Axial chiral cyclopentenyl indol-naphthyl compounds, processes for their preparation and use

Abstract

The application discloses an axially chiral cyclopentenyl and indole-naphthyl compound and a preparation method and application thereof, and the structural formula of the compound is shown in formula 3 and formula 5. The formula 3 compound is obtained by stirring and reacting formula 1 and formula 2 compounds under the action of a chiral phosphoric acid catalyst. The formula 5 compound is obtained by synthesizing the formula 3 compound in two steps. Through biological activity testing, the formula 3 compound has significant cytotoxic activity on PC-3 cancer cells. Through model reaction verification, the formula 5 compound can be used as a chiral ligand or a chiral organic catalyst, and is respectively applied to catalyzing asymmetric allyl coupling reaction and catalyzing asymmetric (4+1) cycloaddition reaction. The method for preparing the axially chiral cyclopentenyl and indole-naphthyl compound is simple in operation, mild in reaction condition, economical and easy in raw material, high in optical purity of the prepared axially chiral compound, high in yield and good in application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to an axially chiral cyclopentenyl-indole-naphthyl compound and its preparation method and application. Background Technology

[0002] Axially chiral cyclopentenyl indole skeletons have broad application prospects in the life sciences. Since the enantiomer of the racemic mixture is often the bioactive component in drug molecules, there is an urgent need to design novel chiral cyclopentenyl indole skeleton compounds and develop efficient methods for their synthesis. Furthermore, due to their unique spatial structure, axially chiral skeletons hold an indispensable position in chiral catalysis, making the development of novel axially chiral cyclopentenyl indole skeleton catalysts of great significance. Currently, research on the cytotoxic activity of existing axially chiral cyclopentenyl indole skeleton compounds against PC-3 cancer cells is insufficient, almost nonexistent, and the development of axially chiral cyclopentenyl indole skeletons as catalysts is rarely reported. The main reason for this is the lack of efficient and highly enantioselective synthetic methods. Summary of the Invention

[0003] One objective of this invention is to provide an axially chiral cyclopentenyl-indole-naphthyl compound that exhibits significant cytotoxic activity against PC-3 cancer cells.

[0004] The second objective of this invention is to provide an axially chiral cyclopentenyl-indole-naphthyl catalyst to meet the needs of basic research and industrial production of catalytic asymmetric reactions.

[0005] A third objective of this invention is to provide a method for synthesizing the above-mentioned axially chiral cyclopentenyl-indole-naphthyl compounds, which has mild reaction conditions, low cost, high yield, and high enantioselectivity.

[0006] The fourth objective of this invention is to provide the application of the above-mentioned axially chiral cyclopentenyl-indole-naphthyl catalysts in catalyzing asymmetric reactions.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] In a first aspect, the present invention provides an axially chiral cyclopentenyl-indole-naphthyl compound, the chemical structure of which is shown in Formulas 3 and 5:

[0009]

[0010] In the formula, R 1 Selected from hydrogen, C1-C3 alkyl groups, and halogens; R 2Selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, and halogen; R 3 Selected from one of hydrogen, aryl, and alkyl; R 4 Selected from one of aryl and heteroaryl groups; R 5 Ar is selected from one of hydrogen or sulfonyl groups; Ar is selected from one of aryl groups.

[0011] Secondly, the present invention also provides a method for synthesizing the above-mentioned axially chiral cyclopentenyl-indole-naphthyl compound, the specific steps of which are as follows:

[0012] (1) Using 3-indole methanol derivative and 2-alkynylnaphthol derivative as reactants, and compounds of formula 1 and formula 2 as reactants, one or two of dichloromethane, ethyl acetate, toluene, acetone or acetonitrile as solvents, and chiral phosphoric acid as catalyst, the reaction is stirred at 0-40℃ for several hours; then, a toluene solution containing 4-dimethylaminopyridine (DMAP), N-phenylbis(trifluoromethanesulfonylimide) and triethylamine is added to the reaction system, and the reaction is continued for 1.5 hours; finally, the mixture is filtered, concentrated, and purified to obtain compound of formula 3; wherein, the molar ratio of compound of formula 1 to compound of formula 2 is 1:1.2 to 2:1;

[0013] (2) Under an inert gas atmosphere, using compound of formula 3 and secondary phosphine oxide as raw materials, dimethyl sulfoxide as reaction solvent, diisopropylethylamine as organic base, palladium acetate and 1,4-bis(diphenylphosphine)butane as catalyst and ligand respectively, the reaction was stirred at 120°C, and the reaction was monitored by TLC until complete. The reaction was extracted with ethyl acetate, concentrated and purified to obtain compound of formula 4.

[0014] (3) Under an inert gas atmosphere, the compound of formula 4 and trichlorosilane were used as raw materials, toluene was used as the reaction solvent, and triethylamine was used as the organic base. The reaction was stirred at 120°C and the reaction was monitored by TLC until complete. The compound of formula 5 was obtained by extraction with ethyl acetate, concentration and purification.

[0015] The structural formula of the compound of formula 1 is as follows: The structural formula of the compound of formula 2 is as follows: The structural formula of the compound of formula 3 is as follows: The structural formula of the compound of formula 4 is as follows: The structural formula of compound 5 is as follows: In the formula, R 1 Selected from hydrogen, C1-C3 alkyl groups, and halogens; R 2 Selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, and halogen; R 3 Selected from one of hydrogen, aryl, and alkyl; R 4 Selected from one of aryl and heteroaryl groups; R 5Ar is selected from one of hydrogen or sulfonyl groups; Ar is selected from one of aryl groups.

[0016] The chiral phosphoric acid is selected from one or two of the following: binaphthalene skeleton derivatives, octahydrobinaphthalene skeleton derivatives, and spirocyclic skeleton derivatives; the structural formula of the binaphthalene skeleton derivative is as follows: In the formula, G is selected from one of 9-anthrayl, 9-phenanthyl, 2,4,6-triisopropylphenyl, triphenylsilyl, 4-chlorophenyl, 2-naphthyl, or 1-naphthyl; the structural formula of the octahydrobinaphthyl skeleton derivative is as follows: In the formula, G' is selected from one of 9-anthrayl, 9-phenanthyl, 2,4,6-triisopropylphenyl, triphenylsilyl, 4-chlorophenyl, 2-naphthyl, or 1-naphthyl; the structural formula of the spirocyclic skeleton derivative is as follows: In the formula, G” is selected from one of 9-anthrayl, 9-phenanthyl, 2,4,6-triisopropylphenyl, triphenylsilyl, 4-chlorophenyl, 2-naphthyl or 1-naphthyl.

[0017] The reaction pathway is as follows:

[0018]

[0019] Preferably, the structural formula of the chiral phosphoric acid described in step (1) is as follows: In the formula, G is selected from 1-naphthyl.

[0020] Preferably, the molar ratio of 4-dimethylaminopyridine, N-phenylbis(trifluoromethanesulfonylimide) and triethylamine in step (1) is 4:5:6.

[0021] Preferably, step (1) purification is performed using silica gel column chromatography, with the eluent being a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 2:1; step (2) purification is performed using silica gel column chromatography, with the eluent being a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 2:1; and step (3) purification is performed using silica gel column chromatography, with the eluent being a mixed solution of toluene and ethyl acetate in a volume ratio of 10:1.

[0022] Thirdly, the present invention also provides the application of axially chiral cyclopentenyl-indole-naphthyl compounds in catalyzing asymmetric allyl coupling reactions.

[0023] Under inert gas protection, using compounds of formula 6 and formula 7 as raw materials, mesitylene as solvent, allyl palladium chloride as catalyst, organophosphine derived from the axially chiral cyclopentenyl-indole-naphthyl compound shown in formula 5 as ligand, and cesium carbonate as inorganic base, the reaction was stirred at 0°C and monitored by TLC until complete. Compound of formula 8 was obtained by extraction, concentration and purification with ethyl acetate.

[0024] The reaction pathway is as follows:

[0025]

[0026] Fourthly, the present invention also provides the application of axially chiral cyclopentenyl-indole-naphthyl compounds in catalytic asymmetric (4+1) cycloaddition reactions.

[0027] Using compounds of formula 9 and formula 10 as raw materials, chloroform as solvent, and organophosphorus derived from the axially chiral cyclopentenyl-indole-naphthyl compound shown in formula 5 as catalyst, the reaction was stirred at 20°C, and the reaction was monitored by TLC until complete. Compound of formula 11 was obtained by extraction, concentration and purification with ethyl acetate.

[0028] The reaction pathway is as follows:

[0029]

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. An axially chiral cyclopentenyl-indole-naphthyl compound of the present invention, through bioactivity testing, shows that this type of compound has certain cytotoxic activity against PC-3 cancer cells, indicating that the axially chiral cyclopentenyl-indole-naphthyl compound synthesized in this invention has application value in the development of novel antitumor drugs.

[0032] 2. The axially chiral cyclopentenyl-indole-naphthyl catalyst provided by this invention can be applied not only to catalyzing asymmetric allyl coupling reactions, but also to catalyzing asymmetric (4+1) cycloaddition reactions, demonstrating that the axially chiral cyclopentenyl-indole-naphthyl catalyst synthesized in this invention has application value in multiple types of catalytic asymmetric reactions.

[0033] 3. The present invention provides a method for synthesizing an axially chiral cyclopentenyl-indole-naphthyl compound, which uses chiral phosphoric acid as a catalyst to obtain high enantioselectivity. In this synthesis method, the product has high enantioselectivity, high yield, and mild reaction process, making it suitable for industrial production. Various types of substrates can be used as reactants to obtain products with diverse and complex structures. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to specific embodiments.

[0035] In the following embodiments, unless otherwise stated, the experimental methods are generally performed under normal conditions or conditions recommended by the manufacturer.

[0036] The compound of Formula 1 described in the following examples can be prepared using the method reported in Angew. Chem. Int. Ed. 2012, 51, 1899; the compound of Formula 2 can be prepared using the method reported in Angew. Chem. Int. Ed. 2022, 61, e202205037; the chiral phosphoric acid catalyst and other reagents can be obtained commercially available.

[0037] The synthetic routes for axially chiral cyclopentenyl-indole-naphthyl compounds 3 or 5 are as follows:

[0038] In the above reaction, the structural formula of the catalyst, chiral phosphoric acid, is as follows:

[0039]

[0040] Example 1

[0041] 0.1 mmol of 3-indole methanol derivative 1a and 0.12 mmol of 2-alkynylnaphthol derivative 2a were added to 1 mL of toluene as reactants, with 0.01 mmol of chiral phosphoric acid as a catalyst, and the reaction was carried out at 25 °C for 4 hours. The mixture was then separated by silica gel column chromatography (eluent was a 2:1 volume mixture of petroleum ether and ethyl acetate) to obtain the axially chiral cyclopentenyl-indole-naphthyl compound 3aa'.

[0042]

[0043] The structural characterization data of product 3aa' in Example 1 are as follows:

[0044] Yield: 87%; Solid; Melting point: 245-247℃; 1 H NMR (400MHz, acetone-d6) δ (ppm): 10.65 (s, 1H), 8.32-8.06 (m, 2H), 7.90-7.79 (m, 2H), 7.37-7.17 (m, 11H), 7.02-6. 93(m,3H),6.93-6.83(m,3H),6.81-6.73(m,3H),6.70-6.60(m,1H),5.21(d,J=16.0Hz,1H),4.90(d,J=15.6Hz,1H); 13C NMR(100MHz,acetone-d6)δ(ppm):173.6,152.0,146.5,144.6,140.7,139.1,136.3,135.8 ,135.7,132.9,129.5,128.9,128.8,128.6,127.9,127.8,127.7,127.6,127.4,127.4,126 .4,126.3,125.3,124.3,123.1,122.8,122.1,121.1,119.5,118.5,118.1,116.1,112.2,1 09.7,62.8,44.0; IR(KBr):3056,2924,2853,1698,1466,1345,1174,1029,828,745,697cm -1 ;ESI FTMS exact mass calcd for(C 41 H 28 N2O2+Na) + Requires m / z 603.2043, found m / z 603.2046; Enantiomeric excess: 99%, determined by HPLC (Daicel Chiralpak OD-H, n-hexane / isopropanol = 85 / 15, flow rate 0.5 mL / min, T = 30℃, 254 nm): t R =21.842(minor),t R =24.782 (major).

[0045] Example 2

[0046] 0.1 mmol of 3-indole methanol derivative 1a and 0.12 mmol of 2-alkynylnaphthol derivative 2a were added to 1 mL of toluene as reactants, with 0.01 mmol of chiral phosphoric acid as a catalyst, and the reaction was carried out at 25 °C for 4 h. Then, a toluene solution containing 0.2 mmol of 4-dimethylaminopyridine (DMAP), 0.25 mmol of N-phenylbis(trifluoromethanesulfonylimide), and 0.3 mmol of triethylamine was added to the reaction system, and the reaction was continued for 1.5 h. Finally, the mixture was separated by silica gel column chromatography (eluting with a 2:1 volume ratio of petroleum ether and ethyl acetate) to obtain the axially chiral cyclopentenyl-indole-naphthyl compound 3aa.

[0047]

[0048] The structural characterization data of product 3aa in Example 2 are as follows:

[0049] Yield: 90%; Solid;1 1H NMR (400 MHz, CDCl3) δ (ppm): 8.48 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 7.99 - 7.93 (m, 2H), 7.64 - 7.58 (m, 1H), 7.54 - 7.48 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.25 - 7.21 (m, 1H), 7.18 - 7.02 (m, 6H), 6.92 - 6.82 (m, 3H), 6.74 - 6.67 (m, 5H), 6.63 - 6.58 (m, 1H), 5.21 (d, J = 16.0 Hz, 1H), 4.47 (d, J = 16.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ (ppm): 173.6, 144.3, 144.1, 141.9, 140.4, 135.0, 134.2, 133.4, 133.0, 132.4, 130.5, 129.4, 128.8, 128.7, 128.3, 128.1, 128.1, 127.6, 127.5, 127.4, 127.4, 127.2, 126.8, 125.8, 125.4, 123.6, 122.0, 121.9, 120.5, 119.2, 119.1, 118.6 (q, J = 318.6 Hz), 112.1, 109.6, 63.7, 44.3; 19 19F NMR (376 MHz, CDCl3) δ (ppm): -73.77; IR (KBr): 3058, 2853, 1702, 1467, 1369, 1247, 1214, 1141, 837, 767, 697 cm -1 ; ESI FTMS exact mass calcd for (C 42 H 27 F3N2O4S + Na) + requires m / z 735.1536, found m / z 735.1530; The enantiomeric excess (ee) value: 99%, determined by HPLC (Daicel Chiralpak IG, n - hexane / isopropanol = 85 / 15, flow rate 1.0 mL / min, T = 30 °C, 254 nm): t R = 9.693 (minor), t R = 15.113 (major).

[0050] Example 3 - 18

[0051] The reaction synthesis route is shown below:

[0052]

[0053] The specific operating steps are shown in Example 2, and the reaction raw materials and yields are shown in Table 1:

[0054] Table 1 * Reactants and yields in Examples 3-18

[0055]

[0056]

[0057] Examples 19-25

[0058] The reaction synthesis route is shown below:

[0059]

[0060] The specific operating steps are shown in Example 2, and the reaction raw materials and yields are shown in Table 2:

[0061] Table 2 * Reactants and yields of Examples 19-25

[0062]

[0063] Examples 26-37

[0064] Table 3 * Reaction products and yields of Examples 26-37

[0065]

[0066]

[0067]

[0068] Example 38

[0069]

[0070] Under an inert gas atmosphere, 0.1 mmol of compound 3aa and 0.4 mmol of diphenylphosphine oxide (Ph₂P(O)H) were used as reactants, dimethyl sulfoxide (DMSO) was used as the reaction solvent, 0.03 mmol of palladium acetate (Pd(OAc)₂) and 0.03 mmol of 1,4-bis(diphenylphosphine)butane (dbbp) were used as catalyst and ligand, respectively, and 0.5 mmol of N,N-diisopropylethylamine (DIPEA) was used as the organic base. The reaction was stirred at 120 °C, and the reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (eluent was a 2:1 volume ratio of petroleum ether and ethyl acetate) to obtain compound 4a.

[0071] The structural characterization data of product 4a are as follows:

[0072] Yield: 90%; Solid; >95% dr; 1 H NMR (400MHz, CDCl3) δ (ppm): 8.72 (d, J = 8.0Hz, 1H), 8.15 (s, 1H), 7.99 (d, J = 7.2Hz, 1H), 7.92 (d, J =8.0Hz,1H),7.81(d,J=8.8Hz,1H),7.65-7.56(m,2H),7.43-7.34(m,3H),7.34-7.26(m,3H),7.25 -7.18(m,3H),7.18-7.14(m,2H),7.14-7.00(m,6H),7.00-6.93(m,1H),6.86-6.73(m,4H),6.69-6 .66(m,1H),6.56-6.46(m,3H),6.40-6.29(m,2H),5.18(d,J=15.6Hz,1H),4.48(d,J=16.0Hz,1H); 13C NMR (100MHz, CDCl3) δ (ppm): 174.2, 143.9, 143.7, 141.9, 141.8, 140.5, 138.6, 135.4, 134.8, 134.4 ,134.2,133.1(d,J=11.2Hz),132.6,131.8(d,J=9.4Hz),131.7,131.6,131.3,131.2,131.1,129.9, 128.9,128.8,128.7,128.6,128.3,128.2,128.1,128.0,127.9,127.7,127.6,127.3,127.2,127.1 ,126.7,126.5,126.0,123.6,123.0,122.3,121.4,119.3(d,J=151.7Hz),112.1,109.2,63.2,44.2; 31 P NMR (162MHz, CDCl3) δ (ppm): 30.07; IR (KBr): 3648,3054,2924,1710,1610,1467,1179,1116,749,695,541cm -1 ;ESI FTMS exact mass calcdfor(C 53 H 37 N2O2P+Na) + Requires m / z 787.2485, found m / z 787.2466; Enantiomeric excess (ee): 99%, determined by HPLC (Daicel Chiralpak IA, n-hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30℃, 254 nm): t R =7.566 (major),t R =11.509 (minor).

[0073] Example 39

[0074]

[0075] Under an inert gas atmosphere, 0.1 mmol of compound 4a and 6.0 mmol of trichlorosilane (HSiCl3) were used as reactants, 1.0 mL of toluene was used as the reaction solvent, and 2.5 mmol of triethylamine was used as the organic base. The reaction was stirred at 120 °C and monitored by TLC until complete. The mixture was extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (eluent was a 10:1 volume ratio of petroleum ether and ethyl acetate) to obtain compound 5a.

[0076] The structural characterization data of product 5a are as follows:

[0077] Yield: 79%; Solid; >95% dr; 1 H NMR (400MHz, acetone-d6) δ (ppm): 10.73 (s, 1H), 8.54 (d, J = 8.4Hz, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.97 (d, J = 8.4Hz,1H),7.66-7.61(m,1H),7.57-7.52(m,1H),7.47(d,J=7.6Hz,1H),7.36(d,J=8.4Hz,1H),7.32-7.27 (m,2H),7.26-7.19(m,7H),7.18-7.06(m,7H),7.04-6.94(m,4H),6.93-6.87(m,1H),6.80-6.75(m,1H),6. 73-6.64(m,2H),6.63-6.54(m,2H),6.50(d,J=8.0Hz,1H),5.24(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H); 13 CNMR(100MHz,acetone-d6)δ(ppm):173.3,145.9,144.6,142.7,142.4,140.8,139.5,139.4,138.9, 138.7,138.6,137.1,137.0,136.1,135.2,133.8,133.3(d,J=19.7Hz),132.9,132.7,132.0,130.7,1 30.6,129.2,128.8,128.5,128.3,128.2,128.1,128.0,127.9,127.8,127.5,127.3,127.2,127.1,12 7.0,126.3,124.8(d,J=6.3Hz),123.2,122.8,121.8,121.1,119.5,118.0,112.4,109.7,63.0,43.7; 31 P NMR (162MHz, acetone-d6) δ (ppm): -14.05; IR (KBr): 3404,3270,3052,2956,2925,1698,1609,1466,1175,1027,743,695,618cm -1 ;ESI FTMS exact mass calcd for(C 53 H 37 N2OP+Na)+ Requires m / z 771.2536, found m / z 771.2517; Enantiomeric excess (ee): 99%, determined by HPLC (Daicel Chiralpak IA, n-hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30℃, 254 nm): t R =8.490 (major),t R =11.283 (minor).

[0078] Example 40

[0079]

[0080] Under inert gas protection, 0.1 mmol of allyl acetate of formula 6 and 0.3 mmol of p-methoxybenzyl alcohol of formula 7 were used as raw materials, 1 mL of mesitylene was used as solvent, 0.005 mol of allyl palladium chloride ([PdCl(π-allyl)]2) and 0.01 mol of formula 5a were used as catalyst and ligand, respectively, and 0.3 mmol of cesium carbonate (Cs2CO3) was used as inorganic base. The reaction was stirred at 0 °C, and the reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (eluent was a 10:1 volume ratio of petroleum ether and ethyl acetate) to obtain compound of formula 8.

[0081] The structural characterization data of product 8 are as follows:

[0082] Yield: 86%; oily; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.52-7.41 (m, 2H), 7.40-7.34 (m, 4H), 7.33-7.27 (m, 5H), 7.26-7.21 (m, 1H), 6.90 (d,J=7.6Hz,2H),6.62(d,J=15.6Hz,1H),6.40-6.28(m,1H),5.01(d,J=7.2Hz,1H),4.52(s,2H),3.82(s,3H); 13 C NMR (100MHz, CDCl3) δ (ppm): 159.2, 141.3, 136.7, 131.5, 130.5, 130.4, 129.4, 128.6, 127.7, 127.7, 127.1 ,126.6,113.8,81.3,69.8,55.3; IR(KBr):3026,2931,2335,1611,1513,1275,1034,1821,750,698.551cm -1Enantiomeric excess (ee): 86%, determined by HPLC (Daicel Chiralpak OJ-H, n-hexane / isopropanol = 85 / 15, flow rate 0.6 mL / min, T = 30℃, 254 nm): t R =22.246 (major),t R =25.579 (minor).

[0083] Example 41

[0084]

[0085] Under inert gas protection, using 0.1 mmol of Formula 9 and 0.2 mmol of Formula 10 as raw materials, 1 mL of chloroform as solvent, and 0.02 mmol of Formula 5a as a chiral catalyst, the reaction was stirred at 20 °C. The reaction was monitored by TLC until complete, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 10:1) to obtain compound of Formula 11.

[0086] The structural characterization data of product 11 are as follows:

[0087] Yield: 75%; oily; >95:5dr; 1 H NMR(400MHz, CDCl3)δ(ppm):7.39-7.27(m,9H),7.25-7.14(m,1H),6.57(s,1H),6.47(s,1H),6.43-6.34(m ,2H),6.33-6.23(m,1H),5.93(s,1H),5.91(s,2H),5.34(d,J=6.0Hz,1H),5.22(s,2H),4.03-3.93(m,1H); 13 C NMR (100MHz, CDCl3) δ (ppm): 165.2, 153.7, 148.0, 142.0, 139.1, 136.7, 135.5, 131.4, 129.9, 128.6, 128.6, 128.4, 128.3, 127.6, 1 26.5,126.2,119.2,105.4,101.3,93.1,87.0,66.8,53.0; IR(KBr):3028,2919,2850,1721,1498,1473,1284,1144,963,771.695cm -1Enantiomeric excess (ee): 45%, determined by HPLC (Daicel Chiralpak OD-H, n-hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30℃, 254 nm): t R =6.326 (minor),t R =7.463 (major).

[0088] The method of this invention not only enables the one-step synthesis of axially chiral cyclopentenyl-indole-naphthyl compounds with high atom economy and environmental friendliness, but also yields the desired axially chiral cyclopentenyl-indole-naphthyl compounds with excellent yield, high enantioselectivity, and diversity. Furthermore, the reactants are readily available, the operation is simple and safe, the conditions are mild, and the post-processing is straightforward, thus possessing significant practical value and potential socio-economic benefits. The axially chiral cyclopentenyl-indole-naphthyl catalysts prepared by this invention have been demonstrated through examples to be effective in catalyzing asymmetric allyl coupling reactions and asymmetric (4+1) cycloaddition reactions.

[0089] Furthermore, the cytotoxic activity of the axially chiral cyclopentenyl-indole-naphthyl compounds synthesized in Examples 2-3, 5, 13, 16-19, 25, and 29 against PC-3 cancer cells was tested using the conventional MTT assay. The results are shown in Table 4. The results indicate that the compounds synthesized in this invention have significant cytotoxic activity against PC-3 cancer cells.

[0090] Table 4. Cytotoxic activity of the compounds in this invention against PC-3 cancer cells.

[0091]

[0092]

[0093] The present invention conducted bioactivity tests on the prepared axially chiral cyclopentenyl-indole-naphthyl compound, and the results showed that it had significant cytotoxic activity against PC-3 cancer cells, indicating that this type of compound is a potential drug lead compound in the development of novel antitumor drugs and has significant application research value.

Claims

1. An axially chiral cyclopentenyl-indole-naphthyl compound, characterized in that, Its chemical structure is shown in formula 5a: 。 2. A method for preparing the axially chiral cyclopentenyl-indole-naphthyl compound according to claim 1, characterized in that, The specific steps are as follows: (1) Using compounds of formula 1a and formula 2a as reactants, toluene as solvent, and chiral phosphoric acid as catalyst, the reaction was stirred at 0-40℃ for several hours; then, a toluene solution containing 4-dimethylaminopyridine, N-phenylbis(trifluoromethanesulfonylimide) and triethylamine was added to the reaction system, and the reaction was continued for 1.5 hours; finally, the mixture was filtered, concentrated, and purified to obtain compound 3aa; wherein the molar ratio of compound 1a to compound 2a was 1:1.

2. (2) Under an inert gas atmosphere, using compound of formula 3aa and secondary phosphine oxide as raw materials, dimethyl sulfoxide as reaction solvent, diisopropylethylamine as organic base, palladium acetate and 1,4-bis(diphenylphosphine)butane as catalyst and ligand respectively, the reaction was stirred at 120°C, and the reaction was monitored by TLC until complete. The reaction was extracted with ethyl acetate, concentrated and purified to obtain compound of formula 4a. (3) Under an inert gas atmosphere, using compound of formula 4a and trichlorosilane as raw materials, toluene as reaction solvent, and triethylamine as organic base, the reaction was stirred at 120°C, and the reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, concentrated, and purified to obtain compound of formula 5a. The structural formula of the compound of formula 1a is as follows: The structural formula of the compound of formula 2a is as follows: The structural formula of the compound of formula 3aa is: The structural formula of the compound of formula 4a is as follows: The structural formula of the compound of formula 5a is as follows: The structural formula of the chiral phosphoric acid is as follows: In the formula, G' is selected from 1-naphthyl.

3. The method for preparing the axially chiral cyclopentenyl-indole-naphthyl compound according to claim 2, characterized in that, The molar ratio of 4-dimethylaminopyridine, N-phenylbis(trifluoromethanesulfonylimide) and triethylamine in step (1) is 4:5:

6.

4. The method for preparing the axially chiral cyclopentenyl-indole-naphthyl compound according to claim 2, characterized in that, Step (1) Purification was performed using silica gel column chromatography, with the eluent being a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 2:1; Step (2) Purification was performed using silica gel column chromatography, with the eluent being a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 2:1; Step (3) Purification was performed using silica gel column chromatography, with the eluent being a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 10:

1.

5. The application of the axially chiral cyclopentenyl-indole-naphthyl compound according to claim 1 in catalyzing asymmetric allyl coupling reactions, characterized in that... The specific steps are as follows: Under the protection of an inert gas, using compounds of formula 6 and formula 7 as raw materials, mesitylene as solvent, allyl palladium chloride as catalyst, organophosphine derived from the axially chiral cyclopentenyl-indole-naphthyl compound shown in formula 5a as ligand, cesium carbonate as inorganic base, the reaction is stirred at 0 °C, the reaction is monitored by TLC until complete, and the compound of formula 8 is obtained by extraction, concentration and purification with ethyl acetate. The structural formula of the compound of formula 6 is as follows: ; The structural formula of the compound of formula 7 is as follows: ; The structural formula of the compound of formula 8 is as follows: .

6. The application of the axially chiral cyclopentenyl-indole-naphthyl compound according to claim 1 in catalyzing asymmetric (4+1) cycloaddition reactions, characterized in that, The specific steps are as follows: using compounds of formula 9 and formula 10 as raw materials, chloroform as solvent, and organophosphorus derived from the axially chiral cyclopentenyl-indole-naphthyl compound shown in formula 5a as catalyst, the reaction is stirred at 20 °C, the reaction is monitored by TLC until complete, and the compound of formula 11 is obtained by extraction, concentration and purification with ethyl acetate. The structural formula of the compound of formula 9 is as follows: ; The structural formula of the compound of formula 10 is as follows: ; The structural formula of the compound of formula 11 is as follows: .

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