A method for synthesizing the natural product Moracin N

Abstract

The application discloses a synthetic method of natural product Moracin N and belongs to the technical field of organic synthesis. The application takes an aldehyde containing a benzene ring as a starting raw material, introduces an isopentenyl group on the benzene ring through a Friedel-Crafts reaction, connects a hydroxyl protecting group to a No. 4 position hydroxyl group of the benzene ring to obtain an intermediate II, then uses a phosphorus ylide reagent to prepare the intermediate II into gem-dibromo olefin to obtain an intermediate III, then under the catalysis of a base and a copper catalyst, the gem-dibromo vinyl group is coupled with an ortho hydroxyl group to form a benzofuran ring to obtain an intermediate IV, then 3,5-dihydroxy bromobenzene is introduced to the right side of the benzofuran ring of the intermediate IV through a Suzuki-Miyaura reaction to obtain an intermediate VI, and finally the hydroxyl protecting group of the intermediate VI is removed to obtain Moracin N. The synthetic route of the application is simple, the reaction condition is mild, the safety is high, the required raw material is cheap and easy to obtain, the total cost is low, and the application is suitable for industrialized preparation.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing the natural product Moracin N. Background Technology

[0002] Moracin N is a natural isopentenyl phenolic compound derived from mulberry leaves, and its general structural formula is shown below:

[0003]

[0004] Studies have shown that Moracin N, as a novel inhibitor of ferroptosis, possesses excellent neuroprotective activity (EC50 < 0.50 μM), antagonizing neuronal cell death by inhibiting ferroptosis through multiple mechanisms. However, obtaining natural Moracin N molecules solely through plant extraction is inefficient and costly. Therefore, there is an urgent need to develop efficient and concise methods for the large-scale synthesis of Moracin N, thereby promoting its development and application in the biomedical field.

[0005] In terms of chemical synthesis, only the Kyeong Lee research group in South Korea has reported a one-pot synthesis of 2-bromo-6-(ethoxymethoxy)-5-(3-methylbut-2-en-1-yl)benzofuran using 2,4-dihydroxy-5-(3-methylbut-2-en-1-yl)benzaldehyde as a raw material and Zn powder. Moracin N was then obtained by coupling via the Suzuki reaction. However, the Zn powder used in this route is a Class 4.3 hazardous material, which is flammable and explosive when wet, and has poor environmental protection and safety in industrial production. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for synthesizing the natural product Moracin N, so as to solve the technical problems of complex and insufficient safety of existing synthetic routes.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a method for synthesizing the natural product Moracin N is provided, comprising the following steps: using an aldehyde containing a benzene ring as a starting material, an isopentenyl group is introduced onto the benzene ring via a Friedel-Crafts reaction to obtain intermediate one; a hydroxyl protecting group is attached to the hydroxyl group at position 4 of intermediate one to obtain intermediate two; then, intermediate two is prepared into a geminal dibromoalkene using a phosphorus ylide reagent to obtain intermediate three; then, under alkaline conditions and catalysis by a copper catalyst, the geminal dibromoethene of intermediate three is coupled with an ortho-hydroxyl group to form a benzofuran ring to obtain intermediate four; then, 3,5-dihydroxybromobenzene is introduced to the right side of the benzofuran ring of intermediate four via a Suzuki-Miyaura reaction to obtain intermediate six; finally, the hydroxyl protecting group of intermediate six is ​​removed to obtain Moracin N.

[0008] Based on the above technical solution, the present invention can be further improved as follows:

[0009] Furthermore, the reagent that provides the hydroxyl protecting group is an ether.

[0010] Furthermore, the method for synthesizing the natural product Moracin N includes the following steps:

[0011] S1. Aldehydes containing benzene rings are mixed with acid catalysts at a molar ratio of 0.5-1.5:1.1-1.6 and reacted for 4-5 hours to obtain intermediate one;

[0012] S2. Add alkali to intermediate one and react for 10-20 min, then add ether and phase transformation catalyst and react for 20-60 min to obtain intermediate two; the molar ratio of intermediate two, alkali, ether and phase transformation catalyst is 0.5-1.5:1.2-1.5:1-1.5:0.03-0.07.

[0013] S3. Intermediate II and phosphorus ylide reagent are mixed at a molar ratio of 1:2.5-3.5 and reacted for 1.5-2.5 h to obtain intermediate III;

[0014] S4. Intermediate III, alkali and copper catalyst are mixed in a molar ratio of 0.5-1.5:3-4:0.03-0.07 and reacted at 75-90℃ for 4-5 hours to obtain intermediate IV.

[0015] S5. Mix 3,5-dihydroxybromobenzene, borate, base and palladium catalyst in a molar ratio of 0.5-1.5:1-2:1-2:0.03-0.07 and react at 90-100℃ for 5-6 h to obtain intermediate five.

[0016] S6. Intermediate IV, Intermediate V, base and palladium catalyst are mixed in a molar ratio of 0.5-1.5:1-2:1.5-2.5:0.03-0.07 and reacted at 70-80℃ for 5-6 hours to obtain Intermediate VI.

[0017] S7. Mix intermediate hexamethasone and cationic resin at a mass ratio of 1-2:1-2 and react at 25-35℃ for 24-48h to obtain Moracin N.

[0018] Furthermore, intermediate one is 2,4-dihydroxy-5-(3-methylbut-2-en-1-yl)benzaldehyde; intermediate two is 4-(ethoxymethoxy)-2-hydroxy-5-(3-methylbut-2-en-1-yl)benzaldehyde; intermediate three is 2-(2,2-dibromovinyl)-5-(ethoxymethoxy)-4-(3-methylbut-2-en-1-yl)phenol; intermediate four is 2-bromo-6-(ethoxymethoxy)-5-(3-methylbut-2-en-1-yl)benzofuran; intermediate five is 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzene-1,3-diol; and intermediate six is ​​5-(6-(ethoxymethoxy)-5-(3-methylbut-2-en-1-yl)benzofuran-2-yl)benzene-1,3-diol).

[0019] Furthermore, the aldehyde containing a benzene ring is 2,4-dihydroxybenzaldehyde.

[0020] Furthermore, the acid catalyst is boron trifluoride diethyl ether and 2-methyl-3-buten-2-ol.

[0021] Furthermore, the molar ratio of boron trifluoride ether to 2-methyl-3-buten-2-ol is 1-1.5:0.03-0.07.

[0022] Furthermore, the base is potassium carbonate, potassium phosphate, or potassium acetate; the ether is 1-chloromethyl ethyl ether, methoxymethyl ether, or chloromethyl methyl ether; and the phase transformation catalyst is tetrabutylammonium iodide.

[0023] Furthermore, the preparation process of phosphorus ylide reagent is as follows: triphenylphosphine, carbon tetrabromide and triethylamine are mixed and reacted at -5 to 5℃ for 10-15 min to obtain the reagent.

[0024] Furthermore, the copper catalyst is cuprous iodide; the borate is pinacol diborate or pinacol borane; and the palladium catalyst is 1,1-bis(diphenylphosphine)ferrocene palladium dichloride.

[0025] Furthermore, cationic resin is 50WX.

[0026] The beneficial effects of this invention are as follows:

[0027] 1. This invention uses triethylamine, which has high safety and good environmental performance, to replace Zn powder in the generation of phosphorus ylide reagents. 1-Chloromethyl ethyl ether (EOM) is used as a reagent to provide hydroxyl protecting groups. Compared with commonly used and carcinogenic 1-chloromethyl methyl ether (MOM) protecting groups, it is safer and the removal conditions are milder. Only cation exchange resin is needed.

[0028] 2. The synthetic route of this invention is simple, the reaction conditions are mild, the safety is high, and the raw materials required are inexpensive and readily available, resulting in a low total cost, making it suitable for industrial preparation. Attached Figure Description

[0029] Figure 1 This is a synthetic route diagram of the present invention;

[0030] Figure 2 High-resolution mass spectrum of Moracin N;

[0031] Figure 3 The 1H NMR spectrum of Moracin N is shown. Detailed Implementation

[0032] The specific embodiments of the present invention are described below to facilitate understanding of the invention by those skilled in the art. Unless otherwise specified, specific conditions are applied according to conventional conditions or the manufacturer's recommendations. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products. However, it should be understood that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, various modifications are obvious as long as they fall within the spirit and scope of the invention as defined and determined by the appended claims. All inventions utilizing the concept of this invention are protected.

[0033] Example 1

[0034] A method for synthesizing the natural product Moracin N is as follows: Figure 1 As shown, it includes the following steps:

[0035] S1. 2,4-Dihydroxybenzaldehyde (3 g, 1 eq, 21.7 mmol) was dissolved in 10 mL of dioxane, followed by the simultaneous addition of boron trifluoride ether (1.3 mL, 5 mol%) and 2-methyl-3-buten-2-ol (3 mL, 1.2 eq, 28.24 mmol). The mixture was stirred for 4 h. After the reaction was completed, 10 mL of ethyl acetate and 30 mL of water were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), and dried with anhydrous magnesium sulfate for 2 h. The mixture was purified by column chromatography (ethyl acetate to n-hexane volume ratio of 1:10) to give 0.4 g of off-white solid intermediate 1 (2,4-dihydroxy-5-(3-methylbuten-2-en-1-yl)benzaldehyde), with a yield of 34%.

[0036] The structure of intermediate one was characterized, and the results are as follows: 1H NMR (600MHz, CDCl3) δ11.18(s,1H),9.61(s,1H),7.16(s,1H),6.30(s,1H),5.22(t,J=7.2Hz,1H),3.23(d,J=7.3Hz,2H),1.72(s,3H),1.69(s,3H);

[0037] S2. Intermediate 1 (0.44 g, 1 eq, 4.8 mmol) was dissolved in 10 mL of anhydrous acetonitrile, followed by the addition of potassium carbonate (0.87 g, 1.3 eq, 6.3 mmol) and a reaction mixture of 1-chloromethyl ethyl ether (0.53 mL, 1.2 eq, 5.8 mmol) and tetrabutylammonium iodide (0.09 g, 5 mol%, 0.24 mmol) and a stirring mixture for 30 min. After the reaction was complete, the mixture was filtered through diatomaceous earth, and 20 μL of the solution was collected. 20 mL of ethyl acetate and 20 mL of water were added to the crude product, and the two phases separated. The aqueous phase was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 3). Finally, the product was dried over anhydrous magnesium sulfate and purified by column chromatography (the volume ratio of ethyl acetate to n-hexane was 1:20) to obtain 0.35 g of the colorless oily intermediate di(4-(ethoxymethoxy)-2-hydroxy-5-(3-methylbut-2-en-1-yl)benzaldehyde), with a yield of 62%.

[0038] The structure of intermediate 2 was characterized, and the results are as follows: 1 H NMR (600MHz, CDCl3) δ11.24(s,1H),9.63(s,1H),7.17(s,1H),6.58(s,1H),5.22(s,2H),5.19(t,1 H),3.65(q,J=7.1Hz,2H),3.17(d,J=7.4Hz,2H),1.69(s,3H),1.63(s,3H),1.16(t,J=7.1Hz,3H);

[0039] S3. Triphenylphosphine (2.38 g, 6 eq, 9.08 mmol) and carbon tetrabromide (1.51 g, 3 eq, 9.1 mmol) were dissolved in dichloromethane, respectively. The triphenylphosphine and carbon tetrabromide solutions were then mixed and reacted at 0 °C for 10 min. Triethylamine (1.26 mL, 6 eq, 9.08 mmol) was then added, and the reaction was continued for 5 min to obtain the phosphorus ylide reagent. Intermediate 2 (0.4 g, 1 eq, 1.51 mmol) was then added to the phosphorus ylide reagent, and the mixture was stirred at 10 °C. Stir for 30 minutes to ensure uniform mixing of the raw materials, then raise the temperature to room temperature and continue stirring until the raw materials disappear. Adjust the pH of the mixture to neutral using a saturated ammonium chloride aqueous solution. Finally, rinse with saturated brine (30 mL × 3), dry with anhydrous magnesium sulfate for 2 hours, and purify by column chromatography (ethyl acetate to n-hexane volume ratio of 1:8) to obtain 0.312 g of the yellow oily intermediate tris(2-(2,2-dibromoethenyl)-5-(ethoxymethoxy)-4-(3-methylbut-2-en-1-yl)phenol, with a yield of 70%.

[0040] The structure of intermediate three was characterized, and the results are as follows: 1 H NMR (600MHz, CDCl3) δ7.43(s,1H),7.31(s,1H),6.54(s,1H),5.19(t,J=1.5Hz,1H),5.14(s,2H) ,3.66(q,J=7.1Hz,2H),3.17(d,J=7.4Hz,2H),1.66(s,3H),1.63(s,3H),1.16(t,J=7.1Hz,3H);

[0041] S4. Add intermediate tris (0.312 g, 1 eq, 0.74 mmol), potassium phosphate (0.55 g, 3.5 eq, 2.6 mmol), cuprous iodide (0.007 g, 5 mol%, 0.005 mmol), and 3 mL of anhydrous tetrahydrofuran to a sealed tube. Stir the mixture at 85 °C for 4 h. After the reaction is complete, cool to room temperature, filter with diatomaceous earth, concentrate, and purify by column chromatography (100% n-hexane) to obtain 0.22 g of the light yellow oily intermediate tetra(2-bromo-6-(ethoxymethoxy)-5-(3-methylbut-2-en-1-yl)benzofuran), with a yield of 55%.

[0042] The structure of intermediate four was characterized, and the results are as follows: 1H NMR (600MHz, CDCl3) δ7.17(s,1H),7.15(s,1H),6.51(s,1H),5.23(t,1H),5.19(s,2H),3. 67(q,J=7.1Hz,2H),3.29(d,J=7.4Hz,2H),1.66(d,J=14.7Hz,6H),1.16(t,J=7.1Hz,3H);

[0043] S5. 3,5-Dihydroxybromobenzene (1.5 g, 1 eq, 7.98 mmol), pinacol diboronate (3.03 g, 1.5 eq, 11.97 mmol), and potassium acetate (1.335 g, 1.5 eq, 11.97 mmol) were added to 15 mL of dioxane. After degassing for 3 min, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.285 g, 5 mol%, 0.59 mmol) was added, and degassing continued for another 3 min. The mixture was then reacted at 100 °C for 6 h. After the reaction was completed, the mixture was filtered with diatomaceous earth and 20 mL of ethyl acetate and 30 mL of water were added. The aqueous phase was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate for 2 h, and purified by column chromatography (the volume ratio of ethyl acetate to n-hexane was 1:6) to give 1.61 g of off-white solid intermediate penta-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl-1,3-diol), with a yield of 85%.

[0044] The structure of intermediate five was characterized, and the results are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.20 (s, 2H), 6.59 (d, J = 2.3Hz, 2H), 6.34 (t, J = 2.3Hz, 1H), 1.32 (s, 12H);

[0045] S6. Add intermediate four (0.22 g, 1 eq, 0.65 mmol), intermediate five (0.19 g, 1.2 eq, 0.78 mmol), potassium phosphate (0.28 g, 2 eq, 1.3 mmol), and 3 mL to the sealed tube. N,N-dimethylformamide and 1 mL of water were degassed for 5 min, and then 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.03 g, 5 mol%) was added. Degassed for another 5 min, and then the mixture was stirred at 75 °C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and 10 mL of ethyl acetate and 10 mL of water were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, and then washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous magnesium sulfate for 2 h and purified by column chromatography (the volume ratio of ethyl acetate to n-hexane was 1:2) to obtain 0.24 g of the light yellow liquid intermediate hexa(5-(6-(ethoxymethoxy)-5-(3-methylbut-2-en-1-yl)benzofuran-2-yl)phenyl-1,3-diol).

[0046] The structure of intermediate six was characterized, and the results are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.51(s,2H),7.38(s,1H),7.34(s,1H),7.16(s,1H),6.75(d,J=2.2Hz,2H),6.28(s,1H ),5.38(s,2H),5.35(t,1H),3.75(q,J=7.1Hz,2H),3.38(d,J=7.5Hz,2H),1.76(s,6H),1.21(t,J=7.1Hz,3H);

[0047] S7. Mix 0.24g of intermediate six and 0.24g of... 50WX cation exchange resin was added to anhydrous MeOH, 2 drops of concentrated hydrochloric acid were added, and the reaction was carried out at 35°C for 42 h. After filtration, the mixture was purified by column chromatography (the volume ratio of ethyl acetate to n-hexane was 1:2) to obtain 0.13 g of white solid Moracin N, with a yield of 64%.

[0048] The structure of Moracin N was characterized, and the results are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.62(s,1H),9.45(s,2H),7.26(s,1H),7.08(s,1H),7.00(s,1H),6.71(d,J=2.1Hz ,2H),6.25(t,J=2.2Hz,1H),5.37(t,1H),3.33(d,J=7.4Hz,2H),1.75(d,J=14.4Hz,6H).HRMS(ESI+):calcd forC19 H 19 O4[M+H] + 311.1278, found 311.1278.

[0049] High-resolution mass spectrum of Moracin N as shown in Figure 2 As shown, the proton NMR spectrum is as follows: Figure 3 As shown.

[0050] Example 2

[0051] A method for synthesizing the natural product Moracin N includes the following steps:

[0052] S1. 2,4-Dihydroxybenzaldehyde (3 g, 1 eq, 21.7 mmol) was dissolved in 10 mL of dioxane, followed by the simultaneous addition of boron trifluoride diethyl ether (1.3 mL, 5 mol%) and 2-methyl-3-buten-2-ol (3 mL, 1.2 eq, 28.24 mmol), and the mixture was stirred for 5 h. After the reaction was completed, 10 mL of ethyl acetate and 30 mL of water were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), and then dried with anhydrous magnesium sulfate for 2 h. The mixture was purified by column chromatography (ethyl acetate to n-hexane volume ratio of 1:10) to obtain intermediate one.

[0053] S2. Intermediate 1 (0.88 g, 2 eq, 9.6 mmol) was dissolved in 20 mL of anhydrous acetonitrile, followed by the addition of potassium carbonate (1.74 g, 2.6 eq, 12.6 mmol) and reaction for 15 min. Then, methoxymethyl ether (1.06 mL, 2.4 eq, 11.6 mmol) and tetrabutylammonium iodide (0.18 g, 5 mol%, 0.48 mmol) were added to the reaction solution and stirred for 60 min. After the reaction was completed, the mixture was filtered through diatomaceous earth. 40 mL of ethyl acetate and 40 mL of water were added to the crude product, and the two phases were separated. The aqueous phase was then extracted with ethyl acetate (40 mL × 3). The organic phases were combined and washed with saturated brine (60 mL × 3). Finally, the mixture was dried over anhydrous magnesium sulfate and purified by column chromatography (ethyl acetate to n-hexane volume ratio of 1:20) to obtain intermediate 2.

[0054] S3. Triphenylphosphine (2.38 g, 6 eq, 9.08 mmol) and carbon tetrabromide (1.51 g, 3 eq, 9.1 mmol) were dissolved in dichloromethane, and then the triphenylphosphine and carbon tetrabromide solutions were mixed and reacted at -5 °C for 10 min. Triethylamine (1.26 mL, 6 eq, 9.08 mmol) was then added, and the reaction was continued for 5 min to obtain phosphorus ylide reagent. Intermediate II (0.4 g, 1 eq, 1.51 mmol) was then added to the phosphorus ylide reagent. The mixture was first stirred at 10 °C for 30 min to ensure homogeneity of the starting materials, then the temperature was raised to room temperature, and the reaction was continued with stirring until the starting materials disappeared. The pH of the mixture was adjusted to neutral with saturated ammonium chloride aqueous solution. Finally, the mixture was washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate for 2 h, and purified by column chromatography (ethyl acetate to n-hexane volume ratio of 1:8) to obtain intermediate III.

[0055] S4. Add intermediate tri (0.624 g, 2 eq, 1.48 mmol), potassium phosphate (1.1 g, 7 eq, 5.2 mmol), cuprous iodide (0.014 g, 5 mol%, 0.01 mmol) and 6 mL of anhydrous tetrahydrofuran to a sealed tube, and stir the reaction at 75 °C for 5 h. After the reaction is completed, cool to room temperature, filter with diatomaceous earth, concentrate, and purify by column chromatography (100% n-hexane) to obtain intermediate tri.

[0056] S5. 3,5-Dihydroxybromobenzene (1.5 g, 1 eq, 7.98 mmol), pinacol diboronate (3.03 g, 1.5 eq, 11.97 mmol), and potassium acetate (1.335 g, 1.5 eq, 11.97 mmol) were added to 15 mL of dioxane. After degassing for 3 min, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.285 g, 5 mol%, 0.56 mmol) was added, and degassing continued for another 3 min. The reaction was then carried out at 90 °C for 6 h. After the reaction was completed, the mixture was filtered with diatomaceous earth and 20 mL of ethyl acetate and 30 mL of water were added. The aqueous phase was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate for 2 h, and purified by column chromatography (ethyl acetate to n-hexane volume ratio 1:6) to obtain intermediate five.

[0057] S6. Add intermediate four (0.22 g, 1 eq, 0.65 mmol), intermediate five (0.38 g, 2.4 eq, 1.56 mmol), potassium phosphate (0.28 g, 2 eq, 1.3 mmol), 3 mL N,N-dimethylformamide and 1 mL water to a sealed tube. After degassing for 5 min, add 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.03 g, 5 mol%) and continue degassing for 5 min. Then stir the reaction at 70 °C for 6 h. After the reaction is completed, cool to room temperature, filter with diatomaceous earth, add 10 mL ethyl acetate and 10 mL water, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 3), dry with anhydrous magnesium sulfate for 2 h, and purify by column chromatography (ethyl acetate to n-hexane volume ratio of 1:2) to obtain intermediate six.

[0058] S7. Mix 0.24g of intermediate six and 0.48g of... 50WX cation exchange resin was added to anhydrous MeOH, followed by 2 drops of concentrated hydrochloric acid. The mixture was then reacted at 25°C for 48 hours. After filtration, the mixture was purified by column chromatography (ethyl acetate to n-hexane volume ratio was 1:2) to obtain Moracin N.

[0059] Example 3

[0060] A method for synthesizing the natural product Moracin N includes the following steps:

[0061] S1. 2,4-Dihydroxybenzaldehyde (3 g, 1 eq, 21.7 mmol) was dissolved in 10 mL of dioxane, followed by the simultaneous addition of boron trifluoride diethyl ether (1.3 mL, 5 mol%) and 2-methyl-3-buten-2-ol (3 mL, 1.2 eq, 28.24 mmol), and the mixture was stirred for 4.5 h. After the reaction was completed, 10 mL of ethyl acetate and 30 mL of water were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), and then dried with anhydrous magnesium sulfate for 2 h. The mixture was purified by column chromatography (ethyl acetate to n-hexane volume ratio of 1:10) to obtain intermediate one.

[0062] S2. Intermediate 1 (0.44 g, 1 eq, 4.8 mmol) was dissolved in 10 mL of anhydrous acetonitrile, followed by the addition of potassium carbonate (0.87 g, 1.3 eq, 6.3 mmol) and reaction for 20 min. Then, chloromethyl methyl ether (0.53 mL, 1.2 eq, 5.8 mmol) and tetrabutylammonium iodide (0.09 g, 5 mol%, 0.24 mmol) were added to the reaction solution and stirred for 60 min. After the reaction was completed, the mixture was filtered through diatomaceous earth. 20 mL of ethyl acetate and 20 mL of water were added to the crude product, and the two phases were separated. The aqueous phase was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 3). Finally, the product was dried over anhydrous magnesium sulfate and purified by column chromatography (ethyl acetate to n-hexane volume ratio of 1:20) to obtain intermediate 2.

[0063] S3. Triphenylphosphine (2.38 g, 6 eq, 9.08 mmol) and carbon tetrabromide (1.51 g, 3 eq, 9.1 mmol) were dissolved in dichloromethane, and then the triphenylphosphine and carbon tetrabromide solutions were mixed and reacted at 5 °C for 5 min. Triethylamine (1.26 mL, 6 eq, 9.08 mmol) was then added, and the reaction was continued for 5 min to obtain phosphorus ylide reagent. Then, intermediate II (0.4 g, 1 eq, 1.51 mmol) was added to phosphorus ylide reagent. The mixture was first stirred at 10 °C for 30 min to ensure homogeneity of the starting materials, then the temperature was raised to room temperature, and the reaction was continued with stirring until the starting materials disappeared. The pH of the mixture was adjusted to neutral with saturated ammonium chloride aqueous solution. Finally, the mixture was washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate for 2 h, and purified by column chromatography (ethyl acetate to n-hexane volume ratio of 1:8) to obtain intermediate III.

[0064] S4. Add intermediate tri (0.312 g, 1 eq, 0.74 mmol), potassium phosphate (0.55 g, 3.5 eq, 2.6 mmol), cuprous iodide (0.007 g, 5 mol%, 0.005 mmol) and 3 mL of anhydrous tetrahydrofuran to a sealed tube, and stir the reaction at 90 °C for 4.5 h. After the reaction is completed, cool to room temperature, filter with diatomaceous earth, concentrate, and purify by column chromatography (100% n-hexane) to obtain intermediate tri.

[0065] S5. 3,5-Dihydroxybromobenzene (1.2 g, 0.8 eq, 6.3 mmol), pinacolborane (1.06 g, 1 eq, 7.87 mmol), and potassium acetate (0.77 g, 1 eq, 7.87 mmol) were added to 15 mL of dioxane. After degassing for 3 min, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.32 g, 5 mol%, 0.39 mmol) was added, and degassing continued for another 3 min. The reaction was then carried out at 90 °C for 5 h. After the reaction was completed, the mixture was filtered with diatomaceous earth and 20 mL of ethyl acetate and 30 mL of water were added. The aqueous phase was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate for 2 h, and purified by column chromatography (ethyl acetate to n-hexane volume ratio 1:6) to obtain intermediate five.

[0066] S6. Add intermediate four (0.11 g, 0.5 eq, 0.325 mmol), intermediate five (0.24 g, 1.5 eq, 0.98 mmol), potassium phosphate (0.21 g, 1.5 eq, 0.975 mmol), 3 mL N,N-dimethylformamide and 1 mL water to a sealed tube. After degassing for 5 min, add 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.03 g, 5 mol%) and continue degassing for 5 min. Then stir the reaction at 80 °C for 5 h. After the reaction is completed, cool to room temperature, filter with diatomaceous earth, add 10 mL ethyl acetate and 10 mL water, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 3), dry with anhydrous magnesium sulfate for 2 h, and purify by column chromatography (ethyl acetate to n-hexane volume ratio of 1:2) to obtain intermediate six.

[0067] S7. Mix 0.24g of intermediate six and 0.36g of... 50WX cation exchange resin was added to anhydrous MeOH, followed by 2 drops of concentrated hydrochloric acid. The mixture was then reacted at 35°C for 24 hours. After filtration, the mixture was purified by column chromatography (the volume ratio of ethyl acetate to n-hexane was 1:2) to obtain Moracin N.

Claims

1. A method for synthesizing a natural product Moracin N, characterized in that, The method comprises the following steps: taking an aldehyde containing a benzene ring as a starting material, introducing an isopentenyl group on the benzene ring through a Friedel-Crafts reaction to obtain an intermediate one; protecting the hydroxyl group at position 4 of the intermediate one to obtain an intermediate two; then preparing the intermediate two into a gem-dibromoalkene using a phosphorus ylide reagent to obtain an intermediate three; then coupling the gem-dibromoalkenyl group of the intermediate three with an ortho-hydroxyl group under the catalysis of a base and a copper catalyst to form a benzofuran ring to obtain an intermediate four; then introducing 3,5-dihydroxybromobenzene to the right side of the benzofuran ring of the intermediate four through a Suzuki-Miyaura reaction to obtain an intermediate six; and finally removing the hydroxyl protecting group of the intermediate six to obtain Moracin N; and the method specifically comprises the following steps: S1, mixing 2,4-dihydroxybenzaldehyde with an acid catalyst in a molar ratio of 0.5-1.5:1.1-1.6 for 4-5 hours to obtain an intermediate one; the acid catalyst is a mixture of boron trifluoride ether and 2-methyl-3-buten-2-ol in a molar ratio of 1-1.5:0.03-0.07; S2, adding a base to the intermediate one and reacting for 10-20 minutes, then adding an ether and a phase transfer catalyst and reacting for 20-60 minutes to obtain an intermediate two; the molar ratio of the intermediate two, the base, the ether, and the phase transfer catalyst is 0.5-1.5:1.2-1.5:1-1.5:0.03-0.07; the ether is 1-chloromethylethyl ether, methoxymethyl ether, or chloromethyl methyl ether; and the phase transfer catalyst is tetrabutylammonium iodide; S3, mixing the intermediate two with a phosphorus ylide reagent in a molar ratio of 1:2.5-3.5 for 1.5-2.5 hours to obtain an intermediate three; the preparation process of the phosphorus ylide reagent is as follows: mixing triphenylphosphine, carbon tetrabromide, and triethylamine, and reacting at-5-5°C for 10-15 minutes; S4, mixing the intermediate three, a base, and a copper catalyst in a molar ratio of 0.5-1.5:3-4:0.03-0.07, and reacting at 75-90°C for 4-5 hours to obtain an intermediate four; the copper catalyst is cuprous iodide; S5, mixing 3,5-dihydroxybromobenzene, a boronizing agent, a base, and a palladium catalyst in a molar ratio of 0.5-1.5:1-2:1-2:0.03-0.07, and reacting at 90-100°C for 5-6 hours to obtain an intermediate five; the boronizing agent is pinacol diboron or pinacol borane; and the palladium catalyst is 1,1-bis(diphenylphosphino)ferrocene palladium dichloride; S6, mixing the intermediate four, the intermediate five, a base, and a palladium catalyst in a molar ratio of 0.5:1-2:1.5-2.5:0.03-0.07, and reacting at 70-80°C for 5-6 hours to obtain an intermediate six; S7, mixing the intermediate six and a cationic resin in a mass ratio of 1-2:1-2, and reacting at 25-35°C for 24-48 hours to obtain Moracin N; the cationic resin is Dowex 50WX.

2. The method of synthesizing natural product Moracin N according to claim 1, characterized in that, The base is potassium carbonate, potassium phosphate, or potassium acetate.

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