A method for synthesizing natural active product 4,5-Dimethoxycandidusin A

Abstract

The invention belongs to the technical field of chemical synthesis, and specifically relates to a method for synthesizing a natural active product 4,5-Dimethoxycandidusin A. The method provides a method for synthesizing the natural active product 4,5-Dimethoxycandidusin A, which can only be extracted from the fermentation broth of an endophytic fungus Aspergillus sp. and has a limited source, with simple steps and mild conditions. The method has a wide source of raw materials, is conducive to the large-scale industrial production of the natural active product 4,5-Dimethoxycandidusin A, and lays a solid foundation for related activity research.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis and more specifically relates to a method for synthesizing a natural active product 4,5-Dimethoxycandidusin A. Background Art

[0002] 4,5-Dimethoxycandidusin A is a representative p-phenyldibenzofuran molecule first extracted from the fermentation broth of the plant endophytic fungus Aspergillus sp. It has significant antibiotic activity and antiproliferative activity and other important biological activities: it has significant antibacterial activity against Xanthomonas oryzae pv.oryzicola Swings, Xanthomonasoryzae pv.Oryzae Swings, Clavibacter michiganense subsp.Sepedonicus, Pseudomonas syringae pv. and Erwinia amylovora (Zhang, W.; Wei, W.; Shi, J.; Chen, C.; Zhao, G.; Jiao, R.; Tan, R. Bioorganic & medicinal chemistry letters 2015, 25, 2698.); against K562 and HepG2 cell line also has significant anti-tumor activity (Han, J.; Lu, F.; Bao, L.; Wang, H.; Chen, B.; Li, E.; Wang, Z.; Xie, L.; Guo, C.; Xue, Y.; Ma, Y.; Liu, H. The Journal of antibiotics 2020, 73, 189.). It can be seen that 4,5-Dimethoxycandidusin A is a multifunctional compound that may become a lead compound for drug discovery and is expected to develop effective new natural drugs.

[0003]

[0004] However, currently 4,5-Dimethoxycandidusin A can only be extracted from the fermentation broth of the plant endophytic fungus Aspergillus sp., and the source is very limited, which has always been the main obstacle for scientists to conduct research. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the existing 4,5-Dimethoxycandidusin A, which can only be extracted from the fermentation broth of the plant endophytic fungus Aspergillus sp. and has a very limited source, and to provide a method for synthesizing the natural active product 4,5-Dimethoxycandidusin A.

[0006] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0007] A method for synthesizing a natural active product 4,5-Dimethoxycandidusin A (i.e., compound 1), the synthetic route is as follows:

[0008]

[0009] The specific steps include:

[0010] S1, using compound 2 as a raw material to undergo bromination reaction with bromine to obtain compound 3;

[0011] S2, compound 3 obtained in step S1 undergoes a methylation reaction with a methylating agent to obtain compound 4;

[0012] S3, compound 4 obtained in step S2 and compound 5 undergo Suzuki coupling reaction in the presence of a palladium catalyst and an alkaline reagent to obtain compound 6;

[0013] S4, the compound 6 obtained in step S3 undergoes an electrophilic substitution reaction with the hydroxyl protecting group to obtain compound 7;

[0014] S5, the compound 7 obtained in step S4 undergoes a bromination reaction with bromine to obtain compound 8;

[0015] S6, compound 8 obtained in step S5 reacts with peracid to produce compound 9 by Baeyer-Villiger reaction;

[0016] S7, using compound 10 as a raw material to undergo a methylation reaction with a methylating agent to obtain compound 11;

[0017] S8, the compound 11 obtained in step S7 undergoes a bromination reaction with bromine to obtain compound 12;

[0018] S9, the compound 12 obtained in step S8 undergoes borylation reaction with a borylation reagent in the presence of an alkaline reagent to obtain compound 13;

[0019] S10. Compound 13 obtained in step S9 undergoes coupling reaction with compound 9 in a reaction system of palladium catalyst, ligand and alkaline reagent to obtain compound 14.

[0020] S11, compound 14 obtained in step S10 undergoes Ullmann reaction in the presence of a metal catalyst and an alkaline reagent to obtain compound 15;

[0021] S12. Compound 15 obtained in step S11 is hydrolyzed under alkaline conditions to obtain compound 1.

[0022] Furthermore, in step S10, the ligand is selected from one or more of 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, n-butylphosphine, triphenylphosphine and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl.

[0023] Furthermore, in step S10, the palladium catalyst is palladium acetate.

[0024] Furthermore, in steps S3 and S10, the coupling reaction temperature is -45 to 160° C. Preferably, the coupling reaction temperature is -45 to 160° C.; more preferably, the coupling reaction temperature is 45 to 160° C.

[0025] Furthermore, in steps S3 and S10, the alkaline agent is selected from one or more of potassium phosphate, sodium phosphate, lithium phosphate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, calcium reagent sodium carboxylate, calcium chloride, sodium acetate, and potassium acetate; preferably, the alkaline agent is selected from one or more of potassium phosphate, sodium phosphate, lithium phosphate, and potassium carbonate; more preferably, the alkaline agent is potassium phosphate or potassium carbonate.

[0026] Further, in step S3, the palladium catalyst is selected from tetrakistriphenylphosphine palladium, palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tri(dibenzylideneacetone) dipalladium, palladium chloride, bis(dibenzylideneacetone)palladium, bis(acetonitrile)palladium dichloride, bis(triphenylphosphine)palladium chloride, 1,1'-bis(diphenylphosphine)ferrocenepalladium dichloride dichloromethane complex, bis(benzonitrile)palladium dichloride, 1,4-bis(diphenylphosphine)butanepalladium chloride, bis(acetonitrile)palladium dichloride, and one or more of allylpalladium chloride dimer.

[0027] Preferably, in step S3, the palladium catalyst is selected from one or more of tetrakistriphenylphosphine palladium, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, tris(dibenzylideneacetone)dipalladium, and palladium chloride; more preferably, tetrakistriphenylphosphine palladium or palladium acetate.

[0028] Preferably, in step S3, a ligand may be added, and the ligand is selected from one or more of 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, n-butylphosphine, triphenylphosphine and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl.

[0029] Furthermore, in steps S3 and S10, the solvent of the coupling reaction is a mixed solution of water and any of the following solvents: benzene, toluene, xylene, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, pyridine, piperidine, phenol, chlorobenzene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide. Preferably, the solvent of the coupling reaction is a mixed solution of water and any of the following solvents: benzene, toluene, xylene, 1,4-dioxane, tetrahydropyran; more preferably, the solvent of the coupling reaction is a mixed solution of water and any of the following solvents: toluene, 1,4-dioxane or tetrahydropyran. Specifically, in step S3, the solvent of the coupling reaction is most preferably a mixed solution of water and dioxane, and in step S10, the solvent of the coupling reaction is most preferably a mixed solution of water and tetrahydrofuran.

[0030] Preferably, the volume ratio of water to any of the above solvents is (1-10):(1-10). More preferably, in step S3, the solvent for the coupling reaction is a mixed solution of water and dioxane, with a volume ratio of 1:(5-6).

[0031] Furthermore, in steps S3 and S10, the coupling reaction is carried out under the protection of an inert gas.

[0032] Furthermore, in step S1, the bromination reaction is carried out in the presence of an acidic reagent. Preferably, the acidic reagent is selected from one or more of hydroiodic acid, sulfuric acid, hydrobromic acid, hydrochloric acid, iodic acid, oxalic acid (oxalic acid), sulfurous acid, phosphoric acid, pyruvic acid, nitrous acid, carbonic acid, citric acid, hydrofluoric acid, malic acid, gluconic acid, formic acid, lactic acid, benzoic acid, acrylic acid, acetic acid (acetic acid), propionic acid, stearic acid, and hydrosulfuric acid.

[0033] Furthermore, in step S1, the temperature of the bromination reaction is room temperature.

[0034] Furthermore, in steps S2 and S7, the methylating agent is selected from one or more of methyl iodide, methyl bromide, dimethyl sulfate, methyl toluenesulfonate, and methyl trifluoromethanesulfonate. Preferably, the methylating agent is methyl iodide or dimethyl sulfate.

[0035] Furthermore, in steps S2 and S7, the methylation reaction is carried out in the presence of an alkaline reagent; preferably, the alkaline reagent is selected from one or more of potassium phosphate, sodium phosphate, lithium phosphate, potassium carbonate, and sodium carbonate; more preferably, the alkaline reagent is selected from one or more of potassium phosphate, potassium carbonate, and sodium carbonate.

[0036] Furthermore, in steps S2 and S7, the temperature of the methylation reaction is room temperature.

[0037] Furthermore, in step S4, the electrophilic substitution reaction is carried out in the presence of an alkaline reagent; preferably, the alkaline reagent is selected from one or both of triethylamine and diisopropylethylamine.

[0038] Furthermore, in step S4, the temperature of the electrophilic substitution reaction is room temperature.

[0039] Preferably, in step S4, the hydroxyl protecting group is methanesulfonyl, pivaloyl, p-toluenesulfonyl, methoxymethyl and 2-tetrahydropyran.

[0040] Further, in steps S5 and S8, the bromination reaction needs to be carried out under acidic conditions. Preferably, the acidic conditions are reached by sulfuric acid, hydrobromic acid, hydrochloric acid, iodic acid, oxalic acid (oxalic acid), sulfurous acid, phosphoric acid, pyruvic acid, nitrous acid, carbonic acid, citric acid, hydrofluoric acid, malic acid, gluconic acid, formic acid, lactic acid, benzoic acid, acrylic acid, acetic acid (acetic acid), propionic acid, stearic acid or hydrosulfuric acid.

[0041] Furthermore, in step S5, the temperature of the bromination reaction is 15-50°C.

[0042] Furthermore, in step S6, the temperature of the Baeyer-Villiger reaction is room temperature.

[0043] Preferably, in step S6, the peroxyacid is meta-chloroperbenzoic acid

[0044] Furthermore, in step S8, the temperature of the bromination reaction is room temperature.

[0045] Furthermore, in step S9, the borylation reaction needs to be carried out under the protection of an inert gas.

[0046] Furthermore, in step S9, the alkaline reagent is selected from one or more of n-butyl lithium, tert-butyl lithium and lithium diisopropylamide.

[0047] Preferably, in step S9, the boronating agent is trimethyl borate and bis(pinacol)diboron.

[0048] Furthermore, in step S9, compound 12 is reacted with an alkaline reagent at -78°C for 0.5 to 1 hour, and after the boronating reagent is added, the reaction is continued for 0.5 hour, and then the temperature is raised to 0°C for 0 to 2 hours.

[0049] Furthermore, in step S11, the alkaline agent is selected from one or more of pyridine, imidazole, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, and triethylamine. Preferably, the alkaline agent is pyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene; more preferably, the alkaline agent is pyridine.

[0050] Preferably, in step S11, the metal catalyst is selected from one or more of cupric oxide, cuprous oxide, ferric oxide, ferrous oxide, iron powder, iodine ketone, and cupric chloride; more preferably, the metal catalyst is selected from one or more of cuprous oxide, ferrous oxide, iron powder, and cupric chloride; most preferably, the metal catalyst is cuprous oxide.

[0051] Furthermore, in step S11, the temperature of the Ullmann reaction is 50-120°C.

[0052] Furthermore, in step S12, the alkaline condition is achieved by potassium phosphate, sodium phosphate, lithium phosphate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, calcium reagent sodium carboxylate, calcium chloride, sodium acetate or potassium acetate.

[0053] Furthermore, in step S12, the hydrolysis temperature is 25-110°C.

[0054] Furthermore, the products after the reaction of steps S1 to S12 are further subjected to post-treatment, and the post-treatment includes concentration, solvent removal, washing, drying, and purification.

[0055] Preferably, the purification is carried out by 200-300 mesh silica gel column chromatography.

[0056] The present invention has the following beneficial effects:

[0057] The present invention provides a method for synthesizing a natural active product 4,5-Dimethoxycandidusin A (i.e., compound 1), and provides a method for synthesizing the natural active product 4,5-Dimethoxycandidusin A, which can only be extracted from the fermentation broth of an endophytic fungus Aspergillus sp. and has a limited source, with simple steps and mild conditions. In addition, the method has a wide source of raw materials, is conducive to the large-scale industrial production of the natural active product 4,5-Dimethoxycandidusin A, and lays a solid foundation for related activity research. DETAILED DESCRIPTION

[0058] The present invention is further described below with reference to specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0059] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0060] Example 1 Synthesis of Compound 3

[0061]

[0062] S1. Compound 2 was used as a raw material to undergo a bromination reaction with bromine to obtain compound 3: 150 mL of glacial acetic acid was added to a dry reaction bottle, 5.0 g (32.9 mmol) of compound 2 (2-hydroxy-5-methoxybenzaldehyde) was added at room temperature, and then 5.4 g (65.7 mmol) of sodium acetate and 5.8 g (36.2 mmol) of bromine were added, and the reaction was stirred at room temperature for 2 hours, and most of the solvent was removed by rotary evaporation at 60°C, and the reaction was stopped when a small amount of solvent remained; the residue was dissolved in 100 mL of ethyl acetate, washed with 300 mL of saturated sodium chloride solution, the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation at 45°C to obtain a residue, and the residue was purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain 5.9 g of compound 3 (yield 78%).

[0063] Example 2 Synthesis of Compound 4

[0064]

[0065] S2, compound 3 and excess iodomethane undergo methylation reaction to obtain compound 4: 20.0g (86.6mmol) of compound 3 and 400mL of N,N-dimethylformamide are added to a dry reaction bottle, and then 18.0g (129.8mmol) of potassium carbonate and 18.4g (129.8mmol) of iodomethane are added, and the reaction is stirred at room temperature for 12 hours, and most of the solvent is removed by rotary evaporation at 70°C, and the reaction is stopped when a small amount of solvent remains; the residue is dissolved in 200mL of ethyl acetate, washed with 600mL of saturated sodium chloride solution, the organic phases are combined and dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation at 45°C to obtain a residue, and the residue is purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 20:1) to obtain 20.8g of compound 4 (yield 98%).

[0066] When the methylating agent is iodomethane, dimethyl sulfate, methyl toluenesulfonate or methyl trifluoromethanesulfonate, and the base is potassium carbonate, sodium carbonate or cesium carbonate, the yield of this step of reaction is between 13% and 87%, as shown in Table 1.

[0067] Table 1 Yields of compound 4 prepared by different reaction systems

[0068] Serial number Methylation reagents Alkaline reagents Yield (%) 1 Methyl iodide Cesium carbonate 87 2 Methyl iodide Potassium carbonate 98 3 Methyl iodide Sodium carbonate 46 4 Dimethyl sulfate Potassium carbonate 79 5 Dimethyl sulfate Sodium carbonate 62 6 Methyl toluenesulfonate Potassium carbonate 37 7 Methyl trifluoromethanesulfonate Potassium carbonate 13

[0069] Example 3 Synthesis of Compound 6

[0070]

[0071] S3, compound 4 and 4-hydroxyphenylboronic acid under Suzuki reaction conditions to produce compound 6: 5.0 g (20.4 mmol) of compound 4, 3.4 g (24.5 mmol) of 4-hydroxyphenylboronic acid (compound 5), 471.5 mg (0.4 mmol) of tetrakistriphenylphosphine palladium, 4.2 g (30.6 mmol) of potassium carbonate, 100 mL of 1,4-dioxane and 20 mL of water were reacted under nitrogen protection at 90°C with stirring for 8 hours, and most of the solvent was removed by rotary evaporation at 50°C, and the reaction was stopped when a small amount of solvent remained; the residue was dissolved in 80 mL of ethyl acetate, and washed with 100 mL of water and 100 mL of saturated sodium chloride solution in sequence, the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation at 45°C to obtain a residue, and the residue was purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain 4.2 g of compound 6 (yield 80%).

[0072] Referring to the above method, compound 6 was prepared using different reaction systems. The results are shown in Table 2.

[0073] Table 2 Yields of compound 6 prepared by different reaction systems

[0074] Serial number catalyst Alkaline reagents Solvents Temperature(℃) Yield (%) 1 <![CDATA[Pd(PPh 3 ) 4 ]]> Potassium carbonate 1,4-Dioxane / Water 90 74 2 <![CDATA[Pd(PPh 3 ) 4 ]]> Potassium carbonate Toluene / water 90 46 3 <![CDATA[Pd(PPh 3 ) 4 ]]> Cesium carbonate 1,4-Dioxane / Water 90 35 4 <![CDATA[Pd(PPh 3 ) 4 ]]> Cesium carbonate Toluene / water 90 48 5 <![CDATA[PdCl 2 (dppf)]]> Cesium carbonate Toluene / water 90 55 6 <![CDATA[Pd(PPh 3 ) 2 Cl 2 ]]> Cesium carbonate Toluene / water 90 37 7 <![CDATA[Pd 2 (dba) 3 ]]> Cesium carbonate Toluene / water 90 48 8 <![CDATA[Pd(OAc) 2 ]]> Potassium Phosphate Tetrahydrofuran / water 65 20 9 <![CDATA[Pd(OAc) 2 / X-Phos]]> Potassium Phosphate Tetrahydrofuran / water 65 49

[0075] As can be seen from the table, the product compound 6 can be prepared under the above conditions.

[0076] Example 4 Synthesis of Compound 7

[0077]

[0078] S4, compound 6 and methylsulfonyl chloride undergo electrophilic substitution reaction to obtain compound 7: 5.0 g (19.3 mmol) of compound 6 and 100 mL of dichloromethane were added to a dry reaction bottle, 2.7 g (23.2 mmol) of methylsulfonyl chloride was added, 2.4 g (23.2 mmol) of triethylamine was added dropwise, and the reaction was stirred at room temperature for 3 hours, and the solvent was concentrated by rotary evaporation at 40°C to obtain a residue; the residue was purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 5:1) to obtain 6.1 g of compound 7 (yield 94%).

[0079] When triethylamine was replaced by diisopropylethylamine, the yield was 93%.

[0080] Example 5 Synthesis of Compound 8

[0081]

[0082] S5. Compound 7 reacts with bromine to obtain compound 8: 4.0 g (11.9 mmol) of compound 7 and 60 mL of glacial acetic acid are added to a dry reaction bottle, 3.8 g (23.8 mmol) of bromine is added dropwise, and the reaction is stirred at 35°C for 24 hours, and most of the solvent is removed by rotary evaporation at 60°C, and the reaction is stopped when a small amount of solvent remains; the residue is dissolved in 50 mL of ethyl acetate, washed with 150 mL of saturated sodium chloride solution, the organic phases are combined and dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation at 45°C to obtain a residue; the residue is purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 5:1) to obtain 2.7 g of compound 8 (yield 55%).

[0083] Example 6 Synthesis of Compound 9

[0084]

[0085] S6, compound 8 and meta-chloroperbenzoic acid undergo Baeyer-Villiger reaction to obtain compound 9: 10.0 g (24.1 mmol) of compound 8 and 400 mL of dichloromethane were added to a dry reaction bottle, 9.8 g (48.2 mmol) of 85% meta-chloroperbenzoic acid was added at 0°C, and the reaction was stirred at 0°C for 1 hour, then the temperature was raised to room temperature and stirred for 24 hours; 400 mL of saturated magnesium thiosulfate solution was added, the organic phases were combined, and the organic phases were washed with 400 mL of saturated sodium bicarbonate solution and 400 mL of saturated sodium chloride solution, respectively. After the organic phases were combined, they were dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation at 40°C to remove the solvent to obtain a residue, which was purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 5:1) to obtain 6.6 g of compound 9 (yield 68%).

[0086] Example 7 Synthesis of Compound 11

[0087]

[0088] S7. Compound 10 was used as a raw material to undergo a methylation reaction with excess iodomethane to obtain compound 11: 20.0 g (138.4 mmol) of compound 10 and 400 mL of N,N-dimethylformamide were added to a dry reaction bottle, and 57.4 g (415.1 mmol) of potassium carbonate and 58.9 g (415.1 mmol) of iodomethane were added, and the reaction was stirred at room temperature for 12 hours, and most of the solvent was removed by rotary evaporation at 70°C, and the reaction was stopped when a small amount of solvent remained; the residue was dissolved in 200 mL of ethyl acetate, washed with 600 mL of saturated sodium chloride solution, the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation at 45°C to obtain a residue; the residue was purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1) to obtain 22.9 g of compound 11 (yield 96%).

[0089] Example 8 Synthesis of Compound 12

[0090]

[0091] S8. Compound 11 reacts with bromine to obtain compound 12: 20.0 g (115.9 mmol) of compound 11 and 200 mL of glacial acetic acid are added to a dry reaction bottle, and 27.8 g (173.8 mmol) of bromine is added. The reaction is stirred at room temperature for 5 hours, and most of the solvent is removed by rotary evaporation at 60°C. The reaction is stopped when a small amount of solvent remains. The residue is dissolved in 200 mL of ethyl acetate, washed with 600 mL of saturated sodium chloride solution, the organic phases are combined and dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation at 45°C to obtain a residue. The residue is purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1) to obtain 23.1 g of compound 12 (yield 79%).

[0092] Example 9 Synthesis of Compound 13

[0093]

[0094] S9. Compound 12 reacts with trimethyl borate in the presence of n-butyl lithium to obtain compound 13: 10.0 g (39.8 mmol) of compound 13 and 200 mL of anhydrous tetrahydrofuran were added to a dry two-necked flask under nitrogen protection. 37.3 mL of 1.6M n-butyllithium n-hexane solution (59.6mmol) was stirred at -78°C for 1 hour; 6.2g (59.6mmol) of trimethyl borate was added dropwise, the mixture was stirred at -78°C for 0.5 hour, then the temperature was raised to 0°C and stirred for 3 hours; 1M hydrochloric acid solution was added to adjust the pH value of the mixture to acidic, stirred at room temperature for 1 hour, and concentrated by rotary evaporation at 45°C to remove most of the solvent, and the reaction was stopped when a small amount of solvent remained; the residue was dissolved in 100mL of ethyl acetate, washed with 300mL of saturated sodium chloride solution, the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation at 45°C to remove the solvent to obtain a residue; the residue was purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain 6.4g of compound 13 (yield 70%).

[0095] Example 10 Synthesis of Compound 14

[0096]

[0097] S10, compound 13 and compound 9 undergo coupling reaction under Suzuki reaction conditions to obtain compound 14: 3.0 g (7.4 mmol) of compound 9, 2.4 g (11.2 mmol) of compound 13, 83.5 mg (37 μmol) of palladium acetate, 5.3 g (11.2 mmol) of 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl, 2.4 g (11.2 mmol) of potassium phosphate, 60 mL of tetrahydrofuran and 10 mL of water were added to a dry reaction bottle. , under nitrogen protection, stirring and reacting at 65°C for 5 hours, rotary evaporation and concentration at 45°C to remove most of the solvent, stopping when a small amount of solvent remains; dissolving the residue in 50 mL of ethyl acetate, washing with 150 mL of saturated sodium chloride solution in sequence, combining the organic phases and drying over anhydrous magnesium sulfate, filtering, and rotary evaporation and concentration at 45°C to remove the solvent to obtain a residue; the residue was purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain 2.8 g of compound 14 (yield 76%).

[0098] Referring to the above method, the reaction system was changed to prepare compound 14. The results are shown in Table 3.

[0099] Table 3 Preparation of compound 14 under different conditions

[0100]

[0101]

[0102] It can be seen from the table that when Pd(PPh 3 ) 4 When PdCl was used as the catalyst, compound 14 could not be obtained even if the alkaline reagent and reaction solvent were changed. Different catalysts were used to investigate their effects on the coupling reaction, but PdCl 2 (dppf), Pd(PPh 3 ) 2 Cl 2 , Pd 2 (dba) 3 None of them could react to give compound 14; when Pd(OAc) 2 When tetrahydrofuran / water was used as a mixed solvent, compound 14 could be obtained, but the yield was low. Considering that this Suzuki coupling step might require a sterically hindered ligand, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (Xphos) was introduced as a co-catalyst in the reaction, which significantly increased the yield to 67%.

[0103] Example 11 Synthesis of Compound 15

[0104]

[0105] S11. Compound 14 under the condition of cuprous oxide undergoes Ullmann reaction to obtain compound 15: 2.0 g (4.0 mmol) of compound 14, 2.9 g (20.2 mmol) of cuprous oxide and 150 mL of pyridine are added to a dry reaction bottle, the mixture is stirred and reacted at 110°C for 12 hours, and most of the solvent is removed by rotary evaporation at 60°C, and the reaction is stopped when a small amount of solvent remains; the residue is dissolved in 30 mL of ethyl acetate, washed with 70 mL of saturated sodium chloride solution in turn, the organic phases are combined and dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation at 45°C to obtain a residue; the residue is purified by 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain 1.6 g of compound 15 (yield 85%).

[0106] In this step, copper oxide, ferrous oxide, iron powder and copper chloride are used as catalysts, and pyridine, imidazole, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylamine are used as alkaline reagents. The yield is between 10 and 68%, as shown in Table 4.

[0107] Table 4 Preparation of compound 15 under different conditions

[0108]

[0109]

[0110] Example 12 Synthesis of the natural active product 4,5-Dimethoxycandidusin A, i.e., compound 1

[0111]

[0112] S12. Compound 15 was hydrolyzed under potassium hydroxide to obtain compound 1: 700.0 mg (1.5 mmol) of compound 15, 50 mL of 1,4-dioxane and 10 mL of water were added to a dry reaction bottle, and then 428.3 mg (7.5 mmol) of potassium hydroxide was added. The mixture was stirred at 50°C for 12 hours, and then the mixture was cooled to room temperature, and then hydrochloric acid solution was added at room temperature to adjust the pH value to 3-4. The mixture was stirred at room temperature for 1 hour, and then the mixture was concentrated by rotary evaporation at 60°C to remove most of the solvent, and the reaction was stopped when a small amount of solvent remained; the residue was dissolved in 30 mL of ethyl acetate, washed with 70 mL of saturated sodium chloride solution in turn, the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation at 45°C to remove the solvent to obtain a residue, and the residue was purified by 200-300 mesh silica gel column chromatography (dichloromethane: methanol = 100:1 to 10:1) to obtain 423.8 mg of compound 1 (yield 73%).

[0113] 1 H NMR(400MHz,DMSO-d6)δ9.61(s,1H),7.43(overlapped,1H),7.43(overlapped,2H),7.43(overla pped,1H),6.86(d,J=8.2Hz,2H),6.74(s,1H),3.99(s,3H),3.86(s,3H),3.85(s,3H),3.78(s,3H). 13 C NMR(101MHz,DMSO)δ157.15,150.42,149.96,149.60,149.03,146.53,136.37,131.48,130.84,1 28.96,115.56,114.62,114.22,106.15,104.42,96.66,61.02,56.54,56.43,56.32.MS(ESI)m / z calcd for C 22 H 20 O 6 [M+H]+:381.13,found:381.10.

[0114] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A method for synthesizing a natural active product 4,5-Dimethoxycandidusin A, characterized in that: The synthetic route is as follows: The specific steps include: S1, using compound 2 as a raw material to undergo bromination reaction with bromine to obtain compound 3; S2, compound 3 obtained in step S1 undergoes a methylation reaction with a methylating agent to obtain compound 4; S3, compound 4 obtained in step S2 and compound 5 undergo Suzuki coupling reaction in the presence of a palladium catalyst and an alkaline reagent to obtain compound 6; S4, the compound 6 obtained in step S3 reacts with a hydroxyl protecting agent to obtain a compound 7; S5, the compound 7 obtained in step S4 undergoes a bromination reaction with bromine to obtain compound 8; S6, compound 8 obtained in step S5 reacts with peracid to produce compound 9 by Baeyer-Villiger reaction; S7, using compound 10 as a raw material to undergo a methylation reaction with a methylating agent to obtain compound 11; S8, the compound 11 obtained in step S7 undergoes a bromination reaction with bromine to obtain compound 12; S9, the compound 12 obtained in step S8 undergoes borylation reaction with a borylation reagent in the presence of an alkaline reagent to obtain compound 13; S10, compound 13 obtained in step S9 and compound 9 undergo coupling reaction in a reaction system of palladium acetate, a ligand, and an alkaline reagent to obtain compound 14; S11, compound 14 obtained in step S10 undergoes Ullmann reaction in the presence of a metal catalyst and an alkaline reagent to obtain compound 15; S12, hydrolyzing the compound 15 obtained in step S11 under alkaline conditions to obtain compound 1; Wherein, R in the compound 13 is H.

2. The synthesis method according to claim 1, characterized in that: In step S10, the ligand is selected from one or more of 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, n-butylphosphine, triphenylphosphine and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl.

3. The synthesis method according to claim 1, characterized in that: In steps S3 and S10, the temperature of the coupling reaction is -45 to 160°C.

4. The synthesis method according to claim 1, characterized in that: In steps S3 and S10, the alkaline reagent is selected from one or more of potassium phosphate, sodium phosphate, lithium phosphate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, calcium reagent sodium carboxylate, sodium acetate, and potassium acetate.

5. The synthesis method according to claim 1, characterized in that: In steps S3 and S10, the solvent for the coupling reaction is a mixed solution of water and any of the following solvents: benzene, toluene, xylene, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, pyridine, piperidine, phenol, chlorobenzene, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide.

6. The synthesis method according to claim 1, characterized in that: In step S3, the palladium catalyst is selected from tetrakistriphenylphosphine palladium, palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tri(dibenzylideneacetone)dipalladium, palladium chloride, bis(dibenzylideneacetone)palladium, bis(triphenylphosphine)palladium chloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride dichloromethane complex, bis(benzonitrile)palladium dichloride, 1,4-bis(diphenylphosphine)butanepalladium chloride, bis(acetonitrile)palladium dichloride, and one or more of allylpalladium chloride dimer.

7. The synthesis method according to claim 1, characterized in that: In steps S3 and S10, the coupling reaction is carried out under the protection of an inert gas.

8. The synthesis method according to claim 1, characterized in that: The products after the reaction in steps S1 to S12 are further subjected to post-treatment, which includes concentration, solvent removal, washing, drying, and purification.

9. The synthesis method according to claim 8, characterized in that: The purification was performed by 200-300 mesh silica gel column chromatography.

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