CN112608296A - Method for synthesizing brazilanin natural product Brazilane - Google Patents
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Abstract
The invention relates to a synthesis method of Brazilane which is a natural product of Brazilane, wherein a diol compound is subjected to acetic anhydride single protection, Mitsunobu reaction, dess-Martin oxidation reaction and intramolecular Prins/Friedel-Crafts series reaction under catalysis of p-toluenesulfonic acid (p-TsOH), and a one-pot method is used for constructing a key indeno-pyran ring framework structure and the like, so that the Brazilane which is a natural product of Brazilane is synthesized. The method uses conventional chemical reagents, has mild reaction conditions, simple operation, relatively high speed and less reaction byproducts, and greatly shortens the synthesis steps, thereby reducing the synthesis cost.
Description
Technical Field
The invention relates to a synthesis method of a key intermediate of a compound with anticancer activity, in particular to a synthesis method of brazilian natural product Brazilane.
Background
Brazilane belongs to the brazilian lignin class of natural products. The brazilin natural products are a special compound in the traditional Chinese medicine sappan wood, are mainly separated from sappan wood, are discovered successively from the beginning of the 50 s of the 20 th century, and are mainly separated and identified as the following 6 compounds: brazilin, Brazilein, Brazilide A, Haematoxylin, Haematoxylane, and Brazilane. The compounds have similar chemical structures and are homoisoflavone derivatives which all have chroman rings. The structure of Brazilane represents the basic skeletal structure of brazilian lignin natural products, and other compounds are the result of oxidation on the basis of the structure. Brazilane and its family compounds have various biological activities and thus have received attention from many researchers. For example, chemists find that the compound has various biological activities of reducing blood sugar, resisting blood platelet, resisting inflammation, resisting bacteria, resisting tumors, protecting liver, resisting cancers and the like. Due to the unique structure and significant biological activity of Brazilane, many chemical researchers have attracted attention and strived towards synthesizing this molecule.
The chemical structure of Brazilane is as follows:
the chemical methods for synthesizing the natural product Brazilane reported in the literature at present mainly comprise: (1) a research paper entitled The synthesis of Brazilin and Haematoxylin published by Morsingh et al in 1970 on Tetrahedron; (2) a research paper entitled First Synthesis of (+) -Brazilane from (+) -Brazilin published by Jinzhu Xu et al in 1996 on Tetrahedron Letters; (3) lee et al, 2008, published in J. Am. chem. Soc. is a research paper entitled Gold-Catalyzed deoxygenetic catalysis of 2,4-Dien-1-als for Stereoselective Synthesis of high purity substistuted cycles; (4) jhillu Singh Yadav et al published a research paper on Tetrahedron in 2014 entitled Formal Synthesis of (+) -brachilin and total Synthesis of (+) -brachylane; (5) a research paper entitled Design and synthesis of a hybrid frame of orange and chrome, and total synthesis of a homoisolavonoid, Brozilane, published by Jinwoo Kim et al in 2018 on org. Biomol. chem. Through the research on the synthesis routes of target molecules synthesized by the scientific researchers at home and abroad, the detailed analysis shows that the currently reported synthesis routes have the problems of semi-synthesis routes which take natural products with little content as raw materials, longer synthesis steps, difficult individual reaction, expensive reagents and higher toxicity. Therefore, a total synthesis route which shortens the synthesis steps, has common and easily-obtained raw materials and more efficient reaction is sought, and the method becomes the key research direction for synthesizing Brazilane and becomes the urgent need of the people.
Disclosure of Invention
The invention aims to provide a brand-new synthesis method of brazilanin natural product Brazilian, which has the advantages of few synthesis steps, common and easily-obtained raw materials and high reaction efficiency.
In order to achieve the purpose, the invention adopts the technical scheme that: a method for synthesizing brazilian natural product Brazilane comprises the following steps:
step one, taking 3, 4-dimethoxy benzyl alcohol of a compound in a formula 1 as an initial raw material, taking dichloromethane as a solvent, adding triethylamine into the initial raw material, adding methanesulfonyl chloride into the initial raw material, and performing a methanesulfonylation reaction to protect a hydroxyl group to obtain a compound in a formula 2;
dissolving sodium hydride in tetrahydrofuran and N, N-dimethylformamide solution, dropwise adding diethyl malonate into the solution, and then dropwise adding the compound shown in the formula 2 into the reaction solution to react to obtain a compound shown in the formula 3;
step three, dripping the compound of the formula 3 dissolved in the tetrahydrofuran solution into the tetrahydrofuran solution of lithium aluminum hydride for reduction reaction to obtain a compound of a formula 4;
step four, reacting the compound of the formula 4 with acetic anhydride under the condition of taking anhydrous acetonitrile as a solvent to obtain a compound of a formula 5;
step five, dissolving the compound of formula 5 and 3-methoxyphenol in tetrahydrofuran, adding onto the mixture3Carrying out a Mitsunobu reaction in the presence of P to obtain a compound of formula 6;
step six, dissolving the compound shown in the formula 6 in methanol, and then adding K2CO3Reacting at room temperature, and performing deacetylation protection reaction to obtain a compound shown in a formula 7;
seventhly, adding a dess-martin oxidant DMP into the compound of the formula 7 at normal temperature, and carrying out an oxidation reaction by using dichloromethane as a solvent to obtain a compound of a formula 8;
step eight, adding p-toluenesulfonic acid into the compound of the formula 8, and carrying out one-pot intramolecular Prins/Friedel-Crafts series reaction by taking dichloromethane as a solvent to obtain a compound of the formula 9;
dissolving the compound shown in the formula 9 in dichloromethane, adding boron tribromide into the dichloromethane, and removing ether for protection to obtain a target product Brazilane;
the reaction formula is as follows:
further, in the first step, under the protection of nitrogen and at 0 ℃, the compound of formula 1 is dissolved in a dichloromethane solvent, triethylamine and methanesulfonyl chloride are sequentially added dropwise, the mixture is moved to room temperature for reaction, the solution gradually becomes light yellow, dichloromethane is used for extraction, an organic phase is collected, reduced pressure concentration is carried out, and the compound of formula 2 is obtained after separation and purification.
Further, in the second step, under the protection of 0 ℃ and nitrogen, dissolving sodium hydride in anhydrous tetrahydrofuran and N, N-dimethylformamide solutions with equal substance amounts, slowly dropwise adding a diethyl malonate solution dissolved in a tetrahydrofuran solvent into the anhydrous tetrahydrofuran and N, N-dimethylformamide solutions, reacting for 30min at 0 ℃, dropwise adding a tetrahydrofuran solution of the compound of the formula 2 into the tetrahydrofuran solution, then moving the tetrahydrofuran solution to room temperature for continuous reaction, adding a saturated ammonium chloride solution for quenching, extracting with ethyl acetate, concentrating under reduced pressure, separating and purifying to obtain the compound of the formula 3.
Further, in the third step, under the protection of 0 ℃ and nitrogen, dissolving lithium aluminum hydride in an anhydrous tetrahydrofuran solvent, adding a solution of the compound of formula 3 dissolved in the tetrahydrofuran solvent, and stirring; then moving to room temperature for reaction, then adding methanol, 15% sodium hydroxide solution, water and 2M hydrochloric acid solution for quenching, extracting with ethyl acetate, decompressing, concentrating, separating and purifying to obtain the compound of formula 4.
Further, in the fourth step, under the conditions of normal temperature and nitrogen protection and with anhydrous acetonitrile as a solvent, tetrabutylammonium acetate and acetic anhydride are added into the compound of the formula 4, the reaction is completed at 40 ℃, and the compound of the formula 5 is obtained through filtration, reduced pressure concentration, separation and purification.
Further, in the fifth step, under the protection of 0 ℃ and nitrogen, dissolving azodicarbonyl dipiperidine (ADDP) in anhydrous tetrahydrofuran, placing in an ice bath for stirring, wherein the solution is yellow, dropwise adding tributylphosphine to the solution under the condition, after the solution becomes colorless, dropwise adding a compound of formula 5 dissolved in THF and 3-methoxyphenol dissolved in THF into the solution, moving the reaction solution to 70 ℃ for refluxing, carrying out Mitsunobu reaction, concentrating under reduced pressure, and separating and purifying to obtain a compound of formula 6.
Further, in the sixth step, the compound of formula 6 is dissolved in a methanol solvent at normal temperature, potassium carbonate is added, the reaction is completed at room temperature, and the compound of formula 7 is obtained by concentration under reduced pressure, separation and purification.
Further, in the seventh step, the compound shown in the formula 7 is dissolved in dichloromethane, then dess-martin oxidant DMP is added, the reaction is completed at normal temperature, and the compound shown in the formula 8 can be obtained by decompression concentration, separation and purification.
Further, in step eight, the compound of formula 8 is dissolved in dichloromethane, 5.0 times of equivalent of p-toluenesulfonic acid is added into the solution under the protection of nitrogen, the reaction is completed at room temperature, and the compound of formula 9 is obtained by concentration under reduced pressure, separation and purification.
Further, in the ninth step, dropwise adding boron tribromide into a solution of a compound of formula 9 dissolved in anhydrous dichloromethane at-78 ℃, reacting at-78 ℃ for 1 hour, then moving to room temperature for continuous reaction, after complete reaction, concentrating under reduced pressure, separating and purifying to obtain the final product Brazilane.
The invention utilizes diol compounds to carry out single protection by acetic anhydride, Mitsunobu reaction, dess-martin oxidation reaction and intramolecular Prins/Friedel-Crafts series reaction under the catalysis of p-toluenesulfonic acid (p-TsOH), and a one-pot method is used for constructing key indeno-ring pyran ring framework structures and other reactions, thereby synthesizing brazilanine natural products Brazilan.
The method uses conventional chemical reagents, has mild reaction conditions, simple operation, relatively high speed and less reaction byproducts, and greatly shortens the synthesis steps, thereby reducing the synthesis cost.
Drawings
Fig. 1 to 12 are NMR charts of the following compounds, respectively.
FIG. 1 shows a compound of formula 3-1H, FIG. 2 is a compound of formula 4-1H, FIG. 3 is a compound of formula 5-1H, FIG. 4 is a compound of formula 5- 13C, FIG. 5 shows a compound of formula 6-1H, FIG. 6 is a compound of formula 6-13C, FIG. 7 is a compound of formula 7-1H, FIG. 8 is a compound of formula 7-13C, FIG. 9 is a compound of formula 9-1H, FIG. 10 is a compound of formula 9-13C, FIG. 11 is Brazilane-1H, FIG. 12 is Brazilane-13C。
Detailed Description
The invention provides a synthesis method of brazilein natural product Brazilane, which is provided by a typical embodiment and has the following reaction formula:
according to the reaction route, the known compound 1 is used as a starting material, and a hydroxyl group is selectively protected by an acetyl group through a protecting group reaction, a lithium aluminum hydride reduction reaction, a Mitsunobu reaction, a dess-Martin oxidation reaction and a one-pot tandem Prins/Friedel-Crafts reaction and the like are carried out under an acidic condition to synthesize the natural product Brazilane.
The synthesis method provided by the embodiment comprises the following reaction steps:
step one, taking 3, 4-dimethoxy benzyl alcohol of a compound in a formula 1 as an initial raw material, taking dichloromethane as a solvent, adding triethylamine into the initial raw material, adding methanesulfonyl chloride into the initial raw material, and performing a methanesulfonylation reaction to protect a hydroxyl group to obtain a compound in a formula 2;
reacting the compound shown in the formula 2 with sodium hydride and diethyl malonate to obtain a compound shown in a formula 3;
thirdly, carrying out lithium aluminum hydride reduction reaction on the compound of the formula 3 in the presence of lithium aluminum hydride to obtain a compound of a formula 4;
step four, reacting the compound of the formula 4 with acetic anhydride in the presence of tetrabutylammonium acetate to obtain a compound of a formula 5;
step five, reacting the compound of formula 5 with 3-methoxyphenol at ADDP and Bu3Carrying out a Mitsunobu reaction in the presence of P to obtain a compound of formula 6;
step six, reacting the compound of formula 6 in methanol with K2CO3Reacting and removing acetyl protecting group to obtain a compound shown in a formula 7;
step seven, adding an oxidant DMP into the compound of the formula 7, and carrying out an oxidation reaction by using dichloromethane as a solvent to obtain a compound of a formula 8;
step eight, reacting the compound of the formula 8 with p-toluenesulfonic acid by using dichloromethane as a solvent to obtain a compound of a formula 9;
and step nine, reacting the compound shown in the formula 9 with boron tribromide in dichloromethane, and removing ether for protection to obtain the product Brazilane.
The method provided by the embodiment realizes the synthesis of the natural product Brazilane, and has the advantages of relatively high reaction rate, fewer byproducts and high reaction yield; reagents used in the whole route are conventional chemical reagents, are cheap and easy to obtain, and greatly reduce the production cost; the whole reaction condition is mild, the operation process is simple, and the method is suitable for industrial production.
The synthesis process claimed in the present invention is further illustrated in detail and fully by the following examples.
Example 1
Synthesis of compounds of formula 2 and compounds of formula 3:
under the protection of nitrogen, a compound of formula 1 (0.5 g, 2.97 mmol) is dissolved in a dichloromethane solvent, triethylamine (0.83 ml, 5.95 mmol) is added dropwise at 0 ℃, methanesulfonyl chloride (0.35 ml, 4.46 mmol) is added, and then the mixture is moved to room temperature to react for 12 hours. After TLC monitoring reaction was complete, quench with water and add anhydrous Na2SO4Drying was carried out, the organic solvent was removed under reduced pressure, the crude product was isolated and purified by column chromatography (ethyl acetate: petroleum ether =1: 10), and the eluate was concentrated to give 2 (0.59 g) as a pale yellow liquid. Yield: 80 percent.
Dissolving sodium hydride (60% in mineral oil; 0.0513 g, 1.28 mmol) in anhydrous tetrahydrofuran (2 mL) and DMF (2 mL) under the protection of nitrogen at 0 ℃, dropwise adding diethyl malonate (0.24 mL, 1.60 mmol) dissolved in tetrahydrofuran (2 mL) into a reaction system, stirring at 0 ℃ for 30 minutes, then dropwise adding a compound (0.2 g, 1.07 mmol) of a formula 2 dissolved in tetrahydrofuran (2 mL) into the reaction system, then transferring to room temperature for reaction for about 12 hours, after TLC detection reaction is finished, cooling the reaction liquid to 0 ℃ and quenching with saturated ammonium chloride solution, extracting with ethyl acetate (3X 5 mL), combining organic phases, and anhydrous Na2SO4Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1: 15), and concentrating the eluate to obtain colorless oily substance 3 (0.3 g). Yield: 90 percent.1H NMR (400 MHz, CDCl3): δ 6.74 (dd, J = 8.7, 4.9 Hz, 2H), 6.71 (s, 1H), 4.19-4.09 (m, 4H), 3.83 (s, 3H), 3.82 (s, 3H), 3.60 (dd, J = 17.0, 9.2 Hz, 1H), 3.14 (d, J= 7.8 Hz, 2H), 1.30 – 1.14 (m, 6H)。
Synthesis of compounds of formula 4:
under the protection of 0 ℃ and nitrogen, dissolving lithium aluminum hydride (0.0053 g and 0.14 mmol) in anhydrous tetrahydrofuran (1 mL), dropwise adding a compound (0.0218 g and 0.07 mmol) of formula 3 dissolved in tetrahydrofuran (1 mL) into the anhydrous tetrahydrofuran, stirring at 0 ℃ for 30 minutes, then moving to room temperature for reaction for 4 hours, after TLC detection reaction is completed, cooling the reaction system to 0 ℃, quenching with methanol, 15% sodium hydroxide solution, water and 2M hydrochloric acid solution, extracting with ethyl acetate (3 × 10 mL), and extracting with anhydrous Na2SO4The extract was dried, filtered to remove solid impurities, and the product was isolated and purified by column chromatography after distillation under reduced pressure (methanol: dichloromethane =1: 20), and finally the eluate was concentrated to give white solid powder 4 (0.014 g). Yield: 87 percent.1H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 9.9 Hz, 1H), 6.72 (d, J = 4.9 Hz, 2H), 3.86 (dd, J = 3.7, 1.6 Hz, 6H), 3.83 – 3.78 (m, 2H), 3.7.-3.65 (m, 2H), 2.57 (dd, J = 7.4, 2.7 Hz, 2H), 2.35 – 2.12 (m, 2H), 2.07-2.02 (m, 1H), 1.30 – 1.20 (m, 1H)。
Synthesis of compounds of formula 5:
dissolving a compound (0.3 g, 1.33 mmol) of a formula 4 in anhydrous acetonitrile (3 ml), adding weighed tetrabutylammonium acetate (0.28 g, 0.93 mmol), adding acetic anhydride (0.19 ml, 1.99 mmol) into the mixed solution, heating to 40 ℃, and stirring for reaction for 10 hours. After completion of the TLC monitoring reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (3X 10 mL), the organic phase was collected, distilled under reduced pressure, and the product was purified by column chromatography (ethyl acetate: petroleum ether =1: 4), and finally the eluate was concentrated to give 5 (0.26 g, yield 73%) as a pale yellow oil.1H NMR (400 MHz, CDCl3): δ 6.77 (d, J = 8.1 Hz, 1H), 6.70 (d, J=5.73Hz, 2H), 4.16 (dd, J = 11.2, 4.6 Hz, 1H), 4.06 (dd, J = 11.2, 6.5 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.58 (dd, J = 11.3, 4.6 Hz, 1H), 3.50 (dd, J = 11.3, 6.1 Hz, 1H), 2.59 (m, 3H), 2.07 (s, 4H). 13C NMR (100 MHz, CDCl3): δ 171.90, 149.02, 147.99, 131.98, 121.16, 112.28, 111.35, 64.16, 62.12, 56.04, 55.97, 42.64, 34.01, 21.07. HRMS (ESI) calcd for C14H21O5 [M+H]+ 269.1389, found 269.1388。
Synthesis of compounds of formula 6:
dissolving ADDP (0.6827 g, 2.71 mmol) in tetrahydrofuran (6 ml) at 0 ℃ under the protection of nitrogen, slowly dropwise adding tributylphosphine (0.77 ml, 3.07 mmol), and after the solution turns colorless from yellow, sequentially dropwise adding a compound (0.33 g, 1.23 mmol) of formula 5 dissolved in tetrahydrofuran (6 ml) and 3-methoxyphenol (0.1 ml, 1.00 mmol) dissolved in tetrahydrofuran (6 ml) into the reaction systeml), then refluxing and heating at 70 ℃ for 12 hours, and after the TLC detection reaction is finished, carrying out reduced pressure distillation and then separating and purifying the product by column chromatography (ethyl acetate: petroleum ether =1: 5), and the eluate was finally concentrated to give a pale yellow liquid 6 (0.3620 g). Yield: 87 percent.1H NMR (400 MHz, CDCl3): δ 7.16 (t, J = 8.2 Hz, 1H), 6.78 (d, J=6.57Hz, 1H), 6.71 (dd, J = 8.1, 1.9 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.52 – 6.44 (m, 3H), 4.23-4.13(m, 2H), 3.91 – 3.83 (m, 5H), 3.78 (s, 3H), 3.75 (s, 3H), 2.81 – 2.70 (m, 2H), 2.42 – 2.35 (m, 1H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.23, 161.01, 160.25, 149.00, 147.64, 131.57, 130.07, 121.26,112.42, 111.36,106.85, 106.53, 101.13, 66.65, 64.48,56.05, 55.85, 55.45, 40.15, 34.15, 21.13. HRMS (ESI) calcd. for C21H27O6 [M+H]+ 375.1808, found 375.1808。
Synthesis of compounds of formula 7:
at room temperature, the compound of formula 6 (0.2746 g, 0.81 mmol) was dissolved in methanol (5 mL), potassium carbonate (0.1683 g, 1.22 mmol) was added, the reaction was stirred at room temperature for 4 hours, after completion of the TLC detection reaction, water was added to quench the reaction, ethyl acetate (3 × 5 mL) was extracted, the product was purified by column chromatography after distillation under reduced pressure (ethyl acetate: petroleum ether =1: 3), and finally the eluate was concentrated to give a pale yellow liquid 7 (0.2401 g). Yield: 89 percent.1H NMR (400 MHz, CDCl3): δ 7.16 (t, J = 8.2 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.72 (dd, J = 10.4, 2.2 Hz, 2H), 6.52 – 6.44 (m, 3H), 3.97 (dd, J = 9.2, 4.5 Hz, 1H), 3.91 (dd, J = 9.2, 5.9 Hz, 1H), 3.84 (s, 3H), 3.80 – 3.71 (m, 8H), 2.74 (d, J = 7.0 Hz, 2H), 2.29 – 2.19 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 160.97, 160.17, 148.96, 147.51, 132.25, 130.08, 121.17, 112.40, 111.31, 106.85, 106.59, 101.09, 68.36, 63.88, 56.02, 55.84, 55.42, 42.90, 34.01. HRMS (ESI) calcd for C19H25O5[M+H]+ 333.1702, found 333.1702。
Synthesis of compounds of formula 8:
dissolving the compound (0.1484 g, 0.45 mmol) of the formula 7 in dichloromethane (3 mL) at room temperature, sequentially adding sodium bicarbonate (0.1313 g, 1.56 mmol) and dess-Martin oxidant (0.38 g, 0.9 mmol), stirring at room temperature for reacting for 4 hours, quenching the reaction with saturated aqueous sodium chloride solution after TLC detection reaction is finished, adding dichloromethane into the mixed system for extraction (3X 10 mL), combining the obtained organic phases, adding anhydrous Na2SO4Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1: 5), and concentrating the eluate to obtain dark yellow thick liquid 8 (0.1224 g). Yield: 83 percent.
Synthesis of a compound of formula 9:
the compound of formula 8 (0.47 g, 1.43 mmol) was dissolved in dichloromethane (6 ml) at room temperature, p-toluenesulfonic acid (1.35 g, 7.11 mmol) was added to the reaction mixture, and the reaction was carried out at room temperature for 1 hour. After completion of TLC detection, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (3X 10 mL), the organic phase was collected, washed with saturated brine, the organic solvent was removed under reduced pressure, the product was purified by column chromatography (ethyl acetate: petroleum ether 1: 10), and the eluate was concentrated to give a white solid 9 (0.24 g). Yield: 51 percent.1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.5 Hz, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.60 (dd, J = 8.4 , 2.6 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 4.23 (d, J = 6.5 Hz, 1H), 4.13 (dd, J = 10.9, 4.4 Hz, 1H), 3.87 – 3.84 (m, 6H), 3.77 (s, 3H), 3.63 (t, J = 10.6 Hz, 1H), 3.18 (dd, J = 15.7, 7.2 Hz, 1H), 2.92 (tdd, J = 6.4, 4.2, 2.0 Hz, 1H), 2.60 (dd, J = 15.7, 2.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 199.31, 155.73, 148.99, 148.38, 137.45, 132.80, 130.87, 116.08, 108.56, 108.15, 108.01, 102.00, 67.04, 56.29, 56.24, 55.50, 43.40, 37.07, 34.22, 29.91. HRMS (ESI) calcd forC19H21O4[M+H]+ 313.1440, found 313.1440。
Synthesis of Brazilane:
the compound of formula 9 (0.1 g) was dissolved in dichloromethane (3 ml) and boron tribromide (1.53 ml, 1.53 mmol, 1M in CH) was reacted at-78 ℃2Cl2) Slowly dropwise adding into the mixture, reacting at the same temperature for 1 hr, transferring to room temperature, reacting for 1 hr, detecting by TLC, quenching with water solution, extracting with ethyl acetate (3 × 10 mL), mixing the organic phases, adding anhydrous MgSO4Drying, filtering to remove solid impurities, distilling under reduced pressure, and separating and purifying the product by column chromatography (ethyl acetate: petroleum ether: dichloromethane =1:1: 1), and finally concentrating the eluate to obtain Brazilane (0.055 g) as a red solid. Yield: and 63 percent.1H NMR (400 MHz, MeOD): δ 7.07 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 6.51 (s, 1H), 6.31 (dd, J = 8.3, 2.5 Hz, 1H), 6.11 (d, J = 2.5 Hz, 1H), 4.00 – 3.89 (m, 2H), 3.36 (t, J = 10.6 Hz, 1H), 2.93 (dd, J = 15.6, 7.1 Hz, 1H), 2.69 – 2.62 (m, 1H), 2.35 (dd, J = 15.6, 1.9 Hz, 1H), 1.89 (s, 1H), 1.15 (t, J=7.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 157.73, 156.79, 145.47, 145.20, 138.37, 133.25, 132.16, 116.76, 112.98, 112.63, 109.67, 104.33, 67.88, 44.28, 38.43, 34.63. HRMS (ESI) calcd for C16H15O4 [M+H]+ 271.0970, found 271.0968。
Claims (10)
1. A method for synthesizing brazilian natural product Brazilane is characterized by comprising the following steps: the method comprises the following steps:
step one, taking 3, 4-dimethoxy benzyl alcohol of a compound in a formula 1 as an initial raw material, taking dichloromethane as a solvent, dropwise adding triethylamine into the initial raw material, then adding methanesulfonyl chloride, and carrying out a methanesulfonylation reaction to protect a hydroxyl group, thereby obtaining a compound in a formula 2;
dissolving sodium hydride in tetrahydrofuran and N, N-dimethylformamide solution, dropwise adding diethyl malonate into the solution, and then dropwise adding the compound shown in the formula 2 into the reaction solution to react to obtain a compound shown in the formula 3;
step three, dripping the compound of the formula 3 dissolved in the tetrahydrofuran solution into the tetrahydrofuran solution of lithium aluminum hydride for reduction reaction to obtain a compound of a formula 4;
step four, reacting the compound of the formula 4 with acetic anhydride under the condition of taking anhydrous acetonitrile as a solvent to obtain a compound of a formula 5;
step five, dissolving the compound of formula 5 and 3-methoxyphenol in tetrahydrofuran, adding onto the mixture3Carrying out a Mitsunobu reaction in the presence of P to obtain a compound of formula 6;
step six, dissolving the compound shown in the formula 6 in methanol, and then adding K2CO3Reacting at room temperature, and performing deacetylation protection reaction to obtain a compound shown in a formula 7;
seventhly, adding a dess-martin oxidant DMP into the compound of the formula 7 at normal temperature, and carrying out an oxidation reaction by using dichloromethane as a solvent to obtain a compound of a formula 8;
step eight, adding p-toluenesulfonic acid into the compound of the formula 8, and carrying out one-pot intramolecular Prins/Friedel-Crafts series reaction by taking dichloromethane as a solvent to obtain a compound of the formula 9;
dissolving the compound shown in the formula 9 in dichloromethane, adding boron tribromide into the dichloromethane, and removing ether for protection to obtain a target product Brazilane;
the reaction formula is as follows:
2. the method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: in the first step, the compound of the formula 1 is dissolved in a dichloromethane solution at 0 ℃ under the protection of nitrogen, then triethylamine and methanesulfonyl chloride are sequentially added dropwise, the mixture is moved to room temperature for reaction, the solution gradually becomes light yellow, dichloromethane is used for extraction, an organic phase is collected, reduced pressure concentration is carried out, and the compound of the formula 2 is obtained after separation and purification.
3. The method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: and step two, dissolving sodium hydride in anhydrous tetrahydrofuran and N, N-dimethylformamide solutions with the same amount of substances at 0 ℃ under the protection of nitrogen, slowly dropwise adding a diethyl malonate solution dissolved in a tetrahydrofuran solvent into the anhydrous tetrahydrofuran and N, N-dimethylformamide solutions to react for 30min at 0 ℃, dropwise adding a tetrahydrofuran solution of the compound of the formula 2 into the tetrahydrofuran solution, then moving the tetrahydrofuran solution to room temperature to continue reacting, adding a saturated ammonium chloride solution to quench, extracting with ethyl acetate, concentrating under reduced pressure, separating and purifying to obtain the compound of the formula 3.
4. The method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: in the third step, under the protection of 0 ℃ and nitrogen, dissolving lithium aluminum hydride in an anhydrous tetrahydrofuran solvent, adding a solution of the compound of formula 3 dissolved in the tetrahydrofuran solvent, and stirring; then moving to room temperature for reaction, then adding methanol, 15% sodium hydroxide solution, water and 2M hydrochloric acid solution for quenching, extracting with ethyl acetate, decompressing, concentrating, separating and purifying to obtain the compound of formula 4.
5. The method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: in the fourth step, under the conditions of normal temperature and nitrogen protection and with anhydrous acetonitrile as a solvent, tetrabutylammonium acetate and acetic anhydride are added into the compound of the formula 4, the reaction is completed at 40 ℃, and the compound of the formula 5 is obtained through filtration, reduced pressure concentration, separation and purification.
6. The method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: in the fifth step, azodicarbonyl dipiperidine (ADDP) is dissolved in anhydrous tetrahydrofuran under the protection of nitrogen and at 0 ℃, the mixture is placed in an ice bath and stirred, the solution is yellow, tributylphosphine is dropwise added into the solution under the condition, after the solution becomes colorless, a compound of a formula 5 dissolved in THF and 3-methoxyphenol dissolved in THF are dropwise added into the solution, the reaction solution is moved to 70 ℃ and refluxed to generate a Mitsunobu reaction, and the compound of the formula 6 is obtained through decompression concentration, separation and purification.
7. The method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: and sixthly, dissolving the compound shown in the formula 6 in a methanol solvent at normal temperature, adding potassium carbonate, reacting completely at room temperature, concentrating under reduced pressure, and separating and purifying to obtain the compound shown in the formula 7.
8. The method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: and seventhly, dissolving the compound shown in the formula 7 in dichloromethane, adding a dess-martin oxidant DMP, reacting completely at normal temperature, concentrating under reduced pressure, and separating and purifying to obtain the compound shown in the formula 8.
9. The method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: and step eight, dissolving the compound shown in the formula 8 in dichloromethane, adding 5.0 time equivalent of p-toluenesulfonic acid into the solution under the protection of nitrogen, completely reacting at room temperature, concentrating under reduced pressure, and separating and purifying to obtain the compound shown in the formula 9.
10. The method for synthesizing brazilian natural product Brazilane according to claim 1, wherein: in the ninth step, dropwise adding boron tribromide into a solution of a compound of formula 9 dissolved in anhydrous dichloromethane at-78 ℃, reacting at-78 ℃ for 1 hour, moving to room temperature for continuous reaction, concentrating under reduced pressure after complete reaction, and separating and purifying to obtain a final product Brazilane.
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