CN111848564B - Preparation method of spirobenzofuran compound - Google Patents
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Abstract
The invention discloses a preparation method of a spirobenzofuran compound, which takes commercially available phloroglucinol and 4-isopropylcyclohexanone as raw materials, respectively synthesizes dihydrochalcone and beta-phellandrene with exocyclic double bond through Friedel-crafts reaction and Wittig reaction to obtain two fragment compounds of hydrogen chalcone and beta-phellandrene, connects the two fragment compounds through oxidation cycloaddition reaction to construct a spirobenzofuran core skeleton, thereby preparing and obtaining natural products adungin C and adungin D. Greatly breaks through the limitation of the natural product source.
Description
Technical Field
The invention relates to the technical field of chemical biomimetic synthesis of natural medicines, in particular to a chemical synthesis method for constructing a spirobenzofuran skeleton structure in a regioselective manner, which is applied to synthesis of natural products or medicines.
Background
The pharmaceutical chemistry is established on the basis of chemistry and biology, and related medicine structures and activities are researched. The research contents comprise finding, modifying and optimizing lead compounds, revealing the action mechanism of the medicine and the physiologically active substance from the molecular level, and researching the metabolic process of the medicine and the physiologically active substance in the body. The relation between the chemical structure and the activity of the medicine is researched, and a new chemical entity is obtained through the design of medicine molecules or the chemical modification of a lead compound to create a new medicine. The direction is also a comprehensive discipline for finding and inventing new drugs, synthesizing chemical drugs, clarifying chemical properties of drugs and researching interaction rules between drug molecules and body cells (biological macromolecules), is an important leading discipline in the pharmaceutical field, has a solid development foundation, accumulates abundant contents and makes important contribution to the health of human beings. For example: in the 50 s, the chemical synthesis of chlorpromazine which is a medicament for treating schizophrenia; in the 80 s, a series of quinolone antibacterial agents represented by norfloxacin and the chemical synthesis of new antibiotics. The development and development of more new medicines are promoted over the years due to the progress of life science and information science, the variety of new medicines is continuously increased, and the rapid development of the medical industry is promoted.
adungin C and adungin D are dihydrochalcone compounds isolated from Piper nigrum (Piper nigrum L.) belonging to Piperaceae family. The natural product can generate antibacterial effect on micrococcus luteus at low concentrations of 2.4 mu g/mL and 2.9 mu g/mL, and shows excellent potential medicinal value and pharmaceutical activity in this respect, and simultaneously has many pharmacological activities and biological activities to be discovered. However, the source plant of the natural product, namely the tree pepper, is limited in China, and only 18.3 mg of aductin C and 5.9 mg of aductin D can be extracted from 1.55 kg of dry tree pepper leaves. Therefore, chemical synthesis of the natural product is essential based on the protection of the natural ecological environment and the limitation of the source of the natural product, as well as from the viewpoints of new drug development and drug leads.
Aiming at the chemical synthesis of the natural product, the synthesis research of the target molecule is carried out by using the [3+2] cycloaddition reaction as a key reaction. Dihydrobenzofuran, a product of the [3+2] cycloaddition reaction of phenol and olefin oxidation, is widely present in active natural product structures such as neolignan and resveratrol oligomer, so that the oxidative cycloaddition reaction of phenol and olefin is widely concerned by organic chemists and is roughly divided into two main types, namely catalytic [3+2] oxidative cycloaddition reaction and direct [3+2] oxidative cycloaddition reaction. Wherein the catalyzed [3+2] oxidation cycloaddition reaction further comprises: ferric salt oxidation, trifluoromethanesulfonic acid oxidation and photocatalysis; the direct [3+2] oxidative cycloaddition reaction further comprises: sodium persulfate oxidation, higher iodine oxidation, ceric ammonium nitrate oxidation, 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ) and its analogues oxidation, metal salts or metal oxides oxidation such as silver acetate, silver oxide and ferric chloride. We can refer to and develop related methods to construct the spirobenzofuran scaffold and apply it in the synthesis of natural products or drug molecules.
In recent years, the oxidation [3+2] cycloaddition reaction has progressed faster, but there are two improvements and solutions that need to be addressed: 1. the selective [3+2] cycloaddition reaction of phenol and polyene compounds to construct spirobenzofuran skeleton has no related report; 2. the oxidation [3+2] cycloaddition reaction is applied to the synthesis of natural products and drug molecules, related literature reports are few, and a great space is still provided for improvement.
Disclosure of Invention
The invention mainly overcomes the defects in the prior art, aims to develop selective [3+2] oxidation cycloaddition reaction, apply the selective [3+2] oxidation cycloaddition reaction to the preparation of natural products aduncun C and D, prepare for the subsequent test of physiological and pharmacological activity, construct a spirobenzofuran skeleton by taking the oxidation [3+2] cycloaddition reaction as the key, and enrich the method for synthesizing the skeleton; the method is applied to the preparation of natural products aduncun C and D, and can embody the application value of the method.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
a preparation method of a spirobenzofuran compound is characterized in that the reaction general formula of the spirobenzofuran compound is as follows:
preferably, the preparation of the spirobenzofuran compound comprises the following steps:
(1) removing water from a reaction vessel, setting the atmosphere in the reaction vessel as an inert gas environment, rapidly adding m-triphenyl phenol and anhydrous potassium carbonate, sequentially adding anhydrous acetone and dimethyl sulfate, gradually heating for reaction, cooling the reaction solution to room temperature after the reaction is finished, distilling the acetone, extracting for multiple times, sequentially washing with hydrochloric acid, water and saturated salt water, drying with anhydrous sodium sulfate, distilling the extraction solvent, concentrating, and separating to obtain colorless oily liquid methoxyl diphenol;
(2) removing water from a reaction vessel, setting the atmosphere in the reaction vessel to be an inert gas environment, rapidly adding 3-phenylpropionic acid and dichloromethane, placing the reaction vessel into a low-temperature reactor at 0 ℃ for precooling, dropwise adding oxalyl chloride, then adding N, N-dimethylformamide, gradually heating up for reaction, distilling excessive oxalyl chloride and dichloromethane solvent after the reaction is finished, and concentrating into a solution A for later use;
(3) removing water from a reaction vessel, setting the atmosphere in the reaction vessel as an inert gas environment, rapidly adding colorless oily liquid methoxyl diphenol, aluminum trichloride and dichloromethane synthesized in the step (1), placing the reaction vessel into a low-temperature reactor at 0 ℃ for precooling, then dropwise adding the standby solution A in the step (2), gradually heating for reaction, after the reaction is finished, adding ice water for quenching reaction, extracting for multiple times, washing with hydrochloric acid solution, water and saturated salt water in sequence, drying with anhydrous sodium sulfate, distilling the extraction solvent, concentrating and separating to obtain white solid dihydrochalcone;
(4) removing water from a reaction vessel, setting the atmosphere in the reaction vessel as an inert gas environment, dissolving 4-isopropylcyclohexanone in anhydrous dichloromethane in the reaction vessel, placing the reaction vessel in a low-temperature reactor at-78 ℃ for precooling, then sequentially adding triethylamine and trimethylsilyl trifluoromethanesulfonate, after the reaction is finished, adding a saturated sodium bicarbonate solution at normal temperature, stirring for 1min to quench the reaction, repeatedly extracting with dichloromethane, sequentially washing with water and saturated salt water, drying with anhydrous sodium sulfate, distilling the extraction solvent dichloromethane, and concentrating to obtain a silyl ether compound which is directly subjected to the next step without further purification; removing water from the other reaction vessel, setting the atmosphere in the reaction vessel as an inert gas environment, dissolving the obtained silicon ether compound in anhydrous dimethyl sulfoxide, adding the silicon ether compound into the reaction vessel, adding palladium acetate at normal temperature, replacing the reaction vessel with an oxygen balloon at one atmosphere for 2 times, after the reaction is finished at the normal temperature for 20 hours, adding a saturated ammonium chloride solution, stirring for one minute to quench the reaction, extracting with diethyl ether for multiple times, washing with water and saturated salt water in sequence, drying with anhydrous sodium sulfate, distilling the extraction solvent diethyl ether, concentrating to obtain a colorless oily liquid B, and directly carrying out the next step without further purification;
(5) removing water from a reaction container, setting the atmosphere in the reaction container to be an inert gas environment, quickly adding methyl triphenyl phosphine iodide, setting the atmosphere in the reaction container to be the inert gas environment again, adding anhydrous tetrahydrofuran, placing the reaction container into a low-temperature reactor at 0 ℃ for precooling, then adding 1.6M n-butyl lithium dropwise within 3 minutes, stirring for thirty minutes at 0 ℃, dissolving the colorless oily liquid B obtained in the step (4) in the anhydrous tetrahydrofuran, then adding the anhydrous tetrahydrofuran dropwise into the reaction container within 5 minutes, gradually raising the temperature to the normal temperature for reaction for one hour, then adding a mixed solution of methanol and water, stirring for one minute for quenching reaction, extracting with dichloromethane for multiple times, sequentially washing with water and saturated salt water, drying with anhydrous sodium sulfate, distilling an extraction solvent dichloromethane, concentrating and separating to obtain colorless oily liquid beta-phellandrene;
(6) removing water from a reaction container, setting the atmosphere in the reaction container as an inert gas environment, rapidly adding ketone dihydrochalcone and beta-phellandrene, setting the atmosphere in the reaction container as the inert gas environment again, adding anhydrous acetonitrile to dissolve, adding silver oxide at normal temperature, gradually raising the temperature to 55 ℃ to react for two hours, cooling to room temperature after the reaction is finished, filtering through a sand core funnel, rinsing with ethyl acetate, distilling the solvent, concentrating, and separating and purifying the generated adungin C and adungin D.
Preferably, in the step (1), the reaction vessel is a round-bottom flask, and the water removal mode is preheating for 10 minutes by an alcohol lamp; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; after the anhydrous potassium carbonate is added, the atmosphere in the reaction container can be set to be an inert gas environment again, and the method is that argon gas is replaced for 3 times; the mol ratio of m-triphenyl phenol, anhydrous potassium carbonate and dimethyl sulfate is 1: 1: 0.33; the acetone is dried by anhydrous calcium chloride in advance and then is used after being distilled under normal pressure, and when the m-triphenyl phenol is 100mmol, the using amount of the acetone is 100 mL; the temperature is raised to react, the temperature is 55 ℃, and the reaction time is 10 hours; the extractant for multiple extractions is ethyl acetate, the extraction times are 2 times, the hydrochloric acid is 1M, and the acid washing times are 2 times; the separation means is column chromatography, the column chromatography is used for separation for 2 times, the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 5:1, and the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 2: 1.
Preferably, in the step (2), the reaction vessel is a round-bottom flask, and the water removal mode is preheating for 10 minutes by an alcohol lamp; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; the precooling time is 5 min; the time for dropwise adding oxalyl chloride is within 8 min; the temperature is increased to react at room temperature for 3 hours; the solvent distillation mode of the excess oxalyl chloride and the dichloromethane is rotary evaporator distillation; the molar ratio of the 3-phenylpropionic acid to the oxalyl chloride is 4: 5; when the amount of the 3-phenylpropionic acid is 40mmol, the amount of dichloromethane used is 4 mL.
Preferably, in the step (3), the reaction vessel is a round-bottom flask, and the water removal mode is preheating for 10 minutes by an alcohol lamp; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; the molar ratio of the methoxyl diphenol to the aluminum trichloride is 1:2, and when the methoxyl diphenol is 20mmol, the addition amount of the dichloromethane is 40 mL; the precooling time is 5 min; the time for adding the standby solution A in the step (2) is within 10 min; the temperature is increased to react, the reaction temperature is room temperature, and the reaction time is 10 hours; the quenching reaction condition is that ice water is added at 0 ℃; the extraction is 2 times of ethyl acetate extraction; the hydrochloric acid is washed by 1M acid for 2 times; the separation means is column chromatography, the column chromatography is used for separation for 2 times, the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 8:1, and the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 5: 1.
Preferably, in the step (4), the reaction vessel is a round-bottom flask, and the water removal mode is preheating for 10 minutes by an alcohol lamp; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; the precooling time is 5 min; the dichloromethane is extracted for 2 times, the washing time is 2 times, and the distillation mode of the extraction solvent dichloromethane is rotary evaporator distillation; the molar ratio of the 4-isopropylcyclohexanone to the triethylamine to the trimethylsilyl trifluoromethanesulfonate to the palladium acetate is 1: 5: 3: 0.1; the multiple extraction times of the dichloromethane are 2 times, and the washing times are 2 times; the times of the ether multiple extraction are 2 times, and the times of the water washing are 2 times.
Preferably, in the step (5), the reaction vessel is a round-bottom flask, and the water removal mode is preheating for 10 minutes by an alcohol lamp; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; after the methyl triphenyl phosphine iodide is added, the argon gas is replaced for 3 times by setting the atmosphere in the reaction container to be an inert gas environment again; the precooling time is 5min, and the molar ratio of the methyl triphenyl phosphine iodide to the n-butyl lithium is 1.1: 1; when the methyl triphenyl phosphine iodide is 22mmol, the methanol and the water are respectively 5 ml; the separation means is column chromatography, the column chromatography is used for separation for 2 times, the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 10:1, and the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 5: 1;
preferably, in the step (6), the reaction vessel is a round-bottom flask, and the water removal mode is preheating for 10 minutes by an alcohol lamp; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; after the ketone dihydrochalcone and the beta-phellandrene are added, the argon gas replacement is carried out for 2 times by setting the atmosphere in the reaction container to be an inert gas environment again; the molar ratio of the ketone dihydrochalcone to the beta-phellandrene to the silver oxide is 1:3: 3; when the addition amount of the ketone dihydrochalcone is 0.5mmol, the addition amounts of the anhydrous acetonitrile and the ethyl acetate are respectively 10 mL; the sand core funnel is filled with column chromatography silica gel with the height of 1 cm; the method for distilling the solvent is rotary evaporator distillation; the separation and purification method is column chromatography or recrystallization;
has the advantages that:
the deep research and development of the oxidation [3+2] cycloaddition reaction have important effects on the development of organic chemistry and pharmaceutical chemistry, and especially, the method is applied to the synthesis of natural product molecules with important physiological and pharmacological activities, so that the value of the method can be reflected greatly. There are still two needs for improvements and solutions: 1. the selective [3+2] cycloaddition reaction of phenol and polyene compounds to construct spirobenzofuran skeleton has no related report; 2. the oxidation [3+2] cycloaddition reaction is applied to the synthesis of natural products and drug molecules, related literature reports are few, and a great space is still provided for improvement. The method for constructing the spirobenzofuran skeleton by using the oxidation [3+2] cycloaddition reaction as a key is capable of enriching the synthesis of the skeleton; the method is applied to the preparation of natural products aduncutin C and D, can reflect the application value of the method, has high preparation yield and low cost, and greatly breaks through the limitation of the natural product source.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example (b):
a300 mL round bottom flask was preheated with an alcohol burner to remove water for 10 minutes, during which time argon was replaced three times. M-trisphenol (99%, 12.7g,100mmol) and anhydrous potassium carbonate (99%, 13.8g,100mmol,1.0equiv) were added rapidly; argon was replaced three times again. Anhydrous acetone (100mL, commercial acetone dried over anhydrous calcium chloride and distilled at atmospheric pressure) was added. Finally adding dimethyl sulfate (99%, 3.2ml,33mmol,0.33 equiv; the protection measures are needed in the process of adding dimethyl sulfate and are carried out in a ventilated kitchen), and gradually raising the temperature to 55 ℃ for reaction for ten hours. After the reaction was completed, it was cooled to room temperature, and acetone was distilled by a rotary evaporator. Extracting with ethyl acetate (2 × 100mL), washing with 1M hydrochloric acid (2 × 20mL), water (20mL) and saturated saline solution (20mL) in sequence, drying with anhydrous sodium sulfate, distilling the extraction solvent ethyl acetate by a rotary evaporator, concentrating, and separating by column chromatography for 2 times, wherein the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 5:1, and the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 2:1, to obtain colorless oily liquid methoxydiphenol, and obtain 7.56g of methoxydiphenol with the yield of 54%.
A100 mL round bottom flask was preheated with an alcohol burner to remove water for 10 minutes, during which time argon was replaced three times. 3-phenylpropionic acid (98%, 6.1g,40mmol,2.0equiv) and dichloromethane (40mL) were added rapidly. It was placed in a low temperature reactor at 0 ℃ and pre-cooled for 5 minutes. Oxalyl chloride (98%, 4.2ml,50mmol,2.5equiv) was added dropwise over 8 minutes, followed by three drops of N, N-dimethylformamide. Gradually raising the temperature to room temperature for three hours. After the reaction is finished, distilling the excessive oxalyl chloride and dichloromethane solvent by a rotary evaporator, and concentrating to obtain a solution A for later use.
At the same time, another 200mL round bottom flask was preheated with an alcohol burner to remove water for 10 minutes, during which time argon was replaced three times. The methoxydiphenol compound (2.8g,20mmol) and aluminium trichloride (99%, 5.4g,40mmol,2.0equiv) were added rapidly. After dichloromethane (40mL) was added, it was placed in a low temperature reactor at 0 ℃ and pre-cooled for 5 minutes. Solution A (98%, 4.2ml,50mmol,2.5equiv) was then added dropwise over 10 minutes, gradually warming to room temperature for ten hours. After completion of the reaction, the reaction was quenched by adding ice water (10mL) at 0 ℃ (this quenching reaction was carried out in a fume hood). Extracting with ethyl acetate (2 × 60mL), washing with 1M hydrochloric acid solution (2 × 15mL), water (10mL) and saturated saline (10mL) in sequence, drying with anhydrous sodium sulfate, distilling the extraction solvent ethyl acetate with a rotary evaporator, concentrating, and separating by column chromatography for 2 times, wherein the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 8:1, and the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 5:1, to obtain white solid dihydrochalcone, and the dihydrochalcone is obtained in an amount of 4.2g, and the total yield is 42%.
The structure was characterized by TLC thin layer chromatography and nuclear magnetic data. The method comprises the following specific steps: rf＝0.3(petroleumether/EtOAc＝2:1)；1H NMR(400MHz,d-DMSO):δ＝12.32(s,2H),7.30-7.15(m,5H),5.96(s,2H),3.74(s,3H),3.33(t,J＝8.0Hz,2H),2.90(t,J＝7.6Hz,2H)ppm；13C NMR(100MHz,d-DMSO):δ＝205.0,166.0,164.5,142.1,128.8(2C),126.3,105.0,93.7,55.8,45.7,30.6ppm.
A100 mL round-bottom flask was preheated at room temperature with an alcohol burner to remove water for 10 minutes, during which time argon was replaced three times. 4-Isopropylcyclohexanone (2.8g,20mmol) was dissolved in anhydrous dichloromethane (10mL) and added to a round-bottomed flask, which was rinsed twice with 20mL of anhydrous dichloromethane. It is placed in a low-temperature reactor at-78 ℃ and precooled for 5 minutes. Triethylamine (13.9mL,100mmol,5.0equiv) and trimethylsilyl triflate (99%, 10.9mL,60mmol,3.0equiv) were then added sequentially. After the reaction was completed, a saturated sodium bicarbonate solution (20mL) was added at room temperature, the reaction was quenched with stirring for one minute, extracted with dichloromethane (2X 100mL), washed with water (2X 20mL) and saturated brine (20mL) in this order, dried over anhydrous sodium sulfate, the extraction solvent dichloromethane was distilled off by a rotary evaporator, and the silyl ether compound obtained after concentration was carried on to the next step without further purification.
A200 mL round-bottom flask was preheated at room temperature with an alcohol burner to remove water for 10 minutes, during which time argon was replaced three times. The silyl ether compound obtained in the previous step was dissolved in anhydrous dimethyl sulfoxide (40mL), added to a round-bottomed flask, and rinsed twice with 20mL of anhydrous dimethyl sulfoxide. Palladium acetate (99%, 454mg,2.0mmol,0.1equiv) was added at normal temperature, and then an oxygen balloon at one atmosphere pressure was substituted for the reaction apparatus 2 times. After twenty hours of reaction at room temperature, a saturated ammonium chloride solution (5mL) was added and the reaction was quenched with stirring for one minute. The extract was extracted with diethyl ether (2X 80mL), washed successively with water (2X 20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, and the extraction solvent was distilled off in diethyl ether by a rotary evaporator. After concentration, colorless oily liquid B was obtained and was carried on to the next step without further purification.
A200 mL round-bottom flask was preheated at room temperature with an alcohol burner to remove water for 10 minutes, during which time argon was replaced three times. Methyltriphenyliodophosphine (98%, 9.07g,22mmol,1.1equiv) was added rapidly and argon replaced again three times. Anhydrous tetrahydrofuran (80mL) was added and placed in a low temperature reactor at 0 ℃ with precooling for 5 minutes. N-butyllithium (1.6M,12.5ml,20mmol,1.0 equiv; n-butyllithium must be added to ensure that there is no water around and protective glasses are worn, n-hexane and dry sandy soil are prepared next to the test bed for possible safety emergencies) is then added dropwise over a period of 3 minutes, and stirring is carried out at this temperature for thirty minutes to give the phosphine ylide reagent. Finally, the colorless oily liquid B obtained in the previous step was dissolved in anhydrous tetrahydrofuran (25mL) and added dropwise to the round-bottomed flask over 5 minutes, followed by rinsing twice with 20mL of anhydrous tetrahydrofuran. After gradually increasing to room temperature for one hour, a mixed solution of methanol (5mL) and water (5mL) was added, and the reaction was quenched with stirring for one minute. Extracting with dichloromethane (2 × 80mL), washing with water (20mL) and saturated saline solution (20mL) in sequence, drying with anhydrous sodium sulfate, distilling the extraction solvent dichloromethane with a rotary evaporator, concentrating, and separating by column chromatography for 2 times, wherein the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 10:1, the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 5:1, so as to obtain colorless oily liquid beta-phellandrene 2.26g, and the total yield is 83%.
The structure was characterized by TLC thin layer chromatography and nuclear magnetic data. The method comprises the following specific steps: rf＝0.85(petroleum ether/EtOAc＝10:1)；1H NMR(400MHz,CDCl3):δ＝6.16(dd,J＝10.0,2.8Hz,1H),5.76(d,J＝8.8Hz,1H),4.76(d,J＝7.6Hz,2H),2.45(dt,J＝14.8,4.4Hz,1H),2.34-2.25(m,1H),2.09-2.05(m,1H),1.81-1.74(m,1H),1.71-1.63(m,1H),1.47-1.37(m,1H),0.93(d,J＝6.8Hz,3H),0.91(d,J＝6.8Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ＝143.7,134.2,129.5,109.9,42.1,31.9,30.2,25.7,19.7,19.5ppm.
A25 mL two-necked flask was preheated with an alcohol burner to remove water for 10 minutes, during which time argon was replaced three times. Ketone dihydrochalcone (136mg,0.5mmol) and beta-phellandrene (102mg,0.75mmol,1.5equiv) were added rapidly, argon was replaced again twice, and then anhydrous acetonitrile (10mL) was added and dissolved. Silver oxide (99%, 175mg, 0.75mmol,1.5equiv) was added at room temperature. The reaction was gradually raised to 55 ℃ for two hours. After the reaction was completed, it was cooled to room temperature. Filtering by a sand core funnel (filling column chromatography silica gel with the height of 1 cm), rinsing by ethyl acetate (10mL), distilling the solvent by a rotary evaporator, and separating and purifying the generated aductin C and aductin D by column chromatography or recrystallization after concentration.
The structure was characterized by TLC thin layer chromatography and nuclear magnetic data. The method comprises the following specific steps: date for (+) -adungin C Rf＝0.64(petroleum ether/EtOAc＝2:1)；νmax＝2953,1603,1434,1375,1302,1233,1146,1089,1017,958,807,701cm–1；1H NMR(400MHz,CDCl3):δ＝13.36(s,1H),7.27 7.15(m,5H),5.99(s,1H),5.85(d,J＝10.0Hz,1H),5.76(d,J＝10.0Hz,1H),3.82(s,3H),3.40-3.25(m,2H),3.04-2.93(m,2H),2.94(d,J＝15.2Hz,1H),2.86(d,J＝15.2Hz,1H),2.20-2.15(m,1H),1.99-1.93(m,1H),1.67-1.49(m,4H),0.85(d,J＝6.8Hz,3H),0.79(d,J＝6.8Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ＝203.4,165.9,161.8,161.1,141.4,136.1,129.2,128.3,125.9,104.5,101.9,91.8,88.1,55.5,44.1,41.7,38.5,35.5,31.6,30.4,21.9,19.5,19.0ppm；HRMS(ESI):calcd.for C26H31O4 +[M+H]+:407.2217,found:407.2218.
Date for(+)-adunctin D Rf＝0.64(petroleum ether/EtOAc＝2:1)；νmax＝2952,1606,1433,1378,1215,1147,1024,962,808cm–1；1H NMR(400MHz,CDCl3):δ＝13.40(s,1H),7.30-7.17(m,5H),5.99(s,1H),5.85(d,J＝10.0Hz,1H),5.77(d,J＝10.0Hz,1H),3.82(s,3H),3.34-3.21(m,2H),2.99(t,J＝8.0Hz,2H),2.93(s,2H),2.11-2.01(m,1H),1.96(ddd,J＝15.2,12.4,2.4Hz,1H),1.86-1.81(m,1H),1.70-1.62(m,1H),1.51-1.40(m,1H),0.93(d,J＝6.8Hz,3H),0.90(d,J＝6.8Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ＝203.6,166.1,161.8,161.3,141.5,133.2,130.6,128.5,128.3,125.9,104.3,101.9,91.8,90.3,55.6,44.4,41.3,38.5,34.7,31.7,31.0,22.8,19.6,19.2ppm；HRMS(ESI):calcd.for C26H30O4Na+[M+Na]+:429.2036,found:429.2036.
Aiming at target natural products adungin C and D, the synthesis scheme is designed.
Starting from commercially available m-triphenol (CAS:108-73-6, 1039M/500 g) and dimethyl sulfate (Me)2SO4)(CAS:77-78-1255-membered/500 ml) to give monomethylated diphenols, which are subsequently reacted with the readily preparable phenylpropionyl chloride (Ph (CH)2COCl { commercially available 3-phenylpropionic acid (CAS:501-52-0, 298 yuan/500 g) and oxalyl chloride (CAS:79-37-8, 948 yuan/2.5 kg) }, and Friedel-crafts reaction is carried out, so that dihydrochalcone can be prepared in a large amount.
Starting from commercially available 4-isopropylcyclohexanone (CAS:5432-85-9, 5000M/100 g) in triethylamine (Et)3N) (CAS:121-44-8, 55 yuan/500 ml) as base, trimethylsilyl trifluoromethanesulfonate (CAS:27607-77-8, 146 yuan/100 g) to obtain a silyl enol ether intermediate compound, then reacting with catalytic amount of palladium acetate (CAS:3375-31-3, 2850 yuan/5 g) and oxygen to obtain 4-isopropylcyclohexenone, and finally carrying out a wittig reaction under the conditions of N-butyllithium (BuLi) (CAS:109-72-8, 165 yuan/500 ml) and methyl triphenyl phosphine iodide (CAS:2065-66-9, 1498 yuan/500 g) to obtain beta-phellandrene.
After two fragmented compounds of hydrogen chalcone and beta-phellandrene are prepared, the two fragmented compounds are connected on the basis of oxidation [3+2] cycloaddition reaction to construct a spirobenzofuran core skeleton, so that natural products of aductin C and aductin D are prepared.
In conclusion, the invention discloses a preparation method of a spirobenzofuran compound, which takes commercially available phloroglucinol and 4-isopropylcyclohexanone as raw materials, respectively synthesizes dihydrochalcone and beta-phellandrene with exocyclic double bond through Friedel-crafts reaction and Wittig reaction to obtain two fragment compounds of hydrogen chalcone and beta-phellandrene, connects the two fragment compounds through oxidation cycloaddition reaction to construct a spirobenzofuran core skeleton so as to prepare and obtain natural products adungin C and adungin D, develops a new method for constructing the structural unit through organic chemical synthesis means and by guiding the synthesis of target natural products adungin C and adungin D, and simultaneously applies the method to the synthesis preparation of natural products adungin C and adungin D with important physiological and pharmacological activities, and the preparation raw materials are easy to obtain, high yield and low cost, and greatly breaks through the limitation of the natural product source.
Although the present invention has been described with reference to the above embodiments, it should be understood that the present invention is not limited to the above embodiments, and those skilled in the art can make various changes and modifications without departing from the scope of the present invention.
Claims (7)
1. A preparation method of a spirobenzofuran compound is characterized in that the reaction general formula of the spirobenzofuran compound is as follows:
wherein the preparation of the spirobenzofuran compound comprises the following steps:
(1) removing water from a reaction vessel, setting the atmosphere in the reaction vessel as an inert gas environment, rapidly adding m-triphenyl phenol and anhydrous potassium carbonate, sequentially adding anhydrous acetone and dimethyl sulfate, gradually heating up for reaction, cooling a reaction solution to room temperature after the reaction is finished, distilling the acetone, extracting for multiple times, sequentially washing with hydrochloric acid, water and saturated salt water, drying anhydrous sodium sulfate, distilling an extraction solvent, concentrating, and separating to obtain colorless oily liquid methoxyl diphenol;
(2) removing water from a reaction vessel, setting the atmosphere in the reaction vessel to be an inert gas environment, rapidly adding 3-phenylpropionic acid and dichloromethane, placing the reaction vessel into a low-temperature reactor at 0 ℃ for precooling, dropwise adding oxalyl chloride, then adding N, N-dimethylformamide, gradually heating up for reaction, distilling excessive oxalyl chloride and dichloromethane solvent after the reaction is finished, and concentrating into a solution A for later use;
(3) removing water from a reaction vessel, setting the atmosphere in the reaction vessel as an inert gas environment, rapidly adding colorless oily liquid methoxyl diphenol, aluminum trichloride and dichloromethane synthesized in the step (1), placing the reaction vessel into a low-temperature reactor at 0 ℃ for precooling, then dropwise adding the standby solution A in the step (2), gradually heating for reaction, after the reaction is finished, adding ice water for quenching reaction, extracting for multiple times, washing with hydrochloric acid solution, water and saturated salt water in sequence, drying with anhydrous sodium sulfate, distilling the extraction solvent, concentrating and separating to obtain white solid dihydrochalcone;
(4) removing water from a reaction vessel, setting the atmosphere in the reaction vessel as an inert gas environment, dissolving 4-isopropylcyclohexanone in anhydrous dichloromethane in the reaction vessel, placing the reaction vessel in a low-temperature reactor at-78 ℃ for precooling, then sequentially adding triethylamine and trimethylsilyl trifluoromethanesulfonate, after the reaction is finished, adding a saturated sodium bicarbonate solution at normal temperature, stirring for 1min to quench the reaction, repeatedly extracting with dichloromethane, sequentially washing with water and saturated salt water, drying with anhydrous sodium sulfate, distilling the extraction solvent dichloromethane, and concentrating to obtain a silyl ether compound which is directly subjected to the next step without further purification; removing water from the other reaction vessel, setting the atmosphere in the reaction vessel as an inert gas environment, dissolving the obtained silicon ether compound in anhydrous dimethyl sulfoxide, adding the silicon ether compound into the reaction vessel, adding palladium acetate at normal temperature, replacing the reaction vessel with an oxygen balloon at one atmosphere for 2 times, after the reaction is finished at the normal temperature for 20 hours, adding a saturated ammonium chloride solution, stirring for one minute to quench the reaction, extracting with diethyl ether for multiple times, washing with water and saturated salt water in sequence, drying with anhydrous sodium sulfate, distilling the extraction solvent diethyl ether, concentrating to obtain a colorless oily liquid B, and directly carrying out the next step without further purification;
(5) removing water from a reaction container, setting the atmosphere in the reaction container to be an inert gas environment, quickly adding methyl triphenyl phosphine iodide, setting the atmosphere in the reaction container to be the inert gas environment again, adding anhydrous tetrahydrofuran, placing the reaction container into a low-temperature reactor at 0 ℃ for precooling, then adding 1.6M n-butyl lithium dropwise within 3 minutes, stirring for thirty minutes at 0 ℃, dissolving the colorless oily liquid B obtained in the step (4) in the anhydrous tetrahydrofuran, then adding the anhydrous tetrahydrofuran dropwise into the reaction container within 5 minutes, gradually raising the temperature to the normal temperature for reaction for one hour, then adding a mixed solution of methanol and water, stirring for one minute for quenching reaction, extracting with dichloromethane for multiple times, sequentially washing with water and saturated salt water, drying with anhydrous sodium sulfate, distilling an extraction solvent dichloromethane, concentrating and separating to obtain colorless oily liquid beta-phellandrene;
(6) removing water from a reaction container, setting the atmosphere in the reaction container as an inert gas environment, rapidly adding dihydrochalcone and beta-phellandrene, setting the atmosphere in the reaction container as the inert gas environment again, adding anhydrous acetonitrile to dissolve, adding silver oxide at normal temperature, gradually raising the temperature to 55 ℃ to react for two hours, cooling to room temperature after the reaction is finished, filtering by a sand core funnel, rinsing with ethyl acetate, distilling the solvent, concentrating, and separating and purifying generated aduncun C and aduncun D.
2. The process for producing a spirobenzofuran compound according to claim 1, wherein in step (1), said reaction vessel is a round-bottomed flask, and the water is removed by preheating with an alcohol burner for 10 minutes; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; after the anhydrous potassium carbonate is added, setting the atmosphere in the reaction container as an inert gas environment again, wherein the method comprises the step of replacing for 3 times by argon; the mol ratio of m-triphenyl phenol, anhydrous potassium carbonate and dimethyl sulfate is 1: 1: 0.33; the acetone is dried by anhydrous calcium chloride in advance and then is used after being distilled under normal pressure, and when the m-triphenyl phenol is 100mmol, the using amount of the acetone is 100 mL; the temperature is raised to react, the temperature is 55 ℃, and the reaction time is 10 hours; the extractant for multiple extractions is ethyl acetate, the extraction times are 2 times, the hydrochloric acid is 1M, and the acid washing times are 2 times; the separation means is column chromatography, the column chromatography is used for separation for 2 times, the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 5:1, and the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 2: 1.
3. A process for preparing a spirobenzofuran compound according to claim 2, wherein in step (2), said reaction vessel is a round-bottomed flask and said water is removed by preheating with an alcohol burner for 10 minutes; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; the precooling time is 5 min; the time for dropwise adding oxalyl chloride is within 8 min; the temperature is increased to react at room temperature for 3 hours; the solvent distillation mode of the excess oxalyl chloride and the dichloromethane is rotary evaporator distillation; the molar ratio of the 3-phenylpropionic acid to the oxalyl chloride is 4: 5; when the amount of the 3-phenylpropionic acid is 40mmol, the amount of dichloromethane used is 4 mL.
4. The process for producing a spirobenzofuran compound according to claim 2, wherein in said step (3), said reaction vessel is a round-bottomed flask, and said water is removed by preheating with an alcohol burner for 10 minutes; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; the molar ratio of the methoxyl diphenol to the aluminum trichloride is 1:2, and when the methoxyl diphenol is 20mmol, the addition amount of the dichloromethane is 40 mL; the precooling time is 5 min; the time for adding the standby solution A in the step (2) is within 10 min; the temperature is increased to react, the reaction temperature is room temperature, and the reaction time is 10 hours; the quenching reaction condition is that ice water is added at 0 ℃; the extraction is 2 times of ethyl acetate extraction; the hydrochloric acid concentration is 1M, and the pickling is carried out for 2 times; the separation means is column chromatography, the column chromatography is used for separation for 2 times, the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 8:1, and the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 5: 1.
5. The process for producing a spirobenzofuran compound according to claim 2, wherein in said step (4), said reaction vessel is a round-bottomed flask, and said water is removed by preheating with an alcohol burner for 10 minutes; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; the precooling time is 5 min; the dichloromethane is extracted for 2 times, the washing time is 2 times, and the distillation mode of the extraction solvent dichloromethane is rotary evaporator distillation; the molar ratio of the 4-isopropylcyclohexanone to the triethylamine to the trimethylsilyl trifluoromethanesulfonate to the palladium acetate is 1: 5: 3: 0.1; the times of the ether multiple extraction are 2 times, and the times of the water washing are 2 times.
6. The process for producing a spirobenzofuran compound according to claim 2, wherein in step (5), said reaction vessel is a round-bottomed flask, and the water is removed by preheating with an alcohol burner for 10 minutes; the method for setting the atmosphere in the reaction container to be an inert gas environment is argon replacement for 3 times; after the methyl triphenyl phosphine iodide is added, the argon gas is replaced for 3 times by setting the atmosphere in the reaction container to be an inert gas environment again; the precooling time is 5min, and the molar ratio of the methyl triphenyl phosphine iodide to the n-butyl lithium is 1.1: 1; when the methyl triphenyl phosphine iodide is 22mmol, the methanol and the water are respectively 5 ml; the separation means is column chromatography, the column chromatography is used for separation for 2 times, the volume ratio of petroleum ether to ethyl acetate in the 1 st elution phase is 10:1, and the volume ratio of petroleum ether to ethyl acetate in the second elution phase is 5: 1.
7. The process for producing a spirobenzofuran compound according to claim 2, wherein in said step (6), said reaction vessel is a round-bottomed flask, and said water is removed by preheating with an alcohol burner for 10 minutes; the method for setting the atmosphere in the reaction container to be the inert gas environment comprises the following steps: argon gas replacement is carried out for 3 times; the method for setting the atmosphere in the reaction container to be the inert gas environment again after adding the dihydrochalcone and the beta-phellandrene comprises the following steps: argon replacement is carried out for 2 times; the molar ratio of the dihydrochalcone to the beta-phellandrene to the silver oxide is 1:3: 3; when the addition amount of the dihydrochalcone is 0.5mmol, the addition amounts of the anhydrous acetonitrile and the ethyl acetate are respectively 10 mL; the sand core funnel is filled with column chromatography silica gel with the height of 1 cm; the method for distilling the solvent is rotary evaporator distillation; the separation and purification method is column chromatography or recrystallization.
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