CN113880750B - 一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法 - Google Patents
一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法 Download PDFInfo
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- CN113880750B CN113880750B CN202111260923.7A CN202111260923A CN113880750B CN 113880750 B CN113880750 B CN 113880750B CN 202111260923 A CN202111260923 A CN 202111260923A CN 113880750 B CN113880750 B CN 113880750B
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- substituted
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- aryl
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- oxindole
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- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 title claims description 21
- 238000001308 synthesis method Methods 0.000 title description 3
- -1 3-substituted-3-bromooxindole Chemical class 0.000 claims abstract description 31
- 239000003446 ligand Substances 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 150000001868 cobalt Chemical class 0.000 claims abstract description 9
- 239000000654 additive Substances 0.000 claims abstract description 7
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- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 6
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- 230000009471 action Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 127
- 239000002808 molecular sieve Substances 0.000 claims description 25
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 23
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
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- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
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- 230000035484 reaction time Effects 0.000 claims description 2
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- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- FJDJVBXSSLDNJB-LNTINUHCSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical group [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FJDJVBXSSLDNJB-LNTINUHCSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 77
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- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 4
- 238000001212 derivatisation Methods 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 238000005481 NMR spectroscopy Methods 0.000 description 53
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- 150000001875 compounds Chemical class 0.000 description 50
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- 238000002360 preparation method Methods 0.000 description 22
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- FCEOGYWNOSBEPV-FDGPNNRMSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FCEOGYWNOSBEPV-FDGPNNRMSA-N 0.000 description 20
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- 229940093499 ethyl acetate Drugs 0.000 description 9
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- ICZGTTIKIXUYGV-UHFFFAOYSA-N 2-(n-methylanilino)ethyl acetate Chemical compound CC(=O)OCCN(C)C1=CC=CC=C1 ICZGTTIKIXUYGV-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
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- 229910052739 hydrogen Inorganic materials 0.000 description 4
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- ACIADIFDPPYYRZ-UHFFFAOYSA-N 1,2,3,6-tetrahydropyrrolo[2,3-e]indole Chemical compound C1=C2NC=CC2=C2NCCC2=C1 ACIADIFDPPYYRZ-UHFFFAOYSA-N 0.000 description 3
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- 125000000753 cycloalkyl group Chemical group 0.000 description 3
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- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 2
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- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07D487/04—Ortho-condensed systems
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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Abstract
本发明涉及一种手性3‑取代‑3‑芳基氧化吲哚类化合物的合成方法，将消旋的3‑取代‑3‑溴氧化吲哚与N,N‑双取代苯胺，在催化剂、手性配体、碱、添加剂以及溶剂的共同作用下，进行不对称Friedel‑Crafts反应，合成手性3‑取代‑3‑芳基氧化吲哚类化合物。与现有技术相比，本发明方法采用廉价易得和环境友好的钴盐催化得到手性3‑取代‑3‑芳基氧化吲哚化合物，反应条件较温和，底物适用性广，为手性3‑取代‑3‑芳基氧化吲哚类化合物的合成提供了新的方法，合成的手性3‑取代‑3‑芳基氧化吲哚化合物通过简单的衍生化，可以得到几种重要活性天然产物的核心骨架，为该类天然产物的合成提供一种潜在的策略，具有很好的应用前景。
Description
技术领域
本发明属于有机化学合成技术领域，尤其是涉及一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法。
背景技术
3,3-双取代氧化吲哚是目前受到广泛关注的一类优势骨架，在药物研发中具有重要研究价值。其中，C3位含有全碳季碳中心的3-取代-3-芳基氧化吲哚作为重要的结构单元，在具有抗炎、抗菌、抗疟、抗病毒、抗肿瘤等生物活性化合物中广泛存在，一直是药物化学家研究的热点领域之一。此外，3-取代-3-芳基氧化吲哚也是重要的有机合成砌块，已被广泛地应用于具有呋喃并二氢吲哚、吡咯并二氢吲哚和苯并呋喃并二氢吲哚等骨架的天然产物分子的全合成研究中。因此，发展新的方法来高效合成手性3-取代-3-芳基氧化吲哚类化合物可以为天然产物和药物分子的合成提供新的思路。现有技术中，手性3-取代-3-芳基氧化吲哚的合成途径主要有：氧化吲哚衍生物C3位的直接官能团化、内酰胺的分子内偶联和吲哚化合物的氧化重排等。例如：2003年，Overman等通过钯催化的分子内的不对称Heck反应，可以由3-烷基-3-芳基氧辛酮类化合物合成具有全碳季碳中心的3取代-3-芳基氧化吲哚化合物(J.Am.Chem.Soc.2003,125,6261)，但产物的对映选择性相对较低，底物的合成难度较大，因而制约了反应的适用范围；2006年，Hayashi等人开发了芳基硼酸与靛红的不对称加成反应，可以合成手性的3-芳基-3-羟基-2-氧化吲哚化合物(Angew.Chem.Int.Ed.2006,45,3353)，该反应需要使用贵金属铑作为催化剂，提高了反应的成本；2008年，Movassaghi等人通过手性2-芳基色氨酸的立体选择性氧化重排，实现了手性3-芳基-3-烷基氧化吲哚的合成(Org.Lett.,2008,10,4009)，该方法需要事先在底物上引入手性中心，大大限制了底物适用范围。因此，本领域的技术人员希望能够对手性3-取代-3-芳基氧化吲哚的合成方法进行改进，获得合成效率更高、更廉价且更环保的合成方法。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种可重复性好，催化剂廉价易得，底物适用范围广，经济性好的手性3-取代-3-芳基氧化吲哚类化合物的合成方法。
本发明的目的可以通过以下技术方案来实现：
一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法，该方法将消旋的3-取代-3-溴氧化吲哚与N,N-双取代苯胺，在钴盐催化剂、手性配体、碱、添加剂以及溶剂的共同作用下，进行不对称Friedel-Crafts反应，合成手性3-取代-3-芳基氧化吲哚类化合物。
合成路线如下：
所述的3-取代-3-溴氧化吲哚的化学结构式为：
所述的N,N-双取代苯胺的化学结构式为：
所述的手性3-取代-3-芳基氧化吲哚类化合物的化学结构式为：
其中，R1、R3选自H、烷基、烷氧基或卤素取代基；
R2选自烷基、支链烷基、环烷基、芳香基、含取代基的芳香基或杂环基；
R4、R5选自烷基、支链烷基、环烷基、杂环基、链状酯基、烯丙基或芳基。
优选地，所述手性配体包括：
其中，R1选自烷基、支链烷基、环烷基或杂环基；
R2选自H或三氟甲基；
R3、R5选自烷基、支链烷基或芳基；
R4选自H、烷基、支链烷基或芳基；
Ar选自芳基。
优选地，所述的钴盐催化剂包括醋酸钴(II)、四水合醋酸钴(II)、六水合硝酸钴(II)、高氯酸钴(II)、六水合四氟硼酸钴(II)、碳酸钴(II)、氯化钴(II)、乙酰丙酮钴(II)、乙酰丙酮钴(III)、双(三氟-2,4-戊二酮)钴(II)或双(2,2,6,6-四甲基-3,5-庚烷二酮)钴(II)中的一种，进一步优选乙酰丙酮钴(II)。
优选地，所述的碱包括碳酸锂、碳酸钠、碳酸钾、碳酸铯、磷酸钠、磷酸钾、碳酸氢钠、碳酸氢钾、磷酸氢二钠、磷酸氢二钾、磷酸二氢钾、三乙胺、N,N-二异丙基乙胺、二异丙胺、三乙烯二胺、4-二甲氨基吡啶或1,8-二偶氮杂双螺环[5.4.0]十一-7-烯中的一种，进一步优选碳酸铯。
优选地，所述的添加剂包括
分子筛、
分子筛、
分子筛、无水硫酸钠、无水硫酸镁、氯化钙、氢化钙或乙酰丙酮中的一种，优选
分子筛。
优选地，所述的有机溶剂包括二氯甲烷、二氯乙烷、三氯甲烷、四氯化碳、1,1,2,2-四氯乙烷、甲苯、乙腈、乙醚、四氢呋喃、1,4-二氧六环、甲醇或N,N-二甲基乙酰胺中的一种，进一步优选二氯甲烷。
优选地，所述的消旋3-取代-3-溴氧化吲哚、N,N-双取代苯胺、钴盐催化剂、手性配体、碱的摩尔比为1.0:1.0～1.5:0.02～0.2:0.02～0.2:0.2～2.0。
优选地，所述的添加剂在溶剂中的浓度为50～100mg/mL。
优选地，所述的消旋的3-取代-3-溴氧化吲哚在溶剂中的浓度为0.02～0.2mol/L。
优选地，所述的不对称Friedel-Crafts反应的温度为-60～30℃，反应时间为1～72h。
本发明方法的设计思路是消旋的3-取代-3-溴氧化吲哚在碱的作用下形成一种氮杂二烯中间体，在钴盐、手性配体的催化下，氮杂二烯中间体与N,N-双取代苯胺发生不对称Fridel-Crafts反应，高效合成手性的3-取代-3-芳基氧化吲哚类化合物。
与现有技术相比，本发明具有以下特点：
1)本发明方法采用廉价环保的金属钴盐作为催化剂，避免了传统工艺中贵金属的使用；
2)本发明方法的反应条件相对简单，底物适用范围广，化学产率较高，对映选择性好，为手性3-取代-3-苯胺氧化吲哚类化合物的合成提供了新的途径；
3)本发明方法可用于几种重要的活性天然产物核心骨架的高效合成，具有较好的应用性。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
本实施方式中，化合物的氢核磁共振谱(1H NMR)由Bruker AVANCE III HD 400测定；质谱(ESI-MS)由Waters ACQUITYTM UPLC&Q-TOF MS Premier测定；旋光由RUDOLPHA21202-J APTV/GW测定；ee值(enantiomeric excesses)由Agilent 1260Infinity IIHPLC测定。所用试剂均为市售试剂。
本发明的合成方法可以制备如下所示的3-取代-3-苯胺氧化吲哚类化合物：
实施例1：化合物(1)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体L5(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N,N-二甲基苯胺(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到白色固体1，收率为95％，ee值为92％。
化合物(1)为：
1H NMR(500MHz,Chloroform-d)δ8.33(s,1H),7.34(d,J＝8.8Hz,2H),7.18(d,J＝7.3Hz,1H),7.13(t,J＝7.3Hz,1H),7.10–6.99(m,4H),6.93(d,J＝6.9Hz,2H),6.69(t,J＝9.1Hz,3H),3.70(d,J＝13.0Hz,1H),3.45(d,J＝12.9Hz,1H),2.93(s,6H).(400MHz,Chloroform-d)13C NMR(100MHz,Chloroform-d)δ180.9,149.7,141.0,136.0,132.3,130.1,127.8,127.8,127.5,127.3,126.4,125.7,121.8,112.6,109.8,57.8,43.4,40.5.HRMS(ESI):m/z calculated for C23H23N2O[M+H]+343.1810,found 343.1813.
(c1,DCM).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.6min,tR(minor)＝12.8min.
实施例2：化合物(2)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N,N-二烯丙基苯胺(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体2，收率为93％，ee值为93％。
化合物(2)为：
1H NMR(400MHz,Chloroform-d)δ8.53(s,1H),7.29(d,J＝8.7Hz,2H),7.21(d,J＝7.3Hz,1H),7.14(t,J＝7.6Hz,1H),7.10–6.99(m,4H),6.94(d,J＝7.3Hz,2H),6.68(t,J＝8.9Hz,3H),5.93–5.76(m,2H),5.24–5.11(m,4H),3.91(d,J＝4.3Hz,4H),3.71(d,J＝12.9Hz,1H),3.43(d,J＝12.9Hz,1H).13C NMR(100MHz,Chloroform-d)δ180.9,147.8,141.0,136.0,133.8,132.3,130.1,127.8,127.7,127.5,126.9,126.4,125.7,121.8,116.0,112.2,109.7,57.9,52.6,43.4.HRMS(ESI):m/z calculated for C27H27N2O[M+H]+395.2123,found 395.2133.
(c 1,DCM,ee 93％).HPLC(Daicel ChiralpakOD-H,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.4min,tR(minor)＝8.3min.
实施例3：化合物(3)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N,N-二(乙基甲醚)苯胺(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到白色固体3，收率为86％，ee值为92％。
化合物(3)为：
1H NMR(500MHz,Chloroform-d)δ8.59(s,1H),7.30(d,J＝8.3Hz,2H),7.19(d,J＝7.3Hz,1H),7.13(t,J＝7.6Hz,1H),7.08–6.99(m,4H),6.93(d,J＝7.4Hz,2H),6.67(t,J＝8.0Hz,3H),3.70(d,J＝13.0Hz,1H),3.54(s,8H),3.43(d,J＝12.9Hz,1H),3.35(s,6H).13CNMR(100MHz,Chloroform-d)δ180.8,146.9,141.0,136.0,132.2,130.1,128.0,127.8,127.5,126.8,126.4,125.7,121.9,111.6,109.7,70.0,58.9,57.8,50.8,43.4.HRMS(ESI):m/z calculated for C27H31N2O3[M+H]+431.2335,found 431.2333.
(c 1,DCM,ee 92％).HPLC(Daicel Chiralpak AD-H,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(minor)＝8.6min,tR(major)＝9.6min.
实施例4：化合物(4)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-苯基哌啶(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到白色固体4，收率为86％，ee值为90％。
化合物(4)为：
1H NMR(400MHz,Chloroform-d)δ8.80(s,1H),7.30(d,J＝8.8Hz,2H),7.11(t,J＝7.3Hz,2H),7.05(d,J＝12.2Hz,1H),7.02–6.96(m,3H),6.89(d,J＝7.2Hz,2H),6.85(d,J＝8.8Hz,2H),6.62(d,J＝7.6Hz,1H),3.64(d,J＝12.9Hz,1H),3.42(d,J＝12.9Hz,1H),3.17–3.03(m,4H),1.65(q,J＝5.6Hz,4H),1.54(q,J＝6.0Hz,2H).13C NMR(100MHz,Chloroform-d)δ180.9,151.1,141.0,135.9,132.1,130.1,129.7,127.8,127.7,127.5,126.4,125.6,121.8,116.2,109.8,57.9,50.2,43.4,25.6,24.2.HRMS(ESI):m/z calculated forC26H27N2O[M+H]+383.2123,found 383.2114.
(c 1,DCM,ee 90％).HPLC(Daicel Chiralpak OD-H,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.3min,tR(minor)＝12.4min.
实施例5：化合物(5)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-苯基吗啉(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到白色固体5，收率为84％，ee值为90％。
化合物(5)为：
1H NMR(500MHz,Chloroform-d)δ8.53(s,1H),7.37(d,J＝8.8Hz,2H),7.18–7.12(m,2H),7.08–6.99(m,4H),6.91(d,J＝7.3Hz,2H),6.86(d,J＝8.9Hz,2H),6.68(d,J＝7.7Hz,1H),3.89–3.80(m,4H),3.67(d,J＝13.0Hz,1H),3.45(d,J＝12.9Hz,1H),3.17–3.09(m,4H).13C NMR(100MHz,Chloroform-d)δ180.5,150.3,140.9,135.8,131.9,130.8,130.1,128.0,127.9,127.5,126.5,125.7,121.9,115.5,109.8,66.8,57.9,49.0,43.4.HRMS(ESI):m/z calculated for C25H25N2O2[M+H]+385.1916,found 385.1917.
(c1,DCM,ee 90％).HPLC(Daicel Chiralpak OD-H,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝6.2min,tR(minor)＝23.2min.
实施例6：化合物(6)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到白色固体6，收率为85％，ee值为94％。
化合物(6)为：
1H NMR(400MHz,Chloroform-d)δ8.62(s,1H),7.33(d,J＝8.7Hz,2H),7.18–7.10(m,2H),7.10–6.98(m,4H),6.92(d,J＝7.2Hz,2H),6.71–6.59(m,3H),4.18(q,J＝7.1Hz,2H),4.03(s,2H),3.67(d,J＝12.9Hz,1H),3.43(d,J＝12.9Hz,1H),3.05(s,3H),1.25(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ180.8,170.9,148.0,141.0,136.0,132.1,130.1,128.0,127.9,127.8,127.5,126.3,125.7,121.8,112.2,109.8,60.8,57.8,54.3,43.4,39.4,14.2.HRMS(ESI):m/z calculated for C26H27N2O3[M+H]+415.2022,found415.2043.
(c 1,DCM,ee 94％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝5.2min,tR(minor)＝12.8min.
实施例7：化合物(7)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-苯基苯胺(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到白色固体7，收率为91％，ee值为90％。
化合物(7)为：
1H NMR(400MHz,Chloroform-d)δ8.33(s,1H),7.40–7.33(m,2H),7.32–7.26(m,2H),7.21(d,J＝7.4Hz,1H),7.18–7.13(m,1H),7.11–6.89(m,11H),6.71(d,J＝7.7Hz,1H),3.71(d,J＝12.9Hz,1H),3.47(d,J＝12.9Hz,1H),3.31(s,3H).13C NMR(100MHz,Chloroform-d)δ180.5,148.6,148.1,140.9,135.8,132.0,131.5,130.1,129.2,128.0,127.8,127.6,126.5,125.7,122.0,121.9,121.3,119.3,109.8,58.1,43.5,40.1.HRMS(ESI):m/z calculated for C28H25N2O[M+H]+405.1967,found 405.1966.
(c1,DCM,ee 90％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝8.8min,tR(minor)＝12.7min.
实施例8：化合物(8)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入3-甲氧基-N,N-二甲基苯胺(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到白色固体8，收率为80％，ee值为90％。
化合物(8)为：
1H NMR(400MHz,Methylene Chloride-d2)δ7.52(d,J＝8.7Hz,1H),7.28(s,1H),7.11–6.98(m,5H),6.98–6.90(m,1H),6.77(d,J＝7.1Hz,2H),6.53(d,J＝7.7Hz,1H),6.45(dd,J＝8.7,2.5Hz,1H),6.21(d,J＝2.4Hz,1H),3.57–3.44(m,2H),3.43(s,3H),2.97(s,6H).13C NMR(100MHz,Methylene Chloride-d2)δ158.4,151.9,141.9,135.9,134.7,130.7,128.0,127.6,127.5,126.7,123.6,122.0,118.6,108.7,105.2,98.2,55.8,42.6,40.8.HRMS(ESI):m/z calculated for C24H25N2O2[M+H]+373.1916,found 373.1911.
(c 1,DCM,ee 90％).HPLC(Daicel Chiralpak OD-H,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.1min,tR(minor)＝11.2min.
实施例9：化合物(9)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入3-氟-N,N-二甲基苯胺(0.24mmol,1.2equiv)，3-溴-3-苄基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体9，收率为78％，ee值为93％。
化合物(9)为：
1H NMR(400MHz,Chloroform-d)δ8.22(s,1H),7.44(t,J＝8.9Hz,1H),7.16(d,J＝7.2Hz,1H),7.13–6.95(m,5H),6.87(d,J＝7.4Hz,2H),6.52(dd,J＝14.9,8.2Hz,2H),6.34(d,J＝15.0Hz,1H),3.61(s,2H),2.92(s,6H).13C NMR(100MHz,Chloroform-d)δ180.3,161.5,151.4,140.8,134.8,133.1,130.2,128.3,127.6,127.4,126.5,123.8,122.0,114.7,109.4,107.7,100.2,55.0,41.7,40.2.HRMS(ESI):m/z calculated for C23H22FN2O[M+H]+361.1716,found 361.1707.
(c 1,DCM,ee 93％).HPLC(DaicelChiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.7min,tR(minor)＝15.2min.
实施例10：化合物(10)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3-溴-3-(4-氯苄基)氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体10，收率为85％，ee值为94％。
化合物(10)为：
1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.29(d,J＝8.7Hz,2H),7.17–7.10(m,2H),7.04(d,J＝7.5Hz,1H),7.00(d,J＝8.2Hz,2H),6.83(d,J＝8.2Hz,2H),6.68(d,J＝8.0Hz,1H),6.62(d,J＝8.7Hz,2H),4.16(q,J＝7.1Hz,2H),4.02(s,2H),3.61(d,J＝13.0Hz,1H),3.37(d,J＝13.0Hz,1H),3.04(s,3H),1.24(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ180.4,170.8,148.1,140.9,134.5,132.3,131.8,131.5,128.0,127.9,127.6,127.6,125.6,122.0,112.2,109.9,60.9,57.6,54.3,42.7,39.4,14.2.HRMS(ESI):m/z calculated for C26H26ClN2O3[M+H]+449.1632,found 449.1667.
(c 1,DCM,ee 94％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝5.8min,tR(minor)＝13.2min.
实施例11：化合物(11)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3-溴-3-(4-甲氧基苄基)氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体11，收率为90％，ee值为93％。
化合物(11)为：
1H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.31(d,J＝8.8Hz,2H),7.13(t,J＝7.8Hz,2H),7.02(t,J＝7.5Hz,1H),6.81(d,J＝8.5Hz,2H),6.68(d,J＝7.6Hz,1H),6.63(d,J＝8.8Hz,2H),6.56(d,J＝8.5Hz,2H),4.17(q,J＝7.1Hz,2H),4.02(s,2H),3.66(s,3H),3.59(d,J＝13.1Hz,1H),3.37(d,J＝13.1Hz,1H),3.04(s,3H),1.24(t,J＝7.1Hz,3H).13CNMR(100MHz,Chloroform-d)δ180.6,170.9,158.0,148.0,140.9,132.3,131.1,128.0,128.0,127.9,127.8,125.7,121.8,112.9,112.2,109.7,60.8,57.8,54.9,54.3,42.7,39.4,14.2.HRMS(ESI):m/z calculated for C27H29N2O4[M+H]+445.2127,found 445.2129.
(c1,DCM,ee 93％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝5.9min,tR(minor)＝14.6min.
实施例12：化合物(12)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3-溴-3-(2-萘甲基)氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体12，收率为87％，ee值为95％。
化合物(12)为：
1H NMR(400MHz,Chloroform-d)δ8.18(s,1H),7.73–7.66(m,1H),7.65–7.58(m,1H),7.49(d,J＝8.4Hz,1H),7.41(s,1H),7.39–7.31(m,4H),7.20(d,J＝7.2Hz,1H),7.12–6.98(m,3H),6.63(d,J＝8.6Hz,2H),6.56(d,J＝7.5Hz,1H),4.18(q,J＝7.1Hz,2H),4.04(s,2H),3.79(d,J＝13.0Hz,1H),3.56(d,J＝13.0Hz,1H),3.04(s,3H),1.25(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ180.4,170.9,148.0,140.9,133.7,132.9,132.1,132.0,129.0,128.5,127.9,127.9,127.7,127.3,126.8,125.8,125.4,125.3,121.8,112.2,109.8,60.8,57.7,54.3,43.6,39.4,14.2.HRMS(ESI):m/z calculated forC27H29N2O4[M+H]+445.2127,found 445.2129.
(c 1,DCM,ee 95％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝6.2min,tR(minor)＝14.6min.
实施例13：化合物(13)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3-溴-3-(噻吩甲基)氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体13，收率为89％，ee值为95％。
化合物(13)为：
1H NMR(400MHz,Chloroform-d)δ8.86(s,1H),7.32(d,J＝8.5Hz,2H),7.20(t,J＝7.5Hz,1H),7.11(d,J＝7.3Hz,1H),7.05(t,J＝7.4Hz,1H),6.93(d,J＝5.0Hz,1H),6.79(d,J＝7.7Hz,1H),6.72(t,J＝4.1Hz,1H),6.64(d,J＝8.4Hz,3H),4.17(q,J＝7.1Hz,2H),4.03(s,2H),3.84(d,J＝14.3Hz,1H),3.66(d,J＝14.3Hz,1H),3.05(s,3H),1.24(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ180.7,170.8,148.1,141.4,137.9,131.9,128.1,127.9,127.2,127.1,126.0,125.5,124.2,122.0,112.2,110.0,60.8,57.3,54.2,39.4,37.8,14.1.HRMS(ESI):m/z calculated for C24H25N2O3S[M+H]+421.1586,found421.1612.
(c 1,DCM,ee 95％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝6.2min,tR(minor)＝14.6min.
实施例14：化合物(14)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3-溴-3-(环己基甲基)氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体14，收率为71％，ee值为94％。
化合物(14)为：
1H NMR(400MHz,Chloroform-d)δ8.52(s,1H),7.25–7.15(m,4H),7.06(t,J＝7.5Hz,1H),6.92(d,J＝7.7Hz,1H),6.57(d,J＝8.9Hz,2H),4.14(q,J＝7.1Hz,2H),3.99(s,2H),3.01(s,3H),2.38(dd,J＝13.9,6.8Hz,1H),2.09(dd,J＝13.9,5.0Hz,1H),1.60–1.44(m,4H),1.22(t,J＝7.1Hz,3H),1.05–0.92(m,4H),0.91–0.78(m,1H).13C NMR(100MHz,Chloroform-d)δ182.0,170.9,147.8,141.0,133.1,129.8,127.7,127.4,125.4,122.1,112.1,109.9,60.8,55.7,54.3,44.8,39.4,34.8,34.7,33.7,26.1,26.1,26.0,14.2.HRMS(ESI):m/z calculated for C26H33N2O3[M+H]+421.2491,found 421.2498.
(c1,DCM,ee 94％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.4min,tR(minor)＝8.6min.
实施例15：化合物(15)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3-溴-3-(乙酸乙酯基)氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体15，收率为98％，ee值为85％，经过异丙醇重结晶后化合物15的ee为93％。
化合物(15)为：
1H NMR(400MHz,Chloroform-d)δ9.03(s,1H),7.26–7.19(m,2H),7.19–7.13(m,2H),7.04(t,J＝7.5Hz,1H),6.92(d,J＝7.7Hz,1H),6.64(d,J＝9.0Hz,2H),3.97–3.84(m,2H),3.58(d,J＝15.9Hz,1H),3.21(d,J＝15.9Hz,1H),2.89(s,6H),0.98(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ181.0,169.8,149.8,141.9,132.1,128.2,127.1,126.4,124.5,122.1,112.5,110.1,60.5,53.1,41.7,40.3,13.7.HRMS(ESI):m/z calculated forC20H23N2O3[M+H]+339.1709,found 339.1701.
(c 1,DCM,ee 93％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝6.1min,tR(minor)＝19.4min.
实施例16：化合物(16)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3-苄基-3-溴-4-氟氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体16，收率为52％，ee值为96％。
化合物(16)为：
1H NMR(400MHz,Chloroform-d)δ8.10(s,1H),7.31–7.26(m,2H),7.12–7.02(m,4H),6.89(dd,J＝7.9,1.3Hz,2H),6.76–6.67(m,1H),6.67–6.59(m,2H),6.42(dd,J＝8.8,2.3Hz,1H),4.17(q,J＝7.1Hz,2H),4.03(s,2H),3.65(d,J＝13.0Hz,1H),3.38(d,J＝13.0Hz,1H),3.05(s,3H),1.24(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ180.7,170.9,162.5,148.2,142.0,135.8,130.1,127.9,127.7,127.6,127.5,126.8,126.6,112.2,108.4,98.2,60.9,57.4,54.3,43.6,39.4,14.2.HRMS(ESI):m/z calculated forC26H26FN2O3[M+H]+433.1927,found 433.1928.
(c 1,DCM,ee 96％).HPLC(Daicel Chiralpak OD-H,hexane/i-PrOH＝60:40,0.5mL/min,254nm):tR(major)＝12.2min,tR(minor)＝44.7min.
实施例17：化合物(17)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N-甲基-N-乙酸乙酯基苯胺(0.24mmol,1.2equiv)，3,5-二溴3-(2-(三异丙基硅基氧基)乙基)氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体17，收率为74％，ee值为94％。
化合物(17)为：
1H NMR(400MHz,Chloroform-d)δ9.35(s,1H),7.33(dd,J＝8.2,1.7Hz,1H),7.27(d,J＝1.5Hz,1H),7.14(d,J＝8.8Hz,2H),6.79(d,J＝8.2Hz,1H),6.59(d,J＝8.9Hz,2H),4.15(q,J＝7.1Hz,2H),4.00(s,2H),3.66–3.47(m,2H),3.02(s,3H),2.81–2.67(m,1H),2.45–2.29(m,1H),1.23(t,J＝7.1Hz,3H),0.96(s,21H).13C NMR(100MHz,Chloroform-d)δ181.3,170.8,148.1,140.3,135.1,130.7,128.1,127.9,127.4,114.8,112.2,111.6,60.9,59.7,54.7,54.2,39.6,39.4,17.9,14.2,11.9.HRMS(ESI):m/z calculated forC30H44BrN2O4Si[M+H]+603.2254,found 603.2263.
(c 1,DCM,ee 94％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.1min,tR(minor)＝11.9min.
实施例18：化合物(18)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入N,N-二甲基苯胺(0.24mmol,1.2equiv)，3-溴-3-(N-乙基邻苯二甲酰亚胺)-5-甲氧基氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应12小时，然后将反应液旋干，柱层析纯化得到黄色固体18，收率为92％，ee值为91％。
化合物(18)为：
1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.71(dd,J＝5.4,3.1Hz,2H),7.64(dd,J＝5.4,3.0Hz,2H),7.21(d,J＝8.9Hz,2H),6.84(d,J＝2.4Hz,1H),6.76(d,J＝8.5Hz,1H),6.61(d,J＝8.9Hz,2H),6.56(dd,J＝8.5,2.5Hz,1H),3.82–3.75(m,1H),3.69–3.63(m,4H),2.86(s,6H),2.81–2.75(m,1H),2.71–2.64(m,1H).13C NMR(100MHz,Chloroform-d)δ180.2,167.9,155.6,149.7,134.1,133.6,133.5,132.0,127.3,126.7,122.9,112.9,112.5,111.6,110.7,55.5,55.2,40.4,34.6,34.3.HRMS(ESI):m/z calculated forC27H26N3O4[M+H]+456.1923,found 456.1916.
(c 1,DCM,ee 91％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝15.0min,tR(minor)＝18.3min.
实施例19：化合物(19)的制备
干燥的反应管中加入乙酰丙钴(II)(0.02mmol,10mol％)、手性配体(0.024mmol,12mol％)和超干二氯甲烷(2.0mL)，室温下搅拌20分钟。随后，将反应管置于低温反应器中，降至-20℃，加入3-((4-甲氧基)苄基)-N,N-二甲基苯胺(0.24mmol,1.2equiv)，3-取代-3-Br-氧化吲哚(0.2mmol,1.0equiv)，碳酸铯(0.2mmol,1.0equiv)和
分子筛(100mg)，反应48小时，然后将反应液旋干，柱层析纯化得到白色固体19，收率为80％，ee值为74％，经过异丙醇重结晶后化合物19的ee为99％。
化合物(19)为：
1H NMR(400MHz,Chloroform-d)δ7.54(d,J＝8.7Hz,1H),7.05–6.88(m,8H),6.77–6.71(m,4H),6.47–6.38(m,2H),6.24(s,1H),6.13(d,J＝7.8Hz,1H),4.71(d,J＝10.5Hz,1H),4.61(d,J＝10.5Hz,1H),3.76(s,3H),3.49(s,2H),2.93(s,6H).13C NMR(100MHz,Chloroform-d)δ180.9,159.2,156.7,151.2,141.3,135.1,134.0,130.2,129.8,128.4,127.6,127.2,126.8,126.2,123.0,121.5,113.3,108.6,104.6,97.7,69.7,55.2,54.9,42.2,40.6.HRMS(ESI):m/z calculated for C31H31N2O3[M+H]+479.2335,found 479.2331.
(c 1,DCM,ee 99％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.7min,tR(minor)＝6.3min.
实施例20：化合物(20)的制备
将实施例15进行衍生化，合成呋喃并二氢吲哚类化合物20，合成路线如下：
第一步：将化合物15(0.20mmol，1.0equiv，93％ee)溶于四氢呋喃(2mL)，依次加入碳酸铯(0.60mmol，3.0equiv)和碘甲烷(1.20mmol，6.0equiv)，于室温下反应5小时。反应结束后过滤，滤液旋干，柱层析(石油醚/乙酸乙酯＝4/1)纯化得到中间产物15a，收率为91％，ee值为92％。
第二步：氩气氛围下，将15a(0.1mmol，1.0equiv，92％ee)溶于超干四氢呋喃(6mL)，在0℃下加入氢化铝锂(0.4mmol，4.0equiv)，随后继续在该温度下反应2小时，反应结束后，小心加入饱和食盐水，直至无氢气放出，然后用乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，减压除去溶剂，经柱层析(石油醚/乙酸乙酯＝20/1)纯化得到化合物20，收率为95％，ee值为92％。
化合物(15a)为：
1H NMR(400MHz,Chloroform-d)δ7.36–7.27(m,2H),7.18(d,J＝9.0Hz,2H),7.09(td,J＝7.6,0.9Hz,1H),6.89(d,J＝7.8Hz,1H),6.67–6.60(m,2H),3.95–3.78(m,2H),3.58(d,J＝16.0Hz,1H),3.24–3.16(m,4H),2.89(s,6H),0.97(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ178.5,169.7,149.8,144.5,131.4,128.3,127.2,126.4,124.3,122.1,112.4,108.0,60.3,52.4,42.1,40.3,26.4,13.8.HRMS(ESI):m/z calculated forC21H25N2O3[M+H]+353.1865,found 353.1869.
(c 1,DCM,ee 92％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝70:30,0.5mL/min,254nm):tR(major)＝13.3min,tR(minor)＝15.4min.
化合物(20)为：
1H NMR(400MHz,Chloroform-d)δ7.24–7.19(m,2H),7.18–7.12(m,1H),7.06–7.00(m,1H),6.75–6.66(m,3H),6.47(d,J＝7.8Hz,1H),5.39(s,1H),4.19–4.10(m,1H),3.61–3.51(m,1H),2.98(s,3H),2.93(s,6H),2.79–2.68(m,1H),2.45(dd,J＝11.9,4.5Hz,1H).13CNMR(100MHz,Chloroform-d)δ150.9,149.3,133.6,131.7,128.1,126.9,124.1,117.5,112.7,105.6,105.3,68.1,59.9,40.8,40.6,30.7.HRMS(ESI):m/z calculated forC19H23N2O[M+H]+295.1810,found 295.1818.
(c 1,DCM,ee 92％).HPLC(Daicel Chiralpak AD-H,hexane/i-PrOH＝80:20,1.0mL/min,254nm):tR(major)＝4.5min,tR(minor)＝5.3min.
实施例21：化合物(21)的制备
将实施例18进行衍生化，合成吡咯并二氢吲哚类化合物21，合成路线如下：
第一步：将化合物18(1.0equiv，98％ee)和乙二胺(2mmol，10.0equiv)溶于正丁醇(2mL)，于室温下反应14小时，然后减压除去溶剂，经柱层析(二氯甲烷/甲醇＝20/1)纯化得到中间产物游离的二胺。随后，将中间产物溶于干燥的二氯甲烷(2mL)，依次加入三乙胺(0.8mmol,4.0equiv)和二碳酸二叔丁酯(0.8mmol，4.0equiv)，室温下反应4小时，反应结束后减压除去溶剂，柱层析纯化得到中间产物18a，收率为72％，ee为97％。
第二步：氩气氛围下，将18a(0.1mmol，1.0equiv，97％ee)溶于超干四氢呋喃(4mL)，将反应体系置于-78℃环境，然后分批滴入三乙基硼氢化锂的四氢呋喃溶液(1.0Min THF，0.25mmol，2.5equiv)，在该温度搅拌反应15分钟，然后升至0℃继续反应15分钟。反应结束后，小心滴入饱和食盐水，直至无氢气释放，随后用乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤，旋干，柱层析(石油醚/乙酸乙酯＝10/1)纯化得到吡咯并二氢吲哚类化合物21，收率为92％，ee为97％。
化合物(18a)为：
1H NMR(400MHz,Chloroform-d)δ7.84(d,J＝8.8Hz,1H),7.14(d,J＝8.9Hz,2H),6.87(dd,J＝8.9,2.5Hz,1H),6.79(d,J＝2.5Hz,1H),6.66(d,J＝8.8Hz,2H),4.39(s,1H),3.80(s,3H),3.00–2.87(m,8H),2.72–2.61(m,1H),2.40–2.26(m,1H),1.60(s,9H),1.38(s,9H).13C NMR(100MHz,Chloroform-d)δ177.1,157.0,155.5,149.6,149.4,133.1,131.6,127.6,116.3,113.4,112.7,110.9,84.0,79.2,55.6,54.9,40.6,37.7,37.1,28.3,28.1.HRMS(ESI):m/z calculated for C29H40N3O6[M+H]+526.2917,found 526.2922.
(c 1,DCM,ee 98％).HPLC(Daicel Chiralpak AD-H,hexane/i-PrOH＝80:20,1.0mL/min,254nm):tR(major)＝6.4min,tR(minor)＝13.1min.
化合物(21)为：
1H NMR(400MHz,Chloroform-d)δ7.39(s,1H),7.11(d,J＝8.8Hz,2H),6.76(d,J＝8.5Hz,2H),6.65(d,J＝8.8Hz,2H),5.83(s,1H),3.77(s,3H),3.24–3.16(m,1H),3.06–2.95(m,1H),2.90(s,6H),2.50(s,1H),2.28–2.18(m,1H),1.57(s,9H),1.41(s,9H).13C NMR(100MHz,Chloroform-d)δ155.9,155.7,149.2,135.9,134.0,131.9,127.2,115.1,112.9,112.5,111.4,92.2,82.1,78.9,55.6,53.5,40.5,37.7,34.8,28.4.HRMS(ESI):m/zcalculated for C29H40N3O5[M+H]+510.2968,found 510.2976.
(c 1,DCM,ee98％).HPLC(Daicel Chiralpak AD-H,hexane/i-PrOH＝80:20,1.0mL/min,254nm):tR(major)＝10.0min,tR(minor)＝14.1min.
实施例22：化合物(22)的制备
将实施例19进行衍生化，合成苯并呋喃并二氢吲哚类化合物22，合成路线如下：
第一步：将化合物19(0.3mmol，1.0equiv，99％ee)和Pd/C(10％Pd，14.5mg，10％)溶于甲醇(15mL)，抽真空，置换氢气，于室温下反应16小时。反应毕，减压除去溶剂，经柱层析(石油醚/乙酸乙酯＝10/1)纯化得到中间产物19a，收率为82％，ee为98％。
第二步：氩气保护下，将19a(0.25mmol，1.0equiv，98％ee)溶于超干四氢呋喃(5mL)，将反应体系置于0℃环境，然后加入四氢铝锂(1.25mmol，5.0equiv)，在该温度下继续反应15分钟，然后升至70℃反应16小时。反应结束后，小心滴入饱和食盐水，直至无氢气释放，随后用乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤，旋干，柱层析(石油醚/乙酸乙酯＝10/1)纯化得到中间产物19b，收率为90％，ee值为98％。
第三步：0℃下，将19b(0.22mmol，1.0equiv，98％ee)溶于超二氯甲烷(5mL)，加入偶氮二甲酸二异丙酯(0.26mmol，1.2equiv)，然后升至室温反应30分钟。反应结束后，减压除去溶剂，经柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物22，收率为75％，ee值为98％。
化合物(19a)为：
1H NMR(400MHz,Chloroform-d)δ10.44(s,1H),7.89(s,1H),7.26–7.20(m,2H),7.20–7.14(m,1H),7.10–7.00(m,3H),6.89(d,J＝8.8Hz,1H),6.84(d,J＝6.6Hz,2H),6.77(d,J＝7.6Hz,1H),6.50(d,J＝2.7Hz,1H),6.17(dd,J＝8.8,2.7Hz,1H),3.96(d,J＝13.4Hz,1H),3.41(d,J＝13.4Hz,1H),2.93(s,6H).13C NMR(100MHz,Chloroform-d)δ183.4,157.5,151.8,140.1,135.7,130.3,130.2,129.2,128.4,127.6,127.5,126.6,122.4,111.6,110.4,104.6,104.0,59.1,41.3,40.3.HRMS(ESI):m/z calculated for C23H23N2O2[M+H]+359.1760,found 359.1768.
(c 1,DCM,ee 98％).HPLC(DaicelChiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝4.7min,tR(minor)＝7.1min.
化合物(19b)为：
1H NMR(400MHz,Chloroform-d)δ7.32(d,J＝8.6Hz,1H),7.16–7.11(m,3H),7.07(t,J＝6.7Hz,2H),6.94(dd,J＝6.5,3.0Hz,2H),6.84(t,J＝7.5Hz,1H),6.68(d,J＝8.8Hz,1H),6.33–6.22(m,2H),3.80–3.64(m,3H),3.52(d,J＝14.3Hz,1H),2.89(s,6H).13C NMR(100MHz,Chloroform-d)δ156.1,150.4,148.2,138.1,134.2,130.4,128.0,127.8,127.7,126.1,124.7,120.8,120.0,111.3,104.5,102.2,56.7,51.2,44.1,40.5.HRMS(ESI):m/zcalculated for C23H25N2O[M+H]+345.1967,found 345.1965.
(c 1,DCM,ee98％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,0.5mL/min,254nm):tR(major)＝9.7min,tR(minor)＝10.9min.
化合物(22)为：
1H NMR(400MHz,Chloroform-d)δ7.28(s,1H),7.23(d,J＝8.3Hz,1H),7.18–7.13(m,3H),7.04–6.98(m,1H),6.94(dd,J＝6.6,2.8Hz,2H),6.79(t,J＝7.4Hz,1H),6.55(d,J＝7.8Hz,1H),6.34(d,J＝8.0Hz,1H),6.18(d,1H),6.15(s,1H),4.77(s,1H),3.43–3.31(m,2H),2.89(s,6H).13C NMR(100MHz,Acetone-d6)δ161.7,152.6,149.5,138.4,134.5,131.2,128.8,128.5,127.2,124.5,123.8,121.1,119.2,109.3,106.1,102.4,95.1,61.4,43.8,41.0.HRMS(ESI):m/z calculated for C23H23N2O[M+H]+343.1810,found 343.1817.
(c 1,DCM,ee 98％).HPLC(Daicel Chiralpak IB,hexane/i-PrOH＝60:40,1.0mL/min,254nm):tR(major)＝8.2min,tR(minor)＝9.0min.
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。
Claims (4)
1.一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法，其特征在于，该方法将消旋的3-取代-3-溴氧化吲哚与N,N-双取代苯胺，在钴盐催化剂、手性配体、碱、添加剂以及溶剂的共同作用下，进行不对称Friedel-Crafts反应，合成手性3-取代-3-芳基氧化吲哚类化合物；
所述的消旋的3-取代-3-溴氧化吲哚的化学结构式为：
；
所述的N,N-双取代苯胺的化学结构式为：
；
所述的手性3-取代-3-芳基氧化吲哚类化合物的化学结构式为：
；
其中，R1、R3选自H、烷基或卤素取代基；
R2选自烷基、芳香基、含取代基的芳香基或杂环基；
R4、R5选自烷基、杂环基、链状酯基、烯丙基或芳基；
所述手性配体为
所述的钴盐催化剂为乙酰丙酮钴(II)；
所述的碱选自碳酸锂、碳酸钠、碳酸钾、碳酸铯中的一种；
所述的添加剂选自3Å分子筛、4Å分子筛、5Å分子筛、无水硫酸钠、无水硫酸镁中的一种；
所述的不对称Friedel-Crafts反应的温度为-60~ -20℃，反应时间为1~72 h。
2.根据权利要求1所述的一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法，其特征在于，所述的溶剂选自二氯甲烷、二氯乙烷、三氯甲烷、四氯化碳、1,1,2,2-四氯乙烷、甲苯、乙腈、乙醚、四氢呋喃、1,4-二氧六环、甲醇或N,N-二甲基乙酰胺中的一种。
3.根据权利要求1所述的一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法，其特征在于，所述的消旋的3-取代-3-溴氧化吲哚、N,N-双取代苯胺、钴盐催化剂、手性配体、碱的摩尔比为1.0 : 1.0~1.5 : 0.02~0.2 : 0.02~0.2 : 0.2~2.0。
4.根据权利要求1所述的一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法，其特征在于，所述的添加剂在溶剂中的浓度为50~100 mg/mL；
所述的消旋的3-取代-3-溴氧化吲哚在溶剂中的浓度为0.02~0.2 mol/L。
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