CN117049995A - 高光学纯度的偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物的制备方法 - Google Patents
高光学纯度的偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物的制备方法 Download PDFInfo
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- AKQOBHZKBDHWQI-BZEFIUHZSA-N O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O Chemical compound O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O AKQOBHZKBDHWQI-BZEFIUHZSA-N 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- JBANFLSTOJPTFW-UHFFFAOYSA-N azane;boron Chemical compound [B].N JBANFLSTOJPTFW-UHFFFAOYSA-N 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical group CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940127108 compound 5g Drugs 0.000 description 1
- 229940126136 compound 5i Drugs 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- ANCBHJKEYPZCTE-UHFFFAOYSA-N ethyl 5-carbamoyl-4-methyl-2-[(2,3,4,5,6-pentafluorobenzoyl)amino]thiophene-3-carboxylate Chemical class CC1=C(C(N)=O)SC(NC(=O)C=2C(=C(F)C(F)=C(F)C=2F)F)=C1C(=O)OCC ANCBHJKEYPZCTE-UHFFFAOYSA-N 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- BGXZIBSLBRKDTP-UHFFFAOYSA-N methyl 9-(4-chloroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Cl)C=C1 BGXZIBSLBRKDTP-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- JBLLRCOZJMVOAE-HSQYWUDLSA-N n-[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methoxy-1h-indole-2-carboxamide Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)C=1NC=2C=CC=C(C=2C=1)OC)C(=O)C=1SC2=CC=CC=C2N=1)[C@@H]1CCNC1=O JBLLRCOZJMVOAE-HSQYWUDLSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000001420 substituted heterocyclic compounds Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及高光学纯度的偕二(杂)芳基甲基取代的α,β‑不饱和酯类化合物的制备方法。本发明方法利用一价铑催化/手性双烯配体作为催化剂，通过重氮分解得到的一价铑金属卡宾对N‑H无保护吲哚、吡咯、呋喃、噻吩及苯并呋喃的C2或C3的选择性不对称官能团化反应实现。本发明方法的催化剂用量低、反应条件温和、操作简便、底物广普性良好、能够以高的收率以及对映选择性得到偕二(杂)芳基甲基取代的α,β‑不饱和酯类化合物。
Description
技术领域
本发明属于化学领域，具体地，本发明涉及一价铑金属卡宾参与的分子间不对称碳-氢键插入反应，制备手性偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物的方法。
背景技术
在有机合成中，过渡金属催化的卡宾插入C-H,X-H(X＝O,N,S,Si)键是构建C-C,C-X键的一类非常重要的方法。其中，催化不对称卡宾插入C-H键的研究已经取得了很大的进展((a)Davies,H.M.L；Beckwith,R.E.J.Chem.Rev.2003,103,2861；(b)Díaz-Requejo,M.M.；Pérez,P.J.Chem.Rev.2008,108,3379；(c)Davies,H.M.L.；Manning,J.R.Nature2008,451,417；(d)Doyle,M.P.；Duffy,R.；Ratnikov,M.；Zhou,L.Chem.Rev.2010,110,704；(e)Davies,H.M.L.；Morton,D.Chem.Soc.Rev.2011,40,1857；(f)Zhu,S.-F.；Zhou,Q.-L.Acc.Chem.Res.2012,45,1365)。本课题组长期致力于研究一价铑卡宾介导的不对称C-H和X-H插入反应，并报道了一系列C1对称手性二烯配体在Rh(I)卡宾介导的不对称B-H、Si-H、C-H插入和oxa-Michael加成级联反应((a)Chen,D.；Zhang,X.；Qi,W.-Y.；Xu,B.；Xu,M.-H.J.Am.Chem.Soc.2015,137,5268；(b)Chen,D.；Zhu,D.-X.；Xu,M.-H.J.Am.Chem.Soc.2016,138,1498；(c)Liu,B.；Xu,M.-H.Chin.J.Chem.2021,39,1911；(d)Zhu,D.-X.；Xia,H.；Liu,J.-G.；Chung,L.W.；Xu,M.-H.J.Am.Chem.Soc.2021,143.2608；(e)Zhu,D.-X.；Liu,J.-G.；Xu,M.-H.J.Am.Chem.Soc.2021,143,8583)。
手性偕二(杂)芳基甲基结构是广泛存在于许多天然产物、生物活性化合物和合成分子中的重要结构单元,特别是含有吲哚和其他芳杂环的手性偕二芳基分子，是一类具有多种潜在生物活性和药物研究价值的独特化合物((a)Prat,M.；Fernández,D.；Buil,M.A.；Crespo,M.I.；Casals,G.；Ferrer,M.；Tort,L.；Castro,J.；Monleón,J.M.；Gavaldà,A.；Miralpeix,M.；Ramos,I.；Doménech,T.；Vilella,D.；Antón,F.；Huerta,J.M.；Espinosa,S.；López,M.；Sentellas,S.；González,M.；Albertí,J.；Segarra,V.；Cárdenas,A.；Beleta,J.；Ryder,H.J.Med.Chem.2009,52,5076；(b)Islam,M.S.；Barakat,A.；Al-Majid,A.M.；Ali,M.；Yousuf,S.；Choudhary,M.I.；Khalil,R.；Ul-Haq,Z.Bioorg.Chem.2018,79,350；(c)Tseng,C.-C.；Baillie,G.；Donvito,G.；Mustafa,M.-A.；Juola,S.-E.；Zanato,C.；Massarenti,C.；Dall'Angelo,S.；Harrison,W.T.A.；Lichtman,A.-H.；Ross,R.-A.；Zanda,M.；Greig,I.-R.J.Med.Chem.2019,62,5049；(d)Zou,Y.-L.；Li,H.-X.；Graham,E.-T.；Deik,A.-A.；Eaton,J.-K.；Wang,W.-L.；Gerardo,S.-G.；Clish,C.-B.；Doench,J.-G.；Schreiber,S.-L.Nat.Chem.Biol.2020,16,302)。
近年来，金属卡宾介导的α-重氮羰基化合物对吲哚的不对称C-H插入反应已有较多成功的报道。利用各种不同的手性金属催化剂如Rh(II)((a)Lian,Y.；Davies,H.M.L.J.Am.Chem.Soc.2010,132,440；(b)Takayuki,G.；Yoshihiro,N.；Takeda,K.；Hisanori,N.；Hashimoto,S.Tetrahedron:Asymmetry.2011,22,907；(c)DeAngelis,A.；Shurtleff,V.-W.；Dmitrenko,O.；Fox,J.-M.J.Am.Chem.Soc.2011,133,1650)、Fe(II)(Cai,Y.；Zhu,S.-F.；Wang,G.-P.；Zhou,Q.-L.Adv.Synth.Catal.2011,353,2939)、Pd(II)(Gao,X.；Wu,B.；Huang,W.-X.；Chen,M.-W.；Zhou,Y.-G.Angew.Chem.Int.Ed.2015,54,11956)、Cu(I)(Gao,X.；Wu,B.；Yam,Z.；Zhou,Y.-G.Org.Biomol.Chem.2016,14,8237)、和Ir(III)(Li,N.；Zhu,W.-J.；Huang,J.-J.；Hao,X.-Q.；Gong,J.-F.；Song,M.-P.Organometallics 2020,39,2222)等配合物可以实现这种转化。
尽管如此，上述方法通常只局限于通过简单的α-重氮化合物原位形成金属卡宾插入吲哚的C3位置获得手性的α-(3-吲哚基)-α-芳基乙酸酯。同时，绝大多数例子都需要对吲哚的氮原子进行保护，因此在进一步的转化中通常需要额外的N上保护基脱除反应。此外，由于吲哚在C3和N1上的亲核反应性使得反应存在多位点的竞争，而且反应的对映选择性控制非常挑战，值得一提的是，目前还没有通过卡宾C-H插入催化吲哚的不对称C2-H官能团化的例子((a)Chan,W.-W.；Yeung,S.-H.；Zhou,Z.-Y.；Chan,A.S.C.；Yu,W.-Y.Org.Lett.2010,12,604；(b)James,M.J.；O'Brien,P.；Taylor,R.J.K.；Unsworth,W.P.Angew.Chem.Int.Ed.2016,55,9671；(c)Arredondo,V.；Hiew,S.C.；Gutman,E.S.；Premachandra,I.D.U.A.；Vranken,D.L.V.Angew.Chem.Int.Ed.2017,56,4156；(d)Ghorai,J.；Chaitanya,M.；Anbarasan,P.Org.Biomol.Chem.2018,16,7346；(e)Nag,E.；Gorantla,S.M.N.V.T.；Arumugam,S.；Kulkarni,A.；Mondal,K.C.；Roy,S.Org.Lett.2020,22,6313；(f)Guha,S.；Gadde,S.；Kumar,N.；Black,D.S.；Sen,S.J.Org.Chem.2021,86,5234；(g)Maiti,D.；Das,R.；Sen,S.J.Org.Chem.2021,86,2522)。
因此，本领域迫切需要发展新的高效、实用、低成本的制备各种结构多样的高光学纯度的手性偕二(杂)芳基甲基取代的α,β-不饱和羰基化合物的方法。
发明内容
本发明的目的就是提供一种高效、实用、低成本的制备各种结构多样的高光学纯度的手性偕二(杂)芳基甲基取代的α,β-不饱和羰基化合物的方法。
本发明的第一方面，提供了高光学纯度的偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物的制备方法，包括步骤:
在有机溶剂中，在一价铑催化剂/手性双烯配体的存在下，式1化合物α-芳乙烯基-α-重氮芳酯对式2化合物N-H无保护取代吲哚的C3位进行碳-氢键不对称插入反应，从而得到式3/或式ent-3所示的手性偕二(杂)芳基甲基-α,β-不饱和酯类化合物；
或者，式1化合物α-芳乙烯基-α-重氮芳酯对式4化合物的C2位进行碳-氢键不对称插入反应，得到式5/或式ent-5所示的手性β-偕二(杂)芳基甲基-α,β-不饱和酯类化合物；
式中，
Ar1、Ar2各自独立地为取代或未取代的C6-30芳基、取代或未取代的5-30元杂芳基，其中，所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基、C3-8环烷基、C3-8环烷氧基，或其组合；
R1为H、取代或未取代的氨基、取代或未取代的C1-10烷基、取代或未取代的C1-6烯基、取代或未取代的C3-8环烷基、取代或未取代的C1-10烷氧基、取代或未取代的3-8元杂环基、取代或未取代的C6-C30芳基；其中，所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：取代或未取代的苯基、5-30元杂芳基、氨基；所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C3-8环烷基、C1-6卤代烷基、硝基；
其中，中的虚线代表无或与/>相邻的两个碳原子构成苯基；
X为O、NH或S；
Y为氢、卤素、羟基、-N(Ra)Rb、C1-30烷氧基、C1-30烷氨基；所述卤素为F、Cl、Br、I；其中，Ra和Rb各自独立地为H、C1-8烷基、或保护基。
在另一优选例中，Ar1、Ar2各自独立地为取代或未取代的C6-10芳基、取代或未取代的5-8元杂芳基，其中，所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基、C3-8环烷基、C3-8环烷氧基，或其组合。
在另一优选例中，R1为H、取代或未取代的氨基、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的C3-8环烷基、取代或未取代的3-8元杂环基、取代或未取代的C6-10芳基；其中，所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：取代或未取代的苯基、5-8元杂芳基、氨基；所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C3-8环烷基、C1-6卤代烷基、硝基。
在另一优选例中，所述的5-30元杂芳基为吡咯、呋喃、噻吩、吲哚、苯并呋喃。
在另一优选例中，所述的式4化合物为取代吲哚、取代吡咯、取代呋喃、取代噻吩、取代苯并呋喃；
在另一优选例中，Y为氢、卤素、羟基、氨基、-NHRb、C1-8烷氧基；所述卤素为F、Cl、Br、I，Rb为保护基。
在另一优选例中，Rb为选自下组的保护基：Boc、Ts、Cbz。
在另一优选例中，所述的Ar1为取代或未取代的苯基、取代或未取代的萘基、取代或未取代的噻吩基、取代或未取代的呋喃基；所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-4卤代烷基、C1-6烷基、C3-8环烷基、C1-4烷氧基、C6-10芳基。
在另一优选例中，所述的Ar2为取代或未取代的苯基、取代或未取代的萘基；所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C3-8环烷基、C1-4卤代烷基。
在另一优选例中，按式1化合物的用量计，所述的一价铑催化剂的用量为0.4～20mol％；所述的手性双烯配体的用量为0.5～25mol％。
在另一优选例中，所述的式3或ent-3化合物的ee值≥80％，较佳地≥90％，更佳地≥95％，最佳地≥98％。
在另一优选例中，所述的式5或ent-5化合物的ee值≥95％，较佳地≥97％，更佳地≥98％，最佳地≥99％。
在另一优选例中，所述的手性双烯配体具有如下结构式：
式中，R2、R3各自独立地为取代或未取代的C6-30芳基，所述的取代基是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、C1-6卤代烷氧基。
在另一优选例中，R2、R3各自独立地为取代或未取代的C6-10芳基，所述的取代基是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、C1-6卤代烷氧基。
在另一优选例中，所述的C6-30芳基为苯基、萘基、蒽基或二茂铁基。
在另一优选例中，R2、R3各自独立地为取代或未取代的苯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的二茂铁基；所述的取代基是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-8环烷基。
在另一优选例中，所述的R2和R3各自独立地为取代或未取代的苯基，所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中，所述的手性双烯配体选自下组：
在另一优选例中，所述的一价铑催化剂选自下组：[Rh(C2H4)2Cl]2、[Rh(C2H4)2OH]2、[Rh(coe)2Cl]2、[Rh(coe)2OH]]2、[Rh(C2H4)2OMe]2、[Rh(coe)2OMe]2，或其组合。
在另一优选例中，所述的式1化合物选自下组：
在另一优选例中，所述的式2化合物选自下组：
在另一优选例中，所述的式4化合物选自下组：
在另一优选例中，所述的方法还具有选自下组的一个或多个特征：
(1)所述的有机溶剂为C1-4的卤代烷烃；所述的C1-4的卤代烷烃选自下组：二氯甲烷、1,2-二氯乙烷，氯仿、1,2-二氯丙烷、1-氯丁烷，或其组合；
(2)反应温度在15-40℃；
(3)反应时间为0.5-24小时。
在本发明的第二方面，提供了一种式7或式ent-7所示的化合物，
式中，
Z为O或OH，A为H、OH或OAr2；
每个独立为双键或单键；
并且当Z为O时，所述与Z相连的为双键，A为OH或OAr2；当Z为OH时，所述与Z相连的/>为单键，A为H；
Ar1、Ar2、R1如本发明第一方面所定义；
其中，式7或ent-7化合物的ee值≥80％，较佳地≥90％，更佳地≥95％，最佳地≥98％。
在另一优选例中，Z为O，A为OH或OAr2。
在另一优选例中，所述的Ar2为
式中，Rc和Rd各自独立地为：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基、C3-8环烷基、C3-8环烷氧基，或其组合；
Re为H、或卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基、C3－8环烷基、C3－8环烷氧基，或其组合。
在另一优选例中，Rc和Rd各自独立地为：卤素、C1-6烷基，或其组合；Re为H、卤素、或C1-6烷基，或其组合。
在另一优选例中，所述的Ar1、Ar2、R1、X、Y、Z或A基团分别为实施例中各具体化合物中所对应的基团。
在另一优选例中，所述的化合物为选自下组的化合物：
在本发明的第三方面，提供了一种式8或式ent-8所示的化合物，
式中，
Z为O或OH，A为H、OH或OAr2；
每个独立为双键或单键；
并且当Z为O时，所述与Z相连的为双键，A为OH或OAr2；当Z为OH时，所述与Z相连的/>为单键，A为H；
Ar1、Ar2、R1、X、Y如本发明第一方面所定义；
其中，所述式8或ent-8化合物的ee值≥95％，较佳地≥97％，更佳地≥98％，最佳地≥99％。
在另一优选例中，Z为O，A为OH或OAr2。
在另一优选例中，所述的Ar1、Ar2、R1、X、Y、Z或A基团分别为实施例中各具体化合物中所对应的基团。
在另一优选例中，所述的化合物为选自下组的化合物：
/>
本发明的第四方面，提供了一种手性双烯配体，所述的手性双烯配体具有如下结构式：
式中，
R4为
R5为取代的苯基其中，Rf、Rg、Rh各自独立地为H、卤素、氰基、硝基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基，或其组合。
在另一优选例中，所述的Rf、Rg、Rh各自独立地为H、卤素、氰基、硝基、C1-6烷基、C1-6卤代烷基，或其组合。
在另一优选例中，所述的Rf、Rg、Rh各自独立地为H、氟、氰基、硝基、三氟甲基，或其组合。
在另一优选例中，所述的手性双烯配体选自下组：
在另一优选例中，所述的手性双烯配体为(R,R)-6j，(S,S)-6j。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，利用一价铑催化剂/手性双烯配合物作为催化剂，通过重氮分解得到的一价铑金属卡宾对N-H无保护的取代吲哚C3位进行不对称碳-氢键插入反应，或是对取代吲哚、取代吡咯、取代呋喃、取代苯并呋喃、取代噻吩的C2位进行碳-氢键不对称插入反应，高效构建具有高光学纯度的偕二(杂)芳基甲基-α,β-不饱和酯类化合物。另外，选择不同构型的手性配体，本发明方法可以得到构型相反的偕二(杂)芳基甲基-α,β-不饱和酯类化合物。在此基础上，完成了本发明实现。
术语
如本文所用，术语“烷基”是指直链、支链或环状烷基，优选为C1-10的烷基，更优选为C1-6烷基。在本发明中，烷基还包括烷基上的一个或多个H被选自下组的取代基所取代的基团：卤素、取代或未取代的苯基、未取代的或被一个或多个卤素取代的C1-6烷基。应理解，该术语还包括C3-10取代或未取代的环烷基。
如本文所用，术语“烷氧基”指C1-C10的直链或支链或环状的烷氧基，在本发明中，烷氧基还包括烷基上的一个或多个H被选自下组的取代基所取代的基团：卤素、取代或未取代的苯基、未取代的或被一个或多个卤素取代的C1-6烷基。
如本文所用，术语“芳基”指C6-C30芳基，代表性的例子为苯基、萘基、蒽基、菲基。在本发明中，芳基还包括芳基上的一个或多个H被选自下组的取代基所取代的基团：卤素、苯基、未取代的或被一个或多个卤素取代的C1-6烷基、未取代的或被一个或多个卤素取代的C1-6烷氧基。
如本文所用，术语“杂芳基”指5-30元杂芳基，代表性的例子为吡啶基、噻吩基、吲哚基、呋喃基。在本发明中，杂芳基还包括杂芳基上的一个或多个H被选自下组的取代基所取代的基团：卤素、苯基、未取代的或被一个或多个卤素取代的C1-6烷基、未取代的或被一个或多个卤素取代的C1-6烷氧基。
如本文所用，术语“一个或多个”通常指1-6个；较佳地1-5个；更佳地1-3个。
如本文所用，术语“Ph”表示苯基。
如本文所用，术语“RT”表示室温，例如15-40℃。
一般地，化合物ee值上限不超过99.9％。
术语“-N(Ra)Rb”是指氨基上的一个或多个氢被取代。
制备方法
本发明的合成方法可以由下述典型反应式表示:
在有机溶剂中，在一价铑催化剂/手性双烯配体存在下，催化以下反应式所示的化合物α-芳乙烯基-α-重氮芳酯1，对N-H无保护取代吲哚2的C3位进行碳-氢键不对称插入反应，从而形成结构式3或ent-3所示的偕二(杂)芳基甲基-α,β-不饱和酯类化合物，或是对取代吲哚、取代吡咯、取代呋喃、取代苯并呋喃、取代噻吩4的C2位进行碳-氢键不对称插入反应，从而形成结构式5或ent-5所示的偕二(杂)芳基甲基-α,β-不饱和酯类化合物；
反应底物1为α-芳乙烯基-α-重氮芳酯，其中，Ar1为未取代或取代的C6-C30芳基、杂芳基，其中所述的取代指具有一个或多个(如1-5个)取代基，其中所述的取代基选自下组：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基、或其组合；所述卤素为F、Cl、Br、或I；其中所述的杂芳基指具有一个或多个(如1-5个)取代基的吡啶、呋喃、噻吩、吲哚；
Ar2为未取代或取代的C6-C30芳基、杂芳基，其中所述的取代指具有一个或多个(如1-5个)取代基，其中所述的取代基选自下组：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基、或其组合；所述卤素为F、Cl、Br、或I；其中所述的杂芳基指具有一个或多个(如1-5个)取代基的吡啶、呋喃、噻吩、吲哚。
反应底物2为N-H无保护取代吲哚，其中，R1为C1-10烷基、取代或未取代的C1-6烯基、取代或未取代的C6-C30芳基、芳基或杂芳基取代的C1-6烷基、氨基及C1-30的一级或二级氨基；其中所述芳基为苯基或者被一个或多个选自下组的取代基所取代的苯基：卤素、C1-6烷基、C1-6卤代烷基、硝基；所述卤素为F、Cl、Br、I；其中所述的杂芳基指具有一个或多个(如1-5个)取代基的吡啶、噻吩、呋喃、吡咯；
反应底物4为取代吲哚、取代吡咯，取代呋喃、取代苯并呋喃或取代噻吩，其中，R1为H、C1-10烷基、取代或未取代的C1-6烯基、取代或未取代的C6-C30芳基、芳基或杂芳基取代的C1-6烷基、氨基及C1-30的一级或二级氨基；其中所述芳基为苯基或者被一个或多个选自下组的取代基所取代的苯基：卤素、C1-6烷基、C1-6卤代烷基、硝基；所述卤素为F、Cl、Br、I；其中所述的杂芳基指具有一个或多个(如1-5个)取代基的吡啶、噻吩、呋喃、吡咯；
X为O、NH或S；
Y为氢、氨基或C1-30的一级或二级氨基、羟基或C1-30烷氧基、氟、氯、溴、碘。
[Rh(I)]指一价铑催化剂，代表性的例子包括(但并不限于)：[Rh(C2H4)2Cl]2、[Rh(C2H4)2OH]2、[Rh(coe)2Cl]2、[Rh(coe)2OH]]2、[Rh(C2H4)2OMe]2、[Rh(coe)2OMe]2或其组合。
本发明中，代表性的手性双烯配体具有如下结构式：
式中，R2、R3各自独立地为取代或未取代的C6-30芳基，所述的取代基是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、C1-6卤代烷氧基。
较佳地，R2、R3各自独立地为取代或未取代的C6-10芳基，所述的取代基是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、C1-6卤代烷氧基。
在一个实施方式中，所述的C6-30芳基为苯基、萘基、蒽基或二茂铁基。
更佳地，R2、R3各自独立地为取代或未取代的苯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的二茂铁基；所述的取代基是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-8环烷基。
最佳地，所述的R2和R3各自独立地为取代或未取代的苯基，所述的取代是指一个或多个(如1-5个)H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基。
在本发明中，手性双烯配体的典型化合物的结构式包括(但并不限于)：
在本发明中，所述的溶剂为常规有机溶剂，可以是C1-4的卤代烷烃为二氯甲烷、1,2-二氯乙烷，氯仿、1,2-二氯丙烷、1-氯丁烷，或其组合。
在本发明上述反应方法中，反应温度没有特别限制，通常为-20℃至回流温度，较佳地为0-50℃，更佳地为15-40℃。
在本发明上述反应方法中，反应时间没有特别限制，通常为0.5-24小时，较佳的为1-24小时。
手性双烯配体
如本文所述，所述的手性双烯配体具有如下结构式：
式中，
R4为
R5为取代的苯基其中，Rf、Rg、Rh各自独立地为H、卤素、氰基、硝基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基，或其组合。
在另一实施方式中，所述的Rf、Rg、Rh各自独立地为H、卤素、氰基、硝基、C1-6烷基、C1-6卤代烷基，或其组合。
在另一优选例中，所述的Rf、Rg、Rh各自独立地为H、氟、氰基、硝基、三氟甲基，或其组合。
典型地，所述的手性双烯配体包括但不限于：
在本发明的一个优选例中，代表性的合成方法可描述如：
将一价铑催化剂和手性双烯的配合物溶于有机溶剂中，依次加入反应底物1和2(或3)并继续反应1-24小时，可以获得本发明所述高光学纯度的手性偕二(杂)芳基甲基-α,β-不饱和酯类化合物。在该反应中，反应底物与一价铑催化剂/手性双烯配体的摩尔比为60:1到1500:1，优选1000:1；反应温度为0-50℃，优选室温(25℃)；反应溶剂优选二氯乙烷。
高光学纯度的手性偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物制备
通过本发明的方法，可快速、高效制备高光学纯度的手性偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物。
在本发明中，一些代表性的高光学纯度的手性偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物列于表1、表2和表3。以催化剂络合物{Rh[(S,S)-6j]Cl}2为例，具有不同取代基的α-芳乙烯基-α-重氮芳酯对具有不同取代基的吲哚、吡咯，呋喃、苯并呋喃或噻吩进行不对称碳-氢键插入反应，可高效制得所需的反应产物，收率(yield)良好，对映选择性(ee)优秀，最高可以达到99％，双键构型以E式为主，最高达到E/Z>99：1；产物绝对构型通过单晶衍射确定。
表1.一价铑催化α-苯乙烯基-α-重氮2,4,6-三甲基苯酯对N-H无保护取代吲哚3-位的不对称碳-氢键插入反应
表2.一价铑催化α-芳乙烯基-α-重氮2,4,6-三甲基苯酯对N-H无保护吲哚3-位的不对称碳-氢键插入反应
表3.一价铑催化α-芳乙烯基-α-重氮2,4,6-三甲基苯酯对取代杂环化合物2-位的不对称碳-氢键插入反应
合成应用
本发明还提供了高光学纯度的手性偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物的应用，尤其在制备具有高光学纯度的合成砌块、生物活性中间体或活性化合物方面的应用。
在本发明的另一优选例中，代表性的用途可描述如下：
在该应用中，对本发明的手性偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物3aa进行氢化还原，从而形成相应含饱和碳链的化合物6a，随后这些化合物可以进一步通过DIBAL-H还原被转化为有用的中间体6c。化合物3aa通过DIBAL-H还原被转化为有用的中间体6d。
在本发明的另一优选例中，代表性的用途可描述如下：
在该应用中，对本发明的手性偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物5a进行氢化还原，从而形成相应含饱和碳链的化合物7a，随后这些化合物可以进一步通过还原被转化为有用的中间体7c。化合物5a通过DIBAL-H还原被转化为有用的中间体7b。
在本发明的另一优选例中，代表性的用途可描述如下：
在该应用中，对本发明的手性偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物5h进行氢化还原，随后对氨基进行保护基脱除，从而形成相应含饱和碳链的芳胺化合物8a，随后这些化合物可以进一步通过桑德迈尔反应被转化为有用的中间体8b、8c或8d；其中，B为氢、氟、氯、溴、碘或羟基。
与现有技术相比，本发明的主要优点：
(a)以一价铑催化剂/手性双烯配体作为催化剂，将简单易得的α-芳乙烯基-α-重氮芳酯作为反应前体，实现了一价铑卡宾对杂芳环化合物的不对称碳-氢键插入反应，用于制备各种手性偕二(杂)芳基甲基-α,β-不饱和酯类化合物；
(b)本发明方法催化剂用量少，底物普适性良好；
(c)本发明方法反应温和，操作简便；
(d)本发明的反应产物的立体选择性高，具有有机合成和药物研发应用前景。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1
化合物3a的合成
实验一：将{Rh[(S,S)-6i]Cl}2(0.003mmol,1.5mol％)配体及吲哚化合物2a(0.2mmol)投入到反应瓶中，无水无氧处理后，加入二氯甲烷(1mL)，于25℃下往体系中加入式1化合物α-苯乙烯基-α-重氮叔丁酯(0.1mmol于1mL二氯乙烷中)，继续反应。TLC监测反应完全。之后，旋干反应液，用硅胶柱层析分离得到产物3a，为白色固体，81％产率，74％ee，E/Z＝94:6。
1H NMR(400MHz,CDCl3)δ8.10(brs,1H),7.70(dd,J＝15.6,6.9Hz,1H),7.40(d,J＝8.0Hz,1H),7.38-7.29(m,5H),7.28-7.23(m,1H),7.16(t,J＝7.5Hz,1H),7.06(t,J＝7.5Hz,1H),6.88(d,J＝1.9Hz,1H),6.03(dd,J＝15.6,1.9Hz,1H),5.17(d,J＝6.9Hz,1H),1.56(s,9H).ESI-MS(m/z,％)334[M+H]+.
实施例2
化合物3b的合成
实验二：将实施例1中所用式1化合物原料换为其余实验操作同实施例1。得到产物3b，为白色固体，95％产率，76％ee，E/Z＝96:4。
1H NMR(400MHz,CDCl3)δ8.12(brs,1H),7.70(dd,J＝15.6,6.9Hz,1H),7.42(d,J＝8.0Hz,1H),7.40-7.30(m,7H),7.29-7.21(m,2H),7.16(t,J＝7.5Hz,1H),7.06(t,J＝7.5Hz,1H),6.89(d,J＝1.9Hz,1H),6.02(dd,J＝15.6,1.9Hz,1H),5.16(d,J＝6.9Hz,1H).ESI-MS(m/z,％)422[M+H]+.
实施例3
化合物3aa和化合物3aa’的合成
实验一：将{Rh[(S,S)-6j]Cl}2(0.003mmol,1.5mol％)配体及吲哚化合物2b(0.2mmol)投入到反应瓶中，无水无氧处理后，加入二氯乙烷(1mL)，于25℃下往体系中加入α-苯乙烯基-α-重氮芳酯1a(0.1mmol于1mL二氯乙烷中)，继续反应。TLC监测反应完全。之后，旋干反应液，用硅胶柱层析分离得到产物3aa，为白色固体，99％产率，93％ee，E/Z＝96:4。
实验二：将实验一中所用配体{Rh[(S,S)-6j]Cl}2换成{Rh[(R,R)-6j]Cl}2，其余实验操作同实验一，得到产物3aa’，为白色固体，99％产率，-93％ee，E/Z＝97:3。
实验三：将实验一中所用络合物{Rh[(S,S)-6j]Cl}2换成{Rh[(S,S)-6b]Cl}2，其余实验操作同实验一，得到产物3aa，为白色固体，99％产率，73％ee，E/Z＝98:2。
实验四：将实验一中所用配体{Rh[(S,S)-6j]Cl}2换成{Rh[(S,S)-6h]Cl}2，其余实验操作同实验一，得到产物3aa，为白色固体，61％产率，84％ee，E/Z＝96:4。
实验五：将实验一中所用配体{Rh[(S,S)-6j]Cl}2换成{Rh[(S,S)-6g]Cl}2，其余实验操作同实验一，得到产物3aa，为白色固体，78％产率，84％ee，E/Z＝93:7。
实验六：将实验一中所用配体{Rh[(S,S)-6j]Cl}2换成{Rh[(S,S)-6i]Cl}2，其余实验操作同实验一，得到产物3aa，为白色固体，82％产率，81％ee，E/Z＝96:4。
实验七：将实验一中所用二氯乙烷溶剂换成四氢呋喃，其余实验操作同实验五，得到产物3aa，为白色固体，44％产率，95％ee，E/Z＝95:5。
实验八：将实验一中所用二氯乙烷溶剂换成乙醚，其余实验操作同实验五，得到产物3aa，为白色固体，91％产率，95％ee，E/Z＝84:16。
实验九：将实验一中所用二氯乙烷溶剂换成甲苯，其余实验操作同实验五，得到产物3aa，为白色固体，99％产率，93％ee，E/Z＝92:8。
实验十：将实验一中所用二氯乙烷溶剂换成二氯甲烷，其余实验操作同实验五，得到产物3aa，为白色固体，98％产率，91％ee，E:Z＝97:3。
1H NMR(400MHz,CDCl3)δ8.12(brs,1H),7.69(dd,J＝15.6,6.9Hz,1H),7.40(d,J＝8.0Hz,1H),7.37-7.28(m,5H),7.28-7.23(m,1H),7.17(t,J＝7.5Hz,1H),7.05(t,J＝7.5Hz,1H),6.87(d,J＝1.9Hz,1H),6.85(s,2H),6.03(dd,J＝15.6,1.9Hz,1H),5.18(d,J＝6.9Hz,1H),2.24(s,3H),2.09(s,6H).13C NMR(101MHz,CDCl3)δ165.1,152.3,146.1,141.4,136.9,135.6,130.1,129.5,129.0,128.8,127.3,126.7,123.0,122.6,121.3,119.9,119.7,116.6,111.6,45.9,21.1,16.6.ESI-MS(m/z,％)396[M+H]+.
实施例4
化合物3ab的合成
将实施例3中所用无保护吲哚2a换为2b，其余实验操作同实施例3，得到产物3ab，为白色固体；95％产率，88％ee，E:Z＝97:3。
1H NMR(400MHz,CDCl3)δ8.20(brs,1H),7.69(dd,J＝15.6,6.4Hz,1H),7.36-7.25(m,5H),7.14-7.06(m,2H),6.85(s,2H),6.83(s,1H),6.73(dd,J＝10.8,7.5Hz,1H),5.99(d,J＝15.6Hz,1H),5.42(d,J＝6.4Hz,1H),2.25(s,3H),2.09(s,6H).13C NMR(126MHz,CDCl3)δ165.1,157.4(d,JCF＝246Hz),152.6,146.2,141.7,139.5(d,JCF＝12.5Hz),135.6,130.2,129.5,128.8(d,JCF＝12.5Hz),127.3,123.3(d,JCF＝7.5Hz),123.1,121.3,115.9(d,JCF＝3.8Hz),115.8(d,JCF＝20Hz),107.7(d,JCF＝3.8Hz),105.4(d,JCF＝18.8Hz),46.2,21.1,16.6.ESI-MS(m/z,％)414[M+H]+.
实施例5
化合物3ac的合成
将实施例3中所用无保护吲哚2a换为2c，其余实验操作同实施例3，得到产物3ac，为白色固体；97％产率，92％ee，E:Z＝97:3。
1H NMR(400MHz,CDCl3)δ8.16(brs,1H),7.66(dd,J＝15.6,6.9Hz,1H),7.37-7.31(m,2H),7.30-7.21(m,4H),7.01(dd,J＝9.6,2.3Hz,1H),6.94-6.88(m,2H),6.85(s,2H),6.03(dd,J＝15.6,1.4Hz,1H),5.11(dd,J＝6.9Hz,1H),2.24(s,3H),2.10(s,6H).13C NMR(126MHz,CDCl3)δ165.1,158.0(d,JCF＝234Hz),152.0,146.1,141.1,135.6,133.4,130.1,129.5,129.1,128.8,127.5,127.1(d,JCF＝8.8Hz),124.8,121.5,116.7(d,JCF＝3.8Hz),112.3(d,JCF＝10.0Hz),111.2(d,JCF＝26.2Hz),104.7(d,JCF＝23.8Hz),45.9,21.1,16.6.ESI-MS(m/z,％)414[M+H]+.
实施例6
化合物3ad的合成
将实施例3中所用无保护吲哚2a换为2d，其余实验操作同实施例3，得到产物3ad，为白色固体；97％产率，92％ee，E:Z＝97:3。
1H NMR(400MHz,CDCl3)δ8.17(brs,1H),7.67(dd,J＝15.6,7.0Hz,1H),7.37-7.22(m,6H),6.98(dd,J＝9.6,2.1Hz,1H),6.85(s,2H),6.84(s,1H),6.80(td,J＝9.2,2.1Hz,1H),6.03(d,J＝15.6Hz,1H),5.14(d,J＝7.0Hz,1H),2.24(s,3H),2.09(s,6H).13C NMR(126MHz,CDCl3)δ165.1,160.4(d,JCF＝234Hz),152.1,146.2,141.2,136.9(d,JCF＝12.5Hz),135.7,130.1,129.5,129.1,128.8,127.4,123.3(d,JCF＝5.0Hz),121.4,120.5(d,JCF＝10.0Hz),116.7,108.8(d,JCF＝23.8Hz),97.9(d,JCF＝26.2Hz),45.9,21.1,16.6.ESI-MS(m/z,％)414[M+H]+.
实施例7
化合物3ae的合成
将实施例3中所用无保护吲哚2a换为2e，其余实验操作同实施例3，得到产物3ae，为白色固体；99％产率，95％ee，E:Z＝98:2。
1H NMR(400MHz,CDCl3)δ8.16(brs,1H),7.66(dd,J＝15.6,6.9Hz,1H),7.48(s,1H),7.38-7.30(m,2H),7.30-7.23(m,3H),7.21(d,J＝8.5Hz,1H),7.4(dd,J＝8.4,1.0Hz,1H),6.88(d,J＝2.4Hz,1H),6.86(s,2H),6.00(d,J＝15.6Hz,1H),5.14(d,J＝.9Hz,1H),2.25(s,3H),2.09(s,6H).13C NMR(126MHz,CDCl3)δ165.0,151.8,146.1,141.0,137.7,135.7,130.1,129.5,129.1,128.8,127.5,125.7,123.6,123.3,121.5,121.0,116.9,116.3,114.6,45.8,21.1,16.6.ESI-MS(m/z,％)474[M+H]+.
实施例8
化合物3af的合成
将实施例3中所用无保护吲哚2a换为2f，其余实验操作同实施例3，得到产物3af，为白色固体；99％产率，92％ee，E:Z＝98:2。
1H NMR(400MHz,CDCl3)δ8.22(brs,1H),7.64(dd,J＝15.5,6.8Hz,1H),7.52(s,1H),7.39-7.31(m,2H),7.31-7.21(m,4H),7.18(d,J＝8.5Hz,1H),6.85(s,3H),6.02(d,J＝15.5Hz,1H),5.11(d,J＝6.8Hz,1H),2.24(s,3H),2.10(s,6H).13C NMR(126MHz,CDCl3)δ165.0,151.9,140.9,135.6,135.5,130.1,129.5,129.2,128.8,128.5,127.5,125.6,124.3,122.2,121.6,116.4,113.3,113.1,45.7,21.1,16.6.ESI-MS(m/z,％)474[M+H]+.
实施例9
化合物3ag的合成
将实施例3中所用无保护吲哚2a换为2g，其余实验操作同实施例3，得到产物3ag，为白色固体；93％产率，88％ee，E:Z＝93:7。
1H NMR(400MHz,CDCl3)δ7.83(brs,1H),7.68(dd,J＝15.6,6.8Hz,1H),7.34(d,J＝4.4Hz,3H),7.29-7.24(m,2H),7.25-7.21(m,1H),6.86(s,2H),6.82(d,J＝2.4Hz,1H),6.66(dd,J＝8.8,2.0Hz,1H),6.49(dd,J＝1.6Hz,1H),6.06(dd,J＝15.6,1.6Hz,1H),5.14(d,J＝2.8Hz,1H),3.24-3.21(m,4H),2.25(s,3H),2.09(s,6H),2.00-1.96(m,4H).13C NMR(101MHz,CDCl3)δ165.1,152.4,146.2,143.5,141.6,135.5,130.1,129.5,128.9,128.0,127.2,123.4,121.2,115.7,112.0,110.7,100.6,49.0,46.1,30.0,25.7,21.1,16.6.ESI-MS(m/z,％)465[M+H]+.
实施例10
化合物3ah的合成
将实施例3中所用无保护吲哚2a换为2h，其余实验操作同实施例3，得到产物3ah，为白色固体；98％产率，94％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ8.31(brs,1H),7.68(dd,J＝15.5,7.1Hz,1H),7.37-7.30(m,4H),7.36-7.26(m,1H),7.03-6.95(m,2H),6.92(d,J＝2.2Hz,1H),6.86(s,2H),6.65(d,J＝7.1Hz,1H),6.03(d,J＝15.5Hz,1H),5.18(d,J＝7.1Hz,1H),3.95(s,3H),2.25(s,3H),2.09(s,6H).13C NMR(126MHz,CDCl3)δ164.9,152.2,146.5,146.2,141.5,135.5,130.1,129.5,129.0,128.9,128.2,127.5,127.3,122.6,121.4,120.5,117.2,112.5,102.5,55.7,46.1,21.1,16.6.ESI-MS(m/z,％)426[M+H]+.
实施例11
化合物3ai的合成
将实施例3中所用无保护吲哚2a换为2i，其余实验操作同实施例3，得到产物3ai，为白色固体；99％产率，94％ee，E:Z＝98:2。
1H NMR(400MHz,CDCl3)δ8.03(brs,1H),7.68(dd,J＝15.6,6.9Hz,1H),7.36-7.30(m,4H),7.29-7.20(m,2H),6.89-6.79(m,5H),6.05(dd,J＝15.6,1.3Hz,1H),5.14(d,J＝6.9Hz,1H),3.75(s,3H),2.25(s,3H),2.09(s,6H).13C NMR(126MHz,CDCl3)δ165.0,154.4,152.2,146.2,141.3,135.6,132.0,130.1,129.5,129.0,128.9,127.3,127.2,123.8,121.3,116.4,112.8,112.3,101.6,56.1,46.0,21.1,16.6.ESI-MS(m/z,％)426[M+H]+.
实施例12
化合物3aj的合成
将实施例3中所用无保护吲哚2a换为2j，其余实验操作同实施例3，得到产物3aj，为白色固体；76％产率，97％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ8.30(brs,1H),7.67(dd,J＝15.6,6.9Hz,1H),7.40-7.24(m,7H),6.98(s,1H),6.93(t,J＝7.8Hz,1H),6.85(s,2H),6.02(d,J＝15.6Hz,1H),5.16(d,J＝6.6Hz,1H),2.24(s,3H),2.09(s,6H).13C NMR(126MHz,CDCl3)δ164.8,151.7,146.1,141.0,135.6,130.1,129.5,129.1,128.8,127.9,127.5,125.1,123.6,121.7,121.2,119.1,118.1,105.2,46.0,21.1,16.6.ESI-MS(m/z,％)474[M+H]+.
实施例13
化合物3ak的合成
将实施例3中所用无保护吲哚2a换为2k，其余实验操作同实施例3，得到产物3ak，为白色固体；95％产率，79％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.91(brs,1H),7.79(dd,J＝15.6,6.6Hz,1H),7.38-7.20(m,7H),7.11(t,J＝7.6Hz,1H),7.00(t,J＝7.5Hz,1H),6.85(s,2H),6.02(d,J＝15.6Hz,1H),5.21(d,J＝6.6Hz,1H),2.35(s,3H),2.25(s,3H),2.10(s,6H).13C NMR(126MHz,CDCl3)δ164.9,152.4,146.2,141.6,135.6,135.5,132.5,130.1,129.5,128.9,128.6,128.1,127.0,121.5,121.4,119.9,119.4,111.1,110.7,45.0,21.1,16.6,12.8.ESI-MS(m/z,％)410[M+H]+.
实施例14
化合物3al的合成
将实施例3中所用无保护吲哚2a换为2l，其余实验操作同实施例3，得到产物3al，为白色固体；92％产率，70％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ8.23(brs,1H),7.80(dd,J＝15.7,6.3Hz,1H),7.50-7.26(m,11H),7.24(d,J＝6.6Hz,1H),7.17(t,J＝7.5Hz,1H),7.02(t,J＝8.0Hz,1H),6.82(s,2H),6.00(d,J＝15.5Hz,1H),5.32(d,J＝6.2Hz,1H),2.22(s,3H),2.06(s,6H).13C NMR(126MHz,CDCl3)δ164.9,152.7,146.2,141.7,136.5,135.5,132.8,130.1,129.5,129.2,128.9,128.9,128.6,128.1,127.0,122.7,121.7,121.2,120.3,111.8,111.5,45.2,21.1,16.6.ESI-MS(m/z,％)472[M+H]+.
实施例15
化合物3am的合成
将实施例3中所用无保护吲哚2a换为2m，其余实验操作同实施例3，得到产物3am，为白色固体；95％产率，72％ee，E:Z>99:1。
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1H NMR(400MHz,CDCl3)δ7.81(brs,1H),7.80(dd,J＝15.6,6.4Hz,1H),7.33-7.27(m,4H),7.27-7.21(m,1H),7.20-7.15(m,2H),6.94(d,J＝8.5Hz,1H),6.86(s,2H),6.00(dd,J＝15.6,1.5Hz,1H),5.18(dd,J＝6.4,1.5Hz,1H),2.36(s,3H),2.33(s,3H),2.25(s,3H),2.10(s,6H).13C NMR(126MHz,CDCl3)δ164.9,152.7,146.2,141.7,135.5,133.9,132.6,130.1,129.5,129.1,128.9,128.6,128.5,127.0,123.1,121.4,119.1,110.6,110.4,45.0,21.9,21.1,16.6,12.8.ESI-MS(m/z,％)424[M+H]+.
实施例16
化合物3ba的合成
将实施例3中所用式1化合物1a更换为1b,其余实验操作同实施例3，得到产物3ba，为白色固体；99％产率，94％ee，E:Z＝95:5。
1H NMR(400MHz,CDCl3)δ8.15(brs,1H),7.64(dd,J＝15.6,6.8Hz,1H),7.36(dd,J＝8.0,2.4Hz,2H),7.31-7.29(m,2H),7.24-7.19(m,3H),7.06(d,J＝6.8Hz,1H),6.92(s,1H),6.86(s,2H),6.02(dd,J＝15.6,1.6Hz,1H),5.16(d,J＝6.8Hz,1H),2.25(s,3H),2.09(s,6H).13C NMR(101MHz,CDCl3)δ164.9,151.6,146.1,139.9,136.9,135.6,133.1,130.2,130.1,129.5,129.2,126.6,123.0,122.8,121.7,120.1,119.6,116.2,111.7,45.3,21.1,16.6.ESI-MS(m/z,％)430[M+H]+.
实施例17
化合物3ca的合成
将实施例3中所用式1化合物1a更换为1c，其余实验操作同实施例3，得到产物3ca，为白色固体；99％产率，88％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ8.14(brs,1H),7.72(dd,J＝15.6,6.8Hz,1H),7.60-7.56(m,4H),7.47-7.37(m,6H),7.34(tt,J＝6.8,1.6Hz,1H),7.21(t,J＝6.8Hz,1H),7.08(t,J＝6.8Hz,1H),6.99(d,J＝2.4Hz,1H),6.86(s,2H),6.08(dd,J＝15.6,1.6Hz,1H),5.24(d,J＝6.8Hz,1H),2.25(s,3H),2.11(s,6H).13C NMR(101MHz,CDCl3)δ165.0,152.0,146.2,141.1,140.5,140.2,137.0,135.6,130.1,129.5,129.3,129.1,127.8,127.6,127.8,126.8,123.1,122.8,121.5,120.1,119.8,116.8,111.6,45.6,21.1,16.6.ESI-MS(m/z,％)472[M+H]+.
实施例18
化合物3da的合成
将实施例3中所用式1化合物1a更换为1d，其余实验操作同实施例3，得到产物3da，为白色固体；95％产率，92％ee，E:Z＝76:24。
1H NMR(400MHz,CDCl3)δ8.16(brs,1H),7.64(dd,J＝15.6,6.8Hz,1H),7.38(d,J＝8.8Hz,2H),7.29-7.19(m,5H),7.07(ddd,J＝7.2,6.8,0.8Hz,1H),6.96(dd,J＝2.8,0.8Hz,1H),6.86(s,2H),6.02(dd,J＝15.6,1.6Hz,1H),5.24(d,J＝6.8Hz,1H),2.25(s,3H),2.10(s,6H).13C NMR(101MHz,CDCl3)δ164.8,151.3,146.1,143.5,136.9,135.6,134.9,130.3,130.1,129.5,129.0,127.6,127.0,126.6,123.0,122.9,121.8,120.2,119.6,116.0,111.7,45.6,21.1,16.6.ESI-MS(m/z,％)430[M+H]+.
实施例19
化合物3ea的合成
将实施例3中所用式1化合物1a更换为1e，其余实验操作同实施例3，得到产物3ea，为白色固体；97％产率，92％ee，E:Z＝97:3。
1H NMR(400MHz,CDCl3)δ8.15(brs,1H),7.67(dd,J＝15.6,6.8Hz,1H),7.44(d,J＝8.4Hz,1H),7.38(d,J＝8.4Hz,1H),7.27-7.07(m,6H),7.01(d,J＝2.0Hz,1H),6.86(s,2H),6.03(dd,J＝15.6,1.6Hz,1H),5.54(d,J＝6.8Hz,1H),2.26(s,3H),2.10(s,6H).13C NMR(101MHz,CDCl3)δ164.9,160.9(d,JCF＝247Hz),150.8,146.2,136.9,135.6,130.3(d,JCF＝4.0Hz),130.3,129.5,129.1(d,JCF＝8.1Hz),128.5(d,JCF＝14.1Hz),126.7,124.7(d,JCF＝4.0Hz),123.1,122.8,121.6,120.2,119.6,116.1,115.9,115.5,111.6,38.4,21.1,16.6.ESI-MS(m/z,％)414[M+H]+.
实施例20
化合物3fa的合成
将实施例3中所用式1化合物1a更换为1f，其余实验操作同实施例3，得到产物3fa，为白色固体；99％产率，96％ee，E:Z＝92:8。
1H NMR(400MHz,CDCl3)δ8.19(brs,1H),7.67(dd,J＝15.6,7.2Hz,1H),7.59(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),7.36(t,J＝8.4Hz,2H),7.21(td,J＝7.6,0.8Hz,1H),7.07(td,J＝7.6,0.8Hz,1H),6.94(d,J＝2.4Hz,1H),6.86(s,2H),6.03(dd,J＝15.6,1.2Hz,1H),5.26(d,J＝7.2Hz,1H),2.25(s,3H),2.10(s,6H).13C NMR(101MHz,CDCl3)δ164.8,151.1,146.1,145.5,137.0,135.7,130.0,129.4(q,JCF＝37.4Hz),126.5,126.0(q,JCF＝4.0Hz),123.1,123.0,122.0,120.2,119.5,115.8,111.8,45.7,21.1,16.6.ESI-MS(m/z,％)464[M+H]+.
实施例21
化合物3ga的合成
将实施例3中所用式1化合物1a更换为1g，其余实验操作同实施例3，得到产物3ga，为白色固体；99％产率，92％ee，E:Z＝98:2。
1H NMR(400MHz,CDCl3)δ8.16(brs,1H),7.64(dd,J＝15.6,7.2Hz,1H),7.42(d,J＝8.4Hz,2H),7.36(t,J＝5.6,Hz,2H)7.19(m,3H),7.06(t,J＝7.6,Hz,1H),6.92(s,1H),6.86(s,2H),6.02(dd,J＝15.6,1.2Hz,1H),5.15(d,J＝7.2Hz,1H),2.25(s,3H),2.09(s,6H).13CNMR(101MHz,CDCl3)δ164.8,151.5,146.1,140.5,137.0,135.6,132.2,130.6,130.1,129.5,126.6,123.0,122.9,121.7,121.2,120.2,119.6,116.1,111.7,45.4,21.1,16.6.ESI-MS(m/z,％)474[M+H]+.
实施例22
化合物3ha的合成
将实施例3中所用式1化合物1a更换为1h，其余实验操作同实施例3，得到产物3ha，为白色固体；84％产率，92％ee，E:Z＝94:6。
1H NMR(400MHz,CDCl3)δ8.12(brs,1H),7.68(dd,J＝15.6,6.8Hz,1H),7.43(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.26(t,J＝8.0,1H),7.19(td,J＝8.0,1.2Hz,1H),7.06(td,J＝8.0,1.2,Hz,1H),6.95(d,J＝1.6Hz,1H),6.91(d,J＝8.0Hz,1H),6.87(s,1H),6.86(s,2H),6.81(dd,J＝8.0,2.4Hz,1H),6.04(dd,J＝15.6,1.2Hz,1H),5.16(d,J＝6.8Hz,1H),3.77(s,3H),2.25(s,3H),2.09(s,6H).13C NMR(101MHz,CDCl3)δ165.0,160.2,152.0,146.2,143.1,136.9,135.6,130.1,130.0,129.5,126.8,123.0,122.7,121.4,121.3,120.0,119.8,116.6,114.9,112.4,111.6,55.5,45.9,21.1,16.6.ESI-MS(m/z,％)426[M+H]+.
实施例23
化合物3ia的合成
将实施例3中所用式1化合物1a更换为1i，其余实验操作同实施例3，得到产物3ia，为白色固体；99％产率，87％ee，E:Z＝95:5。
1H NMR(400MHz,CDCl3)δ8.22(brs,1H),7.66(dd,J＝15.6,7.2Hz,1H),7.46(d,J＝7.6Hz,1H),7.37(d,J＝7.6Hz,1H),7.20(t,J＝7.2Hz,1H),7.09(t,J＝7.2Hz,1H),6.92(s,1H),6.86(s,2H),6.54(s,2H),6.06(dd,J＝15.6,1.2Hz,1H),5.13(d,J＝7.2Hz,1H),3.85(s,3H),3.79(s,6H),2.25(s,3H),2.10(s,6H).13C NMR(101MHz,CDCl3)δ165.0,153.7,152.0,146.1,137.2,136.9,130.0,129.5,126.8,123.1,122.7,121.4,120.0,119.7,116.5,111.7,105.9,61.2,56.4,46.2,30.0,21.1,16.6.ESI-MS(m/z,％)486[M+H]+.
实施例24
化合物3ja的合成
将实施例3中所用式1化合物1a更换为1j，其余实验操作同实施例3，得到产物3ja，为白色固体；99％产率，92％ee，E:Z＝95:5。
1H NMR(400MHz,CDCl3)δ8.14(brs,1H),7.83-7.75(m,5H),7.48-7.45(m,3H),7.42(dd,J＝8.4,1.2Hz,1H),7.36(d,J＝8.4Hz,1H),7.18(td,J＝7.6,0.8Hz,1H),7.03(td,J＝7.6,0.8Hz,1H),6.94(d,J＝2.0Hz,1H),6.85(s,2H),6.07(dd,J＝15.6,1.2Hz,1H),5.36(d,J＝6.8Hz,1H),2.25(s,3H),2.10(s,6H).13C NMR(101MHz,CDCl3)δ165.0,152.0,146.2,139.0,137.0,135.6,133.9,132.9,130.1,129.5,128.7,128.2,128.0,127.3,126.9,126.5,126.2,123.2,122.7,121.6,120.1,119.8,116.6,111.6,46.0,21.1,16.6.ESI-MS(m/z,％)446[M+H]+.
实施例25
化合物3ka的合成
将实施例3中所用式1化合物1a更换为1k，其余实验操作同实施例3，得到产物3ka，为白色固体；99％产率，93％ee，E:Z＝99:1。
1H NMR(400MHz,CDCl3)δ8.11(brs,1H),7.66(dd,J＝15.6,6.8Hz,1H),7.46(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.31(dd,J＝5.2,3.2Hz,1H),7.21(td,J＝8.0,0.8Hz,1H),7.11-7.07(m,2H),7.02(dd,J＝5.2,1.2Hz,1H),6.97(d,J＝2.0Hz,1H),6.86(s,2H),6.07(dd,J＝15.6,1.6Hz,1H),5.28(d,J＝6.8Hz,1H),2.26(s,3H),2.10(s,6H).13C NMR(101MHz,CDCl3)δ165.1,151.7,146.1,142.1,136.9,135.6,130.1,129.5,128.3,126.6,126.2,122.9,122.6,122.3,121.0,120.0,119.6,116.2,111.7,41.3,21.1,16.6.ESI-MS(m/z,％)402[M+H]+.
实施例26
化合物3la的合成
将实施例3中所用式1化合物1a更换为1l，其余实验操作同实施例3，得到产物3la，为白色固体；95％产率，93％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ8.15(brs,1H),7.59(dd,J＝15.6,6.4Hz,1H),7.51(d,J＝7.2Hz,1H),7.41-7.40(m,1H),7.39(t,J＝1.2Hz,1H),7.21(td,J＝7.2,1.2Hz,1H),7.13-7.08(m,2H),6.86(s,2H),6.34(dd,J＝3.2,2.0Hz,1H),6.14(dt,J＝3.2,1.2Hz,1H),6.08(dd,J＝15.6,1.6Hz,1H),5.26(d,J＝6.4Hz,1H),2.25(s,3H),2.09(s,6H).13C NMR(101MHz,CDCl3)δ164.8,154.3,149.3,146.2,142.4,136.8,135.6,130.1,129.5,126.6,123.1,122.8,121.6,120.2,119.6,114.0,111.7,110.7,107.5,39.6,21.1,16.6.ESI-MS(m/z,％)386[M+H]+.
实施例27
化合物3ma的合成
将实施例3中所用式1化合物1a更换为1m，其余实验操作同实施例3，得到产物3ma，为白色固体；93％产率，90％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ8.15(brs,1H),7.67(dd,J＝15.6,6.8Hz,1H),7.50(d,J＝8.0Hz,1H),7.42(dd,J＝8.4,1.2Hz,1H),7.24-7.20(m,2H),7.10td,J＝8.0,1.2Hz,1H),7.08(d,J＝2.0Hz,1H),6.98(dd,J＝5.2,3.6Hz,1H),6.95(dt,J＝3.6,1.2Hz,1H),6.86(s,2H),6.12(dd,J＝15.6,1.2Hz,1H),5.45(d,J＝6.8Hz,1H),2.26(s,3H),2.10(s,6H).13CNMR(101MHz,CDCl3)δ164.9,151.1,146.2,145.2,136.8,135.6,130.1,129.5,127.2,126.5,125.8,125.0,122.9,122.9,121.2,120.2,119.7,116.5,111.7,40.9,21.1,16.6.ESI-MS(m/z,％)402[M+H]+.
实施例28
化合物5a的合成
将实施例3中所用的吲哚化合物2a换为4a，其余实验操作同实施例3，得到产物5a，为棕色油状液体；91％产率，97％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.86(brs,1H),7.55(ddd,J＝15.6,7.2,0.8Hz,1H),7.39-7.35(m,2H),7.30(tt,J＝7.2,1.2Hz,1H),7.25-7.23(m,2H),6.86(s,2H),6.71(dd,J＝4.0,2.4Hz,1H),6.19(dd,J＝5.6,2.8Hz,1H),6.05(s,1H),6.02(d,J＝15.6Hz,1H),4.94(d,J＝7.2Hz,1H),2.26(s,3H),2.09(s,6H).13C NMR(101MHz,CDCl3)δ164.7,150.7,146.1,140.2,135.6,130.8,130.1,129.5,129.3,128.8,127.8,121.8,118.2,108.9,107.6,47.7,21.1,16.6.ESI-MS(m/z,％)346[M+H]+.
实施例29
化合物5b的合成
将实施例3中所用式1化合物1a更换为1i，吲哚化合物2a换为4a，其余实验操作同实施例3，得到产物5b，为棕色油状液体；73％产率，99％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ8.03(brs,1H),7.52(dd,J＝15.6,7.2Hz,1H),6.87(s,2H),6.74(dd,J＝4.0,2.8Hz,1H),6.44(s,2H),6.18(dd,J＝6.0,2.8Hz,1H),6.07-6.05(m,1H),6.05(dd,J＝15.6,1.2Hz,1H),4.87(d,J＝7.2Hz,1H),3.85(s,3H),3.81(s,6H),2.26(s,3H),2.10(s,6H).13C NMR(151MHz,CDCl3)δ164.7,153.9,150.5,146.1,137.5,135.8,135.7,130.6,130.0,129.5,121.7,118.2,108.9,107.5,105.7,61.2,56.4,47.9,21.1,16.6.ESI-MS(m/z,％)436[M+H]+.
实施例30
化合物5c的合成
将实施例3中所用式1化合物1a更换为1l，吲哚化合物2a换为4a，其余实验操作同实施例3，得到产物5c，为棕色油状液体；88％产率，99％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ8.20(brs,1H),7.43(dd,J＝15.6,6.8Hz,1H),7.42-7.41(m,1H),6.86(s,2H),6.74(m,1H),(6.35(dd,J＝4.0,2.8Hz,1H),6.18(dd,J＝6.0,2.8Hz,1H),6.16(d,J＝3.2Hz,1H),6.10-6.08(m,1H),6.02(dd,J＝15.6,1.6Hz,1H),5.04(d,J＝6.8Hz,1H),2.26(s,3H),2.09(s,6H).13C NMR(101MHz,CDCl3)δ164.6,153.0,148.2,146.1,142.8,135.7,130.0,129.5,128.1,122.0,118.4,110.8,109.0,107.5,41.3,21.1,16.6.ESI-MS(m/z,％)336[M+H]+.
实施例31
化合物5d的合成
将实施例3中所用吲哚化合物2a换为4b，其余实验操作同实施例3，得到产物5d，为白色固体；88％产率，99％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.52(dd,J＝15.6,6.8Hz,1H),7.38-7.27(m,6H),6.86(s,2H),6.68(brs,1H),6.02(dd,J＝15.6,1.6Hz,1H),5.72(s,1H),5.03(dd,J＝6.8,1.6Hz,1H),2.26(s,3H),2.10(s,6H),1.46(s,9H).13C NMR(101MHz,CDCl3)δ164.4,153.5,148.7,146.1,141.5,138.5,135.6,130.1,129.5,129.4,128.7,128.0,122.4,121.4,109.0,81.0,45.9,28.6,21.1,16.6.ESI-MS(m/z,％)484[M+Na]+.
实施例32
化合物5e的合成
将实施例3中所用式1化合物1a更换为1g，吲哚化合物2a换为4b，其余实验操作同实施例3，得到产物5e，为白色固体；95％产率，97％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.51-7.45(m,3H),7.30(brs,1H),7.18-7.13(m,3H),6.87(s,2H),6.05(s,1H),5.97(dd,J＝15.6,1.2Hz,1H),5.13(dd,J＝6.4,1.2Hz,1H),2.26(s,3H),2.10(s,6H),1.47(s,9H).13C NMR(101MHz,CDCl3)δ164.3,152.9,148.0,146.0,141.7,137.6,135.7,132.4,130.4,130.0,129.6,122.68,122.0,121.3,109.3,81.1,45.2,28.6,21.1,16.6.ESI-MS(m/z,％)562[M+Na]+.
实施例33
化合物5f的合成
将实施例3中所用式1化合物1a更换为1i，吲哚化合物2a换为4b，其余实验操作同实施例3，得到产物5f，为白色固体；91％产率，97％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.50(dd,J＝15.6,6.8Hz,1H),7.32(d,J＝2.0Hz,1H),6.87(s,2H),6.69(brs,1H),6.51(s,2H),6.03(dd,J＝15.6,1.2Hz,1H),5.75(s,1H),4.96(d,J＝6.8Hz,1H),3.85(s,9H),2.26(s,3H),2.10(s,6H),1.46(s,9H).13C NMR(101MHz,CDCl3)δ164.4,153.9,153.6,148.4,146.0,141.5,137.8,135.7,133.9,130.0,129.6,122.4,121.4,109.2,105.7,81.0,61.2,56.5,46.2,28.6,21.1,16.6.ESI-MS(m/z,％)574[M+Na]+.
实施例34
化合物5g的合成
将实施例3中所用式1化合物1a更换为1k，吲哚化合物2a换为4b，其余实验操作同实施例3，得到产物5g，为白色固体；94％产率，98％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.48(dd,J＝15.6,6.4Hz,1H),7.32(dd,J＝4.8,2.8Hz,1H),7.30(d,J＝2.0Hz,1H),7.13(d,J＝2.8Hz,1H),7.02(dd,J＝4.8,1.2Hz,1H),6.86(s,2H),6.69(brs,1H),6.03(dd,J＝15.6,1.6Hz,1H),5.77(brs,1H),5.11(d,J＝6.4Hz,1H),2.26(s,3H),2.10(s,6H),1.46(s,9H).13C NMR(101MHz,CDCl3)δ164.4,153.5,148.1,146.1,141.4,138.6,135.6,130.0,129.5,127.9,127.0,122.9,122.1,121.3,108.9,81.0,41.4,28.6,21.1,16.6.ESI-MS(m/z,％)490[M+Na]+.
实施例35
化合物5h的合成
将实施例3中所用吲哚化合物2a换为4c，其余实验操作同实施例3，得到产物5h，为白色固体；99％产率，99％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.54(dd,J＝15.6,6.4Hz,1H),7.41-7.26(m,6H),7.17(d,J＝5.6Hz,1H),6.87(s,2H),6.00(brs,1H),5.99(dd,J＝15.6,1.6Hz,1H),5.13(dd,J＝6.4,1.2Hz,1H),2.26(s,3H),2.11(s,6H),1.47(s,9H).13C NMR(101MHz,CDCl3)δ164.4,153.2,149.8,146.1,139.8,135.7,132.9,130.0,129.5,129.4,128.7,128.1,124.8,123.3,122.5,81.2,46.4,28.6,21.1,16.6.ESI-MS(m/z,％)500[M+Na]+.
实施例36
化合物5i的合成
将实施例3中所用式1化合物1a更换为1g，吲哚化合物2a换为4c，其余实验操作同实施例3，得到产物5i，为白色固体；86％产率，99％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.51-7.45(m,3H),7.30(brs,1H),7.17(d,J＝5.2Hz,1H),7.14(dd,J＝8.4,1.6Hz,1H),6.87(s,2H),6.08-6.02(m,1H),5.97(dd,J＝15.6,1.6Hz,1H),5.13(dd,J＝6.4,1.6Hz,1H),2.26(s,3H),2.10(s,6H),1.47(s,9H).13C NMR(101MHz,CDCl3)δ164.2,153.2,149.2,146.0,138.9,135.7,133.0,132.5,130.4,130.0,129.5,125.1,123.5,122.7,122.1,81.2,45.7,28.6,21.1,16.6.ESI-MS(m/z,％)579[M+Na]+.
实施例37
化合物5j的合成
将实施例3中所用式1化合物1a更换为1i，吲哚化合物2a换为4c，其余实验操作同实施例3，得到产物5j，为白色固体；97％产率，97％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.51(dd,J＝15.6,6.8Hz,1H),7.35(brs,1H),7.17(d,J＝6.8Hz,1H),6.88(s,2H),6.49(s,2H),6.12-6.05(m,1H),6.02(dd,J＝15.6,0.8Hz,1H),5.06(dd,J＝6.8,0.8Hz,1H),3.86(s,3H),3.84(s,6H),2.27(s,3H),2.11(s,6H),1.48(s,9H).13C NMR(101MHz,CDCl3)δ164.4,154.0,153.2,149.6,146.0,137.8,135.8,135.3,133.0,130.0,129.6,124.9,123.2,122.4,105.7,81.1,61.2,56.5,46.6,28.6,21.1,16.6.ESI-MS(m/z,％)590[M+Na]+.
实施例38
化合物5k的合成
将实施例3中所用式1化合物1a更换为1k，吲哚化合物2a换为4c，其余实验操作同实施例3，得到产物5k，为白色固体；94％产率，99％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.52(dd,J＝15.6,6.4Hz,1H),7.38-7.36(m,2H),7.17(d,J＝5.6Hz,1H),7.14-7.11(m,1H),7.02(dd,J＝4.8,1.2Hz,1H),6.88(s,2H),6.10(brs,1H),6.03(dd,J＝15.6,1.2Hz,1H),5.23(dd,J＝6.4Hz,1H),,2.28(s,3H),2.12(s,6H),1.50(s,9H).13C NMR(101MHz,CDCl3)δ164.4,153.2,149.3,146.0,140.2,135.7,133.0,130.0,129.5,127.9,127.2,123.2,123.0,122.0,81.1,41.8,28.6,21.1,16.6.ESI-MS(m/z,％)506[M+Na]+.
实施例39
化合物5l的合成
将实施例3中所用吲哚化合物2a换为4d，其余实验操作同实施例3，得到产物5l，为黄色固体；99％产率，95％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.64(dd,J＝15.6,6.8Hz,1H),7.48(dt,J＝7.6,1.2Hz,1H),7.43(dt,J＝7.6,1.2Hz,1H),7.38-7.22(m,7H),6.86(s,2H),6.12(dd,J＝15.6,1.2Hz,1H),5.84(brs,1H),5.26(d,J＝6.4Hz,1H),2.25(s,3H),2.10(s,6H),1.48(s,9H).13C NMR(101MHz,CDCl3)δ164.4,153.7,148.1,146.1,138.4,135.7,130.1,129.5,129.3,128.8,128.0,124.9,123.3,122.8,119.4,112.0,81.3,46.0,28.6,21.1,16.7.ESI-MS(m/z,％)534[M+Na]+.
实施例40
化合物5m的合成
将实施例3中所用式1化合物1a更换为1i，吲哚化合物2a换为4d，其余实验操作同实施例3，得到产物5m，为黄色固体；89％产率，98％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.62(dd,J＝15.6,6.8Hz,1H),7.49(dd,J＝6.8,1.2Hz,1H),7.43(d,J＝7.6Hz,1H),7.31-7.23(m,2H),6.87(s,2H),6.63(s,2H),6.12(dd,J＝15.6,1.6Hz,1H),5.86(brs,1H),5.18(d,J＝6.8Hz,1H),3.85(s,6H),3.84(s,3H),2.26(s,3H),2.11(s,6H),1.49(s,9H).13C NMR(101MHz,CDCl3)δ164.4,153.9,153.7,147.9,146.1,137.8,135.7,133.8,130.0,129.6,126.2,125.0,123.4,122.8,119.4,116.0,111.9,106.0,81.3,61.2,56.5,46.2,28.5,21.1,16.6.ESI-MS(m/z,％)624[M+Na]+.
实施例41
化合物5n的合成
将实施例3中所用吲哚化合物2a换为4e，其余实验操作同实施例3，得到产物5n，为黄色固体；57％产率，99％ee，E:Z>99:1。
1H NMR(400MHz,CDCl3)δ7.66(dt,J＝8.4,1.6Hz,2H),7.45(dd,J＝15.6,6.8Hz,1H),7.41(d,J＝8.4Hz,1H),7.37-7.28(m,5H),7.25-7.19(m,3H),7.07(dd,J＝7.6,7.2Hz,1H),6.98(d,J＝7.6,Hz,1H),6.86(s,2H),6.13(brs,1H),5.16(dd,J＝6.8,1.6Hz,1H),2.38(s,3H),2.26(s,3H),2.10(s,6H).13C NMR(101MHz,CDCl3)δ164.5,154.3,153.8,153.7,148.1,146.0,144.6,144.4,138.6,138.0,136.6,136.1,135.6,130.1,130.0,129.9,129.5,129.2,128.8,127.9,127.7,125.8,125.4,125.0,124.0,123.5,123.3,122.6,119.4,119.0,118.9,114.2,112.0,119.9,44.8,21.8,21.0,16.6.ESI-MS(m/z,％)588[M+Na]+.
实施例42
化合物5o的合成
将实施例3中所用吲哚化合物2a换为4f，其余实验操作同实施例3，得到产物5o，为红色固体；99％产率，97％ee，E:Z＝93:7。
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1H NMR(400MHz,MeOD)δ7.71(dd,J＝15.6,7.2Hz,1H),7.41(dt,J＝7.6,1.2Hz,1H),7.38-7.25(m,6H),7.11-7.01(m,2H),6.87(s,2H),6.12(dd,J＝15.6,1.2Hz,1H),5.32(d,J＝7.2Hz,1H),2.25(s,3H),2.07(s,6H),1.52(s,9H).13C NMR(101MHz,MeOD)δ165.8,151.1,147.0,141.1,136.3,136.1,130.7,129.9,129.7,129.1,128.0,126.5,122.7,122.6,120.2,118.4,112.1,80.4,46.2,28.5,20.6,16.2.ESI-MS(m/z,％)533[M+Na]+.
实施例43
化合物5p的合成
将实施例3中所用式1化合物1a更换为1i，吲哚化合物2a换为4f，其余实验操作同实施例3，得到产物5p，为红色固体；85％产率，95％ee，E:Z>99:1。
1H NMR(400MHz,MeOD)δ7.70(dd,J＝15.6,7.2Hz,1H),7.41(dt,J＝7.6,1.2Hz,1H),7.29(d,J＝8.0,1H),7.12-7.00(m,2H),6.86(s,2H),6.68(s,2H),6.12(dd,J＝15.6,1.2Hz,1H),5.25(d,J＝7.2Hz,1H),3.80(s,6H),3.74(s,3H),2.23(s,3H),2.06(s,6H),1.52(s,9H).13C NMR(101MHz,MeOD)δ165.8,154.5,150.8,147.0,138.0,137.0,136.3,136.0,130.7,129.9,126.5,122.6,120.2,118.4,112.1,106.6,80.4,60.9,56.4,46.4,28.6,20.6,16.2.ESI-MS(m/z,％)623[M+Na]+.
实施例44
化合物5q的合成
将实施例3中所用式1化合物1a更换为1g，吲哚化合物2a换为4f，其余实验操作同实施例3，得到产物5q，为红色固体；94％产率，98％ee，E:Z>99:1。
1H NMR(400MHz,MeOD)δ7.66(dd,J＝15.6,7.6Hz,1H),7.48(dt,J＝8.4,1.6Hz,2H),7.41(dt,J＝7.6,1.2,2H),7.29-7.22(m,3H),7.12-7.01(m,2H),6.84(s,2H),6.12(dd,J＝15.6,1.2Hz,1H),5.28(d,J＝7.6Hz,1H),2.22(s,3H),2.05(s,6H),1.50(s,9H).13CNMR(151MHz,MeOD)δ165.7,150.2,147.0,140.4,136.3,136.1,132.7,131.1,130.7,129.9,126.4,123.0,122.7,121.9,120.3,118.4,112.1,80.4,45.6,28.5,20.6,16.2.ESI-MS(m/z,％)611[M+Na]+.
实施例45
化合物6a的合成
将Pd/C(10mol％)配体及化合物3aa(0.2mmol)投入到反应瓶中，加入甲醇(5mL)，用氢气球置换体系3次后，于25℃下继续反应。TLC监测反应完全。之后，用硅藻土过滤，旋干反应液，用硅胶柱层析分离得到产物6a，为白色固体，97％产率，80％ee。
1H NMR(400MHz,CDCl3)δ8.02(brs,1H),7.49(d,J＝12.0Hz,1H),7.37-7.26(m,5H),7.22-7.12(m,2H),7.07-6.99(m,2H),6.85(s,2H),4.32(t,J＝6.8Hz,1H),2.75-2.55(m,3H),2.51-2.40(m,1H),2.25(s,3H),2.07(s,6H).13C NMR(101MHz,CDCl3)δ172.1,146.2,144.4,136.8,135.6,130.0,129.6,128.9,128.3,127.2,126.7,122.4,121.5,119.8,119.7,119.6,111.4,42.6,32.8,31.5,21.1,16.7.ESI-MS(m/z,％)398[M+H]+.
实施例46
化合物6b的合成
将化合物3aa(0.2mmol)投入到反应瓶中，加入二氯甲烷(2mL)，冷却至-78℃后，缓慢滴加DIBAL-H(0.6mmol,3eq,1.5M in toluene)，在此温度下继续反应。TLC监测反应完全。之后，滴加水淬灭反应，过滤后用乙酸乙酯萃取3次，无水硫酸钠干燥有机相后旋去溶剂，用硅胶柱层析分离得到产物6b，为棕色油状液体，77％产率，91％ee。
1H NMR(400MHz,CDCl3)δ8.02(br,1H),7.37(dd,J＝15.6,8.4Hz,2H),7.32-7.14(m,6H),7.02(ddd,J＝6.8,6.8,1.2Hz,1H),6.89(d,J＝1.6Hz,1H),6.23(ddt,J＝15.6,7.2,1.2Hz,1H),6.23(dtd,J＝15.6,5.6,1.2Hz,1H),4.98(d,J＝7.2Hz,1H),4.18(d,J＝5.6Hz,2H).13C NMR(101MHz,CDCl3)δ143.2,136.6,134.4,130.0,128.4,128.4,126.1,126.4,122.4,122.1,119.8,119.4,118.6,111.1,63.5,45.6.ESI-MS(m/z,％)264[M+H]+.
实施例47
化合物6c的合成
将化合物6a(0.2mmol)投入到反应瓶中，加入二氯甲烷(2mL)，冷却至-78℃后，缓慢滴加DIBAL-H(0.6mmol,3eq,1.5M in toluene)，在此温度下继续反应。TLC监测反应完全。之后，滴加水淬灭反应，过滤后用乙酸乙酯萃取3次，无水硫酸钠干燥有机相后旋去溶剂，用硅胶柱层析分离得到产物6c，为棕色油状液体，两步71％产率，82％ee。
1H NMR(400MHz,Chloroform-d)δ7.99(br,1H),7.44(d,J＝8.0Hz,1H),7.34-7.24(m,5H),7.15(dd,J＝15.2,8.0Hz,2H),7.06(d,J＝2.0Hz,1H),7.01(dd,J＝8.0,7.2Hz,1H),4.18(t,J＝8.0Hz,1H),4.18(t,J＝6.8Hz,2H),2.30-2.07(m,2H),1.71-1.60(m,2H).13C NMR(101MHz,CDCl3)δ145.5,136.8,128.7,128.2,127.3,126.4,122.3,121.3,120.6,119.8,119.6,111.4,63.4,43.1,32.6,31.7.ESI-MS(m/z,％)266[M+H]+.
实施例48
化合物7a的合成
将实施例45中所用的3aa更换为5a,其余实验操作同实施例43，得到产物7a，为棕色油状液体；95％产率，97％ee。
1H NMR(400MHz,CDCl3)δ7.83(brs,1H),7.36-7.30(m,2H),7.27-7.21(m,3H),6.86(s,2H),6.64(dd,J＝4.4,2.8Hz,1H),6.16(dd,J＝6.0,2.8Hz,1H),6.13-6.10(m,1H),4.05(dd,J＝8.4,6.8Hz,1H),2.64-2.51(m,3H),2.44-2.30(m,1H),2.25(s,3H),2.07(s,6H).13CNMR(101MHz,CDCl3)δ171.8,146.2,143.0,135.6,134.3,129.9,129.6,129.2,128.3,127.3,117.4,108.5,105.6,44.3,32.3,31.0,21.1,16.6.ESI-MS(m/z,％)348[M+H]+.
实施例49
化合物7b的合成
将实施例46中所用的3aa更换为5a，其余实验操作同实施例44，得到产物7b，为白色固体；73％产率，98％ee。
1H NMR(400MHz,CDCl3)δ7.96(br,1H),7.33-7.18(m,5H),6.66(dd,J＝4.4,2.8Hz,1H),6.14(dd,J＝6.0,2.8Hz,1H),6.09(ddt,J＝15.6,7.6,1.2Hz,1H),5.92-5.90(m,1H),5.66(dtd,J＝15.6,5.6,1.2Hz,1H),4.70(d,J＝7.6Hz,1H),4.14(d,J＝5.6Hz,2H).13C NMR(151MHz,CDCl3)δ142.4,133.6,133.3,130.9,129.0,128.6,127.2,117.6,108.6,106.8,63.5,47.8.ESI-MS(m/z,％)214[M+H]+.
实施例50
化合物7c的合成
将实施例47中所用的6a更换为7a，其余实验操作同实施例45，得到产物7c，为棕色油状液体；97％产率，97％ee。
1H NMR(400MHz,CDCl3)δ7.88(brs,1H),7.30-7.03(m,5H),6.54-6.52(m,1H),6.06(dd,J＝6.0,2.8Hz,1H),6.00-5.97(m,1H),3.82(dd,J＝8.4,7.2Hz,1H),3.53(t,J＝6.4Hz,2H),2.13-2.05(m,1H),1.99-1.91(m,1H).1.51-1.39(m,2H).13C NMR(101MHz,CDCl3)δ144.0,135.3,128.9,128.3,126.9,117.1,108.3,105.3,63.0,44.8,32.0,31.1.ESI-MS(m/z,％)216[M+H]+.
实施例51
化合物8a的合成
将[Rh(PPh3)3Cl}2(0.01mmol,5mol％)配体、氨-甲硼烷络合物(0.6mmol,3eq)及化合物5h(0.2mmol)投入到反应瓶中，无水无氧处理后，加入二氯甲烷(3mL)，于25℃下继续反应。TLC监测反应完全。之后，旋干反应液，用硅胶柱层析分离得到中间体，将其全部溶于1,4-二氧六环(5mL)，加入盐酸(4M in 1,4-dioxane,50eq)，于25℃下继续反应。TLC监测反应完全。之后，加入饱和碳酸氢钠中和至pH至7-8，乙酸乙酯萃取3次，无水硫酸钠干燥有机相后旋去溶剂，用硅胶柱层析分离得到产物8a，为棕色油状液体，两步69％产率，97％ee。
1H NMR(400MHz,CDCl3)δ7.36-7.30(m,4H),7.27-7.22(m,1H),7.00(d,J＝5.3Hz,1H),6.86(s,2H),6.55(d,J＝5.3Hz,1H),4.17(dd,J＝8.2,7.1Hz,1H),3.40(brs,2H),2.65-2.60(m,2H),2.57-2.37(m,2H),2.25(s,3H),2.08(s,6H).13C NMR(101MHz,CDCl3)δ171.9,146.2,143.2,141.0,135.7,129.9,129.6,129.2,128.1,127.2,122.3,121.9,120.2,43.1,32.2,32.1,21.1,16.6.ESI-MS(m/z,％)380[M+H]+.
实施例52
化合物8b的合成
将8a(0.1mmol)投入到反应瓶中，加入四氢呋喃(1mL)，冷却至0℃后依次加入HBF4(2eq)和亚硝酸钠(1.2eq in 0.1mL H2O)，于此温度下继续反应40分钟。再依次加入[Rh(cod)Cl]2(3.0mol％)和Et3SiH(2.0eq)，缓慢升至室温反应4h。TLC监测反应完全。之后，加入EA淬灭反应，并用EA萃取3次，合并有机相，用无水硫酸钠干燥后过滤，旋干溶剂，用硅胶柱层析分离得到产物8b，为无色油状液体，72％产率，96％ee。
1H NMR(400MHz,CDCl3)δ7.30-7.22(m,3H),7.21-7.05(m,3H),6.91-6.81(m,2H),6.78(s,2H),4.23(t,J＝7.1Hz,1H),2.56-2.38(m,4H),2.18(s,3H),2.00(s,6H).13C NMR(101MHz,CDCl3)δ171.5,148.5,146.2,143.8,135.6,129.9,129.6,129.1,128.0,127.3,127.0,124.5,124.2,46.4,32.8,32.5,21.1,16.6.ESI-MS(m/z,％)387[M+Na]+.
实施例53
化合物8c的合成
将氯化亚铜(0.5mmol,5.0eq)投入到反应瓶A中，加入盐酸(4N in H2O,0.5mL)并于室温下搅拌10分钟。将化合物8a投入到反应瓶B中，依次加入四氢呋喃(1mL)和盐酸(4Nin H2O,0.1mL)，冷却至0℃后缓慢加入亚硝酸钠(1.2eq in 0.1mL H2O)，于此温度下继续反应40分钟。将反应瓶A冷却至0℃，将反应瓶B中生成的重氮盐溶液用注射器吸入并缓慢滴加至反应瓶A，随后缓慢升至室温反应。TLC监测反应完全。之后，加入EA淬灭反应，并用EA萃取3次，合并有机相，用无水硫酸钠干燥后过滤，旋干溶剂，用硅胶柱层析分离得到产物8c，为无色油状液体，58％产率，97％ee。
1H NMR(400MHz,CDCl3)δ7.36-7.28(m,4H),7.17(dd,J＝5.2,1.2Hz,1H),6.96-6.88(m,2H),6.86(s,2H),4.31(dd,J＝8.5,6.0Hz,1H),2.68-2.43(m,4H),2.25(s,3H),2.08(s,6H).13C NMR(101MHz,CDCl3)δ171.5,148.5,146.2,143.8,135.6,129.9,129.6,129.1,128.0,127.3,127.0,124.5,124.2,46.4,32.8,32.5,21.1,16.7.ESI-MS(m/z,％)421[M+Na]+.
实施例54
化合物8d的合成
将8a(0.1mmol)投入到反应瓶中，加入四氢呋喃(1mL)，冷却至0℃后依次加入H2SO4(4M in H2O,0.1mL)和亚硝酸钠(1.2eq,0.12mmol in 0.1mL H2O)，于此温度下继续反应40分钟。再依次加入氧化亚铜(0.1mmol,1eq)和硫酸铜(1mmol,10.0eq)，缓慢升至室温反应。TLC监测反应完全。之后，加入EA淬灭反应，并用EA萃取3次，合并有机相，用无水硫酸钠干燥后过滤，旋干溶剂，用硅胶柱层析分离得到产物8d，为无色油状液体，88％产率，97％ee。
Colorless oil,33.4mg,88％yield,97％ee.[α]25 D＝-3.43(c 1.16,CHCl3).1HNMR(400MHz,CDCl3)δ7.36-7.29(m,4H),7.17(dd,J＝5.1,1.2Hz,1H),6.98-6.87(m,2H),6.86(s,2H),4.31(dd,J＝8.4,6.2Hz,1H),2.68-2.43(m,4H),2.26(s,3H),2.08(s,6H).13CNMR(101MHz,CDCl3)δ171.5,148.5,146.2,143.8,135.6,129.9,129.6,129.1,128.0,127.3,127.0,124.5,124.2,46.4,32.8,32.5,21.1,16.7.ESI-MS(m/z,％)403[M+Na]+.
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在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种高光学纯度的偕二(杂)芳基甲基取代的α,β-不饱和酯类化合物的制备方法，其特征在于，包括步骤：
在有机溶剂中，在一价铑催化剂/手性双烯配体的存在下，式1化合物α-芳乙烯基-α-重氮芳酯对式2化合物N-H无保护取代吲哚的C3位进行碳-氢键不对称插入反应，从而得到式3/或式ent-3所示的手性偕二(杂)芳基甲基-α,β-不饱和酯类化合物；
或者，式1化合物α-芳乙烯基-α-重氮芳酯对式4化合物的C2位进行碳-氢键不对称插入反应，得到式5/或式ent-5所示的手性β-偕二(杂)芳基甲基-α,β-不饱和酯类化合物；
式中，
Ar1、Ar2各自独立地为取代或未取代的C6-30芳基、取代或未取代的5-30元杂芳基，其中，所述的取代是指一个或多个H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基、C3-8环烷基、C3-8环烷氧基，或其组合；
R1为H、取代或未取代的氨基、取代或未取代的C1-10烷基、取代或未取代的C1-6烯基、取代或未取代的C3-8环烷基、取代或未取代的C1-10烷氧基、取代或未取代的3-8元杂环基、取代或未取代的C6-C30芳基；其中，所述的取代是指一个或多个H被选自下组的基团取代：取代或未取代的苯基、5-30元杂芳基、氨基；所述的取代是指一个或多个H被选自下组的基团取代：卤素、C1-6烷基、C3-8环烷基、C1-6卤代烷基、硝基；
其中，中的虚线代表无或与/>相邻的两个碳原子构成苯基；
X为O、NH或S；
Y为氢、卤素、羟基、-N(Ra)Rb、C1-30烷氧基、C1-30烷氨基；所述卤素为F、Cl、Br、I；其中，Ra和Rb各自独立地为H、C1-8烷基或保护基。
2.如权利要求1所述的方法，其特征在于，所述的Ar1为取代或未取代的苯基、取代或未取代的萘基、取代或未取代的噻吩基、取代或未取代的呋喃基；所述的取代是指一个或多个H被选自下组的基团取代：卤素、C1-4卤代烷基、C1-6烷基、C3-8环烷基、C1-4烷氧基、C6-10芳基；所述的Ar2为取代或未取代的苯基、取代或未取代的萘基；所述的取代是指一个或多个H被选自下组的基团取代：卤素、C1-6烷基、C3-8环烷基、C1-4卤代烷基。
3.如权利要求1所述的方法，其特征在于，按式1化合物的用量计，所述的一价铑催化剂的用量为0.4～20mol％；所述的手性双烯配体的用量为0.5～25mol％。
4.如权利要求1所述的方法，其特征在于，所述的手性双烯配体具有如下结构式：
式中，R2、R3各自独立地为取代或未取代的C6-30芳基，所述的取代基是指一个或多个H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、C1-6卤代烷氧基。
5.如权利要求4所述的方法，其特征在于，R2、R3各自独立地为取代或未取代的苯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的二茂铁基；所述的取代基是指一个或多个H被选自下组的基团取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-8环烷基。
6.如权利要求1所述的方法，其特征在于，所述的一价铑催化剂选自下组：[Rh(C2H4)2Cl]2、[Rh(C2H4)2OH]2、[Rh(coe)2Cl]2、[Rh(coe)2OH]]2、[Rh(C2H4)2OMe]2、[Rh(coe)2OMe]2，或其组合。
7.如权利要求1所述的方法，其特征在于，所述的方法还具有选自下组的一个或多个特征：
(1)所述的有机溶剂为C1-4的卤代烷烃；所述的C1-4的卤代烷烃选自下组：二氯甲烷、1,2-二氯乙烷，氯仿、1,2-二氯丙烷、1-氯丁烷，或其组合；
(2)反应温度在15-40℃；
(3)反应时间为0.5-24小时。
8.一种式7或式ent-7所示的化合物，其特征在于，
式中，
Z为O或OH，A为H、OH或OAr2；
每个独立为双键或单键；
并且当Z为O时，所述与Z相连的为双键，A为OH或OAr2；当Z为OH时，所述与Z相连的为单键，A为H；
Ar1、Ar2、R1如权利要求1所定义；
其中，式7或ent-7化合物的ee值≥80％。
9.一种式8或式ent-8所示的化合物，其特征在于，
式中，
Z为O或OH，A为H、OH或OAr2；
每个独立为双键或单键；
并且当Z为O时，所述与Z相连的为双键，A为OH或OAr2；当Z为OH时，所述与Z相连的为单键，A为H；
Ar1、Ar2、R1、X、Y如权利要求1所定义；
其中，所述式8或ent-8化合物的ee值≥95％。
10.一种手性双烯配体，其特征在于，所述的手性双烯配体具有如下结构式：
式中，
R4为
R5为取代的苯基其中，Rf、Rg、Rh各自独立地为H、卤素、氰基、硝基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、苄氧基，或其组合。
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