A process for the synthesis of R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compounds

Abstract

The application provides a method for synthesizing an R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrenone compound, which comprises the following steps: mixing a 9,10-phenanthrenequinone compound shown in formula 2, an indole compound shown in formula 3 and a chiral catalyst in an organic solvent, and performing reaction to obtain an R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrenone compound shown in formula 4. The application can obtain the R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrenone compound as a main product, the enantiomeric excess value of which is up to 97%, the yield is good (75%-95%), and the absolute configuration of the target compound is determined as R through X-single crystal diffraction experiment. It is found through cell experiment that a series of synthesized compounds have good antitumor activity, and the application provides a basis for the research of chiral drugs.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing an R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrenone compound. BACKGROUND

[0002] As an important member of the quinone family, 9,10-phenanthrenequinone plays an extremely important role in the fields of photochemistry, electrochemistry and organic synthesis. Studies have shown that 9,10-phenanthrenequinone has important uses in medical and drug development, and exhibits activities such as anti-tumor, anti-inflammatory, and anti-mold. Its ortho carbonyl structure and high conjugated phenanthrene plane have good charge dispersion capacity, and are often used as model compounds in electrochemical research. In addition, its unique triplet state activity makes it have important value in photodynamic and photochemical reactions.

[0003] However, there is no report on the asymmetric Friedel-Crafts reaction of 9,10-phenanthrenequinone as a substrate with indole in the field of asymmetric catalysis. SUMMARY

[0004] The purpose of the present application is to provide a method for synthesizing an R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrenone compound. The method in the present application obtains a main product of R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrenone compound, with an enantiomeric excess value of up to 97%, a good yield (75%-95%), and the absolute configuration of the target compound determined by X-single crystal diffraction experiment is R. Through cell experiments, it is found that a series of synthesized compounds have good anti-tumor activity, which provides a basis for the research of chiral drugs.

[0005] The present application provides a method for synthesizing an R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrenone compound, comprising the following steps:

[0006] Mixing 9,10-phenanthrenequinone compound shown in formula 2, indole compound shown in formula 3 and chiral catalyst in an organic solvent to obtain R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrenone compound shown in formula 4;

[0007] The chiral catalyst has a structure as described in any one of formula 1a to formula 1h;

[0008]

[0009] In formulae 2-4, R1 is hydrogen or halogen, R2 is hydrogen or halogen, and R3 is hydrogen, halogen, methyl or methoxy.

[0010] Preferably, R1 is hydrogen or bromine, R2 is hydrogen or bromine, and R3 is hydrogen, chlorine, fluorine, methyl or methoxy.

[0011] Preferably, the molar ratio of the 9,10-phenanthrenequinone compound and the indole compound is 1:(1-10).

[0012] Preferably, the molar ratio of the 9,10-phenanthrenequinone compound and the indole compound is 1:(5-10).

[0013] Preferably, the molar amount of the chiral catalyst is 5-20% of the molar amount of the 9,10-phenanthrenequinone compound.

[0014] Preferably, the molar amount of the chiral catalyst is 10-15% of the molar amount of the 9,10-phenanthrenequinone compound.

[0015] Preferably, the organic solvent comprises one or more of dichloromethane, trichloromethane, 1,2-dichloroethane, toluene, diethyl ether, acetonitrile, and ethyl acetate.

[0016] Preferably, the temperature of the reaction is 0-30°C, and the time of the reaction is 18-30 hours.

[0017] Preferably, after the reaction is complete, the product is separated and purified by column chromatography to obtain the R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrone compound.

[0018] Preferably, the eluent used in the column chromatography separation and purification is n-hexane and ethyl acetate in a volume ratio of 5:1.

[0019] The present application provides a method for synthesizing an R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrone compound, comprising the following steps: mixing a 9,10-phenanthrenequinone compound shown in formula 2, an indole compound shown in formula 3, and a chiral catalyst in an organic solvent, and reacting to obtain an R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrone compound shown in formula 4; the chiral catalyst has a structure shown in any one of formula 1a-1h; in formulae 2-4, R1 is hydrogen or halogen, R2 is hydrogen or halogen, and R3 is hydrogen, halogen, methyl, or methoxy. The asymmetric Friedel-Crafts reaction of different substituted 9,10-phenanthrenequinone and indole is catalyzed by a chiral squaramide catalyst. The main product is an R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrone compound, the enantiomeric excess value is up to 97%, the yield is good (75%-95%), and the absolute configuration of the target compound is determined by X-single crystal diffraction experiment to be R. The present application has the advantages of simple operation, mild reaction conditions, and environmental friendliness, opens up a new way for synthesizing a series of R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrone compounds, and through cell experiments, it is found that the synthesized series of compounds have good antitumor activity, and provide a basis for the research of chiral drugs.

[0020] Compared with the prior art, the present application has the following advantages:

[0021] 1. Innovation, at present, there is no report on asymmetric Friedel-Crafts reaction of different substituted 9,10-phenanthrenequinone and indole.

[0022] 2. The reaction has high enantioselectivity, good yield and complete reaction, and no by-product is detected by nuclear magnetic hydrogen spectrum and carbon spectrum, so that high enantiomeric optical purity compound can be obtained.

[0023] 3. The method provided by the present application has wide substrate universality, and the 10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrone compound generated by the reaction has potential antitumor activity.

[0024] 4. The operation is simple, the reaction condition is mild, and the environment is friendly. BRIEF DESCRIPTION OF DRAWINGS

[0025] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or prior art description will be briefly introduced below. Obviously, the drawings in the following description are only embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor on the basis of the provided drawings.

[0026] Figure 1 The nuclear magnetic hydrogen spectrum of compound 5aaa prepared in example 28 of the present application is shown in the following figure:

[0027] Figure 2 The nuclear magnetic carbon spectrum of compound 5aaa prepared in example 28 of the present application is shown in the following figure:

[0028] Figure 3 The HPLC spectrum of compound 5aaa prepared in example 28 of the present application (racemic product) is shown in the following figure:

[0029] Figure 4 The HPLC spectrum of compound 5aaa prepared in example 28 of the present application (R configuration product) is shown in the following figure:

[0030] Figure 5 The nuclear magnetic hydrogen spectrum of compound 5gaa prepared in example 48 of the present application is shown in the following figure:

[0031] Figure 6 The nuclear magnetic carbon spectrum of compound 5gaa prepared in example 48 of the present application is shown in the following figure:

[0032] Figure 7 The HPLC spectrum of compound 5gaa prepared in example 48 of the present application (racemic product) is shown in the following figure:

[0033] Figure 8 HPLC chart of compound 5gaa (R configuration product) prepared for the preparation of example 48 of the present application;

[0034] Figure 9 X-single crystal diffraction test result of compound 5gaa prepared for the preparation of example 48 of the present application;

[0035] Figure 10 Proliferation inhibition effect of doxorubicin as a positive control drug in the application example on tumor cells;

[0036] Figure 11 Proliferation inhibition effect of (R)-4g compound in the application example on tumor cells;

[0037] Figure 12 Proliferation inhibition effect of (R)-4q compound in the application example on tumor cells;

[0038] Figure 13 Proliferation inhibition effect of (R)-4u compound in the application example on tumor cells. DETAILED DESCRIPTION

[0039] The present application provides a method for synthesizing an R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound, comprising the following steps:

[0040] Mixing 9,10-phenanthrenequinone compound shown in formula 2, indole compound shown in formula 3 and chiral catalyst in organic solvent, and reacting to obtain R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound shown in formula 4;

[0041] The chiral catalyst has the structure described in any one of formula 1a to formula 1h;

[0042]

[0043] In formulae 2 to 4, R1 is hydrogen or halogen, R2 is hydrogen or halogen, and R3 is hydrogen, halogen, methyl or methoxy.

[0044] In the present application, R1 is preferably hydrogen or bromine, R2 is preferably hydrogen or bromine, and R3 is preferably hydrogen, chlorine, fluorine, methyl or methoxy.

[0045] In the present application, the molar ratio of the 9,10-phenanthrenequinone compound and the indole compound is preferably 1:(1-10), more preferably 1:(5-10), such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, preferably a range value with the above-mentioned any value as the upper limit or lower limit.

[0046] In the present application, the molar amount of the chiral catalyst is 5-20% of the molar amount of the 9,10-phenanthrenequinone compound, more preferably 10-15%, such as 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, preferably a range value with any of the above values as the upper limit or lower limit.

[0047] In the present application, the organic solvent is preferably one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, diethyl ether, acetonitrile and ethyl acetate, more preferably dichloromethane.

[0048] In the present application, the temperature of the reaction is preferably 0-30°C, more preferably 0-25°C, such as 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, preferably a range value with any of the above values as the upper limit or lower limit; the time of the reaction is preferably 18-30 hours, more preferably 20-28 hours, most preferably 24-26 hours.

[0049] After the reaction is completed, the present application preferably separates and purifies the reaction product by column chromatography to obtain the R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrone compound.

[0050] In the present application, the elution machine used for column chromatography separation and purification is a mixture of n-hexane and ethyl acetate, and the volume ratio of the n-hexane and ethyl acetate is preferably 5:1.

[0051] The specific chiral catalyst used in the present application can catalyze the asymmetric Friedel-Crafts reaction of different substituted 9,10-phenanthrenequinone and indole to obtain the corresponding 10-hydroxy-10-(1H-indol-3-)-9-phenanthrone compound, and has the advantages of high yield and high enantiomeric excess value.

[0052] In order to further illustrate the present application, the following embodiments provide a method for synthesizing the R-10-hydroxy-10-(1H-indol-3-)-9-phenanthrone compound, but it should not be understood as limiting the scope of protection of the present application.

[0053] Examples 1-14

[0054] Into a dry and sealed reaction tube, 0.10 mmol of 9,10-phenanthrenequinone, 0.10-1.00 mmol of indole (see Table 1 for specific amount) and 10 mol% of chiral catalyst (see Table 1 for specific type) were placed, a magnetic stir bar was added, 1 mL of dichloromethane was added by syringe, and the reaction mixture was stirred at room temperature for 24 h on a magnetic stirrer. The reaction progress was monitored by TLC. After the reaction was completed, the pure product was isolated by silica gel column chromatography with eluent of n-hexane: ethyl acetate 5:1. The reaction scheme and the structure of chiral squaramide catalyst are as follows:

[0055]

[0056] The yield is the isolated yield, and the enantiomeric excess (ee) of the product was determined by HPLC on a chiral OD-H column. See Table 1 for details.

[0057] Table 1. Reaction yield and enantiomeric excess (ee) in Examples 1-14

[0058]

[0059] The catalysts la-1h were applied to the asymmetric Friedel-Crafts reaction of phenanthrenequinone and indole in dichloromethane at room temperature for 24 h in order to screen the best catalyst. As shown in Table 1, all catalysts could successfully catalyze the reaction, but the yield of the target product was low (40%-45%), and the enantioselectivity was 6%-38%. Among them, the ee value and yield obtained by using catalyst le were the best. By increasing the amount of indole, both the yield and enantioselectivity of the reaction were improved. And the best amount ratio of phenanthrenequinone and indole was determined to be 1:7 (Example 12).

[0060] Examples 15-27

[0061] Into a dry and sealed reaction tube, 0.10 mmol of 9,10-phenanthrenequinone, 0.70 mmol of indole and 10 mol% of catalyst le were placed, a magnetic stir bar was added, 1 mL of dichloromethane or other solvents (see Table 2 for specific solvent) was added by syringe, and the reaction mixture was stirred at room temperature or 0°C (see Table 2 for specific temperature) for 24 h on a magnetic stirrer. The reaction progress was monitored by TLC. After the reaction was completed, the pure product was isolated by silica gel column chromatography with eluent of n-hexane: ethyl acetate 5:1. The reaction scheme and the structure of catalyst le are as follows:

[0062]

[0063] The yield is the isolated yield, and the enantiomeric excess (ee) of the product was determined by HPLC on a chiral OD-H column. See Table 2 for details.

[0064] Table 2. Reaction yield and enantiomeric excess (ee) in Examples 15-27

[0065]

[0066] Different reaction conditions have a great impact on the enantioselectivity of the reaction. The yield and ee value are optimal when dichloromethane is used as the solvent (Example 15). However, toluene and diethyl ether cannot make the reaction proceed (Examples 18, 19). The screening results of the amount of catalyst show that 10 mol% of catalyst le is the most suitable. The yield and enantioselectivity are reduced when the amount of catalyst is reduced to 5 mol% or increased to 20 mol% (Examples 23, 24 vs. Example 15). When the reaction temperature is reduced from room temperature to 0°C, the enantioselectivity and yield of the product are not improved (Example 22 vs. Example 15). In addition, the reaction concentration is diluted by half; the addition of molecular sieves or additives such as benzoic acid does not improve the stereoselectivity of the reaction (Examples 25, 26, 27 vs. Example 15). Based on these experiments, the optimal conditions are determined to be dichloromethane as the solvent, 10 mol% of catalyst le, and reaction at room temperature.

[0067] Example 28

[0068] Substituted 0.10 mmol 9,10-phenanthrenequinone, 0.70 mmol indole (see Table 3 for specific structures), and 10 mol% cat. le were placed in a dry and closed reaction tube, a magnetic stirrer was added, 1 mL of dichloromethane was added with a syringe, and it was placed in a magnetic stirrer at room temperature for 24 h, and the reaction progress was monitored by TLC. After the reaction was completed, the pure product was separated by silica gel column chromatography, and the eluent was n-hexane: ethyl acetate 5:1. The reaction formula and cat. le structure are as follows:

[0069]

[0070] The compound 4a prepared in Example 28 was subjected to nuclear magnetic detection, mass spectrometry detection, and HPLC detection, and the results are as follows:

[0071] 1 H NMR (500 MHz, Chloroform-d) δ 7.98-–7.93 (m, 1H), 7.92-–7.84 (m, 3H), 7.79 (ddd, J = 7.5, 1.5, 0.5 Hz, 1H), 7.75-–7.71 (m, 1H), 7.56 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 7.53-–7.46 (m, 2H), 7.27–-7.23 (m, 1H), 7.22–-7.19 (m, 1H), 7.16–-7.09 (m, 2H), 6.36 (dd, J = 3.0, 2.0 Hz, 1H), 4.80 (s, 1H);

[0072] 13 C NMR (125 MHz, Chloroform-d) δ 200.9, 139.7, 137.0, 136.6, 134.5, 130.0, 129.4, 128.8, 128.6, 128.4, 127.8, 127.7, 125.3, 124.2, 123.7, 122.7, 122.4, 120.4, 117.7, 111.3;

[0073] HRMS (ESI) m / z: [M + Na]+calcd for C + calcd for C 22 H 15 NO2Na: 348.1000; found 348.1005; [α] D 25 = 25.7 (c 0.50, MeOH) (70% ee);

[0074] HPLC (Chiralcel OD-H, hexane: i PrOH = 82:18, 1.0 mL / min, 254 nm), t R =

[0075] 21.3 min (minor), 30.5 min (major).

[0076] Example 29

[0077] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0078] Example 30

[0079] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0080] Example 31

[0081] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0082] The compound 4d prepared in Example 31 was subjected to NMR detection, mass spectrometry detection and HPLC detection, and the results were as follows:

[0083] 1 H NMR (500 MHz, Chloroform-d) δ 7.99 - -7.95 (m, 1H), 7.95 - -7.87 (m, 3H), 7.84 (ddd, J = 7.5, 1.5, 0.5 Hz, 1H), 7.60 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 7.56 - -7.50 (m, 2H), 7.39 (ddt, J = 10.0, 2.5, 0.5 Hz, 1H), 7.31 (td, J = 7.5, 1.0 Hz, 1H), 7.16 (ddd, J = 9.0, 4.5, 0.5 Hz, 1H), 6.91 (td, J = 9.0, 2.5 Hz, 1H), 6.46 (dd, J = 3.0, 1.0 Hz, 1H), 4.77 (s, 1H);

[0084] 13 C NMR (125 MHz, Chloroform-d) δ 200.7, 159.0, 139.5, 137.0, 134.6, 133.1, 130.0, 129.4, 128.7, 128.6, 128.4, 127.8, 127.6, 125.8, 123.8, 122.8, 117.9, 111.9 (d, J = 15.0 Hz), 111.0 (d, J = 26.2 Hz), 105.6 (d, J = 25.0 Hz);

[0085] HRMS (ESI) m / z: [M + Na] + calcd for C 22 H 14 FNO2Na: 366.0906; found 366.0901; [a] D 25 = +52.0 (c 0.51, MeOH) (48% ee);

[0086] HPLC (Chiralcel OD-H, hexane: EtOH = 90:10, 1.0 mL / min, 254 nm), t i PrOH = 75:25, 1.0 mL / min, 254 nm), t R =

[0087] 13.4 min (minor), 22.3 min (major).

[0088] Example 32

[0089] The compound R-10-hydroxy-10-(lH-indol-3-yl)-9-phenanthrenone was prepared according to the procedure of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, as specified in Table 3.

[0090] The compound 4e prepared in Example 32 was subjected to NMR, mass and HPLC analysis, and the results were as follows:

[0091] 1 H NMR (500 MHz, Chloroform-d) δ 7.96 - -7.85 (m, 4H), 7.82 (ddd, J = 7.5, 1.5, 0.5 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.58 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 7.53 - -7.46 (m, 2H), 7.28 (td, J = 7.5, 1.0 Hz, 1H), 7.12 (dd, J = 8.5, 0.5 Hz, 1H), 7.08 (dd, J = 8.5, 2.0 Hz, 1H), 6.39 (t, J = 2.5 Hz, 1H), 4.76 (s, 1H);

[0092] 13 C NMR (125 MHz, Chloroform-d) δ 200.7, 139.4, 137.0, 135.0, 134.7, 129.9, 129.5, 128.8, 128.6, 128.5, 127.9, 127.6, 126.2, 125.4, 123.8, 122.9, 122.8, 120.1, 117.6, 112.3;

[0093] HRMS (ESI) m / z: [M + Na] + calcd for C 22 H 14 ClNO2Na: 382.0611; found 382.0617; [a] D 25 = +42.3 (c 0.58, MeOH) (48% ee);

[0094] HPLC (Chiralcel OD-H, hexane: i PrOH = 75:25, 1.0 mL / min, 254 nm), t R =

[0095] 12.4 min (minor), 20.8 min (major).

[0096] Example 33

[0097] The compound of R-10-hydroxy-10-(lH-indol-3-yl)-9-phenanthrenone was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0098] The compound 4f prepared in Example 33 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0099] 1 H NMR (500 MHz, Chloroform-d) δ 7.96 - -7.91 (m, 1H), 7.91- -7.88 (m, 1H), 7.88- -7.85 (m, 1H), 7.80 (dd, J = 7.5, 1.5 Hz, 2H), 7.59- -7.52 (m, 2H), 7.52- -7.46 (m, 2H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.95 (dd, J = 8.5, 1.5 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 4.79 (s, 1H), 2.45 (s, 3H);

[0100] 13 C NMR (125 MHz, Chloroform-d) δ 200.8, 139.8, 137.0, 135.0, 134.4, 130.0, 129.7, 129.4, 128.8, 128.5, 128.3, 127.9, 127.7, 125.5, 124.3, 124.1, 123.6, 122.7, 120.0, 117.0, 111.0, 21.6;

[0101] HRMS (ESI) m / z: [M + Na] + calcd for C 23 H 17 NO2Na: 362.1157; found: 362.1151; [a] D 25 = 28.9 (c 0.57, MeOH) (80% ee);

[0102] HPLC (Chiralcel OD-H, hexane: i PrOH = 75:25, 1.0 mL / min, 254 nm), t R =

[0103] 11.2 min (minor), 16.8 min (major).

[0104] Example 34

[0105] The compound R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0106] The compound 4g prepared in Example 34 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0107] 1 H NMR (500 MHz, Chloroform-d) δ 8.01 - -7.96 (m, 1H), 7.95–-7.91 (m, 1H), 7.90 (ddt, J = 8.0, 1.0, 0.5 Hz, 1H), 7.84 (ddd, J = 7.5, 1.5, 0.5 Hz, 2H), 7.59 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 7.54–-7.49 (m, 2H), 7.29 (td, J = 7.5, 1.0 Hz, 1H), 7.16-–7.10 (m, 2H), 6.81 (ddd, J = 9.0, 2.5, 0.5 Hz, 1H), 6.40 (dd, J = 3.0, 0.5 Hz, 1H), 4.77 (s, 1H), 3.88 (s, 3H); as Figure 1 shown;

[0108] 13 C NMR (125 MHz, Chloroform-d) δ 200.7, 154.5, 139.7, 137.0, 134.5, 131.7, 130.0, 129.4, 128.8, 128.6, 128.4, 127.8, 127.7, 125.7, 124.9, 123.6, 122.8, 117.1, 112.9, 112.0, 101.9, 55.8; as Figure 2 shown;

[0109] HRMS (ESI) m / z: [M + Na] calcd for C + calcd for C 23 H 17 NO3Na: 378.1106; found: 378.1101; [a] D 25 = 35.6 (c 0.47, MeOH) (97% ee);

[0110] HPLC (Chiralcel OD-H, hexane: iPrOH = 75:25, 1.0 mL / min, 254 nm), t R =

[0111] 14.2 min (minor), 20.6 min (major), as shown. Figures 3-4

[0112] Example 35

[0113] The R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0114] The compound 4h prepared in Example 35 was subjected to NMR detection, mass spectrometry detection and HPLC detection, and the results were as follows:

[0115] 1 H NMR (500 MHz, Chloroform-d) δ 7.99 - -7.93 (m, 1H), 7.92 - -7.83 (m, 3H), 7.79 (ddd, J = 7.7, 1.5, 0.5 Hz, 1H), 7.65 (ddt, J = 8.7, 5.3, 0.7 Hz, 1H), 7.58 (ddd, J = 8.0, 7.4, 1.5 Hz, 1H), 7.52 - -7.46 (m, 2H), 7.31 - -7.26 (m, 1H), 6.93 - -6.85 (m, 2H), 6.35 (dd, J = 2.7, 1.5 Hz, 1H), 4.75 (s, 1H);

[0116] 13 C NMR (125 MHz, Chloroform-d) δ 201.0, 139.5, 137.1, 136.7, 134.6, 130.0, 129.4, 128.7, 128.6, 128.4, 127.8, 127.6, 124.5, 123.7, 122.8, 121.9, 121.5 (d, J = 10.0 Hz), 118.0, 109.2 (d, J = 25.0 Hz), 97.6 (d, J = 25.0 Hz);

[0117] HRMS (ESI) m / z: [M + Na] calcd for C + calcd for C 22 H 14 FNO2Na: 366.0906; found 366.0910; [a] D 25 = 18.6 (c 0.52, MeOH) (54% ee);​

[0118] HPLC (Chiralcel OD-H, hexane: EtOH = 90:10, 1.0 mL / min, 254 nm), t i PrOH = 75:25, 1.0 mL / min, 254 nm), t R

[0119] 10.4 min (minor), 15.3 min (major).

[0120] Example 36

[0121] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0122] The compound 4i prepared in Example 36 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0123] 1 H NMR (500 MHz, Chloroform-d) δ 7.98 - -7.85 (m, 4H), 7.78 (ddd, J = 7.5, 1.5, 0.5 Hz, 1H), 7.65 - -7.60 (m, 1H), 7.58 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 7.53 - -7.46 (m, 2H), 7.30 - -7.26 (m, 1H), 7.20 (ddt, J = 2.0, 1.5, 0.5 Hz, 1H), 7.08 (dd, J = 8.5, 2.0 Hz, 1H), 6.58 - -6.13 (m, 1H), 4.76 (s, 1H);

[0124] 13 C NMR (125 MHz, Chloroform-d) δ 200.9, 139.4, 137.0, 134.7, 130.0, 129.5, 128.8, 128.6, 128.5, 127.8, 127.6, 124.8, 123.9, 123.8, 122.8, 121.4, 121.2, 118.1, 111.2;

[0125] HRMS (ESI) m / z: [M + Na] calcd for C + calcd for C 22 H 14 ClNO2Na: 382.0611; found 382.0615; [a] D 25 = 36.4 (c 0.48, MeOH) (60% ee);​

[0126] HPLC (Chiralcel OD-H, hexane: EtOH = 90:10, 1.0 mL / min, 254 nm), t i PrOH = 75:25, 1.0 mL / min, 254 nm), t R

[0127] 10.4 min (minor), 15.1 min (major).

[0128] Example 37

[0129] The R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0130] The compound 4j prepared in Example 37 was subjected to NMR detection, mass spectrometry detection and HPLC detection, and the results were as follows:

[0131] 1 H NMR (500 MHz, Chloroform-d) δ 8.03 - -7.95 (m, 1H), 7.94 - -7.90 (m, 1H), 7.90 - -7.86 (m, 1H), 7.85 - -7.75 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.57 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 7.54 - -7.48 (m, 2H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 7.04 - -6.93 (m, 2H), 6.30 (d, J = 2.7 Hz, 1H), 4.80 (s, 1H), 2.41 (s, 3H);

[0132] 13 C NMR (125 MHz, Chloroform-d) δ 200.9, 139.7, 137.1, 137.0, 134.4, 132.2, 130.0, 129.3, 128.8, 128.5, 128.3, 127.8, 127.6, 123.6, 123.1, 122.7, 122.2, 120.0, 117.5, 111.2, 21.5;

[0133] HRMS (ESI) m / z: [M + Na] calcd for C + calcd for C 23 H 17 NO2Na: 362.1157; found: 362.1153; [a] D 25 ​= 74.6 (c 0.60, MeOH) (56% ee);

[0134] HPLC (Chiralcel OD-H, hexane: i PrOH = 75:25, 1.0 mL / min, 254 nm), t R =

[0135] 13.6 min (minor), 16.6 min (major).

[0136] Example 38

[0137] The R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, as shown in Table 3.

[0138] The compound 4k prepared in Example 38 was subjected to NMR detection, mass spectrometry detection and HPLC detection, and the results were as follows:

[0139] 1 H NMR (500 MHz, Chloroform-d) δ 7.98 - -7.91 (m, 1H), 7.91 - -7.87 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.82- -7.73 (m, 2H), 7.60- -7.52 (m, 2H), 7.52- -7.44 (m, 2H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 6.77 (dd, J = 9.0, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.23 (d, J = 2.5 Hz, 1H), 4.76 (s, 1H), 3.75 (s, 3H);

[0140] 13 C NMR (126 MHz, Chloroform-d) δ 200.9, 156.5, 139.6, 137.5, 137.0, 134.5, 130.0, 129.3, 128.7, 128.6, 128.3, 127.8, 127.6, 123.6, 123.2, 122.7, 121.0, 119.6, 117.7, 110.3, 94.8, 55.5;

[0141] HRMS (ESI) m / z: [M + Na] calcd for C + calcd for C 23 H 17 NO3Na: 378.1106; found: 378.1111; [a]D 25 = 53.4 (c 0.50, MeOH) (54% ee);

[0142] HPLC (Chiralcel OD-H, hexane: EtOH = 90:10, 1.0 mL / min, 254 nm), t i PrOH = 75:25, 1.0 mL / min, 254 nm), t R =

[0143] 17.2 min (minor), 24.6 min (major).

[0144] Example 39

[0145] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from Example 28, see Table 3.

[0146] Example 40

[0147] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from Example 28, see Table 3.

[0148] The compound 4m prepared in Example 40 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0149] 1 H NMR (500 MHz, Chloroform-d) δ 7.98 - - 7.93 (m, 1H), 7.92 - - 7.88 (m, 1H), 7.87 (dd, J = 8.0, 1.0 Hz, 1H), 7.81 - - 7.72 (m, 2H), 7.59 - - 7.53 (m, 2H), 7.53 - - 7.46 (m, 2H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 7.03 (dd, J = 8.0, 7.0 Hz, 1H), 6.94 (dt, J = 7.0, 1.0 Hz, 1H), 6.37 (dd, J = 6.0, 2.5 Hz, 1H), 4.79 (s, 1H), 2.32 (s, 3H);

[0150] 13C NMR (125 MHz, Chloroform-d) δ 200.8, 139.7, 137.0, 136.2, 134.5, 130.0, 129.4, 128.8, 128.6, 128.4, 127.8, 127.7, 124.8, 123.9, 123.7, 123.0, 122.7, 120.6, 120.4, 118.3, 118.1, 16.4;

[0151] HRMS (ESI) m / z: [M + Na]+ calculated for C + calcd for C 23 H 17 NO2Na: 362.1157; found: 362.1152; [α] D 25 = 49.1 (c 0.53, MeOH) (52% ee);

[0152] HPLC (Chiralcel OD-H, hexane: EtOH = 75:25, 1.0 mL / min, 254 nm), t i = 49.1 (c 0.53, MeOH) (52% ee); R = 49.1 (c 0.53, MeOH) (52% ee);

[0153] 12.9 min (minor), 17.8 min (major).

[0154] Example 41

[0155] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0156] The compound 4n prepared in Example 41 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0157] 1H NMR (500 MHz, Chloroform-d) δ 8.12 (s, 1H), 8.03 - -7.97 (m, 1H), 7.95- -7.91 (m, 1H), 7.91 - -7.86 (m, 1H), 7.82 (dd, J = 7.5, 1.5 Hz, 1H), 7.58 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 7.55 - -7.49 (m, 2H), 7.32 (dt, J = 8.0, 1.0 Hz, 1H), 7.27 (td, J = 7.5, 1.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.61 (dd, J = 8.0, 0.5 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 4.81 (s, 1H), 3.88 (s, 3H);

[0158] 13 C NMR (125 MHz, Chloroform-d) δ 200.8, 146.1, 139.7, 137.0, 134.46, 130.0, 129.4, 128.8, 128.6, 128.4, 127.8, 127.7, 127.3, 126.6, 123.7, 122.8, 120.9, 118.2, 113.0, 102.2, 55.2;

[0159] HRMS (ESI) m / z: [M + Na] + calcd for C 23 H 17 NO3Na: 378.1106; found: 378.1103; [a] D 25 = 31.4 (c 0.55, MeOH) (56% ee);

[0160] HPLC (Chiralcel OD-H, hexane: i PrOH = 75:25, 1.0 mL / min, 254 nm), t R =

[0161] 24.9 min (minor), 28.1 min (major).

[0162] Example 42

[0163] The R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from Example 28, see Table 3.

[0164] The compound 4o prepared in Example 42 was subjected to NMR, mass and HPLC tests, and the results were as follows:

[0165] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (d, J = 3.0 Hz, 1H), 8.07 (dd, J = 8.5, 4.5 Hz, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.5 Hz, 1H), 7.74 (dd, J = 8.5, 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.66 - 7.62 (m, 1H), 7.29 (dt, J = 8.0, 1.0 Hz, 1H), 7.05 (ddd, J = 8.0, 7.0, 1.5 Hz, 1H), 6.98 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.53 (s, 1H), 6.39 (d, J = 2.5 Hz, 1H);

[0166] 13 C NMR (125 MHz, DMSO-d6) δ 196.2, 143.9, 136.8, 136.6, 134.2, 131.4, 130.8, 130.2, 129.2, 128.4, 126.4, 126.0, 125.0, 124.6, 122.9, 121.8, 121.5, 120.6, 119.2, 114.7, 111.8, 77.5;

[0167] HRMS (ESI) m / z: [M + Na] + calcd for C 22 H 13 Br2NO2Na: 503.9211; found: 503.9215; [a] D 25 = 58.0 (c 0.62, MeOH) (68% ee);

[0168] HPLC (Chiralcel OD-H, hexane: i PrOH = 85:15, 1.0 mL / min, 254 nm), t R =

[0169] 13.6 min (major), 16.2 min (minor).

[0170] Example 43

[0171] The compound of R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0172] The compound 4p prepared in Example 43 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0173] 1 H NMR (500 MHz, DMSO-d6) δ 10.83 (d, J = 3.0 Hz, 1H), 8.06 (dd, J = 8.5, 3.5 Hz, 2H), 7.95 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.5 Hz, 1H), 7.73 (dd, J = 8.5, 2.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 2.0, 1.0 Hz, 1H), 7.17 (dd, J = 8.5, 1.0 Hz, 1H), 6.88 (dd, J = 8.5, 1.5 Hz, 1H), 6.48 (s, 1H), 6.29 (d, J = 2.5 Hz, 1H), 2.35 (s, 3H);

[0174] 13 C NMR (125 MHz, DMSO-d6) δ 196.0, 144.0, 136.8, 135.0, 134.2, 131.4, 131.0, 130.8, 130.3, 129.2, 128.4, 127.6, 126.9, 126.3, 126.0, 125.3, 124.6, 123.2, 122.9, 121.8, 120.2, 114.2, 111.5, 77.6, 21.4;

[0175] HRMS (ESI) m / z: [M + Na] + calcd for C 23 H 15 Br2NO2Na: 517.9367; found: 517.9361; [a] D 25 = 80.4 (c 0.59, MeOH) (63% ee);

[0176] HPLC (Chiralcel OD-H, hexane: i PrOH = 93:7, 1.0 mL / min, 254 nm), t R = 30.2

[0177] min (major), 33.1 min (minor).

[0178] Example 44

[0179] The R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0180] The compound 4q prepared in Example 44 was subjected to NMR detection, mass spectrometry detection and HPLC detection, and the results were as follows:

[0181] 1 H NMR (500 MHz, DMSO-d6) δ 10.85 (d, J = 3.0 Hz, 1H), 8.06 (dd, J = 8.5, 5.0 Hz, 2H), 7.98 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.5 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.18 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.70 (dd, J = 9.0, 2.5 Hz, 1H), 6.51 (s, 1H), 6.38 (d, J = 3.0 Hz, 1H), 3.72 (s, 3H);

[0182] 13 C NMR (126 MHz, DMSO-d6) δ 195.9, 153.2, 143.8, 136.8, 134.2, 131.7, 131.4, 130.9, 130.3, 129.2, 128.4, 126.4, 126.0, 125.4, 125.3, 122.9, 121.9, 114.1, 112.5, 111.6, 102.3, 77.5, 55.2;

[0183] HRMS (ESI) m / z: [M + Na] + calcd for C 23 H 15 Br2NO3Na: 533.9316; found: 533.9319; [a] D 25 = 23.4 (c 0.46, MeOH) (94% ee);

[0184] HPLC (Chiralcel OD-H, hexane: i PrOH = 85:15, 1.0 mL / min, 254 nm), t R =

[0185] 17.3 min (major), 33.7 min (minor).

[0186] Example 45

[0187] The R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0188] The compound 4r prepared in Example 45 was subjected to NMR detection, mass spectrometry detection and HPLC detection, and the results were as follows:

[0189] 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.13 - -8.06 (m, 3H), 7.96 (dd, J = 12.0, 2.5 Hz, 2H), 7.84 (dd, J = 8.5, 2.5 Hz, 1H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.38 - -7.32 (m, 1H), 7.02 (dd, J = 8.5, 2.0 Hz, 1H), 6.58 (s, 1H), 6.42 (d, J = 2.5 Hz, 1H);

[0190] 13 C NMR (125 MHz, DMSO-d6) δ 196.1, 176.8, 137.4, 137.0, 136.9, 134.2, 133.5, 133.0, 131.5, 131.0, 130.5, 130.2, 129.2, 128.3, 126.8, 126.3, 126.0, 125.6, 123.7, 122.9, 122.7, 121.9, 121.8, 119.5, 115.1, 111.4, 77.3;

[0191] HRMS (ESI) m / z: [M + Na] calcd for C + calcd for C 22 H 12 Br2ClNO2Na: 537.8821; found: 537.8826; [a] D 25 = 73.1 (c 0.57, MeOH) (60% ee);

[0192] HPLC (Chiralcel OD-H, hexane:i PrOH = 90:10, 1.0 mL / min, 254 nm), t R =

[0193] 17.8 min (minor), 20.1 min (major).

[0194] Example 46

[0195] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0196] The compound 4s prepared in Example 46 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0197] 1 H NMR (500 MHz, DMSO-d6) δ 10.74 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.5, 2.5 Hz, 2H), 7.96 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.5 Hz, 1H), 7.72 (dd, J = 8.5, 2.0 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.65 (dd, J = 9.0, 2.5 Hz, 1H), 6.49 (s, 1H), 6.23 (d, J = 2.5 Hz, 1H), 3.71 (s, 3H);

[0198] 13 C NMR (125 MHz, DMSO-d6) δ 196.3, 155.7, 143.9, 137.4, 136.8, 134.3, 131.4, 130.8, 130.2, 129.2, 128.4, 126.3, 126.0, 123.4, 122.9, 121.8, 121.2, 119.4, 114.8, 109.5, 94.8, 77.6, 55.1;

[0199] HRMS (ESI) m / z: [M + Na] calcd for C + calcd for C 23 H 15 Br2NO3Na: 533.9316; found: 533.9312; [a] D 25 = 23.7 (c 0.49, MeOH) (52% ee);

[0200] HPLC (Chiralcel OD-H, hexane: EtOH = 90:10, 1.0 mL / min, 254 nm), t i PrOH = 85:15, 1.0 mL / min, 254 nm), t R

[0201] 17.8 min (minor), 19.9 min (major).

[0202] Example 47

[0203] The R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0204] The compound 4t prepared in Example 47 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0205] 1 H NMR (500 MHz, DMSO-d6) δ 10.79 (d, J = 3.0 Hz, 1H), 8.43 (dd, J = 6.0, 2.0 Hz, 2H), 7.79 - 7.71 (m, 2H), 7.61 - 7.51 (m, 2H), 7.51 - 7.44 (m, 1H), 7.21 - 7.09 (m, 1H), 6.87 (dd, J = 8.5, 1.5 Hz, 1H), 6.36 (s, 1H), 6.27 (d, J = 2.5 Hz, 1H), 2.39 (s, 3H);

[0206] 13 C NMR (125 MHz, DMSO-d6) δ 196.9, 141.3, 136.7, 135.0, 132.4, 132.1, 131.0, 129.8, 129.1, 128.6, 128.4, 127.4, 127.0, 126.6, 125.4, 124.5, 123.0, 122.1, 120.3, 114.6, 111.4, 77.5, 21.4;

[0207] HRMS (ESI) m / z: [M + Na] calcd for C + C 23 H 15 Br2NO2Na: 517.9367; found: 517.9363; [a] D 25 = 84.18 (c 0.55, MeOH) (60% ee);

[0208] ​HPLC (Chiralcel OD-H, hexane: EtOH = 90:10, 1.0 mL / min, 254 nm), t i PrOH = 90:10, 1.0 mL / min, 254 nm), t R =

[0209] 22.7 min (minor), 25.0 min (major).

[0210] Example 48

[0211] The R-10-hydroxy-10-(1H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0212] The X-single crystal diffraction test was performed on the compound 4u prepared in Example 48, and the absolute configuration was determined as R, as shown in Figure 9

[0213] The compound 4u prepared in Example 48 was subjected to nuclear magnetic detection, mass spectrometry and HPLC detection, and the results were as follows:

[0214] 1 H NMR (500 MHz, DMSO-d6) δ 10.80 (d, J = 3.0 Hz, 1H), 8.44 (dd, J = 5.0, 1.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 1H), 7.76 - 7.72 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 8.0, 1.5 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.69 (dd, J = 9.0, 2.5 Hz, 1H), 6.38 (dd, J = 11.0, 2.5 Hz, 2H), 3.72 (s, 3H); as Figure 5 shown;

[0215] 13 C NMR (125 MHz, DMSO-d6) δ 196.8, 153.2, 141.1, 136.7, 132.4, 132.1, 131.7, 131.0, 129.9, 129.1, 128.7, 128.4, 127.0, 126.6, 125.5, 125.2, 122.1, 114.6, 112.4, 111.4, 102.4, 77.3, 55.2; as Figure 6 shown;

[0216] HRMS (ESI) m / z: [M + Na] Calcd for C + calcd for C​23 H 15 Br2NO3Na: 533.9316; found: 533.9311 ; [a] D 25 = 581.8 (c 0.61, MeOH) (97% ee);

[0217] HPLC (Chiralcel OD-H, hexane: i PrOH = 85: 15, 1.0 mL / min, 254 nm), t R =

[0218] 19.5 min (minor), 23.2 min (major), as Figures 7-8 indicated.

[0219] Example 49

[0220] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0221] The compound 4v prepared in Example 49 was subjected to NMR, mass and HPLC tests, and the results were as follows:

[0222] 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (d, J = 2.5 Hz, 1H), 8.64 (d, J = 2.0 Hz, 2H), 8.44 (dd, J = 6.0, 2.0 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.78 - 7.72 (m, 4H), 7.68 (d, J = 8.5 Hz, 1H), 7.61 - 7.51 (m, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.48 (s, 1H), 6.41 (d, J = 2.5 Hz, 1H);

[0223] 13 C NMR (125 MHz, DMSO-d6) δ 197.0, 177.7, 140.9, 137.0, 136.7, 135.9, 132.7, 132.5, 132.2, 130.9, 130.8, 130.7, 130.0, 129.8, 129.1, 128.9, 128.1, 127.7, 127.1, 126.7, 126.3, 125.6, 123.8, 122.2, 122.1, 119.5, 115.6, 111.4, 77.2;

[0224] HRMS (ESI) m / z: [M + Na]+calcd for C + calcd for C 22 H 12 Br2ClNO2Na: 537.8821; found: 537.8825; [α] D 25 = 82.0 (c 0.49, MeOH) (58% ee);

[0225] HPLC (Chiralcel AD-H, hexane: EtOH = 70:30, 1.0 mL / min, 254 nm), t i PrOH = 70:30, 1.0 mL / min, 254 nm), t R =

[0226] 15.9 min (major), 24.3 min (minor).

[0227] Example 50

[0228] The R-10-hydroxy-10-(1 H-indol-3-yl)-9-phenanthrenone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2and R3were different from those of Example 28, see Table 3.

[0229] The compound 4w prepared in Example 50 was subjected to NMR, MS and HPLC tests, and the results were as follows:

[0230] 1 H NMR (500 MHz, DMSO-d6) δ 10.71 (d, J = 2.5 Hz, 1H), 8.43 (dd, J = 8.0, 2.0 Hz, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.73 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 - -7.53 (m, 2H), 7.52 - 7.48 (m, 1H), 6.76 (dd, J = 2.5, 0.5 Hz, 1H), 6.63 (dd, J = 9.0, 2.5 Hz, 1H), 6.37 (s, 1H), 6.21 (d, J = 2.5 Hz, 1H), 3.70 (s, 3H);

[0231] 13C NMR (125 MHz, DMSO-d6) δ 197.1, 155.6, 141.2, 137.4, 136.7, 132.4, 132.1, 130.9, 129.8, 129.0, 128.7, 128.4, 127.0, 126.6, 123.3, 122.0, 121.2, 119.4, 115.3, 109.3, 94.7, 77.4, 55.1;

[0232] HRMS (ESI) m / z: [M + Na]+ calculated for C + calcd for C 23 H 15 Br2NO3Na: 533.9316; found: 533.9312; [a] D 25 = 82.8 (c 0.52, MeOH) (56% ee);

[0233] HPLC (Chiralpak AS, hexane: i PrOH = 80:20, 1.0 mL / min, 254 nm), t R = 17.4

[0234] min (minor), 26.4 min (major).

[0235] The products of Examples 28-50 were assayed for yield and the ee of the products was determined by HPLC on chiral OD-H, AD-H, AS-H columns. Details are shown in Table 3.

[0236] Table 3. Yield and enantiomeric excess (ee) of the reaction in Examples 28-50

[0237]

[0238] The optimal catalyst conditions were applied to the reactions of different substituted phenanthrene quinones and indoles. Most of the screened indoles could react smoothly to give the corresponding products in 48-97% ee and good yields (Examples 28, 31-38, 40-41). When various substituents (R3) on the benzene ring of indole (C4, C5, C6 and C7) were investigated, it was found that the substituent at C4 position had a negative effect on the catalytic performance, leading to the failure of the reaction (Examples 29, 30). Secondly, it was found that the electron-donating groups (Me and OMe) at C5 position were beneficial to the improvement of enantioselectivity (Examples 33, 34), especially when 5-OMe indole was used as the substrate, the highest enantioselectivity (97% ee) was obtained. In addition, the effects of the electron- withdrawing or electron-donating groups at C6 position on the stereoselectivity were similar (Examples 35-38). It is worth mentioning that the substituent at C7 position had a great effect on the catalyst. The reactions of 7-Me and 7-OMe indoles proceeded smoothly to give the products with moderate enantioselectivity (Examples 40, 41), while the halogen groups at C7 position of indole led to the failure of the reaction (Example 39). In addition, when 2,7-dibromo or 3,6-dibromo substituted phenanthrene quinone was used as the substrate, it could react with 5-OMe indole to give the products with excellent enantioselectivity (Examples 44, 48). From the above experimental results, it can be seen that the substituents and their positions have a significant effect on the enantioselectivity, and the best enantiomeric excess is obtained when 5-OMe substituted indole is used as the substrate (Examples 34, 44, 48).

[0239] Study on the Anti-tumor Activity of the Compounds

[0240] The R configuration products 4g(R), 4q(R) and 4u(R) prepared from Example 34, Example 44 and Example 48, respectively, have the following structures:

[0241]

[0242] The above compounds were used in mouse breast cancer cells (4T1), with doxorubicin as the positive control, and the experiment was carried out by CCK-8 method. The inhibitory effects of the positive control and (R)-4g, (R)-4q and (R)-4u on the proliferation of tumor cells are shown in Figures 10-13 The results show that the three groups of phenanthrene quinone derivatives all have anti-tumor activity, and the inhibitory effects of (R)-4g and (R)-4u at higher concentrations are better than that of the positive control. Through the comparison of the anti-tumor activities of the three groups of compounds, it can be known that the configuration and the position of the substituent group of the phenanthrene quinone derivatives have a great influence on the anti-tumor activity.

[0243] The above merely describes the preferred embodiments of the present application, and it should be pointed out that, for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as falling within the protection scope of the present application.

Claims

1. A method for synthesizing R-10-hydroxy-10-(1H-indole-3-)-9-phenanthone, comprising the following steps: The 9,10-phenanthrenequinone compound shown in Formula 2, the indole compound shown in Formula 3, and the chiral catalyst were mixed in an organic solvent and reacted to obtain the R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrone compound shown in Formula 4. The chiral catalyst has the structure described in any one of Formulas 1a to 1h; In equations 2-4, R1 is hydrogen or halogen, and R2 is hydrogen or halogen. R3 has a substitution position of C5, C6 or C7 on the indole benzene ring. When the substitution position of R3 is C5 or C6, R3 is hydrogen, halogen, methyl or methoxy. When the substitution position of R3 is C7, R3 is hydrogen, methyl or methoxy. The organic solvent is one or more of dichloromethane, trichloromethane, 1,2-dichloroethane, acetonitrile, and ethyl acetate.

2. The method according to claim 1, characterized in that, R1 is hydrogen or bromine, and R2 is hydrogen or bromine.

3. The method according to claim 1, characterized in that, The molar ratio of the 9,10-phenanthroquinone compound to the indole compound is 1:(1~10).

4. The method according to claim 1, characterized in that, The molar ratio of the 9,10-phenanthroquinone compound to the indole compound is 1:(5~10).

5. The method according to claim 1, characterized in that, The molar amount of the chiral catalyst is 5 to 20% of the molar amount of the 9,10-phenanthroquinone compound.

6. The method according to claim 5, characterized in that, The molar amount of the chiral catalyst is 10 to 15% of the molar amount of the 9,10-phenanthroquinone compound.

7. The method according to claim 1, characterized in that, The reaction temperature is 0~30℃, and the reaction time is 18~30 hours.

8. The method according to claim 1, characterized in that, After the reaction was complete, the product was purified by column chromatography to obtain the compound R-10-hydroxy-10-(1H-indole-3-)-9-phenanthone.

9. The method according to claim 8, characterized in that, The eluent used in the column chromatography separation and purification was n-hexane and ethyl acetate in a volume ratio of 5:1.

Images