A chiral benzooxanone compound and its synthesis method and application

Abstract

The present invention provides a chiral benzooxanone compound and a synthesis method and application thereof. The synthesis method of the chiral benzooxanone compound of the present invention comprises the following steps: in a solvent, under the catalysis of an iridium catalyst system, a γ-methylene-δ-valerolactone compound I and an o-methylenephenol II undergo a [4+4] cycloaddition reaction, and then an oxidation reaction is performed to obtain a chiral benzooxanone compound III; the iridium catalyst system is composed of an iridium catalyst and a chiral ligand, and the chiral ligand has a structure shown in formula IV; the present invention constructs a chiral benzooxanone compound through an iridium-catalyzed asymmetric cycloaddition reaction, which has the advantages of convenient operation, simplicity, high yield, cheap and easy-to-obtain reaction raw materials, low catalyst cost, wide application range of substrates, good diastereoselectivity, high enantioselectivity, etc.

Description

Technical Field

[0001] The invention relates to a chiral benzooxanone compound and a synthesis method and application thereof, belonging to the technical field of organic synthesis. Background Art

[0002] The benzo oxocinone structural skeleton is widely present in natural products that have been isolated and has wide applications in synthetic chemistry and medicinal chemistry. For example, Protosappanin A is a natural sesquiterpenoid compound that has good inhibitory activity against lung cancer and breast cancer cells (Fitoterapia, 2014, 92, 280-284); (+)-heliannuol K, extracted from the rhizome of sunflower, has allelopathic and allelopathic effects (Synthetic Commun., 2015, 45, 663-691); Integrastatin A has the activity of inhibiting HIV-1 integrase and has entered clinical research as a drug for the treatment of AIDS (Curr. Med. Chem., 2003, 10, 1795-1810; Tetrahedron, 2022, 109, 132671). Based on the biological and pharmaceutical activities of benzooxacinone compounds, the development of effective methods for convenient and efficient synthesis of benzooxacinone compounds, especially chiral benzooxacinone compounds, has increasingly attracted the research interest of organic chemists.

[0003] The key to synthesizing chiral oxanthone compounds is the construction of a chiral eight-membered cyclic ether skeleton. The synthesis methods of this type of skeleton that have been discovered include: transition metal catalysis, ring expansion, Claisen rearrangement, olefin transposition reaction, and catalytic tandem cycloaddition reaction, etc. Among them, the cycloaddition reaction mediated by dipole ions has become an extremely effective and widespread synthetic strategy to construct various chiral cyclic ether compounds since its discovery (Qian, DY; Zhang, JL Acc. Chem. Res. 2020, 53, 2358-2371). In 2021, the research group of Danqian Xu used in situ generated o-benzoquinone and acetylenone as substrates, and achieved an intermolecular asymmetric conjugate addition cascade reaction in two steps under the catalysis of organic bifunctional small molecules, synthesizing chiral eight-membered cyclic ether compounds with enone structures (Qi, S.-S.; Yin, H.; Wang, Y.-F.; Xu, D.-Q. Org. Lett. 2021, 23, 2471-2476). In 2022, the research group of Xiaoxun Li used γ-methylene-δ-valerolactone as a 1,4-synthon to react with o-benzoquinone with a special conjugated olefin structure, and completed an intermolecular asymmetric [4+4] cycloaddition reaction under the co-catalysis of palladium and phosphoramidite ligands to obtain a series of chiral eight-membered cyclic ether compounds (Org. Chem. Front., 2022, 9, 3493-3498).

[0004] According to existing reports, there are only the above two examples of synthetic strategies for constructing chiral eight-membered cyclic ethers through intermolecular asymmetric cycloaddition reactions, and there is currently no method for directly constructing chiral benzooxacinone compounds through intermolecular cycloaddition strategies. Therefore, continuing to develop asymmetric synthesis strategies to prepare chiral benzooxacinone compounds has important practical significance and application value.

[0005] Colon cancer is a common malignant tumor of the digestive tract that occurs in the colon. It often occurs at the junction of the rectum and the sigmoid colon. Its incidence ranks third among gastrointestinal tumors. The incidence of colon cancer in my country has been on the rise in recent years, and the incidence increases with age. At present, the treatment of colon cancer is still a difficult problem in medicine. Its treatment is mainly surgical resection combined with radiotherapy and chemotherapy. However, due to the characteristics of rapid recurrence and easy metastasis of colon cancer, and the series of complications associated with surgery, the search for effective targeted therapeutic drugs has become the focus of the treatment of colon cancer. Summary of the invention

[0006] In view of the deficiencies of the prior art, the present invention provides a chiral benzooxacinone compound and a synthesis method and application thereof. The present invention uses a commercial iridium catalyst with a simple structure and low price and a chiral ligand as a catalytic system to achieve efficient asymmetric synthesis of chiral benzooxacinone compounds, and the obtained chiral benzooxacinone compounds have good anti-colon cancer cell activity.

[0007] Terminology Note:

[0008] Room temperature: has the well-known meaning in the art, referring to 25±5°C.

[0009] The technical solution adopted by the present invention is as follows:

[0010] A method for synthesizing a chiral benzooxanone compound comprises the following steps:

[0011] In a solvent, under the catalysis of an iridium catalyst system, a γ-methylene-δ-valerolactone compound I and an o-methylenephenol II undergo a [4+4] cycloaddition reaction, followed by an oxidation reaction to obtain a chiral benzooxanone compound III; the iridium catalyst system comprises an iridium catalyst and a chiral ligand, and the chiral ligand has a structure shown in formula IV;

[0012]

[0013] Among them, in the structural formula of the compound of formula I, R 1 is phenyl or substituted phenyl, wherein the substituents of the substituted phenyl are independently selected from one or two of methoxy, methyl, halogen and nitro;

[0014] In the structural formula of the compound of formula II, R 2 It is a C1-C3 alkoxy group or a 3,4-dimethoxy group.

[0015] According to the preferred embodiment of the present invention, in the structure of the compound of formula I, the R 1 is phenyl, 4-bromophenyl, 4-phenylphenyl, 3-methylphenyl or 3-methoxyphenyl;

[0016] In the structural formula of the compound of formula II, R 2 It is 4-methoxy or 3,4-dimethoxy.

[0017] According to the present invention, in the compound of formula II, R 2 When it is 3,4-dimethoxy, the compound of formula II has the following structure:

[0018]

[0019] Preferably according to the present invention, the solvent is ethylbenzene, toluene, tetrahydrofuran, 1,4-dioxane, chlorobenzene or p-xylene; the ratio of the volume of the solvent to the molar number of γ-methylene-δ-valerolactone compound I is 5-20 mL:1 mmol; and the solvent is treated to be anhydrous and oxygen-free.

[0020] Preferably according to the present invention, the iridium catalyst is [Ir(cod)Cl]2, [IrCp*Cl2]2 or IrCl3; the molar ratio of iridium in the iridium catalyst to γ-methylene-δ-valerolactone compound I is 0.01 to 0.1:1; the molar ratio of iridium in the iridium catalyst to chiral ligand is 1:2 to 2.2.

[0021] Preferably according to the present invention, the molar ratio of the γ-methylene-δ-valerolactone compound I to the o-methylenephenol II is 1:1.

[0022] According to the preferred embodiment of the present invention, the reaction system in which the γ-methylene-δ-valerolactone compound I and o-methylenephenol II undergo a [4+4] cycloaddition reaction is further added Molecular sieve; The ratio of the mass of the molecular sieve to the molar number of the γ-methylene-δ-valerolactone compound I is 1-2 g:1 mmol, and its function is to further remove trace amounts of water in the reaction system.

[0023] Preferably according to the present invention, the cycloaddition reaction is carried out under a protective gas atmosphere, and the protective gas is nitrogen or argon.

[0024] Preferably according to the present invention, the temperature of the cycloaddition reaction is -20°C to room temperature.

[0025] Preferably according to the present invention, the cycloaddition reaction time is 2 to 40 hours, more preferably 10 to 24 hours.

[0026] Preferably, according to the present invention, the post-treatment steps of the reaction liquid obtained by the cycloaddition reaction are as follows: water is added to the obtained reaction liquid, followed by extraction with ethyl acetate, and the solvent is removed from the obtained organic phase to obtain a cycloaddition product; the ratio of the added volume of the water to the molar number of the γ-methylene-δ-valerolactone compound I is 20-30 mL:1.

[0027] Preferably, according to the present invention, the oxidation reaction comprises the steps of: dissolving the cycloaddition product in acetone, and then adding potassium osmate, N-methylmorpholine oxide and sodium periodate to carry out an oxidation reaction;

[0028] Further preferably, the ratio of the volume of acetone to the molar number of γ-methylene-δ-valerolactone compound I is 3-8 mL:1 mmol.

[0029] Further preferably, the molar ratio of the potassium osmate to the γ-methylene-δ-valerolactone compound I is 0.01 to 0.05:1; the molar ratio of the N-methylmorpholine oxide to the γ-methylene-δ-valerolactone compound I is 0.2 to 0.8:1; and the molar ratio of the sodium periodate to the γ-methylene-δ-valerolactone compound I is 0.2 to 0.8:1.

[0030] Preferably according to the present invention, the temperature of the oxidation reaction is room temperature; and the time of the oxidation reaction is 2 to 4 hours.

[0031] According to the present invention, the reaction liquid obtained after the oxidation reaction can be separated and characterized by conventional separation and purification methods. Preferably, the post-treatment steps of the reaction liquid obtained after the oxidation reaction of γ-methylene-δ-valerolactone compound I and o-methylenephenol II are as follows: add water to the obtained reaction liquid, then extract with ethyl acetate, remove the solvent from the obtained organic phase, and obtain a crude product; the ratio of the added volume of the water to the molar number of the γ-methylene-δ-valerolactone compound I is 20 to 30 mL: 1; the obtained crude product is separated by silica gel column chromatography to obtain chiral benzooxinone compound III, and the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate and petroleum ether in the mixed solvent is 0.03 to 0.1: 1.

[0032] The present invention also provides a chiral benzooxanone compound prepared by the above preparation method, which has a structure shown in Formula III;

[0033]

[0034] Among them, R 1 is phenyl or substituted phenyl, wherein the substituents of the substituted phenyl are independently selected from one or two of methoxy, methyl, halogen and nitro; R 2 It is a C1-C3 alkoxy group or a 3,4-dimethoxy group.

[0035] According to the present invention, the chiral benzooxinone compounds are used in the preparation of anti-colon cancer drugs.

[0036] According to the present invention, the γ-methylene-δ-valerolactone compound I is synthesized from 2-methylene-1,3-propanediol and the corresponding aryl carboxylic acid ester by a known method (see document: J.Am.Chem.Soc.2007,129,12356-12357), and the reaction route is as follows:

[0037]

[0038] In the above formula, the substituent R 1 As mentioned above.

[0039] According to the present invention, the o-quinone methide II is synthesized by the corresponding aromatic formaldehyde by a known method (see literature: Angew. Chem. Int. Ed. 2018, 57, 16185-16189), and the reaction route is shown in the following formula:

[0040]

[0041] In the above formula, the substituent R 2 As mentioned above.

[0042] The technical features and beneficial effects of the present invention are as follows:

[0043] The present invention provides a novel method for constructing chiral benzooxanone compounds by iridium-catalyzed asymmetric cycloaddition reaction. The method of the present invention has the following advantages: (1) using a simple-structured, low-cost iridium catalyst and a simple and easy-to-synthesize chiral ligand as the catalytic system, the method has the advantages of low catalyst cost, high efficiency, and small amount of catalyst; (2) good diastereoselectivity (dr>10:1) and high enantioselectivity (ee>95%); (3) the reaction raw materials are cheap and easy to obtain, the atom economy is good, and the substrate has a wide range of applicability; (4) the reaction conditions are mild, the operation is convenient and simple, and the yield is high; (5) the obtained product has good anti-tumor (colon cancer) cell activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is a graph showing the inhibitory performance of the compounds synthesized in Examples 1-6 in Application Example 1 on colon cancer cells (HCT-116).

[0045] Figure 2 The inhibition rate of different concentrations of compound IIIb on colon cancer cells (HCT-116) in Application Example 2 and the concentration-inhibition rate curve are shown.

[0046] Figure 3 The inhibition rate of different concentrations of compound IIIc on colon cancer cells (HCT-116) in Application Example 3 and the concentration-inhibition rate curve are shown.

[0047] Figure 4 The inhibition rate of different concentrations of compound IIIf in Application Example 4 on colon cancer cells (HCT-116) and the concentration-inhibition rate curve are shown. DETAILED DESCRIPTION

[0048] The present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited thereto.

[0049] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and raw materials can be obtained from commercial sources or prepared according to known methods unless otherwise specified.

[0050] The solvents used in the examples were treated to be anhydrous and oxygen-free, and the treatment method is the prior art.

[0051] The yields described in the examples are molar yields.

[0052] The chiral ligands used in the examples can be directly purchased.

[0053] Example 1

[0054] Synthesis of Methyl (9R,10S)-10-(4-methoxyphenyl)-7-oxo-9-phenyl-7,8,9,10-tetrahydro-6H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]oxoctane-9-carboxylate (Ⅲa)

[0055] The reaction route is as follows:

[0056]

[0057] The steps are as follows:

[0058] Under nitrogen protection, [Ir(cod)Cl]2 (0.005 mmol, 3.4 mg), chiral ligand (0.022 mmol, 15.2 mg) and 2 mL of tetrahydrofuran were added to a dry 5 mL reaction bottle and stirred at room temperature for 15 min. The resulting mixture was then transferred to a flask containing 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylic acid methyl ester Ia (49.3 mg, 0.2 mmol), 6-(4-methoxybenzyl)benzo[d][1,3]dioxol-5-ol IIa (51.6 mg, 0.2 mmol) and The mixture was placed in a flask containing 500 mg of 1-methylenediamine (300 mg) and stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL * 3), and the organic phase was dried to obtain a cycloaddition product. The cycloaddition product was dissolved in 1 mL of acetone, potassium osmate dihydrate (1.9 mg, 5 umol), N-methylmorpholine oxide (11.7 mg, 0.1 mmol) and sodium periodate (22 mg, 0.1 mmol) were added, and stirred at room temperature for 3 h. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL * 3), and the organic phase was dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent EA / PE = 0.03-0.1:1, v / v) to obtain the target product (61 mg) with a yield of 66%.

[0059] The characterization data of the obtained product (IIIa) are as follows:

[0060] White solid, melting point = 104-106 ° C; 61 mg, 66% yield; dr = 4:1, 95% ee; [Daicel Chiralpak IC-U (0.3cm×10cm), n-hexane / 2-propanol=95 / 5, v=0.3mL·min -1,λ=254nm, t(major)=5.8min, t(minor)=10.5min];

[0061] 1 H NMR (400MHz, CDCl3) δ7.23-7.00(m,7H),6.58-6.56(m,2H),5.88(s,1H),5.84(s,1H),5.34(s,1H),4.90(s,1H),4.66(d,J= 12.2Hz,1H),4.47(s,1H),4.29(d,J=12.2Hz,1H),3.77(s,3H),3.67(s,3H),3.11(d,J=13.6Hz,1H),2.76(d,J=13.6Hz,1H);

[0062] 13 C NMR (100 MHz, CDCl3); 13 C NMR (100MHz, CDCl3) δ198.6,174.3,157.2,150.7,146.7,143.8,143.0,141.6,134.4,132 .2,129.3,127.8,120.4,112.8,111.7,102.1,101.3,82.1,61.3,55.1,51.5,49.6,46.5;

[0063] HRMS (ESI) m / z calcd.for C 27 H 25 O7[M+H] + :461.1600,found:461.1597.

[0064] Example 2

[0065] Synthesis of Methyl (9R,10S)-10-(Benzo[d][1,3]dioxol-5-yl)-7-oxo-9-phenyl-7,8,9,10-tetrahydro-6H-[1,3]dioxacyclo[4',5':4,5]benzo[1,2-b]oxoctane-9-carboxylate (Ⅲb)

[0066] The reaction route is as follows:

[0067]

[0068] The steps are as follows:

[0069] Under nitrogen protection, [Ir(cod)Cl]2 (0.005 mmol, 3.4 mg), chiral ligand (0.022 mmol, 15.2 mg) and 2 mL of tetrahydrofuran were added to a dry 5 mL reaction bottle and stirred at room temperature for 15 min. The resulting mixture was then transferred to a flask containing 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylic acid methyl ester Ia (49.3 mg, 0.2 mmol), 6-(benzo[d][1,3]dioxan-5-ylmethyl)benzo[d][1,3]dioxan-5-ol IIb (54.4 mg, 0.2 mmol) and The mixture was placed in a flask containing 500 mg of zeolite (300 mg) and stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL * 3), and the organic phase was dried to obtain a cycloaddition product. The cycloaddition product was dissolved in 1 mL of acetone, potassium osmate dihydrate (1.9 mg, 5 umol), N-methylmorpholine oxide (11.7 mg, 0.1 mmol) and sodium periodate (22 mg, 0.1 mmol) were added, and stirred at room temperature for 2 h. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL * 3), and the organic phase was dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent EA / PE = 0.03-0.1:1, v / v) to obtain the target product (61 mg) with a yield of 65%.

[0070] The characterization data of the obtained product (IIIb) are as follows:

[0071] White solid, melting point = 144-146 ° C; 61 mg, 65% yield; dr = 20: 1, 94% ee; [Daicel Chiralpak IA-3 (0.46cm×25cm), n-hexane / 2-propanol=95 / 5, v=1.0mL·min -1 ,λ=254nm, t(major)=13.9min, t(minor)=10.4min];

[0072] 1H NMR (400MHz, CDCl3) δ7.16 (d, J = 4.3Hz, 4H), 7.12-7.06 (m, 1H), 6.64 (s, 1H), 6 .55(s,1H),6.46(d,J=8.1Hz,1H),5.87(s,1H),5.83(s,1H),5.78(s,1H),5.77 (s,1H),5.29(s,1H),4.89(s,1H),4.66(d,J=12.1Hz,1H),4.54(s,1H),4.28( d,J=12.2Hz,1H),3.78(s,3H),3.14(d,J=13.5Hz,1H),2.78(d,J=13.6Hz,1H);

[0073] 13 C NMR (100MHz, CDCl3) δ198.3,174.1,150.5,146.8,146.7,145.1,143.8,143.0,141.6,136.1,128 .9,127.9,127.7,126.5,124.5,111.7,107.2,102.1,101.2,100.6,82.1,61.5,51.4,50.5,46.6;

[0074] HRMS (ESI) m / z calcd.for C 27 H 23 O8[M+H] + :475.1395,found:475.1396.

[0075] Example 3

[0076] Synthesis of Methyl (9R,10S)-9-(4-bromophenyl)-10-(4-methoxyphenyl)-7-oxo-7,8,9,10-tetrahydro-6H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]oxine-9-carboxylate (Ⅲc)

[0077] The reaction route is as follows:

[0078]

[0079] The steps are as follows:

[0080] Under nitrogen protection, [Ir(cod)Cl]2 (0.005 mmol, 3.4 mg), chiral ligand (0.022 mmol, 15.2 mg) and 2 mL of tetrahydrofuran were added to a dry 5 mL reaction bottle and stirred at room temperature for 15 min. The resulting mixture was then transferred to a flask containing 3-(4-bromophenyl)-5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylic acid methyl ester Ib (65.1 mg, 0.2 mmol), 6-(4-methoxybenzyl)benzo[d][1,3]dioxol-5-ol IIa (51.6 mg, 0.2 mmol) and The mixture was placed in a flask containing 500 mg of zeolite (300 mg) and stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL * 3), and the organic phase was dried to obtain a cycloaddition product. The cycloaddition product was dissolved in 1 mL of acetone, potassium osmate dihydrate (1.9 mg, 5 umol), N-methylmorpholine oxide (11.7 mg, 0.1 mmol) and sodium periodate (22 mg, 0.1 mmol) were added, and stirred at room temperature for 3 h. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL * 3), and the organic phase was dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent EA / PE = 0.03-0.1:1, v / v) to obtain the target product (63 mg) with a yield of 60%.

[0081] The characterization data of the obtained product (IIIc) are as follows:

[0082] White solid, melting point = 112-114 ° C; 63 mg, 60% yield; dr = 19: 1, 94% ee; [Daicel Chiralpak IA-3 (0.46cm×25cm), n-hexane / 2-propanol=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(major)=15.2min, t(minor)=10.2min];

[0083] 1H NMR (400MHz, CDCl3) δ7.29 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8. 6Hz,2H),6.56(s,1H),6.51(s,1H),5.88(d,J=1.5Hz,1H),5.83(d,J=1.4Hz,1H), 5.30(s,1H),4.92(s,1H),4.64(d,J=12.2Hz,1H),4.44(s,1H),4.27(d,J=12.2H z,1H),3.76(s,3H),3.69(s,3H),3.06(d,J=13.6Hz,1H),2.69(d,J=13.6Hz,1H);

[0084] 13 C NMR (100MHz, CDCl3) δ198.1,173.9,157.3,150.8,146.8,143.9,142.0,141.3,133.9,132 .1,130.9,129.7,129.0,120.6,120.4,102.2,101.3,81.9,60.8,55.1,51.6,49.2,46.4;

[0085] HRMS (ESI) m / z calcd.for C 27 H 24 O7Br[M+H] + :539.0705,found:539.0702.

[0086] Example 4

[0087] Synthesis of Methyl (9R,10S)-9-(3-methoxyphenyl)-10-(4-methoxyphenyl)-7-oxo-7,8,9,10-tetrahydro-6H-[1,3]dioxacyclo[4',5':4,5]benzo[1,2-b]oxine-9-carboxylate (Ⅲd)

[0088] The reaction route is as follows:

[0089]

[0090] The steps are as follows:

[0091] Under nitrogen protection, [Ir(cod)Cl]2 (0.005 mmol, 3.4 mg), chiral ligand (0.022 mmol, 15.2 mg) and 2 mL of tetrahydrofuran were added to a dry 5 mL reaction bottle and stirred at room temperature for 15 min. The resulting mixture was then transferred to a flask containing 3-(3-methoxyphenyl)-5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylic acid methyl ester Ic (55.2 mg, 0.2 mmol), 6-(4-methoxybenzyl)benzo[d][1,3]dioxol-5-ol IIa (51.6 mg, 0.2 mmol) and The mixture was placed in a flask containing 500 mg of zeolite (300 mg) and stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL * 3), and the organic phase was dried to obtain a cycloaddition product. The cycloaddition product was dissolved in 1 mL of acetone, potassium osmate dihydrate (1.9 mg, 5 umol), N-methylmorpholine oxide (11.7 mg, 0.1 mmol) and sodium periodate (22 mg, 0.1 mmol) were added, and stirred at room temperature for 2.5 h. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL * 3), and the organic phase was dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent EA / PE = 0.03-0.1:1, v / v) to obtain the target product (60 mg) with a yield of 60%.

[0092] The characterization data of the obtained product (IIId) are as follows:

[0093] White solid, melting point = 108-110 ° C; 60 mg, 60% yield; dr = 20:1, 90% ee; [Daicel Chiralpak IA-3 (0.46cm×25cm), n-hexane / 2-propanol=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(major)=20.8min, t(minor)=12.9min];

[0094] 1H NMR(400MHz, CDCl3)δ7.17(d,J=8.7Hz,2H),7.08(t,J=8.0Hz,1H),6.82-6.70(m,2H),6.64 (dd,J=8.2,2.5Hz,1H),6.57(dd,J=8.7,6.0Hz,2H),5.87(d,J=1.5Hz,1H),5.83(d,J=1.5H z,1H),5.31(s,1H),4.91(s,1H),4.65(d,J=12.1Hz,1H),4.53(s,1H),4.29(d,J=12.2Hz,1 H),3.76(s,3H),3.68(s,3H),3.68(s,3H),3.12(d,J=13.6Hz,1H),2.76(d,J=13.6Hz,1H);

[0095] 13 C NMR (100MHz, CDCl3) δ198.7,174.1,159.1,157.2,150.6,146.7,144.6,143.8,141.6,134.5,132.1 ,129.2,128.7,120.4,120.3,111.8,111.6,102.2,101.2,82.1,61.3,55.3,55.1,51.4,49.9,46.4;

[0096] HRMS (ESI) m / z calcd.for C 28 H 27 O8[M+H] + :491.17069,found:491.1712.

[0097] Example 5

[0098] Synthesis of Methyl (9R,10S)-9-([1,1'-biphenyl]-4-yl)-10-(4-methoxyphenyl)-7-oxo-7,8,9,10-tetrahydro-6H-[1,3]dioxacyclo[4',5':4,5]benzo[1,2-b]oxoctane-9-carboxylate (Ⅲe)

[0099] The reaction route is as follows:

[0100]

[0101] The steps are as follows:

[0102] Under nitrogen protection, [Ir(cod)Cl]2 (0.005 mmol, 3.4 mg), chiral ligand (0.022 mmol, 15.2 mg) and 2 mL of tetrahydrofuran were added to a dry 5 mL reaction bottle and stirred at room temperature for 15 min. The resulting mixture was then transferred to a flask containing 3-(3-methoxyphenyl)-5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylic acid methyl ester Id (64.5 mg, 0.2 mmol), 6-(4-methoxybenzyl)benzo[d][1,3]dioxol-5-ol IIa (51.6 mg, 0.2 mmol) and The mixture was placed in a flask containing 500 mg of zeolite (300 mg) and stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL*3), and the organic phase was dried to obtain a cycloaddition product. The cycloaddition product was dissolved in 1 mL of acetone, potassium osmate dihydrate (1.9 mg, 5 umol), N-methylmorpholine oxide (11.7 mg, 0.1 mmol) and sodium periodate (22 mg, 0.1 mmol) were added, and stirred at room temperature for 3 h. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL*3), and the organic phase was dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: EA / PE=0.03-0.1:1, v / v) to obtain the target product (59 mg) with a yield of 55%.

[0103] The characterization data of the obtained product (IIIea) are as follows:

[0104] White solid, melting point = 102-104 ° C; 59 mg, 55% yield; dr = 20: 1, 94% ee; [Daicel Chiralpak IA-3 (0.46cm×25cm), n-hexane / 2-propanol=75 / 25, v=1.0mL·min -1 ,λ=254nm, t(major)=9.1min, t(minor)=7.3min];

[0105] 1H NMR (400MHz, CDCl3) δ7.54 (d, J = 7.4Hz, 2H), 7.44 -7.37(m,4H),7.30(t,J=7.3Hz,1H),7.26-7.17(m,4H),6.63-6.53(m,2H),5.89(d,J=1.4Hz,1H),5.84(d,J=1.5Hz,1H),5.38(s,1H),4.92(s ,1H),4.67(d,J=12.2Hz,1H),4.49(s,1H),4.30(d,J=12.2Hz,1H),3.80(s,3H),3.67(s,3H),3.13(d,J=13.6Hz,1H),2.79(d,J=13.6Hz,1H);

[0106] 13 C NMR (100MHz, CDCl3) δ198.6,174.3,157.2,150.8,146.7,143.9,142.0,141.5,140.4,139.0,134.3,132 .2,129.3,128.8,128.3,127.3,127.0,126.4,111.7,102.2,101.3,82.1,61.0,55.1,51.6,49.5,46.4;

[0107] HRMS (ESI) m / z calcd.for C 33 H 29 O7[M+H] + :537.1913,found:537.1915.

[0108] Example 6

[0109] Synthesis of Methyl (9R,10S)-10-(4-methoxyphenyl)-7-oxo-9-(m-tolyl)-7,8,9,10-tetrahydro-6H-[1,3]dioxacyclo[4',5':4,5]benzo[1,2-b]oxine-9-carboxylate (Ⅲf)

[0110] The reaction route is as follows:

[0111]

[0112] The steps are as follows:

[0113] Under nitrogen protection, [Ir(cod)Cl]2 (0.005 mmol, 3.4 mg), chiral ligand (0.022 mmol, 15.2 mg) and 2 mL of tetrahydrofuran were added to a dry 5 mL reaction bottle and stirred at room temperature for 15 minutes. The resulting mixture was then transferred to a flask containing 5-methylene-2-oxo-3-(m-tolyl)tetrahydro-2H-pyran-3-carboxylic acid methyl ester Ie (52.0 mg, 0.2 mmol), 6-(4-methoxybenzyl)benzo[d][1,3]dioxol-5-ol IIa (51.6 mg, 0.2 mmol) and The mixture was placed in a flask containing 500 mg of zeolite (300 mg) and stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL*3), and the organic phase was dried to obtain a cycloaddition product. The cycloaddition product was dissolved in 1 mL of acetone, potassium osmate dihydrate (1.9 mg, 5 umol), N-methylmorpholine oxide (11.7 mg, 0.1 mmol) and sodium periodate (22 mg, 0.1 mmol) were added, and stirred at room temperature for 3 h. After the reaction was completed, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (5 mL*3), and the organic phase was dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: EA / PE=0.03-0.1:1, v / v) to obtain the target product (67 mg) with a yield of 55%.

[0114] The characterization data of the obtained product (IIIf) are as follows:

[0115] White solid, melting point = 112-114 ° C; major isomer, 67 mg, 70% yield; dr = 20:1, 94% ee; [Daicel Chiralpak IA-3 (0.46cm×25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(major)=8.1min, t(minor)=6.1min];

[0116] 1H NMR (400MHz, CDCl3) δ7.15(d,J=8.4Hz,2H),7.03(t,J=7.8Hz,1H),6.95(d,J=7.3Hz,2H) ,6.90(d,J=7.3Hz,1H),6.56(d,J=7.4Hz,2H),5.88(d,J=1.4Hz,1H),5.83(d,J=1.5Hz,1 H),5.31(s,1H),4.90(s,1H),4.66(d,J=12.1Hz,1H),4.49(s,1H),4.29(d,J=12.1Hz,1H ),3.77(s,3H),3.67(s,3H),3.11(d,J=13.6Hz,1H),2.76(d,J=13.6Hz,1H),2.23(s,3H);

[0117] 13 C NMR (101MHz, CDCl3) δ198.2,174.4,157.1,150.6,146.6,143.8,142.9,141.6,137.3,134.5,132.2 ,129.4,128.5,127.7,127.2,124.9,120.4,102.1,101.2,82.1,61.3,55.1,51.4,49.8,46.5,21.7;

[0118] HRMS (ESI) m / z calcd.for C 28 H 27 O7[M+H] + :475.1757,found:475.1760.

[0119] Comparative Example 1

[0120] The synthesis method of methyl (9R,10S)-10-(4-methoxyphenyl)-7-oxo-9-phenyl-7,8,9,10-tetrahydro-6H-[1,3]dioxane [4',5':4,5]benzo[1,2-b]oxooctane-9-carboxylate (IIIa) is as described in Example 1, except that: without adding a chiral ligand, the reaction cannot proceed and no product is obtained.

[0121] Comparative Example 2

[0122] The synthesis method of methyl (9R, 10S)-10-(4-methoxyphenyl)-7-oxo-9-phenyl-7,8,9,10-tetrahydro-6H-[1,3]dioxane [4',5':4,5]benzo[1,2-b]oxoctane-9-carboxylate (IIIa) is as described in Example 1, except that: Molecular sieve, the reaction time is 40h, the yield of the obtained product is 35%, and the reaction yield and reaction rate are lower than those in Example 1 of the present invention.

[0123] Comparative Example 3

[0124] The synthesis method of (9S,10S)-9-(3,5-dichlorophenyl)-7-methylene-10-((E)-phenylvinyl)-7,8,9,10-tetrahydro-6H-[1,3]dioxazolo[4',5',4,5]benzo[1,2-b]oxooctanoic acid-9-carboxylic acid (IIIa) is as described in Example 1, except that: without adding iridium catalyst, the reaction cannot proceed and no product is obtained.

[0125] Application Example 1: Inhibitory activity of the compounds synthesized in Example 1-6 on colon cancer cells (HCT-116)

[0126] The CKK8 colorimetric method was used to test the inhibitory effects of the compounds synthesized in Examples 1-6 on colon cancer cell (HCT-116) cell proliferation.

[0127] The colon cancer cells (HCT-116) used were purchased from Shanghai Saibaikang Biotechnology Co., Ltd. The culture medium used was a complete cell culture medium prepared in a ratio of (culture medium: fetal bovine serum = 9:1), and the culture medium type was RPMI1640.

[0128] The specific steps are as follows:

[0129] (1) Sample solution preparation: The compound to be tested was dissolved in DMSO, filtered and sterilized at 0.22 μm to prepare a stock solution with a concentration of 10 mM. The stock solution was diluted with culture medium to prepare a total drug concentration of 5 μM to obtain a sample solution. At the same time, the culture medium to which an equal volume of DMSO was added was used as a control solution.

[0130] (2) Take colon cancer cells (HCT-116) in the logarithmic growth phase and count the cells. Adjust the cell concentration to 6×10 3 The cells were inoculated into a 96-well plate at a density of 10 cells / well and cultured in a 37°C, 5% CO2 incubator.

[0131] (3) After the cells were grown for 24 hours, the cell culture medium was discarded, and 100 μL of sample solution and control solution were added to each well. After 72 hours of incubation at 37°C and 5% CO2, the culture medium was removed, each well was washed three times with PBS, and 100 μL / well of culture medium containing 10% CCK-8 was added. Then, the cells were incubated in a 37°C constant temperature incubator containing 5% CO2 for 2 hours. The absorbance at 450 nm was detected by an ELISA instrument, and the cell survival rate was calculated. The experiment was repeated 3 times and the average value was taken. The results are shown in Figure 1 .

[0132] Depend on Figure 1 It can be seen that the chiral benzooxinone compounds of the present invention have a proliferation inhibitory effect on colon cancer cells (HCT-116), especially compounds IIIc and IIIf have an inhibition rate of more than 80% on colon cancer cells (HCT-116), which provides a scientific basis for the development of new anti-colon cancer candidate drugs. We further determined the IC50 values ​​of IIIb, IIIc and IIIf on colon cancer cells (HCT-116).

[0133] Application Example 2: IC50 of the half-maximal inhibitory concentration of the synthetic compound IIIb on colon cancer cells (HCT-116)

[0134] The specific test steps are as described in Application Example 1, except that: Step (1) Preparation of sample solution: Dissolve the test compound IIIb in DMSO, filter and sterilize at 0.22 μm to obtain a 100 μM sample stock solution, and then use complete culture medium to dilute to working concentrations of 0.5, 1, 2, 3, 5, 20, and 50 μM, respectively, to obtain sample solution.

[0135] The absorbance values ​​of each group were input into Excel and the relative activity was calculated (relative activity % = (OD value of experimental group - background OD value) / (mean OD value of control group - background OD value) × 100), where the background OD value is the absorbance of only adding CCK8 reagent and culture medium. The relative activity values ​​were input into GraphPad Prism for plotting, and the test results were plotted in Figure 2 As shown in Figure 2 As shown, the synthetic compound IIIfc of the present invention exhibited excellent inhibitory activity against gastric cancer cells (SGC-7901), with an IC50 value of 4.86 μM.

[0136] Application Example 3: IC50 of the half-maximal inhibitory concentration of the synthetic compound IIIc on colon cancer cells (HCT-116)

[0137] The specific test method is shown in Application Example 2

[0138] The test results are in Figure 3 As shown in Figure 3 As shown, the synthetic compound IIIfc of the present invention exhibited excellent inhibitory activity against colon cancer cells (HCT-116), with an IC50 value of 0.89 μM.

[0139] Application Example 4: IC50 of the half-maximal inhibitory concentration of the synthetic compound IIIf on colon cancer cells (HCT-116)

[0140] The specific test method is as shown in Application Example 2, except that the concentration of the sample solution in step (1) is 0.1, 0.5, 1, 2, 5, 20 μM.

[0141] The test results are in Figure 4 As shown in Figure 4 As shown, the synthetic compound IIIf of the present invention exhibits excellent inhibitory activity against colon cancer cells (HCT-116), with an IC50 value of 0.35 μM.

[0142] The above are only some embodiments of the present invention, and are not intended to limit the present invention in any form. Any simple modification, equivalent change or modification made to the above embodiments according to the invention shall fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a chiral benzooxanone compound, comprising the following steps: In a solvent, under the catalysis of an iridium catalyst system, a γ-methylene-δ-valerolactone compound I and an o-methylenephenol II undergo a [4+4] cycloaddition reaction, followed by an oxidation reaction to obtain a chiral benzooxanone compound III; the iridium catalyst system comprises an iridium catalyst and a chiral ligand, and the chiral ligand has a structure shown in formula IV; the iridium catalyst is [Ir(cod)Cl]2, [IrCp*Cl2]2 or IrCl3; in, In the structural formula of the compound of formula I, R 1 is phenyl or substituted phenyl, wherein the substituents of the substituted phenyl are independently selected from one or two of methoxy, methyl, halogen and nitro; In the structural formula of the compound of formula II, R 2 It is a C1-C3 alkoxy group or a 3,4-dimethoxy group.

2. The method for synthesizing chiral benzooxanone compounds according to claim 1, characterized in that: In the structural formula of the compound of formula I, the R 1 is phenyl, 4-bromophenyl, 4-phenylphenyl, 3-methylphenyl or 3-methoxyphenyl; In the structural formula of the compound of formula II, R 2 It is 4-methoxy or 3,4-dimethoxy.

3. The method for synthesizing chiral benzooxanone compounds according to claim 1, characterized in that: The solvent is ethylbenzene, toluene, tetrahydrofuran, 1,4-dioxane, chlorobenzene or p-xylene; the ratio of the volume of the solvent to the molar number of the γ-methylene-δ-valerolactone compound I is 5-20 mL:1 mmol; the solvent is treated to be anhydrous and oxygen-free.

4. The method for synthesizing chiral benzooxanone compounds according to claim 1, characterized in that: The molar ratio of iridium in the iridium catalyst to the γ-methylene-δ-valerolactone compound I is 0.01-0.1:1; the molar ratio of iridium in the iridium catalyst to the chiral ligand is 1:2-2.

2.

5. The method for synthesizing chiral benzooxanone compounds according to claim 1, characterized in that: The molar ratio of the γ-methylene-δ-valerolactone compound I to the o-methylenephenol II is 1:

1.

6. The method for synthesizing chiral benzooxanone compounds according to claim 1, characterized in that: The reaction system of the [4+4] cycloaddition reaction of γ-methylene-δ-valerolactone compound Ⅰ and o-methylenephenol Ⅱ is also added Molecular sieve; The ratio of the mass of the molecular sieve to the molar number of the γ-methylene-δ-valerolactone compound I is 1 to 2 g: 1 mmol; The cycloaddition reaction is carried out under a protective gas atmosphere, wherein the protective gas is nitrogen or argon; The temperature of the cycloaddition reaction is -20°C to room temperature; the time of the cycloaddition reaction is 2 to 40 hours; The post-treatment steps of the reaction liquid obtained from the cycloaddition reaction are as follows: water is added to the obtained reaction liquid, followed by extraction with ethyl acetate, and the solvent is removed from the obtained organic phase to obtain a cycloaddition product; the ratio of the added volume of the water to the molar number of the γ-methylene-δ-valerolactone compound I is 20 to 30 mL:

1.

7. The method for synthesizing chiral benzooxanone compounds according to claim 1, characterized in that: The oxidation step is: dissolving the cycloaddition product in acetone, and then adding potassium osmate, N-methylmorpholine oxide and sodium periodate to carry out oxidation reaction.

8. The method for synthesizing chiral benzooxanone compounds according to claim 7, characterized in that: The ratio of the volume of acetone to the molar number of γ-methylene-δ-valerolactone compound I is 3-8 mL:1 mmol; The molar ratio of the potassium osmate to the γ-methylene-δ-valerolactone compound I is 0.01 to 0.05:1; the molar ratio of the N-methylmorpholine oxide to the γ-methylene-δ-valerolactone compound I is 0.2 to 0.8:1; the molar ratio of the sodium periodate to the γ-methylene-δ-valerolactone compound I is 0.2 to 0.8:1; The temperature of the oxidation reaction is room temperature; the time of the oxidation reaction is 2 to 4 hours; Water is added to the obtained reaction solution, and then extracted with ethyl acetate, and the obtained organic phase is freed from the solvent to obtain a crude product; the ratio of the added volume of the water to the molar number of the γ-methylene-δ-valerolactone compound I is 20-30 mL:1; the obtained crude product is separated by silica gel column chromatography to obtain a chiral benzooxinone compound III, and the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the mixed solvent is 0.03-0.1:

1.

9. A chiral benzooxanone compound, characterized in that: Prepared by the preparation method described in claim 1, having the structure shown in formula III; Among them, R 1 is phenyl or substituted phenyl, wherein the substituents of the substituted phenyl are independently selected from one or two of methoxy, methyl, halogen and nitro; R 2 It is a C1-C3 alkoxy group or a 3,4-dimethoxy group.

10. Use of the chiral benzooxinone compound according to claim 9 in the preparation of anti-colon cancer drugs.

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