Chiral indolo[2,3-a]hydroquinolines, catalytic synthesis method and anti-influenza virus application thereof

Abstract

This invention discloses a chiral indodo[2,3-] a Hydrogenated quinazon compounds, their catalytic synthesis methods, and their applications against influenza viruses belong to the field of biomedicine. The chiral indodo[2,3-] a The structures of hydrogenated quinazons are shown in general formula (I) or (II). In this invention, substituted 3,4-dihydro-β-carboline and substituted enal are used as reactants, or substituted 3,4-dihydro-β-carboline and substituted 2-hydroxycinnamaldehyde are used as reactants. An organic small molecule catalyst, a base, and the oxidant 3,3',5,5'-tetratert-butylbiphenylquinone are added, and the reaction is carried out in an organic solvent at 0-40°C for 6-48 hours to obtain the chiral indolo[2,3-] shown in general formula (I) or (II). a Hydrogenated quinazonium compounds. The chiral indodo[2,3-] synthesized in this invention... a Hydrogenated quinazons have good anti-influenza virus activity and can be used to prepare anti-influenza virus drugs.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and particularly relates to a chiral indodo[2,3-] a Catalytic synthesis of hydrogenated quinazons and their application against influenza viruses Background Technology

[0002] Influenza viruses belong to the genus *Influenzavirus* of the family Orthomyxoviridae. They are single-stranded, negative-sense RNA viruses that are commonly transmitted from birds to humans, causing influenza. Influenza is an acute respiratory illness that spreads rapidly and is highly contagious, often leading to high morbidity and mortality rates in humans and livestock. This poses a significant threat to human health and places a heavy burden on economic development. Currently, effective treatments for influenza viruses include vaccines and chemotherapy. Vaccines are one of the most effective methods against the virus; however, influenza viruses are highly variable, have many subtypes, and a wide range of hosts, often spreading rapidly. Furthermore, vaccine development and efficacy cycles are lengthy, meaning they may not be immediately effective. Simultaneously, due to the overuse of antibiotics and other drugs, drug-resistant strains of varying degrees have emerged. Therefore, the development of novel and effective drugs targeting the virus and the related diseases it causes is of paramount importance.

[0003] Indodo[2,3- a Hydroquinazons refer to a class of polycyclic nitrogen-containing molecules formed by fusion of a hydrogenated quinazon skeleton starting from the 2 and 3 positions of indole. They are an important component of monoterpenoid indole alkaloids. These natural products not only have diverse skeleton structures but also exhibit a wide range of pharmacological activities, such as adrenaline blocking, antiarrhythmic, anticancer, and antimalarial effects. In the past few decades, the development of novel indole[2,3- a Methods for hydrogenating quinazonium skeletons, as well as the total synthesis and structural modification of related natural products to meet the research needs of broader and deeper pharmacological activity evaluation, have always been one of the research hotspots of medicinal chemists and synthetic chemists, especially in the field of asymmetric catalytic synthesis.

[0004] In 2009, Fisher's group reported a one-pot synthesis of indole[2,3-]indo ... a A method for hydrogenating quinolizidine compounds (Franzén, J.; Fisher, A. Asymmetric Alkaloid Synthesis: A One-PotOrganocatalytic Reaction to Quinolizidine Derivatives). Angew. Chem. Int. Ed. ,2009, 48(787-791). However, in this work, the authors only reported reactions involving aromatic-substituted enalls. In 2011, Guo's group screened enalls with different alkane substitutions based on tryptophan derivatives and found that the size of the alkane substituent had a significant impact on enantioselectivity. For example, hydroxyethyl-substituted enal substrates yielded 97% enantioselectivity, while methyl-substituted enalls only had 70% enantioselectivity (Dai, X.; Wu, X.; Fang, H.; Nie, L.; Chen, J.; Deng, H.; Cao, W.; Zhao, G. Enantioselective Organocatalyzed CascadeReactions to Highly Functionalized Quinolizidines). Tetrahedron , 2011, 67 ,3034-3040).

[0005] Limited substrate scope and unstable enantioselectivity of products pose challenges to chiral indodo[2,3-] a The study of the bioactivity of hydrogenated quinazons presents challenges. Furthermore, there have been no reports of antiviral activity against influenza viruses in this class of compounds. Therefore, the development of new chiral indoles and [2,3-] a The development of hydrogenated quinazons and their use in the production of antiviral drugs for influenza will be of great significance. Summary of the Invention

[0006] To address the aforementioned problems in the existing technology, the first objective of this invention is to provide a chiral indo[2,3-]in ... a Hydrogenated quinazon compounds.

[0007] A second object of the present invention is to provide a chiral indodo[2,3-] a An asymmetric catalytic synthesis method for quinazine compounds is proposed, which is simple to operate, has high yield, and exhibits excellent enantioselectivity.

[0008] A third object of the present invention is to provide the above-mentioned chiral indo[2,3-] a The application of quinazons as antiviral drugs for influenza.

[0009] To achieve the above objectives, the present invention first provides a chiral indo[2,3-]in ... a Quinazine compounds, characterized by having a structure as shown in general formula (I) or (II):

[0010]

[0011] Wherein, R is selected from one of 2-chlorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-thiophene, 2-methyl-1,3-dioxolanecycloyl, and 4-ethide-tert-butyldiphenylsiloxane.

[0012] R 1 Selected from hydrogen or methyl.

[0013] R 2 Selected from hydrogen, methyl, or benzyl.

[0014] R 3 It is selected from one of hydrogen, 5-chloro, 5-methoxy, 6-chloro, 6-bromine, 6-fluoro, 6-methyl, 6-methoxy, 7-fluoro, 8-bromine, 8-methyl, and 6,7-dichloro.

[0015] R 4 It is selected from hydrogen, 3-methyl or 5-methoxy.

[0016] The present invention also provides chiral indoles [2,3-]represented by general formula (I) or (II). a A catalytic synthesis method for hydrogenated quinazon compounds, characterized by comprising the following steps:

[0017]

[0018] Using substituted 3,4-dihydro-β-carbazoline and substituted enal as reactants, an organic small molecule catalyst, a base, and the oxidant 3,3',5,5'-tetratert-butylbiphenylquinone (DQ) were added. The reaction was carried out in an organic solvent at 0-40 °C for 6-48 hours to obtain the chiral indoline [2,3-] shown in general formula (I). a Hydrogenated quinazon compounds.

[0019]

[0020] Using substituted 3,4-dihydro-β-carbazoline and substituted 2-hydroxycinnamaldehyde as reactants, an organic small molecule catalyst, a base, and the oxidant 3,3',5,5'-tetratert-butylbiphenylquinone (DQ) were added. The reaction was carried out in an organic solvent at 0-40 °C for 6-48 hours to obtain the chiral indoline [2,3-] shown in general formula (II). a Hydrogenated quinazon compounds.

[0021] The organic small molecule catalyst includes one or more of the chiral nitrogen heterocyclic carbene precursor (NHC) catalysts.

[0022] The base is an inorganic or organic base, including but not limited to sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, potassium tert-butoxide, cesium carbonate, triethylamine, 1,8-diazabicycloundec-7-ene, etc.

[0023] In molar amounts, the amount of the organic small molecule catalyst is 5 to 20% of the substituted enal or substituted 2-hydroxycinnamate; the amount of the substituted 3,4-dihydro-β-carbazoline is 1 to 2 times that of the substituted enal or substituted 2-hydroxycinnamate; the amount of the base is 1 to 3 times that of the substituted enal or substituted 2-hydroxycinnamate; and the amount of 3,3',5,5'-tetratert-butylbiphenylquinone (DQ) is 1 to 3 times that of the substituted enal or substituted 2-hydroxycinnamate.

[0024] The organic solvents include, but are not limited to, dichloromethane, 1,2-dichloroethane, ethyl acetate, diethyl ether, tetrahydrofuran, 1,4-dioxane, or toluene.

[0025] The chemical structural formula of the substituted 3,4-dihydro-β-carbazoline is as follows: , where R 1 Selected from hydrogen, methyl; R 2 Selected from hydrogen, methyl, benzyl; R 3 It is selected from one of hydrogen, 5-chloro, 5-methoxy, 6-chloro, 6-bromine, 6-fluoro, 6-methyl, 6-methoxy, 7-fluoro, 8-bromine, 8-methyl, and 6,7-dichloro.

[0026] The chemical structural formula of the substituted enal is as follows: R is selected from one of the alkyl groups such as 2-chlorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-thiophene, 2-methyl-1,3-dioxolanecycloyl, and 4-ethimide-tert-butyldiphenylsiloxoethyl.

[0027] The chemical structural formula of the substituted 2-hydroxycinnamaldehyde is as follows: , where R 4 It is selected from one of hydrogen, 3-methyl, and 5-methoxy.

[0028] In a preferred embodiment, the amount of the organic small molecule catalyst is 10% of the substituted enal or substituted 2-hydroxycinnamaldehyde, measured in molar amounts.

[0029] In a preferred embodiment, the chemical structural formula of the organic small molecule catalyst includes, but is not limited to:

[0030] ;

[0031] Mes represents mesitylexyl.

[0032] In a preferred embodiment, the amount of 3,4-dihydro-β-carbazoline is 1.2 times that of substituted enal or substituted 2-hydroxycinnamaldehyde, measured in molar amounts.

[0033] In a preferred embodiment, the amount of alkali used is 1.0 times that of the substituted enal or the substituted 2-hydroxycinnamaldehyde, measured in molar amounts.

[0034] In a preferred embodiment, the amount of 3,3',5,5'-tetratert-butylbiphenylquinone used is 2.0 times that of the substituted enal or the substituted 2-hydroxycinnamaldehyde, in molar quantities.

[0035] In the above technical solution, after the reaction is completed, the product can be separated by simple column chromatography (the eluent is preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product.

[0036] The present invention also provides chiral indoles [2,3-] as shown in general formula (I) or (II) as described above. a Use of hydrogenated quinazons in the preparation of antiviral drugs for influenza.

[0037] The influenza viruses mentioned include, but are not limited to, various types of influenza A viruses and their different subtypes.

[0038] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0039] (1) In view of the shortcomings of existing antiviral drugs for influenza, this invention, based on organic synthesis methodology, rationally designed and synthesized a novel class of chiral indo[2,3-] a Hydrogenated quinazons can be used to prepare drugs related to the treatment of influenza viruses.

[0040] (2) The chiral indopol[2,3-] synthesized in this invention a Hydrogenated quinazons exhibit good antiviral activity against influenza viruses. In preliminary screening, at a working concentration of 10 µM, compounds 3aa, 3ka, 3ab, and 3ad all showed significant antiviral activity against PR8 virus. Among them, compound 3aa showed the best IC50 against PR8 / H1N1. 50 =12.2 ± 1.0 μM, for Vir09 / H1N1 IC 50 =3.6 ± 0.5 μM, IC50 for Aichi / H3N2 50 =14.1 ± 1.1 μM.

[0041] (3) The target product can be obtained directly from commercially available raw materials through simple conversion, which reduces the difficulty of synthesis and is suitable for large-scale preparation. Attached Figure Description

[0042] Figure 1 It is the IC50 of compound 3aa against different subtypes of influenza A virus. 50 value.

[0043] Figure 2 This is a diagram showing the cytotoxicity of compound 3aa to different cells.

[0044] Figure 3 This is a graph showing the effect of compound 3aa on the survival rate of mice infected with influenza A virus.

[0045] Figure 4 This is a graph showing the effect of compound 3aa on the weight changes of mice infected with influenza A virus.

[0046] Figure 5 This is a graph showing the effect of compound 3aa on lung tissue lesions in mice infected with influenza A virus.

[0047] Figure 6 This is a graph showing the effect of compound 3aa on the viral titer in the lung tissue of mice infected with influenza A virus. Detailed Implementation

[0048] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0049] Example 1:

[0050]

[0051] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (1.9 mg, 5 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3aa (30 mg), with a yield of 95% and ee = 98%. Analysis of product 3aa yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 25 / 75; Flow rate = 1.0 mL / min; t R1 = 6.64 min, 99.06%; t R2 = 11.77 min, 0.94%; [α]D 23 = 8.0 ( c = 0.2, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.28 (s,1H), 7.53 (d, J = 7.8 Hz, 1H), 7.34 - 7.25 (m, 5H), 7.24 - 7.20 (m, 2H), 7.14 (t, J = 7.8 Hz, 1H), 5.59 (d, J = 4.1 Hz, 1H), 4.40 (dt, J = 11.0, 5.4 Hz, 1H),3.92 - 3.82 (m, 2H), 2.94 - 2.88 (m, 3H), 2.79 (dd, J = 15.7, 10.4 Hz, 1H); 13 C NMR(101 MHz, CDCl3): d 168.8, 142.8, 137.3, 130.9, 128.9, 127.6, 127.09, 127.06,126.6, 123.7, 120.1, 119.0, 112.5, 111.0, 103.3, 40.0, 39.3, 37.3, 20.6; IR(neat): n 3324, 2926, 1646, 1633, 1513, 1401, 1264, 1235, 1097, 1019, 802, 745cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 21 H 19 N2O: 315.1492; found: 315.1495。

[0052] Example 2:

[0053]

[0054] Dihydro-β-carbaline compound 1ba (23.8 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 48 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ba (31 mg), with a yield of 95% and ee = 98%. Analysis of product 3ba yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 8.09 min, 99.00%; t R2 = 11.30 min, 1.00%; [α] D 23 = 41.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.09 (s,1H), 7.36-7.32 (m, 3H), 7.28 (d, J = 7.1 Hz, 3H), 7.22 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 5.56 (d, J = 4.2 Hz, 1H), 4.41 (dt, J = 12.4, 5.1Hz, 1H), 3.93-3.81 (m, 2H), 2.95-2.90 (m, 3H), 2.80 (dd, J = 15.7, 10.4 Hz,1H), 2.45 (s, 3H); 13 C NMR (101 MHz, CDCl3): d168.8, 142.8, 135.6, 131.1,129.5, 128.9, 128.1, 127.7, 127.1, 126.9, 125.3, 118.7, 112.2, 110.7, 103.0,40.0, 39.3, 37.3, 21.4, 20.6; IR (neat): n 3243, 2926, 1639, 1404, 1317,1264, 1238, 1043, 806, 787, 670 cm –1 HRMS (ESI): m / z [M + H] + calcd. forC 22 H 21 N2O: 329.1648; found: 329.1646.

[0055] Example 3:

[0056]

[0057] Dihydro-β-carbaline compound 1ca (25.7 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (4.2 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 40 °C for 6 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ca (33 mg), with a yield of 92% and ee = 97%. Analysis of product 3ca yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 6.90 min, 98.26%; t R2 = 7.51 min, 1.74%; [α] D 23 = 25.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.20 (s,1H), 7.35 - 7.31 (m, 2H), 7.27 - 7.26 (m, 2H), 7.25 (s, 1H), 7.22 (d, J = 8.8 Hz,1H), 6.96 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.8, 2.4 Hz, 1H), 5.58 (d, J =4.2 Hz, 1H), 4.40 (dt, J = 12.7, 5.4 Hz, 1H), 3.92 - 3.83 (m, 5H), 2.95 - 2.89(m, 3H), 2.79 (dd, J = 15.7, 10.3 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.8,154.4, 142.8, 132.4, 131.0, 128.9, 128.4, 127.07, 127.05, 127.0, 113.9,112.3, 111.8, 103.1, 100.6, 55.8, 40.0, 39.3, 37.3, 20.7; IR (neat): n 2925,2350, 1650, 1519, 1455, 1402, 1258, 1172, 1108, 802 cm –1 ; HRMS (ESI): m / z [M +H] + calcd. for C 22 H 21 N2O2: 345.1598; found: 345.1596。

[0058] Example 4:

[0059]

[0060] Dihydro-β-carbaline compound 1da (24.3 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3da (31 mg), with a yield of 92% and ee = 97%. Analysis of product 3da yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.34 min, 98.36%; t R2 = 9.46 min, 1.64%; [α] D 23 = 22.0 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO- d 6): d 11.43(s, 1H), 7.38-7.24 (m, 7H), 7.00 (td, J = 9.4, 2.6 Hz, 1H), 6.01 (d, J = 4.5Hz, 1H), 4.11 (dt, J = 12.8, 5.5 Hz, 1H), 3.99-3.93 (m, 1H), 3.91-3.86 (m,1H), 2.87-2.80 (m, 3H), 2.70 (dd, J = 15.5, 9.2 Hz, 1H); 13 C NMR (101 MHz, DMSO- d 6): d 167.7, 158.1 ( J = 230.9 Hz), 143.0, 134.0, 130.5, 130.0, 128.7,127.1, 126.8, 126.2 (J = 10.1 Hz), 112.2 ( J = 9.6 Hz), 110.9 ( J = 12.0 Hz), 110.7 ( J = 9.1 Hz), 104.5, 103.7 ( J = 23.2 Hz), 39.4, 38.7, 36.2, 20.2; IR(neat): n 3326, 2925, 1650, 1545, 1523, 1455, 1330, 1097, 802 cm –1 HRMS(ESI): m / z [M + H] + calcd. for C 21 H 18 FN2O: 333.1398; found: 333.1401.

[0061] Example 5:

[0062]

[0063] Dihydro-β-carboline compound 1ea (26.2 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous dichloromethane solution (1 mL) was then added. After reacting the reaction mixture at 40 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ea (32 mg), with a yield of 94% and ee = 97%. Analysis of product 3ea yielded the following results: Large diene chiral ID column; i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.08 min, 98.53%; t R2 = 8.26 min, 1.47%; [α] D 23 = 28.0 ( c = 0.1, CH2Cl2);1 1H NMR (400 MHz, CDCl3): d 8.44 (s, 1H), 7.49 (d, J J = 1.8 Hz, 1H), 7.34 - 7.31 (m, 2H), 7.26 - 7.21 (m, 4H), 7.17 (dd, J J = 8.6, 1.9 Hz, 1H), 5.56 (d, J J = 4.1 Hz, 1H), 4.38 (dt, J J = 12.7, 5.4 Hz, 1H), 3.93 - 3.84 (m, 2H), 2.94 - 2.87 (m, 3H), 2.79 (dd, J J = 15.7, 10.3 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): d 168.7, 142.5, 135.6, 130.7, 129.0, 128.9, 127.7, 127.2, 127.0, 125.7, 123.8, 118.5, 112.01, 111.98, 104.1, 39.9, 39.2, 37.3, 20.5; IR (neat): n 3349, 2925, 1654, 1545, 1456, 1332, 1201, 1124, 744 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 ClN2O: 349.1102; found: 349.1106。

[0064] Example 6:

[0065]

[0066] Dihydro-β-carboline compound 1fa (31.4 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (4.2 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 48 h, the reaction mixture was directly separated by silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3fa (35 mg), with a yield of 90% and ee = 97%. Analysis of the product's 3FA yielded the following results: Large diene chiral ID column; i PrOH / Hexane = 15 / 85; Flow rate = 1.0 mL / min; t R1 = 10.05 min, 98.52%; t R2 =11.83 min, 1.48%; [α] D 23 = 28.9 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.52 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.34-7.27 (m, 3H), 7.25-7.23 (m, 3H),7.19 (d, J = 8.6 Hz, 1H), 5.65 (d, J = 4.1 Hz, 1H), 4.37 (dt, J = 12.6, 5.4Hz, 1H), 3.92-3.81 (m, 2H), 2.94-2.85 (m, 3H), 2.75 (dd, J = 15.7, 10.3 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d168.7, 142.5, 135.9, 130.6, 128.9, 128.8,128.3, 127.2, 127.0, 126.4, 121.6, 113.2, 112.5, 111.9, 104.2, 39.9, 39.2,37.3, 20.5; IR (neat): n 2925, 1659, 1645, 1564, 1410, 1350, 1264, 1033, 803,745 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 BrN2O: 393.0597; found: 393.0599.

[0067] Example 7:

[0068]

[0069] Dihydro-β-carbaline compound 1ga (32.2 mg, 0.15 mmol, 1.5 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (7.4 mg, 20 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (122.5 mg, 0.30 mmol, 3.0 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were placed in a dry reaction flask. Anhydrous ethyl acetate solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 48 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ga (28 mg), with a yield of 82% and ee = 98%. Analysis of product 3ga yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 30 / 70; Flow rate = 1.0 mL / min; t R1 = 6.00 min, 1.23%; t R2 = 6.75min, 98.77%; [α] D 23 = 83.3 ( c = 0.15, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d8.16 (s, 1H), 7.35 - 7.31 (m, 2H), 7.27 - 7.25 (m, 3H), 7.13 (t, J J = 8.0 Hz, 1H), 6.92 (d, J J = 8.1 Hz, 1H), 6.50 (d, J J = 7.8 Hz, 1H), 5.50 (d, J J = 4.1 Hz, 1H), 4.37 (dt, J J = 12.8, 5.3 Hz, 1H), 3.92 (s, 3H), 3.90 - 3.80 (m, 2H), 3.23 - 3.10 (m, 2H), 2.94 (dd, J J = 15.7, 6.4 Hz, 1H), 2.79 (dd, J J = 15.6, 10.4 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): d 168.7, 155.0, 143.0, 138.6, 131.0, 128.9, 127.1, 127.0, 126.1, 124.5, 117.0, 112.7, 104.2, 102.3, 100.1, 55.2, 40.1, 39.5, 37.3, 22.4; IR (neat): n 2969, 2925, 1652, 1402, 1259, 1173, 1105, 1026, 801 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O2: 345.1598; found: 345.1594。

[0070] Example 8:

[0071]

[0072] Dihydro-β-carboline compound 1ha (43.7 mg, 0.20 mmol, 2.0 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (4.8 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and 1,8-diazabicycloundec-7-ene (30.4 mg, 0.20 mmol, 2.0 equiv) were loaded into a dry reaction flask. Anhydrous 1,2-dichloroethane solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 48 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ha (31 mg), with a yield of 88% and ee = 98%. Analysis of product 3ha yielded the following results: Grande chalcedony chiral ID column; i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 =12.66 min, 98.76%; t R2 = 15.31 min, 1.24%; [α] D 23 = 84.0 ( c = 0.15, CH2Cl2); 1 HNMR (400 MHz, CDCl3): d 8.72 (s, 1H), 7.33-7.30 (m, 2H), 7.25-7.22 (m, 3H),7.20 (dd, J = 7.5, 1.4 Hz, 1H), 7.10-7.04 (m, 2H), 5.65 (d, J = 4.1 Hz, 1H), 4.35 (dt, J = 12.9, 5.3 Hz, 1H), 3.91-3.79 (m, 2H), 3.35 (dt, J = 16.7, 5.2Hz, 1H), 3.24-3.18 (m, 1H), 2.93 (dd, J = 15.7, 6.4 Hz, 1H), 2.78 (dd, J =15.7, 10.4 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d168.6, 142.6, 138.3, 130.7,128.9, 128.4, 127.2, 127.0, 126.8, 124.2, 124.0, 120.7, 112.4, 109.7, 103.9,39.9, 39.3, 37.4, 22.2; IR (neat): n 3249, 2925, 1652, 1631, 1403, 1332,1136, 1124, 745 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 ClN2O: 349.1102; found: 349.1106.

[0073] Example 9:

[0074]

[0075] Dihydro-β-carbaline compound 1ia (24.3 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (31.8 mg, 0.30 mmol, 3.0 equiv) were loaded into a dry reaction flask. Anhydrous diethyl ether solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 24 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ia (29 mg), with a yield of 87% and ee = 98%. Analysis of product 3ia yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.03 min, 98.98%; t R2 = 10.59 min, 1.02%; [α] D 20 = 25.0 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d8.23 (s,1H), 7.45 (dd, J J = 8.6, 5.3 Hz, 1H), 7.35 - 7.32 (m, 2H), 7.27 - 7.25 (m, 3H),7.02 (dd, J J = 9.4, 2.2 Hz, 1H), 6.92 - 6.87 (m, 1H), 5.56 (d, J J = 4.2 Hz, 1H),4.40 (dt, J J = 12.7, 5.4 Hz, 1H), 3.94 - 3.84 (m, 2H), 2.95 - 2.90 (m, 3H), 2.80(dd, J J = 15.7, 10.3 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.7, 162.0 ( J J =238.7 Hz), 142.7, 137.4 ( J J = 12.4 Hz), 130.7, 128.9, 128.0 ( J J = 3.6 Hz),127.1, 127.0, 123.3, 119.9 ( J J = 10.2 Hz), 112.5, 109.0 ( J J = 24.5 Hz), 103.2,97.7 ( J J = 26.3 Hz), 40.0, 39.2, 37.3, 20.6; IR (neat): n 3345, 2970, 1640,1545, 1462, 1264, 1098, 1023, 802, 671 cm –1 ; HRMS (ESI): m / z [M + H] + calcd.for C 21 H 18 FN2O: 333.1398; found: 333.1402。

[0076] Example 10:

[0077]

[0078] Dihydro-β-carbaline compound 1ja (23.8 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium bicarbonate (25.2 mg, 0.30 mmol, 3.0 equiv) were placed in a dry reaction flask. Anhydrous diethyl ether solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ja (27 mg), with a yield of 82% and ee = 98%. Analysis of product 3ja yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.49 min, 98.82%; t R2 = 10.25min, 1.18%; [α] D 23 = 35.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.08 (s,1H), 7.40-7.28 (m, 6H), 7.09-7.05 (m, 2H), 5.65 (d, J = 4.1 Hz, 1H), 4.43(dt, J = 12.7, 5.3 Hz, 1H), 3.95-3.82 (m, 2H), 2.96-2.90 (m, 3H), 2.81 (dd, J = 15.7, 10.5 Hz, 1H), 2.48 (s, 3H); 13 C NMR (101 MHz, CDCl3): d 168.8, 142.9,136.9, 131.0, 129.0, 128.1, 127.4, 127.1, 126.3, 124.4, 120.4, 120.3, 116.8,113.2, 103.2, 40.0, 39.3, 37.4, 20.8, 16.7; IR (neat): n3320, 2928, 1646,1401, 1331, 1264, 1236, 1032, 802, 744 cm –1 HRMS (ESI): m / z [M + H] + calcd.for C 22 H 21 N2O: 329.1648; found: 329.1644.

[0079] Example 11:

[0080]

[0081] Dihydro-β-carboline compound 1ka (31.4 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and potassium carbonate (20.7 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous 1,4-dioxane solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly separated by silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ka (34 mg), with a yield of 87% and ee = 99%. Analysis of the product's 3ka yielded the following results: Large diene chiral ID bars; i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 8.83 min, 99.47%; t R2 =12.39 min, 0.53%; [α] D 20 = 16.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.14 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.7 Hz, 3H), 7.30 (d, J = 7.6 Hz, 3H), 7.04 (t, J= 7.8 Hz, 1H), 5.70 (d, J = 4.2 Hz, 1H), 4.43 (dt, J = 12.8, 5.4 Hz, 1H), 3.98-3.84 (m, 2H), 2.98-2.92 (m, 3H), 2.83 (dd, J =15.7, 10.4 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.6, 142.6, 135.9, 130.5,129.0, 128.2, 127.8, 127.2, 127.1, 125.9, 121.4, 118.2, 113.6, 104.5, 104.3,39.8, 39.1, 37.4, 20.8; IR (neat): n 2926, 1665, 1565, 1412, 1264, 1034, 802,745 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 BrN2O: 393.0597; found: 393.0597.

[0082] Example 12:

[0083]

[0084] Dihydro-β-carbaline compound 1la (30.2 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and potassium tert-butoxide (11.2 mg, 0.10 mmol, 1.0 equiv) were placed in a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3la (32 mg), with a yield of 83% and ee = 99%. Analysis of product 3la yielded the following results: [Section: Daicel chiral ID column;] iPrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 6.68 min, 99.25%; t R2 = 7.47 min, 0.75%; [α] D 20 = 28.9 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.30 (s,1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.36-7.32 (m, 2H), 7.28-7.24 (m, 3H), 5.64(d, J = 4.2 Hz, 1H), 4.39 (dt, J = 12.8, 5.4 Hz, 1H), 3.94-3.83 (m, 2H), 2.95-2.86 (m, 3H), 2.80 (dd, J = 15.7, 10.3 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.6, 142.4, 135.9, 130.5, 129.5, 129.0, 127.3, 127.2, 127.0, 126.4,124.3, 120.0, 112.5, 111.9, 104.6, 39.8, 39.0, 37.3, 20.4; IR (neat): n 3348,2926, 1659, 1456, 1429, 1412, 1333, 1240, 1030, 802, 744 cm –1 HRMS (ESI): m / z[M + H] + calcd. for C 21 H 17 Cl2N2O: 383.0712; found: 383.0715.

[0085] Example 13:

[0086]

[0087] Dihydro-β-carbaline compound 1ma (29.8 mg, 0.15 mmol, 1.5 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (8.4 mg, 20 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and triethylamine (20.2 mg, 0.20 mmol, 2.0 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ma (24 mg), with a yield of 80% and ee = 96%. Analysis of product 3ma yielded the following results: [Daicel chiral AD column;] i PrOH / Hexane = 10 / 90; Flow rate = 1.0 mL / min; t R1 = 11.31 min, 2.23%; t R2 = 13.33 min, 97.77%; [α] D 20 = -15.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 7.57(d, J = 7.9 Hz, 1H), 7.40-7.36 (m, 2H), 7.33-7.30 (m, 5H), 7.17 (ddd, J =8.0, 6.3, 1.7 Hz, 1H), 5.85 (d, J = 4.2 Hz, 1H), 4.38 (dt, J = 12.5, 5.3 Hz,1H), 4.02-3.94 (m, 1H), 3.90-3.84 (m, 4H), 2.98-2.91 (m, 3H), 2.77 (dd, J =15.8, 10.8 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d169.0, 143.0, 139.5, 131.5,129.1, 129.0, 127.13, 127.08, 125.1, 123.4, 119.8, 119.0, 113.5, 109.4,106.6, 39.8, 39.4, 37.6, 32.9, 20.9; IR (neat): n 2927, 1667, 1640, 1546,1401, 1205, 1101, 744 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O:329.1648; found: 329.1654.

[0088] Example 14:

[0089]

[0090] Dihydro-β-carbaline compound 1na (32.9 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.8 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3na (33 mg), with a yield of 82% and ee = 95%. Analysis of product 3na was performed using a large-diameter chiral IC column; i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 18.84 min, 97.32%; t R2 = 21.84 min, 2.68%; [α] D 20 = -32.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d7.63 (d, J J = 7.8 Hz, 1H), 7.30 - 7.26 (m, 5H), 7.22 - 7.19 (m, 4H), 7.06 - 7.13 (m, 2H), 6.96 - 6.93 (m, 2H), 5.59 - 5.44 (m, 3H), 4.47 (dt, J J = 12.6, 5.2 Hz, 1H), 3.83 - 3.78 (m, 2H), 3.03 - 2.99 (m, 2H), 2.86 (dd, J J = 15.8, 6.2 Hz, 1H), 2.62 (dd, J J = 15.8, 11.1 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 169.1, 142.6, 139.9, 137.4, 130.8, 129.0, 128.9, 128.7, 127.4, 126.84, 126.77, 125.8, 125.4, 123.8, 120.3, 119.1, 114.1, 109.7, 106.8, 48.7, 40.1, 39.2, 37.2, 21.1; IR (neat): n 2932, 1676, 1456, 1373, 1333, 1263, 1029, 801, 742, 701 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 28 H 25 N2O: 405.1961; found: 405.1955。

[0091] Example 15:

[0092]

[0093] Dihydro-β-carboline compound 1oa (23.8 mg, 0.12 mmol, 1.2 equiv), enal 2aa (13.2 mg, 0.10 mmol, 1.0 equiv), catalyst (4.8 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (65.2 mg, 0.20 mmol, 2.0 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly separated by silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3oa (29 mg), with a yield of 87% and ee = 82%. Analysis of product 3oa yielded the following results: Large diene chiral ID column; i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 12.03 min, 90.81%; t R2 = 16.01 min, 9.19%; [α] D 23 = 38.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.40 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.33-7.30 (m, 2H), 7.26-7.23 (m, 2H), 7.21-7.15 (m, 3H), 4.87 (ddd, J = 12.7, 5.0, 3.8 Hz, 1H),3.60 (dd, J = 7.2, 3.2 Hz, 1H), 3.46 (ddd, J = 12.6, 10.2, 4.8 Hz, 1H), 3.04-2.94 (m, 3H), 2.80 (dd, J = 15.6, 3.3 Hz, 1H), 2.26 (s, 3H); 13 C NMR (101 MHz, CDCl3): d167.9, 140.5, 136.9, 129.0, 128.5, 127.3, 127.2, 127.1, 125.7,123.4, 120.2, 118.8, 113.7, 113.4, 111.1, 45.3, 39.6, 39.4, 21.0, 19.0; IR(neat): n 3319, 2928, 1646, 1628, 1455, 1330, 1265, 1236, 1028, 802, 744 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O: 329.1648; found: 329.1642.

[0094] Example 16:

[0095]

[0096] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ab (14.6 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ab (30 mg), with a yield of 90% and ee = 96%. Analysis of product 3ab was performed using a large-diameter chiral ID column; i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 8.46 min, 97.94%; t R2 = 13.50 min, 2.06%; [α] D 23 = 14.0 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.11 (s,1H), 7.54 (d, J J = 7.9 Hz, 1H), 7.34 (d, J J = 8.1 Hz, 1H), 7.25 (t, J J = 8.1 Hz,1H), 7.18 - 7.11 (m, 5H), 5.57 (d, J J = 4.1 Hz, 1H), 4.41 (dt, J J = 12.6, 5.4 Hz,1H), 3.91 - 3.84 (m, 2H), 2.96 - 2.89 (m, 3H), 2.79 (dd, J J = 15.6, 10.3 Hz, 1H),2.72 (s, 3H); 13 C NMR (101 MHz, CDCl3): d 168.8, 139.8, 137.3, 136.7, 130.8,129.6, 127.7, 126.9, 126.7, 123.7, 120.2, 119.0, 112.6, 111.0, 103.5, 40.1,39.3, 36.9, 21.0, 20.6; IR (neat): n 3319, 2928, 1646, 1455, 1401, 1264,1023, 801, 744 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O: 329.1648;found: 329.1644。

[0097] Example 17:

[0098]

[0099] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ac (16.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ac (32 mg), with a yield of 91% and ee = 95%. Analysis of product 3ac yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 25 / 75; Flow rate = 1.0 mL / min; t R1 = 9.47 min, 97.42%; t R2 = 13.86 min, 2.58%; [α] D 23 = 16.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.10 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.23-7.12 (m, 4H), 6.88-6.86 (m, 2H), 5.57 (d, J = 4.0 Hz, 1H), 4.39 (dt, J = 12.8, 5.6 Hz, 1H),3.92-3.87 (m, 2H), 3.79 (s, 3H), 2.97-2.88 (m, 3H), 2.77 (dd, J = 15.6, 10.4Hz, 1H); 13 C NMR (101 MHz, CDCl3): d168.8, 158.6, 137.2, 134.8, 130.8, 128.0,127.7, 126.7, 123.7, 120.2, 119.0, 114.3, 112.6, 111.0, 103.6, 55.3, 40.2,39.2, 36.5, 20.6; IR (neat): n 3305, 2926, 1643, 1623, 1494, 1402, 1264,1244, 1030, 745 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O2: 345.1598; found: 345.1596.

[0100] Example 18:

[0101]

[0102] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ad (15.0 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ad (32 mg), with a yield of 96% and ee = 98%. Analysis of product 3ad yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.65 min, 99.08%; t R2 = 11.82 min, 0.92%; [α] D 23 = 8.0 ( c = 0.15, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.24 (s,1H), 7.55 (d, J J = 7.9 Hz, 1H), 7.34 (d, J J = 8.1 Hz, 1H), 7.24-7.21 (m, 3H),7.16-7.12 (m, 1H), 7.03-6.99 (m, 2H), 5.56 (d, J J = 4.2 Hz, 1H), 4.36 (dt, J J =12.6, 5.5 Hz, 1H), 3.95-3.87 (m, 2H), 2.97-2.89 (m, 3H), 2.76 (dd, J J = 15.6,10.0 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.6, 163.1 ( J J = 244.0 Hz), 138.4,137.3, 131.1, 128.6 ( J J = 7.9 Hz), 127.5, 126.6, 123.8, 120.2, 119.1, 115.8 ( J J = 21.1 Hz), 112.7, 111.0, 102.8, 40.2, 39.3, 36.6, 20.6; IR (neat): n 3327,2926, 1648, 1513, 1455, 1401, 1340, 1264, 1235, 1161, 1019, 802 cm –1 ; HRMS(ESI): m / z [M + H] + calcd. for C 21 H 18 FN2O: 333.1398; found: 333.1'401。

[0103] Example 19:

[0104]

[0105] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ae (16.6 mg, 0.10 mmol, 1.0 equiv), catalyst (4.2 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and potassium phosphate (63.6 mg, 0.30 mmol, 3.0 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 24 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ae (30 mg), with a yield of 87% and ee = 99%. Analysis of product 3ae yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.94 min, 99.31%; t R2 = 11.48 min, 0.69%; [α] D 23 = 14.7 ( c = 0.15, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.39 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.34-7.27 (m, 3H), 7.24-7.12 (m, 4H), 5.57 (d, J = 4.0 Hz, 1H), 4.34-4.29 (m, 1H), 3.95-3.84 (m, 2H), 2.96-2.87 (m, 3H), 2.74 (dd, J = 15.6, 9.9 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.5, 141.2,137.4, 132.9, 131.4, 129.0, 128.5, 127.5, 126.6, 123.8, 120.2, 119.1, 112.8,111.1, 102.4, 40.0, 39.4, 36.8, 20.6; IR (neat): n 3324, 2926, 1646, 1633,1513, 1401, 1264, 1235, 1097, 1019, 802, 745 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 ClN2O: 349.1102; found: 349.1105.

[0106] Example 20:

[0107]

[0108] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2af (21.0 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3af (36 mg), with a yield of 92% and ee = 97%. Analysis of product 3af yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 25 / 75; Flow rate = 1.0 mL / min; t R1 = 6.79 min, 98.64%; t R2 = 8.80 min, 1.36%; [α] D 23 = 6.7 ( c = 0.15, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.25 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.32, 2H), 7.34 (d, J = 8.1, 1H), 7.24 (d,J = 7.5, 1H), 7.16-7.13 (m, 3H), 5.55 (d, J = 4.2 Hz, 1H), 4.35 (dt, J = 18.2, 5.5 Hz, 1H), 3.94-3.85 (m, 2H), 2.96-2.88 (m, 3H), 2.75 (dd, J =15.6, 10.0 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.4, 141.7, 137.3, 132.0,131.4, 128.8, 127.4, 126.6, 123.9, 120.9, 120.2, 119.1, 112.9, 111.1, 102.2,39.9, 39.3, 36.8, 20.6; IR (neat): n 3308, 2926, 2344, 1659, 1633, 1545,1409, 1264, 744 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 BrN2O: 393.0597; found: 393.0597.

[0109] Example 21:

[0110]

[0111] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ag (16.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ag (32 mg), with a yield of 94% and ee = 99%. Analysis of product 3ag yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 10.42 min, 99.34%; t R2 = 14.88 min, 0.66%; [α] D 23 = 54.2 ( c = 0.15, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.42 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.25-7.21 (m, 3H),7.15 (t, J = 7.3 Hz, 1H), 6.93-6.86 (m, 2H), 5.63 (d, J = 4.8 Hz, 1H), 4.30-4.25 (m, 1H), 4.13 (t, J = 5.9 Hz, 2H), 3.82 (s, 3H), 2.96-2.90 (m, 3H), 2.81(dd, J = 15.7, 8.3 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d169.3, 156.8, 137.2,131.0, 130.2, 128.1, 127.9, 127.2. 126.6, 123.5, 120.7, 120.0, 118.9, 112.0,111.0, 110.5, 103.0, 55.3, 39.3, 37.9, 30.7, 20.6; IR (neat): n 3305, 2926,1644, 1495, 1402, 1245, 1030, 802, 745 cm –1 HRMS (ESI): m / z [M + H] + calcd.for C 22 H 21 N2O2: 345.1598; found: 345.1594.

[0112] Example 22:

[0113]

[0114] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ah (16.6 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (122.5 mg, 0.30 mmol, 3.0 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 40 °C for 24 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ah (33 mg), with a yield of 96% and ee = 99%. Analysis of product 3ah yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 9.66 min, 99.32%; t R2 = 13.60 min, 0.68%; [α] D 23 = 31.8 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.41 (s,1H), 7.55 (d, J J = 7.9 Hz, 1H), 7.39 (dd, J J = 7.4, 1.6 Hz, 1H), 7.34 - 7.30 (m,2H), 7.24 - 7.12 (m, 4H), 5.63 (d, J J = 4.8 Hz, 1H), 4.40 (m, 1H), 4.15 - 4.12 (m,2H), 3.02 - 2.93 (m, 3H), 2.81 (dd, J J = 15.8, 8.2 Hz, 1H); 13 C NMR (101 MHz,CDCl3): d 168.6, 139.6, 137.3, 133.4, 131.6, 129.9, 128.3, 127.8, 127.5,127.4, 126.6, 123.7, 120.1, 119.0, 112.6, 111.1, 101.4, 39.4, 37.9, 33.8,20.6; IR (neat): n 3219, 2925, 1651, 1546, 1455, 1332, 1045, 744, 699 cm –1 ;HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 ClN2O: 349.1102; found: 349.1102。

[0115] Example 23:

[0116]

[0117] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ai (14.6 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ai (31 mg), with a yield of 96% and ee = 99%. Analysis of product 3ai was performed using a large-diameter chiral ID column; i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.49 min, 99.35%; t R2 =11.91 min, 0.65%; [α] D 23 = 20.9 ( c = 0.15, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.35 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.25-7.20(m, 2H), 7.15-7.12 (m, 1H), 7.08-7.05 (m, 3H), 5.60 (d, J = 4.0 Hz, 1H), 4.44(dt, J = 12.7, 5.3 Hz, 1H), 3.90-3.82 (m, 2H), 2.95-2.88 (m, 3H), 2.79 (dd, J = 15.7, 10.6 Hz, 1H), 2.34 (s, 3H); 13 C NMR (101 MHz, CDCl3): d168.9, 142.7,138.5, 137.3, 130.8, 128.8, 127.82, 127.80, 127.7, 126.6, 124.1, 123.6,120.1, 119.0, 112.5, 111.0, 103.5, 40.0, 39.3, 37.3, 21.4, 20.6; IR (neat): n 3319, 2928, 1646, 1628, 1455, 1330, 1265, 1236, 1028, 802, 744 cm –1 HRMS(ESI): m / z [M + H] + calcd. for C 22 H 21 N2O: 329.1648; found: 329.1643.

[0118] Example 24:

[0119]

[0120] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2aj (16.6 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3aj (30 mg), with a yield of 87% and ee = 99%. Analysis of product 3aj yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 30 / 70; Flow rate = 1.0 mL / min; t R1 = 7.28 min, 99.27%; t R2 = 9.84 min, 0.73%; [α] D 23 = 18.0 ( c = 0.1, CH2Cl2); 11H NMR (400 MHz, CDCl3): d 8.15 (s, 1H), 7.55 (d, J J = 7.9 Hz, 1H), 7.35 (d, J J = 8.1 Hz, 1H), 7.27 - 7.26 (m, 2H), 7.25 - 7.24 (m, 2H), 7.16 - 7.12 (m, 2H), 5.54 (d, J J = 4.2 Hz, 1H), 4.38 (dt, J J = 12.6, 5.4 Hz, 1H), 3.95 - 3.88 (m, 2H), 2.97 - 2.91 (m, 3H), 2.78 (dd, J J = 15.7, 10.1 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): d 168.3, 144.8, 137.3, 134.7, 131.5, 130.2, 127.4, 127.3 (2C), 126.6, 125.3, 123.9, 120.2, 119.1, 113.0, 111.1, 102.0, 39.9, 39.3, 37.1, 20.6; IR (neat): n 3249, 2926, 1652, 1628, 1544, 1456, 1402, 1332, 1205, 744 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 ClN2O: 349.1102; found: 349.1104。

[0121] Example 25:

[0122]

[0123] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ak (13.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 40 °C for 48 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ak (28 mg), with a yield of 86% and ee = 99%. Analysis of product 3ak yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 30 / 70; Flow rate = 1.0 mL / min; t R1 = 6.15 min, 99.28%; t R2 = 12.15 min, 0.72%; [α] D 23 = 72.9 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.22 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.34-7.30 (m, 2H), 7.25-7.21 (m, 1H), 7.15-7.11 (m, 1H), 7.08-7.07 (m, 1H), 7.02 (dd, J = 5.0, 1.2 Hz, 1H), 5.63 (d, J =4.5 Hz, 1H), 4.26 (dt, J = 12.8, 5.7 Hz, 1H), 4.04-3.98 (m, 2H), 2.97-2.92(m, 3H), 2.83 (dd, J = 15.6, 9.3 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.9,142.8, 135.6, 130.4, 128.9, 127.6, 126.7, 126.5, 125.7, 123.8, 120.5, 118.5,112.0, 111.9, 103.8, 39.18, 39.16, 32.5, 20.5; IR (neat): n 3290, 2927, 1644,1403, 1264, 1332, 1055, 799 cm –1 HRMS (ESI): m / z [M + H] + calcd. forC 19 H 17 N2OS: 321.1056; found: 321.1056.

[0124] Example 26:

[0125]

[0126] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2al (14.2 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and cesium carbonate (48.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3al (21 mg), with a yield of 65% and ee = 98%. Analysis of product 3al yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 25 / 75; Flow rate = 1.0 mL / min; t R1 = 12.54 min, 99.19%; t R2 = 17.87 min, 0.81%; [α] D 23 = 57.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d8.33 (s,1H), 7.52 (d, J = 6.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.24 (t, J = 7.0 Hz,1H), 7.13 (t, J = 7.9 Hz, 1H), 5.48 (d, J = 4.8 Hz, 1H), 4.16 (dt, J = 12.8,5.8 Hz, 1H), 4.04 - 3.95 (m, 5H), 2.93 (t, J = 6.0 Hz, 2H), 2.88 - 2.83 (m, 1H),2.73 - 2.71 (m, 2H), 1.37 (s, 3H); 13 C NMR (101 MHz, CDCl3): d 169.3, 137.3,131.8, 127.9, 126.7, 123.6, 120.0, 119.0, 112.4, 111.0, 110.9, 98.6, 65.09,65.06, 40.0, 39.2, 33.0, 21.4, 20.5; IR (neat): n 3349, 2945, 1668, 1605,1446, 1462, 1180, 1031, 744 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. forC 19 H 21 N2O3: 325.1547; found: 325.1551。

[0127] Example 27:

[0128]

[0129] Dihydro-β-carbaline compound 1aa (36.8 mg, 0.20 mmol, 2.0 equiv), enal 2am (36.5 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (122.5 mg, 0.30 mmol, 3.0 equiv), and triethylamine (30.3 mg, 0.30 mmol, 3.0 equiv) were loaded into a dry reaction flask. Anhydrous toluene solution (1 mL) was then added. After reacting the reaction mixture at 25 °C for 12 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3am (43 mg), with a yield of 78% and ee = 99%. Analysis of product 3am yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 5 / 95; Flow rate = 1.0 mL / min; t R1 = 12.00 min, 99.47%; t R2 = 23.13 min, 0.53%; [α] D 20 = 12.0 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 7.71 (s, 1H), 7.68 (d, J = 6.6 Hz, 2H), 7.63 (d, J = 6.6 Hz, 2H), 7.52 (d, J = 7.9 Hz,1H), 7.47-7.42 (m, 1H), 7.39-7.36 (m, 3H), 7.32 (t, J = 6.8 Hz, 3H), 7.24 (t, J = 6.9 Hz, 1H), 7.14 (t, J = 6.8 Hz, 1H), 5.78 (q, J = 7.0 Hz, 1H), 5.26 (d, J = 3.3 Hz, 1H), 4.63 (dt, J= 12.7, 3.7 Hz, 1H), 4.21-4.14 (m, 2H), 3.88-3.82 (m, 1H), 3.45-3.38 (m, 1H), 2.95-2.80 (m, 2H), 2.66-2.51 (m, 2H), 1.73(d, J = 6.9 Hz, 3H), 1.03 (s, 9H); 13 C NMR (101 MHz, CDCl3): d 169.4, 138.1,137.1, 135.7, 135.6, 133.7, 133.2, 130.4, 129.7, 127.8, 127.72, 127.67 (2C),126.6, 123.4, 123.2, 120.0, 118.9, 111.9, 110.9, 103.5, 65.8, 39.1, 36.4,31.1, 26.8, 20.5, 19.3, 13.1; IR (neat): n 3296, 2934, 2862, 1740, 1659,1642, 1403, 1264, 1113, 803, 744 cm –1 HRMS (ESI): m / z [M + H] + calcd. forC 35 H 39 N2O2Si: 547.2775; found: 547.2770.

[0130] Example 28:

[0131]

[0132] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (4.2 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 48 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3an (27 mg), with a yield of 82% and ee = 97%. Analysis of product 3an yielded the following results: [Section: Daicel chiral IA column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.60 min, 1.74%; t R2 = 19.58 min, 98.26%; [α] D 23 = 29.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 11.43 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.29 (dd, J =7.7, 1.7 Hz, 1H), 7.22-7.14 (m, 2H), 7.06 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H),6.98 (td, J = 7.4, 1.2 Hz, 1H), 6.81 (dd, J = 8.2, 1.2 Hz, 1H), 4.77 (dd, J =12.9, 4.0 Hz, 1H), 3.33 (s, 1H), 3.07 (td, J = 12.6, 4.1 Hz, 1H), 2.96 (ddd, J= 13.3, 4.4, 2.4 Hz, 1H), 2.93-2.79 (m, 2H), 2.67 (ddd, J = 15.7, 12.3, 5.2Hz, 1H), 2.55 (t, J = 2.2 Hz, 1H), 2.36 (dd, J = 13.3, 2.0 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.3, 151.7, 136.9, 132.8, 129.9, 128.9, 125.9, 125.8,123.0, 122.0, 119.5, 119.4, 117.3, 112.2, 110.9, 82.6, 42.1, 35.9, 31.9,28.4, 21.3; IR (neat): n 3826, 3461, 2932, 2858, 1960, 1667, 1636, 1408, 1019,863 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 19 N2O2: 330.1368; found: 330.1369.

[0133] Example 29:

[0134]

[0135] Dihydro-β-carbaline compound 1ba (23.8 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (4.2 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3bn (21 mg), with a yield of 62% and ee = 96%. Analysis of product 3bn yielded the following results: [Section: Daicel chiral IA column;]i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.47 min, 2.18%; t R2 = 13.86 min, 97.82%; [α] D 23 = 45.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): d 8.33 (s,1H), 7.37 (s, 1H), 7.25 (d, J = 11.4 Hz, 3H), 7.19 - 7.10 (m, 2H), 7.08 (dd, J = 8.4, 1.9 Hz, 1H), 6.95 (td, J = 7.5, 1.3 Hz, 1H), 6.81 (dd, J = 8.2, 1.3Hz, 2H), 5.00 - 4.86 (m, 1H), 3.35 - 3.11 (m, 2H), 2.91 - 2.65 (m, 5H), 2.47(s, 3H), 2.25 (dd, J = 13.3, 2.1 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.6,151.5, 135.2, 131.8, 129.5, 129.24, 128.9, 126.4, 125.2, 124.6, 122.1, 119.0,117.2, 112.5, 111.3, 82.2, 41.9, 36.5, 32.9, 28.8, 21.6, 21.3; IR (neat): n 3449. 2930, 2861, 1636, 1407, 1241, 1107, 1021, 864, 716 cm –1 HRMS (ESI): m / z[M + H] + calcd. for C 22 H 21 N2O2: 345.1598; found: 345.1599.

[0136] Example 30:

[0137]

[0138] Dihydro-β-carbaline compound 1ca (25.4 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.8 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were placed in a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3cn (21 mg), with a yield of 62% and ee = 97%. Analysis of product 3cn yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 9.07 min, 3.24%; t R2 = 14.56 min, 96.76%; [α] D 23 = 58.0 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.25 (s, 1H), 7.29 (dd, J = 8.2, 2.0 Hz, 2H), 7.17 (ddd, J = 8.9, 7.4, 1.7 Hz, 1H),7.03 (d, J = 2.5 Hz, 1H), 6.97 (td, J = 7.4, 1.2 Hz, 1H), 6.87-6.77 (m, 2H), 4.76 (dd, J = 13.3, 4.3 Hz, 1H), 3.77 (s, 3H), 3.33 (dt, J = 4.8, 2.5 Hz, 1H), 3.06 (td, J= 12.6, 4.1 Hz, 1H), 2.99-2.85 (m, 2H), 2.81 (dd, J = 16.2,3.1 Hz, 1H), 2.64 (ddd, J = 15.6, 12.3, 5.2 Hz, 1H), 2.53 (d, J = 2.2 Hz, 1H), 2.35 (dd, J = 13.3, 2.0 Hz, 1H); 13 C NMR (101 MHz, DMSO): d 168.3, 153.9,151.7, 133.3, 131.9, 129.9, 128.9, 126.1, 125.8, 121.9, 117.3, 113.2 112.9,110.6, 101.0, 82.6, 55.8, 42.0, 35.9, 31.9, 28.1, 21.4; IR (neat): 3790, 3457, 2931, 2859, 1591, 1383, 1239, 1020, 801, 703 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O3: 361.1547; found: 361.1546.

[0139] Example 31:

[0140]

[0141] Dihydro-β-carbaline compound 1da (25.4 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3dn (26 mg), with a yield of 75% and ee = 97%. Analysis of product 3dn yielded the following results: [Section: Daicel chiral ID column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 8.71 min, 2.67%; t R2 = 10.18 min, 97.33%; [α] D 23 = 51.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.54 (s, 1H), 7.39 (dd, J = 8.9, 4.5 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.18 (ddd, J = 8.9,7.4, 1.7 Hz, 1H), 7.13 - 6.92 (m, 2H), 6.81 (dd, J = 8.2, 1.2 Hz, 1H), 4.79 -4.70 (m, 1H), 3.38 - 3.30 (m, 1H), 3.05 (td, J = 12.6, 4.0 Hz, 1H), 2.98 -2.75 (m, 3H), 2.63 (ddd, J = 15.7, 12.3, 5.2 Hz, 1H), 2.58 - 2.48 (m, 1H), 2.37 (dd, J = 13.3, 2.0 Hz, 1H); 1313C NMR (101 MHz, CDCl3): d 167.9, 157.4 (d, J C-F J = 231.9 Hz), 151.1, 134.3, 133.1, 129.5, 128.5, 126.0 (d, J C-F J = 10.1 Hz),125.3, 121.6, 116.9, 113.3 (d, J C-F J = 9.9 Hz), 111.2 (d, J C-F J = 5.0 Hz), 111.2(d, J C-F J = 26.1 Hz), 104.2 (d, J C-F J = 23.2 Hz), 82.0, 41.6, 35.4, 31.4, 27.9,20.8;IR (neat): n 3790, 3455, 2928, 2843, 1733, 1663, 1369, 1272, 1026, 811 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 FN2O2: 349.1347; found: 349.1343。

[0142] Example 32:

[0143]

[0144] Dihydro-β-carboline compound 1ea (26.2 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly separated by silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3en (32 mg), with a yield of 88% and ee = 96%. Product 3en was analyzed, and the results are as follows: Daicel chiral IA column; iPrOH / Hexane = 20 / 80; flow rate = 1.0 mL / min; t R1 = 7.82 min, 2.10%; t R2 =10.69 min, 97.90%; [α] D 23 = 59.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.65 (s, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.29 (dd, J = 7.6, 1.7 Hz, 1H), 7.22 - 7.13 (m, 2H), 6.98 (td, J = 7.4, 1.2 Hz, 1H), 6.81 (dd, J = 8.2, 1.2 Hz, 1H), 4.75 (ddd, J = 12.9, 5.3, 1.4 Hz, 1H), 3.34(dt, J = 4.8, 2.4 Hz, 1H), 3.05 (td, J = 12.7, 4.0 Hz, 1H), 2.97 - 2.79 (m,3H), 2.64 (ddd, J= 15.8, 12.4, 5.3 Hz, 1H), 2.54 (d, J = 2.3 Hz, 1H), 2.37(dd, J = 13.3, 2.1 Hz, 1H); 13 C NMR (101 MHz, DMSO): d 168.3, 151.5, 135.3,134.4, 129.9, 128.9, 126.9, 125.7, 124.1, 122.9, 122.0, 118.8, 117.3, 113.7,110.8, 82.4, 41.9, 35.7, 31.8, 28.3, 21.1; IR (neat): n 3790. 3452, 2930, 2860,1747, 1635, 1379, 1235, 1018, 800 cm –1 HRMS (ESI): m / z [M + H] + calcd. forC 21 H 18 ClN2O2: 365.1051; found: 365.1049.

[0145] Example 33:

[0146]

[0147] Dihydro-β-carboline compound 1fa (31.6 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3fn (33 mg), with a yield of 79% and ee = 97%. Analysis of product 3fn yielded the following results: Daicel chiral IA column; iPrOH / Hexane = 20 / 80; flow rate = 1.0 mL / min; t R1= 7.98 min, 1.64%; t R2 =10.60 min, 98.36%;[α] D 23 = 36.0 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.62 (s, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 8.7, 2.0 Hz, 1H), 7.26 (dd, J = 7.6, 1.6 Hz, 1H), 7.16 (td, J = 7.7, 1.7Hz, 1H), 6.97 (td, J = 7.4, 1.2 Hz, 1H), 6.77 (dd, J = 8.2, 1.2 Hz, 1H), 4.69(dd, J = 13.1, 4.7 Hz, 1H), 3.32 (dt, J = 4.7, 2.4 Hz, 1H), 3.03 (td, J =12.7, 4.0 Hz, 1H), 2.94 - 2.75 (m, 3H), 2.61 (ddd, J = 15.9, 12.4, 5.3 Hz,1H), 2.51 (d, J = 17.3 Hz, 1H), 2.30 (dd, J = 13.3, 2.0 Hz, 1H); 13 C NMR (101MHz, DMSO): d 170.1, 152.0, 136.3, 134.7, 130.67, 129.8, 128.3, 126.3(2C),123.1, 122.5, 118.0, 115.0, 112.8, 111.6, 83.1, 42.6, 36.8, 32.5, 28.8, 21.7;IR (neat): n3773, 3451, 2929, 2862, 1959, 1667, 1606, 1386, 1271, 757 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 BrN2O2: 409.0546; found: 409.0541.

[0148] Example 34:

[0149]

[0150] Dihydro-β-carboline compound 1ga (21.4 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly separated by silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3gn (28 mg), with a yield of 79% and ee = 96%. Analysis of product 3gn yielded the following results: Daicel chiral IA column; iPrOH / Hexane = 20 / 80; flow rate = 1.0 mL / min; t R1 = 7.59 min, 1.90%; t R2 =11.84 min, 98.10%; [α] D 23 = 51.2 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.37 (s, 1H), 7.28 (dd, J = 7.6, 1.7 Hz, 1H), 7.21-7.13 (m, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.97 (dtd, J= 7.4, 3.6, 1.2 Hz, 2H), 6.80 (dd, J = 8.2, 1.2Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 4.71 (dd, J = 12.5, 4.8 Hz, 1H), 3.84 (s,3H), 3.32 (dt, J = 4.8, 2.4 Hz, 1H), 3.12 - 2.97 (m, 2H), 2.96 - 2.83 (m, 2H), 2.76 (ddd, J = 16.6, 13.4, 5.2 Hz, 1H), 2.53 (d, J = 2.2 Hz, 1H), 2.33 (dd, J = 13.3, 2.1 Hz, 1H); 13 C NMR (101 MHz, DMSO): d 168.3, 155.0, 151.7, 138.2, 131.0, 129.9, 128.9, 125.8, 123.8, 121.9, 117.3, 116.0, 110.4, 105.4, 99.8, 82.6, 55.7, 42.0, 36.0, 32.0, 28.4, 23.4; IR (neat): n 3857, 3460, 2929, 2859, 1965, 1666, 1628, 1464, 1020, 852 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O3: 361.1547; found: 361.1546。

[0151] Example 35:

[0152]

[0153] Dihydro-β-carboline compound 1ha (25.9 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 48 h, the reaction mixture was directly separated by silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3hn (32 mg), with a yield of 87% and ee = 95%. Product 3hn was analyzed, and the results are as follows: Daicel chiral IA column; iPrOH / Hexane = 20 / 80; flow rate = 1.0 mL / min; t R1 = 7.08 min, 2.52%; t R2 = 8.24 min, 97.48%; [α] D 23 = 34.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.79 (s, 1H), 7.36 (dd, J = 8.1, 0.9 Hz, 1H), 7.30 (dd, J = 7.7, 1.7 Hz, 1H), 7.22 -7.16 (m, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.06 (dd, J = 7.6, 0.9 Hz, 1H), 6.98(td, J = 7.4, 1.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.2 Hz, 1H), 4.74 (dd, J =13.4, 4.4 Hz, 1H), 3.35 (d, J = 3.1 Hz, 1H), 3.22 (dd, J = 16.0, 2.6 Hz, 1H), 3.06 (td, J= 12.6, 3.9 Hz, 1H), 2.98 - 2.78 (m, 3H), 2.56 - 2.51 (m, 1H), 2.37 (dd, J = 13.2, 2.0 Hz, 1H); 13 C NMR (101 MHz, CDCl3): d 168.3, 151.5,138.1, 134.1, 123.0, 129.0, 125.8, 125.8, 123.7, 123.0, 122.06, 119.9, 117.3,111.4, 110.5, 82.4, 41.2, 35.8, 31.9, 28.4, 23.0; IR (neat): n 3788, 3457,2930, 2859, 1961, 1667, 1606, 1480, 1022, 863 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 ClN2O2: 365.1051; found: 365.1049.

[0154] Example 36:

[0155]

[0156] Dihydro-β-carbaline compound 1ia (24.1 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3in (29 mg), with a yield of 82% and ee = 97%. Analysis of product 3in yielded the following results: [Section: Daicel chiral IA column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1= 7.52 min, 1.23%; t R2 = 16.43min, 98.77%;[α] D 23 = 53.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.54 (s,1H), 7.39 (dd, J = 8.9, 4.6 Hz, 1H), 7.35-7.26 (m, 2H), 7.18 (ddd, J = 8.8,7.5, 1.7 Hz, 1H), 7.08-6.94 (m, 2H), 6.81 (dd, J = 8.2, 1.2 Hz, 1H), 4.76(dd, J = 13.0, 5.1 Hz, 1H), 3.36 (s, 1H), 3.06 (td, J = 12.6, 4.0 Hz, 1H),2.98-2.76 (m, 3H), 2.64 (ddd, J = 15.5, 12.3, 5.2 Hz, 1H), 2.57-2.50 (m, 1H),2.37 (dd, J = 13.3, 2.1 Hz, 1H); 13 C NMR (101 MHz, DMSO): d 168.3, 157.4 (d, J C-F = 232.0 Hz), 151.6, 134.75, 133.6, 129.9, 128.9, 126.0 (d, J C-F = 10.1Hz), 125.8, 122.01, 117.3, 113.2 (d, J C-F = 9.7 Hz), 111.2 (d, J C-F = 4.8 Hz),111.2 (d, J C-F = 26.2 Hz), 104.2 (d, J C-F= 23.1 Hz), 82.5, 42.0, 35.8, 31.9,28.4, 21.2; IR (neat): n 3855, 3452, 2932, 1933, 1593, 1241, 1136, 1036, 855,799 cm –1 HRMS (ESI): m / z [M + H] + calcd. for C 21 H 18 FN2O2: 349.1347; found: 349.1343.

[0157] Example 37:

[0158]

[0159] Dihydro-β-carbaline compound 1ja (24.1 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3jn (24 mg), with a yield of 69% and ee = 97%. Analysis of product 3jn yielded the following results: [Section: Daicel chiral IA column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 5.57 min, 1.54%; t R2 = 7.30 min, 98.46%; [α] D 23 = 47.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.12 (s,1H), 7.40 - 7.33 (m, 1H), 7.30 (dd, J= 7.6, 1.7 Hz, 1H), 7.18 (ddd, J = 8.9, 7.3, 1.6 Hz, 1H), 6.98 (td, J = 6.6, 1.9 Hz, 3H), 6.82 (dd, J = 8.2, 1.2 Hz, 1H), 4.77 (dd, J = 13.1, 4.6 Hz, 1H), 3.33 (s, 1H), 3.18 (ddd, J = 13.2, 4.3, 2.4 Hz, 1H), 3.07 (td, J = 12.6, 4.0 Hz, 1H), 2.87 (dd, J = 29.3, 4.1 Hz, 1H), 2.83 (dd, J = 27.5, 4.7 Hz, 1H), 2.66 (ddd, J = 15.7, 12.3, 5.2 Hz, 1H), 2.58 - 2.50 (m, 1H), 2.48 (s, 3H), 2.31 (dd, J = 13.3, 2.0 Hz, 1H); 13 C NMR(101 MHz, DMSO): d 168.4, 151.7, 136.5, 132.7, 129.9, 128.9, 125.9, 125.5, 123.5, 121.9, 121.5, 119.7, 117.3, 116.8, 111.3, 82.7, 42.1, 35.9, 31.7, 28.4, 21.4, 17.4;IR (neat): n 3747, 3454, 2930, 2863, 1959, 1732, 1625, 1408, 1019, 862 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O2: 345.1598; found: 345.1599。

[0160] Example 38:

[0161]

[0162] Dihydro-β-carbaline compound 1Ka (31.6 mg, 0.12 mmol, 1.2 equiv), enal 2AN (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3KN (30 mg), with a yield of 73% and ee = 92%. Analysis of product 3KN yielded the following results: [Section: Daicel chiral IA column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 6.61 min, 4.20%; t R2 = 9.30 min, 95.80%; [α] D 23 = 47.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.51 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 7.7, 0.9 Hz, 1H), 7.30 (dd, J =7.6, 1.6 Hz, 1H), 7.23 - 7.14 (m, 1H), 7.01 (t, J = 7.7 Hz, 1H), 7.00 - 6.95(m, 1H), 6.83 (dd, J = 8.1, 1.2 Hz, 1H), 4.78 (ddd, J = 12.9, 5.3, 1.4 Hz,1H), 3.37 (dd, J = 4.4, 2.4 Hz, 1H), 3.33-3.29 (m, 1H), 3.05 (td, J= 12.6,3.9 Hz, 1H), 2.96 - 2.78 (m, 2H), 2.67 (ddd, J = 15.8, 12.4, 5.2 Hz, 1H),2.59 - 2.50 (m, 1H), 2.28 (d, J = 11.6 Hz, 1H); 13 C NMR (101 MHz, DMSO): d 168.4, 151.6, 135.4, 134.2, 129.9, 128.8, 127.6, 125.9, 125.7, 121.9, 121.0,118.9, 117.2, 112.4, 104.8, 82.7, 42.0, 35.7, 31.2, 28.2, 21.4; IR (neat): n 3790, 3475, 2903, 2862, 1958, 1667, 1606, 1385, 1271, 751 cm –1 HRMS (ESI): m / z[M + H] + calcd. for C 21 H 18 BrN2O2: 409.0546; found: 409.0541.

[0163] Example 39:

[0164]

[0165] Dihydro-β-carbaline compound 1la (31.6 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 40 °C for 6 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ln (30 mg), with a yield of 73% and ee = 92%. Analysis of product 3ln yielded the following results: [Section: Daicel chiral IA column;] iPrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 8.91 min, 4.19%; t R2 = 13.12 min, 95.81%; [α] D 23 = 51.7 ( c = 0.1, CH2Cl2); 1 1H NMR (400 MHz, DMSO): d 11.83 (s, 1H), 7.84 (s, 1H), 7.62 (s, 1H), 7.30 (dd, J = 7.6, 1.7 Hz, 1H), 7.18 (td, J = 7.7, 1.7 Hz, 1H), 6.98 (td, J = 7.5, 1.2 Hz, 1H), 6.83 (dd, J = 8.1, 1.2 Hz, 1H), 4.75 (dd, J = 12.8, 5.0 Hz, 1H), 3.35 (s, 1H), 3.04 (td, J = 12.7, 4.0 Hz, 1H), 2.96 - 2.81 (m, 3H), 2.63 (ddd, J = 15.7, 12.3, 5.2 Hz, 1H), 2.55 (s, 1H), 2.38 (dd, J = 13.2, 2.0 Hz, 1H); 13 13C NMR (101 MHz, DMSO): d 168.3, 151.5, 135.8, 135.9, 130.0, 129.0, 125.9, 125.8, 125.2, 122.2, 122.1, 120.9, 117.3, 113.7, 111.2, 82.4, 42.0, 35.7, 31.8, 28.3, 21.1; IR (neat): n 3455, 2931, 2862, 1747, 1630, 1546, 1408, 1157, 1022, 854 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C21 H 17 Cl2N2O2: 398.0589; found: 398.0589.

[0166] Example 40:

[0167]

[0168] Dihydro-β-carbaline compound 1MA (23.8 mg, 0.12 mmol, 1.2 equiv), enal 2AN (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were placed in a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 48 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3Mn (29 mg), with a yield of 84% and ee = 98%. Analysis of product 3Mn yielded the following results: [Section: Daicel chiral IA column;] i PrOH / Hexane = 10 / 90; Flow rate = 1.0 mL / min; t R1 = 13.14 min, 1.22%; t R2 =14.68 min, 98.78%; [α] D 23 = 38.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 7.56 (dt, J = 7.9, 0.9 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 7.6, 1.7 Hz, 1H), 7.26 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.20 (ddd, J = 8.3, 7.4,1.7 Hz, 1H), 7.10 (td, J = 7.5, 0.9 Hz, 1H), 7.01 (td,J = 7.4, 1.2 Hz, 1H), 6.88 (dd, J = 8.1, 1.2 Hz, 1H), 4.78 (ddd, J = 12.6, 4.8, 1.5 Hz, 1H), 3.81 (s, 3H), 3.35 (d, J = 4.9 Hz, 1H), 3.07 (ddd, J = 13.4, 4.7, 2.3 Hz, 1H), 3.01 – 2.88 (m, 2H), 2.81 (ddd, J = 15.7, 3.7, 1.6 Hz, 1H), 2.64 (ddd, J = 15.6, 12.3, 4.8 Hz, 1H), 2.55 (dt, J = 17.5, 2.2 Hz, 1H), 2.33 (dd, J = 13.4, 2.0 Hz, 1H); 13 C NMR (101 MHz, DMSO): d 168.3, 151.4, 138.6, 133.0, 130.0, 129.0, 126.0, 125.2, 123.3, 122.2, 119.8, 119.5, 117.4, 112.9, 110.5, 83.4, 42.0, 36.5, 32.1, 31.6, 28.1, 21.8; IR (neat): n 3462, 2930, 2861, 1959, 1667, 1606, 1385, 1272, 867, 759 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 22 H 21 N2O2: 345.1598; found: 345.1599。

[0169] Example 41:

[0170]

[0171] Dihydro-β-carbaline compound 1na (32.9 mg, 0.12 mmol, 1.2 equiv), enal 2an (14.8 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3nn (26 mg), with a yield of 62% and ee = 87%. Analysis of product 3nn yielded the following results: [Section: Daicel chiral IA column;] i PrOH / Hexane = 10 / 90; Flow rate = 1.0 mL / min; t R1 = 9.03 min, 6.48%; t R2 = 10.75 min, 93.52%; [α] D 23 = -16.0 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 7.62 (d, J = 7.3 Hz, 1H), 7.31-7.11 (m, 7H), 7.10 (ddd, J = 8.0, 6.5, 1.6 Hz, 1H),7.06-7.00 (m, 2H), 6.96 (td, J = 7.4, 1.2 Hz, 1H), 6.74 (dd, J = 8.1, 1.2 Hz,1H), 5.53 (s, 2H), 4.82 (ddd, J = 12.6, 4.8, 1.5 Hz, 1H), 3.22 (t, J = 5.3Hz, 1H), 3.01 (td, J = 12.5, 3.5 Hz, 1H), 2.94-2.82 (m, 2H), 2.70 (ddd, J=15.2, 12.4, 4.7 Hz, 2H), 2.55-2.45 (m, 1H), 2.30 (dd, J = 13.5, 1.9 Hz, 1H); 13 C NMR (101 MHz, DMSO): d 168.2, 151.1, 138.5, 138.3, 133.2, 130.0, 129.0(2C), 128.9, 127.4, 126.3 (2C), 125.8, 125.8, 123.6, 122.2, 120.2, 119.7,117.4, 113.7, 111.3, 83.5, 48.2, 41.9, 36.5, 32.4, 28.0, 21.9; IR (neat): n 3796, 3707, 3463, 2931, 1958, 1667, 1606, 1386, 1271, 757 cm –1 HRMS (ESI): m / z[M + H] + calcd. for C 28 H 25 N2O2: 421.1911; found: 421.1909.

[0172] Example 42:

[0173]

[0174] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ao (16.6 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ao (29 mg), with a yield of 81% and ee = 94%. Analysis of product 3ao yielded the following results: [Section: Daicel chiral IA column;] iPrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 7.72 min, 3.23%; t R2 = 16.70 min, 96.77%; [α] D 23 = 47.3 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.42 (s,1H), 7.53 (d, J = 7.9 Hz, 1H), 7.42 - 7.34 (m, 1H), 7.26 - 7.10 (m, 2H), 7.05(ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.64 (dd, J = 8.3, 0.9 Hz, 1H), 6.44 (dd, J = 8.3, 0.9 Hz, 1H), 4.75 (dd, J = 13.4, 4.4 Hz, 1H), 3.84 (s, 3H), 3.44 (tt, J = 4.5, 1.9 Hz, 1H), 3.05 (td, J = 12.6, 4.0 Hz, 1H), 2.93 - 2.73 (m, 3H),2.66 (ddd, J = 15.6, 12.3, 5.2 Hz, 1H), 2.47 (d, J = 2.2 Hz, 1H), 2.32 (dd, J = 13.3, 2.1 Hz, 1H); 13 C NMR (101 MHz, DMSO): d 168.7, 157.5, 152.3, 136.9,132.8, 129.0, 125.8, 122.9, 119.5, 119.4, 113.6, 112.1, 110.9, 109.9, 103.9,82.3, 56.2,39.6, 35.8, 31.9, 23.2, 21.3; IR (neat): n3441, 2927, 2858, 2375,2348, 1598, 1412, 1265, 1022, 751 cm –1 HRMS (ESI): m / z [M + H] + calcd. forC 22 H 21 N2O3: 361.1547; found: 361.1546.

[0175] Example 43:

[0176]

[0177] Dihydro-β-carbaline compound 1aa (22.1 mg, 0.12 mmol, 1.2 equiv), enal 2ap (16.6 mg, 0.10 mmol, 1.0 equiv), catalyst (3.7 mg, 10 mol%), 3,3',5,5'-tetratert-butylbiphenylquinone (53.1 mg, 0.13 mmol, 1.3 equiv), and sodium carbonate (15.9 mg, 0.15 mmol, 1.5 equiv) were loaded into a dry reaction flask. Anhydrous tetrahydrofuran solution (1 mL) was then added. After reacting the reaction mixture at 0 °C for 20 h, the reaction mixture was directly subjected to silica gel column chromatography (preferably using petroleum ether:ethyl acetate = 10:1~5:1) to obtain the target product 3ap (26 mg), with a yield of 75% and ee = 96%. Analysis of product 3ap yielded the following results: [Section: Daicel chiral IA column;] i PrOH / Hexane = 20 / 80; Flow rate = 1.0 mL / min; t R1 = 5.50 min, 1.87%; t R2 = 15.26 min, 98.13%; [α] D 23 = 37.7 ( c = 0.1, CH2Cl2); 1 H NMR (400 MHz, DMSO): d 11.40 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.20-7.14 (m, 2H), 7.05 (ddd, J= 7.9, 7.0, 1.0 Hz, 1H), 6.79 (dd, J = 7.7, 0.9 Hz, 1H), 6.62(s, 1H), 4.76 (dd, J = 12.8, 4.6 Hz, 1H), 3.29 (s, 1H), 3.06 (td, J = 12.6,4.0 Hz, 1H), 2.93 (ddd, J = 13.2, 4.4, 2.4 Hz, 1H), 2.89-2.79 (m, 2H), 2.66(ddd, J = 15.7, 12.3, 5.2 Hz, 1H), 2.46 (s, 1H), 2.33 (dd, J = 13.2, 2.1 Hz,1H), 2.22 (s, 3H); 13 C NMR (101 MHz, DMSO): d 168.3, 151.5, 138.4, 136.9,132.9, 129.6, 125.9, 122.9, 122.8, 122.8, 119.5, 119.8, 117.5, 112.1, 110.8,82.5, 42.1, 35.8, 32.1, 28.1, 21.3, 21.2; IR (neat): n 3858, 3463, 2932, 2862,1732, 1667, 1636, 1408, 1020, 865 cm –1 HRMS (ESI): m / z [M + H] + calcd. forC 22 H 21 N2O2: 345.1598; found: 345.1599.

[0178] Application Example 1: Test of the anti-influenza A virus activity of the compound prepared in this invention

[0179] Anti-influenza A virus activity was assessed using the inhibition rate of viral cytopathic effect (CPE), with ribavirin as a positive control. MDCK cells were infected with influenza A virus PR8 / H1N1 with a multiplicity of infection (MOI) of 0.1, followed by treatment with specified concentrations of compounds for 48 hours, with each concentration containing three parallel wells. Cells were then fixed with 4% formaldehyde solution at room temperature for 20 minutes. After removal, the cells were stained with 0.1% crystal violet for 30 minutes. After washing the culture plates, the crystal violet staining intensity of each well was measured at 570 nm. The results are shown in Table 1. In the initial screening, compounds 3aa-3ap all exhibited varying degrees of anti-influenza A virus activity at a working concentration of 10 μM. Among them, compounds 3aa, 3ka, 3ab, and 3ad showed significant anti-influenza A virus activity, with the optimal compound 3aa achieving an inhibition rate of 96.2% against PR8 virus. The activity of the optimal compound 3aa was then evaluated.

[0180] Table 1. Inhibition rate of chiral indo[2,3-a]hydroquinazine compounds against PR8 virus

[0181]

[0182]

[0183] Following CPE testing, three strains (PR8 / H1N1, Vir09 / H1N1, and Aichi / H3N2, MOI=0.1) were used to evaluate the activity of the optimal compound 3aa. The IC50 was calculated based on the test results. 50 The result is as follows Figure 1 As shown, compound 3aa exhibited good antiviral activity against different subtypes of influenza A virus. The IC50 values ​​of compound 3aa against different influenza virus subtypes were calculated. 50 IC for PR8 / H1N1 50 =12.2 ± 1.0 μM, for Vir09 / H1N1 IC 50 =3.6 ± 0.5 μM, IC50 for Aichi / H3N2 50 =14.1 ± 1.1 μM. All of the above results indicate that compound 3aa possesses broad-spectrum anti-IAV activity, with the best inhibitory activity against the prevalent H1N1 strain Vir09.

[0184] Application Example 2: Safety Evaluation of Compound 3aa

[0185] This invention uses the MTT assay to test the cytotoxicity of compound 3aa and to preliminarily evaluate its safety. The specific experimental steps are as follows:

[0186] MDCK, A549, and Vero cells cultured in 96-well plates were treated with specified concentrations of the compound to establish a control group without the compound. Each concentration contained three parallel wells. After incubating the cells with the compound at 37°C for 48 hours, 10 μL of PBS solution containing MTT (final concentration: 0.5 mg / mL) was added to each well, followed by incubation at 37°C for another 4 hours. Subsequently, 180 μL of formazan crystals dissolved in DMSO was added to each well, and the absorbance was measured at 570 nm using a microplate reader. Cell viability percentage was calculated using the following formula: Cell viability (%) = A compound / A Mock × 100.

[0187] Experimental results are as follows Figure 2 As shown, compound 3aa exhibited low cytotoxicity in MDCK, Vero, and A549 cells. The cytotoxicity of compound 3aa to different cell types was calculated. 50 CC in MDCK cells 50 =479.6 ± 2.6 μM, CC in Vero cells 50 =464.9 ± 2.7 μM, CC in A549 cells 50 =115.0 ± 2.0 μM. These results indicate that compound 3aa has low cytotoxicity.

[0188] Application Example 3: Evaluation of the in vivo anti-influenza A virus activity of compound 3aa

[0189] The experimental methods and steps are as follows:

[0190] To investigate the activity of compound 3aa in vivo, a mouse pneumonia model was first established: PR8 virus (500 PFU / mouse) was diluted in 40 μL of PBS and administered to mice intranasally. Mice were then randomly assigned to different experimental groups, with 20 mice in each group. Four hours after inoculation, mice received oral treatment with baloxavir (10 mg / kg / day), oseltamivir (10 mg / kg / day), compound 3aa (5 or 10 mg / kg / day), or placebo, respectively, once daily for four consecutive days. On the third day after inoculation, mice were weighed and induced into a coma via spinal dislocation, and lung tissue was harvested and weighed. Samples were collected on this day for hematoxylin-eosin staining histopathological examination. Clinical symptoms and weight changes in the remaining mice were observed daily.

[0191] Experimental results are as follows Figure 3As shown, mice in the placebo control group began to die on day 4 after infection, and all died by day 10, indicating that influenza virus infection reduces the survival rate of mice. Although mice in the positive control oseltamivir group (10 mg / kg / day) and baloxavir group (10 mg / kg / day) still experienced mortality, they maintained high survival rates of 45% and 80%, respectively. After administration of compound 3aa, the survival rate of mice significantly increased compared to the placebo control group. The high-dose compound 3aa group (10 mg / kg / day) had a survival rate of 50%, superior to the oseltamivir group but lower than the baloxavir group. The low-dose compound 3aa group (5 mg / kg / day) exhibited superior in vivo anti-influenza A virus activity, with a survival rate of 70%, higher than the high-dose group and close to the baloxavir group, indicating that low-dose compound 3aa showed a more significant and effective in vivo anti-influenza A virus effect.

[0192] In in vivo activity evaluation, mouse weight change is an important indicator. By weighing and recording mice daily and feeding them according to the number of mice, the protective effect of the compound can be inferred from the changes in mouse weight. Results are as follows... Figure 4 As shown, the mice in the blank control group steadily increased in weight, while the mice in the placebo control group continuously decreased in weight until all died on day 10, accompanied by flu-like symptoms such as chills and limb weakness. In the positive control groups (oseltamivir and baloxavir), although weight decreased in the early stages of infection, the mice began to gradually regain weight on days 8 and 7 after infection, respectively, and the symptoms gradually disappeared. The compound 3aa administration group also significantly reversed the weight loss caused by influenza A virus infection in mice and alleviated related flu symptoms. In the high-dose compound 3aa group, the mice gradually regained weight on day 8 after infection, but the rate of recovery was relatively slow, similar to the oseltamivir group. The low-dose compound 3aa group showed a more significant protective effect; the mice's weight began to recover steadily from day 7 after infection, and the rate of weight recovery was close to that of the baloxavir group and superior to the oseltamivir group. The flu-like symptoms in the mice also gradually disappeared. In summary, compound 3aa effectively alleviated weight loss in mice and reduced symptoms caused by influenza A virus infection. The low-dose group of compound 3aa showed better efficacy than the high-dose group, and was superior to the oseltamivir group, approaching the efficacy of the baloxavir group. These results indicate that compound 3aa possesses excellent in vivo anti-influenza A virus activity.

[0193] Next, histological sections of mouse lung tissue were stained with hematoxylin and eosin (HE) to directly observe related phenomena in the lungs. The results are as follows: Figure 5 As shown, the lung tissue structure of mice in the blank control group was clear and showed no inflammatory factor infiltration or congestion. The lung tissue of mice in the placebo control group showed obvious inflammatory factor infiltration and congestion. The inflammatory factor infiltration and congestion in the lung tissue of mice in the positive control group (oseltamivir and baloxavir) were significantly alleviated. After administration of compound 3aa, the inflammation and congestion in the lung tissue of mice were also significantly alleviated, and the effects of different doses of compound 3aa were similar. Compared with the positive control group, the effect of compound 3aa was better than that of the oseltamivir group, but slightly less than that of the baloxavir group. These results indicate that the compound 3aa group showed a relatively effective inhibitory effect on inflammation in the early stage of infection in mice, alleviating lung inflammation caused by influenza virus infection. These results further verify that compound 3aa has good in vivo anti-influenza A virus activity.

[0194] Finally, the viral titer in mouse lung tissue was further evaluated using a plaque assay. After influenza virus infects cells, viral plaques gradually form; each plaque represents one virus. The corresponding viral titer (PFU / mL) can be calculated based on the number of plaques and the dilution factor. Mouse lung tissue homogenates were diluted 1000-fold and used to infect MDCK cells for a plaque assay, followed by plaque counting. The results are as follows: Figure 6 As shown, the viral titer in the lung tissue homogenate of the placebo control group was approximately 1.8 × 10⁻⁶. 4 The viral titer of lung tissue homogenate in the oseltamivir positive group was approximately 4.1 × 10⁻⁶ PFU / mL. 3 The viral titer in the lung tissue homogenate of the positive drug baloxavir group was approximately 1.0 × 10⁻⁶ PFU / mL. 3 The viral titer of lung tissue homogenate in the high-dose group of compound 3aa was approximately 1.9 × 10⁻⁶ PFU / mL. 3 The viral titer of lung tissue homogenate in the low-dose group of compound 3aa was approximately 1.8 × 10⁻⁶ PFU / mL. 3 PFU / mL. The results showed that compound 3aa could reduce the viral load in the lung tissue of mice infected with influenza virus and effectively reduce viral replication.

[0195] In summary, the optimal anti-influenza virus compound 3aa of this invention exhibits excellent anti-influenza A virus activity in mice, significantly improving the survival rate of mice infected with influenza virus, reversing weight loss caused by virus infection, significantly inhibiting lung tissue enlargement caused by viral infection, and significantly reducing viral proliferation in the lungs of mice. Its overall effect is superior to oseltamivir and close to that of baloxavir. This indicates that compound 3aa possesses good in vivo anti-influenza virus activity.

[0196] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A chiral indodo[2,3-] a Hydrogenated quinazon compounds, characterized in that, The structure is shown in general formula (I) or (II): ； Wherein, R is selected from one of 2-chlorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, and 3-thiophene; R 1 Selected from hydrogen or methyl; R 2 Selected from hydrogen or benzyl; R 3 It is selected from one of hydrogen, 5-chloro, 5-methoxy, 6-chloro, 6-bromo, 6-fluoro, 6-methyl, 6-methoxy, 7-fluoro, 8-bromo, 8-methyl, and 6,7-dichloro; R 4 Selected from 3-methyl or 5-methoxy.

2. A chiral indoline[2,3- a A catalytic synthesis method for hydrogenated quinazon compounds, characterized in that, Includes the following steps: ； Using substituted 3,4-dihydro-β-carbazoline and substituted enal as reactants, an organic small molecule catalyst, a base, and the oxidant 3,3',5,5'-tetratert-butylbiphenylquinone were added. The reaction was carried out in an organic solvent at 0-40 °C for 6-48 hours to obtain the chiral indoline[2,3-]represented by general formula (I). a Hydrogenated quinazon compounds; or, ； Using substituted 3,4-dihydro-β-carbazoline and substituted 2-hydroxycinnamaldehyde as reactants, an organic small molecule catalyst, a base, and the oxidant 3,3',5,5'-tetratert-butylbiphenylquinone were added. The reaction was carried out in an organic solvent at 0-40 °C for 6-48 hours to obtain the chiral indoline [2,3-] shown in general formula (II). a Hydrogenated quinazon compounds; The chemical structural formula of the substituted 3,4-dihydro-β-carbazoline is as follows: , where R 1 Selected from hydrogen, methyl; R 2 Selected from hydrogen, methyl, benzyl; R 3 It is selected from one of hydrogen, 5-chloro, 5-methoxy, 6-chloro, 6-bromo, 6-fluoro, 6-methyl, 6-methoxy, 7-fluoro, 8-bromo, 8-methyl, and 6,7-dichloro; The chemical structural formula of the substituted enaldehyde is as follows: R is selected from one of 2-chlorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, and 3-thiophene; The chemical structural formula of the substituted 2-hydroxycinnamaldehyde is as follows: , where R 4 Selected from one of hydrogen, 3-methyl, and 5-methoxy; The organic small molecule catalyst is one of the following compounds: ； Mes represents mesitylexyl.

3. The chiral indopol[2,3-] as described in claim 2 a A catalytic synthesis method for hydrogenated quinazon compounds, characterized in that, In molar amounts, the amount of the organic small molecule catalyst is 5 to 20% of the substituted enal or substituted 2-hydroxycinnamaldehyde; the amount of the substituted 3,4-dihydro-β-carbazoline is 1 to 2 times that of the substituted enal or substituted 2-hydroxycinnamaldehyde; the amount of the base is 1 to 3 times that of the substituted enal or substituted 2-hydroxycinnamaldehyde; and the amount of the oxidant is 1 to 3 times that of the substituted enal or substituted 2-hydroxycinnamaldehyde.

4. The chiral indopol[2,3-] as described in claim 2 a A catalytic synthesis method for hydrogenated quinazon compounds, characterized in that, The base is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, potassium tert-butoxide, cesium carbonate, triethylamine, and 1,8-diazabicycloundec-7-ene.

5. The chiral indopol[2,3-] as described in claim 2 a A catalytic synthesis method for hydrogenated quinazon compounds, characterized in that: The organic solvent is one of dichloromethane, 1,2-dichloroethane, ethyl acetate, diethyl ether, tetrahydrofuran, 1,4-dioxane, or toluene.

6. The chiral indopol[2,3-] as described in claim 2 a A catalytic synthesis method for hydrogenated quinazon compounds, characterized in that: After the reaction is complete, the process also includes a purification step by column chromatography.

7. The chiral indopol[2,3-] as described in claim 6 a A catalytic synthesis method for hydrogenated quinazon compounds, characterized in that: The eluent for the column chromatography is a mixture of ethyl acetate and petroleum ether.

8. The chiral indodo[2,3-] as described in claim 1 a Use of hydrogenated quinazons in the preparation of antiviral drugs for influenza.

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