％):411[(M(37Cl))+,0.89],409[(M(35Cl))+,2.66],57(100)；HRMS Calcd for C24H24 35ClNO3[M+]:409.1439；Found:409.1440.
实施例21
操作同实施例2,Pd(PPh3)4(57.9mg,0.05mmol),1t(482.6mg,1.2mmol),2b(170.4mg,1.0mmol)，MeCN(5.0mL)反应18小时得3tb(430.7mg,95％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.78(d,J＝8.4Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.44(d,J＝8.4Hz,1H,ArH),7.34-7.26(m,1H,ArH),7.24-7.18(m,1H,ArH),7.09(d,J＝7.2Hz,1H,ArH),6.96(s,1H,ArH),4.80-4.70(quintet,J＝7.2Hz,1H,＝CH),4.63-4.55(m,1H,one proton of＝CH2),4.50-4.38(m,1H,one proton of＝CH2),3.10-3.00(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.75(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝201.4,175.7,149.1,139.0,137.0,136.8,133.4,132.3,131.2,128.2,127.3,126.5,126.1,117.7,116.3,84.6,82.5,74.7,56.6,38.7,28.1,20.0；IR(neat,cm-1):3019,2979,1955,1768,1729,1466,1331,1287,1254,1149,1106；MS(70eV,EI)m/z(％):355[(M(81Br)-Boc+H)+,4.4],353[(M(79Br)-Boc+H)+,6.28],57(100)；HRMS Calcd for C24H24 79BrNO3[M+]:453.0934；Found:453.0928.
实施例22
操作同实施例2,Pd(PPh3)4(58.0mg,0.05mmol),1u(309.2mg,1.2mmol),2a(203.7mg,1.0mmol)，MeCN(5.0mL)反应13.5小时得3ua(295.1mg,96％)，固体，[淋洗剂:石油醚/乙酸乙酯＝16/1]，m.p.＝64.6-66.4℃(石油醚/二氯甲烷)；1H NMR(400MHz,CDCl3)δ＝7.38-7.16(m,6H,ArH),7.09(dd,J1＝8.0Hz,J2＝2.0Hz,1H,ArH),6.90(d,J1＝2.0Hz,1H,ArH),4.80-4.68(quintet,J＝7.2Hz,1H,＝CH),4.57-4.49(m,1H,one proton of＝CH2),4.48-4.40(m,1H,one proton of＝CH2),3.18(s,3H,CH3),3.00-2.90(m,2H,CH2)；13C NMR(100MHz,CDCl3)δ＝210.0,177.7,145.2,138.6,134.1,129.8,128.6,127.6,126.9,126.1,122.2,108.9,84.1,74.7,56.1,37.0,26.4；IR(neat,cm-1):3060,1956,1710,1602,1492,1465,1428,1364,1313,1292,1241,1190,1172,1134,1086,1070,1035,1013；MS(70eV,EI)m/z(％):311[(M(37Cl))+,11.89],309[(M(35Cl))+,34.60],256(100)；Anal.Calcd forC19H16ClNO:C 73.66,H 5.21；Found:C 73.76,H 5.18.
实施例23
操作同实施例2,Pd(PPh3)4(57.8mg,0.05mmol),1v(422.3mg,1.2mmol),2b(169.0mg,1.0mmol)，MeCN(5.0mL)反应12小时得3vb(361.8mg,89％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,1.0L]，1H NMR(400MHz,CDCl3)δ＝7.96(s,1H,ArH),7.59(d,J＝8.0Hz,1H,ArH),7.34-7.18(m,2H,ArH),7.12-7.06(m,2H,ArH),6.77(d,J＝8.0Hz,1H,ArH),4.70-4.68(quintet,J＝7.0Hz,1H,CH),4.62-4.54(m,1H,one proton of＝CH2),4.50-4.40(m,1H,one proton of＝CH2),3.10-3.00(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.74(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.0,149.1,140.8,136.99,136.96,133.9,132.2,129.7,128.1,127.3,126.1,124.7,124.3,115.4,84.7,82.6,74.7,56.4,38.6,28.0,20.0；IR(neat,cm-1):2979,2931,1956,1770,1730,1601,1472,1426,1374,1336,1281,1246,1089,1037；MS(70eV,EI)m/z(％):411[(M(37Cl))+,0.97],409[(M(35Cl))+,2.83],57(100)；HRMS Calcd forC19H16 35ClNO[(M-Boc+H)+]:309.0915；Found:309.0914.
实施例24
操作同实施例2,Pd(PPh3)4(28.9mg,0.025mmol),1w(241.4mg,0.6mmol),2b(85.2mg,0.5mmol)，MeCN(2.5mL)，3wb(99.9mg,44％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝100/1,1.2L]，1H NMR(400MHz,CDCl3)δ＝8.11(d,J＝1.6Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.32-7.18(m,3H,ArH),7.07(d,J＝7.2Hz,1H,ArH),6.71(d,J＝8.0Hz,1H,ArH),4.70-4.68(quintet,J＝7.6Hz,1H,＝CH),4.62-4.55(m,1H,one proton of＝CH2),4.48-4.40(m,1H,one proton of＝CH2),3.10-3.00(m,1H,one proton of CH2),2.99-2.90(m,1H,one proton of CH2),1.74(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,175.9,149.0,140.9,136.93,136.88,132.2,130.2,128.1,127.6,127.2,126.0,124.7,121.7,118.1,84.7,82.5,74.7,56.4,38.5,28.0,20.0；IR(neat,cm-1):2981,1955,1767,1730,1601,1472,1416,1369,1334,1284,1244,1144,1101；MS(70eV,EI)m/z(％):455[(M(81Br))+,1.36],453[(M(79Br))+,1.42],57(100)；HRMS Calcd for C24H24 79BrNO3[M+]:453.0940；Found:453.0942.
实施例25
操作同实施例2,Pd(PPh3)4(28.9mg,0.025mmol),1x(214.7mg,0.6mmol),2b(85.5mg,0.5mmol)，MeCN(2.5mL)反应13小时得3xb(190.2mg,92％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,1.2L]，1H NMR(400MHz,CDCl3)δ＝7.60(d,J＝8.0Hz,1H,ArH),7.33-7.24(m,2H,ArH),7.21(t,J＝7.4Hz,1H,ArH),7.07(d,J＝7.6Hz,1H,ArH),7.01(t,J＝7.8Hz,1H,ArH),6.77-6.70(m,1H,ArH),4.84-4.75(quintet,J＝7.6Hz,1H,＝CH),4.63-4.55(m,1H,one proton of＝CH2),4.45-4.48(m,1H,one proton of＝CH2),3.12-3.05(m,1H,one proton of CH2),3.04-2.94(m,1H,one proton of CH2),1.77(s,3H,CH3),1.63(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.4,176.6,148.0,137.4,137.3,136.8,134.7,132.2,129.8,128.1,127.2,126.0,125.2,122.0,118.4,85.2,82.5,74.6,57.2,38.5,27.6,20.0；IR(neat,cm-1):2976,2920,1956,1755,1732,1606,1582,1485,1462,1447,1369,1349,1314,1256,1224,1198,1180,1144,1125,1032；MS(70eV,EI)m/z(％):311[(M(37Cl)-Boc+H)+,14.55],309[(M(35Cl)-Boc+H)+,42.24],57(100)；HRMS Calcd forC19H16 35ClNO[(M-Boc+H)+]:309.0915；Found:309.0914.
实施例26
操作同实施例2,Pd(PPh3)4(28.9mg,0.025mmol),1y(234.5mg,0.6mmol),2b(85.2mg,0.5mmol)，MeCN(2.5mL)反应16小时得3yb(188.5mg,85％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，1H NMR(400MHz,CDCl3)δ＝7.62(d,J＝7.6Hz,1H,ArH),7.57(d,J＝8.0Hz,1H,ArH),7.32-7.26(m,1H,ArH),7.25-7.14(m,2H,ArH),7.04(d,J＝7.2Hz,1H,ArH),7.00(d,J＝7.2Hz,1H,ArH),4.82-4.74(quintet,J＝7.4Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.40-4.31(m,1H,one proton of＝CH2),3.14-3.06(m,1H,one proton of CH2),3.02-2.93(m,1H,one proton of CH2),1.74(s,3H,CH3),1.60(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.4,176.6,148.9,137.1,136.8,134.4,132.3,128.2,127.2,127.0,126.8(q,J＝4.7Hz),126.1,124.4,123.5(q,J＝270.0Hz),116.0(q,J＝33.4Hz),85.5,82.2,74.6,56.0,38.6,27.5,20.0；19F NMR(376MHz,CDCl3)δ＝-59.0；IR(neat,cm-1):2987,1953,1791,1730,1601,1460,1442,1371,1328,1302,1276,1241,1217,1128,1098,1077；MS(70eV,EI)m/z(％):343[(M-Boc+H)+,36.5],57(100)；HRMS Calcd forC20H16F3NO[(M-Boc+H)+]:343.1179；Found:343.1179.
实施例27
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入Pd(PPh3)4(0.005mmol),碳酸铯(1.2equiv)，1z(0.1mmol),和2a(0.24mmol)/MeCN(0.5mL)，将Schlenk反应管置于预置的50℃油浴中，搅拌13小时(通过薄层层析色谱检测(TLC)),将Schlenk反应管提出油浴恢复至室温后，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用60mL的乙醚淋洗，浓缩，入17.5μL的二溴甲烷，0.8mL氘代氯仿，核磁氢谱分析，得消旋的3-(2,3-丁二烯基)氧化吲哚酮类化合物3za 82％核磁收率。
实施例28
操作同实施例2,Pd(PPh3)4(0.005mmol),9a(0.12mmol),2b(0.1mmol)，MeCN(0.5mL)反应18小时得10ab 69％核磁收率。
实施例29
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入碳酸钾(0.2mmol),[Pd(π-cinnamyl)Cl]2(0.0025mmol),(R)-DTBM-Segphos(0.0075mmol),2b(0.1mmol)，1h(0.2mmol),乙醚(0.5mL),水(0.1mmol)，加入后立即加入一只内回流管，放入预置的20℃冷浴中开始搅拌12h，将Schlenk反应管提出冷浴，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用50mL的乙醚淋洗，浓缩，加入17.5μL的二溴甲烷，0.8mL氘代氯仿，核磁氢谱分析，得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3hb69％核磁收率。快速柱层析后液相色谱分析得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3hb 74％ee。
实施例30
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入碳酸钾(0.2mmol),[Pd(π-cinnamyl)Cl]2(0.0025mmol),(R)-DTBM-Segphos(0.006mmol),1h(0.2mmol)，四氢呋喃(0.3ml)，放入25℃油浴中搅拌半小时，后放入5℃冷浴中搅拌10min，加入2b(0.1mmol),四氢呋喃(0.2ml)，继续搅拌12小时；将Schlenk反应管提出冷浴，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用50mL的乙醚淋洗，浓缩，加入17.5μL的二溴甲烷，0.8mL氘代氯仿，核磁氢谱分析，得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3hb 79％核磁收率。快速柱层析后液相色谱分析得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3hb 76％ee。
实施例31
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入[Pd(π-cinnamyl)Cl]2(0.0025mmol),(R)-DTBM-Segphos(0.006mmol),碳酸钾(0.2mmol),N-甲基吡咯烷酮(0.3ml)，放入30℃油浴中搅拌半小时，加入1h(0.2mmol),2b(0.2mmol)，N-甲基吡咯烷酮(0.2ml)，继续搅拌12小时；将Schlenk反应管提出冷浴，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用50mL的乙醚淋洗，浓缩，加入17.5μL的二溴甲烷，0.8mL氘代氯仿，核磁氢谱分析，得原料2b 91％核磁回收。
实施例32
操作步骤：Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入Pd(dba)2(0.005mmol),(R)-L*(0.005mmol),1h(0.087mmol)，将Schlenk反应管置于乙醇-丙酮浴中冷却，加入，2b(0.1mmol)，DMPU(0.5mL)，抽换气3次，将Schlenk反应管置于水浴中解冻，解冻后立即放入预置的-30℃冷浴中，搅拌12-13小时；将Schlenk反应管提出冷浴，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用50mL的乙醚淋洗，浓缩，加入17.5μL的二溴甲烷，0.8mL氘代氯仿，核磁氢谱分析，得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3hb核磁收率。快速柱层析后液相色谱分析得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3hb ee值。
实施例33
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入Pd(dba)2(16.6mg,0.029mmol),(R)-DTBM-Biphep(33.5mg,0.029mmol),1h(323.4mg,1.0mmol)，将Schlenk反应管置于乙醇-丙酮浴中冷却，加入2b(194.5mg,1.14mmol)，DMPU(5mL)，抽换气3次，将Schlenk反应管置于水浴中解冻，解冻后立即放入预置的-30℃冷浴中，搅拌36小时(通过薄层层析色谱检测(TLC))；将Schlenk反应管提出冷浴，所得混合液用15mL水和15mL乙酸乙酯稀释后，用乙酸乙酯萃取(15mL×3)，合并有机相，用水洗涤(10mL×3)，用饱和食盐水洗涤(10mL×3)，用一定量的无水硫酸钠干燥，过滤，浓缩，快速柱层析[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3hb(345.9mg,92％)，油状液体，91％ee(HPLC conditions:ChiralcelIC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝6.8min,tR(major)＝12.6min)；[α]D 28＝-62.59(c＝0.75,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.86(d,J＝8.0Hz,1H,ArH),7.62(d,J＝8.0Hz,1H,ArH),7.40-7.15(m,3H,ArH),7.13-7.00(m,2H,ArH),6.83(d,J＝7.2Hz,1H,ArH),4.80-4.70(quintet,J＝7.2Hz,1H,＝CH),4.62-4.52(m,1H,one proton of＝CH2),4.46-4.36(m,1H,one proton of＝CH2),3.13-2.86(m,2H,CH2),1.73(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.5,149.3,139.9,137.5,137.1,132.1,131.2,128.2,127.8,127.3,125.9,124.7,123.4,114.6,84.2,82.8,74.4,56.6,38.7,28.1,19.9；IR(neat,cm-1):2981,1956,1793,1764,1728,1606,1478,1464,1394,1369,1344,1289,1249,1199,1144,1092,1074,1045；MS(70eV,EI)m/z(％):375[M+,3.97],57(100)；HRMS Calcd for C24H25NO3[M+]:375.1829；Found:375.1831.
实施例34
操作同实施例33,Pd(dba)2(16.6mg,0.029mmol),(R)-DTBM-Biphep(33.5mg,0.029mmol),1i(337.6mg,1.0mmol),2b(194.5mg,1.14mmol)，DMPU(5.0mL)反应36小时得(R)-3ib(338.6mg,87％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，91％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝6.1min,tR(major)＝7.1min)；[α]D 23＝-44.24(c＝0.85,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.87(d,J＝8.4Hz,1H,ArH),7.65-7.58(m,1H,ArH),7.34-7.25(m,3H,ArH),7.20-7.14(m,1H,ArH),7.10-7.03(m,1H,ArH),6.85-6.80(m,1H,ArH),4.80-4.68(quintet,J＝7.4Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.43-4.35(m,1H,one proton of＝CH2),3.10-3.02(m,1H,one proton of CH2),3.00-2.88(m,1H,oneproton of CH2),2.21-2.08(m,1H,one proton of CH2),1.97-1.84(m,1H,one proton ofCH2),1.65(s,9H,CH3×3),0.80(t,J＝7.4Hz,3H,CH3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.8,149.4,142.9,139.6,136.8,132.3,129.9,128.1,128.0,127.4,125.7,124.6,123.5,114.8,84.1,82.8,74.4,56.3,39.2,28.1,25.0,14.0；IR(neat,cm-1):2979,1955,1764,1728,1604,1474,1461,1393,1369,1343,1290,1249,1144,1091,1042,1017；MS(70eV,EI)m/z(％):389[M+,3.95],57(100)；HRMS Calcd for C20H19NO[(M-Boc+H)+]:289.1461；Found:289.1464.
实施例35
操作同实施例33，Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(33.4mg,0.029mmol),1j(339.2mg,1.0mmol),2b(194.3mg,1.14mmol)，DMPU(5.0mL)反应39小时得(R)-3jb(367.5mg,94％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝30/1,1.4L]，58％ee(HPLC conditions:Chiralcel AD-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(major)＝8.6min,tR(minor)＝9.9min)；[α]D 23＝-110.78(c＝0.63,CHCl3)；1HNMR(400MHz,CDCl3)δ＝7.83(d,J＝8.0Hz,1H,ArH),7.58-7.52(m,1H,ArH),7.32-7.18(m,2H,ArH),7.08-6.98(m,2H,ArH),6.85-6.75(m,2H,ArH),4.85-4.74(quintet,J＝7.2Hz,1H,＝CH),4.60-4.52(m,1H,one proton of＝CH2),4.42-4.34(m,1H,one proton of＝CH2),3.46(s,3H,CH3),3.03-2.86(m,2H,CH2),1.66(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,177.3,156.7,149.7,140.3,131.8,129.7,128.9,127.6,127.1,124.0,122.8,120.9,114.2,112.3,83.6,82.9,74.3,55.6,53.9,36.6,28.1；IR(neat,cm-1):2980,1956,1767,1718,1604,1491,1479,1465,1438,1393,1368,1292,1251,1146,1094,1076,1050,1023；MS(70eV,EI)m/z(％):391[M+,9.85],57(100)；HRMS Calcd for C19H17NO2[(M-Boc+H)+]:291.1254；Found:291.1254.
实施例36
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(33.4mg,0.029mmol),1k(351.4mg,0.91mmol,91％纯度),2b(194.3mg,1.14mmol)，DMPU(5.0mL)反应41小时得(R)-3kb(347.1mg,95％)，固体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，85％ee(HPLC conditions:Chiralcel AD-H column,hexane/i-PrOH＝97/3,1.0mL/min,λ＝214nm,tR(major)＝7.4min,tR(minor)＝8.1min)；[α]D 24＝-21.11(85％ee)(c＝0.97,CHCl3)；[α]D 19＝-22.36(89％ee)(c＝0.61,CHCl3)；m.p.＝93.4-94.4℃(89％ee)(石油醚/二氯甲烷)；1H NMR(400MHz,CDCl3)δ＝7.86(d,J＝8.0Hz,1H,ArH),7.65-7.53(m,1H,ArH),7.35-7.20(m,4H,ArH),7.05(t,J＝7.6Hz,1H,ArH),6.85-6.82(m,1H,ArH),4.83-4.73(quintet,J＝7.6Hz,1H,＝CH),4.60-5.50(m,1H,one proton of＝CH2),4.42-4.36(m,1H,one proton of＝CH2),3.08-3.00(m,1H,one proton of CH2),2.97-2.88(m,1H,oneproton of CH2),2.24-2.14(quintet,J＝6.6Hz,1H,CH),1.64(s,9H,CH3×3),1.04(d,J＝6.8Hz,3H,CH3),0.54(d,J＝6.4Hz,3H,CH3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.7,149.5,148.2,139.2,135.9,133.1,128.2,128.1,127.4,127.3,125.7,124.4,123.5,114.8,84.0,82.9,74.4,56.2,39.3,29.5,28.1,23.3,23.1；IR(neat,cm-1):3058,2978,2931,2870,1955,1763,1728,1604,1463,1368,1343,1289,1248,1142,1090,1041,1017；MS(70eV,EI)m/z(％):403[M+,4.37],57(100)；Anal.Calcd for C26H29NO3:C 77.39,H 7.24；Found:C 77.23,H 7.26.
实施例37
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(33.4mg,0.029mmol),1l(337.5mg,1.0mmol),2b(194.0mg,1.14mmol),DMPU(5.0mL)反应37小时得(R)-3lb(379.3mg,97％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，92％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝6.7min,tR(major)＝14.6min)；[α]D 20＝-41.33(c＝1.37,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.85(d,J＝8.4Hz,1H,ArH),7.49(d,J＝8.0Hz,1H,ArH),7.33-7.27(m,1H,ArH),7.12-7.04(m,2H,ArH),6.90-6.80(m,2H,ArH),4.80-4.68(quintet,J＝7.6Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.43-4.36(m,1H,one proton of＝CH2),3.09-3.00(m,1H,one proton of CH2),2.98-2.88(m,1H,one proton of CH2),2.28(s,3H,CH3),1.69(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.7,149.3,139.9,137.4,136.8,134.6,133.0,131.5,128.1,127.3,126.5,124.6,123.4,114.6,84.1,82.9,74.4,56.3,38.7,28.1,20.7,19.8；IR(neat,cm-1):2981,2930,1956,1765,1729,1606,1477,1463,1369,1344,1289,1249,1145,1091,1044,1018；MS(70eV,EI)m/z(％):389[M+,2.75],57(100)；HRMS Calcd for C20H19NO[(M-Boc+H)+]:289.1461；Found:289.1463.
实施例38
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(34.0mg,0.030mmol),1m(337.5mg,1.0mmol),2b(194.1mg,1.14mmol),DMPU(5.0mL)反应37小时得(R)-3mb(363.2mg,93％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，92％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝6.4min,tR(major)＝10.2min)；[α]D 27＝-51.50(c＝0.92,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.85(d,J＝8.0Hz,1H,ArH),7.42(s,1H,ArH),7.33-7.28(m,1H,ArH),7.10-7.04(m,1H,ArH),7.03-6.97(m,1H,ArH),6.86(d,J＝1.6Hz,1H,ArH),6.86-6.81(m,1H,ArH),4.80-4.68(quintet,J＝7.8Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.44-4.38(m,1H,one proton of＝CH2),3.10-3.02(m,1H,one proton of CH2),3.00-2.91(m,1H,one proton of CH2),2.38(s,3H,CH3),1.67(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.6,149.3,140.0,137.2,135.2,133.9,132.0,131.4,128.4,128.2,128.1,124.7,123.5,114.6,84.2,82.9,74.4,56.5,38.7,28.1,21.3,19.4；IR(neat,cm-1):2980,2930,2871,1956,1764,1606,1477,1463,1369,1344,1290,1249,1145,1093,1045,1003；MS(70eV,EI)m/z(％):389[M+,2.76],57(100)；HRMS Calcdfor C20H19NO[(M-Boc+H)+]:289.1461；Found:289.1464.
实施例39
操作同实施例33,Pd(dba)2(16.8mg,0.029mmol),(R)-DTBM-Biphep(33.5mg,0.029mmol),1n(353.5mg,1.0mmol),2b(194.1mg,1.14mmol),DMPU(5.0mL)反应40小时得(R)-3nb(373.0mg,92％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,1.2L]，92％ee(HPLC conditions:Chiralcel AD-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝8.2min,tR(major)＝13.0min)；[α]D 27＝-35.15(c＝0.73,CHCl3)；1HNMR(400MHz,CDCl3)δ＝7.85(d,J＝8.4Hz,1H,ArH),7.53(d,J＝8.8Hz,1H,ArH),7.33-7.24(m,1H,ArH),7.13-7.04(m,1H,ArH),6.88-6.75(m,2H,ArH),6.64-6.57(m,1H,ArH),4.72-4.68(quintet,J＝7.6Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.43-4.38(m,1H,one proton of＝CH2),3.77(s,3H,OCH3),3.08-2.97(m,1H,one proton of CH2),2.94-2.88(m,1H,one proton of CH2),1.70(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.8,158.9,149.4,139.8,138.6,131.6,129.8,128.5,128.1,124.7,123.4,117.9,114.6,110.5,84.1,82.9,74.4,56.1,55.1,38.9,28.1,20.1；IR(neat,cm-1):2980,1956,1791,1764,1729,1607,1576,1501,1463,1345,1290,1247,1212,1145,1092,1047,1002；MS(70eV,EI)m/z(％):405[M+,5.14],57(100)；HRMS Calcd forC20H19NO2[(M-Boc+H)+]:305.1410；Found:305.1411.
实施例40
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(34.0mg,0.030mmol),1o(357.8mg,1.0mmol),2b(194.3mg,1.14mmol)，DMPU(5.0mL)反应37小时得(R)-3ob(392.6mg,93％,97％纯度)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，87％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝5.1min,tR(major)＝7.6min)；[α]D 23＝-53.81(c＝1.00,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.86(d,J＝8.0Hz,1H,ArH),7.54(d,J＝8.8Hz,1H,ArH),7.32(t,J＝8.0Hz,1H,ArH),7.29-7.22(m,1H,ArH),7.12-7.04(m,2H,ArH),6.81(d,J＝7.2Hz,1H,ArH),4.80-4.68(quintet,J＝7.4Hz,1H,＝CH),4.62-4.50(m,1H,one proton of＝CH2),4.45-4.37(m,1H,one proton of＝CH2),3.07-2.96(m,1H,one proton of CH2),2.95-2.86(m,1H,one proton of CH2),1.71(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.1,149.2,139.9,139.2,136.2,133.6,131.9,130.7,128.8,128.4,125.9,124.8,123.4,114.7,84.4,82.6,74.6,56.2,38.8,28.1,19.7；IR(neat,cm-1):2980,1956,1765,1729,1601,1473,1343,1291,1250,1147,1093,1034,1008；MS(70eV,EI)m/z(％):411[(M(Cl37))+,0.50],409[(M(35Cl))+,1.24],57(100)；HRMS Calcd for C19H16 35ClNO[(M-Boc+H)+]:309.0915；Found:309.0910.
实施例41
操作同实施例33,Pd(dba)2(16.6mg,0.029mmol),(R)-DTBM-Biphep(33.6mg,0.029mmol),1p(339.5mg,1.0mmol),2b(193.2mg,1.14mmol)，DMPU(5.0mL)反应36小时得(R)-3pb(380.4mg,97％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,1.0L]，93％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝7.8min,tR(major)＝15.5min)；[α]D 25＝-81.85(c＝0.69,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.72(d,J＝8.0Hz,1H,ArH),7.61(d,J＝7.6Hz,1H,ArH),7.32-7.24(m,1H,ArH),7.21(d,J＝7.4Hz,1H,ArH),7.12-7.03(m,2H,ArH),6.63(s,1H,ArH),4.80-4.70(quintet,J＝7.2Hz,1H,＝CH),4.62-4.53(m,1H,one proton of＝CH2),4.48-4.38(m,1H,one proton of＝CH2),3.10-3.00(m,1H,one proton of CH2),3.00-2.90(m,1H,oneproton of CH2),2.24(s,3H,CH3),1.75(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.7,149.4,137.7,137.6,137.2,134.4,132.1,131.2,128.7,127.8,127.3,125.9,123.9,114.4,84.0,83.0,74.4,56.6,38.7,28.1,21.0,19.9；IR(neat,cm-1):2980,2931,2839,1956,1792,1766,1726,1597,1486,1458,1394,1335,1291,1281,1249,1108,1074,1044,1000；MS(70eV,EI)m/z(％):389[M+,9.87],57(100)；HRMS Calcd forC25H27NO3[M+]:389.1985；Found:389.1988.
实施例42
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(33.6mg,0.029mmol),1q(353.5mg,94％,0.94mmol),2b(194.1mg,1.14mmol)，DMPU(5.0mL)反应36小时得(R)-3qb(266.2mg,69％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,1.2L]，93％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝9.3min,tR(major)＝20.9min)；[α]D 26＝-58.79(c＝1.03,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.79(d,J＝8.8Hz,1H,ArH),7.60(d,J＝7.6Hz,1H,ArH),7.32-7.24(m,1H,ArH),7.22-7.17(m,1H,ArH),7.06(d,J＝7.2Hz,1H,ArH),6.85-6.78(m,1H,ArH),6.39(d,J＝2.4Hz,1H,ArH),4.80-4.58(quintet,J＝7.4Hz,1H,＝CH),4.63-4.55(m,1H,oneproton of＝CH2),4.50-4.40(m,1H,one proton of＝CH2),3.70(s,3H,CH3),3.12-3.03(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.76(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.2,176.4,157.1,149.4,137.4,137.2,133.4,132.6,132.1,127.8,127.3,125.9,115.6,113.0,109.6,83.9,82.9,74.5,56.9,55.5,38.7,28.1,19.9；IR(neat,cm-1):2980,2935,2836,1955,1763,1725,1598,1485,1459,1393,1369,1337,1296,1275,1250,1149,1107,1074,1033；MS(70eV,EI)m/z(％):405[M+,13.56],57(100)；HRMS Calcd for C25H27NO4[M+]:405.1935；Found:405.1934.
实施例43
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(33.5mg,0.029mmol),1r(341.4mg,1.0mmol),2b(194.3mg,1.14mmol)，DMPU(5.0mL)反应36小时得(R)-3ra(353.7mg,90％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，94％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝5.7min,tR(major)＝9.0min)；[α]D 29＝-53.48(c＝1.55,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.90-7.87(m,1H,ArH),7.59(d,J＝8.0Hz,1H,ArH),7.32-7.18(m,2H,ArH),7.08(d,J＝7.2Hz,1H,ArH),7.06-6.97(m,1H,ArH),6.57(dd,J1＝7.6Hz,J2＝2.8Hz,1H,ArH),4.81-4.60(quintet,J＝7.4Hz,1H,＝CH),4.63-5-4.54(m,1H,one proton of＝CH2),4.48-4.38(m,1H,one proton of＝CH2),3.12-3.04(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.75(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.1,160.2(d,J＝242.5Hz),149.3,137.0,136.9,135.9(d,J＝2.4Hz),133.6(d,J＝7.9Hz),132.2,128.1,127.3,126.1,116.0(d,J＝7.9Hz),114.7(d,J＝22.1Hz),111.0(d,J＝24.5Hz),84.4,82.5,74.6,56.8,38.7,28.1,19.9；19F NMR(376MHz,CDCl3)δ＝-117.9；IR(neat,cm-1):2980,2931,1956,1768,1728,1608,1478,1342,1298,1258,1145,1100,1034；MS(70eV,EI)m/z(％):393[M+,5.72],57(100)；HRMS Calcdfor C24H24FNO3[M+]:393.1735；Found:393.1737.
实施例44
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(33.5mg,0.029mmol),1s(357.9mg,1.2mmol),2b(194.2mg,1.14mmol)，DMPU(5.0mL)反应41小时得(R)-3sb(373.1mg,91％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，94％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝5.4min,tR(major)＝8.0min)；[α]D 27＝-64.76(c＝1.18,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.83(d,J＝8.8Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.35-7.18(m,3H,ArH),7.08(d,J＝7.2Hz,1H,ArH),6.82(s,1H,ArH),4.82-4.68(quintet,J＝7.2Hz,1H,＝CH),4.64-4.55(m,1H,one proton of＝CH2),4.50-4.38(m,1H,one proton of＝CH2),3.12-3.02(m,1H,one proton of CH2),3.00-2.88(m,1H,one proton of CH2),1.75(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,175.8,149.1,138.5,137.0,136.8,133.1,132.2,130.2,128.2,128.1,127.3,126.1,123.7,115.9,84.6,82.5,74.7,56.6,38.7,28.1,20.0；IR(neat,cm-1):2980,1955,1769,1729,1469,1370,1332,1288,1254,1149,1107；MS(ESI):m/z 312[(M(37Cl)-Boc+H)+],310[(M(35Cl)-Boc+H)+]；HRMSCalcd for C24H24 35ClNO3[M+]:409.1439；Found:409.1448.
实施例45
操作同实施例33,Pd(dba)2(16.6mg,0.029mmol),(R)-DTBM-Biphep(33.5mg,0.029mmol),1t(402.1mg,1.0mmol),2b(194.2mg,1.14mmol)，DMPU(5.0mL)反应36小时得(R)-3tb(407.7mg,90％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,0.8L]，93％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝5.4min,tR(major)＝8.2min)；[α]D 31＝-54.59(c＝1.02,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.78(d,J＝8.4Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.44(d,J＝8.8Hz,1H,ArH),7.34-7.15(m,2H,ArH),7.09(d,J＝7.2Hz,1H,ArH),6.96(s,1H,ArH),4.80-4.70(quintet,J＝7.2Hz,1H,＝CH),4.63-4.56(m,1H,one proton of＝CH2),4.50-4.40(m,1H,one proton of＝CH2),3.10-3.00(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.75(s,3H,CH3),1.64(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.4,175.7,149.1,139.0,137.0,136.8,133.4,132.3,131.2,128.2,127.3,126.5,126.1,117.7,116.3,84.6,82.5,74.7,56.6,38.7,28.1,20.0；IR(neat,cm-1):2981,1956,1794,1768,1730,1598,1468,1394,1370,1333,1290,1252,1148,1105,1065,1034；MS(70eV,EI)m/z(％):455[(M(81Br))+,3.75],453[(M+(79Br)),3.78],57(100)；HRMS Calcdfor C24H24 79BrNO3[M+]:453.0934；Found:453.0934.
实施例46
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入Pd(dba)2(2.7mg,0.005mmol),(R)-DTBM-Biphep(5.9mg,0.005mmol),1v(31.0mg,0.087mmol)，将Schlenk反应管置于乙醇-丙酮浴中冷却，加入，2b(17.3mg,0.1mmol)，DMPU(0.5mL)，抽换气3次，将Schlenk反应管置于水浴中解冻，解冻后立即放入预置的-30oC冷浴中，搅拌12小时(通过薄层层析色谱检测(TLC))；将Schlenk反应管提出冷浴，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用50mL的乙醚淋洗，浓缩，加入17.5μL的二溴甲烷，0.8mL氘代氯仿，核磁氢谱分析，得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3vb 92％核磁收率。快速柱层析后液相色谱分析得手性的3-(2,3-丁二烯基)氧化吲哚酮类化合物(R)-3vb 88％ee。
实施例47
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Segphos(34.1mg,0.029mmol),1v(357.9mg,1.0mmol),2b(194.0mg,1.14mmol)，DMPU‘’(5.0mL)反应12小时得(R)-3vb(368.6mg,90％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝50/1,1.0L]，90％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝5.6min,tR(major)＝8.9min)；[α]D 24＝-66.94(c＝0.68,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.95(d,J＝1.6Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.32-7.26(m,1H,ArH),7.24-7.18(m,1H,ArH),7.10-7.04(m,2H,ArH),6.76(d,J＝8.0Hz,1H,ArH),4.80-4.68(quintet,J＝7.6Hz,1H,＝CH),4.62-4.54(m,1H,one proton of＝CH2),4.48-4.38(m,1H,one proton of＝CH2),3.10-3.00(m,1H,one proton of CH2),2.98-2.90(m,1H,oneproton of CH2),1.74(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.0,149.1,140.8,136.99,136.96,133.9,132.2,129.7,128.1,127.3,126.1,124.7,124.3,115.4,84.7,82.6,74.7,56.4,38.6,28.0,20.0；IR(neat,cm-1):2980,2931,2869,1955,1770,1730,1605,1476,1422,1394,1370,1336,1285,1244,1143,1101,1076,1038,1010；MS(70eV,EI)m/z(％):411[(M(37Cl))+,0.90],409[(M(35Cl))+,2.15],57(100)；HRMSCalcd for C19H16 35ClNO[(M-Boc+H)+]:309.0915；Found:309.0913.
实施例48
操作同实施例33,Pd(dba)2(16.6mg,0.029mmol),(R)-DTBM-Biphep(33.4mg,0.029mmol),1w(402.3mg,1.0mmol),2b(194.2mg,1.14mmol)，DMPU(5.0mL)反应36小时得(R)-3wb(396.2mg,87％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，91％ee(HPLC conditions:Chiralcel AD-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝4.6min,tR(major)＝4.9min)；[α]D 23＝-58.99(c＝1.49,CHCl3)；1H NMR(400MHz,CDCl3)δ＝8.11(d,J＝2.0Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.32-7.18(m,3H,ArH),7.07(d,J＝7.2Hz,1H,ArH),6.71(d,J＝7.6Hz,1H,ArH),4.80-4.68(quintet,J＝7.4Hz,1H,＝CH),4.62-4.54(m,1H,one proton of＝CH2),4.50-4.40(m,1H,one protonof＝CH2),3.10-3.00(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.74(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,175.9,149.0,140.9,136.93,136.89,132.2,130.2,128.1,127.6,127.2,126.0,124.7,121.7,118.1,84.7,82.5,74.7,56.4,38.6,28.0,20.0；IR(neat,cm-1):2981,1955,1768,1730,1601,1473,1417,1370,1334,1284,1243,1198,1144,1101,1064,1031,1006；MS(70eV,EI)m/z(％):455[(M(81Br))+,1.04],453[(M(79Br))+,1.04],57(100)；HRMS Calcd forC24H24 79BrNO3[M+]:453.0940；Found:453.0943.
实施例49
操作同实施例46，Pd(dba)2(2.7mg,0.005mmol),(R)-DTBM-Biphep(5.9mg,0.005mmol),1x(31.5mg,0.088mmol)，2b(17.3mg,0.1mmol)，DMPU(0.5mL),反应14.8小时得(R)-3xb(88％核磁收率(R)-3xb，87％ee)。
实施例50
操作同实施例33,Pd(dba)2(16.6mg,0.029mmol),(R)-DTBM-Segphos(34.2mg,0.029mmol),1x(357.8mg,1.0mmol),2b(194.1mg,1.14mmol)，DMPU(5.0mL)反应37小时得(R)-3xb(348.4mg,85％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,1.2L]，91％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝8.2min,tR(major)＝12.2min)；[α]D 23＝-78.85(c＝0.86,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.60(d,J＝7.6Hz,1H,ArH),7.32-7.24(m,2H,ArH),7.24-7.18(m,1H,ArH),7.07(d,J＝7.2Hz,1H,ArH),7.01(t,J＝7.8Hz,1H,ArH),6.75-6.61(m,1H,ArH),4.85-4.75(quintet,J＝7.6Hz,1H,＝CH2),4.62-4.55(m,1H,one proton of＝CH),4.45-4.37(m,1H,one proton of＝CH2),3.14-3.04(m,1H,one proton of CH2),3.04-2.91(m,1H,one proton of CH2),1.77(s,3H,CH3),1.63(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.4,176.6,148.0,137.3,137.2,136.8,134.6,132.2,129.8,128.1,127.1,126.0,125.2,122.0,118.4,85.2,82.5,74.6,57.2,38.5,27.6,19.9；IR(neat,cm-1):3065,2983,2934,1956,1787,1745,1464,1447,1395,1370,1348,1246,1146,1118,1073,1036；MS(70eV,EI)m/z(％):311[(M(37Cl)-Boc+H)+,9.55],309[(M(35Cl)-Boc+H)+,27.29],57(100)；HRMS Calcd for C19H16 35ClNO[(M-Boc+H)+]:309.0915；Found:309.0915.
实施例51
操作同实施例33,Pd(dba)2(16.7mg,0.029mmol),(R)-DTBM-Biphep(34.0mg,0.030mmol),1y(391.2mg,1.0mmol),2b(194.5mg,1.14mmol)，DMPU(5.0mL)反应39小时得(R)-3yb(381.4mg,86％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L]，83％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝5.5min,tR(major)＝6.9min)；[α]D 27＝-47.08(c＝0.96,CHCl3)；1H NMR(400MHz,CDCl3)δ＝7.62(d,J＝7.6Hz,1H,ArH),7.56(d,J＝8.0Hz,1H,ArH),7.32-7.26(m,1H,ArH),7.25-7.15(m,2H,ArH),7.08(d,J＝7.6Hz,1H,ArH),7.00(d,J＝7.2Hz,1H,ArH),4.83-4.74(quintet,J＝7.2Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.40-4.30(m,1H,one proton of＝CH2),3.14-3.05(m,1H,one proton of CH2),3.04-2.92(m,1H,one proton of CH2),1.74(s,3H,CH3),1.60(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.4,176.6,148.9,137.1,136.7,134.4,132.3,128.2,127.2,127.0,126.8(q,J＝4.5Hz),126.1,124.4,123.5(q,J＝270.2Hz),116.0(q,J＝33.5Hz),85.5,82.2,74.6,56.0,38.6,27.5,19.9；19F NMR(376MHz,CDCl3)δ＝-59.0；IR(neat,cm-1):2985,1955,1793,1753,1603,1446,1371,1329,1249,1217,1140,1098,1077,1037；MS(70eV,EI)m/z(％):343[(M-Boc+H)+,32.07],57(100)；HRMS Calcd for C20H16F3NO[(M-Boc+H)+]:343.1179；Found:343.1181.
实施例52
操作同实施例33,Pd(dba)2(83.4mg,0.145mmol),(R)-DTBM-Biphep(167.0mg,0.145mmol),1w(2011.5mg,5.0mmol),2b(970.2mg,5.7mmol)，DMPU(25mL)反应40小时得(R)-3wb(2.2505g,99％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,1.2L]，92％ee(HPLC conditions:Chiralcel IC column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝5.5min,tR(major)＝8.2min)；[α]D 20＝-58.99(c＝0.93,CHCl3)；1H NMR(400MHz,CDCl3)δ＝8.11(d,J＝2.0Hz,1H,ArH),7.59(d,J＝7.6Hz,1H,ArH),7.32-7.16(m,3H,ArH),7.07(d,J＝7.2Hz,1H,ArH),6.71(d,J＝8.0Hz,1H,ArH),4.80-4.70(quintet,J＝7.5Hz,1H,＝CH),4.63-4.55(m,1H,one proton of＝CH2),4.50-4.60(m,1H,one protonof＝CH2),3.10-3.00(m,1H,one proton of CH2),3.00-2.90(m,1H,one proton of CH2),1.74(s,3H,CH3),1.65(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,175.9,149.1,140.9,137.0,136.9,132.2,130.3,128.1,127.7,127.3,126.1,124.7,121.7,118.1,84.8,82.6,74.7,56.4,38.6,28.1,20.0.
应用实施例1
Schlenk反应管连接上氩气钢瓶，抽换气3次，依次加入3wb(90.7mg,0.2mmol)，二氯甲烷(10mL)，将Schlenk反应管放入0℃冰水浴中，加入三氟乙酸(1.5mL,d＝1.535g/mL,2.3025g,20mmol)。冰水浴自然恢复至室温，反应管共搅拌4小时后(通过薄层层析色谱检测(TLC))，旋蒸除去溶剂。采用硅胶柱层析进行分离纯化[淋洗剂:石油醚/乙酸乙酯＝10/1,0.4L)]，得产物4(51.1mg,72％)，油状液体，1H NMR(400MHz,CDCl3)δ＝9.61(s,1H,NH),7.64(d,J＝7.6Hz,1H,ArH),7.30(t,J＝7.6Hz,1H,ArH),7.27-7.18(m,1H,ArH),7.12-7.00(m,3H,ArH),6.70(d,J＝7.6Hz,1H,CH2),4.86-4.75(quintet,J＝7.2Hz,1H,＝CH),4.60-4.50(m,1H,one proton of＝CH2),4.47-4.38(m,1H,one proton of＝CH2),3.12-2.92(m,2H,CH2),1.80(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ＝210.2,181.1,142.4,137.3,136.5,132.1,131.9,128.0,127.4,126.2,125.7,125.1,121.4,113.3,83.0,74.6,56.6,37.6,19.6；IR(neat,cm-1):1955,1734,1609,1479,1449,1372,1239,1148,1094,1044,1017；MS(70eV,EI)m/z(％):355[(M(81Br))+,25.2],353[(M(79Br))+,25.93],221(100)；HRMS Calcdfor C19H16 79BrNO[M+]:353.0410；Found:353.0411.
应用实施例2
操作同应用实施例1，(R)-3wb(91.0mg,0.2mmol)，二氯甲烷(10mL)，三氟乙酸(1.5mL,d＝1.535g/mL,2.3025g,20mmol)反应4小时得(R)-4(57.2mg,74％,92％纯度)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝20/1,0.4L,石油醚/乙酸乙酯＝10/1,0.4L]，92％ee(HPLC conditions:Chiralcel AD-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝10.7min,tR(major)＝15.7min)；[α]D 28＝-34.26(c＝1.13,CHCl3).1HNMR(400MHz,CDCl3)δ＝9.85(s,1H,NH),7.64(d,J＝7.2Hz,1H,ArH),7.30(t,J＝7.2Hz,1H,ArH),7.22(t,J＝6.4Hz,1H,ArH),7.12-6.97(m,3H,ArH),6.74-6.60(m,1H,ArH),4.86-4.77(quintet,J＝6.3Hz,1H,＝CH),4.62-4.50(m,1H,one proton of＝CH2),4.48-4.38(m,1H,one proton of＝CH2),3.12-2.90(m,2H,CH2),1.79(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ＝210.2,181.3,142.5,137.3,136.5,132.1,131.9,128.0,127.4,126.2,125.7,125.0,121.4,113.4,83.0,74.6,56.6,37.5,19.6；IR(neat,cm-1):1954,1710,1607,1478,1447,1323,1280,1208,1112,1058,1016；MS(70eV,EI)m/z(％):355[(M(81Br))+,24.27],353[(M(79Br))+,24.01],221(100)；HRMS Calcd for C19H16 79BrNO[M+]:353.0410；Found:353.0412.
应用实施例3
Schlenk反应管连接上氩气钢瓶，抽换气3次，依次加入3wb(91.0mg,0.2mmol)，二氯甲烷(10mL)，将Schlenk反应管放入0℃冰水浴中，加入三氟乙酸(1.5mL,d＝1.535g/mL,2.3025g,20mmol)。冰水浴自然恢复至室温，反应管共搅拌4小时后(通过薄层层析色谱检测(TLC))，用5mL二氯甲烷转移入尖底瓶，旋蒸除去溶剂。
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入上一步的产物，硝基甲烷(2mL)，N-碘代丁二酰亚胺(54.2mg,0.24mmol)，室温反应1.5小时后(通过薄层层析色谱检测(TLC))，旋蒸除去溶剂，采用硅胶柱层析进行分离纯化[淋洗剂:石油醚/乙酸乙酯＝50/1,1.2L]，得产物5(47.3mg,47％)，油状液体，1H NMR(400MHz,CDCl3)δ＝7.69(s,1H,ArH),7.42(d,J＝7.6Hz,1H,ArH),7.30-7.15(m,3H,ArH),7.02(d,J＝7.2Hz,1H,ArH),6.91(d,J＝8.0Hz,1H,ArH),5.34-5.27(m,1H,＝CH),3.88-3.60(m,2H,CH2),3.49(dd,J1＝17.8Hz,J2＝6.6Hz,1H,one proton of CH2),2.26(d,J＝17.6Hz,1H,one proton of CH2),1.88(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ＝181.0,153.4,151.8,138.8,137.6,132.7,132.3,128.2,128.0,127.1,126.3,123.9,123.8,121.9,98.5,51.9,30.5,19.3,-1.5；IR(neat,cm-1):2959,2922,2856,1716,1659,1579,1448,1326,1302,1263,1231,1192,1138,1048；MS(70eV,EI)m/z(％):481[(M(81Br))+,14.52],479[(M(79Br))+,13.04],354(100)；HRMS Calcd for C19H15 79BrINO[M+]:478.9376；Found:478.9364.
应用实施例4
操作同应用实施例3，(R)-3wb(91.2mg,0.2mmol)，二氯甲烷(10mL)，三氟乙酸(1.5mL,d＝1.535g/mL,2.3025g,20mmol)，硝基甲烷(2mL)，N-碘代丁二酰亚胺(54.2mg,0.24mmol)，反应4小时得第一步产物，反应3小时得第二步产物(R)-5(73.8mg,73％)，固体，[淋洗剂:石油醚/乙酸乙酯＝40/1,0.8L]，90％ee(HPLC conditions:Chiralcel AD-Hcolumn,hexane/i-PrOH＝97/3,1.0mL/min,λ＝214nm,tR(major)＝18.0min,tR(minor)＝19.6min)；[α]D 27＝-68.33(c＝3.38,CHCl3)；m.p.＝165.1-166.1℃(＞99％ee)(石油醚/二氯甲烷)；1H NMR(400MHz,CDCl3)δ＝7.75-7.67(m,1H,ArH),7.29(d,J＝7.6Hz,1H,ArH),7.30-7.15(m,3H,ArH),7.02(d,J＝7.2Hz,1H,ArH),6.91(d,J＝8.0Hz,1H,ArH),5.33-5.26(m,1H,＝CH),3.86-3.70(m,2H,CH2),3.49(dd,J1＝17.6Hz,J2＝6.4Hz,1H,one proton ofCH2),2.26(d,J＝17.6Hz,1H,one proton of CH2),1.88(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ＝181.0,153.4,151.8,138.8,137.6,132.7,132.3,128.2,128.0,127.1,126.3,123.9,123.8,122.0,98.5,51.9,30.5,19.3,-1.5；IR(neat,cm-1):2922,2856,1715,1658,1579,1448,1326,1302,1263,1230,1192,1138,1048；MS(70eV,EI)m/z(％):481[(M(81Br))+,11.36],479[(M(79Br))+,12.8],354(100)；Anal.Calcd for C19H15BrINO:C 47.53,H 3.15；Found:C 47.76,H 3.17.
应用实施例5
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入Pd(PPh3)4(11.7mg,0.01mmol),无水磷酸钾(85.2mg,0.4mmol),3-硝基苯基硼酸6(100.5mg,0.6mmol),3wb(91.0mg,0.2mmol)/二甲基甲酰胺(2.0mL)，将Schlenk反应管置于预置的50oC油浴中，搅拌24小时(通过薄层层析色谱检测(TLC)),将Schlenk反应管提出油浴恢复至室温后，所得混合液用10mL水和4mL乙酸乙酯稀释后，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水洗涤(10mL×3)，用一定量的无水硫酸钠干燥，过滤，浓缩，快速柱层析得7(56.2mg,56％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L；石油醚/乙酸乙酯＝50/1,0.4L]，1H NMR(400MHz,CDCl3)δ＝8.48(t,J＝2.0Hz,1H,ArH),8.26-8.18(m,2H,ArH),7.96(d,J＝7.6Hz,1H,ArH),7.68-7.62(m,2H,ArH),7.40-7.28(m,2H,ArH),7.24-7.20(m,1H,ArH),7.09(d,J＝7.2Hz,1H,ArH),6.97(d,J＝8.0Hz,1H,ArH),4.84-4.76(quintet,J＝7.6Hz,1H,＝CH),4.63-4.58(m,1H,one proton of＝CH2),4.50-4.40(m,1H,one proton of＝CH2),3.16-3.06(m,1H,one proton of CH2),3.07-2.98(m,1H,one proton of CH2),1.79(s,3H,CH3),1.68(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.3,149.4,148.8,142.6,140.9,139.0,137.2,137.1,133.1,132.2,131.8,129.8,128.1,127.4,126.1,124.1,123.6,122.3,122.1,113.7,84.7,82.8,74.7,56.6,38.7,28.1,20.1；IR(neat,cm-1):2966,2931,1955,1792,1767,1728,1614,1530,1501,1473,1417,1369,1346,1258,1147,1028；MS(70eV,EI)m/z(％):396[(M-Boc+H)+,72.3],343(100)；HRMS Calcd for C25H20N2O3[(M-Boc+H)+]:396.1468；Found:396.1465.
应用实施例6
操作同应用实施例5，Pd(PPh3)4(11.6mg,0.01mmol)，无水磷酸钾(85.2mg,0.4mmol),3-硝基苯基硼酸6(100.7mg,0.6mmol)，(R)-3wb(90.8mg,0.2mmol)，甲基甲酰胺(2.0mL)，反应24小时得7(61.3mg,62％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝80/1,0.8L；石油醚/乙酸乙酯＝50/1,0.8L]，90％ee(HPLC conditions:Chiralcel AD-Hcolumn,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,tR(minor)＝12.7min,tR(major)＝18.5min)；[α]D 28＝-12.32(c＝2.24,CHCl3).1H NMR(400MHz,CDCl3)δ＝8.48(t,J＝1.8Hz,1H,ArH),8.26-8.18(m,2H,ArH),7.96(d,J＝7.6Hz,1H,ArH),7.66-7.59(m,2H,ArH),7.52-7.28(m,2H,ArH),7.24-7.18(m,1H,ArH),7.09(d,J＝7.6Hz,1H,ArH),6.97(d,J＝8.0Hz,1H,ArH),4.84-4.76(quintet,J＝7.4Hz,1H,CH),4.63-4.56(m,1H,one proton of＝CH2),4.50-4.40(m,1H,one proton of＝CH2),3.16-3.08(m,1H,one proton of CH2),3.07-2.98(m,1H,one proton of CH2),1.79(s,3H,CH3),1.68(s,9H,CH3×3)；13C NMR(100MHz,CDCl3)δ＝210.3,176.3,149.4,148.8,142.6,140.9,139.0,137.2,137.1,133.1,132.2,131.8,129.8,128.1,127.4,126.1,124.1,123.6,122.3,122.1,113.7,84.7,82.8,74.7,56.6,38.7,28.1,20.1；IR(neat,cm-1):2979,2929,2856,1955,1792,1767,1728,1614,1530,1501,1474,1417,1369,1346,1278,1257,1104,1029；MS(70eV,EI)m/z(％):396[(M-Boc+H)+,74.85],344(100)；HRMS Calcd for C25H20N2O3[(M-Boc+H)+]:396.1468；Found:396.1465.
应用实施例7
Schlenk反应管经热烘枪干燥后，连接氩气钢瓶抽凉至室温，抽换气3次，在氩气保护下依次加入氯化亚铜(1.0mg,0.01mmol),Xantphos(5.8mg,0.01mmol),叔丁醇钠(3.9mg,0.04mmol),联硼酸频那醇酯(61.2mg,0.24mmol)，异丙醇(24.5mg,0.4mmol),3wb(90.7mg,0.2mmol)/乙醚(0.6mL)，将Schlenk反应管置于预置的25℃油浴中，搅拌8小时(通过薄层层析色谱检测(TLC)),将Schlenk反应管提出油浴恢复至室温后，反应液用硅胶短柱(高:3cm,直径:3.5cm)过滤，并用50mL的乙醚淋洗，浓缩，快速柱层析[淋洗剂:石油醚/乙酸乙酯＝100/1,0.8L,石油醚/乙酸乙酯＝80/1,0.8L]得8(43.3mg,34％,91％纯度)，油状液体，1HNMR(400MHz,CDCl3)δ＝8.11(d,J＝1.6Hz,1H,ArH),7.74(d,J＝7.6Hz,1H,ArH),7.32-7.16(m,3H,ArH),7.05(d,J＝7.2Hz,1H,ArH),6.70(d,J＝8.0Hz,1H,ArH),5.75(d,J＝3.2Hz,1H,one proton of＝CH2),5.60-5.56(m,1H,one proton of＝CH2),2.45-2.28(m,2H,CH2),2.12-2.00(m,1H,one proton of CH2),1.97-1.85(m,1H,one proton of CH2),1.73(s,3H,CH3),1.65(s,9H,CH3×3),1.30-1.18(m,12H,CH3×4)；13C NMR(100MHz,CDCl3)δ＝176.5,149.2,140.8,137.5,137.0,132.2,131.1,130.3,127.9,127.7,127.6,126.0,124.8,121.5,118.1,84.8,83.5,56.1,38.6,29.6,28.1,24.8,20.0；IR(neat,cm-1):2963,2922,2868,1771,1731,1601,1461,1416,1369,1338,1312,1285,1259,1142,1095,1015；MS(ESI):m/z 606[(M(81Br,11B)+Na)+],482[(M(79Br,11B)-Boc+H)+]；HRMS Calcd forC30H37 11B81BrNNaO5[(M+Na)+]:606.1820；Found:606.1813.
应用实施例8
操作同应用实施例7，氯化亚铜(1.0mg,0.01mmol),Xantphos(5.9mg,0.01mmol),叔丁醇钠(3.9mg,0.04mmol),联硼酸频那醇酯(61.0mg,0.24mmol),异丙醇(24.3mg,0.4mmol),(R)-3wb(90.7mg,0.2mmol)，乙醚(0.6mL)反应6小时得(R)-8(86.2mg,73％)，油状液体，[淋洗剂:石油醚/乙酸乙酯＝100/1,0.8L,石油醚/乙酸乙酯＝80/1,0.8L]，92％ee(HPLC conditions:Chiralcel IA-H column,hexane/i-PrOH＝99.6/0.4,1.0mL/min,λ＝214nm,tR(minor)＝7.2min,tR(major)＝7.8min)；[α]D 28＝-22.78(c＝1.74,CHCl3).1H NMR(400MHz,CDCl3)δ＝8.12(d,J＝2.0Hz,1H,ArH),7.74(d,J＝7.6Hz,1H,ArH),7.32-7.17(m,3H,ArH),7.05(d,J＝7.2Hz,1H,ArH),6.70(d,J＝8.0Hz,1H,ArH),5.75(d,J＝3.2Hz,1H,one proton of＝CH2),5.60-5.55(m,1H,one proton of＝CH2),2.43-2.28(m,2H,CH2),2.12-2.00(m,1H,one proton of CH2),1.96-1.85(m,1H,one proton of CH2),1.73(s,3H,CH3),1.65(s,9H,CH3×3),1.30-1.18(m,12H,CH3×4)；13C NMR(100MHz,CDCl3)δ＝176.5,149.2,140.8,137.4,137.0,132.2,131.1,130.3,127.8,127.7,127.6,126.0,124.8,121.5,118.1,84.7,83.5,56.1,38.5,29.6,28.1,24.8,20.0；IR(neat,cm-1):2979,2930,2868,1769,1731,1601,1474,1417,1369,1337,1311,1285,1243,1199,1141,1100,1065,1039,1010；MS(ESI):m/z 606[(M(81Br,11B)+Na)+],482[(M(79Br,11B)-Boc+H)+]；HRMSCalcd for C30H37 11B81Br NaNO5[(M+Na)+]:606.1820；Found:606.1815.
应用实施例9
分子对接筛选化合物对SRAS-CoV-2主蛋白3CL水解酶的活性：
分子对接采用药物分子设计软件首先，利用中的LigPrep模块，将所制备的化合物产生3个理论上结构优势的构象；然后，对SRAS-CoV-2主蛋白3CL水解酶的晶体复合物(PDB Code：6LU7)进行蛋白预处理，主要包括氨基酸修复、质子化、pH设为7.0等，其他设为默认参数。对接程序使用中的Glide模块，首先，产生蛋白受体Grid文件，定义所要对接的结合位点；然后，采用超高精度XP进行分子对接。根据打分函数Glide gscore排序(见下表2)，化合物(R)-5的对接打分最高为-7.8，并分析化合物(R)-5与SRAS-CoV-2主蛋白3CL水解酶的结合模式，其中，(R)-5的碘可以与Thr26的羰基形成O-pi相互作用，溴苯可以与Leu141和Met165形成疏水相互作用。结合模式如图1所示((R)-5：绿色球棍模型；3CL水解酶：浅粉色)：
表2
应用实施例10
3-(2,3-丁二烯基)氧化吲哚酮类化合物及其相关衍生物对SRAS-CoV-2主蛋白3CL水解酶的抑制活性。
重组的SARS-CoV-2主蛋白3CL水解酶(终浓度30nM)与浓度分别为10和1μM的化合物(R)-5和5稀释液混匀，稀释buffer为50mM Tris-HCl，pH 7.3，1mM EDTA，总体积80μL孵育10分钟。在反应液中加入20μM fluorogenic 40μL引发反应体系。再使用Bio-Tek Synergy4plate reader于320nm(激发)/405nm(发射)处，每隔30秒测量一次荧光信号，持续10分钟。计算不同浓度化合物以及空白对照DMSO的反应Vmax，计算化合物对3CL水解酶的抑制率。所有实验数据均采用GraphPad Prism软件进行分析(具体数据见下表3)。
表3
本发明并非局限于上面描述的具体实施例。在不背离发明设想的精神和范围下，对本发明进行的一些修改、添加、重写或者翻译也应当落入本发明权利要求的保护范畴内，并且以所附的权利要求书为保护范围。除此之外，尽管本说明书中使用了一些特定约束的术语，但这些术语只是为了方便说明，并不对本发明的保护范围构成任何限制。
- 上一篇：一种医用注射器针头装配设备
- 下一篇：用于预防或治疗脂质代谢相关疾病的化合物