Sesquiterpenoid laurene derivatives, their synthesis and application in preventing and controlling plant viral and bacterial diseases

Abstract

The present invention relates to sesquiterpenoid laurene derivatives I-1 to I-14, their preparation methods, and their use in preventing and treating plant viral pathogens and fungi. The present invention develops an efficient synthesis method for sesquiterpenoid laurene derivatives, laying a foundation for the synthesis and biological activity research of such sesquiterpenes. The sesquiterpenoid derivatives I-1 to I-14 of the present invention have anti-plant viral activity and can inhibit tobacco mosaic virus. Furthermore, the compounds exhibit broad-spectrum anti-plant pathogen activity.

Description

Technical Field

[0001] The invention relates to a sesquiterpene laurene derivative, a preparation method thereof and an application thereof in preventing and treating plant viral pathogens and fungi, and belongs to the technical field of agricultural protection. Background Art

[0002] Crop pests and diseases have a significant impact on agricultural development, affecting not only crop yields but also crop quality. Their main characteristics are their rapid spread, and a single crop can be affected by multiple pests and pathogens, resulting in complex symptoms and extremely difficult treatment. Reports indicate that plant diseases caused by bacteria, fungi, and viruses cause $220 billion in economic losses annually, significantly impacting food security. Traditional pest control relies primarily on chemical pesticides. While effective in controlling pests and diseases, they still present numerous challenges. In today's world of sustainable development, many highly toxic pesticides are still being used inappropriately. Their misuse can cause significant harm to humans and other organisms. Therefore, the research and development and utilization of natural pesticides are urgent. Natural pesticide research and development includes various approaches, including random screening, analogous synthesis, natural product models, and rational biological design, with natural product models garnering the most attention.

[0003] Laurene (Structural Formula 1) is a hydrocarbon sesquiterpenoid compound derived from the red algae of the genus Laurentia. Its structural characteristic is the presence of 1, 2, and 3-substituted cyclopentenes. It was first isolated from Laurencia glandulifera by the Irie research group at Hokkaido University (Tetrahedron Lett. 1965, 6, 3619-3624.). Its sesquiterpenoid analogs have been found to be effective antifungal, antibiotic, neurotrophic, and anti-lipid peroxidation drugs. To date, there has been no application of this compound in the prevention and treatment of plant viral and fungal diseases.

[0004] Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention provides sesquiterpene laurene derivatives and their preparation methods and applications in preventing and treating plant viral and fungal diseases. The sesquiterpene derivatives of the present invention have excellent anti-plant viral and fungal activity.

[0006] The sesquiterpene derivatives I of the present invention are compounds represented by the following I-1 to I-14 (Structural Formula 2).

[0007]

[0008] Preparation method of I-1 to I-14 in structural formula 2:

[0009] Synthesis of sesquiterpene derivatives I-1 to I-2: Prepared according to the method shown in formula 1, first using toluene as solvent and p-toluenesulfonic acid as catalyst, 2-methyl-1,3-cyclopentanedione (1) and isobutanol (2) are heated under reflux at 110°C for 12 hours to generate isobutoxy-2-methylcyclopentene-1-one (3), then under argon protection, using anhydrous tetrahydrofuran as solvent, adding the corresponding Grignard reagent at 0°C, reacting for 15 minutes, then transferring to room temperature, continuing the reaction for 6 hours, and quenching with hydrochloric acid to obtain 2-methyl-3-aryl-cyclopent-2-ene-1-one 4, finally under argon protection, using nickel acetylacetonate as catalyst and anhydrous tetrahydrofuran as solvent, reacting with trimethylaluminum for 20 hours to obtain 2,3-dimethyl-3-arylcyclopentane-1-one I-1 to I-2.

[0010]

[0011] Synthesis of sesquiterpene derivative I-3: Prepared according to the method shown in Equation 2, first using acetonitrile as solvent and ferric chloride as catalyst, 2,3-dimethyl-3-(p-methoxyphenyl)cyclopentane-1-one (I-2) and N-bromosuccinimide (NBS) react at 0°C for 15 minutes, and then transferred to room temperature for 5 hours to generate 3-(3,5-dibromo-4-methoxyphenyl)-2,3-dimethylcyclopentane-1-one (I-3).

[0012]

[0013] Synthesis of sesquiterpene derivative I-4: Prepared according to the method shown in Equation 3, using ethylene glycol dimethyl ether as solvent and sodium hydride as base, 2,3-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclopentane-1-one (I-1) and iodomethane are methylated at 0°C to produce I-4.

[0014]

[0015] Synthesis of sesquiterpene derivatives I-5 to I-7: Prepared according to the method shown in Equation 4, first using anhydrous tetrahydrofuran as solvent, at 0°C, zinc powder, carbon dibromide and titanium tetrachloride were added in sequence, and the reaction was continued for 15 minutes, then transferred to room temperature, 2,3-dimethyl-3-arylcyclopentane-1-one (I-1 to I-3) was added, and the reaction was carried out at room temperature for 12 hours to generate I-5 to I-7.

[0016]

[0017] Synthesis of sesquiterpene derivative I-8: Prepared according to the method shown in Equation 5, first, using N,N-dimethylacetamide as solvent, palladium trifluoroacetate as catalyst, bipyridine as ligand, 2-methylcyclopent-2-en-1-one (5) and p-tolueneboronic acid are reacted at 80°C reflux for 24 hours to generate 2-methyl-3-(p-tolyl)cyclopentane-1-one (6), then using anhydrous tetrahydrofuran as solvent, at 0°C, zinc powder, carbon dibromide and titanium tetrachloride are added in sequence, the reaction is continued for 15 minutes, and then the reaction is transferred to room temperature, ketone (6) is added, and the reaction is carried out at room temperature for 12 hours to generate I-8.

[0018]

[0019] Synthesis of sesquiterpene derivative I-9: Prepared according to the method shown in Equation 6, first using methanol and water (V / V=9 / 1) as solvent, palladium trifluoroacetate as catalyst, bipyridine as ligand, heating to 60°C, reacting for 15 minutes, then transferring to room temperature, adding 3-methylcyclopent-2-ene-1-one (7) and p-tolueneboronic acid, reacting at room temperature for 24 hours to generate 3-methyl-3-(p-tolyl)cyclopentane-1-one (8), then using anhydrous tetrahydrofuran as solvent, at 0°C, adding zinc powder, carbon dibromide and titanium tetrachloride in sequence, continuing the reaction for 15 minutes, then transferring to room temperature, adding ketone (8), and reacting at room temperature for 12 hours to generate I-9.

[0020]

[0021] Synthesis of sesquiterpene derivative I-10: Prepared according to the method shown in Equation 7, the synthesis of compound 11 was completed using the schemes of Equations 1 and 4, followed by reaction at room temperature for 48 hours using dichloromethane as solvent, silica gel as catalyst, and hydrochloric acid as an acidic environment to obtain compound 3-methoxy-4-methyl-1-(1,2,3-trimethylcyclopent-3-en-1-yl)benzene (I-10).

[0022]

[0023] Synthesis of sesquiterpene derivative I-11: Prepared according to the method shown in Equation 8, the synthesis of compound 13 was completed according to the scheme of Equation 1. Subsequently, compound 13 was reacted with hydroxylamine hydrochloride at 60°C for 1 hour using water and ethanol as solvents and sodium acetate as a catalyst to obtain compound 2,3-dimethyl-3-(p-tolyl)cyclopentane-1-one oxime (I-11).

[0024]

[0025] Synthesis of sesquiterpene derivative I-12: Prepared according to the method shown in Equation 9, the synthesis of compound 13 was completed according to the scheme of Equation 1. Subsequently, ethanol was used as a solvent and triethylamine provided an alkaline environment. Compound 13 was reacted with hydrazine hydrate at 78°C for 5 hours to obtain compound (2,3-dimethyl-3-(p-tolyl)cyclopentylidene)hydrazine (1-12).

[0026]

[0027] Synthesis of sesquiterpene derivative I-13: Prepared according to the method shown in Equation 10, using pyridine as solvent, compound I-12 reacts with p-toluenesulfonyl chloride at room temperature for 12 hours to obtain compound N′-(2,3-dimethyl-3-(p-tolyl)cyclopentylidene)-4-methylbenzenesulfonylhydrazide (I-13).

[0028]

[0029] Synthesis of sesquiterpene derivative I-14: Prepared according to the method shown in formula 11, compound 13 was reacted with 2-phenylthiazole-4-carbohydrazide at 100°C for 5 hours using ethanol as solvent to obtain compound N′-(2,3-dimethyl-3-(p-tolyl)cyclopentylidene)-2-phenylthiazole-4-carbohydrazide (I-14).

[0030]

[0031] The sesquiterpene derivatives I-1 to I-14 of the present invention exhibit excellent activity against plant viruses and pathogens, and can effectively inhibit eight plant pathogens, including tobacco mosaic virus (TMV) and cucumber wilt, peanut brown spot, apple ring spot, wheat sheath blight, tomato early blight, rice blast, pepper phytophthora, and rapeseed sclerotia. DETAILED DESCRIPTION

[0032] The following examples and biological test results can be used to further illustrate the present invention, but are not intended to limit the present invention.

[0033] Example 1: Synthesis of Sesquiterpene Derivative I-1

[0034] The first step is the synthesis of compound isobutoxy-2-methylcyclopentene-1-one (3): 2-methyl-1,3-cyclopentanedione (1) (5 g, 44.64 mmol), isobutanol (2) (10 mL), toluene (50 mL), and p-toluenesulfonic acid (250 mg, 1.45 mmol) were added to a 250 mL round-bottom flask, and the mixture was heated under reflux at 110° C. for twelve hours. The reaction was monitored by TLC to be complete. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and subjected to column chromatography (V (petroleum ether): V (ethyl acetate) = 2:1) to obtain 6.4 g of the product as a yellow oil with a yield of 85%.1 H NMR (400MHz, CDCl3) δ3.93 (d, J=6.5Hz, 2H, (CH3)2CHCH2O), 2.65 (s, 2H, COCH2), 2.49-2.39 (m, 2H, CH2 CH2C), 2.04 (dt, J=13.3, 6.6Hz, 1H, CH3CH), 1.64 (d, J=1.5Hz, 3H, CH3C), 1.14-0.89 (m, 6H, (CH3)2CH). 13 C NMR (100MHz, CDCl3) δ205.5, 184.6, 115.8, 75.4, 33.3, 28.6, 25.1, 18.8, 5.9.HRMS (EI): Cacld for C 10 H 16 O2[M] + 168.1145, found 168.1149.

[0035] Step 2, synthesis of 2-methyl-3-(4-(trifluoromethyl)phenyl)cyclopent-2-en-1-one (4-1): isobutoxy-2-methylcyclopentene-1-one (3) (5 g, 29.8 mmol) and 60 mL of anhydrous tetrahydrofuran were added to a 500 mL four-necked flask under Ar protection. (4-(trifluoromethyl)phenyl)magnesium bromide (35.7 mL, 35.7 mmol) was gradually added at 0°C. After 15 minutes, the mixture was brought to room temperature and the reaction was continued for 12 hours. The reaction was completed by TLC. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and purified by column chromatography (V(petroleum ether):V(ethyl acetate)=5:1) to obtain 5.3 g of the product as a yellow oil with a yield of 74%. 1 HNMR (400MHz, CDCl3) δ7.73 (d, J=8.2Hz, 2H, ArH), 7.62 (d, J=8.1Hz, 2H, ArH), 2.97 -2.87 (m, 2H, COCH2CH2), 2.65-2.51 (m, 2H, COCH2CH2), 1.96 (t, J=2.1Hz, 3H, CH3C). 13 C NMR (100MHz, CDCl3) δ209.6, 164.9, 142.09, 139.99, 138.19, 131.39, 131.0, 127.8, 125.6, 34.0, 29.4, 9.8.HRMS (EI): Cacld for C 13 H 11 F3O[M] + 240.0757, found 240.0751.

[0036] Step 3, synthesis of 2,3-dimethyl-3-(4-(trifluoromethyl)phenyl)cyclopentane-1-one (I-1): 2-methyl-3-(4-(trifluoromethyl)phenyl)cyclopent-2-ene-1-one (4-1) (5.04 g, 21 mmol), nickel acetylacetonate (0.27 g, 1.05 mmol) and 60 mL of redistilled tetrahydrofuran were added to a 500 mL four-necked flask, with Ar protection, and trimethylaluminum (12.6 mL, 25.2 mmol) was gradually added at 0°C. After 15 minutes, the mixture was brought to room temperature and the reaction was continued for 12 hours. The reaction was completed by TLC detection, and the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and purified by column chromatography (V(petroleum ether):V(ethyl acetate)=10:1) to give 4.4 g of the product as a yellow oil with a yield of 81%. 1 H NMR (400MHz, CDCl3) (for 2:1 inseparable mixture of diastereomers) δ7.61 (dd, J=12.8, 8.3Hz, 3H, ArH), 7.54-7.48 (m, 2H, ArH), 7.30 (t , J=7.5Hz, 1H, ArH), 2.66-2.58 (m, 1H, CHCH3), 2.54-2.42 (m, 3H, COCH2CH2), 2.42-2. 30(m, 1.5H, 0.5CHCH3+1COCH2CH2), 2.20-2.11(m, 2H, COCH2CH2), 1.43(s, 1.5H, CCH 3), 1.24 (s, 3H, CCH3), 1.06 (d, J=7.0Hz, 3H, CHCH3), 0.82 (d, J=7.4Hz, 1.5H, CHCH3). 13 C NMR (100MHz, CDCl3) δ220.3, 218.8, 151.5, 127.1, 125.9, 125.6, 125.5, 125.5, 125.5, 125.4, 125.4, 1 22.8, 115.5, 54.9, 54.1, 46.9, 46.2, 36.1, 34.97, 34.86, 31.7, 29.7, 20.6, 12.1, 8.6.HRMS (EI): Cacld for C 14 H 15 F3O[M] + 256.1070, found 256.1073.

[0037] Example 2: Synthesis of Sesquiterpene Derivative I-2

[0038] The first step is the synthesis of 2-(4-methoxyphenyl)-2-methylcyclopent-2-ene-1-one (4-2): isobutoxy-2-methylcyclopentene-1-one (3) (7.5 g, 44.6 mmol) and 60 mL of redistilled tetrahydrofuran were added to a 500 mL four-necked flask. Under argon protection, (4-(methoxy)phenyl)magnesium bromide (45 mL, 45 mmol) was gradually added at 0°C. After 15 minutes, the mixture was brought to room temperature and the reaction was continued for 12 hours. The reaction was completed by TLC detection. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and purified by column chromatography (V (petroleum ether): V (ethyl acetate) = 5:1) to obtain 6.8 g of the product as a yellow oil with a yield of 75%. 1 H NMR (400MHz, CDCl3) δ7.63-7.43 (m, 2H, ArH), 7.07-6.83 (m, 2H, ArH), 3.86 (s, 3H, OCH3), 2.99-2. 81 (m, 2H, COCH2CH2), 2.61-2.41 (m, 2H, COCH2CH2), 1.99 (t, J=1.9Hz, 3H, CH3C). HRMS (EI): Cacld for C 13 H 14 O2[M] + 202.0988, found 202.0992.

[0039] Step 2, synthesis of 2,3-dimethyl-3-(p-methoxyphenyl)cyclopentane-1-one (I-2): 2-(4-methoxyphenyl)-2-methylcyclopent-2-ene-1-one (4-2) (6 g, 29.7 mmol), nickel acetylacetonate (0.38 g, 1.49 mmol) and 60 mL of redistilled tetrahydrofuran were added to a 500 mL four-necked flask. Under argon protection, trimethylaluminum (17.8 mL, 35.6 mmol) was gradually added at 0°C. After 15 minutes, the mixture was brought to room temperature and the reaction was continued for 12 hours. The reaction was completed by TLC detection. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and purified by column chromatography (V (petroleum ether): V (ethyl acetate) = 10:1) to give 5.1 g of the product as a yellow oil with a yield of 79%. 1H NMR (400MHz, CDCl3) (for 5:1 inseparable mixture of diastereomers) δ7.33-7.28(m, 2H, ArH), 7.12-7.06(m, 0.4H, ArH), 6.92-6.88(m, 2H, ArH), 6.88-6.84( m, 0.4H, ArH), 3.81 (s, 3H, OCH3), 3.79 (s, 1H, OCH3), 2.56 (qd, J=6.9, 1.0Hz, 1H, CHCH3), 2.48 (dd, J=2.8, 1. 3Hz, 0.2H, CHCH3), 2.47-2.39(m, 1.2H, COCH2CH2), 2.38-2.25(m, 1.2H, COCH2CH2), 2.19-2.00(m, 2.4H, CO CH2CH2), 1.40 (s, 1H, CCH3), 1.19 (s, 3H, CCH3), 1.02 (d, J=7.0Hz, 3H, CHCH3), 0.83 (t, J=8.0Hz, 1H, CHCH3). 13 C NMR (100MHz, CDCl3) δ219.7, 157.9, 139.5, 127.7, 126.5, 113.8, 55.4, 55.3, 54.4, 45.4, 36.4, 35.2, 32.4, 29.8, 20.6, 11.8, 8.6.HRMS (EI): Cacld for C 14 H 18 O2[M] + 218.1301, found 218.1307.

[0040] Example 3: Synthesis of Sesquiterpene Derivative 3-(3,5-dibromo-4-methoxyphenyl)-2,3-dimethylcyclopentane-1-one I-3

[0041] 2,3-Dimethyl-3-(p-methoxyphenyl)cyclopentan-1-one (I-2) (1.0 g, 4.59 mmol) was dissolved in 50 mL of acetonitrile, and ferric chloride (0.74 g, 4.59 mmol) and NBS (1.63 g, 9.18 mmol) were gradually added at 0°C, and the temperature was raised to room temperature. The reaction was allowed to react for 5 h. TLC detected the completion of the reaction, and the mixture was desolvated, washed with brine, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to desolvate, and purified by column chromatography (V (petroleum ether): V (ethyl acetate) = 20:1) to give 1.2 g of a white oily solid with a yield of 70% and a melting point of 64-65°C. 1H NMR (400MHz, CDCl3) (for 6:1 inseparable mixture of diastereomers) δ7.49 (d, J=4.1Hz, 2H, ArH), 7.30 (s, 0.3H, ArH), 3.89 (d, J=2.9 Hz, 3.3H, OCH3), 2.50 (dt, J=6.1, 4.9Hz, 1H, CHCH3), 2.49-2.42 (m, 1.3H, COCH2CH2) , 2.42-2.27(m, 1.3H, COCH2CH2), 2.13-2.06(m, 2H, COCH2CH2), 1.37(s, 0.5H, CCH3 ), 1.18 (s, 3H, CCH3), 1.03 (d, J = 7.0Hz, 3H, CHCH3), 0.83 (d, J = 7.4Hz, 0.5H, CHCH3). 13 C NMR (100MHz, CDCl3) δ218.8, 151.5, 127.1, 125.9, 125.57, 125.53, 125.49, 125.45, 125.41, 125.38, 1 22.8, 115.5, 54.9, 54.1, 46.9, 46.2, 36.1, 34.97, 34.86, 31.7, 29.7, 20.6, 12.1, 8.6.HRMS (EI): Cacld forC 14 H 16 Br2O2[M] + 373.9512, found 373.9515.

[0042] Example 4: Synthesis of sesquiterpene derivative I-4.

[0043] 2,3-Dimethyl-3-(4-(trifluoromethyl)phenyl)cyclopentane-1-one (I-1) (1.0 g, 3.9 mmol) was dissolved in 20 mL of ethylene glycol dimethyl ether, and sodium hydride (0.12 g, 4.9 mmol) was gradually added at 0°C. After reacting for 15 min, iodomethane (2.22 g, 15.6 mmol) was added, and the mixture was warmed to room temperature and reacted for 12 h. The reaction was detected by TLC to be complete. The mixture was desolvated, washed with brine, extracted with ethyl acetate, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo to desolvate, and purified by column chromatography (V (petroleum ether): V (ethyl acetate) = 20:1) to give 0.6 g of a yellow liquid with a yield of 60%. 1H NMR (400MHz, CDCl3) δ7.62 (d, J=8.4Hz, 2H, ArH), 7.52 (d, J=8.4Hz, 2H, ArH), 2.70 (dd, J=21.8, 10.8Hz, 1H, CH2CH2CO), 2.61-2 .42 (m, 2H, CH2CH2CO), 1.99 (ddd, J=12.4, 8.8, 1.7Hz, 1H, CH2CH2CO), 1.30 (s, 3H, CCH3), 1.21 (s, 3H, CCH3), 0.62 (s, 3H, CCH3). 13 C NMR (100MHz, CDCl3) δ221.5, 149.3, 126.9, 125.9, 125.3, 125.2, 125.2, 125.1, 53.2, 48.9, 33.6, 29.7, 25.3, 22.1, 18.5.HRMS (EI): Cacld forC 15 H 17 F3O[M] + 270.1226, found 270.1228.

[0044] Example 5: Synthesis of Sesquiterpene Derivative I-5

[0045] Tetrahydrofuran (80 mL) and Zn powder (2.5 g, 39 mmol) were added to a 500 mL round-bottom flask. Dibromomethane (6.78 g, 39 mmol) and 1 M titanium tetrachloride (7.4 g, 39 mmol) were added at 0°C. The temperature was raised to room temperature and the reaction was carried out for 30 min. A THF solution of 2,3-dimethyl-3-(p-tolyl)cyclopentan-1-one (I-1) (2.0 g, 7.8 mmol) was added and the reaction was carried out for 20 h. The reaction was monitored to be complete by TLC. The temperature was lowered to 0°C and quenched by adding aqueous NaOH solution. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to remove the solvent, and purified by column chromatography (n-hexane) to obtain 1.2 g of a yellow oily liquid with a yield of 62%. 1H NMR (400MHz, CDCl3) (for 2:1 inseparable mixture of diastereomers) δ7.60-7.48 (m, 5H, ArH), 7.33 (t, J=6.5Hz, 1H, ArH), 4.97-4.94 (m, 1H, CCH2), 4.91-4.89 (m, 1H, CCH2), 4.86 (dd, J=4.7, 2.3Hz, 1H, CCH2), 2.74 (dd, J=5.9, 2.8Hz, 1H, CHCH3), 2.63-2.60 (m, 0.5H, CHCH3), 2.60-2.54 (m, 2H, CH2CCH2CH2), 2.53-2.42 (m, 1H, CH2CCH2CH2), 2.2 6 (ddd, J=18.1, 12.3, 6.1Hz, 0.5H, CH2CCH2CH2), 2.01-1.89 (m, 1H, CH2CCH2CH2), 1.86 (dd, J=12.8, 6.9Hz, 0.5H, CH2CCH2CH2), 1.79 (ddd, J=12. 6, 8.5, 2.4Hz, 1H, CH2CCH2CH2), 1.31 (s, 1.5H, CCH3), 1.12 (d, J=0.5Hz, 3H, CCH3), 0.93 (d, J=6.8Hz, 3H, CHCH3), 0.69 (d, J=7.1Hz, 1.5H, CHCH3). 13 C NMR (100MHz, CDCl3) δ156.6, 155.6, 127.3, 126.4, 125.1, 125.0, 106.2, 105.6, 50.4, 49.5, 4 8.6, 48.3, 39.8, 35.9, 34.5, 29.7, 29.5, 29.4, 29.0, 24.0, 19.0, 17.1, 11.7.HRMS (EI): Cacld for C 15 H 17 F3[M] + 254.1277, found 254.1281.

[0046] Example 6: Synthesis of Sesquiterpene Derivative I-6

[0047] Tetrahydrofuran (80 mL) and Zn powder (1.49 g, 23 mmol) were added to a 500 mL round-bottom flask. Dibromomethane (3.99 g, 23 mmol) and 1 M titanium tetrachloride (4.35 g, 23 mmol) were added at 0°C. The temperature was raised to room temperature and the reaction was carried out for 30 min. A THF solution of 2,3-dimethyl-3-(p-methoxyphenyl)cyclopentan-1-one (I-2) (0.5 g, 2.3 mmol) was added and the reaction was carried out for 20 h. The reaction was monitored to be complete by TLC. The temperature was lowered to 0°C and quenched by adding aqueous NaOH solution. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to remove the solvent, and purified by column chromatography (n-hexane) to obtain 0.28 g of a colorless oily liquid with a yield of 57%. 1 H NMR (400MHz, CDCl3) (for 4:1 inseparable mixture of diastereomers) δ7.27-7.21(m, 2H, ArH), 7.08-7.03(m, 0.5H, ArH), 6.82-6.77(m, 2H, ArH), 6.77-6.74(m, 0.5H, ArH), 4.86-4 .83 (m, 1H, CCH2), 4.79 (dd, J=4.0, 2.1Hz, 0.5H, CCH2), 4.76 (d, J=2.0Hz, 1H, CCH2), 3.72 (d, J=5.1Hz, 4H, OCH3), 2.60 (d, J=3.3 Hz, 1H, CHCH3), 2.52-2.42 (m, 1.5H, CH2CCH2CH2), 2.41-2.32 (m, 1H, CH2CCH2CH2), 1.92-1.80 (m, 1H, CH2CCH2CH2), 1.72-1.60 (m, 1H, CH2CCH2CH2), 1.20 (s, 0.75H, CCH3), 1.00 (s, 3H, CCH3), 0.85 (d, J = 6.7Hz, 3H, CHCH3), 0.63 (d, J = 7.1Hz, 0.75H, CHCH3). 13 C NMR (100MHz, CDCl3) δ156.3, 140.4, 136.5, 130.7, 126.2, 126.0, 124.5, 120.8, 112.3, 54. 2, 53.3, 50.8, 47.0, 40.5, 34.8, 29.3, 23.3, 22.8, 14.0, 13.3, 11.7, 9.2.HRMS (EI): Cacld for C 15 H 20 O[M] + 216.1509, found 216.1516.

[0048] Example 7: Synthesis of Sesquiterpene Derivative I-7

[0049] Tetrahydrofuran (80 mL) and Zn powder (1.21 g, 18.6 mmol) were added to a 500 mL round-bottom flask. Dibromomethane (3.24 g, 18.6 mmol) and 1 M titanium tetrachloride (3.53 g, 18.6 mmol) were added at 0°C. The temperature was raised to room temperature and the reaction was carried out for 30 min. A THF solution of 3-(3,5-dibromo-4-methoxyphenyl)-2,3-dimethylcyclopentane-1-one (I-3) (0.7 g, 1.86 mmol) was added and the reaction was carried out for 20 h. The reaction was monitored to be complete by TLC. The temperature was lowered to 0°C and quenched by adding aqueous NaOH solution. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to remove the solvent, and purified by column chromatography (n-hexane) to obtain 0.40 g of a colorless oily liquid with a yield of 58%. 1 H NMR (400MHz, CDCl3) (for 3:1 inseparable mixture of diastereomers) δ7.49 (s, 2H, ArH), 7.32 (s, 0.6H, ArH), 4.95-4.92 (m, 1H, CCH2), 4.89 (d, J=1.6Hz, 0.7H, CCH2), 4.84 (dd, J=5.1, 2.7H z, 1H, CCH2), 2.62 (dd, J=5.9, 2.7Hz, 1H, CHCH3), 2.57-2.49 (m, 2H, CH2CCH2CH2), 2.44 (ddd, J=8.6, 4.2, 2.2Hz, 0.6H, CH2CCH2CH2), 2.4 1-2.37 (m, 0.3H, CHCH3), 2.21-2.12 (m, 0.3H, CH2CCH2CH2), 1.88 (dt, J=10.6, 10.1Hz, 1H, CH2CCH2CH2), 1.81-1.76 (m, 0.3H, CH2CCH2C H2), 1.76-1.71 (m, 1H, CH2CCH2CH2), 1.25 (s, 1H, CCH3), 1.05 (s, 3H, CCH3), 0.92 (d, J=6.7Hz, 3H, CHCH3), 0.72 (d, J=7.1Hz, 1H, CHCH3). 13C NMR (100MHz, CDCl3) δ150.9, 149.9, 146.6, 146.4, 142.1, 141.3, 126.1, 125.3, 112.6, 112.3, 101 .2, 100.5, 55.3, 45.1, 43.7, 43.5, 42.5, 34.6, 29.2, 24.2, 23.7, 13.7, 12.0, 6.4.HRMS (EI): Cacld forC 15 H 18 Br2O[M] + 371.9719, found 371.9725.

[0050] Example 8: Synthesis of Sesquiterpene Derivative I-8

[0051] Step 1, Synthesis of 2-methyl-3-(p-tolyl)cyclopentane-1-one (6): In a 250 mL four-necked flask, add N,N-dimethylacetamide (40 mL), palladium trifluoroacetate (0.12 g, 0.52 mmol), and bipyridine (0.097 g, 0.62 mmol). The mixture was evacuated three times and allowed to react for 1 h. 2-Methylcyclopent-2-en-1-one (5) (1 g, 10.4 mmol) and p-tolueneboronic acid (2.83 g, 20.8 mmol) were then added. The mixture was heated to 80°C and allowed to react for 24 h. The reaction was monitored by TLC for completion. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (V(petroleum ether):V(ethyl acetate)=15:1) to obtain 1.5 g of a yellow liquid with a yield of 77%. 1 H NMR (400MHz, CDCl3) δ7.20-7.11 (m, 4H, ArH), 2.77 (td, J=12.0, 5.6Hz, 1H, CHCH3), 2.58-2.47 (m, 1H, CHAr), 2 .35 (s, 3H, ArCH3), 2.34-2.16 (m, 3H, CH2CH2CO), 2.01-1.85 (m, 1H, CH2CH2CO), 1.03 (d, J=6.9Hz, 3H, CHCH3). 13 C NMR (100MHz, CDCl3) δ220.0, 139.3, 136.5, 129.4, 127.0, 51.4, 50.6, 37.8, 29.7, 21.1, 12.2.HRMS (EI): Cacld for C 13 H 16 O[M] + 188.1196, found 188.1199.

[0052] Step 2, synthesis of sesquiterpene derivative I-8: Tetrahydrofuran (80 mL) and Zn powder (3.45 g, 53.1 mmol) were added to a 500 mL round-bottom flask. Dibromomethane (9.24 g, 53.1 mmol) and 1 M titanium tetrachloride (10.08 g, 53.1 mmol) were added at 0°C. The temperature was raised to room temperature and the reaction was carried out for 30 min. A THF solution of 2-methyl-3-(p-tolyl)cyclopentane-1-one (6) (1 g, 5.31 mmol) was added and the reaction was carried out for 20 h. The reaction was monitored by TLC to be complete. The temperature was lowered to 0°C and quenched by adding aqueous NaOH solution. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated in vacuo to remove the solvent. 0.59 g of colorless oily liquid was obtained by column chromatography (n-hexane) with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ7.12 (s, 4H, ArH), 4.91 (d, J=2.1Hz, 1H, CH2), 4.82 (d, J=2.1Hz, 1H, CH2), 2.56 (dd, J=9.0, 1.8Hz, 1H, CHCH3), 2.50-2.41 (m, 2H, C H2CH2CCH2), 2.41-2.37 (m, 1H, CHAr), 2.33 (s, 3H, ArCH3), 2.09-1.98 (m, 1H, CH2CH2CCH2), 1.81-1.66 (m, 1H, CH2CH2CO), 1.00 (d, J=6.3Hz, 3H, CHCH3). 13 C NMR (100MHz, CDCl3) δ143.6, 143.4, 135.4, 135.3, 133.6, 133.0, 129.1, 129.1, 127.5, 127.4, 122.6, 104.4, 56 .2, 54.0, 53.7, 51.1, 46.5, 40.3, 37.4, 33.3, 32.8, 31.8, 21.1, 18.1, 16.2, 14.8, 14.2, 12.5.HRMS (EI): Cacld for C 14 H 18 [M] + 186.1404, found 186.1407.

[0053] Example 9: Synthesis of Sesquiterpene Derivative I-9

[0054] Step 1: Synthesis of 3-methyl-3-(p-tolyl)cyclopentane-1-one (8): Methanol (45 mL), water (5 mL), palladium trifluoroacetate (86 mg, 0.26 mmol), and bipyridine (60 mg, 0.39 mmol) were added to a 250 mL four-necked flask. Under Ar protection, the mixture was heated to 60°C for 15 min, cooled to room temperature, and 3-methylcyclopent-2-en-1-one (7) (2.5 g, 26.0 mmol) and p-tolueneboronic acid (7.07 g, 52.0 mmol) were added. The mixture was reacted at room temperature for 24 h. The reaction was monitored by TLC for completion. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to remove the solvent, and separated by column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain 4 g of a white solid with a yield of 81% and a melting point of 76-77°C. 1 H NMR (400MHz, CDCl3) δ7.21-7.12 (m, 4H, ArH), 2.63 (d, J=17.7Hz, 1H, COCH2C), 2.45 (d, J=11.2Hz, 1H, COC H2C), 2.43-2.34(m, 2H, CH2CH2CO), 2.33(s, 3H, ArCH3), 2.30-2.21(m, 2H, CH2CH2CO), 1.37(s, 3H, CCH3). 13 C NMR (100MHz, CDCl3) δ218.8, 145.58, 135.9, 129.3, 125.4, 52.4, 43.5, 36.6, 35.9, 29.5, 20.9.HRMS (EI): Cacldfor C 13 H 16 O[M] + 188.1196, found 188.1202.

[0055] Step 2, synthesis of sesquiterpene derivative I-9: Tetrahydrofuran (80 mL) and Zn powder (6.89 g, 106 mmol) were added to a 500 mL round-bottom flask. Dibromomethane (18.4 g, 106 mmol) and 1 M titanium tetrachloride (20.1 g, 106 mmol) were added at 0°C. The temperature was raised to room temperature and the reaction was carried out for 30 min. A THF solution of 3-methyl-3-(p-tolyl)cyclopentane-1-one (8) (2 g, 10.6 mmol) was added and the reaction was carried out for 20 h. The reaction was monitored by TLC to be complete. The temperature was lowered to 0°C and quenched by adding aqueous NaOH solution. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated in vacuo to remove the solvent. 0.59 g of colorless oily liquid was obtained by column chromatography (n-hexane) with a yield of 60%. 1H NMR (400MHz, CDCl3) δ7.21-7.18 (m, 2H, ArH), 7.11 (d, J=7.9Hz, 2H, ArH), 4.99-4.93 (m, 1H, CH2), 4.90-4.85 (m, 1H, CH2), 2.66 (d, J=15.7Hz, 1H, C H2CCH2C), 2.53-2.49 (m, 1H, CH2CCH2C), 2.47-2.41 (m, 2H, CH2CH2CCH2), 2.31 (s, 3H, ArCH3), 2.04-1.89 (m, 2H, CH2CH2CCH2), 1.24 (s, 3H, CCH3). 13 C NMR (100MHz, CDCl3) δ151.9, 147.9, 139.3, 134.9, 133.6, 128.9, 125.8, 122.8, 106.4, 52.4, 52.0, 48.0, 47.3, 41.8, 39.2, 36.3, 31.7, 30.60(s), 28.90(s), 28.24(s), 21.04(s), 16.87(s).HRMS(EI): Cacldfor C 14 H 18 [M] + 186.1404, found 186.1409.

[0056] Example 10: Synthesis of Sesquiterpene Derivative I-10

[0057] The first step is the synthesis of 3-(2-methoxy-4-methylphenyl)-2-methylcyclopent-2-ene-1-one (9): isobutoxy-2-methylcyclopentene-1-one (3) (10 g, 59.5 mmol) and 60 mL of redistilled tetrahydrofuran were added to a 500 mL four-necked flask. Under argon protection at 0°C, (2-methoxy-4-methylphenyl)magnesium bromide (89 mL, 89 mmol) was gradually added. After 15 minutes, the mixture was brought to room temperature and the reaction was continued for 12 hours. The reaction was completed by TLC. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and purified by column chromatography (V(petroleum ether):V(ethyl acetate)=10:1) to obtain 9.5 g of the product as a yellow oil with a yield of 74%. 1H NMR (400MHz, CDCl3) δ7.05 (t, J=6.0Hz, 1H, ArH), 6.83 (dd, J=7.7, 0.6Hz, 1H, ArH), 6.78 (d, J=7.5Hz, 1H, ArH), 3.82 (s, 3H, OCH3), 2.91-2.84 (m, 2H, COCH2CH2), 2.54-2.47 (m, 2H, COCH2CH2), 2.40 (s, 3H, ArCH3), 1.70 (t, J=2.0Hz, 3H, CH3C). 13 C NMR (100MHz, CDCl3) δ210.4, 167.7, 156.3, 140.7, 138.0, 128.7, 123.1, 121.1, 112.1, 55.3, 34.4, 30.5, 21.8, 9.6.HRMS (EI): Cacld for C 14 H 16 O2[M] + 216.1145, found 216.1141.

[0058] Step 2, synthesis of 4-(2-methoxy-4-methylphenyl)-2,3-dimethylcyclopentane-1-one (10): 3-(2-methoxy-4-methylphenyl)-2-methylcyclopent-2-ene-1-one (9) (7 g, 32.4 mmol), nickel acetylacetonate (0.42 g, 1.85 mmol) and 60 mL of redistilled tetrahydrofuran were added to a 500 mL four-necked flask. Trimethylaluminum (24.3 mL, 48.6 mmol) was gradually added under argon protection at 0°C. After 15 minutes, the mixture was brought to room temperature and the reaction was continued for 12 hours. The reaction was completed by TLC. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and purified by column chromatography (V(petroleum ether):V(ethyl acetate)=20:1) to obtain 5.8 g of the product as a yellow oil with a yield of 78%. 1H NMR(400MHz,CDCl3)(for 3∶1inseparable mixture of diastereomers)δ7.07(d,J=7.7Hz,1.35H,ArH),6.76(m,1.7H,ArH),6.68(s,1H,ArH),3.83(s,1H,OCH3),3.77(s,3H,OCH3),3.04(d,J=7.0Hz,0.3H,CHCH3),2.71(q,J=7.5Hz,1H,CHCH3),2.40(m,3H,2COCH2CH2+1ArCH3),2.34(s,4H,3ArCH3+1COCH2CH2),2.29(q,J=6.0Hz,1H,COCH2CH2),2.13-2.06(m,1H,COCH2CH2),1.33(s,3H,CCH3),1.22(s,1H,CCH3),1.03(d,J=7.0Hz,1H,CHCH3),0.69(d,J=7.5Hz,3H,CHCH3). 13 CNMR(100MHz,CDCl3)δ223.3,221.3,158.1,157.0,137.7,137.5,131.8,131.6,126.9,126.88,121.2,121.0,112.7,111.6,55.0,54.7,53.5,51.9,45.7,45.5,35.1,34.7,32.7,32.2,27.1,21.3,19.9,13.1,9.4.HRMS(EI):Cacld for C 15 H 20 O2[M] + 232.1458,found232.1462.

[0059] Step 3, synthesis of 1-(1,2-dimethyl-3-methylenecyclopentyl)-2-methoxy-4-methylbenzene (11): Tetrahydrofuran (80 mL) and Zn powder (11.2 g, 172 mmol) were added to a 500 mL round-bottom flask. Dibromomethane (30 g, 172 mmol) and 1 M titanium tetrachloride (32.6 g, 172 mmol) were added at 0°C. The temperature was raised to room temperature and the reaction was carried out for 30 min. A THF solution of 4-(2-methoxy-4-methylphenyl)-2,3-dimethylcyclopentane-1-one (10) (4 g, 17.2 mmol) was added and the reaction was carried out for 20 h. The reaction was monitored by TLC to be complete. The temperature was lowered to 0°C and quenched by adding aqueous NaOH solution. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated in vacuo to remove the solvent. Column chromatography (n-hexane) was performed to obtain 2.46 g of a colorless oily liquid with a yield of 62%. 1 H NMR (400MHz, DMSO-d6) δ6.90 (d, J=7.8Hz, 1H, ArH), 6.70 (s, 1H, ArH), 6.61 (dd, J=7.7, 0.7Hz, 1H, ArH), 4.87 (s, 1H, CCH2), 4.77 (d, J=1.2Hz, 1H, CCH2), 3.70 (s, 3H, OCH3), 2.92-2.82 (m, 1H, CHCH3) , 2.33 (td, J=9.8, 2.3Hz, 2H, CH2CCH2CH2), 2.20 (s, 3H, ArCH3), 2.08 (ddd, J=26.5, 12.8, 7.6Hz, 1 H, CH2CCH2CH2), 1.72-1.64 (m, 1H, CH2CCH2CH2), 1.03 (s, 3H, CCH3), 0.47 (t, J=9.6Hz, 3H, CHCH3). 13 C NMR (100MHz, DMSO-d6) δ158.3, 157.4, 136.8, 132.8, 127.7, 121.3, 112.4, 106.8, 55.5, 48.7, 48.4, 34.6, 28.0, 26.3, 21.3, 20.0.HRMS (EI): Cacld forC 16 H 22 O[M] + 230.1666, found 230.1673.

[0060] Step 4, Synthesis of Sesquiterpene Derivative I-10: Dichloromethane (80 mL), silica gel (10 g), 1-(1,2-dimethyl-3-methylenecyclopentyl)-2-methoxy-4-methylbenzene (11) (3 g, 13.0 mmol), and HCl (65.22 mmol) were added to a 250 mL round-bottom flask and reacted at room temperature for 48 h. The reaction was monitored by TLC to be complete. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated in vacuo to remove the solvent, and separated by column chromatography (n-hexane) to obtain 1.38 g of a yellow oily liquid with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ6.89 (d, J=7.3Hz, 1H, ArH), 6.71 (d, J=8.3Hz, 2H, ArH), 5.55-5.50 (m, 1H, CHCH2), 3.75 (s, 3H, OCH3), 2.47 (ddd, J=14.8, 6.4, 2.7Hz, 1H, CHCH3), 2.35 (s, 3H, ArCH3), 2.11-1.95 (m, 2H, CHCH2), 1.00 (d, J=6.7Hz, 3H, CHCH3), 0.95 (s, 3H, CCH3), 0.82 (s, 3H, ArCCH3). 13 C NMR (100MHz, CDCl3) δ157.4, 150.3, 137.9, 131.0, 127.1, 125.0, 120.5, 111.7, 55.6, 49.2, 44.9, 38.5, 26.1, 21.6, 20.4, 14.4.HRMS (EI): Cacld forC 16 H 22 O[M] + 230.1665, found 230.1668.

[0061] Example 11: Synthesis of Sesquiterpene Derivative I-11

[0062] The first step is the synthesis of 2-methyl-3-(p-tolyl)cyclopent-2-ene-1-one (12): isobutoxy-2-methylcyclopentene-1-one (3) (5 g, 29.7 mmol) and 60 mL of redistilled tetrahydrofuran were added to a 500 mL four-necked flask. Under argon protection at 0°C, (4-methylphenyl)magnesium bromide (35.6 mL, 35.6 mmol) was gradually added. After 15 minutes, the mixture was brought to room temperature and the reaction was continued for 12 hours. The reaction was completed by TLC. The product was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and purified by column chromatography (V (petroleum ether): V (ethyl acetate) = 10:1) to obtain 4.3 g of the product as a yellow oil with a yield of 77%. 1H NMR (400MHz, CDCl3) δ7.45 (d, J=8.2Hz, 2H, ArH), 7.27 (d, J=7.9Hz, 2H, ArH), 2.90 (ddd, J=6.6, 4.3, 2.0Hz , 2H, COCH2), 2.53 (ddd, J=7.0, 5.7, 4.8Hz, 2H, CH2CH2), 2.41 (s, 3H, ArCH3), 1.97 (t, J=2.0Hz, 3H, CH3C). 13 C NMR (100MHz, CDCl3) δ210.1, 166.8, 139.9, 135.8, 133.5, 129.3, 127.6, 34.0, 29.2, 21.4, 10.0.HRMS (EI): Cacld for C 13 H 14 O[M] + 186.1039, found186.1039.

[0063] Step 2, synthesis of 2,3-dimethyl-3-(p-tolyl)cyclopentane-1-one (13): 2-methyl-3-(p-tolyl)cyclopent-2-ene-1-one (13) (6.1 g, 32.8 mmol), nickel acetylacetonate (0.42 g, 1.64 mmol) and 60 mL of redistilled tetrahydrofuran were added to a 500 mL four-necked flask. Trimethylaluminum (20 mL, 40 mmol) was gradually added at 0°C under argon protection. After 15 minutes, the mixture was brought to room temperature and the reaction was continued for 12 hours. The reaction was completed by TLC detection. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and purified by column chromatography (V (petroleum ether): V (ethyl acetate) = 20:1) to obtain 5.3 g of the product as a yellow oil with a yield of 80%. 1H NMR (400MHz, CDCl3) (for 2:1 inseparable mixture of diastereomers) δ7.31-7.26 (m, 2H, ArH), 7.18 (d, J=8.0Hz, 2H, ArH), 7.13 (d, J=8.0Hz, 1H, ArH), 7.08-7.04 (m, 1H, ArH), 2.59 (dd, J=6.9, 0.8Hz, CHCH3), 2.49-2.39 (m, 3H, COCH2 CH2), 2.34(s, 3H, ArCH3), 232(s, 1.5H, ArCH3), 2.16-2.05(m, 3H, COCH2CH2), 1.40(s, 1.5 H, CCH3), 1.19 (s, 3H, CCH3), 1.03 (d, J=7.0Hz, 3H, CHCH3), 0.82 (d, J=7.3Hz, 1.5H, CHCH3). 13 C NMR (100MHz, CDCl3) δ220.2, 144.4, 135.9, 129.7, 129.2, 129.1, 126.6, 125.4, 120.4, 115.4, 55.3, 54.4, 46.4, 45.8, 36.4, 35.2, 35.1, 32.2, 29.9, 20.9, 20.6, 11.9, 8.7.HRMS (EI): Cacld for C 14 H 18 O[M] + 202.1352, found 202.1358.

[0064] Step 3, Synthesis of 2,3-dimethyl-3-(p-tolyl)cyclopentane-1-one oxime I-11: In a 100 mL round-bottom flask, water (18 mL), hydroxylamine hydrochloride (2.1 g, 30 mmol), and sodium acetate (1.97 g, 24 mmol) were added. Under stirring, an ethanol solution (7 mL) of 2,3-dimethyl-3-(p-tolyl)cyclopentane-1-one (13) (4 g, 20 mmol) was added. The mixture was heated to 60° C. and reacted for 15 h. The reaction was monitored by TLC to be complete. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to remove the solvent, and purified by column chromatography (V (petroleum ether): V (ethyl acetate) = 20:1) to obtain 4.0 g of a white solid product with a yield of 92% and a melting point of 126-128° C. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H, OH), 7.30 (d, J=8.2Hz, 2H, ArH), 7.13 (d, J=8.1Hz, 2H, ArH), 2.83 (q, J=6.6Hz, 1H, CHCH3), 2.45-2.37 (m, 2H, CH2C=NOH) , 2.27 (s, 3H, ArCH3), 1.91 (dt, J=20.3, 10.1Hz, 1H, CH2CAr), 1.77 (ddd, J=12. 4, 7.3, 3.1Hz, 1H, CH2CAr), 1.04 (s, 3H, CHCCH3), 0.90 (d, J=6.8Hz, 3H, CHCCH3). 13 C NMR (100MHz, DMSO-d6) δ165.0, 144.0, 134.7, 128.8, 125.7, 46.7, 37.7, 24.5, 20.4, 19.1, 10.8.HRMS (ESI): Cacld for C 14 H 18 NO[MH] - 216.1394, found 216.1398.

[0065] Example 12: Synthesis of Sesquiterpene Derivative I-12

[0066] 2,3-Dimethyl-3-(p-tolyl)cyclopentan-1-one (13) (2.0 g, 10 mmol), ethanol (50 mL), triethylamine (5 g), and hydrazine hydrate (5 g, 100 mmol) were added to a 250 mL round-bottom flask and refluxed at 78°C for 5 h. The reaction was complete when monitored by TLC. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (V (dichloromethane): V (methanol) = 20:1) to give 1.6 g of a yellow oily solid (yield: 74%), melting point: 93-95°C. 1HNMR(400MHz, DMSO-d6)(for 5:1 inseparable mixture of diastereomers) δ7.31 (dd, J=12.3, 8.3Hz, 2.5H, ArH), 7.12 (dd, J=15.6, 7.5Hz, 2.5H, ArH), 5.52 (d , J=15.1Hz, 2H, NH2), 2.93-2.85 (m, 0.2H, CHCH3), 2.71 (q, J=6.6Hz, 1H, CHCH3), 2.26 (q, J=4.6Hz, 6H , CH2C=NNH2+ArCH3), 1.92 (dt, J=19.7, 9.9Hz, 1.2H, CH2CAr), 1.86-1.75 (m, 1.3H, CH2CAr), 1.17 (s , 0.6H, CHCCH3), 1.00 (s, 3H, CHCCH3), 0.86 (d, J=6.8Hz, 3H, CHCCH3), 0.62 (d, J=7.1Hz, 0.6H, CHCCH3). 13 C NMR (100MHz, DMSO-d6) δ159.4, 158.1, 145.0, 144.0, 135.0, 129.3, 129.2, 129.1, 127.1, 126 .1, 49.1, 48.2, 47.6, 46.8, 383, 32.7, 29.7, 24.4, 20.9, 19.6, 16.2, 11.4.HRMS (ESI): Cacld for C 14 H 21 N2[M+H] + 217.1699, found 217.1675.

[0067] Example 13: Synthesis of Sesquiterpene Derivative I-13

[0068] I-12 (0.4 g, 1.85 mmol), pyridine (20 mL), and p-toluenesulfonyl chloride (0.39 g, 2.03 mmol) were added to a 100 mL round-bottom flask and allowed to react at room temperature for 12 hours. TLC monitored the reaction for completion. Extraction was performed with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (V (petroleum ether): V (ethyl acetate) = 20:1) to afford 0.5 g of a yellow solid, a yield of 73%, with a melting point of 131-132°C. 1H NMR (400MHz, DMSO-d6) (for 3:1 inseparable mixture of diastereomers) δ9.95 (s, 1.3H, NH), 7.78-7.70 (m, 3H, ArH), 7.41-7.35 (m, 3H, ArH), 7.26 (d, J=8.2Hz, 2H, ArH) , 7.10 (d, J=8.1Hz, 2H, ArH), 7.04 (d, J=6.5Hz, 1H, ArH), 2.76 (q, J=6.7Hz, 1H, CHCH3), 2.47-2.41 (m, 1.3H, CH2C =N), 2.38 (d, J=3.5Hz, 4H, ArCH3), 2.35-2.28 (m, 1.3H, CH2C=N), 2.25 (d, J=2.5Hz, 4H, ArCH3), 1.96-1.72 (m, 2. 5H, CH2CAr), 1.12 (s, 1H, CCH3), 0.91 (s, 3H, CCH3), 0.76 (d, J=6.7Hz, 3H, CHCH3), 0.53 (d, J=7.1Hz, 1H, CHCH3). 13 C NMR (100MHz, DMSO-d6) δ170.5, 169.2, 144.3, 143.5, 143.2, 136.8, 135.3, 129.8, 129.7, 129.2, 129.1, 127.9, 127.8, 127. 0, 126.1, 49.6, 48.9, 47.7, 46.8, 38.0, 35.8, 32.7, 29.5, 29.0, 26.7, 26.3, 21.5, 20.9, 19.5, 15.6, 10.9.HRMS (ESI): Cacld forC 21 H 27 N2O2S[M+H] + 371.1788, found 371.1794.

[0069] Example 14: Synthesis of sesquiterpene derivative I-14.

[0070] A 250 mL round-bottom flask was charged with 2,3-dimethyl-3-(p-tolyl)cyclopentan-1-one (13) (1 g, 4.95 mmol), ethanol (50 mL), and 2-phenylthiazole-4-carbohydrazide (0.54 g, 2.48 mmol). The mixture was refluxed at 100°C for 5 h, cooled to room temperature, and the reaction was complete after monitoring by TLC. The mixture was washed with brine and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (V (dichloromethane): V (methanol) = 20:1) to give 0.7 g of a yellow solid, with a yield of 69%, and a melting point of 89-90°C. 1 H NMR (400MHz, DMSO-d6) (for 3:1 inseparable mixture of diastereomers) δ 10.26 (d, J=9.0Hz, 1.4H, NH), 8.48 (d, J=3.5Hz, 1H, ArH), 8.08 (dd, J=6.4, 3.1Hz, 3H, ArH) , 7.60-7.51 (m, 5H, ArH), 7.36 (d, J=8.2Hz, 2H, ArH), 7.19-7.13 (m, 4H, ArH), 3.00 (t, J=6.7Hz, 1H, CHCH3), 2.71 (dd, J=9.5, 5.1Hz, 2.5H, CH2C=N), 2.28 (d, J=3.8Hz, 4H, ArCH3), 2.11-2.00 (m, 1.3H, CH2CAr), 1.98-1.89 (m, 1. 3H, CH2CAr), 1.25 (s, 1H, CCH3), 1.11 (s, 3H, CCH3), 1.00 (d, J=6.8Hz, 3H, CHCH3), 0.76 (d, J=7.2Hz, 1H, CHCH3). 13 CNMR (100MHz, CDCl3) δ149.6, 132.1, 131.1, 126.6, 124.5, 120.5, 115.5, 107.0, 83.9, 52.6, 29.9, 29.4, 28.2.HRMS (ESI): Cacld for C 24 H 26 N3OS[M+H] + 404.1791, found 404.1795.

[0071] Example 15: Determination of anti-tobacco mosaic virus activity, the determination procedure is as follows:

[0072] 1. Virus purification and concentration determination:

[0073] Virus purification and concentration determination were performed according to the Tobacco Mosaic Virus Standard Operating Procedure (SOP) developed by the Institute of Elemental Biology and Biotechnology at Nankai University. The crude virus extract was centrifuged twice with polyethylene glycol, the concentration was determined, and the extract was refrigerated at 4°C until use.

[0074] 2. Preparation of compound solution:

[0075] After weighing, the original drug was dissolved in DMF to prepare 1×10 5 μg / mL stock solution, and then diluted to the required concentration with an aqueous solution containing 1‰ Tween 80; the ribavirin preparation is directly diluted with water.

[0076] 3. In vivo protection:

[0077] Select uniformly growing Sanxi tobacco plants at the 3-5 leaf stage and spray the entire plant with the pesticide, with three replicates per treatment. A 1‰ Tween 80 aqueous solution was also used as a control. After 24 hours, emery (500 mesh) was sprinkled on the leaves. A brush dipped in the virus solution was gently rubbed twice along the entire leaf surface along the veins, supporting the underside of the leaf with the palm of your hand. The virus concentration was 10 μg / mL. After inoculation, the leaves were rinsed with running water. Three days later, the number of lesions was recorded and the efficacy was calculated.

[0078] 4. In vivo therapeutic effect:

[0079] Select uniformly growing Sansi tobacco plants at the 3-5 leaf stage. Use a brush to inoculate the entire leaf with the virus at a concentration of 10 μg / mL. Rinse with running water after inoculation. After the leaves have dried, spray the entire plant with the pesticide. Repeat each treatment three times, using a 1‰ Tween 80 aqueous solution as a control. After three days, record the number of lesions and calculate the efficacy.

[0080] 5. In vivo passivation effect:

[0081] Select uniformly growing Sansi tobacco plants at the 3-5 leaf stage. Mix the agent with an equal volume of virus sap and inactivate it for 30 minutes. Then, inoculate by friction at a virus concentration of 20 μg / mL. Immediately rinse with running water after inoculation. Repeat three times. Use a 1‰ Tween 80 aqueous solution as a control. Count the number of lesions after three days and calculate the results.

[0082] Inhibition rate (%) = [(number of control lesions - number of treated lesions) / number of control lesions] × 100%

[0083] All compounds were first tested for in vivo inactivation activity against tobacco mosaic virus at a treatment dose of 500 μg / mL. Compounds with relative inhibition rates greater than 40% were further tested for in vivo therapeutic and protective activity at a treatment dose of 500 μg / mL, and for in vivo inactivation, therapeutic, and protective activity against tobacco mosaic virus at a treatment dose of 100 μg / mL. The commercial anti-plant virus agent ribavirin was used as a positive control.

[0084] Table 1 Test results of anti-tobacco mosaic virus (TMV) activity of sesquiterpene derivatives I-1 to I-14:

[0085]

[0086] From the data in the table, it can be seen that the sesquiterpene derivatives I-1 to I-14 all showed good anti-TMV activity at a treatment dose of 500 μg / mL, among which derivatives I-5, I-13, and I-14 all showed anti-TMV activity comparable to that of ribavirin.

[0087] Example 9: Antibacterial activity test, the determination procedure is as follows:

[0088] In vitro bactericidal test, bacterial growth rate determination method (plate method):

[0089] Dissolve a certain amount of drug in an appropriate amount of acetone, then dilute to the desired concentration with an aqueous solution containing 200μg / mL emulsifier. Then, pipette 1mL of the drug solution into each culture dish, add 9mL of culture medium, shake well, and make a 50μg / mL drug-containing plate. Use a plate with 1mL of sterilized water as a blank control. Use a 4mm diameter punch to cut the bacterial disc along the outer edge of the mycelium and transfer it to the drug-containing plate. Repeat each treatment three times. Place the culture dish in a constant temperature incubator at 24±1℃ and culture. After 48 hours, observe the expanded diameter of each treatment bacterial disc, calculate the average value, and compare it with the blank control to calculate the relative inhibition rate.

[0090]

[0091] Table 2 Test results of anti-plant pathogenic fungi activity of sesquiterpene derivatives I-1 to I-14:

[0092]

[0093] At a concentration of 50 μg / mL, the sesquiterpenes exhibited broad-spectrum inhibitory activity against all eight tested fungi. Compounds I-4, I-7, I-10, I-11, and I-14 exhibited significant antibacterial activity against apple ring rot, with inhibition rates exceeding 60%. Compounds I-7 and I-10 achieved inhibition rates of 90% and 94% respectively. Some compounds exhibited superior inhibitory activity against selected strains compared to commercially available carbendazim and chlorothalonil.

Claims

1. A sesquiterpene laurene derivative, characterized in that: The sesquiterpene laurene derivative is one of the following structural formulas I-1 to I-14 2. Use of the sesquiterpene derivatives I-1 to I-14 according to claim 1 in preventing and treating plant viral diseases, characterized in that: The plant virus is tobacco mosaic virus.

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