Method for synthesizing R-10-hydroxy-10-(1H-indole-3)-9-phenanthrene ketone compound

Abstract

The invention provides a method for synthesizing an R-10-hydroxy-10-(1H-indole-3)-9-phenanthrene ketone compound, which comprises the following steps: mixing a 9, 10-phenanthrene quinone compound as shown in a formula 2, an indole compound as shown in a formula 3 and a chiral catalyst in an organic solvent, and reacting to obtain the R-10-hydroxy-10-(1H-indole-3)-9-phenanthrene ketone compound as shown in a formula 4. According to the method, the main product, namely the R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrone compound, can be obtained, the enantiomeric excess value of the R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrone compound is up to 97%, the yield is good (75%-95%), and the absolute configuration of the target compound is determined to be R through an X-single crystal diffraction experiment. Cell experiments find that a series of synthesized compounds have good anti-tumor activity, and a basis is provided for research of chiral drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing an R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound. Background Art

[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 treatment and drug development, and exhibits anti-tumor, anti-inflammatory and antifungal activities. Its ortho-carbonyl structure and highly conjugated phenanthrene plane have good charge dispersion ability and are often used as model compounds in electrochemical research. Its unique triplet activity makes it of great value in photodynamics and photochemical reactions.

[0003] However, in the field of asymmetric catalysis, the asymmetric Friedel-Crafts reaction of 9,10-phenanthrenequinone with indole has not been reported. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrenone compounds. The main product obtained by the method of the present invention is R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrenone compounds, 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 to be R by X-ray single crystal diffraction experiments. Cell experiments show that a series of synthesized compounds have good anti-tumor activity, which provides a basis for the research of chiral drugs.

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

[0006] The 9,10-phenanthrenequinone compound shown in Formula 2, the indole compound shown in Formula 3 and a chiral catalyst are mixed in an organic solvent and reacted to obtain the R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrene ketone compound shown in Formula 4;

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

[0008]

[0009] In formulae 2 to 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 to the indole compound is 1:(1-10).

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

[0013] Preferably, the molar amount of the chiral catalyst is 5 to 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 includes one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, ether, acetonitrile and ethyl acetate.

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

[0017] Preferably, after the reaction is completed, the product is separated and purified by column chromatography to obtain an R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrenone compound.

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

[0019] The present invention provides a method for synthesizing an R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrone compound, comprising the following steps: mixing a 9,10-phenanthronequinone 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-indole-3-)-9-phenanthrone compound shown in Formula 4; the chiral catalyst has a structure described in any one of Formulas 1a to 1h; in Formulas 2 to 4, R1 is hydrogen or halogen, R2 is hydrogen or halogen, and R3 is hydrogen, halogen, methyl or methoxy. The chiral amide catalyst is used to catalyze the asymmetric Friedel-Crafts reaction of differently substituted 9,10-phenanthronequinone and indole. The main product is R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrone compound, 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 to be R by X-ray single crystal diffraction experiment. The invention has the advantages of simple operation, mild reaction conditions, environmental friendliness, etc., opens up a new way for synthesizing a series of R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrone compounds, and cell experiments show that the synthesized series of compounds have good anti-tumor activity, which provides a basis for the research of chiral drugs.

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

[0021] 1. It is innovative. Currently, there is no report on the asymmetric Friedel-Crafts reaction of differently substituted 9,10-phenanthrenequinone and indole.

[0022] 2. The reaction has high enantioselectivity, good yield, complete reaction, no by-products detected by H-NMR and C-NMR, and can obtain highly enantiomeric optically pure compounds.

[0023] 3. The substrate universality of the method provided by the present invention is relatively wide, and the 10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound generated by the reaction has potential anti-tumor activity.

[0024] 4. Easy operation, mild reaction conditions and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0026] Figure 1 This is the H NMR spectrum of compound 5aaa prepared in Example 28 of the present invention;

[0027] Figure 2 This is the NMR carbon spectrum of compound 5aaa prepared in Example 28 of the present invention;

[0028] Figure 3 HPLC spectrum of compound 5aaa prepared in Example 28 of the present invention (racemic product);

[0029] Figure 4 HPLC spectrum of compound 5aaa prepared in Example 28 of the present invention (R-configuration product);

[0030] Figure 5 This is the H NMR spectrum of compound 5gaa prepared in Example 48 of the present invention;

[0031] Figure 6 This is the NMR carbon spectrum of compound 5gaa prepared in Example 48 of the present invention;

[0032] Figure 7 This is the HPLC spectrum of compound 5gaa prepared in Example 48 of the present invention (racemic product);

[0033] Figure 8 This is the HPLC spectrum of compound 5gaa prepared in Example 48 of the present invention (R-configuration product);

[0034] Fig. 9 This is the X-ray single crystal diffraction test result of the compound 5gaa prepared in Example 48 of the present invention;

[0035] Fig.10 The inhibitory effect of the positive control drug doxorubicin on tumor cell proliferation in the application example of the present invention;

[0036] Fig.11 The inhibitory effect of the (R)-4g compound in the application example of the present invention on the proliferation of tumor cells;

[0037] Fig.12 The (R)-4q compound in the application example of the present invention has an inhibitory effect on the proliferation of tumor cells;

[0038] Fig.13 This is the inhibitory effect of the (R)-4u compound in the application example of the present invention on the proliferation of tumor cells. DETAILED DESCRIPTION

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

[0040] The 9,10-phenanthrenequinone compound shown in Formula 2, the indole compound shown in Formula 3 and a chiral catalyst are mixed in an organic solvent and reacted to obtain the R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrene ketone compound shown in Formula 4;

[0041] The chiral catalyst has a 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 invention, 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 invention, the molar ratio of the 9,10-phenanthrenequinone compound to 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 any of the above values ​​as the upper or lower limit.

[0046] In the present invention, the molar amount of the chiral catalyst is 5 to 20% of the molar amount of the 9,10-phenanthrenequinone compound, and more preferably 10 to 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 or lower limit.

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

[0048] In the present invention, the reaction temperature 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 or lower limit; the reaction time is preferably 18-30 hours, more preferably 20-28 hours, and most preferably 24-26 hours.

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

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

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

[0052] In order to further illustrate the present invention, a method for synthesizing R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound provided by the present invention is described in detail below in conjunction with examples, but it should not be construed as limiting the scope of protection of the present invention.

[0053] Examples 1 to 14

[0054] 0.10mmol 9,10-phenanthrenequinone, 0.10-1.00mmol indole (specific amount see Table 1) and 10mol% chiral catalyst (specific type see Table 1) were placed in a dry and sealed reaction tube, a magnetic bar was added, 1mL dichloromethane was added with a syringe, and the reaction was placed in a magnetic stirrer at room temperature for 24h, 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 the structure of the chiral amide catalyst are as follows:

[0055]

[0056] The yield is the isolated yield, and the enantiomeric excess (ee) of the product is determined by HPLC chiral OD-H column. Details are shown in Table 1.

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

[0058]

[0059] Catalysts 1a-1h were applied to the asymmetric Friedel-Crafts reaction of phenanthrenequinone and indole, with dichloromethane as solvent and the reaction was carried out at room temperature for 24 hours in order to screen out the best catalyst. As shown in Table 1, all catalysts can successfully catalyze the reaction, and the yield of the target product is low (40%-45%), and the enantioselectivity is 6%-38%. Among them, the ee value and yield obtained when catalyst 1e is used are the best. By increasing the amount of indole, the yield and enantioselectivity of the reaction are improved. It is determined that the optimal dosage ratio of phenanthrenequinone and indole is 1:7 (Example 12).

[0060] Examples 15 to 27

[0061] 0.10mmol 9,10-phenanthrenequinone, 0.70mmol indole and 10mol% catalyst 1e were placed in a dry and sealed reaction tube, a magnetic bar was added, 1mL dichloromethane or other solvent (see Table 2 for details) was added with a syringe, and the mixture was placed in a magnetic stirrer at room temperature or 0°C (see Table 2 for details) for 24h, 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 the structure of catalyst 1e are as follows:

[0062]

[0063] The yield is the isolated yield, and the enantiomeric excess (ee) of the product is determined by HPLC chiral OD-H column. Details are shown in Table 2.

[0064] Table 2 Reaction yields and enantiomeric excess (ee) in Examples 15 to 27

[0065]

[0066] Different reaction conditions have a great influence on the enantioselectivity of the reaction. When dichloromethane is used as the solvent, the yield and ee value are optimal (Example 15). However, toluene and ether cannot make the reaction proceed (Examples 18 and 19). The results of the catalyst dosage screening show that 10 mol% catalyst 1e is most suitable. When the catalyst dosage is reduced to 5 mol% or increased to 20 mol%, the yield and enantioselectivity are reduced (Examples 23 and 24 vs. Example 15). When the reaction temperature is reduced from room temperature to 0°C, the enantioselectivity and yield of the product do not increase (Example 22 vs. Example 15). In addition, the reaction concentration is diluted by half; add Additives such as molecular sieves or benzoic acid did not improve the stereoselectivity of the reaction (Examples 25, 26, 27 vs. Example 15). Based on these experiments, the optimal conditions were determined to be dichloromethane as solvent, 10 mol% catalyst 1e, and room temperature reaction.

[0067] Embodiment 28

[0068] 0.10mmol 9,10-phenanthrenequinone, 0.70mmol indole (see Table 3 for specific structure) and 10mol% cat.1e were placed in a dry and sealed reaction tube, a magnetic bar was added, 1mL dichloromethane was added with a syringe, and the mixture was placed in a magnetic stirrer to react at room temperature for 24h, and the reaction progress was monitored by TLC. After the reaction, 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.1e structure are as follows:

[0069]

[0070] Compound 4a prepared in Example 28 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows:

[0071] 1 H NMR (500MHz, Chloroform-d) δ7.98--7.93(m,1H),7.92--7.84(m,3H),7.79(ddd,J=7.5,1.5,0.5Hz,1H),7.75--7.71(m,1H),7.56(ddd,J=8. 0,7.5,1.5Hz,1H),7.53--7.46(m,2H),7.27--7.23(m,1H),7.22--7.1 9(m,1H),7.16–-7.09(m,2H),6.36(dd,J=3.0,2.0Hz,1H),4.80(s,1H);

[0072] 13 C NMR(125MHz,Chloroform-d)δ200.9,139.7,137.0,136.6,134.5,130.0,129.4,128.8 ,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] + Calculate for C 22 H 15 NO2Na:348.1000; found348.1005; [α] D 25 =25.7(c 0.50, MeOH)(70%ee);

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

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

[0076] Embodiment 29

[0077] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0078] Embodiment 30

[0079] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0080] Embodiment 31

[0081] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0083] 1 1H 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 13C 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; [α] D 25 = +52.0 (c 0.51, MeOH) (48% ee);

[0086] HPLC (Chiralcel OD-H, hexane: 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 R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0090] Compound 4e prepared in Example 32 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows:

[0091] 1 H NMR(500MHz,Chloroform-d)δ7.96–-7.85(m,4H),7.82(ddd,J=7.5,1.5,0.5Hz,1H),7.71(d,J=2.0Hz,1H),7.58(ddd,J=8.0,7.5,1.5Hz,1H), 7.53-–7.46(m,2H),7.28(td,J=7.5,1.0Hz,1H),7.12(dd,J=8.5,0.5Hz,1H),7.08(dd,J=8.5,2.0Hz,1H),6.39(t,J=2.5Hz,1H),4.76(s,1H);

[0092] 13 C NMR(125MHz,Chloroform-d)δ200.7,139.4,137.0,135.0,134.7,129.9,129.5,128.8 ,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] + Calculate for C 22 H 14 ClNO2Na:382.0611; found382.0617; [α] D 25 =+42.3(c 0.58, MeOH)(48%ee);

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

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

[0096] Embodiment 33

[0097] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0098] Compound 4f prepared in Example 33 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows:

[0099] 1 H NMR(500MHz,Chloroform-d)δ7.96--7.91(m,1H),7.91--7.88(m,1H),7.88--7.85(m,1H),7.80(dd,J=7.5,1.5Hz,2H),7.59--7.52(m,2H),7.52 -–7.46(m,2H),7.25(td,J=7.5,1.0Hz,1H),7.08(d,J=8.5Hz,1H),6.95(dd,J=8.5,1.5Hz,1H),6.28(d,J=2.5Hz,1H),4.79(s,1H),2.45(s,3H);

[0100] 13 C NMR(125MHz,Chloroform-d)δ200.8,139.8,137.0,135.0,134.4,130.0,129.7,129.4,128.8 ,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] + Calculate for C 23 H 17 NO2Na:362.1157; found:362.1151; [α] D 25 =28.9(c 0.57, MeOH)(80%ee);

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

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

[0104] Embodiment 34

[0105] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0107] 1 H NMR(500MHz,Chloroform-d)δ8.01--7.96(m,1H),7.95--7.91(m,1H),7.90(ddt,J= 8.0,1.0,0.5Hz,1H),7.84(ddd,J=7.5,1.5,0.5Hz,2H),7.59(ddd,J=8.0,7.5,1.5H z,1H),7.54--7.49(m,2H),7.29(td,J=7.5,1.0Hz,1H),7.16--7.10(m,2H),6.81(d dd,J=9.0,2.5,0.5Hz,1H),6.40(dd,J=3.0,0.5Hz,1H),4.77(s,1H),3.88(s,3H); such as Figure 1 As 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; Figure 2 As shown;

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

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

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

[0112] Embodiment 35

[0113] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0115] 1 H NMR (500MHz, Chloroform-d) δ7.99--7.93(m,1H),7.92--7.83(m,3H),7.79(ddd,J=7.7,1.5,0.5Hz,1H),7.65(ddt,J=8.7,5.3,0.7Hz,1H) ,7.58(ddd,J=8.0,7.4,1.5Hz,1H),7.52--7.46(m,2H),7.31--7.26(m,1H),6.93--6.85(m,2H),6.35(dd,J=2.7,1.5Hz,1H),4.75(s,1H);

[0116] 13 C NMR(125MHz,Chloroform-d)δ201.0,139.5,137.1,136.7,134.6,130.0,129.4,128.7,128.6,128.4,127.8 ,127.6,124.5,123.7,122.8,121.9,121.5(d,J=10.0Hz),118.0,109.2(d,J=25.0Hz),97.6(d,J=25.0Hz);

[0117] HRMS(ESI)m / z:[M+Na] + Calculate for C 22 H 14 FNO2Na:366.0906; found366.0910; [α] D 25 =18.6(c 0.52, MeOH)(54%ee);

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

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

[0120] Embodiment 36

[0121] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0122] Compound 4i prepared in Example 36 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows:

[0123] 1 H NMR(500MHz,Chloroform-d)δ7.98--7.85(m,4H),7.78(ddd,J=7.5,1.5,0.5Hz,1H),7.65--7.60(m,1H),7.58(ddd,J=8.0,7.5,1.5Hz,1H) ,7.53--7.46(m,2H),7.30--7.26(m,1H),7.20(ddt,J=2.0,1.5,0.5Hz,1H),7.08(dd,J=8.5,2.0Hz,1H),6.58--6.13(m,1H),4.76(s,1H);

[0124] 13 C NMR(125MHz,Chloroform-d)δ200.9,139.4,137.0,134.7,130.0,129.5,128.8,12 8.6,128.5,127.8,127.6,124.8,123.9,123.8,122.8,121.4,121.2,118.1,111.2;

[0125] HRMS(ESI)m / z:[M+Na] + Calculate for C 22 H 14 ClNO2Na:382.0611; found382.0615; [α] D 25 =36.4(c 0.48, MeOH)(60%ee);

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

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

[0128] Embodiment 37

[0129] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0131] 1 H NMR(500MHz,Chloroform-d)δ8.03--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=8.0Hz,1H),7.57(ddd ,J=8.0,7.5,1.5Hz,1H),7.54-–7.48(m,2H),7.25(td,J=7.5,1.0Hz,1H ),7.04–-6.93(m,2H),6.30(d,J=2.7Hz,1H),4.80(s,1H),2.41(s,3H);

[0132] 13 C NMR(125MHz,Chloroform-d)δ200.9,139.7,137.1,137.0,134.4,132.2,130.0,129.3,12 8.8,128.5,128.3,127.8,127.6,123.6,123.1,122.7,122.2,120.0,117.5,111.2,21.5;

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

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

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

[0136] Embodiment 38

[0137] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0139] 1 H NMR(500MHz,Chloroform-d)δ7.98--7.91(m,1H),7.91--7.87(m,1H),7.85(d,J=8.0Hz,1H),7.82--7.73(m,2H),7.60--7.52(m,2H),7.52-- 7.44(m,2H),7.25(td,J=7.5,1.0Hz,1H),6.77(dd,J=9.0,2.5Hz,1H),6.65(d,J=2.5Hz,1H),6.23(d,J=2.5Hz,1H),4.76(s,1H),3.75(s,3H);

[0140] 13 C NMR(126MHz,Chloroform-d)δ200.9,156.5,139.6,137.5,137.0,134.5,130.0,129.3,128. 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] + Calculate for C 23 H 17 NO3Na:378.1106; found:378.1111; [α]D 25 =53.4(c 0.50, MeOH)(54%ee);

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

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

[0144] Embodiment 39

[0145] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0146] Embodiment 40

[0147] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0149] 1 H NMR(500MHz,Chloroform-d)δ7.98--7.93(m,1H),7.92--7.88(m,1H),7.87(dd,J=8.0,1.0Hz,1H),7.81--7.72(m,2H),7.59--7.53(m,2H),7.53--7.4 6(m,2H),7.25(td,J=7.5,1.0Hz,1H),7.03(dd,J=8.0,7.0Hz,1H),6.94(dt ,J=7.0,1.0Hz,1H),6.37(dd,J=6.0,2.5Hz,1H),4.79(s,1H),2.32(s,3H);

[0150] 13C NMR(125MHz,Chloroform-d)δ200.8,139.7,137.0,136.2,134.5,130.0,129.4,128.8,128.6 ,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] + Calculate for C 23 H 17 NO2Na:362.1157; found:362.1152; [α] D 25 =49.1(c 0.53, MeOH)(52%ee);

[0152] HPLC (ChiralcelOD-H, hexane: i PrOH=75:25,1.0mL / min,254nm),t R =

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

[0154] Embodiment 41

[0155] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0157] 1H NMR(500MHz,Chloroform-d)δ8.12(s,1H),8.03--7.97(m,1H),7.95--7.91(m,1H),7. 91–-7.86(m,1H),7.82(dd,J=7.5,1.5Hz,1H),7.58(ddd,J=8.0,7.5,1.5Hz,1H),7.55 -–7.49(m,2H),7.32(dt,J=8.0,1.0Hz,1H),7.27(td,J=7.5,1.0Hz,1H),7.05(t,J=8. 0Hz,1H),6.61(dd,J=8.0,0.5Hz,1H),6.38(d,J=2.5Hz,1H),4.81(s,1H),3.88(s,3H);

[0158] 13 C NMR(125MHz,Chloroform-d)δ200.8,146.1,139.7,137.0,134.46,130.0,129.4,128.8,1 28.6,128.4,127.8,127.7,127.3,126.6,123.7,122.8,120.9,118.2,113.0,102.2,55.2;

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

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

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

[0162] Embodiment 42

[0163] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0164] Compound 4o prepared in Example 42 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows:

[0165] 1 H NMR(500MHz,DMSO-d6)δ10.97(d,J=3.0Hz,1H),8.07(dd,J=8.5,4.5Hz,2H),7.97( d,J=2.0Hz,1H),7.81(dd,J=8.5,2.5Hz,1H),7.74(dd,J=8.5,2.0Hz,1H),7.70(d,J =2.0Hz,1H),7.66-7.62(m,1H),7.29(dt,J=8.0,1.0Hz,1H),7.05(ddd,J=8.0,7.0 ,1.5Hz,1H),6.98(ddd,J=8.0,7.0,1.0Hz,1H),6.53(s,1H),6.39(d,J=2.5Hz,1H);

[0166] 13 C NMR(125MHz,DMSO-d6)δ196.2,143.9,136.8,136.6,134.2,131.4,130.8,130.2,129.2,1 28.4,126.4,126.0,125.0,124.6,122.9,121.8,121.5,120.6,119.2,114.7,111.8,77.5;

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

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

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

[0170] Embodiment 43

[0171] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0173] 1 H NMR(500MHz,DMSO-d6)δ10.83(d,J=3.0Hz,1H),8.06(dd,J=8.5,3.5Hz,2H),7 .95(d,J=2.0Hz,1H),7.81(dd,J=8.5,2.5Hz,1H),7.73(dd,J=8.5,2.0Hz,1H), 7.71(d,J=2.0Hz,1H),7.47(dd,J=2.0,1.0Hz,1H),7.17(dd,J=8.5,1.0Hz,1H) ,6.88(dd,J=8.5,1.5Hz,1H),6.48(s,1H),6.29(d,J=2.5Hz,1H),2.35(s,3H);

[0174] 13 C NMR (125MHz, DMSO-d6) δ196.0,144.0,136.8,135.0,134.2,131.4,131.0,130.8,130.3,129.2,128. 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] + Calculate for C 23 H 15 Br2NO2Na:517.9367; found:517.9361; [α] D 25 =80.4(c 0.59, MeOH)(63%ee);

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

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

[0178] Embodiment 44

[0179] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0181] 1 H NMR (500MHz, DMSO-d6) δ10.85(d,J=3.0Hz,1H),8.06(dd,J=8.5,5.0Hz,2H),7.98(d,J=2.0Hz,1H),7.81(dd,J=8.5,2.5Hz,1H),7.76–7 .71(m,2H),7.18(d,J=9.0Hz,1H),7.04(d,J=2.5Hz,1H),6.70(dd,J=9.0,2.5Hz,1H),6.51(s,1H),6.38(d,J=3.0Hz,1H),3.72(s,3H);

[0182] 13 C NMR (126MHz, DMSO-d6) δ195.9,153.2,143.8,136.8,134.2,131.7,131.4,130.9,130.3,129. 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] + Calculate for C 23 H 15 Br2NO3Na:533.9316; found:533.9319; [α] D 25 =23.4(c 0.46, MeOH)(94%ee);

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

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

[0186] Embodiment 45

[0187] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0189] 1 H NMR(500MHz,DMSO-d6)δ11.07(d,J=2.5Hz,1H),8.25(d,J=8.5Hz,1H),8.13– -8.06(m,3H),7.96(dd,J=12.0,2.5Hz,2H),7.84(dd,J=8.5,2.5Hz,1H),7.75 (dd,J=8.5,2.0Hz,1H),7.70(d,J=2.5Hz,1H),7.66(d,J=8.5Hz,1H),7.38-– 7.32(m,1H),7.02(dd,J=8.5,2.0Hz,1H),6.58(s,1H),6.42(d,J=2.5Hz,1H);

[0190] 13 C NMR (125MHz, DMSO-d6) δ196.1,176.8,137.4,137.0,136.9,134.2,133.5,133.0,131.5,131.0,130.5,130. 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] + Calculate for C 22 H 12 Br2ClNO2Na:537.8821; found:537.8826; [α] D 25 =73.1(c 0.57, MeOH)(60%ee);

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

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

[0194] Embodiment 46

[0195] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0196] Compound 4s prepared in Example 46 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows:

[0197] 1 H NMR (500MHz, DMSO-d6) δ10.74(d,J=2.5Hz,1H),8.05(dd,J=8.5,2.5Hz,2H),7.96(d,J=2.0Hz,1H),7.81(dd,J=8.5,2.5Hz,1H),7.72(dd,J=8.5,2.0Hz ,1H),7.69(d,J=2.5Hz,1H),7.49(d,J=9.0Hz,1H),6.77(d,J=2.5Hz,1H),6 .65(dd,J=9.0,2.5Hz,1H),6.49(s,1H),6.23(d,J=2.5Hz,1H),3.71(s,3H);

[0198] 13 C NMR(125MHz,DMSO-d6)δ196.3,155.7,143.9,137.4,136.8,134.3,131.4,130.8,130.2,129 .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] + Calculate for C 23 H 15 Br2NO3Na:533.9316; found:533.9312; [α] D 25 =23.7(c 0.49, MeOH)(52%ee);

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

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

[0202] Embodiment 47

[0203] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0205] 1 H NMR(500MHz,DMSO-d6)δ10.79(d,J=3.0Hz,1H),8.43(dd,J=6.0,2.0Hz,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=8.5,1.5Hz,1H),6.36(s,1H),6.27(d,J=2.5Hz,1H),2.39(s,3H);

[0206] 13 C NMR (125MHz, DMSO-d6) δ196.9,141.3,136.7,135.0,132.4,132.1,131.0,129.8,129.1,128. 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] + Calculate for C 23 H 15 Br2NO2Na:517.9367; found:517.9363; [α] D 25 =84.18(c 0.55, MeOH)(60%ee);

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

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

[0210] Embodiment 48

[0211] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

[0212] The compound 4u prepared in Example 48 was subjected to X-ray single crystal diffraction test. Fig. 9 As shown, its absolute configuration is determined to be R.

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

[0214] 1 H NMR (500MHz, DMSO-d6) δ10.80(d,J=3.0Hz,1H),8.44(dd,J=5.0,1.5Hz,2H),7.80(d,J=8.5Hz,1H),7.76–7.72(m,1H),7.60(d,J=8.0Hz,1H),7. Such as Figure 5 As 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; Figure 6 As shown;

[0216] HRMS(ESI)m / z:[M+Na] + Calculate for C23 H 15 Br2NO3Na:533.9316; found:533.9311; [α] D 25 =581.8(c 0.61, MeOH)(97%ee);

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

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

[0219] Embodiment 49

[0220] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0222] 1 H NMR (500MHz, DMSO-d6) δ11.04(d,J=2.5Hz,1H),8.64(d,J=2.0Hz,2H),8.44(dd,J=6.0,2.0Hz,2H),7.93(d,J=8.5Hz,2H),7.78-7.72(m ,4H),7.68(d,J=8.5Hz,1H),7.61-–7.51(m,2H),7.32(d,J=2.0Hz,1H),7.01(dd,J=8.5,2.0Hz,1H),6.48(s,1H),6.41(d,J=2.5Hz,1H);

[0223] 13 C NMR (125MHz, DMSO-d6) δ197.0,177.7,140.9,137.0,136.7,135.9,132.7,132.5,132.2,130.9,130.8,130.7,130. 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] + Calculate 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: i PrOH=70:30,1.0mL / min,254nm),t R =

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

[0227] Embodiment 50

[0228] The R-10-hydroxy-10-(1H-indole-3-)-9-phenanthronone compound was prepared according to the preparation method of Example 28, except that the substituents R1, R2 and R3 were different from those in Example 28, see Table 3 for details.

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

[0230] 1 H NMR (500MHz, DMSO-d6) δ10.71(d,J=2.5Hz,1H),8.43(dd,J=8.0,2.0Hz,2H),7.78(d,J=8.5Hz,1H),7.73(dd,J=8.5,2.0Hz,1H),7.58–-7 .53(m,2H),7.52–7.48(m,1H),6.76(dd,J=2.5,0.5Hz,1H),6.63(dd,J=9.0,2.5Hz,1H),6.37(s,1H),6.21(d,J=2.5Hz,1H),3.70(s,3H);

[0231] 13C NMR(125MHz,DMSO-d6)δ197.1,155.6,141.2,137.4,136.7,132.4,132.1,130.9,129.8,129 .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] + Calculate for C 23 H 15 Br2NO3Na:533.9316; found:533.9312; [α] D 25 =82.8(c 0.52, MeOH)(56%ee);

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

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

[0235] The products of Examples 28 to 50 were measured, and the yields were the isolated yields. The ee values ​​of the products were measured by HPLC chiral OD-H, AD-H, and AS-H columns. Details are shown in Table 3.

[0236] Table 3 Yield and enantiomeric excess (ee) of the reactions in Examples 28 to 50

[0237]

[0238] The optimal catalyst conditions were applied to the reaction of different substituted phenanthrenequinones and indoles. Most of the screened indoles reacted smoothly and obtained the corresponding products with 48-97% ee and good yields (Examples 28, 31-38, 40-41). When studying various substituents (R3) on the indole benzene ring (C4, C5, C6 and C7), it was found that the substituent at the C4 position had an adverse effect on the catalytic performance, resulting in the failure of the reaction to proceed (Examples 29, 30). Secondly, it was found that the electron-donating group (Me and OMe) at the C5 position was beneficial to improve the enantioselectivity (Examples 33, 34), especially when 5-OMe indole was used as the substrate, the highest enantioselectivity (97% ee) was obtained. In addition, the electron-withdrawing or electron-donating group at the C6 position also had a similar effect on stereoselectivity (Examples 35-38). It is worth mentioning that the substituent at the C7 position has a great influence on the action of the catalyst. The reaction of 7-Me and 7-OMe indole proceeded smoothly to obtain products with moderate enantioselectivity (Examples 40 and 41), while the halogen group at the C7 position of indole prevented the reaction from proceeding (Example 39). In addition, when 2,7-dibromo or 3,6-dibromo substituted phenanthrenequinone was used as a substrate, it was able to react with 5-OMe indole (Examples 44 and 48) to obtain excellent enantioselectivity. From the above experimental results, it can be seen that the substituent and its position have a significant effect on the enantioselectivity, among which the best enantiomeric excess was obtained when 5-OMe substituted indole was used as a substrate (Examples 34, 44, and 48).

[0239] Study on the anti-tumor activity of application example compounds

[0240] The R-configuration product 4g(R) prepared in Example 34, the R-configuration product 4q(R) prepared in Example 44, and the R-configuration product 4u(R) prepared in Example 48 were used respectively, and the structures are shown below:

[0241]

[0242] The above compounds were used in mouse breast cancer cells (4T1), and doxorubicin was used as a positive control drug. The CCK-8 method was used to perform the experiment. The positive control drug and (R)-4g, (R)-4q and (R)-4u had an inhibitory effect on the proliferation of tumor cells. Figure 10 to Figure 13 As shown in the results, the three groups of phenanthrenequinone derivatives all have anti-tumor activity, among which (R)-4g and (R)-4u have better inhibitory effects than the positive control drug at higher concentrations. The comparison of the anti-tumor activities of the three groups of compounds shows that the different configurations and positions of the substituent groups of phenanthrenequinone derivatives have a great influence on their anti-tumor activity.

[0243] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing an R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrenone compound, comprising the following steps: The 9,10-phenanthrenequinone compound shown in Formula 2, the indole compound shown in Formula 3 and a chiral catalyst are mixed in an organic solvent and reacted to obtain the R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrene ketone compound shown in Formula 4; The chiral catalyst has a structure described in any one of Formula 1a to Formula 1h; In formulae 2 to 4, R1 is hydrogen or halogen, R2 is hydrogen or halogen, and R3 is hydrogen, halogen, methyl or methoxy.

2. The method according to claim 1, characterized in that R1 is hydrogen or bromine, R2 is hydrogen or bromine, and R3 is hydrogen, chlorine, fluorine, methyl or methoxy.

3. The method according to claim 1, characterized in that The molar ratio of the 9,10-phenanthrenequinone 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-phenanthrenequinone 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 5-20% of the molar amount of the 9,10-phenanthrenequinone compound.

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

7. The method according to claim 1, characterized in that The organic solvent includes one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, ether, acetonitrile and ethyl acetate.

8. The method according to claim 1, characterized in that The reaction temperature is 0 to 30° C., and the reaction time is 18 to 30 hours.

9. The method according to claim 1, characterized in that: After the reaction is completed, the product is separated and purified by column chromatography to obtain R-10-hydroxy-10-(1H-indole-3-)-9-phenanthrenone compound.

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

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