Chiral indolo-azaspiro oxoindole compound as well as synthesis method and application thereof

Abstract

The invention discloses a chiral indolo-azaspiro oxoindole compound as well as a synthesis method and application thereof. The chemical structural formula of the compound is shown as a formula 3. The synthesis method comprises the following steps: adding a compound isatin in a formula 1 and a compound (2-aminobenzyl) indole in a formula 2 as reaction raw materials into an organic solvent, carrying out a stirring reaction at a certain temperature under the catalysis of a chiral phosphoric acid catalyst, tracking the reaction by TLC until the reaction is complete, filtering, concentrating, and purifying. According to the chiral indolo-azaspiro oxoindole compound synthesized by the invention, a biological activity test shows that the derivative has relatively high sensitivity and relatively strong cytotoxic activity on human liver cancer HepG2 cells. According to the method, reaction conditions are relatively conventional, the reaction process is mild, simple and convenient, the cost is low, the method is suitable for industrial large-scale production, and the application range of the method is widened; and more substrates are used as reactants, so that products with various structures are obtained, the yield is high, and the enantioselectivity is high.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a chiral indole-aza-spiro-oxidized indole compound, its synthesis method, and its applications. Background Technology

[0002] Chiral nitrogen-based spirocycloindole derivatives possess a wide range of biological activities, such as antimalarial, anti-HIV, and antiviral activity. However, due to the high ring strain during the formation of the seven-membered ring and the difficulty in constructing the quaternary carbon stereocenter of the spiroring, their catalytic asymmetric synthesis still faces severe challenges. This makes the research on efficient and highly stereoselective synthetic methodologies for these compounds both of great value and of practical necessity.

[0003] To date, there are few reports on the catalytic asymmetric synthesis of chiral nitrogen-based spirocyclic indole derivatives. Existing methods mainly rely on the [4+3] cycloaddition reaction strategy. For example, Angew. Chem., Int. Ed. 2016, 55 ,11110 J. Org. Chem. 2018, 83 , 15225 Angew. Chem., Int. Ed. 2019 , 58, 12190 Org. Chem. Front. 2023, 10 , 3347 Reports have shown that indigo-derived enaldehydes, as three-carbon building blocks, can undergo [4+3] cycloaddition reactions with different four-carbon building blocks via nitrogen heterocyclic carbene catalysis or nitrogen heterocyclic carbene / transition metal co-catalysis strategies to construct chiral nitrogen heterocyclic spiro-oxidized indole skeletons. Angew. Chem., Int. Ed. 2019, 58 Article 15021 reported the enantioselective [4+3] cycloaddition reaction of MBH carbonate with allyl carbonate to synthesize chiral azidospiroindole derivatives under the synergistic catalysis of a tertiary amine / chiral iridium complex. Despite these methods, efficient synthetic strategies for constructing chiral azidospiroindole derivatives remain very limited, thus urgently requiring the development of new methods and strategies for their synthesis. Currently, there are no reports on chiral indole-azidospiroindole derivatives, and no studies have investigated their synthetic methods or cytotoxicity against human HepG2 liver cancer cells. Summary of the Invention

[0004] One objective of this invention is to provide a chiral indole-azazospiro-indole compound and its application, which exhibits good sensitivity and cytotoxic activity against human hepatocellular carcinoma HepG2 cells.

[0005] The second objective of this invention is to provide a method for synthesizing the above-mentioned chiral indole-aza-spiro-oxidized indole compound. This method is mild, simple, safe and easy to operate, and has the advantages of low cost, high yield and high enantioselectivity.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is: a chiral indole-azo-spiro-oxidized indole compound, the chemical structural formula of which is shown in Formula 3: ; In Formula 3, R is selected from benzyl or allyl; R 1 Selected from one of hydrogen, 5-fluoro, 5-chloro, 5-bromine, 5-methyl, 5-methoxy, 6-fluoro, 6-bromine, and 7-methyl; R 2 Selected from one of hydrogen, 4-methyl, 5-chloro, and 5-methyl; R 3 It is selected from one of hydrogen, 3'-methyl, 4'-chloro, 4'-methyl, 5'-bromo, 5'-methyl, 6'-chloro, and 6'-methyl.

[0007] The present invention also provides a method for synthesizing the above-mentioned chiral indole-aza-spiro-oxidized indole compounds, the specific steps of which are as follows: indigo of formula 1 and (2-aminobenzyl)indole of formula 2 are added to an organic solvent as reactants, and the reaction is stirred for 0.5-6 days under the catalysis of a chiral phosphoric acid catalyst at a temperature of -30-50 °C. The reaction is monitored by TLC until complete, and the compound of formula 3 is obtained by filtration, concentration and purification. The molar ratio between indigo of Formula 1 and (2-aminobenzyl)indole of Formula 2 is 1:(0.3-3); the molar ratio between indigo of Formula 1 and the chiral phosphoric acid catalyst is 1:(0.05-0.25). The structural formula of the compound indigo in formula 1 is as follows: In Formula 1, R is selected from benzyl or allyl; R 1 It is selected from one of hydrogen, 5-fluoro, 5-chloro, 5-bromine, 5-methyl, 5-methoxy, 6-fluoro, 6-bromine, and 7-methyl; The structural formula of compound (2-aminobenzyl)indole of formula 2 is as follows: In Equation 2, R 2 Selected from one of hydrogen, 4-methyl, 5-chloro, and 5-methyl; R 3 It is selected from one of hydrogen, 3'-methyl, 4'-chloro, 4'-methyl, 5'-bromo, 5'-methyl, 6'-chloro, and 6'-methyl.

[0008] Preferably, the chiral phosphoric acid catalyst is selected from one of the following: a binatidine skeleton derivative, an octahydrobinatidine skeleton derivative, and a spirocyclic skeleton derivative; the binatidine skeleton derivative is a compound of formula 4, and its structural formula is [structural formula missing]. In the formula, G is selected from one of 4-chlorophenyl, 9-anthrayl, 9-phenanthyl, 2,4,6-triisopropylphenyl, 2-naphthyl, 1-naphthyl, and triphenylsilyl; the octahydrobinaphthyl skeleton derivative is a compound of formula 5, the structural formula of which is... In the formula, G is selected from 2,4,6-triisopropylphenyl; the spirocyclic skeleton derivative is a compound of formula 6, whose structural formula is [insert structural formula here]. In the formula, G is selected from 2,4,6-triisopropylphenyl.

[0009] Preferably, the chiral phosphoric acid catalyst is a compound of formula 4, with the following structural formula: In the formula, G is selected from 2,4,6-triisopropylphenyl.

[0010] Preferably, the organic solvent is selected from one of 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, toluene, fluorobenzene, chlorobenzene, bromobenzene, o-dimethylbenzene, m-dimethylbenzene, and p-dimethylbenzene; the ratio of the volume of the organic solvent to the molar amount of indigo of Formula 1 is (2.5-80) mL: 1 mmol.

[0011] Preferably, the organic solvent is toluene; the ratio of the volume of the organic solvent to the molar amount of indigo of Formula 1 is 80 mL: 1 mmol.

[0012] Preferably, the reaction time is 60 hours.

[0013] Preferably, the purification is performed using a silica gel plate or silica gel column, and the eluent is a toluene / acetone mixture with a volume ratio of 10:1.

[0014] The present invention also provides the use of the above-mentioned chiral indole-azospiro-indole compound in the preparation of a drug for inhibiting human liver cancer HepG2 cells.

[0015] Compared with the prior art, the present invention has the following beneficial effects: (1) The chiral indole-azazospiro-oxidized indole compounds synthesized in this invention, through bioactivity testing, showed that these derivatives have high sensitivity and strong cytotoxic activity against human liver cancer cells HepG2, indicating that the chiral indole-azazospiro-oxidized indole compounds synthesized in this invention are expected to be applied in the pharmaceutical field. (2) The reaction conditions for synthesizing chiral indole-azazospiro-oxidized indole compounds are relatively conventional. The reaction process is mild, simple, easy to operate, and low in cost, making it suitable for large-scale industrial production and broadening the scope of application of this method. The present invention uses a variety of substrates as reactants to obtain products with diverse and complex structures, and the yield and enantioselectivity are high. Attached Figure Description

[0016] Figure 1The image shows an X-ray single crystal image of the product prepared in Example 5. Detailed Implementation

[0017] The present invention will be further described in detail below with reference to the embodiments.

[0018] In the following embodiments, unless otherwise stated, the experimental methods are generally performed under normal conditions or conditions recommended by the manufacturer.

[0019] The (2-aminobenzyl)indole was described in the literature. Synthesis 2016, 48, The method described in 4548 is used for preparation; the chiral phosphoric acid catalyst and other reagents are commercially available or obtained in accordance with known literature; the experimental methods described are generally performed under standard conditions or conditions recommended by the manufacturer.

[0020] Example 1 The synthetic route for the chiral indole nazospiro-oxidized indole compound 3aa is as follows: 0.1 mmol of indigo formula 1a and (2-aminobenzyl)indole 2a were added to an organic solvent (the molar ratio of the organic solvent to the molar amount of indigo 1a was (2.5-80) mL: 1 mmol) as reactants (the molar ratio between compound (2-aminobenzyl)indole of formula 2 and indigo of formula 1 was (0.3-3): 1)). The reaction was carried out under the action of chiral phosphoric acid (formula 4, 5 or 6) (5-25 mol% of indigo), stirred at -30-50 °C for 12-60 h. The reaction was monitored by TLC until the end. After filtration and concentration, the mixture was purified and separated by silica gel plate (column) chromatography (the eluent was a mixed solution of toluene and acetone in a volume ratio of 10:1) to obtain the chiral indole-aza-spiro-oxidized indole compound formula 3aa. The yield and enantiomers are shown in Table 1.

[0021] Table 1. Effects of different types of chiral phosphoric acid, solvent and volume, reaction temperature, reaction time, equivalence ratio, and catalytic amount of chiral phosphoric acid on the enantiomer ratio and yield of the reaction. Note: In Table 1, er represents the enantiomer ratio. The level of the enantiomer ratio directly reflects the level of enantioselectivity. From the data in Table 1, the optimal reaction conditions can be obtained as follows: chiral phosphoric acid is formula 4f, the amount of chiral phosphoric acid is 10 mol% of indigo, the solvent is toluene, the volume of organic solvent is 8.0 mL, the reaction temperature is 50 ℃, the equivalence ratio is formula 1a: formula 2a = 1:1.2, and the reaction time is 60 hours.

[0022] The steps for obtaining product formula 3aa under optimal reaction conditions in Example 1 are as follows: 0.1 mmol of indigo 1a and 0.12 mmol of (2-aminobenzyl)indole 2a were added to the organic solvent toluene (8.0 mL) as reactants. The mixture was stirred at 50 °C for 60 h in the presence of 0.01 mmol of chiral phosphoric acid 4f. The reaction was monitored by TLC until completion. After filtration and concentration, the mixture was purified by silica gel plate (column) chromatography (eluent was a mixture of toluene and acetone in a volume ratio of 10:1) to obtain the chiral indole azidospirooxyindole compound 3aa.

[0023] The structural characterization data of product formula 3aa obtained under the optimal reaction conditions in Example 1 are as follows: white solid; mp >300 o C; [a] D 20 = -33.0 (c 0.40, CHCl3); 1 H NMR (400MHz, CDCl3) δ 7.69 (d, J = 7.2 Hz, 1H), 7.44 – 7.25 (m, 7H), 7.18 – 6.98 (m,6H), 6.93 (dd, J = 7.5, 5.0 Hz, 2H), 6.87 (dd, J = 7.6, 1.2 Hz, 1H), 6.82 –6.76 (m, 1H), 5.05 – 4.78 (m, 2H), 4.40 – 4.20 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 174.8, 143.3, 142.1, 138.5, 136.2, 135.6, 131.0, 130.7, 130.1,129.1, 128.2, 128.0, 127.6, 127.0, 126.1, 125.5, 124.5, 123.4, 122.5, 119.7,118.6, 113.6, 110.8, 109.7, 65.6, 44.2, 28.7; IR (KBr): 3309, 3056, 2923,2360, 1717, 1608, 1457, 1342, 1171, 979, 744; ESI FTMS exact mass calcd for(C 30 H 23 N3O-H)- requires m / z 440.1763, found m / z 440.1777; Enantiomeric ratio:92:8, determined by HPLC (Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R = 10.710 min (major), t R = 6.953min (minor). The synthesis methods of Examples 2-10 are the same as those for the product formula 3aa obtained under optimal reaction conditions in Example 1. The synthesis methods of Examples 7 and 8 are identical to those of Example 1, except that the reaction time is 3 days. The reaction routes are shown below: The reactants, products, and yields are shown in Table 2 below: Table 2. Reactants, products, enantiomer ratios, and yields of Examples 1-10 Note: In Table 2, er represents the enantiomer ratio. The level of the enantiomer ratio directly reflects the level of enantioselectivity.

[0024] X-ray single-crystal data of the chiral indole-3ea compound (formula 3ea) prepared in Example 5 are shown in Table 3, and the spectra are as follows: Figure 1 As shown.

[0025] Table 3. X-ray single-crystal data of chiral indole-azospiro-indole compounds of formula 3ea .

[0026] The synthesis methods of Examples 11-20 are the same as those of the product formula 3aa obtained under optimal reaction conditions in Example 1. The synthesis methods of Examples 12, 14, and 20 are identical to those of Example 1, except that the reaction time is 5.5 days, and the synthesis methods of Examples 15, 17, and 19 are identical except that the reaction time is 6 days. The reaction routes are shown below: The products, enantioselectivity, and yields are shown in Table 4 below: Table 4. Reactants, products, enantiomer ratios, and yields of Examples 5, 11-20 Note: In Table 4, er represents the enantiomer ratio. The level of the enantiomer ratio directly reflects the level of enantioselectivity.

[0027] As shown in Tables 2 and 4, the method of the present invention can not only achieve the synthesis of chiral indole-aza-spiro-oxidized indole compounds in one step, obtain high enantioselectivity and excellent yield, high atom economy, environmental friendliness and wide applicability, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-processing and diversified product structure, thus having great implementation value and potential social and economic benefits.

[0028] The chiral indole-azazospiro-oxidized indole compounds of this invention were used to test the cytotoxic activity of some compounds against human hepatocellular carcinoma HepG2 cells using the MTT assay. The experimental procedure was as follows: HepG2 cells were seeded at a density of 5000 cells / 100 µL of culture medium in 96-well plates, with five concentration gradients (100, 50, 25, 12.5, and 6.25 µg / mL). After 12 hours of adherent culture, different concentrations of the test compound 3 were added to the culture medium, and the cells were cultured for another 24 hours. Cells without the addition of compound 3 served as the control group, and cells with only culture medium served as the blank group. After the compound stimulation, 20 µL of 0.5 mg / mL MTT was added to each well, and the cells were incubated at 37°C for 4 hours. The supernatant was removed, and 100 µL of dimethyl sulfoxide was added to each well. The culture plate was shaken, and the optical density (OD) value was read at 490 nm. Finally, the IC50 of the test compound 3 was calculated. 50 The results are shown in Table 5. The results indicate that the compounds synthesized in this invention have strong cytotoxic activity against human hepatocellular carcinoma HepG2 cells. Among them, compound 3eh exhibited the strongest activity, showing the strongest inhibitory effect (IC50) against human hepatocellular carcinoma HepG2 cells. 50 =22.37μg / mL).

[0029] Table 5. Cytotoxic activity of the compounds in this invention. The chemical structural formulas and test data of the chiral indole-aza-spiro-oxidized indole compounds prepared in Examples 2-20 are as follows: The preparation of Example 2 ( R )-1'-Allyl-7,12-Dihydro- 5H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ba): yield: 66% (25.9 mg); white solid; m.p. >300 o C; [a] D 20 =+20.5 (c 0.15, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.72 – 7.66 (m, 1H), 7.37 –7.31 (m, 2H), 7.15 – 7.04 (m, 6H), 7.01 – 6.94 (m, 2H), 6.84 (d, J = 6.8 Hz,1H), 6.76 (dd, J = 7.4, 1.2 Hz, 1H), 5.92 (ddt, J = 15.8, 10.9, 5.6 Hz, 1H),5.39 – 5.29 (m, 2H), 4.46 – 4.20 (m, 4H), 3.77 (s, 1H); 13 C NMR (100 MHz,CDCl3) δ 174.4, 143.2, 142.3, 138.6, 135.6, 131.5, 130.8, 130.5, 130.1,129.0, 127.6, 126.92, 126.1, 125.7, 124.5, 123.3, 122.5, 119.7, 118.6, 118.5,113.8, 110.8, 109.7, 65.6, 42.8, 28.7; IR (KBr): 3567, 3326, 2360, 1706,1609, 1457, 1361, 1262, 748, 669; ESI FTMS exact mass calcd for (C 26 H 21 N3O-H) - requires m / z 390.1607, found m / z 390.1633; Enantiomeric ratio: 90:10,determined by HPLC (Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flowrate 1.0 mL / min, T = 25 o C, 254 nm): t R= 8.203 min (major), t R = 5.917 min (minor). The preparation of Example 3 ( R )-1'-benzyl-5'-fluoro-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ca): yield: 99% (45.4 mg); white solid; mp >300 o C; [a] D 20 =-35.8 (c 0.77, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.73 – 7.65 (m, 1H), 7.41 –7.27 (m, 6H), 7.17 – 7.03 (m, 6H), 6.95 (td, J = 8.8, 2.6 Hz, 1H), 6.85 –6.78 (m, 2H), 6.55 (dd, J = 7.6, 2.6 Hz, 1H), 5.02 – 4.77 (m, 2H), 4.40 –4.19 (m, 2H), 3.82 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 174.7, 159,3 (d, J =241.8 Hz), 142.8, 138.7, 137.8, 135.8, 135.6, 132.4 (d, J = 7.6 Hz), 130.0,129.2, 128.3, 127.9, 127.5, 127.0, 125.7, 124.8, 122.7, 119.8, 118.6, 116.4(d, J = 23.5 Hz), 114.00 (d, J = 24.8 Hz), 113.8, 110.7, 110.4 (d, J= 7.8Hz), 65.8, 44.3, 28.6; IR (KBr): 3447, 2360, 2342, 1636, 1559, 1489, 1457,741; ESI FTMS exact mass calcd for (C 30 H 22 FN3O-H) - requires m / z 458.1669, foundm / z 458.1678; Enantiomeric ratio: 93:7, determined by HPLC (Daicel ChiralpakOD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R = 12.497 min (major), t R = 7.343 min (minor). The preparation of Example 4 ( R )-1'-benzyl-5'-chloro-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3da): yield: 96% (45.8 mg); white solid; mp >300 o C; [a] D 20 = +14.8 (c 0.64, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.1 Hz, 1H),7.41 – 7.30 (m, 6H), 7.23 – 6.98 (m, 7H), 6.91 – 6.74 (m, 3H), 5.01 – 4.78(m, 2H), 4.37 – 4.22 (m, 2H), 3.80 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 174.4,142.7, 140.5, 138.5, 135.7, 135.6, 132.4, 129.9, 129.1, 128.8, 128.3, 127.9,127.4, 127.0, 126.4, 125.6, 124.8, 122.7, 119.8, 118.6, 113.9, 110.8, 110.7,65.6, 44.2, 28.6; IR (KBr): 3447, 2360, 1733, 1699, 1653, 1559, 1473; ESIFTMS exact mass calcd for (C 30 H 22 ClN3O-H) - requires m / z 474.1373, found m / z474.1378; Enantiomeric ratio: 95:5, determined by HPLC (Daicel Chiralpak OD,hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R =13.033 min (major), t R = 7.790 min (minor). The preparation of Example 5 ( R )-1'-benzyl-5'-bromo-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ea): yield: 96% (50.0 mg); white solid; mp >300 o C; [a] D 20 = +27.6 (c 0.34, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 6.2, 2.4 Hz,1H), 7.43 – 7.28 (m, 7H), 7.18 – 7.05 (m, 5H), 7.02 (s, 1H), 6.97 (d,J = 2.0Hz, 1H), 6.81 (d, J = 8.3 Hz, 2H), 5.03 – 4.81 (m, 2H), 4.37 – 4.24 (m, 2H), 3.80 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 174.3, 142.8, 141.0, 138.6, 135.7,132.9, 132.8, 129.9, 129.2, 129.1, 128.4, 127.9, 127.5, 127.0, 125.7, 124.8,122.8, 119.9, 118.7, 116.1, 113.9, 111.2, 110.8, 65.5, 44.3, 28.6; IR (KBr):3447, 2360, 1716, 1647, 1507, 1474, 1457, 741; ESI FTMS exact mass calcd for(C 30 H 22 BrN3O-H) - requires m / z 518.0868, found m / z 518.0887; Enantiomeric ratio:96:4, determined by HPLC (Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R = 13.427 min (major), t R = 8.677min (minor). The preparation of Example 6 ( R )-1'-benzyl-5'-methyl-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3fa): yield: 84% (38.2 mg); white solid; mp >300 o C; [a] D 20 = +8.3 (c 0.32, CHCl3);1 H NMR (400 MHz, CDCl3) δ 7.73 – 7.67 (m, 1H), 7.42 –7.29 (m, 6H), 7.16 – 7.03 (m, 6H), 7.01 (s, 1H), 6.85 – 6.73 (m, 3H), 5.06 –4.78 (m, 2H), 4.38 – 4.24 (m, 2H), 2.16 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ174.7, 143.3, 139.6, 138.2, 136.3, 135.6, 133.2, 131.0, 130.9, 130.3, 129.1,128.1, 127.6, 126.9, 125.4, 124.4, 122.5, 119.6, 118.6, 113.4, 110.7, 109.5,65.7, 44.2, 28.7, 21.0; IR (KBr): 3447, 2922, 2361, 1717, 1654, 1491, 1340,1185, 742; ESI FTMS exact mass calcd for (C 31 H 25 N3O-H) - requires m / z 454.1920, found m / z 454.1919; Enantiomeric ratio: 96:4, determined by HPLC (DaicelChiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R = 10.907 min (major), t R = 7.753 min (minor). The preparation of Example 7 ( R )-1'-benzyl-5'-methoxy-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ga): Yield: 87% (41.2 mg); white solid; m.p. >300 o °C; [α] D 20 = -3.5 (c 0.46, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.66 (m, 1H), 7.46 –7.28 (m, 6H), 7.18 – 7.01 (m, 6H), 6.87 – 6.75 (m, 3H), 6.40 (d, J J = 2.4 Hz,1H), 5.05 – 4.78 (m, 2H), 4.42 – 4.22 (m, 2H), 3.55 (s, 3H); 13 13C NMR (100 MHz,CDCl3) δ 174.7, 156.4, 143.2, 138.5, 136.3, 135.6, 135.1, 132.0, 130.7,129.1, 128.1, 127.6, 126.9, 125.7, 124.6, 122.5, 119.7, 118.6, 115.6, 113.5,111.9, 110.8, 110.4, 66.0, 55.7, 44.3, 28.7; IR (KBr): 3447, 2360, 1700,1653, 1559, 1489, 1457, 742; ESI FTMS exact mass calcd for (C 31 24 25 H - N3O2-H) o requires m / z 470.1869, found m / z 470.1872; Enantiomeric ratio: 94:6,determined by HPLC (Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flowrate 1.0 mL / min, T = 25 R °C, 254 nm): t R R = 14.393 min (major), t Prepared in Example 8 ([[]] R)-1'-benzyl-6'-fluoro-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ha): yield: 67% (30.8 mg); white solid; mp >300 o C; [a] D 20 =-18.6 (c 0.31, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 6.3, 2.1 Hz,1H), 7.43 – 7.31 (m, 6H), 7.18 – 7.05 (m, 5H), 7.02 (s, 1H), 6.85 – 6.75 (m,2H), 6.70 – 6.56 (m, 2H), 5.01 – 4.79 (m, 2H), 4.39 – 4.23 (m, 2H), 3.80 (s,1H); 13 C NMR (100 MHz, CDCl3) δ 174.9, 163.9 (d, J = 246.5 Hz), 143.7 (d, J =11.7 Hz), 142.9, 138.5, 135. 6, 130.3, 129.2, 129.0, 128.4, 127.9, 127.5,127.3 (d, J = 9.8 Hz), 126.9, 126.3 (d, J = 3.0 Hz), 125.6, 124.6, 122.6,119.7, 118.5, 113.7, 110.7, 109.6 (d, J = 22.3 Hz), 98.5 (d, J = 27.6 Hz),65.2, 44.3, 28.6; IR (KBr): 3447, 2360, 1717, 1636, 1559, 1507, 1457, 749;ESI FTMS exact mass calcd for (C 30 H 22 FN3O-H) -requires m / z 458.1669 found m / z458.1678; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak OD,hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R =12.240 min (major), t R = 7.590 min (minor). The preparation of Example 9 ( R )-1'-benzyl-6'-bromo-2-methyl-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ib): yield: 90% (47.9 mg); white solid; mp >300 o C; [a] D 20 = -10.3 (c 0.40, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.41 – 7.29 (m, 6H), 7.14 – 7.02 (m, 4H), 6.94 (s, 3H), 6.76 (dd, J = 7.3, 1.3 Hz, 1H),6.69 – 6.58 (m, 1H), 4.95 – 4.74 (m, 2H), 4.37 – 4.16 (m, 2H), 3.77 (s, 1H),2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 143.4, 142.8, 138.7, 135.6,133.9, 130.0, 129.8, 129.2, 129.0, 128.3, 127.8, 127.7, 127.2, 126.9, 126.2,125.7, 124.7, 124.2, 123.7, 118.2, 113.4, 113.0, 110.5, 65.3, 44.2 28.5,21.6; IR (KBr): 3446, 2359, 2341, 1715, 1635, 1481, 1334, 1249, 511; ESI FTMSexact mass calcd for (C 31 H 24 BrN3O-H) - requires m / z 532.1025 found m / z 532.1032;Enantiomeric ratio: 92:8, determined by HPLC (Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R = 10.743 min(major), t R = 6.970 min (minor). The preparation of Example 10 ( R )-1'-benzyl-2,7'-dimethyl-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3jb): yield: 81% (38.0 mg); white solid; mp >300 o C; [a] D 20 = -8.4 (c 0.32, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.40 – 7.25 (m, 6H), 7.15 – 6.91 (m, 6H), 6.90 – 6.71 (m, 3H), 5.24 (d, J = 28.8 Hz, 3H), 4.37 – 4.21 (m, 2H), 3.84 (s, 1H), 2.45 (d, J = 12.0 Hz, 6H); 13 C NMR (100MHz, CDCl3) δ 176.0, 143.2, 140.3, 138.5, 137.8, 133.9, 131.7, 131.0, 129.1,129.0, 128.9, 127.9, 127.6, 126.9, 126.3, 125.7, 124.4, 124.2, 123.4, 120.5,118.2, 113.1, 110.4, 65.0, 45.3, 28.7, 21.6, 19.3; IR (KBr): 3627, 3030,2919, 1715, 1599, 1471, 1350, 1180, 749; ESI FTMS exact mass calcd for(C 32 H 27 N3O-H) - requires m / z 468.2076 found m / z 468.2066; Enantiomeric ratio:90:10, determined by HPLC (Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R = 12.207 min (major), t R = 6.617min (minor). The preparation of Example 13 ( R )-1'-benzyl-5'-bromo-2-methyl-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3eb): yield: 89% (47.4 mg); white solid; mp >300 o C;[a] D 20 = +18.8 (c 0.53, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.39 –7.27 (m, 7H), 7.16 – 7.06 (m, 2H), 6.94 (s, 4H), 6.81 – 6.72 (m, 2H), 4.98 –4.73 (m, 2H), 4.27 (q, J = 15.7 Hz, 2H), 3.78 (s, 1H), 2.47 (s, 3H); 13 C NMR(100 MHz, CDCl3) δ 174.3, 142.8, 141.0, 138.7, 135.7, 134.0, 132.8, 130.0,129.22, 129.1, 128.3, 127.9, 127.7, 127.0, 125.7, 124.8, 124.3, 118.3, 116.1,113.5, 111.2, 110.5, 65.6, 44.2, 28.6, 21.6; IR (KBr): 3447, 2360, 1716,1647, 1473, 1339, 534; ESI FTMS exact mass calcd for (C 31 H 24 BrN3O-H) - requiresm / z 532.1025 found m / z 532.1025; Enantiomeric ratio: 96:4, determined by HPLC(Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T =25 o C, 254 nm): t R = 16.633 min (major), t R = 8.303 min (minor). The preparation of Example 11 ( R )-1'-benzyl-5'-bromo-1-methyl-7,12-dihydro-5H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ec): yield: 82% (44.0 mg); white solid; mp >300 o C; [a] D 20 = +9.6 (c 0.46, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.39 – 7.30 (m, 7H), 7.17 –7.06 (m, 2H), 7.00 – 6.92 (m, 3H), 6.88 – 6.77 (m, 4H), 4.89 (dd, J = 81.2,15.2 Hz, 2H), 4.72 – 4.51 (m, 2H), 3.77 (s, 1H), 2.88 (s, 3H); 13 C NMR (100MHz, CDCl3) δ 174.7, 143.3, 142.9, 138.7, 135.9, 135.6, 130.1, 129.3, 129.1,128.4, 127.9, 127.5, 127.0, 125.8, 124.8, 123.3, 122.7, 119.8, 118.6, 113.9,110.8, 110.4, 65.3, 44.3, 28.6; IR (KBr): 3649, 3031, 2360, 1717, 1604, 1474,1339, 1168, 745; ESI FTMS exact mass calcd for (C 31 H 24 BrN3O-H) - requires m / z532.1025 found m / z 532.1025; Enantiomeric ratio: 95:5, determined by HPLC(Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T =25 o C, 254 nm): t R= 20.160 min (major), t R = 8.217 min (minor). The preparation of Example 12 ( R )-1'-benzyl-5'-bromo-2-chloro-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ed): yield: 70% (38.6 mg); white solid; mp >300 o C; [a] D 20 = +27.6 (c 0.31, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 1.7 Hz, 1H),7.42 – 7.25 (m, 7H), 7.18 – 7.02 (m, 4H), 6.99 – 6.88 (m, 2H), 6.83 – 6.73(m, 2H), 4.96 – 4.75 (m, 2H), 4.29 – 4.15 (m, 2H), 3.77 (s, 1H); 13 C NMR (100MHz, CDCl3) δ 174.3, 142.8, 141.0, 138.6, 135.7, 134.0, 132.8, 130.0, 129.2,129.1, 128.3, 127.9, 127.70, 127.0, 125.7, 124.8, 124.3, 118.3, 116.1, 113.5,111.2, 110.5, 65.6, 44.2, 28.6, 21.6; IR (KBr): 3446, 2360, 1705, 1653, 1559,1473, 1339, 534; ESI FTMS exact mass calcd for (C 30 H 21 BrClN3O-H) -requires m / z552.0479 found m / z 552.0476; Enantiomeric ratio: 95:5, determined by HPLC(Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T =25 o C, 254 nm): t R = 14.417 min (major), t R = 7.407 min (minor). The preparation of Example 14 ( R )-1'-benzyl-5'-bromo-8-methyl-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ee): yield: 80% (42.9 mg); white solid; mp >300 o C; [a] D 20 = +17.7 (c 0.73, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.2 Hz, 1H),7.44 – 7.27 (m, 6H), 7.22 (d, J = 7.0 Hz, 1H), 7.18 – 6.95 (m, 6H), 6.85 –6.65 (m, 2H), 4.94 (s, 2H), 4.40 – 4.17 (m, 2H), 3.86 (s, 1H), 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 140.9, 140.9, 139.7, 135.7, 135.4, 133.8,132.7, 132.6, 130.3, 129.1, 128.9, 128.3, 127.7, 127.4, 127.0, 125.0, 122.7,119.8, 118.5, 116.0, 113.9, 111.2, 110.8, 65.2, 44.2, 28.8, 18.0; IR (KBr):3447, 2360, 1636, 1559, 1507, 1457, 518; ESI FTMS exact mass calcd for(C 31 H 24 BrN3O-H) - requires m / z 532.1025 found m / z 532.1030; Enantiomeric ratio:97:3, determined by HPLC (Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R = 24.583 min (major), t R = 10.037min (minor). The preparation of Example 15 ( R )-1'-benzyl-5'-bromo-9-chloro-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ef): yield: 67% (36.4 mg); white solid; mp >300 o C;[a] D 20 = +26.6 (c 0.52, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.66 (m, 1H),7.46 – 7.26 (m, 7H), 7.16 – 7.04 (m, 5H), 7.02 (s, 1H), 6.86 – 6.79 (m, 2H),5.00 – 4.82 (m, 2H), 4.26 (s, 2H), 3.75 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ173.8, 144.0, 141.1, 136.4, 135.6, 133.2, 132.3, 131.9, 130.0, 129.4, 129.2,129.1, 128.4, 127.9, 127.3, 125.0, 124.4, 122.9, 119.9, 118.5, 116.2, 113.4,111.3, 110.8, 65.4, 44.2, 28.1; IR (KBr): 3447, 2360, 2342, 1717, 1650, 1559,1473, 669; ESI FTMS exact mass calcd for (C 30 H 21 BrClN3O-H) - requires m / z552.0479 found m / z 552.0480; Enantiomeric ratio: 92:8, determined by HPLC(Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T =25 o C, 254 nm): t R = 13.783 min (major), t R = 8.540 min (minor). The preparation of Example 16 ( R )-1'-benzyl-5'-bromo-9-methyl-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3eg): yield: 90% (48.1 mg); white solid; mp >300o C;[a] D 20 = +9.0 (c 0.70, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 6.2, 2.3Hz, 1H), 7.42 – 7.28 (m, 6H), 7.22 (d, J = 7.6 Hz, 1H), 7.17 – 6.99 (m, 4H),6.97 – 6.86 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 5.02 – 4.77 (m,2H), 4.36 – 4.14 (m, 2H), 3.74 (s, 1H), 2.27 (s, 3H); 13 C NMR (100 MHz, CDCl3)δ 174.2, 142.5, 141.0, 136.6, 135.7, 135.6, 135.3, 132.8, 132.7, 129.9,129.2, 128.9, 128.2, 127.9, 127.5, 126.4, 125.4, 122.7, 119.7, 118.6, 116.0,114.2, 111.1, 110.7, 65.5, 44.2, 28.2, 21.0; IR (KBr): 3450, 2360, 2090,1636, 1540, 1474, 1339, 537; ESI FTMS exact mass calcd for (C 31 H 24 BrN3O-H) - requires m / z 532.1025 found m / z 532.1035; Enantiomeric ratio: 95:5,determined by HPLC (Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flowrate 1.0 mL / min, T = 25 o C, 254 nm): t R = 13.623 min (major), t R = 10.657 min(minor). The preparation of Example 17 ( R )-1'-benzyl-5',10-dibromo-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3eh): yield: 70% (42.0 mg); white solid; mp >300 o C; [a] D 20 = +90.3 (c 0.42, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.71 – 7.65 (m, 1H), 7.45 –7.26 (m, 7H), 7.18 – 7.04 (m, 5H), 7.01 (s, 1H), 6.88 – 6.79 (m, 2H), 5.01 –4.82 (m, 2H), 4.26 (s, 2H), 3.75 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 173.8,144.0, 141.1, 136.4, 135.6, 133.2, 132.3, 131.9, 130.1, 129.4, 129.2, 128.4,127.9, 127.3, 125.0, 124.4, 122.9, 119.9, 118.5, 116.2, 113.4, 111.3, 110.8,65.3, 44.2, 28.1; IR (KBr): 3651, 2923, 2361, 1719, 1560, 1474, 1081, 740;ESI FTMS exact mass calcd for (C 30 H 21 Br2N3O-H) - requires m / z 595.9973 found m / z595.9970; Enantiomeric ratio: 95:5, determined by HPLC (Daicel Chiralpak OD,hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R=13.520 min (major), t R = 8.477 min (minor). The preparation of Example 18 ( R )-1'-benzyl-5'-bromo-10-methyl-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ei): yield: 94% (50.2 mg); white solid; mp >300 o C;[a] D 20 = +14.6 (c 0.81, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.73 – 7.65 (m, 1H), 7.41 – 7.29 (m, 6H), 7.19 – 6.93 (m, 7H), 6.75 (dd, J = 34.1, 8.1 Hz, 2H),5.01 – 4.80 (m, 2H), 4.33 – 4.19 (m, 2H), 2.31 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 174.3, 141.0, 139.9, 138.5, 135.7, 135.6, 134.4, 132.8, 130.0,129.9, 129.2, 128.3, 127.8, 127.4, 127.4, 125.7, 122.7, 119.8, 118.6, 116.0,114.0, 111.2, 110.7, 65.5, 44.2, 28.5, 20.9; IR (KBr): 3447, 2360, 1717,1653, 1559, 1507, 669; ESI FTMS exact mass calcd for (C 31 H 24 BrN3O-H) -requiresm / z 532.1025 found m / z 532.1022; Enantiomeric ratio: 95:5, determined by HPLC(Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T =25 o C, 254 nm): t R = 14.743 min (major), t R = 9.023 min (minor). The preparation of Example 19 ( R )-1'-benzyl-5'-bromo-11-chloro-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ej): yield: 60% (33.2 mg); white solid; mp >300 o C; [a] D 20 =+40.0 (c 0.36, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.81 – 7.76 (m, 1H), 7.43 –7.32 (m, 6H), 7.22 – 6.98 (m, 7H), 6.83 (d, J = 8.4 Hz, 1H), 6.77 – 6.70 (m,1H), 5.03 – 4.81 (m, 2H), 4.66 – 4.48 (m, 2H), 3.84 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 174.0, 144.2, 140.9, 137.4, 135.5, 133.0, 132.9, 132.5, 129.5,129.2, 128.4, 127.8, 127.4, 126.9, 125.0, 124.3, 122.9, 120.0, 118.8, 116.2,113.3, 111.3, 110.7, 65.5, 44.2, 23.5; IR (KBr): 3447, 2360, 2342, 1636,1559, 1507, 1473; ESI FTMS exact mass calcd for (C 30 H 21 BrClN3O-H) - requires m / z552.0479 found m / z 552.0463; Enantiomeric ratio: 95:5, determined by HPLC(Daicel Chiralpak OD, hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T =25 o C, 254 nm): t R = 10.723 min (major), t R = 9.320 min (minor). The preparation of Example 20 ( R )-1'-benzyl-5'-bromo-11-methyl-7,12-dihydro-5 H -spiro[benzo[6,7]aza[3,4- b Indole-6,3'-indoline]-2'-one (3ek): yield: 83% (44.3 mg); white solid; mp >300 o C; [a] D 20 =+38.6 (c 0.49, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.76 – 7.69 (m, 1H), 7.41 –7.28 (m, 6H), 7.17 – 6.96 (m, 6H), 6.93 (d, J= 2.0 Hz, 1H), 6.79 (d, J = 8.4Hz, 1H), 6.67 (dd, J = 7.2, 1.5 Hz, 1H), 5.02 – 4.79 (m, 2H), 4.42 – 4.27 (m,2H), 2.51 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 174.4, 142.6, 140.9, 138.6,135.7, 135.5, 135.2, 132.8, 132.7, 130.0, 129.2, 129.2, 128.3, 127.8, 127.5,127.1, 125.9, 124.1, 122.6, 119.8, 118.4, 116.0, 114.4, 111.2, 110.8, 65.6,44.2, 22.6, 20.4; IR (KBr): 3447, 2919, 2849, 2360, 1716, 1653, 1473, 1339;ESI FTMS exact mass calcd for (C 31 H 24 BrN3O-H) - requires m / z 532.1025 found m / z532.1026; Enantiomeric ratio: 96:4, determined by HPLC (Daicel Chiralpak OD,hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 25 o C, 254 nm): t R =13.630 min (major), t R = 8.017 min (minor).

Claims

1. A chiral indole-azo-spiro-oxidized indole compound, characterized in that, Its chemical structural formula is shown in Formula 3: ； In Formula 3, R is selected from benzyl or allyl; R 1 Selected from one of hydrogen, 5-fluoro, 5-chloro, 5-bromine, 5-methyl, 5-methoxy, 6-fluoro, 6-bromine, and 7-methyl; R 2 Selected from one of hydrogen, 4-methyl, 5-chloro, and 5-methyl; R 3 It is selected from one of hydrogen, 3'-methyl, 4'-chloro, 4'-methyl, 5'-bromo, 5'-methyl, 6'-chloro, and 6'-methyl.

2. A method for synthesizing the chiral indole-azo-spiro-oxidized indole compound according to claim 1, characterized in that, The specific steps are as follows: Indigo, compound of formula 1, and (2-aminobenzyl)indole, compound of formula 2, are added to an organic solvent as reaction raw materials. Under the catalysis of a chiral phosphoric acid catalyst, the reaction is stirred for 0.5-6 days at a temperature of -30-50 °C. The reaction is monitored by TLC until complete. After filtration, concentration, and purification, compound of formula 3 is obtained. The molar ratio between indigo of Formula 1 and (2-aminobenzyl)indole of Formula 2 is 1:(0.3-3); the molar ratio between indigo of Formula 1 and the chiral phosphoric acid catalyst is 1:(0.05-0.25). The structural formula of the compound indigo in formula 1 is as follows: In Formula 1, R is selected from benzyl or allyl; R 1 It is selected from one of hydrogen, 5-fluoro, 5-chloro, 5-bromine, 5-methyl, 5-methoxy, 6-fluoro, 6-bromine, and 7-methyl; The structural formula of compound (2-aminobenzyl)indole of formula 2 is as follows: In Equation 2, R 2 Selected from one of hydrogen, 4-methyl, 5-chloro, and 5-methyl; R 3 It is selected from one of hydrogen, 3'-methyl, 4'-chloro, 4'-methyl, 5'-bromo, 5'-methyl, 6'-chloro, and 6'-methyl.

3. The method for synthesizing a chiral indole-azospiro-oxidized indole compound according to claim 2, characterized in that, The chiral phosphoric acid catalyst is selected from one of the following: a binatidine skeleton derivative, an octahydrobinatidine skeleton derivative, and a spirocyclic skeleton derivative; the binatidine skeleton derivative is a compound of formula 4, and its structural formula is [structural formula missing]. In the formula, G is selected from one of 4-chlorophenyl, 9-anthrayl, 9-phenanthyl, 2,4,6-triisopropylphenyl, 2-naphthyl, 1-naphthyl, and triphenylsilyl; the octahydrobinaphthyl skeleton derivative is a compound of formula 5, the structural formula of which is... In the formula, G is selected from 2,4,6-triisopropylphenyl; the spirocyclic skeleton derivative is a compound of formula 6, whose structural formula is [insert structural formula here]. In the formula, G is selected from 2,4,6-triisopropylphenyl.

4. The method for synthesizing a chiral indole-azospiro-oxidized indole compound according to claim 3, characterized in that, The chiral phosphoric acid catalyst described is a compound of formula 4, and its structural formula is as follows: In the formula, G is selected from 2,4,6-triisopropylphenyl.

5. A method for synthesizing a chiral indole-azospiro-oxidized indole compound according to claim 2 or 3, characterized in that, The organic solvent is selected from one of 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, toluene, fluorobenzene, chlorobenzene, bromobenzene, o-dimethylbenzene, m-dimethylbenzene, and p-dimethylbenzene; the ratio of the volume of the organic solvent to the molar amount of indigo in Formula 1 is (2.5-80) mL: 1 mmol.

6. The method for synthesizing a chiral indole-azospiro-oxidized indole compound according to claim 5, characterized in that, The organic solvent is toluene; the volume ratio of the organic solvent to the molar amount of indigo, compound of formula 1, is 80 mL: 1 mmol.

7. A method for synthesizing a chiral indole-azospiro-oxidized indole compound according to claim 2 or 3, characterized in that, The reaction time is 60 hours.

8. A method for synthesizing a chiral indole-azospiro-oxidized indole compound according to claim 2 or 3, characterized in that, The purification is performed using a silica gel plate or silica gel column, with the eluent being a toluene / acetone mixture at a volume ratio of 10:

1.

9. The use of the chiral indole-azospiro-indole compound as described in claim 1 in the preparation of a drug for inhibiting human hepatocellular carcinoma HepG2 cells.

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