Process for the preparation of alpha, beta-unsaturated ester compounds substituted with gem-di(hetero)arylmethyl groups of high optical purity

Abstract

The present application relates to a preparation method of high optical purity di (hetero) arylmethyl substituted alpha, beta-unsaturated ester compounds. The method uses monovalent rhodium catalysis / chiral diene ligand as a catalyst, and realizes the selective asymmetric functionalization reaction of C2 or C3 of N-H unprotected indole, pyrrole, furan, thiophene and benzofuran by the monovalent rhodium metal carbene obtained by diazo decomposition. The catalyst used in the method has low dosage, mild reaction conditions, simple operation, good substrate universality, and can obtain di (hetero) arylmethyl substituted alpha, beta-unsaturated ester compounds with high yield and enantioselectivity.

Description

Technical Field

[0001] This invention belongs to the field of chemistry. Specifically, this invention relates to a method for preparing chiral geminal di(hetero)arylmethyl-substituted α,β-unsaturated ester compounds by an intermolecular asymmetric carbon-hydrogen bond insertion reaction involving monovalent rhodium metal carbene. Background Technology

[0002] In organic synthesis, transition metal-catalyzed carbene insertion into CH,XH (X = O, N, S, Si) bonds is a crucial method for constructing CC,CX bonds. Significant progress has been made in the study of catalytic asymmetric carbene insertion into CH bonds ((a) Davies, HML; Beckwith, REJ Chem. Rev. 2003, 103, 2861; (b) Díaz-Requejo, MM; Pérez, PJ Chem. Rev. 2008, 108, 3379; (c) Davies, HML; Manning, JRN Nature 2008, 451). ,417;(d)Doyle,MP;Duffy,R.;Ratnikov,M.;Zhou,L.Chem.Rev.2010,110,704;(e)Davies,HML;Mo rton, D. Chem. Soc. Rev. 2011, 40, 1857; (f) Zhu, S.-F.; Zhou, Q.-L. Acc. Chem. Res. 2012, 45, 1365). Our research group has long been dedicated to studying asymmetric CH and XH insertion reactions mediated by monovalent rhodium carbene, and has reported a series of C1 symmetrical chiral diene ligands in Rh(I) carbene-mediated asymmetric BH, Si-H, CH insertion and oxa-Michael addition cascades ((a) Chen, D.;Zhang, X.;Qi, W.-Y.;Xu, B.;Xu, M.-HJAm. Chem. Soc. 2015, 137, 5268; (b) Chen, D.;Zhu, D.-X.;Xu, M.-HJAm. C hem.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.; Chu ng, LW; Xu, M.-HJAm.Chem.Soc.2021,143.2608; (e) Zhu, D.-X.; Liu, J.-G.; Xu, M.-HJAm.Chem.Soc.2021,143,8583).

[0003] Chiral geminal diarylmethyl structures are important structural units widely found in many natural products, bioactive compounds, and synthetic molecules. In particular, chiral geminal diaryl molecules containing indole and other aromatic heterocycles represent a unique class of compounds with diverse potential biological activities and drug research value. ((a) Prat, M.; Fernández, D.; Buil, MA; Crespo, MI; Casals, G.; Ferrer, M.; Tort, L.; Castro, J.; Monleón, JM; Gavaldà, A.; Miralpe) ix, M.; Ramos, I.; Doménech, T.; Vilella, D.; Antón, F.; Huerta, JM; Espinosa, S.; López, M.; Sentellas, S.; González, M.; Albertí, J.; Segarra, V.; Cárdenas, A.; Beleta, J.; Ryder, HJ Med. Chem. 2009, 52, 5076; (b) Islam, MS; Barakat, A.; Al-Maj id, AM; Ali, M.; Yousuf, S.; Choudhary, MI; 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, WTA; Lichtman, A.- H.; Ross, R.-A.; Zanda, M.; Greig, I.-RJMed.Chem.2019,62,5049; (d) Zou, Y.-L.; Li, H.-X.; Graham, E.-T.; Deik, A.-A.; E aton, J.-K.; Wang, W.-L.; Gerardo, S.-G.; Clish, C.-B.; Doench, J.-G.; Schreiber, S.-L. Nat. Chem. Biol. 2020, 16, 302).

[0004] In recent years, there have been many successful reports of asymmetric CH insertion reactions of indole mediated by metal carbene α-diazocarbonyl compounds. Various chiral metal catalysts have been used, such as Rh(II) ((a) Lian, Y.; Davies, HML 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.- Complexes such as 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), and Ir(III)(Li,N.;Zhu,W.-J.;Huang,J.-J.;Hao,X.-Q.;Gong,J.-F.;Song,M.-P.Organometallics 2020,39,2222) can achieve this transformation.

[0005] Nevertheless, the methods described above are generally limited to obtaining chiral α-(3-indolyl)-α-aryl acetates by simply forming a metal carbene in situ from an α-diazo compound and inserting it into the C3 position of an indole. Furthermore, most examples require protection of the nitrogen atom of the indole, thus necessitating additional nitrogen-protecting group removal reactions in further transformations. Furthermore, the nucleophilic reactivity of indole at C3 and N1 leads to multi-site competition in the reaction, and the enantioselectivity control of the reaction is very challenging. It is worth noting that there are currently no examples of asymmetric C2-H functionalization of indole catalyzed by carbene CH insertion ((a) Chan, W.-W.; Yeung, S.-H.; Zhou, Z.-Y.; Chan, ASC; Yu, W.-Y. Org. Lett. 2010, 12, 604; (b) James, MJ; O'Brien, P.; Taylor, RJK; Unsworth, W.P. Angew. Chem. Int. Ed. 2016, 55, 9671; (c) Arredondo, V.; Hiew, SC; Gutman, ES; Premachandra, IDUA; Vranken, DLVAngew.Chem.Int.Ed.2017,56,4156;(d)Ghorai,J.;Chaitanya,M.;Anbarasan,P.Org.Biomol.Chem.2018,16,7346;(e)Nag,E.;Gorantla,SMNVT;Arumugam,S.;Kulkarni,A.;M ondal, KC; Roy, S. Org. Lett. 2020, 22, 6313; (f) Guha, S.; Gadde, S.; Kumar, N.; Black, DS; Sen, SJOrg. Chem. 2021, 86, 5234; (g) Maiti, D.; Das, R.; Sen, SJ Org. Chem. 2021, 86, 2522).

[0006] Therefore, there is an urgent need in this field to develop new, efficient, practical, and low-cost methods for preparing a variety of structurally diverse chiral geminal methyl-substituted α,β-unsaturated carbonyl compounds with high optical purity. Summary of the Invention

[0007] The purpose of this invention is to provide an efficient, practical, and low-cost method for preparing various structurally diverse chiral geminal di(hetero)arylmethyl-substituted α,β-unsaturated carbonyl compounds with high optical purity.

[0008] A first aspect of the present invention provides a method for preparing high-optical-purity geminitromethyl-substituted α,β-unsaturated ester compounds, comprising the steps of:

[0009] In an organic solvent, in the presence of a monovalent rhodium catalyst / chiral diene ligand, the α-arylevinyl-α-diazoarylester of Formula 1 undergoes a carbon-hydrogen bond asymmetric insertion reaction on the C3 position of the unprotected substituted indole of Formula 2, thereby yielding the chiral geminal diaryleylmethyl-α,β-unsaturated ester compound shown in Formula 3 / or ent-3.

[0010] Alternatively, the α-arylevinyl-α-diazoaryl ester of Formula 1 undergoes a carbon-hydrogen bond asymmetric insertion reaction at the C2 position of the compound of Formula 4 to obtain the chiral β-gemethylenedi(hetero)arylmethyl-α,β-unsaturated ester compound shown in Formula 5 / or ent-5.

[0011]

[0012] In the formula,

[0013] Ar 1 Ar 2 Each is independently either substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 5-30 membered heteroaryl groups, wherein the substitution refers to one or more (e.g., 1-5) H atoms being substituted by groups selected from the group consisting of: halogens, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy groups, or combinations thereof;

[0014] R 1 H, substituted or unsubstituted amino group, substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 1-6 alkenyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C6-C 30 Aryl; wherein the substitution refers to one or more (e.g., 1-5) H atoms being substituted by a group selected from the group consisting of: substituted or unsubstituted phenyl, 5-30 membered heteroaryl, amino; the substitution refers to one or more (e.g., 1-5) H atoms being substituted by a group selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Halogenated alkyl groups, nitro groups;

[0015] in, The dashed line in the middle represents none or equal to Two adjacent carbon atoms form a phenyl group;

[0016] X is O, NH, or S;

[0017] Y represents hydrogen, halogen, hydroxyl group, -N(Ra)Rb, or C. 1-30 Alkoxy, C 1-30 Alkylamino; the halogen is F, Cl, Br, I; wherein Ra and Rb are each independently H and C. 1-8 Alkyl groups or protecting groups.

[0018] In another preferred example, Ar 1 Ar 2 Each is independently either substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-8 membered heteroaryl, wherein the substitution refers to one or more (e.g., 1-5) H atoms being substituted by groups selected from the group consisting of: halogens, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy groups, or combinations thereof.

[0019] In another preferred embodiment, R 1 H, substituted or unsubstituted amino group, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl; wherein the substitution refers to one or more (e.g., 1-5) H atoms being substituted by a group selected from the group consisting of: substituted or unsubstituted phenyl, 5-8 membered heteroaryl, amino; the substitution refers to one or more (e.g., 1-5) H atoms being substituted by a group selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Halogenated alkyl groups, nitro groups.

[0020] In another preferred embodiment, the 5-30 heteroaryl group is pyrrole, furan, thiophene, indole, or benzofuran.

[0021] In another preferred embodiment, the compound of formula 4 is a substituted indole, a substituted pyrrole, a substituted furan, a substituted thiophene, or a substituted benzofuran;

[0022] In another preferred embodiment, Y is hydrogen, halogen, hydroxyl, amino, -NHRb, C 1-8 Alkyl groups; the halogens are F, Cl, Br, I, and Rb is a protecting group.

[0023] In another preferred embodiment, Rb is a protecting group selected from the group consisting of Boc, Ts, and Cbz.

[0024] In another preferred embodiment, the Ar 1 The substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, or substituted or unsubstituted furanyl groups; the substitution refers to one or more (e.g., 1-5) H atoms being substituted by groups selected from the group consisting of halogens, C... 1-4 Haloalkyl, C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-4 Alkoxy, C 6-10 Aryl.

[0025] In another preferred embodiment, the Ar 2 The substituted or unsubstituted phenyl group, or the substituted or unsubstituted naphthyl group; the substitution refers to one or more (e.g., 1-5) H atoms being replaced by groups selected from the group consisting of: halogens, C... 1-6 Alkyl, C 3-8 cycloalkyl, C 1-4 Halogenated alkyl groups.

[0026] In another preferred embodiment, the amount of the monovalent rhodium catalyst is 0.4–20 mol% based on the amount of the compound of Formula 1; and the amount of the chiral diene ligand is 0.5–25 mol%.

[0027] In another preferred embodiment, the ee value of the compound of formula 3 or ent-3 is ≥80%, more preferably ≥90%, more preferably ≥95%, and most preferably ≥98%.

[0028] In another preferred embodiment, the ee value of the compound of formula 5 or ent-5 is ≥95%, more preferably ≥97%, more preferably ≥98%, and most preferably ≥99%.

[0029] In another preferred embodiment, the chiral diene ligand has the following structural formula:

[0030]

[0031] In the formula, R 2 R 3 Each is independently either substituted or unsubstituted C 6-30 aryl, where the substituent refers to one or more (e.g., 1-5) H atoms being replaced by groups selected from the group consisting of: halogens, C atoms, etc. 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups.

[0032] In another preferred embodiment, R 2 R 3 Each is independently either substituted or unsubstituted C 6-10 aryl, where the substituent refers to one or more (e.g., 1-5) H atoms being replaced by groups selected from the group consisting of: halogens, C atoms, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups.

[0033] In another preferred embodiment, the C 6-30 The aryl group is phenyl, naphthyl, anthracene, or ferrocene.

[0034] In another preferred embodiment, R 2 R 3 Each of the following is independently a substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthraceneyl, or substituted or unsubstituted ferroceneyl; the substituent refers to one or more (e.g., 1-5) H atoms being substituted by groups selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl.

[0035] In another preferred embodiment, the R 2 and R 3 Each is independently a substituted or unsubstituted phenyl group, wherein substitution refers to one or more (e.g., 1-5) H atoms being substituted by groups selected from the group consisting of halogens, C atoms, and so on. 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

[0036] In another preferred embodiment, the chiral diene ligand is selected from the group consisting of:

[0037]

[0038] In another preferred embodiment, the monovalent rhodium catalyst is selected from the group consisting of [Rh(C2H4)2Cl]2, [Rh(C2H4)2OH]2, [Rh(coe)2Cl]2, [Rh(coe)2OH]]2, [Rh(C2H4)2OMe]2, [Rh(coe)2OMe]2, or combinations thereof.

[0039] In another preferred embodiment, the compound of formula 1 is selected from the group consisting of:

[0040]

[0041]

[0042] In another preferred embodiment, the compound of formula 2 is selected from the group consisting of:

[0043]

[0044] In another preferred embodiment, the compound of formula 4 is selected from the group consisting of:

[0045]

[0046]

[0047] In another preferred embodiment, the method further has one or more features selected from the group consisting of:

[0048] (1) The organic solvent is C 1-4 Halogenated alkanes; the C 1-4 The haloalkanes are selected from the group consisting of: dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dichloropropane, 1-chlorobutane, or combinations thereof;

[0049] (2) The reaction temperature is 15-40℃;

[0050] (3) The reaction time is 0.5-24 hours.

[0051] In a second aspect of the invention, a compound represented by formula 7 or formula ent-7 is provided.

[0052]

[0053] In the formula,

[0054] Z represents O or OH, and A represents H, OH, or OAr. 2 ;

[0055] Each It can be a double bond or a single bond;

[0056] And when Z is 0, the one connected to Z It is a double bond, and A is OH or OAr. 2 When Z is OH, the part connected to Z... It is a single bond, A is H;

[0057] Ar 1 Ar 2 R 1 As defined in the first aspect of this invention;

[0058] Wherein, the ee value of the compound of formula 7 or ent-7 is ≥80%, preferably ≥90%, more preferably ≥95%, and most preferably ≥98%.

[0059] In another preferred embodiment, Z is O, and A is OH or OAr. 2 .

[0060] In another preferred embodiment, the Ar 2 for

[0061] In the formula, Rc and Rd are independently represented by: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy groups, or combinations thereof;

[0062] Re is H, or halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, C 3－8 cycloalkyl, C 3－8 Cycloalkoxy groups, or combinations thereof.

[0063] In another preferred embodiment, Rc and Rd are each independently: halogen, C 1-6 Alkyl groups or combinations thereof; Re is H, halogen, or C. 1-6 Alkyl groups, or combinations thereof.

[0064] In another preferred embodiment, the Ar 1 Ar 2 R 1 The X, Y, Z or A groups are the corresponding groups in the specific compounds in the examples.

[0065] In another preferred embodiment, the compound is selected from the group consisting of:

[0066]

[0067]

[0068] In a third aspect of the invention, a compound represented by formula 8 or ent-8 is provided.

[0069]

[0070] In the formula,

[0071] Z represents O or OH, and A represents H, OH, or OAr. 2 ;

[0072] Each It can be a double bond or a single bond;

[0073] And when Z is 0, the one connected to Z It is a double bond, and A is OH or OAr. 2 When Z is OH, the part connected to Z... It is a single bond, A is H;

[0074] Ar 1 Ar 2 R 1 X, Y are as defined in the first aspect of this invention;

[0075] Wherein, the ee value of the compound of formula 8 or ent-8 is ≥95%, preferably ≥97%, more preferably ≥98%, and most preferably ≥99%.

[0076] In another preferred embodiment, Z is O, and A is OH or OAr. 2 .

[0077] In another preferred embodiment, the Ar 1 Ar 2 R 1 The X, Y, Z or A groups are the corresponding groups in the specific compounds in the examples.

[0078] In another preferred embodiment, the compound is selected from the group consisting of:

[0079]

[0080]

[0081] In a fourth aspect, the present invention provides a chiral diene ligand having the following structural formula:

[0082]

[0083] In the formula,

[0084] R 4 for

[0085] R 5 substituted phenyl Among them, R f R g R h Each is independently H, halogen, cyano, nitro, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, or combinations thereof.

[0086] In another preferred embodiment, the R f R g R h Each is independently H, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, or combinations thereof.

[0087] In another preferred embodiment, the R f R g R h Each of them is independently H, fluorine, cyano, nitro, trifluoromethyl, or a combination thereof.

[0088] In another preferred embodiment, the chiral diene ligand is selected from the group consisting of:

[0089]

[0090] In another preferred embodiment, the chiral diene ligand is (R,R)-6j or (S,S)-6j.

[0091] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0092] Through extensive and in-depth research, the inventors utilized a monovalent rhodium catalyst / chiral diene complex as a catalyst to efficiently construct gem-di(hetero)arylmethyl-α,β-unsaturated ester compounds with high optical purity by using monovalent rhodium metal carbene obtained from diazo decomposition to perform asymmetric C-H bond insertion reactions on the C3 position of unprotected substituted indoles of NH4+, or on the C2 position of substituted indoles, substituted pyrroles, substituted furans, substituted benzofurans, and substituted thiophenes. Furthermore, by selecting chiral ligands with different configurations, the method of this invention can yield gem-di(hetero)arylmethyl-α,β-unsaturated ester compounds with opposite configurations. Based on this, the present invention was completed.

[0093] the term

[0094] As used herein, the term "alkyl" refers to a straight-chain, branched, or cyclic alkyl group, preferably C14. 1-10 Alkyl groups, more preferably C14 groups. 1-6Alkyl group. In this invention, the alkyl group further includes a group in which one or more H atoms on the alkyl group are replaced by substituents selected from the group consisting of: halogens, substituted or unsubstituted phenyl groups, unsubstituted or C atoms substituted with one or more halogens. 1-6 Alkyl. It should be understood that the term also includes C. 3-10 Substituted or unsubstituted cycloalkyl groups.

[0095] As used herein, the term "alkoxy" refers to C1-C 10 The alkoxy group is a straight-chain, branched, or cyclic alkoxy group. In this invention, the alkoxy group also includes a group in which one or more H atoms on the alkyl group are replaced by substituents selected from the group consisting of: halogens, substituted or unsubstituted phenyl groups, unsubstituted or substituted C atoms with one or more halogens. 1-6 alkyl.

[0096] As used in this article, the term "aryl" refers to C6-C 30 Aryl groups, representative examples of which are phenyl, naphthyl, anthraceneyl, and phenanthrene, are also included in this invention. In this invention, the aryl group further includes groups in which one or more H atoms on the aryl group are replaced by substituents selected from the group consisting of halogens, phenyl groups, unsubstituted or halogen-substituted C atoms. 1-6 Alkyl, unsubstituted, or C substituted with one or more halogens 1-6 Alkyl group.

[0097] As used herein, the term "heteroaryl" refers to a 5-30 member heteroaryl group, with representative examples being pyridyl, thiophene, indolyl, and furanyl. In this invention, the heteroaryl group also includes a group in which one or more H atoms on the heteroaryl group are substituted by substituents selected from the group consisting of halogens, phenyl groups, unsubstituted C atoms, or C atoms substituted with one or more halogens. 1-6 Alkyl, unsubstituted, or C substituted with one or more halogens 1-6 Alkyl group.

[0098] As used herein, the term "one or more" generally refers to 1-6; preferably 1-5; and more preferably 1-3.

[0099] As used in this article, the term "Ph" refers to phenyl.

[0100] As used in this article, the term “RT” refers to room temperature, such as 15-40°C.

[0101] Generally, the upper limit of the ee value of a compound is no more than 99.9%.

[0102] The term "-N(Ra)Rb" refers to the substitution of one or more hydrogen atoms on an amino group.

[0103] Preparation method

[0104] The synthesis method of this invention can be represented by the following typical reaction formula:

[0105]

[0106] In an organic solvent, in the presence of a monovalent rhodium catalyst / chiral diene ligand, the following compound α-arylene-α-diazoarylene ester 1 is catalyzed to undergo a carbon-hydrogen bond asymmetric insertion reaction at the C3 position of an NH unprotected substituted indole 2, thereby forming a gem-di(hetero)arylmethyl-α,β-unsaturated ester compound as shown in formula 3 or ent-3; or a carbon-hydrogen bond asymmetric insertion reaction at the C2 position of a substituted indole, substituted pyrrole, substituted furan, substituted benzofuran, or substituted thiophene 4, thereby forming a gem-di(hetero)arylmethyl-α,β-unsaturated ester compound as shown in formula 5 or ent-5.

[0107] Reaction substrate 1 is an α-arylene-α-diazo arylate, wherein Ar 1 C6-C, whether unsubstituted or substituted 30 Aryl, heteroaryl, wherein the substitution refers to having one or more (e.g., 1-5) substituents, wherein the substituents are selected from the group consisting of halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, or combinations thereof; the halogen is F, Cl, Br, or I; wherein the heteroaryl group refers to pyridine, furan, thiophene, or indole having one or more (e.g., 1-5) substituents;

[0108] Ar 2 C6-C, whether unsubstituted or substituted 30 Aryl, heteroaryl, wherein the substitution refers to having one or more (e.g., 1-5) substituents, wherein the substituents are selected from the group consisting of halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, or combinations thereof; the halogen is F, Cl, Br, or I; wherein the heteroaryl group refers to pyridine, furan, thiophene, or indole having one or more (e.g., 1-5) substituents.

[0109] Substrate 2 is an NH-unprotected substituted indole, wherein R 1 C 1-10 Alkyl, substituted or unsubstituted C 1-6 alkenyl, substituted or unsubstituted C6-C 30 C substituted with aryl, aryl or heteroaryl 1-6 Alkyl, amino and C 1-30The primary or secondary amino group; wherein the aryl group is a phenyl group or a phenyl group substituted with one or more substituents selected from the group consisting of: halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, nitro; the halogen is F, Cl, Br, I; wherein the heteroaryl refers to pyridine, thiophene, furan, pyrrole having one or more (e.g., 1-5) substituents;

[0110] Reaction substrate 4 is a substituted indole, a substituted pyrrole, a substituted furan, a substituted benzofuran, or a substituted thiophene, wherein R 1 For H, C 1-10 Alkyl, substituted or unsubstituted C 1-6 alkenyl, substituted or unsubstituted C6-C 30 C substituted with aryl, aryl or heteroaryl 1-6 Alkyl, amino and C 1-30 The primary or secondary amino group; wherein the aryl group is a phenyl group or a phenyl group substituted with one or more substituents selected from the group consisting of: halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, nitro; the halogen is F, Cl, Br, I; wherein the heteroaryl refers to pyridine, thiophene, furan, pyrrole having one or more (e.g., 1-5) substituents;

[0111] X is O, NH, or S;

[0112] Y is hydrogen, amino, or C. 1-30 Primary or secondary amino, hydroxyl or C 1-30 Alkyl groups, fluorine, chlorine, bromine, and iodine.

[0113] [Rh(I)] refers to a monovalent rhodium catalyst, and representative examples include (but are not limited to): [Rh(C2H4)2Cl]2, [Rh(C2H4)2OH]2, [Rh(coe)2Cl]2, [Rh(coe)2OH]]2, [Rh(C2H4)2OMe]2, [Rh(coe)2OMe]2 or combinations thereof.

[0114] In this invention, a representative chiral diene ligand has the following structural formula:

[0115]

[0116] In the formula, R 2 R 3 Each is independently either substituted or unsubstituted C 6-30 aryl, where the substituent refers to one or more (e.g., 1-5) H atoms being replaced by groups selected from the group consisting of: halogens, C atoms, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups.

[0117] Ideally, R 2 R 3 Each is independently either substituted or unsubstituted C 6-10 aryl, where the substituent refers to one or more (e.g., 1-5) H atoms being replaced by groups selected from the group consisting of: halogens, C atoms, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Halogenated alkoxy groups.

[0118] In one implementation, the C 6-30 The aryl group is phenyl, naphthyl, anthracene, or ferrocene.

[0119] Better yet, R 2 R 3 Each of the following is independently a substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthraceneyl, or substituted or unsubstituted ferroceneyl; the substituent refers to one or more (e.g., 1-5) H atoms being substituted by groups selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl.

[0120] Ideally, the R 2 and R 3 Each is independently a substituted or unsubstituted phenyl group, wherein substitution refers to one or more (e.g., 1-5) H atoms being substituted by groups selected from the group consisting of halogens, C atoms, and so on. 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

[0121] In this invention, the structural formulas of typical compounds of chiral diene ligands include (but are not limited to):

[0122]

[0123] In this invention, the solvent is a conventional organic solvent, which can be C 1-4 The haloalkanes are dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dichloropropane, 1-chlorobutane, or combinations thereof.

[0124] In the above-described reaction method of the present invention, the reaction temperature is not particularly limited, and is usually from -20°C to reflux temperature, preferably 0-50°C, and more preferably 15-40°C.

[0125] In the above-described reaction method of the present invention, the reaction time is not particularly limited, and is usually 0.5-24 hours, preferably 1-24 hours.

[0126] Chiral diene ligands

[0127] As described herein, the chiral diene ligand has the following structural formula:

[0128]

[0129] In the formula,

[0130] R 4 for

[0131] R 5 substituted phenyl Among them, R f R g R h Each is independently H, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, or combinations thereof.

[0132] In another embodiment, the R f R g R h Each is independently H, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, or combinations thereof.

[0133] In another preferred embodiment, the R f R g R h Each of them is independently H, fluorine, cyano, nitro, trifluoromethyl, or a combination thereof.

[0134] Typically, the chiral diene ligands include, but are not limited to:

[0135]

[0136] In a preferred embodiment of the present invention, a representative synthesis method may be described as follows:

[0137] A complex of a monovalent rhodium catalyst and a chiral diene is dissolved in an organic solvent, and reaction substrates 1 and 2 (or 3) are added sequentially, with the reaction continued for 1-24 hours to obtain the high optical purity chiral geminal di(hetero)arylmethyl-α,β-unsaturated ester compounds described in this invention. In this reaction, the molar ratio of reaction substrate to monovalent rhodium catalyst / chiral diene ligand is 60:1 to 1500:1, preferably 1000:1; the reaction temperature is 0-50°C, preferably room temperature (25°C); and the preferred reaction solvent is dichloroethane.

[0138] Preparation of high optical purity chiral geminal di(hetero)arylmethyl-substituted α,β-unsaturated esters

[0139] The method of this invention can rapidly and efficiently prepare chiral geminal di(hetero)arylmethyl-substituted α,β-unsaturated ester compounds with high optical purity.

[0140] In this invention, some representative high-optical-purity chiral geminal methyl-substituted α,β-unsaturated ester compounds are listed in Tables 1, 2, and 3. Taking the catalyst complex {Rh[(S,S)-6j]Cl}2 as an example, α-arylene-α-diazo arylates with different substituents can undergo asymmetric carbon-hydrogen bond insertion reactions with indole, pyrrole, furan, benzofuran, or thiophene with different substituents, which can efficiently produce the desired reaction products with good yields and excellent enantioselectivity (ee), reaching up to 99%. The double bond configuration is predominantly E-type, with the highest E / Z ratio reaching >99:1. The absolute configuration of the product is determined by single-crystal diffraction.

[0141] Table 1. Rhodium-catalyzed asymmetric C-H bond insertion reaction of α-styryl-α-diazo-2,4,6-trimethylphenyl ester into the 3-position of an unprotected NH-substituted indole.

[0142]

[0143] Table 2. Rhodium-catalyzed asymmetric C-H bond insertion reaction of α-arylevinyl-α-diazo-2,4,6-trimethylphenyl ester into the 3-position of unprotected indole in NH4+.

[0144]

[0145] Table 3. Rhodium-catalyzed asymmetric C-H bond insertion reaction at the 2-position of substituted heterocyclic compounds with α-arylevinyl-α-diazo-2,4,6-trimethylphenyl ester.

[0146]

[0147] Synthetic applications

[0148] The present invention also provides applications of chiral geminal di(hetero)aryl methyl-substituted α,β-unsaturated ester compounds with high optical purity, particularly in the preparation of synthetic building blocks, bioactive intermediates or active compounds with high optical purity.

[0149] In another preferred embodiment of the invention, a representative use can be described as follows:

[0150]

[0151] In this application, the chiral geminal di(hetero)arylmethyl-substituted α,β-unsaturated ester compound 3aa of the present invention is hydrogenated to form the corresponding compound 6a containing a saturated carbon chain. These compounds can then be further converted to the useful intermediate 6c by DIBAL-H reduction. Compound 3aa is converted to the useful intermediate 6d by DIBAL-H reduction.

[0152] In another preferred embodiment of the invention, a representative use can be described as follows:

[0153]

[0154] In this application, the chiral geminal di(hetero)arylmethyl-substituted α,β-unsaturated ester compound 5a of the present invention is hydrogenated and reduced to form the corresponding compound 7a containing a saturated carbon chain. These compounds can then be further reduced to convert into a useful intermediate 7c. Compound 5a is converted into a useful intermediate 7b by DIBAL-H reduction.

[0155] In another preferred embodiment of the invention, a representative use can be described as follows:

[0156]

[0157] In this application, the chiral geminal di(hetero)arylmethyl-substituted α,β-unsaturated ester compound 5h of the present invention is hydrogenated and reduced, followed by removal of the protecting group from the amino group, thereby forming the corresponding aromatic amine compound 8a containing a saturated carbon chain. These compounds can then be further converted into useful intermediates 8b, 8c or 8d via the Sandmeier reaction; wherein B is hydrogen, fluorine, chlorine, bromine, iodine or hydroxyl.

[0158] The main advantages of this invention compared to existing technologies are:

[0159] (a) Using a monovalent rhodium catalyst / chiral diene ligand as a catalyst and readily available α-arylene-α-diazoaryl ester as a reaction precursor, the asymmetric carbon-hydrogen bond insertion reaction of monovalent rhodium carbene into heteroaryl ring compounds was realized, which was used to prepare various chiral geminal di(hetero)arylmethyl-α,β-unsaturated ester compounds.

[0160] (b) The method of the present invention requires a small amount of catalyst and has good substrate versatility;

[0161] (c) The method of the present invention has a mild reaction and is easy to operate;

[0162] (d) The reaction products of the present invention have high stereoselectivity and are promising for applications in organic synthesis and drug development.

[0163] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0164] Example 1

[0165] Synthesis of compound 3a

[0166] Experiment 1: The ligand {Rh[(S,S)-6i]Cl}2 (0.003 mmol, 1.5 mol%) and indole compound 2a (0.2 mmol) were added to a reaction flask. After anhydrous and oxygen-free treatment, dichloromethane (1 mL) was added, and α-styryl-α-diazo-tert-butyl ester (Formula 1) was added to the system at 25 °C. (0.1 mmol in 1 mL dichloroethane) and the reaction continued. The reaction was monitored by TLC until complete. Afterward, the reaction mixture was evaporated to dryness and separated by silica gel column chromatography to obtain product 3a, a white solid, in 81% yield, 74% ee, E / Z = 94:6.

[0167]

[0168] 1 H 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=7.5H z,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] + .

[0169] Example 2

[0170] Synthesis of compound 3b

[0171] Experiment 2: Replace the compound of formula 1 used in Example 1 with... The remaining experimental procedures were the same as in Example 1. Product 3b was obtained, which was a white solid with a 95% yield, 76% ee, and E / Z = 96:4.

[0172]

[0173] 1 H 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] + .

[0174] Example 3

[0175] Synthesis of compounds 3aa and 3aa'

[0176] Experiment 1: The ligand {Rh[(S,S)-6j]Cl}₂ (0.003 mmol, 1.5 mol%) and indole compound 2b (0.2 mmol) were added to a reaction flask. After anhydrous and oxygen-free treatment, dichloroethane (1 mL) was added, and α-styryl-α-diazoaryl ester 1a (0.1 mmol in 1 mL dichloroethane) was added to the system at 25 °C. The reaction was continued. TLC monitoring showed the reaction was complete. Afterward, the reaction mixture was evaporated to dryness, and product 3aa was obtained by silica gel column chromatography as a white solid, 99% yield, 93% ee, E / Z = 96:4.

[0177] Experiment 2: Replace the ligand {Rh[(S,S)-6j]Cl}2 used in Experiment 1 with {Rh[(R,R)-6j]Cl}2, and perform the other experimental procedures as in Experiment 1. The product 3aa' was obtained as a white solid with a yield of 99%, -93% ee, and E / Z = 97:3.

[0178] Experiment 3: Replace the complex {Rh[(S,S)-6j]Cl}2 used in Experiment 1 with {Rh[(S,S)-6b]Cl}2, and perform the other experimental procedures as in Experiment 1. The product 3aa was obtained as a white solid with a yield of 99% and an ee of 73%, and an E / Z ratio of 98:2.

[0179] Experiment 4: Replace the ligand {Rh[(S,S)-6j]Cl}2 used in Experiment 1 with {Rh[(S,S)-6h]Cl}2, and perform the other experimental procedures as in Experiment 1. The product 3aa was obtained as a white solid with a yield of 61%, ee of 84%, and E / Z = 96:4.

[0180] Experiment 5: Replace the ligand {Rh[(S,S)-6j]Cl}2 used in Experiment 1 with {Rh[(S,S)-6g]Cl}2, and perform the other experimental procedures as in Experiment 1. The product 3aa was obtained as a white solid with a yield of 78%, ee of 84%, and E / Z = 93:7.

[0181] Experiment 6: Replace the ligand {Rh[(S,S)-6j]Cl}2 used in Experiment 1 with {Rh[(S,S)-6i]Cl}2, and perform the other experimental procedures as in Experiment 1. The product 3aa was obtained as a white solid with a yield of 82% and an ee of 81%, and an E / Z ratio of 96:4.

[0182] Experiment 7: Replace the dichloroethane solvent used in Experiment 1 with tetrahydrofuran, and follow the same experimental procedures as in Experiment 5. The product 3aa was obtained as a white solid with a yield of 44% and an ee of 95%, with an E / Z ratio of 95:5.

[0183] Experiment 8: Replace the dichloroethane solvent used in Experiment 1 with diethyl ether, and follow the same experimental procedures as in Experiment 5. The product 3aa was obtained as a white solid with a yield of 91% and an ee of 95%, and an E / Z ratio of 84:16.

[0184] Experiment 9: Replace the dichloroethane solvent used in Experiment 1 with toluene, and follow the same experimental procedures as in Experiment 5. The product 3aa was obtained as a white solid with a yield of 99% and an ee of 93%, with an E / Z ratio of 92:8.

[0185] Experiment 10: Replace the dichloroethane solvent used in Experiment 1 with dichloromethane, and follow the same experimental procedures as in Experiment 5. The product 3aa was obtained as a white solid with a yield of 98% and an ee of 91%. The E:Z ratio was 97:3.

[0186]

[0187] 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=7.5H z,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). 13 C 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] + .

[0188] Example 4

[0189] Synthesis of compound 3ab

[0190] The unprotected indole 2a used in Example 3 was replaced with 2b, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3ab, which was a white solid; 95% yield, 88% ee, E:Z = 97:3.

[0191]

[0192] 1 H 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). 13 C NMR (126MHz, CDCl3) δ165.1,157.4(d,J CF =246Hz),152.6,146.2,141.7,139.5(d,J CF=12.5Hz),135.6,130.2,129.5,128.8(d,J CF =12.5Hz), 127.3, 123.3 (d, J) CF =7.5Hz),123.1,121.3,115.9(d,J CF =3.8Hz), 115.8(d,J CF =20Hz), 107.7(d,J CF =3.8Hz), 105.4(d,J CF =18.8Hz),46.2,21.1,16.6.ESI-MS(m / z,%)414[M+H] + .

[0193] Example 5

[0194] Synthesis of compound 3ac

[0195] The unprotected indole 2a used in Example 3 was replaced with 2c, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3ac, which was a white solid; 97% yield, 92% ee, E:Z = 97:3.

[0196]

[0197] 1 H 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). 13 C NMR(126MHz,CDCl3)δ165.1,158.0(d,J CF =234Hz),152.0,146.1,141.1,135.6,133.4,130.1,129.5,129.1,128.8,127.5,127.1(d,J CF =8.8Hz),124.8,121.5,116.7(d,J CF =3.8Hz), 112.3(d,J CF =10.0Hz), 111.2(d,J CF =26.2Hz), 104.7(d,J)CF =23.8Hz),45.9,21.1,16.6.ESI-MS(m / z,%)414[M+H] + .

[0198] Example 6

[0199] Synthesis of compound 3ad

[0200] The unprotected indole 2a used in Example 3 was replaced with 2d, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3ad, which was a white solid; 97% yield, 92% ee, E:Z = 97:3.

[0201]

[0202] 1 H 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). 13 C NMR(126MHz,CDCl3)δ165.1,160.4(d,J CF =234Hz),152.1,146.2,141.2,136.9(d,J CF =12.5Hz),135.7,130.1,129.5,129.1,128.8,127.4,123.3(d,J CF =5.0Hz), 121.4, 120.5(d,J) CF =10.0Hz), 116.7, 108.8 (d, J) CF =23.8Hz), 97.9(d,J CF =26.2Hz),45.9,21.1,16.6.ESI-MS(m / z,%)414[M+H] + .

[0203] Example 7

[0204] Synthesis of compound 3ae

[0205] The unprotected indole 2a used in Example 3 was replaced with 2e, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3ae, which was a white solid; 99% yield, 95% ee, E:Z = 98:2.

[0206]

[0207] 1 H 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,1 H),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). 13 C 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] + .

[0208] Example 8

[0209] Synthesis of compound 3af

[0210] The unprotected indole 2a used in Example 3 was replaced with 2f, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3af, which was a white solid; 99% yield, 92% ee, E:Z = 98:2.

[0211]

[0212] 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). 13 C 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] + .

[0213] Example 9

[0214] Synthesis of compound 3ag

[0215] The unprotected indole 2a used in Example 3 was replaced with 2g, and the rest of the experimental procedures were the same as in Example 3. 3ag of product was obtained, which was a white solid; 93% yield, 88% ee, E:Z = 93:7.

[0216]

[0217] 1 H NMR(400MHz, CDCl3) δ7.83(brs,1H),7.68(dd,J=15.6,6.8Hz,1H),7.34(d,J=4.4H z,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),5.1 4(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) δ165.1,152.4,146.2,143.5,141.6,135.5,130.1,129.5,128.9,128.0,127.2,1 23.4,121.2,115.7,112.0,110.7,100.6,49.0,46.1,30.0,25.7,21.1,16.6.ESI-MS(m / z,%)465[M+H] + .

[0218] Example 10

[0219] Synthesis of compound 3ah

[0220] The unprotected indole 2a used in Example 3 was replaced with 2h, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3ah, which was a white solid; 98% yield, 94% ee, E:Z>99:1.

[0221]

[0222] 1 H 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). 13 C NMR (126MHz, CDCl3) δ164.9,152.2,146.5,146.2,141.5,135.5,130.1,129.5,129.0,128.9,128.2,12 7.5,127.3,122.6,121.4,120.5,117.2,112.5,102.5,55.7,46.1,21.1,16.6.ESI-MS(m / z,%)426[M+H] + .

[0223] Example 11

[0224] Synthesis of compound 3ai

[0225] The unprotected indole 2a used in Example 3 was replaced with 2i, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3ai, which was a white solid; 99% yield, 94% ee, E:Z = 98:2.

[0226]

[0227] 1 H 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). 13 C NMR (126MHz, CDCl3) δ165.0,154.4,152.2,146.2,141.3,135.6,132.0,130.1,129.5,129.0,128.9,12 7.3,127.2,123.8,121.3,116.4,112.8,112.3,101.6,56.1,46.0,21.1,16.6.ESI-MS(m / z,%)426[M+H] + .

[0228] Example 12

[0229] Synthesis of compound 3aj

[0230] The unprotected indole 2a used in Example 3 was replaced with 2j, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3aj, which was a white solid; 76% yield, 97% ee, E:Z>99:1.

[0231]

[0232] 1 H 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] + .

[0233] Example 13

[0234] Synthesis of compound 3ak

[0235] The unprotected indole 2a used in Example 3 was replaced with 2k, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3ak, which was a white solid; 95% yield, 79% ee, E:Z>99:1.

[0236]

[0237] 1 H 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). 13 C NMR (126MHz, CDCl3) δ164.9,152.4,146.2,141.6,135.6,135.5,132.5,130.1,129.5,128.9,128.6,12 8.1,127.0,121.5,121.4,119.9,119.4,111.1,110.7,45.0,21.1,16.6,12.8.ESI-MS(m / z,%)410[M+H] + .

[0238] Example 14

[0239] Synthesis of compound 3al

[0240] The unprotected indole 2a used in Example 3 was replaced with 2l, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3al, which was a white solid; 92% yield, 70% ee, E:Z>99:1.

[0241]

[0242] 1 H 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). 13 C 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] + .

[0243] Example 15

[0244] Synthesis of compound 3am

[0245] The unprotected indole 2a used in Example 3 was replaced with 2m, and the rest of the experimental procedures were the same as in Example 3. The product 3am was obtained as a white solid with a yield of 95% and an ee of 72%. The E:Z ratio was greater than 99:1.

[0246]

[0247] 1 H 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] + .

[0248] Example 16

[0249] Synthesis of compound 3ba

[0250] Replace compound 1a of Formula 1 used in Example 3 with 1b, and perform the other experimental procedures as in Example 3 to obtain product 3ba, which is a white solid; 99% yield, 94% ee, E:Z = 95:5.

[0251]

[0252] 1 H 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,3 H),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). 13 C 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] + .

[0253] Example 17

[0254] Synthesis of compound 3ca

[0255] Replace compound 1a of Formula 1 used in Example 3 with 1c, and perform the remaining experimental procedures as in Example 3 to obtain product 3ca, which is a white solid; 99% yield, 88% ee, E:Z>99:1.

[0256]

[0257] 1 H 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). 13 C 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] + .

[0258] Example 18

[0259] Synthesis of compound 3da

[0260] Replace compound 1a of Formula 1 used in Example 3 with 1d, and perform the remaining experimental procedures as in Example 3 to obtain product 3da, which is a white solid; 95% yield, 92% ee, E:Z = 76:24.

[0261]

[0262] 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). 13 C 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] + .

[0263] Example 19

[0264] Synthesis of compound 3ea

[0265] Replace compound 1a of Formula 1 used in Example 3 with 1e, and perform the remaining experimental procedures as in Example 3 to obtain product 3ea, which is a white solid; 97% yield, 92% ee, E:Z = 97:3.

[0266]

[0267] 1 H 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). 13 C NMR(101MHz,CDCl3)δ164.9,160.9(d,J CF =247Hz),150.8,146.2,136.9,135.6,130.3(d,J CF=4.0Hz),130.3,129.5,129.1(d,J CF =8.1Hz), 128.5(d,J CF =14.1Hz), 126.7, 124.7 (d, J) CF =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] + .

[0268] Example 20

[0269] Synthesis of compound 3fa

[0270] Replace compound 1a of Formula 1 used in Example 3 with 1f, and perform the remaining experimental procedures as in Example 3 to obtain product 3fa, which is a white solid; 99% yield, 96% ee, E:Z = 92:8.

[0271]

[0272] 1 H 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). 13 C NMR (101MHz, CDCl3) δ164.8,151.1,146.1,145.5,137.0,135.7,130.0,129.4(q,J CF =37.4Hz), 126.5, 126.0(q,J) CF =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] + .

[0273] Example 21

[0274] Synthesis of compound 3ga

[0275] The compound 1a of Formula 1 used in Example 3 was replaced with 1g, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3ga, which was a white solid; 99% yield, 92% ee, E:Z = 98:2.

[0276]

[0277] 1 H 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). 13 CNMR (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] + .

[0278] Example 22

[0279] Synthesis of compound 3ha

[0280] The compound 1a of Formula 1 used in Example 3 was replaced with 1h, and the rest of the experimental procedures were the same as in Example 3. The product 3ha was obtained as a white solid with a yield of 84%, ee of 92%, and E:Z = 94:6.

[0281]

[0282] 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). 13 C NMR (101MHz, CDCl3) δ165.0,160.2,152.0,146.2,143.1,136.9,135.6,130.1,130.0,129.5,126.8,123.0,12 2.7,121.4,121.3,120.0,119.8,116.6,114.9,112.4,111.6,55.5,45.9,21.1,16.6.ESI-MS(m / z,%)426[M+H] + .

[0283] Example 23

[0284] Synthesis of compound 3ia

[0285] Replace compound 1a of Formula 1 used in Example 3 with 1i, and perform the remaining experimental procedures as in Example 3 to obtain product 3ia, which is a white solid; 99% yield, 87% ee, E:Z = 95:5.

[0286]

[0287] 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=7.2H z,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). 13 C NMR (101MHz, CDCl3) δ165.0,153.7,152.0,146.1,137.2,136.9,130.0,129.5,126.8,123.1,122.7,1 21.4,120.0,119.7,116.5,111.7,105.9,61.2,56.4,46.2,30.0,21.1,16.6.ESI-MS(m / z,%)486[M+H] + .

[0288] Example 24

[0289] Synthesis of compound 3ja

[0290] Replace compound 1a of Formula 1 used in Example 3 with 1j, and perform the remaining experimental procedures as in Example 3 to obtain product 3ja, which is a white solid; 99% yield, 92% ee, E:Z = 95:5.

[0291]

[0292] 1 H 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),6.0 7(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] + .

[0293] Example 25

[0294] Synthesis of compound 3ka

[0295] Replace compound 1a of Formula 1 used in Example 3 with 1k, and perform the remaining experimental procedures as in Example 3 to obtain product 3ka, which is a white solid; 99% yield, 93% ee, E:Z = 99:1.

[0296]

[0297] 1 H NMR (400MHz, CDCl3) δ8.11(brs,1H),7.66(dd,J=15.6,6.8Hz,1H),7.46(d,J=8.0H z,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,1 H),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). 13 C 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] + .

[0298] Example 26

[0299] Synthesis of compound 3la

[0300] The compound 1a of Formula 1 used in Example 3 was replaced with 1l, and the rest of the experimental procedures were the same as in Example 3, to obtain product 3la, which was a white solid; 95% yield, 93% ee, E:Z>99:1.

[0301]

[0302] 1 H NMR(400MHz, CDCl3) δ8.15(brs,1H),7.59(dd,J=15.6,6.4Hz,1H),7.51(d,J=7.2 Hz,1H),7.41-7.40(m,1H),7.39(t,J=1.2Hz,1H),7.21(td,J=7.2,1.2Hz,1H),7.1 3-7.08(m,2H),6.86(s,2H),6.34(dd,J=3.2,2.0Hz,1H),6.14(dt,J=3.2,1.2Hz,1 H),6.08(dd,J=15.6,1.6Hz,1H),5.26(d,J=6.4Hz,1H),2.25(s,3H),2.09(s,6H). 13 C 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] + .

[0303] Example 27

[0304] Synthesis of compound 3ma

[0305] The compound 1a of Formula 1 used in Example 3 was replaced with 1m, and the rest of the experimental procedures were the same as in Example 3. The product 3ma was obtained as a white solid with a yield of 93%, ee of 90%, and E:Z > 99:1.

[0306]

[0307] 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),7.0 8(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). 13 CNMR (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] + .

[0308] Example 28

[0309] Synthesis of compound 5a

[0310] The indole compound 2a used in Example 3 was replaced with 4a, and the rest of the experimental procedures were the same as in Example 3, to obtain product 5a, which is a brown oily liquid; 91% yield, 97% ee, E:Z>99:1.

[0311]

[0312] 1 H 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] + .

[0313] Example 29

[0314] Synthesis of compound 5b

[0315] In Example 3, compound 1a of Formula 1 was replaced with 1i, and indole compound 2a was replaced with 4a. The remaining experimental procedures were the same as in Example 3, and product 5b was obtained, which was a brown oily liquid with a yield of 73%, 99% ee, and E:Z > 99:1.

[0316]

[0317] 1 H 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). 13 C 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] + .

[0318] Example 30

[0319] Synthesis of compound 5c

[0320] In Example 3, compound 1a of Formula 1 was replaced with 1l, and indole compound 2a was replaced with 4a. The remaining experimental procedures were the same as in Example 3, and product 5c was obtained, which was a brown oily liquid with a yield of 88%, ee of 99%, and E:Z > 99:1.

[0321]

[0322] 1 H 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),6.1 8(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). 13 C 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] + .

[0323] Example 31

[0324] Synthesis of compound 5d

[0325] Replace indole compound 2a used in Example 3 with 4b, and perform the remaining experimental procedures as in Example 3 to obtain product 5d, which is a white solid; 88% yield, 99% ee, E:Z>99:1.

[0326]

[0327] 1 H 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] + .

[0328] Example 32

[0329] Synthesis of compound 5e

[0330] In Example 3, compound 1a of Formula 1 was replaced with 1g, and indole compound 2a was replaced with 4b. The remaining experimental procedures were the same as in Example 3, and product 5e was obtained as a white solid with a yield of 95% and an ee of 97%, and an E:Z ratio of 99:1.

[0331]

[0332] 1 H 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). 13 C 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] + .

[0333] Example 33

[0334] Synthesis of compound 5f

[0335] In Example 3, compound 1a of Formula 1 was replaced with 1i, and indole compound 2a was replaced with 4b. The remaining experimental procedures were the same as in Example 3, and product 5f was obtained, which was a white solid with a yield of 91% and an ee of 97%, and an E:Z ratio of 99:1.

[0336]

[0337] 1 H 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). 13 C 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] + .

[0338] Example 34

[0339] Synthesis of 5g of compound

[0340] In Example 3, compound 1a of Formula 1 was replaced with 1k, and indole compound 2a was replaced with 4b. The remaining experimental procedures were the same as in Example 3. 5g of product was obtained as a white solid with a yield of 94%, ee of 98%, and E:Z > 99:1.

[0341]

[0342] 1 H 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] + .

[0343] Example 35

[0344] Synthesis of compound 5h

[0345] The indole compound 2a used in Example 3 was replaced with 4c, and the rest of the experimental procedures were the same as in Example 3. The product 5h was obtained as a white solid with a 99% yield, 99% ee, and E:Z > 99:1.

[0346]

[0347] 1 H 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), 6.0 0(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). 13 C 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] + .

[0348] Example 36

[0349] Synthesis of compound 5i

[0350] In Example 3, compound 1a of Formula 1 was replaced with 1g, and indole compound 2a was replaced with 4c. The remaining experimental procedures were the same as in Example 3, and product 5i was obtained, which was a white solid with a yield of 86%, ee of 99%, and E:Z > 99:1.

[0351]

[0352] 1 H 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). 13 C 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] + .

[0353] Example 37

[0354] Synthesis of compound 5j

[0355] In Example 3, compound 1a of Formula 1 was replaced with 1i, and indole compound 2a was replaced with 4c. The remaining experimental procedures were the same as in Example 3, and product 5j was obtained, which was a white solid with a yield of 97% and an ee of 97%. The E:Z ratio was greater than 99:1.

[0356]

[0357] 1 H 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] + .

[0358] Example 38

[0359] Synthesis of compound 5k

[0360] In Example 3, compound 1a of Formula 1 was replaced with 1k, and indole compound 2a was replaced with 4c. The remaining experimental procedures were the same as in Example 3, and product 5k was obtained as a white solid with a yield of 94%, ee of 99%, and E:Z > 99:1.

[0361]

[0362] 1 H 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). 13 C NMR (101MHz, CDCl3) δ164.4,153.2,149.3,146.0,140.2,135.7,133.0,130.0,129.5,12 7.9,127.2,123.2,123.0,122.0,81.1,41.8,28.6,21.1,16.6.ESI-MS(m / z,%)506[M+Na] + .

[0363] Example 39

[0364] Synthesis of compound 5l

[0365] The indole compound 2a used in Example 3 was replaced with 4d, and the rest of the experimental procedures were the same as in Example 3, to obtain product 5l, which was a yellow solid; 99% yield, 95% ee, E:Z>99:1.

[0366]

[0367] 1 H 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,7 H),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). 13 C NMR (101MHz, CDCl3) δ164.4,153.7,148.1,146.1,138.4,135.7,130.1,129.5,129.3,128.8,12 8.0,124.9,123.3,122.8,119.4,112.0,81.3,46.0,28.6,21.1,16.7.ESI-MS(m / z,%)534[M+Na] + .

[0368] Example 40

[0369] Synthesis of compound 5m

[0370] In Example 3, compound 1a of Formula 1 was replaced with 1i, and indole compound 2a was replaced with 4d. The remaining experimental procedures were the same as in Example 3, and product 5m was obtained as a yellow solid with a yield of 89%, ee of 98%, and E:Z > 99:1.

[0371]

[0372] 1 H 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) δ164.4,153.9,153.7,147.9,146.1,137.8,135.7,133.8,130.0,129.6,126.2,125.0,1 23.4,122.8,119.4,116.0,111.9,106.0,81.3,61.2,56.5,46.2,28.5,21.1,16.6.ESI-MS(m / z,%)624[M+Na] + .

[0373] Example 41

[0374] Synthesis of compound 5n

[0375] Replacing indole compound 2a with 4e in Example 3, and performing the remaining experimental procedures as in Example 3, yielded product 5n, a yellow solid; 57% yield, 99% ee, E:Z>99:1.

[0376]

[0377] 1 H 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),7.0 7(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). 13 C 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] + .

[0378] Example 42

[0379] Synthesis of compound 5o

[0380] The indole compound 2a used in Example 3 was replaced with 4f, and the rest of the experimental procedures were the same as in Example 3, to obtain product 5o, which was a red solid; 99% yield, 97% ee, E:Z = 93:7.

[0381]

[0382] 1 H 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). 13 C 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] + .

[0383] Example 43

[0384] Synthesis of compound 5p

[0385] In Example 3, compound 1a of Formula 1 was replaced with 1i, and indole compound 2a was replaced with 4f. The remaining experimental procedures were the same as in Example 3, and product 5p was obtained as a red solid with a yield of 85%, ee of 95%, and E:Z > 99:1.

[0386]

[0387] 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). 13 C NMR(101MHz,MeOD)δ165.8,154.5,150.8,147.0,138.0,137.0,136.3,136.0,130.7,129.9,126.5,12 2.6,120.2,118.4,112.1,106.6,80.4,60.9,56.4,46.4,28.6,20.6,16.2.ESI-MS(m / z,%)623[M+Na] + .

[0388] Example 44

[0389] Synthesis of compound 5q

[0390] In Example 3, compound 1a of Formula 1 was replaced with 1g, and indole compound 2a was replaced with 4f. The remaining experimental procedures were the same as in Example 3, and product 5q was obtained as a red solid with a yield of 94% and an ee of 98%, and an E:Z ratio of 99:1.

[0391]

[0392] 1 H 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] + .

[0393] Example 45

[0394] Synthesis of compound 6a

[0395] Pd / C (10 mol%) ligand and compound 3aa (0.2 mmol) were added to a reaction flask, followed by the addition of methanol (5 mL). The system was purged three times with hydrogen balloons, and the reaction was continued at 25 °C. The reaction was monitored by TLC until complete. The mixture was then filtered through diatomaceous earth, evaporated to dryness, and separated by silica gel column chromatography to obtain product 6a as a white solid, 97% yield, 80% ee.

[0396]

[0397] 1 H 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),7.07-6.9 9(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). 13 C 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] + .

[0398] Example 46

[0399] Synthesis of compound 6b

[0400] Compound 3aa (0.2 mmol) was added to a reaction flask, followed by dichloromethane (2 mL). After cooling to -78 °C, DIBAL-H (0.6 mmol, 3 eq, 1.5 M in toluene) was slowly added dropwise, and the reaction continued at this temperature. The reaction was monitored by TLC until complete. The reaction was then quenched with water, filtered, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed by evaporation, and the product 6b was separated by silica gel column chromatography as a brown oily liquid, 77% yield, 91% ee.

[0401]

[0402] 1 H 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). 13 C 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] + .

[0403] Example 47

[0404] Synthesis of compound 6c

[0405] Compound 6a (0.2 mmol) was added to a reaction flask, followed by dichloromethane (2 mL). After cooling to -78 °C, DIBAL-H (0.6 mmol, 3 eq, 1.5 M in toluene) was slowly added dropwise, and the reaction was continued at this temperature. The reaction was monitored by TLC until complete. The reaction was then quenched with water, filtered, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed by evaporation, and the product 6c was separated by silica gel column chromatography. The product was a brown oily liquid, with a two-step yield of 71% and an ee of 82%.

[0406]

[0407] 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). 13 C 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] + .

[0408] Example 48

[0409] Synthesis of compound 7a

[0410] Replace 3aa used in Example 45 with 5a, and perform the remaining experimental procedures as in Example 43 to obtain product 7a, which is a brown oily liquid; 95% yield, 97% ee.

[0411]

[0412] 1 H 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). 13 CNMR (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] + .

[0413] Example 49

[0414] Synthesis of compound 7b

[0415] Replace 3aa used in Example 46 with 5a, and perform the remaining experimental procedures as in Example 44 to obtain product 7b, which is a white solid; 73% yield, 98% ee.

[0416]

[0417] 1 H 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). 13 C 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] + .

[0418] Example 50

[0419] Synthesis of compound 7c

[0420] Replace 6a used in Example 47 with 7a, and perform the remaining experimental procedures as in Example 45 to obtain product 7c, which is a brown oily liquid; 97% yield, 97% ee.

[0421]

[0422] 1 H 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] + .

[0423] Example 51

[0424] Synthesis of compound 8a

[0425] The [Rh(PPh3)3Cl}2 (0.01 mmol, 5 mol%) ligand, the amino-borane complex (0.6 mmol, 3 eq), and compound 5h (0.2 mmol) were added to a reaction flask. After anhydrous and oxygen-free treatment, dichloromethane (3 mL) was added, and the reaction was continued at 25 °C. The reaction was monitored by TLC until complete. The reaction mixture was then evaporated to dryness, and the intermediate was separated by silica gel column chromatography. The intermediate was completely dissolved in 1,4-dioxane (5 mL), and hydrochloric acid (4 M in 1,4-dioxane, 50 eq) was added. The reaction was continued at 25 °C. The reaction was monitored by TLC until complete. The mixture was then neutralized to pH 7-8 with saturated sodium bicarbonate, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. Product 8a was obtained by silica gel column chromatography as a brown oily liquid, with a two-step yield of 69% and 97% ee.

[0426]

[0427] 1 H 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). 13 C 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] + .

[0428] Example 52

[0429] Synthesis of compound 8b

[0430] 8a (0.1 mmol) was added to a reaction flask, followed by tetrahydrofuran (1 mL). After cooling to 0 °C, HBF4 (2 eq) and sodium nitrite (1.2 eq in 0.1 mL H2O) were added sequentially, and the reaction was continued at this temperature for 40 minutes. Then, [Rh(cod)Cl]2 (3.0 mol%) and Et3SiH (2.0 eq) were added sequentially, and the mixture was slowly heated to room temperature for 4 hours. The reaction was monitored by TLC until complete. Subsequently, the reaction was quenched with EA, and the mixture was extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. Product 8b was obtained by silica gel column chromatography as a colorless oily liquid, with a yield of 72% and an ee of 96%.

[0431]

[0432] 1 H 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). 13 C 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] + .

[0433] Example 53

[0434] Synthesis of compound 8c

[0435] Cuprous chloride (0.5 mmol, 5.0 eq) was added to reaction flask A, followed by hydrochloric acid (4 N in H2O, 0.5 mL) and stirring at room temperature for 10 minutes. Compound 8a was added to reaction flask B, followed by tetrahydrofuran (1 mL) and hydrochloric acid (4 N in H2O, 0.1 mL). After cooling to 0°C, sodium nitrite (1.2 eq in 0.1 mL H2O) was slowly added, and the reaction was continued at this temperature for 40 minutes. Reaction flask A was cooled to 0°C, and the diazonium salt solution generated in reaction flask B was drawn into the solution using a syringe and slowly added dropwise to reaction flask A. The mixture was then slowly brought to room temperature. The reaction was monitored by TLC until complete. The reaction was then quenched with EA, and the mixture was extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. Product 8c was obtained by silica gel column chromatography as a colorless oily liquid, 58% yield, 97% ee.

[0436]

[0437] 1 H 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). 13 C 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] + .

[0438] Example 54

[0439] Synthesis of compound 8d

[0440] Add 0.1 mmol of 8a to a reaction flask, add tetrahydrofuran (1 mL), cool to 0 °C, then add H2SO4 (4 M in H2O, 0.1 mL) and sodium nitrite (1.2 eq, 0.12 mmol in 0.1 mL H2O) sequentially, and continue the reaction at this temperature for 40 minutes. Then add cuprous oxide (0.1 mmol, 1 eq) and copper sulfate (1 mmol, 10.0 eq) sequentially, and slowly raise the temperature to room temperature. Monitor the reaction for completeness by TLC. Afterward, quench the reaction with EA, and extract three times with EA. Combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate the solvent, and separate by silica gel column chromatography to obtain product 8d, a colorless oily liquid, 88% yield, 97% ee.

[0441]

[0442] Colorless oil,33.4mg,88%yield,97%ee.[α] 25 D = -3.43 (c 1.16, CHCl3). 1 HNMR(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). 13 CNMR (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] + .

[0443]

[0444]

[0445]

[0446]

[0447] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing an α,β-unsaturated ester compound, characterized in that, Including the following steps: In an organic solvent, in the presence of a monovalent rhodium catalyst and a chiral diene ligand, the α-arylevinyl-α-diazoarylester of Formula 1 undergoes a carbon-hydrogen bond asymmetric insertion reaction on the C3 position of the NH unprotected substituted indole of Formula 2, thereby yielding the α,β-unsaturated ester compound shown in Formula 3 or ent-3. Alternatively, in an organic solvent, in the presence of a monovalent rhodium catalyst and a chiral diene ligand, the α-arylevinyl-α-diazoarylesterol of Formula 1 undergoes a carbon-hydrogen bond asymmetric insertion reaction at the C2 position of the compound of Formula 4 to obtain the α,β-unsaturated ester compound shown in Formula 5 or ent-5. In the formula, Ar 1 For substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-membered heteroaryl, wherein the substitution refers to one or more H atoms being substituted by groups selected from the group consisting of: halogens, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C6 aryl; Ar 2 For substituted or unsubstituted C 6-10 aryl, wherein the substitution refers to the substitution of one or more H atoms by a group selected from the group consisting of halogens, C, and hydroxyl groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; R 1 For H, 4-F, 5-F, 6-F, 5-Br, 6-Br, 7-Br, C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered heterocyclic groups, C6 aryl; in, The dashed line in the middle represents none or equal to Two adjacent carbon atoms form a phenyl group; X is O, NH, or S; Y is hydrogen, halogen, hydroxyl group, or -NHRb; the halogen is F, Cl, Br, or I; and Rb is H or C. 1-8 Alkyl group or protecting group; the protecting group is Boc, Ts or Cbz; in, The chiral diene ligands are selected from the following group: ； The monovalent rhodium catalyst is selected from the following group: [Rh(C2H4)2Cl]2, [Rh(C2H4)2OH]2, [Rh(coe)2Cl]2, [Rh(coe)2OH]]2, [Rh(C2H4)2OMe]2, [Rh(coe)2OMe]2.

2. The method as described in claim 1, characterized in that, R 1 For H, 4-F, 5-F, 6-F, 5-Br, 6-Br, 7-Br, C 1-6 Alkyl, C 1-6 Alkoxy, C6 aryl.

3. The method as described in claim 1, characterized in that, The Ar 1 The substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, or substituted or unsubstituted furanyl groups; the substitution refers to one or more H atoms being substituted by groups selected from the group consisting of halogens, C... 1-4 Haloalkyl, C 1-6 Alkyl, C 1-4 Alkyl, C6 aryl; The Ar 2 The substituted or unsubstituted phenyl group, or the substituted or unsubstituted naphthyl group; the substitution refers to one or more H atoms being substituted by a group selected from the group consisting of: halogens, C... 1-6 Alkyl, C 1-4 Halogenated alkyl groups.

4. The method as described in claim 1, characterized in that, The compound of formula 2 is selected from the following group: 。 5. The method as described in claim 1, characterized in that, The compound of formula 1 is selected from the following group: 。 6. The method as described in claim 1, characterized in that, The amount of the monovalent rhodium catalyst is 0.4–20 mol based on the amount of compound of Formula 1; the amount of the chiral diene ligand is 0.5–25 mol.

7. The method as described in claim 1, characterized in that, The compound of formula 4 is selected from the following group: 。 8. The method as described in claim 1, characterized in that, R 2 and R 3 Each is independently selected from the group consisting of: substituted or unsubstituted phenyl groups, substituted or unsubstituted naphthyl groups; the substituent refers to one or more H atoms that are substituted by groups selected from the group consisting of: halogens, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups.

9. The method as described in claim 1, characterized in that, The monovalent rhodium catalyst is selected from the following group: [Rh(C2H4)2Cl]2, [Rh(C2H4)2OH]2, [Rh(coe)2Cl]2.

10. The method as described in claim 1, characterized in that, The method also has one or more features selected from the group consisting of: (1) The organic solvent is C 1-4 Halogenated alkanes; the C 1-4 The haloalkanes are selected from the following group: dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dichloropropane, and 1-chlorobutane; (2) The reaction temperature is between 15-40 ℃; (3) The reaction time is 0.5-24 hours.

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