Synthetic method of natural product (+)-Machaeriols B

Abstract

The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing the natural product (+)-Machaeriols B. This method uses 2-fluorotoluene and N,3,5-trimethoxy-N-methylbenzamide as starting materials to synthesize the main benzofuran framework. The method for synthesizing benzofuran derivatives described herein is significant for the development of synthesizing benzofuran derivatives. The entire route only involves three steps, with a short route and simple preparation of raw materials.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing a natural product (+)-Machaeriols B. Background Art

[0002] (+)-Machaeriols B is a natural product containing a benzofuran structure, which is isolated from the bark of Picea jezoensis var. microsperma. It has been reported that it has in vitro antibacterial activity against Staphylococcus aureus, and in addition, it also shows strong in vitro anti-malarial activity against Plasmodium falciparum. These important activities have attracted attention, which has promoted the great development of methods for synthesizing this natural product.

[0003]

[0004] The main framework structure of this natural product contains 2-arylbenzofuran, and many methods for synthesizing 2-arylbenzofuran have been reported, as follows:

[0005] (1) The process of palladium-catalyzed Sonogashira coupling-cyclization reaction of o-bromophenol and terminal alkyne to synthesize 2-arylbenzofuran reaction. (VILLEMIN D, GOUSSU D. Palladium in homogeneous and supported catalysis: synthesis of functional acetylenics and cyclization to heterocycles [J]. Heterocycles, 1989, 29(7): 1255-61).

[0006] (2) The process of copper-catalyzed Sonogashira coupling-cyclization reaction of o-bromophenol and terminal alkyne to synthesize 2-arylbenzofuran reaction (THOMAS A M, ASHA S, MENON R, et a1. One-Pot Synthesis of Benzofurans via Cu-Catalyzed Tandem Sonogashira Coupling-Cyclization Reactions [J]. Chemistry Select, 2019, 4(19): 5544-7.).

[0007] (3) Using Sc(OTf)3 as a catalyst and triethyl formate as an additive, 1,4-addition and cyclization reactions of 1,4-benzoquinone and aryl methyl ketones were carried out to synthesize benzofuran derivatives (WU F, BAI R, GU Y. Synthesis of Benzofurans from Ketones and 1,4-Benzoquinones[J]. Adv Synth Catal, 2016, 358(14): 2307-16.).

[0008] (4) t The intermolecular addition reaction of BuOK-mediated alkyl radicals to aldehyde compounds was carried out to synthesize benzofuran through intramolecular cyclization (ZHENG H-X, SHAN X-H, QU J-P, et al. Strategy for Overcoming Full Reversibility of Intermolecular Radical Addition to Aldehydes: Tandem C-H and C-O Bonds Cleaving Cyclization of (Phenoxymethyl)arenes with Carbonyls to Benzofurans[J]. Org Lett, 2018, 20(11): 3310-3.).

[0009] There are still many problems in synthesizing 2-arylbenzofurans using these methods. For example, expensive transition metal catalysts are used, and multiple steps of reactions need to be designed to synthesize the final product. Using a more efficient and simple method to synthesize 2-arylbenzofurans is of great significance for synthesizing such natural products. Summary of the Invention

[0010] The present invention provides a new route for synthesizing the natural product (+)-Machaeriols B. Moreover, the synthesis method of the present invention is simple, has a short route, low cost, and the starting materials are simple and easy to synthesize, without the need to prepare complex precursors. The synthesis route of the natural product (+)-Machaeriols B introduced in the present invention is shown in Formula 2.

[0011]

[0012] The specific synthesis method of the natural product (+)-Machaeriols B of the present invention comprises the following steps:

[0013] (1) Synthesis of 2-(3,5-dimethoxyphenyl)benzofuran

[0014] Under argon protection, cesium bis(trimethylsilyl)amide was added to tetrahydrofuran, o-fluorotoluene was added, and the mixture was stirred evenly. Then N,3,5-trimethoxy-N-methylbenzamide was added. The mixture was refluxed at 180 °C for 12 hours, cooled to room temperature, quenched with water, the solvent was removed under reduced pressure, and the crude product was separated by column chromatography to obtain the product 2-(3,5-dimethoxyphenyl)benzofuran.

[0015] (2) Synthesis of 5-(benzofuran-2-yl)benzene-1,3-diol

[0016] Under argon protection, 2-(3,5-dimethoxyphenyl)benzofuran was added to dichloromethane, the reaction system was cooled to -78 °C, boron tribromide was slowly added dropwise to the reaction system, and the mixture was stirred. The temperature of the system was slowly raised to room temperature and stirred for 24 hours. The reaction was quenched with water, the solvent was removed under reduced pressure, and the crude product was separated by column chromatography to obtain the product 5-(benzofuran-2-yl)benzene-1,3-diol.

[0017] (3) Synthesis of (+)-Machaeriols B

[0018] Under argon protection, 5-(benzofuran-2-yl)benzene-1,3-diol was added to m-xylene, citronellal 5 was added, ethylenediamine-N,N'-diacetic acid (EDDA) was added, and triethylamine was added. The mixture was refluxed at 160 °C for 24 hours. The reaction was quenched with water, the solvent was removed under reduced pressure, and the crude product was separated by column chromatography to obtain the product (+)-Machaeriols B.

[0019] Description of the accompanying drawings

[0020] The accompanying drawings are the hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product of Example 3. Figure 1A It is the hydrogen spectrum nuclear magnetic resonance spectrum. Figure 1B It is the carbon spectrum nuclear magnetic resonance spectrum. The hydrogen spectrum and carbon spectrum of the product obtained in Example 3 are respectively Figure 1A and Figure 1B . Specific examples

[0021] Example 1

[0022] Under an argon atmosphere, cesium bis(trimethylsilyl)amide (175.8 mg, 0.6 mmol) was added to a microwave tube, then 1 mL of 2-fluorotoluene and 1 mL of tetrahydrofuran were added, and the mixture was stirred evenly. N,3,5-trimethoxy-N-methylbenzamide (67.5 mg, 0.3 mmol) was added. The mixture was refluxed at 180 °C for 12 hours, cooled to room temperature, quenched with water, the solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether) to obtain 2-(3,5-dimethoxyphenyl)benzofuran (35.8 mg, 47% yield), which was a white solid.

[0023] Example 2

[0024] Under an argon atmosphere, 2-(3,5-dimethoxyphenyl)benzofuran (33.0 mg, 0.13 mmol) was added to dichloromethane (5 mL). The reaction system was cooled to -78 °C, and boron tribromide (79 mg, 0.31 mmol) was slowly added dropwise to the reaction system. The mixture was stirred for reaction, and the temperature of the system was slowly raised to room temperature and stirred for 24 hours. Ice water was added to quench the reaction, and the solvent was removed under reduced pressure. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the product 5-(benzofuran-2-yl)benzene-1,3-diol (28.2 mg, 96%), which was a red-brown solid.

[0025] Example 3

[0026] Under an argon atmosphere, 5-(benzofuran-2-yl)benzene-1,3-diol (27.1 mg, 0.12 mmol) was added to m-xylene (0.2 mL), citronellal 5 (40.8 mg, 0.27 mmol) was added, ethylenediamine-N,N'-diacetic acid (EDDA) (4.19 mg, 0.024 mmol) was added, and triethylamine (0.2 mL) was added. The mixture was refluxed at 160 °C for 24 hours. Water was added to quench the reaction, and the solvent was removed under reduced pressure. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the product (+)-Machaeriols B (28.2 mg, 65%), which was a brown solid. The 1H NMR and 13C NMR spectra of the product are Figure 1A and Figure 1B , and the spectral data are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ: 7.54 (d, J = 6.9 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.27 - 7.17 (m, 2H), 6.91 (d, J = 1.6 Hz, 1H), 6.88 (s, 1H), 6.78 (d, J = 1.6 Hz, 1H), 5.11 (s, 1H), 3.07 (d, J = 12.8 Hz, 1H), 2.51 (td, J = 11.1, 2.6 Hz, 1H), 1.86 (dd, J = 7.1, 4.1 Hz, 2H), 1.66 (s, 1H), 1.54 - 1.46 (m, 1H), 1.40 (s, 3H), 1.18 - 1.07 (m, 5H), 0.95 (d, J = 6.6 Hz, 3H), 0.84 - 0.74 (m, 1H) ppm 13 13C{ 11H NMR (101 MHz, Chloroform-d) δ: 155.66, 155.61, 155.41, 154.78, 129.64, 129.29, 124.20, 122.93, 120.95, 114.04, 111.17, 107.11, 104.00, 101.23, 49.09, 38.82, 35.76, 35.54, 32.99, 28.12, 27.80, 22.70, 19.16 ppm.

Claims

1. A synthetic method of natural product (+)-Machaeriols B, characterized in that: 2-Fluorotoluene (1) and N,3,5-trimethoxy-N-methylbenzamide (2) are synthesized into 2-(3,5-dimethoxyphenyl)benzofuran (3) under an argon atmosphere with the action of cesium bis(trimethylsilyl)amide through a nucleophilic addition-cyclization process, as shown in Formula 1. 2-(3,5-Dimethoxyphenyl)benzofuran (3) is demethylated with boron tribromide and then reacts with citronellal, and is catalyzed by ethylenediamine acetic acid to synthesize (+)-Machaeriols B.

2. The synthesis method according to claim 1, wherein 2-(3,5-Dimethoxyphenyl)benzofuran is synthesized by the method shown in Formula 1, and the solvents used are tetrahydrofuran, 2-methyltetrahydrofuran, and cyclopentyl methyl ether.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of 2-fluorotoluene, N,3,5-trimethoxy-N-methylbenzamide, and cesium bis(trimethylsilyl)amide is: 3-50:1-2:1-3.

4. The synthesis method according to claim 1, characterized in that, 2-(3,5-Dimethoxyphenyl)benzofuran is synthesized by the method shown in Formula 1, and the reaction temperature is 110°C to 180°C.

Images