Synthetic method of bisabolane sesquiterpenes and derivatives thereof

Abstract

The invention discloses a synthetic method of bisabolane sesquiterpenes and derivatives thereof, and belongs to the technical field of chemical synthesis. The preparation method comprises the following steps: carrying out MOM protection on a phenolic hydroxyl group by using a cheap and easily available compound 1, carrying out benzyl bromination, sodium acetate hydrolysis, benzyl alcohol MOM protection, Grignard reagent addition and Burge reagent elimination, and removing an MOM protecting group under an HCl condition to obtain the natural product Aspergillus A. The method comprises the following steps: carrying out Wolff-Kishner-Huang reduction on a cheap and easily available compound 10, removing a methyl protecting group by using boron tribromide, and carrying out MOM protection on a phenolic hydroxyl group to obtain a compound 13; the preparation method comprises the following steps: carrying out benzyl bromination on a compound 6, carrying out Negishi coupling reaction on the compound 6 and a compound 13, carrying out 1, 2 addition and Burge reagent elimination, and simultaneously removing an MOM protecting group to obtain the natural product YHB-17. Similarly, the natural product YHB-14 is obtained by using the method. A brand new synthesis strategy is used, reaction repeatability is high, operability is good, and the requirement of large-scale industrial production can be met.

Description

TECHNICAL FIELD

[0001] The application relates to a synthetic method of guggulane sesquiterpenes and derivatives thereof, and belongs to the technical field of chemical synthesis. BACKGROUND

[0002] Guggulane sesquiterpenes contain many natural products, and a secondary metabolite produced by a Pacific fungus Aspergillus sp. MCCC 3A00392 is a main source. The compounds not only have a unique guggulane skeleton, but also most of the compounds show good biological and pharmacological activities. In 2011, Jariya Sakayaroj's research group [1]The isolation of Aspergillusense A was first reported, and its antioxidant activity was tested (Trisuwan K.; Rukachaisirikul V.; Kaewpet M.; et al. Sesquiterpene and Xanthone Derivatives from the Sea Fan-Derived Fungus Aspergillus sydowii PSU-F154. J. Nat. Prod., 2011, 74, 1663-1667.). In 2018, the She Zhigang research group first reported the isolation of YHB-14, and found that the compound has good α-glucosidase inhibitory activity (Wu Y.-N.; Chen Y.; Huang X.-S.; et al. α-Glucosidase Inhibitors: Diphenyl Ethers and Phenolic Bisabolane Sesquiterpenoids from the Mangrove Endophytic Fungus Aspergillus flavus QQSG-3. Mar. Drugs, 2018, 16, 307-315.). In 2024, the Yang Xianwen research group reported the activity research of YHB-17 and YHB-14, further explored the structure-activity relationship, and found that the C-6 phenolic hydroxyl group in YHB-14 plays an important role in inhibiting tumor necrosis factor TNF-induced necrotic apoptosis (Yu H.-Y.; Chen Y.-S.; Wang Y.; et al. Anti-necroptosis and anti-ferroptosis compounds from the Deep-Sea-Derived fungus Aspergillus sp. MCCC 3A00392. Bioorg. Chem., 2024, 144, 107175-107187. The activity of this type of compound is excellent, but its natural source is extremely scarce.

[0003] Therefore, the present application solves the above-mentioned source problem of the compound by means of total synthesis, and provides a material basis for further research on biological activity. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a synthetic method for rapidly and efficiently synthesizing bisabolane-type sesquiterpenes and derivatives thereof, so as to realize efficient preparation of bisabolane-type sesquiterpenes and derivatives thereof and meet the needs of biological activity testing.

[0005] To achieve the above object, the present application adopts the following technical means:

[0006] The synthesis method of the guggulane type sesquiterpene and its derivatives comprises the following steps:

[0007] Step one: compound 1 is dissolved in a mixed solution of dichloromethane and toluene, bromomethyl methyl ether, diisopropylethylamine and tetrabutylammonium iodide are added, and the reaction is carried out at 65 DEG C; after the reaction is completed, the solvent is spin-dried, dissolved in carbon tetrachloride, N-bromosuccinimide and azobisisobutyronitrile are added, and the reaction is carried out at 80 DEG C to obtain compound 2;

[0008]

[0009] Step two: compound 2 is dissolved in dimethyl sulfoxide, sodium acetate is added, and the reaction is carried out at 80 DEG C; after the reaction is completed, it is extracted and spin-dried, dissolved in methanol / water system, and potassium carbonate is added to obtain compound 3;

[0010]

[0011] Step three: compound 3 is dissolved in a mixed solution of dichloromethane and toluene, bromomethyl methyl ether, diisopropylethylamine and tetrabutylammonium iodide are added, and the reaction is carried out at 50 DEG C to obtain compound 4;

[0012]

[0013] Step four: compound 4 is dissolved in ether solution, Grignard reagent is added at-78 DEG C, and the reaction is carried out to obtain compound 5;

[0014]

[0015] Step five: compound 5 is dissolved in tetrahydrofuran solution, and Burgess reagent is added, and the reaction is carried out at 50 DEG C; methanol is added, and 2M HCl is reacted at room temperature to obtain natural product Aspergillusense A and compound 6;

[0016]

[0017] Step six: compound 7 is dissolved in diethylene glycol, hydrazine hydrate is added, and the reaction is carried out for 30 minutes, then potassium hydroxide is added at 150 DEG C to obtain compound 8;

[0018]

[0019] Step seven: compound 8 is dissolved in dichloromethane solution, boron tribromide is added, and the reaction is carried out at-78 DEG C to obtain compound 9;

[0020]

[0021] Step eight: compound 9 was dissolved in a mixture of dichloromethane and toluene, bromomethyl methyl ether, diisopropylethylamine and tetrabutylammonium iodide were added, and the reaction was carried out at 65 °C to obtain compound 10;

[0022]

[0023] Step nine: compound 11 was dissolved in carbon tetrachloride solution, N- bromosuccinimide and azobisisobutyronitrile were added, and the reaction was carried out at 85 °C to obtain compound 12;

[0024]

[0025] Step ten: compound 12 was dissolved in tetrahydrofuran solution, n-butyllithium, zinc chloride were added at-78 °C, dichlorobis(triphenylphosphine)palladium and compound 10 were slowly added to room temperature, and the reaction was carried out at 80 °C to obtain compound 13;

[0026]

[0027] Step eleven: compound 13 was dissolved in tetrahydrofuran solution, Grignard reagent was added at-78 °C, and the reaction was carried out for 30 min to obtain compound 14;

[0028]

[0029] Step twelve: compound 14 was dissolved in tetrahydrofuran solution, and Burgess reagent was added, after the reaction was completed, 2M HCl was added to remove the protecting group; extraction, rotary evaporation, dissolution in chloroform solution, addition of trifluoroacetic acid, and reaction to obtain natural product YHB-17.

[0030]

[0031] Step thirteen: compound 2 was obtained by the same operation as step ten;

[0032]

[0033] Step fourteen: compound 15 was obtained by the same operation as step eleven;

[0034]

[0035] Step fifteen: compound 16 was obtained by the same operation as step twelve to obtain compound YHB-14;

[0036]

[0037] In the present application, preferably, in step one, the molar ratio of compound 1, bromomethyl methyl ether, diisopropylethylamine and tetrabutylammonium iodide is 1:1.3:1.6:0.1, the volume ratio of dichloromethane and toluene is 1:2, and the reaction time is 2 h; the molar ratio of compound 1, N-bromosuccinimide and azobisisobutyronitrile is 1:1.2:0.1, and the reaction time is 1 h, to obtain compound 2.

[0038] In the present application, preferably, in step two, the molar ratio of compound 2, sodium acetate and potassium carbonate is 1:2.0:2.0, and the concentration of dimethyl sulfoxide solution is 0.1 M.

[0039] In the present application, preferably, in step three, the molar ratio of compound 3, bromomethyl methyl ether, diisopropylethylamine and tetrabutylammonium iodide is 1:2.0:3.0:0.2, the volume ratio of dichloromethane and toluene is 1:2, and the reaction time is 2 h, to obtain compound 4.

[0040] In the present application, preferably, in step four, the molar ratio of compound 4 and Grignard reagent is 1:2.0, the temperature is -78 ℃, and the reaction time is 30 min, to obtain compound 5.

[0041] In the present application, preferably, in step five, the molar ratio of compound 5 and Burgess reagent is 1:3.0, the reaction concentration is 0.08 M, and the reaction time is 15 min, to obtain natural product Aspergillusense A and compound 6 after removing the protecting group.

[0042] In the present application, preferably, in step six, the molar ratio of compound 7, hydrazine hydrate and potassium hydroxide is 1:3.0:3.5, the concentration of diethylene glycol is 0.7 M, the temperature is 150 ℃, and the reaction time is 2.5 h, to obtain compound 8.

[0043] In the present application, preferably, in step seven, the molar ratio of compound 8 and boron tribromide is 1:2.0, to obtain compound 9.

[0044] In the present application, preferably, in step eight, the molar ratio of compound 9, bromomethyl methyl ether, diisopropylethylamine and tetrabutylammonium iodide is 1:3.0:4.5:0.15, and the reaction time is 2 h, to obtain compound 10.

[0045] In the present application, preferably, in step nine, the molar ratio of compound 11, N-bromosuccinimide and azobisisobutyronitrile is 1:1.2:0.1, and the reaction time is 1 h, to obtain compound 12.

[0046] In the present application, preferably, in step ten, the molar ratio of compound 12, compound 10, n-butyllithium, zinc chloride and dichlorobistriphenylphosphine palladium is 1:1.7:1.8:1.9:0.05, to obtain compound 13.

[0047] In the present application, preferably, in step eleven, the molar ratio of compound 13 and Grignard reagent is 1:2, and the concentration of tetrahydrofuran solution is 0.1M, to obtain 14.

[0048] In the present application, preferably, in step twelve, the ratio of compound 14 and Burgess reagent is 1:3.0, and the reaction temperature is 50℃, and then the protecting group is removed, to obtain compound YHB-17.

[0049] In the present application, preferably, in step thirteen, the molar ratio of compound 2, compound 10, n-butyllithium, zinc chloride and dichlorobistriphenylphosphine palladium is 1:1.7:1.8:1.9:0.05, to obtain compound 15.

[0050] In the present application, preferably, in step fourteen, the molar ratio of compound 15 and Grignard reagent is 1:2.0, to obtain compound 16.

[0051] In the present application, preferably, in step fifteen, the molar ratio of compound 16 and Burgess reagent is 1:3.0, to obtain compound YHB-14.

[0052] Compared with the prior art, the present application has the following advantages:

[0053] The present application provides a new method for synthesizing guggulane type sesquiterpenes and derivatives thereof. In the present application, the phenolic hydroxyl group of compound 1 is protected by MOM, benzyl bromination is performed, sodium acetate hydrolysis is performed, benzyl alcohol MOM protection is performed, Grignard reagent addition is performed, and Burgess reagent elimination is performed, and then the MOM protecting group is removed under HCl conditions to obtain natural product Aspergillusense A. In the present application, compound 10 is cheap and easy to obtain, Wolff-Kishner-Huang reduction is performed, boron tribromide is used to remove the methyl protecting group, the phenolic hydroxyl group is protected by MOM to obtain compound 13. Compound 6 is subjected to benzyl bromination, then subjected to Negishi coupling reaction with 13, subjected to 1,2 addition, subjected to Burgess reagent elimination, and subjected to removal of the MOM protecting group under HCl conditions to obtain natural product YHB-17. Similarly, the method is used to obtain natural product YHB-14. The present application uses a new synthesis strategy, has high reaction repeatability and good operability, and can meet the needs of large-scale industrial production. Compared with the prior art, the present application has the following advantages:

[0054] 1) The present application is by simple substrate, by dichloroditolylphosphine palladium mediated Negishi coupling reaction, simple and efficient construction of two fragments of the coupling product. By Grignard reagent addition reaction, efficient construction of the basic skeleton of the target natural product. Respectively, the longest linear step 8, 6, 6 step reaction to obtain natural product Aspergillusense A, YHB-14 and YHB-17, the total yield is 23%, 35% and 40%, respectively, the efficient total synthesis of Aspergillusense A, YHB-14 and YHB-17.

[0055] 2) Aspergillusense A, YHB-14 and YHB-17 are first synthesized.

[0056] 3) The present application uses a new synthetic strategy, especially using Negishi coupling reaction to couple two fragments, efficient and simple to get intermediates 13 and 15.

[0057] 4) The key intermediates involved in the synthetic method of the present application can be used as a lead compound library to supplement the compound library for active compound screening. BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 is the synthetic route of Aspergillusense A;

[0059] Figure 2 is the synthetic route of YHB-17;

[0060] Figure 3 is the synthetic route of YHB-14. DETAILED DESCRIPTION

[0061] The technical scheme of the present application will be described in detail below in combination with specific examples and their drawings. The examples described herein are specific embodiments of the present application, which are used to illustrate the concept of the present application; these descriptions are explanatory and exemplary, and should not be understood as limiting the embodiments of the present application and the protection scope of the present application. In addition to the examples described herein, those skilled in the art can also use other technical solutions based on the disclosure of the present application claims and their descriptions, which include technical solutions that make any obvious substitutions and modifications to the examples described herein.

[0062] The following is the specific synthesis process and structure characterization data of the compounds of the present application. The synthetic route of the present application is shown in Figure 1 、 2 , 3.

[0063] Example 1 Preparation of compound 2

[0064] Compound 1 (5.0 g, 33.3 mmol, 1.00 equiv.) was dissolved in a mixed solvent of dichloromethane (80 ml) and toluene (160 ml), and bromomethyl methyl ether (3.6 ml, 43.3 mmol, 1.30 equiv.), diisopropylethylamine (9.3 ml, 53.3 mmol, 1.60 equiv.) and tetrabutylammonium iodide (1.2 g, 3.3 mmol, 0.10 equiv.) were added, and the reaction was carried out at 50 °C. After 2 h, the reaction was complete, and the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3 x 100 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 200 ml of carbon tetrachloride, and N-bromosuccinimide (7.1 g, 40.0 mmol, 1.20 equiv.) and azobisisobutyronitrile (0.6 g, 3.3 mmol, 0.10 equiv.) were added in sequence, and the reaction was carried out at 80 °C. After 1 h, the reaction was complete, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (3 x 100 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Separation was carried out by thin layer chromatography (PE / EA = 10: 1) to obtain compound 2 (6.91 g, 76%, 2 steps) as a yellowish liquid.

[0065] R f = 0.3 (PE / EA = 5: 1).

[0066] 1 H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 1.6Hz, 1H), 7.07 (dd, J = 8.0, 1.6 Hz, 1H), 5.29 (s, 2H), 4.45 (s, 2H), 3.59 –3.35 (m, 3H), 2.65 – 2.48 (m, 3H).

[0067] 13 C NMR (100 MHz, CDCl3): δ 199.25, 156.64, 143.47, 130.91, 128.98,122.46, 115.50, 94.69, 56.68, 32.45, 31.83.

[0068] HRMS (ESI) (m / z) calcd. for C 11H 14 O3 79 Br [M + H] + : 273.0120, found273.0123.

[0069] Preparation of compound 3 of example 2

[0070] Compound 2 (500 mg, 1.9 mmol, 1.00 equiv.) was dissolved in dimethyl sulfoxide (20 ml), sodium acetate (318 mg, 3.9 mmol, 2.00 equiv.) was added, and the reaction was carried out at 80 °C. After 1 h, the starting material was completely reacted, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3 x 30 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methanol (16 ml) and water (8 ml), potassium carbonate (536 mg, 3.9 mmol, 2.00 equiv.) was added, and the reaction was carried out at room temperature. After 2 h, the starting material was completely reacted, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3 x 30 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Thin layer chromatography (PE / EA = 2: 1) was used to separate the residue to obtain compound 3 (212 mg, 55%, 2 steps) as a yellow liquid.

[0071] R f = 0.1 (PE / EA = 3: 1).

[0072] 1 H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 7.9 Hz, 1H), 7.18 (s, 1H),7.00 (d, J = 8.0 Hz, 1H), 5.28 (s, 2H), 4.70 (s, 2H), 3.50 (s, 3H), 2.62 (s,3H), 2.26 (s, 1H).

[0073] 13 C NMR (100 MHz, CDCl3): δ 199.69, 156.79, 147.33, 130.68, 128.04,119.73, 112.77, 94.49, 64.65, 56.63, 31.86.

[0074] HRMS (ESI) (m / z) calcd. for C 11 H 15O4 [M + H] + : 211.0964, found211.0962.

[0075] Preparation of compound 4 of example 3

[0076] Compound 3 (212 mg, 1.00 mmol, 1.00 equiv.) was dissolved in a mixed solvent of toluene (16 ml) and dichloromethane (8 ml), and bromomethyl methyl ether (164.8 μl, 2.02 mmol, 2.00 equiv.), diisopropylethylamine (527.4 μl, 3.03 mmol, 3.00 equiv.) and tetrabutylammonium iodide (36.9 mg, 0.10 mmol, 0.20 equiv.) were added, and the reaction was carried out at 50 ℃. After 2 h, the reaction was complete, and the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3 x 30 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by flash column chromatography thin layer chromatography (PE / EA = 5: 1) to obtain compound 4 (222 mg, 87%) as a light yellow liquid.

[0077] R f = 0.3 (PE / EA = 3: 1).

[0078] 1 H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 1.4Hz, 1H), 7.02 (dd, J = 8.0, 1.5 Hz, 1H), 5.29 (s, 2H), 4.71 (s, 2H), 4.59 (s,2H), 3.51 (s, 3H), 3.41 (s, 3H), 2.62 (s, 3H).

[0079] 13 C NMR (100 MHz, CDCl3): δ199.51, 156.70, 144.35, 130.55, 128.26,120.67, 113.70, 96.11, 94.55, 68.68, 56.60, 55.60, 31.86.

[0080] HRMS (ESI) (m / z) calcd. for C 13 H 19 O5 [M + H] +: 255.1222, found255.1223.

[0081] Preparation of compound 5 of example 4

[0082] Magnesium powder (42 mg, 1.73 mmol, 2.00 equiv.) was added to 10 ml of super dry ether, a few drops of 1,2-dibromoethane were added, stirred at 40 °C for 5 minutes, 4-methyl bromopentane (286 mg, 1.73 mmol, 2.00 equiv.) was added slowly dropwise, the reaction was carried out for 30 minutes, placed at -78 °C, compound 4 (220 mg, 0.87 mmol, 1.00 equiv.) was added. After 30 minutes of reaction, the raw material reacted completely, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3 x 30 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. Isolated by flash column chromatography thin layer chromatography (PE / EA = 10: 1) to obtain compound 5 (270 mg, 92%) as a light yellow liquid.

[0083] R f = 0.5 (PE / EA = 2: 1).

[0084] 1 H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 7.9 Hz, 1H), 7.13 (d, J = 1.7Hz, 1H), 6.98 (dd, J = 7.9, 1.6 Hz, 1H), 5.28 (s, 2H), 4.71 (s, 2H), 4.56 (s,2H), 3.73 (s, 1H), 3.50 (s, 3H), 3.41 (s, 3H), 1.94 (m, 1H), 1.81 (m, 1H),1.57 (s, 3H), 1.48 (m, 1H), 1.30 – 1.16 (m, 2H), 1.16 – 1.05 (m, 2H), 0.82(s, 3H), 0.80 (s, 3H).

[0085] 13 C NMR (100 MHz, CDCl3): δ 154.75, 138.14, 134.92, 127.12, 121.28,113.88, 95.98, 94.52, 75.26, 69.05, 56.57, 55.54, 42.64, 39.56, 28.00, 27.80,22.74 (2C), 22.36.

[0086] HRMS (ESI) (m / z) calcd. for C 19 H 32 O5 23 Na [M + Na] + : 363.214, found 363.214.

[0087] Preparation of Aspergillusense A

[0088] Compound 5 (270 mg, 0.79 mmol, 1.00 equiv.) was dissolved in super dry tetrahydrofuran (10 ml), and added with Burgess reagent (568 mg, 2.38 mmol, 3.00 equiv.) and reacted at 50 °C. After 15 minutes, the raw material reacted completely, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3x10 ml), the organic phase was combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude reaction. The crude reaction was dissolved in methanol (8 ml), and added with 2M HCl (4 ml) and reacted at room temperature. After 5 hours, the raw material reacted completely, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3x10 ml), the organic phase was combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Aspergillusense A (130 mg, 70%, 2 steps) and compound 6 (28 mg, 15%, 2 steps) were separated by thin layer chromatography (PE / EA=5: 1) through flash column chromatography to obtain a yellowish liquid.

[0089] Aspergillusense A:

[0090] R f = 0.3 (PE / EA=2: 1).

[0091] 1H NMR (600 MHz, CDC13): δ 7.07 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 6.88 (dd, J = 7.8, 1.7 Hz, 1H), 5.61 (s, 1H), 5.58 - 5.52 (m, 1H), 4.63 (s, 2H), 2.25 - 2.18 (m, 2H), 1.98 (dd, J = 1.6, 0.8 Hz, 3H), 1.64 - 1.58 (m, 2H), 1.36 - 1.31 (m, 2H), 1.26 (s, 1H), 0.94 (s, 3H), 0.92 (s, 3H).

[0092] 13 C NMR (151 MHz, CDC13): δ 152.20, 141.23, 132.23, 131.67, 130.56, 128.59, 118.78, 113.92, 65.24, 38.75, 27.96, 26.52, 22.66 (3C), 18.05.

[0093] HRMS (ESI) (m / z) calcd. for C 15 H 22 O2 [M] + : 234.1620, found 234.1622.

[0094] Compound 6:

[0095] R f = 0.3 (PE / EA = 2: 1).

[0096] 1H NMR (400 MHz, CDC13): δ 7.07 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 6.88 (dd, J = 7.8, 1.7 Hz, 1H), 5.61 (s, 1H), 5.58 - 5.52 (m, 1H), 4.63 (s, 2H), 2.25 - 2.18 (m, 2H), 1.98 (dd, J = 1.6, 0.8 Hz, 3H), 1.64 - 1.58 (m, 2H), 1.36 - 1.31 (m, 2H), 1.26 (s, 1H), 0.94 (s, 3H), 0.92 (s, 3H).

[0097] 1 H NMR (600 MHz, CDC13): δ 7.02 (d, J = 7.7 Hz, 1H), 6.94 (s, 1H), 6.91 (d, J = 7.7 Hz, 1H), 5.71 (tt, J = 7.3, 1.3 Hz, 1H), 5.20 (s, 1H), 4.66 (s, 2H), 2.03 - 1.93 (m, 3H), 1.82 (q, J = 7.6 Hz, 2H), 1.67 - 1.59 (m, 1H), 1.46 (dt, J = 13.3, 6.7 Hz, 1H), 1.19 (q, J = 7.2 Hz, 2H), 0.77 (s, 3H), 0.78 (s, 3H).

[0098] 13 C NMR (151 MHz, CDC13): δ 151.86, 141.63, 132.25, 130.84, 128.81, 127.24, 119.02, 113.44, 65.31, 38.82, 27.59, 27.22, 25.33, 22.55.

[0099] HRMS (ESI) (m / z) calcd. for C 15 H 22 O2 [M] + : 234.1620, found 234.1622.

[0100] Preparation of compound 8 of example 6

[0101] Compound 7 (2.0 g, 8.66 mmol, 1.00 equiv.) was dissolved in diethylene glycol (12 ml), 80% hydrazine hydrate (1.6 ml, 25.97 mmol, 3.00 equiv.) was added, and the reaction was carried out at 110 °C. After 15 minutes, potassium hydroxide (1.7 g, 30.30 mmol, 3.50 equiv.) was added, and the reaction was carried out at 150 °C. After 2.5 h, the reaction was complete, it was cooled to 0 °C, quenched with 2M HC1, extracted with ethyl acetate (3 x 50 ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. This was isolated by flash column chromatography thin layer chromatography (PE / EA = 10: 1) to obtain compound 8 (1.65 g, 88%) as a yellowish liquid.

[0102] R f = 0.6 (PE / EA = 2: 1).

[0103] 1 H NMR (400 MHz, CDCl3): δ 6.90 (d, J = 1.9 Hz,), 6.62 (d, J = 1.9 Hz,1H), 5.73 (s, 1H), 3.87 (s, 3H), 2.26 (s, 3H).

[0104] 13 C NMR (101 MHz, CDCl3): δ 147.05, 140.89, 130.57, 124.81, 111.13,107.96, 56.38, 20.95.

[0105] HRMS (ESI) (m / z) calcd. for C8H8O2 79 Br [M-H ] - : 214.9713, found 214.971.

[0106] Preparation of compound 9 of example 7

[0107] Compound 8 (1.65 g, 7.60 mmol, 1.00 equiv.) was dissolved in super dry dichloromethane (30 ml), 1M boron tribromide (15.20 ml, 15.20 mmol, 2.00 equiv.) was added, and the reaction was carried out at -78 °C. After 5h the reaction was complete, the reaction was quenched slowly with methanol, extracted with dichloromethane (3x50 ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Compound 9 (1.50 g, 97%) was isolated as a yellowish liquid by flash column chromatography thin layer chromatography (PE / EA = 4: 1).

[0108] R f = 0.4 (PE / EA = 2: 1).

[0109] 1 H NMR (400 MHz, CDCl3): δ 6.82 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 2.0Hz, 1H), 5.36 (s, 1H), 5.28 (s, 1H), 2.23 (s, 3H).

[0110] 13 C NMR (101 MHz, CDCl3): δ 144.35, 138.00, 132.13, 123.44, 115.82,109.21, 20.73.

[0111] HRMS (ESI) (m / z) calcd. for C7H6O2 79 Br [M-H ] - : 200.95567, found 200.9554.

[0112] Preparation of compound 10 of example 8

[0113] Compound 9 (1.50 g, 7.39 mmol, 1.00 equiv.) was dissolved in a mixed solvent of toluene (20 ml) and dichloromethane (10 ml), and bromomethyl methyl ether (1.8 ml, 22.16 mmol, 3.00 equiv.), diisopropylethylamine (5.8 ml, 33.25 mmol, 4.50 equiv.) and tetrabutylammonium iodide (408.9 mg, 1.11 mmol, 0.15 equiv.) were added, and the reaction was carried out at 40 °C. After 2 h, the reaction was complete, and the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3 x 40 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Compound 10 (1.96 g, 91%) was obtained as a light yellow liquid by thin layer chromatography (PE / EA = 7: 1) on a flash column.

[0114] R f = 0.6 (PE / EA = 3: 1).

[0115] 1 H NMR (400 MHz, CDCl3): δ 7.03 (s, 1H), 6.90 (s, 1H), 5.17 (s, 2H),5.14 (s, 2H), 3.66 (s, 3H), 3.49 (s, 3H), 2.26 (s, 3H).

[0116] 13 C NMR (101 MHz, CDCl3): δ 150.75, 141.90, 135.55, 126.86, 117.52,116.75, 98.93, 95.34, 58.02, 56.41, 21.00.

[0117] HRMS (ESI) (m / z) calcd. for C 11 H 15 O4 79 Br 23 Na [M + Na] + : 313.0045,found 313.0042.

[0118] Preparation of compound 12 of example 9

[0119] Compound 11 (3.0 g, 22.36 mmol, 1.00 equiv.) was dissolved in carbon tetrachloride (100 ml), N-bromosuccinimide (4.8 g, 26.83 mmol, 1.20 equiv.) and azobisisobutyronitrile (367 mg, 2.24 mmol, 0.10 equiv.) were added successively, and the reaction was carried out at 80 °C. After 1 h, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (3 x 100 ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Compound 12 (4.10 g, 86%) was obtained as a yellowish liquid by flash column chromatography thin layer chromatography (PE / EA = 50: 1).

[0120] R f = 0.5 (PE / EA = 10: 1).

[0121] 1 H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.1Hz, 2H), 4.50 (s, 2H), 2.60 (s, 3H).

[0122] 13 C NMR (100 MHz, CDCl3): δ 197.49, 142.92, 137.02, 129.36 (2C),128.95(2C), 32.24, 26.79.

[0123] HRMS (ESI) (m / z) calcd. for C9H 10 O 79 Br [M + H] + : 212.9909, found 212.9906.

[0124] Preparation of compound 13 of example 10

[0125] Compound 10 (465 mg, 1.60 mmol, 1.70 equiv.) was dissolved in super dry tetrahydrofuran (20 ml) and placed at -78 °C, 2.4 M n-butyllithium (0.70 ml, 1.69 mmol, 1.80 equiv.) was added, after 30 minutes of reaction, 1 M zinc chloride solution (1.78 ml, 1.78 mmol, 1.90 equiv.) was added. After 3 h of stirring, it was slowly brought to room temperature, compound 12 (200 mg, 0.94 mmol, 1.00 equiv.) and dichlorotriphenylphosphine palladium (33 mg, 0.05 mmol, 0.05 equiv.) were added in this order. It was brought to 80 °C and after 30 minutes of reaction the starting material was completely reacted, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 30 ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. It was isolated by flash column chromatography thin layer chromatography (PE / EA = 8: 1) to obtain compound 13 (268 mg, 83%) as a yellowish liquid.

[0126] R f = 0.3 (PE / EA = 5: 1).

[0127] 1 H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0Hz, 2H), 6.85 (d, J = 2.0 Hz, 1H), 6.56 – 6.51 (m, 1H), 5.18 (s, 2H), 5.06(s, 2H), 4.08 (s, 2H), 3.54 (s, 3H), 3.51 (s, 3H), 2.57 (s, 3H), 2.23 (s,3H).

[0128] 13 C NMR (100 MHz, CDCl3): δ 197.99, 149.73, 147.06, 142.84, 135.26,134.36, 134.03, 129.19 (2C), 128.67 (2C), 124.47, 115.66, 99.32, 95.23,57.61, 56.39, 36.09, 26.70, 21.32.

[0129] HRMS (ESI) (m / z) calcd. for C 20 H 25O5 [M + H] + : 345.1696, found345.1694.

[0130] Preparation of compound 14 of example 11

[0131] Magnesium powder (38 mg, 1.56 mmol, 2.00 equiv.) was added to super dry tetrahydrofuran (8 ml), a few drops of 1,2-dibromoethane were added, stirred at 40 °C for 5 minutes, 4-methylbromopentane (257 mg, 1.56 mmol, 2.00 equiv.) was added slowly dropwise, the reaction was carried out for 30 minutes, placed at -78 °C, compound 13 (268 mg, 0.78 mmol, 1.00 equiv.) was added. After 30 minutes of reaction, the raw material reacted completely, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3x15 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. Separated by flash column chromatography thin layer chromatography (PE / EA = 8: 1) to obtain compound 14 (269 mg, 80%) as a light yellow liquid.

[0132] R f = 0.3 (PE / EA = 5: 1).

[0133] 1 H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.9Hz, 2H), 6.83 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 5.18 (s, 2H),5.05 (s, 2H), 4.02 (s, 2H), 3.55 (s, 3H), 3.51 (s, 3H), 2.22 (s, 3H), 1.75(dt, J = 9.7, 4.3 Hz, 2H), 1.68 (s, 1H), 1.53 (s, 3H), 1.46 (dq, J = 12.6,6.4 Hz, 1H), 1.25 (d, J = 7.7 Hz, 1H), 1.13 (ddt, J = 11.7, 8.1, 5.1 Hz, 3H),0.82 (s, 3H), 0.80 (s, 3H).

[0134] 13C NMR (100 MHz, CDCl3): δ 149.70, 145.88, 142.73, 139.29, 135.15,134.14, 128.78 (2C), 124.95 (2C), 124.62, 115.36, 99.26, 95.27, 74.77, 57.60,56.37, 44.51, 39.37, 35.52, 30.16, 27.96, 22.75, 22.68, 21.92, 21.35.

[0135] HRMS (ESI) (m / z) calcd. for C 26 H 38 O5 23 Na [M + Na] + : 453.2611, found453.2606.

[0136] Preparation of natural product YHB-17

[0137] Compound 14 (269 mg, 0.62 mmol, 1.00 equiv.) was dissolved in super dry tetrahydrofuran (10 ml), and added with Burgess reagent (447 mg, 1.87 mmol, 3.00 equiv.) at 50 °C. After 15 minutes, the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 15 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was directly used in the next step without further purification.

[0138] The crude product was dissolved in methanol (5 ml) at room temperature, and added with 2M HCl (5 ml). After 2h, the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 15 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was directly used in the next step without further purification.

[0139] The crude product was dissolved in chloroform (10 ml), and added with trifluoroacetic acid (3 μl, 0.03 mmol, 0.05 equiv.) at 60 °C. After 24h, the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 15 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was separated by flash column chromatography thin layer chromatography (PE / EA = 5: 1) to obtain compound YHB-17 (142 mg, 70%) as a yellowish liquid.

[0140] R f = 0.6 (PE / EA = 3: 1).

[0141] 1 H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3Hz, 2H), 6.60 (d, J = 2.0 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 5.77 (ddt, J =7.2, 5.9, 1.4 Hz, 1H), 5.14 (s, 1H), 4.75 (s, 1H), 3.94 (s, 2H), 2.23 (s,3H), 2.23 – 2.16 (m, 2H), 2.02 (d, J = 1.2 Hz, 3H), 1.62 (dp, J = 13.2, 6.6Hz, 1H), 1.34 (dt, J = 8.8, 6.8 Hz, 2H), 0.94 (s, 3H), 0.93 (s, 3H).

[0142] 13 C NMR (100 MHz, CDCl3): δ 143.92, 142.39, 139.54, 137.89, 134.00,130.51, 128.78, 128.50, 127.61, 126.06, 123.16, 114.48, 38.88, 36.22, 27.86,26.80, 22.71, 20.92, 15.78.

[0143] HRMS (ESI) (m / z) calcd. for C 22 H 27 O2 [M - H] - : 323.2011, found323.2011.

[0144] Preparation of compound 15 of example 13

[0145] Compound 10 (465 mg, 1.60 mmol, 1.70 equiv.) was dissolved in super dry tetrahydrofuran (20 ml) and placed at -78 °C, 2.4 M n-butyllithium (0.70 ml, 1.69 mmol, 1.80 equiv.) was added, after 30 minutes of reaction, 1 M zinc chloride solution (1.78 ml, 1.78 mmol, 1.90 equiv.) was added. After 3 h of stirring, it was slowly brought to room temperature, compound 2 (257 mg, 0.94 mmol, 1.00 equiv.) and dichlorotriphenylphosphine palladium (33 mg, 0.05 mmol, 0.05 equiv.) were added in this order. It was brought to 80 °C and after 30 minutes of reaction the starting material was completely reacted, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 30 ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. It was isolated by flash column chromatography thin layer chromatography (PE / EA = 5: 1) to obtain compound 15 as a yellowish liquid (316 mg, 83%).

[0146] R f = 0.3 (PE / EA = 3: 1).

[0147] 1 H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H),6.88 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H), 6.53 (s, 1H), 5.25 (s, 2H), 5.18 (s,2H), 5.06 (s, 2H), 4.02 (s, 2H), 3.56 (s, 3H), 3.50 (d, J = 2.8 Hz, 6H), 2.62(s, 3H), 2.23 (s, 3H).

[0148] 13 C NMR (100 MHz, CDCl3): δ 199.47, 156.71, 149.67, 147.79, 142.84,134.28, 134.01, 130.57, 126.88, 124.39, 122.51, 115.71, 115.52, 99.32, 95.27,94.59, 57.60, 56.58, 56.39, 36.16, 31.89, 21.32.

[0149] HRMS (ESI) (m / z) calcd. for C 22 H 28 O7 23 Na [M + Na] + : 427.1727, found427.1718.

[0150] Preparation of compound 16 of example 14

[0151] Magnesium powder (38 mg, 1.56 mmol, 2.00 equiv.) was added to super dry tetrahydrofuran (8 ml), a few drops of 1,2-dibromoethane were added, stirred at 40 °C for 5 minutes, 4-methyl bromopentane (257 mg, 1.56 mmol, 2.00 equiv.) was added slowly dropwise, the reaction was carried out for 30 minutes, placed at -78 °C, compound 13 (316 mg, 0.78 mmol, 1.00 equiv.) was added. After the reaction was carried out for 30 minutes, the raw material was completely reacted, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3x15 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. Separated by flash column chromatography thin layer chromatography (PE / EA=6: 1) to obtain compound 16 (307 mg, 80%) as a light yellow liquid.

[0152] R f = 0.6(PE / EA=1.5: 1).

[0153] 1H NMR (400 MHz, CDC13): δ 7.19 (d, J = 7.9 Hz, 1H), 7.02 (s, 1H), 6.83 (s, 1H), 6.80 (s, 1H), 6.54 (s, 1H), 5.24 (s, 2H), 5.18 (s, 2H), 5.05 (s, 2H), 3.99 (s, 2H), 3.89 (s, 1H), 3.56 (d, J = 1.3 Hz, 3H), 3.51 (d, J = 1.3 Hz, 3H), 3.49 (d, J = 1.3 Hz, 3H), 2.22 (s, 3H), 1.86 (dtd, J = 29.6, 12.8, 6.8 Hz, 2H), 1.56 (s, 3H), 1.48 (dt, J = 13.2, 6.6 Hz, 1H), 1.24 (ddq, J = 25.4, 12.1, 6.2 Hz, 2H), 1.11 (q, J = 7.0 Hz, 2H), 0.82 (s, 3H), 0.81 (s, 3H).

[0154] 13 C NMR (100 MHz, CDC13): δ 154.68, 149.64, 142.76, 141.22, 134.87, 134.12, 133.05, 126.97, 124.49, 122.41, 115.48, 115.23, 99.26, 95.30, 94.58, 75.21, 57.58, 56.56, 56.37, 42.79, 39.55, 35.64, 27.99, 27.64, 22.75, 22.73, 22.40, 21.34.

[0155] HRMS (ESI) (m / z) calcd. for C 28 H 42 O7 23 Na [M + Na] + : 513.2822, found513.2822.

[0156] Example 15 Preparation of Natural Product YHB-14

[0157] Compound 16 (307 mg, 0.63 mmol, 1.00 equiv.) was dissolved in super dry tetrahydrofuran (10 ml), and added with Burgess reagent (447 mg, 1.87 mmol, 3.00 equiv.) at 50 °C. After 15 minutes, the reaction was complete, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 15 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification.

[0158] The crude product was dissolved in methanol (5 ml) at room temperature, and added with 2M HCl (5 ml). After 2h, the reaction was complete, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 15 ml), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was separated by flash column chromatography thin layer chromatography (PE / EA = 5: 1) to obtain compound YHB-14 (142 mg, 70%) as a yellowish liquid.

[0159] R f = 0.4 (PE / EA = 2: 1).

[0160] 1 H NMR (400 MHz, CDCl3): δ 7.01 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 12.5Hz, 2H), 6.60 (s, 1H), 6.55 (s, 1H), 5.57 (s, 1H), 5.54 (t, J = 7.4 Hz, 1H),5.11 (s, 1H), 4.74 (s, 1H), 3.89 (s, 2H), 2.23 (s, 3H), 2.19 (d, J = 7.7 Hz,2H), 1.96 (s, 3H), 1.59 (dd, J = 13.9, 7.0 Hz, 1H), 1.32 (q, J = 7.4 Hz, 2H),0.93 (d, J = 1.4 Hz, 3H), 0.92 (d, J = 1.4 Hz, 3H).

[0161] 13C NMR (100 MHz, CDCl3): δ 152.16, 143.97, 140.33, 139.73, 131.91,131.77, 130.29, 129.28, 128.59, 127.31, 123.06, 120.48, 115.45, 114.54,38.73, 36.15, 27.92, 26.49, 22.65 (2C), 20.92, 18.02.

[0162] HRMS (ESI) (m / z) calcd. for C 22 H 27 O3 [M - H] - : 339.19657, found339.1961.

[0163] The above described embodiments are merely preferred embodiments of the present application, and are not intended to limit the scope of the present application. Any modification and improvement made by those skilled in the art to the technical solutions of the present application without departing from the design spirit of the present application shall fall within the protection scope of the present application as defined by the claims.

Claims

1. A method for synthesizing bisabolane-type sesquiterpenes and their derivatives, characterized in that, Includes the following steps: Step 1: Dissolve compound 1 in a mixed solution of dichloromethane and toluene, add bromomethyl methyl ether, diisopropylethylamine and tetrabutylamine iodide, and react at 65°C; after the reaction is complete, evaporate the solvent, dissolve in carbon tetrachloride, add N-bromosuccinimide and azobisisobutyronitrile, and react at 80°C to obtain compound 2. ； Step 2: Dissolve compound 2 in dimethyl sulfoxide, add sodium acetate, and react at 80°C; after the reaction is complete, extract and evaporate to dryness, dissolve in methanol / water system, add potassium carbonate, and obtain compound 3; ； Step 3: Compound 3 was dissolved in a mixed solution of dichloromethane and toluene, and bromomethyl methyl ether, diisopropylethylamine and tetrabutylamine iodide were added. The mixture was reacted at 50°C to obtain compound 4. ； Step 4: Compound 4 is dissolved in diethyl ether solution, and Grignard reagent is added at -78 °C to react and give compound 5; ； Step 5: Compound 5 was dissolved in tetrahydrofuran solution, Burgess reagent was added, and the reaction was carried out at 50 °C; methanol and 2M HCl were added, and the reaction was carried out at room temperature to obtain the natural product Aspergillusense A and compound 6. ； Step 6: Compound 7 was dissolved in diethylene glycol, and hydrazine hydrate was added and reacted for 30 minutes. Then potassium hydroxide was added and reacted at 150 °C to obtain compound 8. ； Step 7: Compound 8 was dissolved in dichloromethane solution, boron tribromide was added, and the reaction was carried out at -78 °C to obtain compound 9; ； Step 8: Compound 9 was dissolved in a mixed solution of dichloromethane and toluene, and bromomethyl methyl ether, diisopropylethylamine and tetrabutylamine iodide were added. The mixture was reacted at 65 °C to give compound 10. ； Step 9: Dissolve compound 11 in carbon tetrachloride solution, add N-bromosuccinimide and azobisisobutyronitrile and react at 85 °C to obtain compound 12; ； Step 10: Dissolve compound 12 in tetrahydrofuran solution, add n-butyllithium, zinc chloride, and dichlorotriphenylphosphine palladium and compound 10 at -78 °C, then heat to 80 °C to react and obtain compound 13; ； Step 11: Compound 13 was dissolved in tetrahydrofuran solution, and Grignard reagent was added at -78 °C. The reaction was carried out for half an hour to obtain compound 14. ； Step 12: Compound 14 was dissolved in tetrahydrofuran solution, Burgess reagent was added, and after the reaction was complete, 2M HCl was added to remove the protecting group; the mixture was extracted and dried, dissolved in chloroform solution, and trifluoroacetic acid was added to give the natural product YHB-17. ； Step 13: Compound 2 is processed in the same way as in Step 10 to obtain Compound 15; ； Step Fourteen: Compound 15 is processed in the same way as in Step Eleven to obtain Compound 16; ； Step 15: Compound 16 was subjected to the same operation as in Step 12 to obtain compound YHB-14; 。 2. The method according to claim 1, characterized in that: In step one, the molar ratio of compound 1, bromomethyl methyl ether, diisopropylethylamine, and tetrabutylamine iodide was 1:1.3:1.6:0.1, the volume ratio of dichloromethane and toluene was 1:2, and the reaction time was 2 h; the molar ratio of compound 1, N-bromosuccinimide, and azobisisobutyronitrile was 1:1.2:0.1, and the reaction time was 1 h, yielding compound 2. In step two, the molar ratio of compound 2, sodium acetate, and potassium carbonate is 1:2.0:2.0, and the concentration of the dimethyl sulfoxide solution is 0.1 M.

3. The method according to claim 1, characterized in that: In step three, the molar ratio of compound 3, bromomethyl methyl ether, diisopropyl ethylamine, and tetrabutyl iodide is 1:2.0:3.0:0.2, the volume ratio of dichloromethane and toluene is 1:2, and the reaction time is 2 hours, to obtain compound 4.

4. The method according to claim 1, characterized in that: In step four, the molar ratio of compound 4 to Grignard reagent was 1:2.0, the temperature was -78 °C, and the reaction time was 30 minutes, yielding compound 5.

5. The method according to claim 1, characterized in that: In step five, the molar ratio of compound 5 to Burgess reagent was 1:3.0, the reaction concentration was 0.08 M, and the reaction time was 15 minutes. After removing the protecting group, the natural product Aspergillusense A and compound 6 were obtained. In step six, the molar ratio of compound 7, hydrazine hydrate, and potassium hydroxide was 1:3.0:3.5, the diethylene glycol concentration was 0.7M, the temperature was 150 °C, and the reaction time was 2.5 h, yielding compound 8.

6. The method according to claim 1, characterized in that: In step seven, the molar ratio of compound 8 to boron tribromide is 1:2.0, yielding compound 9.

7. The method according to claim 1, characterized in that: In step eight, the molar ratio of compound 9, bromomethyl methyl ether, diisopropyl ethylamine, and tetrabutyl iodide was 1:3.0:4.5:0.15, and the reaction time was 2 hours, yielding compound 10.

8. The method according to claim 1, characterized in that: In step nine, the molar ratio of compound 11, N-bromosuccinimide, and azobisisobutyronitrile was 1:1.2:0.1, and the reaction time was 1 h, to obtain compound 12; In step ten, the molar ratio of compound 12, compound 10, n-butyllithium, zinc chloride, and dichlorotriphenylphosphine palladium is 1:1.7:1.8:1.9:0.05, yielding compound 13.

9. The method according to claim 1, characterized in that: In step eleven, the molar ratio of compound 13 to Grignard reagent was 1:2, and the concentration of tetrahydrofuran solution was 0.1M, to obtain compound 14; In step 12, the ratio of compound 14 to Burgess reagent was 1:3.0, the reaction temperature was 50℃, and then the protecting group was removed to obtain compound YHB-17.

10. The method according to claim 1, characterized in that: In step thirteen, the molar ratio of compound 2, compound 10, n-butyllithium, zinc chloride, and dichlorotriphenylphosphine palladium is 1:1.7:1.8:1.9:0.05, yielding compound 15; In step fourteen, the molar ratio of compound 15 to Grignard reagent is 1:2.0 to obtain compound 16; In step fifteen, the molar ratio of compound 16 to Burgess reagent is 1:3.0 to obtain compound YHB-14.

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