A tetrahydrophenanthrene-2(1h)-one compound, a preparation method and application thereof

Abstract

The application discloses a tetrahydrophenanthrene-2(1 H )-ketone compound, a preparation method and application. The application uses cyclohexanediamine arylamide derivatives with excellent asymmetric catalytic performance to construct a tetrahydrophenanthrene-2(1 H )-ketone compound containing four continuous quaternary carbon chiral centers in one pot. Through activity evaluation, it is found that the compound has good inhibition activity on human lung adenocarcinoma cells A549, and as a lead compound, provides a new idea for development of a new type of anticancer drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of fine organic chemistry and biomedicine, and particularly relates to a tetrahydrophenanthrene-2(1H)-one compound constructed by Michael addition reaction, a preparation method and an application thereof. Background Art

[0002] Phenanthrene and its derivatives hold a significant position in organic chemistry due to their unique structures and properties, and their synthesis remains a hot topic of research. Studies on the synthesis of tetrahydrophenanthrene-2(1H)-one compounds, important phenanthrene derivatives, contribute to a deeper understanding of organic chemical reaction mechanisms, enrich the theory of organic synthetic chemistry, and provide a theoretical foundation for the development of new synthetic methods and strategies. Tetrahydrophenanthrene-2(1H)-one compounds are key scaffolds found in biologically active natural products (J. Nat. Prod. 2011, 74, 181–184) and in the synthesis of bioactive compounds and their precursors. In medicinal chemistry, functional groups such as the ketocarbonyl group in their structures can undergo a variety of chemical reactions, introducing various substituents to improve the hydrophilicity, lipophilicity, and metabolic stability of drug molecules, thus opening up new possibilities for the development of new drugs. For example, abietane-type diterpenoids bearing a cyanoenone functional group are novel and highly effective inhibitors of nitric oxide (NO) production in mouse macrophages. They have also been shown to be orally active in preliminary in vivo inflammatory models (J. Org. Chem. 2006, 71, 8, 3314–3316). Octahydrophenanthrene-2,7-diol derivatives act as pathway-selective or "dissociative" agonists of the glucocorticoid receptor (GR) (J. Med. Chem. 2009, 52, 6, 1731–1743). Chirality is an essential property of nature. Over the past three decades, the enormous demand for single-enantiomer chiral compounds in the pharmaceutical and fine chemical industries has driven the rapid development of asymmetric synthetic methodologies. Although tetrahydrophenanthrene-2(1H)-one is an important building block, the direct asymmetric synthesis of this hydrophenanthrene skeleton remains imperfect. Therefore, the construction of this scaffold in a stereocontrolled manner is highly desirable. In terms of the asymmetric synthesis of hydrophenanthrenones, the You group explored several examples of the asymmetric synthesis of tetrahydrophenanthren-2(1H)-one with two stereocenters via intramolecular Michael addition desymmetrization of 2,5-cyclohexadienone (Org. Lett. 2011,13 Chauhan's group synthesized hydrophenanthrenones with multiple stereocenters via aromatic amide-catalyzed domino 1,4- / 1,4-addition desymmetrization (Org. Lett. 2023, 25, 43, 7911–7916).

[0003] The one-pot construction of tetrahydrophenanthrene-2(1H)-one compounds containing multiple stereocenters through Michael addition desymmetrization of 2,5-cyclohexenone is of great significance for the discovery of lead compounds and drug development. Summary of the Invention

[0004] In response to the problems existing in the prior art, the present invention aims to provide a tetrahydrophenanthrene-2(1H)-one compound, a preparation method, and applications thereof. Through a rational reaction design, 1,3-cyclohexanedione compounds are reacted with chloronitroolefins in the presence of cyclohexanediamine aromatic amide catalysts, resulting in the successful one-pot asymmetric construction of tetrahydrophenanthrene-2(1H)-one compounds containing four consecutive quaternary carbon chiral centers. The compound exhibits a strong inhibitory effect on human lung adenocarcinoma cell A549 and can be used as a lead compound, providing a new option for the development of novel drugs.

[0005] The first aspect of the present invention provides a tetrahydrophenanthrene-2(1H)-one compound represented by formula (I):

[0006]

[0007] In formula (I), the R 1 is methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, or ethynyl; and X, Y, Ar, and Het are each independently any one of the following structures:

[0008]

[0009] X=O, CH2

[0010] Y═O, CH2, RCH, R2C, PhCH, or BnCH.

[0011] Preferably, the tetrahydrophenanthrene-2(1H)-one compound represented by formula (I) is one of the following:

[0012]

[0013] The second aspect of the present invention provides a method for preparing a tetrahydrophenanthrene-2(1H)-one compound represented by formula (I), comprising: dissolving a base, a catalyst, and a compound represented by formula (II) in a solvent under air atmosphere, stirring for 3 minutes, then adding a compound represented by formula (III), stirring at room temperature for 10 hours, monitoring the completion of the reaction by TLC, and evaporating the reaction solution under reduced pressure until no liquid flows out to obtain a yellow oily liquid; the yellow oily liquid is subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 8:1 to 3:1 as eluent, collecting the effluent with an Rf value of 0.2-0.4, and evaporating under reduced pressure to dryness to obtain the tetrahydrophenanthrene-2(1H)-one compound represented by formula (I);

[0014] The catalyst is cyclohexanediamine thiourea or cyclohexanediamine aromatic amide;

[0015] The base is selected from any one of N-ethyldiisopropylamine, triethylenediamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate trihydrate, potassium bicarbonate, and sodium bicarbonate, preferably potassium bicarbonate; the solvent is an organic solvent, and the organic solvent is any one of dichloromethane, 1,2-dichloroethane, ethyl acetate, chloroform, diethyl ether, methyl tert-butyl ether, acetonitrile, n-hexane, toluene, mesitylene, trifluorotoluene, chlorobenzene, and nitrobenzene, preferably nitrobenzene;

[0016] The reaction formula is as follows:

[0017]

[0018] In formula (I), R 1 , Ar and Het are the same as R in formula (III) 1 , Ar, Het; X and Y in formula (Ⅰ) are the same as X and Y in formula (Ⅱ).

[0019] Preferably, the catalyst is selected from cyclohexanediamine thiourea C1 or differently substituted cyclohexanediamine aromatic amides C2, C3, and C4, wherein the structural formulas of C1, C2, C3, and C4 are as follows:

[0020]

[0021] Preferably, the ratio of the amount of the compound represented by formula (III) to the amount of the compound represented by formula (II) is 1:1-5, preferably 1:1.5; the ratio of the amount of the compound represented by formula (III) to the amount of the catalyst is 1:0.01-0.1, preferably 1:0.1; the ratio of the amount of the compound represented by formula (III) to the amount of the base is 1:1-5, preferably 1:1; the volume of the solvent used is 10-60 mL / mmol, preferably 20 mL / mmol, based on the amount of the compound represented by formula (III).

[0022] The third aspect of the present invention provides a use of a tetrahydrophenanthrene-2(1H)-one compound in the preparation of a drug for treating anti-tumor, wherein the tumor is caused by human lung adenocarcinoma cell A549.

[0023] Through rational reaction design, the present invention reacts 1,3-cyclohexanedione compounds with chloronitroolefins in the presence of a cyclohexanediamine aromatic amide derivative catalyst, successfully achieving the asymmetric construction of tetrahydrophenanthren-2(1H)-one compounds containing four consecutive quaternary carbon chiral centers in a one-pot process. This development of a concise and efficient synthetic strategy provides a more direct and convenient approach for the asymmetric construction of tetrahydrophenanthren-2(1H)-one compounds containing multiple stereocenters. Activity evaluation revealed that the compounds of the present invention exhibited a strong inhibitory effect against human lung adenocarcinoma cell line A549, suggesting their potential as lead compounds, providing new insights into the development of anticancer drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Compound Ⅰ-1 1 H NMR spectrum;

[0025] Figure 2 Compound Ⅰ-1 13 C NMR spectrum;

[0026] Figure 3 Compound I-20 1 H NMR spectrum;

[0027] Figure 4 Compound I-20 13 C NMR spectrum. DETAILED DESCRIPTION

[0028] The present invention is further described below in conjunction with specific embodiments to facilitate a better understanding of the present technical solution.

[0029] Example 1

[0030] Preparation of (4bS,8aS,8bR,13bS)-4b-methoxy-8b-nitro-8a,8b,10,11,12,13b-hexahydrophenanthro[9,10-b]benzofuran-7,13(4bH,8H)-dione Ⅰ-1:

[0031]

[0032] At room temperature, 1,3-cyclohexanedione II (0.3 mmol, 1.5 eq.), nitrobenzene (4 mL) and cyclohexanediamine aromatic amide catalyst C2 (0.02 mmol, 0.1 eq.) were added to the reaction tube. Potassium bicarbonate (0.4 mmol, 2.0 eq.) was stirred at room temperature for 3 minutes, and then chloronitroolefin II (0.075 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature and the reaction was completed by TLC. The reaction solution was directly subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 8:1 to 3:1 as eluents. The effluent with an Rf value of 0.2-0.4 was collected and evaporated to dryness under reduced pressure to obtain a white solid product I-1 (72% yield; 98% ee; >20:1 dr). The H NMR spectrum showed Figure 1 As shown, 13 C NMR spectrum Figure 2 shown.

[0033] Product Ⅰ-1 was detected by high performance liquid chromatography and nuclear magnetic resonance spectroscopy (4bS,8aS,8bR,13bS)-4b-methoxy-8b-nitro-8a,8b,10,11,12,13b-hexahydrophenanthrene

[0034] [9,10-b]Benzofuran-7,13(4bH,8H)-dione, calculate the diastereomeric excess.

[0035] High performance liquid chromatography was performed using Shimadzu HPLC (AD-H, OD-H, IA, Amylose-2 chiral columns), mobile phase: V n-hexane / V isopropanol = 60:40-75:25, flow rate: 0.5-1.0 mL / min, detection wavelength: 254 nm.

[0036] Example 2-20

[0037] According to the similar method of Example 1, only R in the compound represented by formula I was replaced as shown in Table 1, and the effluent with Rf value of 0.2-0.4 was collected to obtain the corresponding compounds represented by formula I, wherein I1-20 1 H NMR spectrum Figure 3 As shown, 13 C NMR spectrum Figure 4 The H NMR spectrum results and high-resolution mass spectrometry data of the above compounds are listed in Table 1. As can be seen from the above, the structures of the above compounds are correct and are all compounds shown in Formula I.

[0038] Table 1 H NMR spectrum data and high-resolution mass spectrum data of the compound represented by formula I

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] Application example: Application of tetrahydrophenanthren-2(1H)-one compounds in the evaluation of anticancer activity

[0048] 1. Preparation before the experiment

[0049] Experimental equipment: 100mm culture dish, 96-well plate, EP tube, pipette tip, etc.

[0050] Culture medium: DMEM medium containing 10% fetal bovine serum and 1% double antibody.

[0051] Drug stock solution: Use DMSO and culture medium to prepare drug stock solutions with concentrations of 1, 10, 25, 50, 75, and 100 μM (first dissolve in DMSO, then dilute with fresh culture medium). The culture medium with the same volume of DMSO added is the blank control group, and the DMSO solution of DOX is the positive control group.

[0052] 2. Determination of tumor growth inhibition ability

[0053] Human lung adenocarcinoma cell line A549 (2.5×10 3 ) were seeded in 96-well plates in triplicate. After 24 hours of incubation at 37°C, the suspension was replaced with fresh medium containing different doses of drug (1, 10, 25, 50, 75, and 100 μM). Negative control wells containing drug-free medium and solvent control wells were set up with the same volume of DMSO. The cells were incubated at 37°C for 48 hours. Then, 100 μL of 0.5 mg / mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (first dissolved in PBS and then diluted in fresh medium) was added to each well and incubated for another 4 hours. The medium was then removed, and the MTT formazan precipitate was dissolved in 100 μL of DMSO, mechanically shaken for 10 minutes, and immediately read at 570 nm using a microplate reader (FlexStation 3, Molecular Devices).

[0054] Cell inhibition rate = [OD 570(Negative control well) – OD 570 (dose hole)] / OD 570 (Negative control wells) x 100%.

[0055] The growth inhibition rates of the compounds of Formula I on human lung adenocarcinoma cell A549 were measured by the above method and the results are shown in Table 2.

[0056] Table 2 Growth inhibition rate of the compound represented by formula I on human lung adenocarcinoma cell A549

[0057]

[0058]

[0059] The above results show that this series of compounds has good inhibitory activity against human lung adenocarcinoma cell A549, which further proves that the asymmetric synthesis method of this type of compound developed by us can be used as a lead compound, providing new ideas for the development of anticancer drugs.

Claims

1. A tetrahydrophenanthrene-2(1H)-one compound represented by formula (I): In formula (I), the R 1 is methyl, ethyl, n-propyl, isopropyl, or tert-butyl; X, Y, and R 2 -Ar / Het are each independently any one of the structures shown below: X=O, CH2; Y═O, CH 2 , or PhCH.

2. A tetrahydrophenanthrene-2(1H)-one compound, characterized in that The compound shown is one of the following:

3. The method for preparing the tetrahydrophenanthrene-2(1H)-one compound according to claim 1, wherein The method comprises the following steps: dissolving a base, a catalyst and a compound represented by formula (II) in a solvent under air atmosphere, stirring for 3 minutes, then adding a compound represented by formula (III), stirring at room temperature for 10 hours, monitoring the completion of the reaction by TLC, and subjecting the reaction solution to reduced pressure rotary evaporation until no liquid flows out, thereby obtaining a yellow oily liquid; subjecting the yellow oily liquid to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 8:1-3:1 as eluent, collecting an effluent with an Rf value of 0.2-0.4, and subjecting the effluent to reduced pressure rotary evaporation to dryness, thereby obtaining a tetrahydrophenanthrene-2(1H)-one compound represented by formula (I); The base is any one of N-ethyldiisopropylamine, triethylenediamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate trihydrate, potassium bicarbonate, and sodium bicarbonate; The solvent is an organic solvent, and the organic solvent is selected from any one of dichloromethane, 1,2-dichloroethane, ethyl acetate, chloroform, ether, methyl tert-butyl ether, acetonitrile, n-hexane, toluene, mesitylene, trifluorotoluene, chlorobenzene, and nitrobenzene; The catalyst is cyclohexanediamine aromatic amide C2, and the structural formula of C2 is:

4. The method for preparing tetrahydrophenanthrene-2(1H)-one compounds according to claim 3, wherein The ratio of the amount of the compound represented by formula (III) to the amount of the compound represented by formula (II) is 1:1-5; the ratio of the amount of the compound represented by formula (III) to the amount of the catalyst is 1:0.01-0.1; the ratio of the amount of the compound represented by formula (III) to the amount of the base is 1:1-5; the volume of the solvent used is 10-60 mL / mmol based on the amount of the compound represented by formula (III).

5. Use of the tetrahydrophenanthrene-2(1H)-one compound according to claim 1 in the preparation of an anti-tumor drug, wherein the tumor is caused by human lung adenocarcinoma cell A549.

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