Monoterpene phenol diterpenoid compounds, intermediate compounds thereof, and synthesis methods

Abstract

The present invention belongs to the field of synthesis of bioactive natural products, and specifically provides monoterphenyl phenol diterpenoid compounds and intermediate compounds thereof. The structural formula of the monoterphenyl phenol diterpenoid compound is shown as formula (V), and the structural formula of the intermediate compound is shown as formula (I), formula (II), formula (III) or formula (IV). This patent also provides a synthesis method of the monoterphenyl phenol diterpenoid compound and the intermediate compound thereof. By using simple and easily available chemical raw materials, a series of intermediate compounds for synthesizing monoterphenyl phenol diterpenoid compounds with novel structures are obtained through one-step or multi-step reactions, and a series of monoterphenyl phenol diterpenoid compounds are prepared. The synthesis process of the present invention is simple, green and environmentally friendly, highly efficient, with mild conditions and high yields. The prepared monoterphenyl phenol diterpenoid compounds have significant effects on anti-tumor, anti-oxidation, anti-osteoporosis and anti-depression, etc., and have broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of bioactive natural products, and particularly relates to monoterpene phenol heteroterpenoid compounds and intermediate compounds thereof, and a synthesis method. Background Art

[0002] As a subclass of natural terpenes, Meroterpenes have structural diversity and a wide range of biological activities. Among them, Meroterpenoids of the monoterpene phenol family are isolated from Psoralea corylifolia (Chinese name: Psoralea fruit, which is a well-known medicinal plant and has been widely used in China, India and other countries since ancient times to treat various diseases). In 2012, Wu and Cheng et al. isolated Pscoracorylifol F (1a) from this medicinal plant. Subsequently, other groups have continuously isolated some new Meroterpenoids natural products from the research on its chemical composition and biological activities, such as 7α, 8β-hydroxy-12β-bakuchiol C (1b), 7β, 8α-hydroxy-12β-bakuchiol F (1c), Corypsoriol J (1d), Corypsoriol H (1e), 8α-hydroxy-Cyclobakuchiol C (1f), Psoracorylifol G (1g), Corypsoriol I (1h) and other analogs. Although Meroterpenes natural products only have a poly-substituted cyclohexane as the core skeleton, more than 40 have been isolated so far. The structures of some compounds are shown below:

[0003]

[0004] These Meroterpenes have a wide range of important biological activities, including anti-cancer, antioxidant, anti-osteoporosis and anti-depression, etc. However, after consulting the literature, there is currently no report on the total synthesis of Meroterpenes natural products such as Pscoracorylifol F (1a), 7α, 8β-hydroxy-12β-bakuchiol C (1b), 7β, 8α-hydroxy-12β-bakuchiol F (1c), Corypsoriol J (1d), Corypsoriol H (1e), 8α-hydroxy-Cyclobakuchiol C (1f), Psoracorylifol G (1g), Corypsoriol I (1h) with four consecutive adjacent stereocenters.

[0005] In view of the above technical problems, the present invention provides a concise and efficient synthesis method for multifunctionalized meroterpenes, and specifically provides intermediate compounds and their synthesis methods in the synthesis process. Summary of the Invention

[0006] In view of the complex chiral total synthesis in the background art, the object of the present invention is to provide monoterpene phenol diterpenoid compounds, intermediate compounds thereof, and synthesis methods. The technical solutions are as follows:

[0007] The primary object of the present invention is to provide intermediate compounds for synthesizing monoterpene phenol diterpenoid compounds, characterized in that the structural formulas of the intermediate compounds are as shown in formula (Ⅰ), formula (Ⅱ), formula (Ⅲ), or formula (Ⅳ):

[0008]

[0009] Among them, in formula (Ⅰ), R4 is OH, C=O, or OMe; R2 is H, OH, or OMe.

[0010] Preferably, the structural formulas of the intermediate compounds are as follows:

[0011] The second object of the present invention is to provide a synthesis method for monoterpene phenol diterpenoid compounds and / or the intermediate compounds, and the method includes the following steps:

[0012] (1) Using 2-methylcyclohexanone as the starting material, synthesize intermediate compound 3 shown in formula (Ⅲ) of claim 1:

[0013]

[0014] (2) Selectively construct two stereocenters of intermediate compound 2 or 2' as described in claim 2 from intermediate compound 3 obtained in step (1) through a copper-mediated "one-pot" Michael addition / arylation reaction:

[0015]

[0016] (3) Through stereoselective reduction, regioselective oxidation, and transformation of removing methyl groups of intermediate compound 2 or 2', obtain the intermediate compounds and / or monoterpene phenol diterpenoid compounds shown in formula (Ⅴ):

[0017]

[0018] Among them, R1 is R2 is H or OMe, and R3 is H or OH.

[0019] Preferably, the method described in step (1) is specifically as follows:

[0020] ① First, 2-methylcyclohexanone reacts with methyl acrylate through Michael addition to obtain intermediate compound 5. The reaction is as follows:

[0021]

[0022] ② Intermediate compound 5 is oxidized by IBX and hydrolyzed under alkaline conditions to obtain intermediate compound 4. The reaction is as follows:

[0023]

[0024] ③ Intermediate compound 4 is decarboxylated under the catalysis of a palladium catalyst to generate intermediate compound 3. The reaction is as follows:

[0025]

[0026] Preferably, the base used for hydrolysis under alkaline conditions in step ② is sodium hydroxide, the palladium catalyst in step ③ is dichlorobis(triphenylphosphine)palladium, and the temperature of the decarboxylation reaction is 130 °C.

[0027] Preferably, the copper salts mediated by copper in step (2) are cuprous cyanide and copper acetate.

[0028] Preferably, the Michael addition reagent in step (2) is organolithium copper reagent, the arylation reagent is diaryliodonium salt, the temperature of the Michael addition reaction is -78 °C and 25 °C, and the time is 2 to 12 hours.

[0029] Preferably, the synthesis of the monoterpenoid phenol heteroterpenoid compound in step (3) specifically includes the following steps:

[0030] S1: Intermediate compound 2 is stereoselectively reduced to obtain intermediate compounds 8 and 8'. The reaction is as follows:

[0031]

[0032] S2: Intermediate compounds 8 and 8' are respectively deprotected from the methyl group under the action of boron tribromide to obtain the natural product Psoracorylifol F (1a) and intermediate compound 9. The reaction is as follows:

[0033]

[0034] S3: Psoracorylifol F (1a) is selectively epoxidized and reduced to obtain compound 1b. The reaction is as follows:

[0035]

[0036] S4: The methyl protection of the alcohol of Compound 8 under basic conditions gives Intermediate Compound 10, and the reaction is as follows:

[0037]

[0038] S5: The selective removal of the methyl group of Intermediate Compound 10 under basic conditions gives Intermediate Compound 11, and the reaction is as follows:

[0039]

[0040] S6: The selective oxidation and reduction of Intermediate Compound 11 on the aromatic ring gives the natural product Corypsoriol J (1c), and the reaction is as follows:

[0041]

[0042] S7: The enolization of Intermediate Compound 2 under basic conditions gives Intermediate Compound 12, and the reaction is as follows:

[0043]

[0044] S8: Intermediate Compound 12 undergoes stereoselective reduction and removal of the methyl group to give Compound 1d, and the reaction is as follows:

[0045]

[0046] S9: Intermediate Compound 2' undergoes stereoselective reduction with sodium borohydride to give Intermediate Compounds 14 and 14', and the reaction is as follows:

[0047]

[0048] S10: Intermediate Compounds 14 and 14' respectively undergo demethylation reactions under basic conditions to give the natural products Corypsoriol H (1e) and psoracorylifol G (1h), and the reaction is as follows:

[0049]

[0050] S11: The selective epoxidation and reduction of Compound Corypsoriol H (1e) gives Compound 1g, and the reaction is as follows:

[0051]

[0052] S12: Intermediate Compound 14 undergoes methyl protection of the alcohol, selective removal of the methyl group under basic conditions, and finally selective oxidation and reduction of the aromatic ring to give Compound 1h, and the reaction is as follows:

[0053]

[0054] Preferably, in S1, the reducing agent for the stereoselective reduction is sodium borohydride, and the reaction temperature is -60°C;

[0055] In S2, the demethylating agent is boron tribromide or potassium carbonate and benzenethiol, and the reaction temperature is -78 to 0°C or 230°C;

[0056] In S3, the oxidizing agent for the regioselective oxidation is m-chloroperoxybenzoic acid, the reducing agent is lithium aluminum hydride, the oxidation temperature is 5°C, and the reduction temperature is 70°C;

[0057] In S4, the basic condition is provided by sodium hydride;

[0058] In S5, the reagent for selectively removing methyl is potassium carbonate and benzenethiol, and the reaction temperature is 230°C;

[0059] In S6, the oxidizing agent for the selective oxidation on the aromatic ring is IBX, the reducing agent is sodium borohydride, 0°C;

[0060] In S7, the base is lithium hexamethyldisilazide, and the reaction temperature is -78 to 20°C;

[0061] In S8, the reducing agent for the stereoselective reduction is sodium borohydride, and the demethylating agent is potassium carbonate and benzenethiol;

[0062] In S9, the reducing agent for the stereoselective reduction is sodium borohydride, and the reaction temperature is -60°C;

[0063] In S10, the demethylating agent is potassium carbonate and benzenethiol, and the reaction temperature is 230°C;

[0064] In S11, the oxidizing agent for the regioselective oxidation is m-chloroperoxybenzoic acid, the reducing agent is lithium aluminum hydride, the oxidation temperature is 5°C, and the reduction temperature is 70°C;

[0065] In S12, the oxidizing agent for the selective oxidation on the aromatic ring is IBX, the reducing agent is sodium borohydride, 0°C.

[0066] Preferably, the organic catalyst is a thiourea catalyst

[0067] The beneficial effects of the present invention are as follows: The present invention provides intermediate compounds for synthesizing monoterpene phenol heteroterpenoid compounds, and also provides a method for synthesizing monoterpene phenol heteroterpenoid compounds and their intermediate compounds. Using simple and readily available raw materials, a series of intermediate compounds for synthesizing monoterpene phenol heteroterpenoid compounds with novel structures are obtained through one-step or stepwise reactions, and monoterpene phenol heteroterpenoid compounds are prepared. The synthesis process of the present invention is simple, green, environmentally friendly, efficient, with mild conditions and high yields. The prepared monoterpene phenol heteroterpenoid compounds have significant effects such as anti-tumor, anti-oxidation, anti-osteoporosis, and anti-depression, and have broad application prospects. Detailed implementation manners

[0068] The following are the preferred embodiments of the present invention. It should be understood that the preferred embodiments described herein are only for the purpose of illustrating and explaining the present invention, and are not used to limit the present invention.

[0069] The total synthesis reactions of the monoterpene phenol heteroterpenoid compounds and their intermediate compounds of the present invention are as follows:

[0070]

[0071] The preparation process of the catalyst (Cat.1) of the present invention can refer to the literature "Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.; Yamaguchi, K.; Ishikawa, T., Modified guanidines as potential chiral superbases. 2. Preparation Of 1,3-unsubstituted and 1-substituted 2-iminoimidazolidine derivatives and a related guanidine by the 2-chloro-1,3-dimethylimidazolinium chloride-induced cyclization of thioureas. J. Org. Chem., 2000, 65, 7774."

[0072] Example 1: Preparation of Compound 5

[0073] 2-Methylcyclohexanone 6 (0.50 mmol, 1.0 equiv) and methyl acrylate (1.00 mmol, 2.0 equiv) were dissolved in 0.5 mL of toluene. Cat.1 (0.10 mmol, 20 mol%) was added at room temperature, and the system was heated to 90 °C and reacted for 48 h. Then the system was cooled to room temperature and directly purified by silica gel column chromatography to obtain the product compound 5 (colorless oil, 83.3 g, 85% yield).

[0074] 1 H NMR (400 MHz, CDCl3) δ: 3.59 (s, 3H), 2.34 - 2.29 (m, 2H), 2.27 - 2.21 (m, 1H), 2.13 - 2.05 (m, 1H), 2.01 - 1.93 (m, 1H), 1.80 - 1.65 (m, 6H), 1.56 - 1.51 (m, 1H), 1.00 (s, 3H);

[0075] 13 C NMR (100 MHz, CDCl3) δ: 214.8, 173.7, 51.3, 47.6, 38.9, 38.4, 32.2, 28.7, 27.1, 22.1, 20.7; HRMS (ESI) m / z found 221.1449, calculated for C 11 H 16 O3 [M + Na] + 221.1448;

[0076] Example 2: Preparation of Compound 4

[0077] At room temperature, compound 5 (6.6 g, 31 mmol) was dissolved in a DMSO:PhMe (3:1 / v:v) solution. IBX (26.1 g, 93.3 mmol) was added to the stirred solution. The system was heated to 85 °C and reacted. Monitored by TLC, after the raw materials were reacted, it was cooled to room temperature, saturated NaHCO3 (300 mL) and diethyl ether (300 mL) were added successively and stirred, and then filtered through diatomaceous earth. The organic layer was separated and the aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product S1. The crude product S1 without purification was used for the next step.

[0078] To a solution of S1 (5.16 g, 26.3 mmol, 1.0 equiv) in MeOH (11 mL) was added 2 mol / L aqueous NaOH (26.3 mL, 52.7 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 2 h and then methanol was evaporated under reduced pressure. The aqueous layer was washed with Et2O (1×100 mL), the pH of the aqueous layer was adjusted to pH 4 using 1 mol / L HCl (30 mL), and then with EtOAc (3×100 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give the carboxylic acid compound 4 as a yellow oil (4.64 g, 97% yield, 83% yield over two steps).

[0079] 1 H NMR (400 MHz, CDCl3) δ: 11.18 (br s, 1H), 6.87 (dt, J = 10.0, 4.0 Hz, 1H), 5.91 (dt, J = 10.4, 1.6 Hz, 1H), 2.40 - 2.26 (m, 4H), 1.92 - 1.76 (m, 4H), 1.09 (s, 3H);

[0080] 13 C NMR (100 MHz, CDCl3) δ: 203.4, 179.6, 148.8, 128.4, 43.8, 33.6, 31.1, 29.1, 23.0, 21.6;

[0081] HRMS (ESI) m / z found 205.0835, calculated for C 18 H 24 O2 [M+Na] + 205.0832;

[0082] Example 3: Preparation of Compound 3

[0083] Under Ar conditions, PdCl2(PPh3)2 (15.4 mg, 0.022 mmol, 2% equiv), Xantphos (15.0 mg, 0.026 mmol, 2.4% equiv), (t-Bu)4biphenol (45.2 mg, 0.11 mmol, 0.01 equiv) and compound 4 (2.0 g, 11.0 mmol, 1.0 equiv) were successively added to a 25 mL two-necked round-bottom flask equipped with a distillation head and a 10 mL round-bottom receiving flask. The closed system was connected to a vacuum manifold and equipped with a needle valve. The system was evacuated and purged with Ar three times, and the first portion of acetic anhydride (6.0 mmol, 1.2 equiv) was added via syringe through the septum on top of the distillation head. The flask was placed in a preheated oil bath at 60 °C and quickly heated to 130 °C. When the oil bath temperature reached 120 °C, the needle valve was closed, and acetic acid was distilled under reduced pressure into a receiving flask cooled to -78 °C. When the oil bath temperature reached 130 °C, after distillation for about 3 min, the system was evacuated. After 30 min, the system was backfilled with argon, and the second portion of acetic anhydride (2.5 mmol, 0.5 equiv) was added via syringe. Then, after the system reacted for 5 min, acetic acid was again distilled off under reduced pressure, and the system was evacuated. Acetic anhydride (0.3, 0.2 equiv) was added in the same manner every 30 min as follows. After the reaction for 2 h, the reaction was stopped and cooled to room temperature under argon. The distillate and the dark red reaction mixture were added to a saturated aqueous NaHCO3 solution, stirred for 30 min, and the two-phase mixture was extracted three times with CH2Cl2. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel to give compound 3 (1.04 g, 70% yield).

[0084] 1 H NMR (400 MHz, CDCl3) δ: 6.93 - 6.88 (m, 1H), 5.97 (dt, J = 10.0, 2.0 Hz, 1H), 5.93 (dd, J = 17.6, 10.8 Hz, 1H), 5.05 (dd, J = 10.8, 0.4 Hz, 1H), 5.00 (dd, J = 17.6, 0.4 Hz, 1H), 2.44 - 2.31 (m, 2H), 2.03 - 1.97 (m, 1H), 1.93 - 1.86 (m, 1H), 1.20 (s, 3H);

[0085] 13 C NMR (100 MHz, CDCl3) δ: 201.4, 149.1, 140.3, 128.5, 114.0, 47.9, 34.5, 23.3, 22.6;

[0086] HRMS(ESI) m / z found 137.0962, calculated for C 11 H 16 O3 [M+H] + 137.0961.

[0087] Example 4: Preparation of Intermediate Compound 2

[0088] At -78 °C, isopropenyllithium solution (0.4 M in Et2O, 0.16 mL, 0.4 mmol) was added dropwise to a suspension of CuCN (89.56 mg, 1.0 mmol, 1.0 equiv) in anhydrous Et2O (1.0 mL), and the mixture was stirred at -78 °C for 1 hour to obtain a homogeneous and transparent solution. Compound 3 (136 mg, 1.0 mmol, 1.0 equiv) was added dropwise to the reaction flask, and the solution immediately turned orange-yellow. TLC was used for detection. After the raw materials were completely reacted, the reaction system was warmed to -20 °C, and the co-solvent DMF (10.0 mL), additive Cu(OAc)2 (181 mg, 1.0 mmol), and diaryliodonium salt (MeOPh)2IOTf (980 mg, 2.0 mmol) were added. TLC was used for detection. After the 1,4-addition intermediate was completely converted, the reaction mixture was quenched with saturated NH4Cl solution (5 mL) at 0 °C, extracted with EtOAc (3 × 90 mL), the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate compounds 2 and 2'.

[0089] Compound 2:

[0090] 1 H NMR (400 MHz, CDCl3) δ: 6.93 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.23 (dd, J = 17.6, 10.8 Hz, 1H), 5.10 (d, J = 10.8 Hz, 1H), 5.04 (d, J = 17.6 Hz, 1H), 4.60 (br s, 2H), 3.84 (d, J = 12.4 Hz, 1H), 3.77 (s, 3H), 2.74 (td, J = 12.4, 3.6 Hz, 1H), 2.19 - 2.08 (m, 1H), 2.03 - 1.84 (m, 3H), 1.59 (s, 3H), 1.44 (s, 3H);

[0091] 1313C NMR (100 MHz, CDCl3) δ: 212.1, 158.2, 145.8, 142.9, 130.3, 129.0, 113.4, 112.8, 112.3, 56.0, 55.1, 53.1, 50.5, 36.7, 27.3, 23.0, 18.8;

[0092] HRMS (ESI) m / z found 285.1846, calculated for C 18 H 24 O2 [M+H] + 285.1849.

[0093] Compound 2':

[0094] 1 1H NMR (600 MHz, CDCl3) δ: 6.93 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.06 (dd, J = 17.4, 10.2 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 5.07 (d, J = 18.0 Hz, 1H), 4.59 (br s, 1H), 4.57 (br s, 1H), 3.90 (d, J = 12.6 Hz, 1H), 3.78 (s, 3H), 2.74 (t, J = 13.2 Hz, 1H), 2.17 - 2.08 (m, 2H), 1.81 - 1.75 (m, 2H), 1.55 (s, 3H), 1.17 (s, 3H);

[0095] 13 13C NMR (150 MHz, CDCl3) δ: 211.2, 158.2, 145.8, 142.8, 130.3, 129.0, 116.0, 113.4, 112.6, 56.8, 55.1, 53.9, 52.2, 39.0, 28.2, 24.8, 18.6;

[0096] HRMS (ESI) m / z found 285.1846, calculated for C 18 H 24 O2 [M+H] + 285.1849.

[0097] Example 5: Preparation of Compounds 8 and 8'

[0098] Under an argon atmosphere, intermediate compound 2 (75 mg, 0.26 mmol) was dissolved in 6 mL of methanol solution. The system was cooled to -60 °C, and sodium borohydride (98.8 mg, 2.6 mmol) was added. The mixture was stirred for 2 hours. 10 mL of water was added, and then methanol was removed under reduced pressure. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic phases were combined, washed with brine, dried over Na2SO4, and filtered. After drying over Na2SO4 and concentrating under reduced pressure, compound 8 (colorless needles, 60.8 mg, 82% yield) and a small amount of diastereomer 8' (white solid, 7.6 mg, 10% yield) were obtained by silica gel column chromatography. Compound 8:

[0099] 1 H NMR (400 MHz, CDCl3) δ: 7.12 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.92 (dd, J = 17.6, 10.8 Hz, 1H), 5.11 (dd, J = 17.6, 1.2 Hz, 1H), 5.07 (dd, J = 10.8, 0.8 Hz, 1H), 4.53 (br s, 2H), 4.78 (s, 3H), 3.45 (d, J = 10.4 Hz, 1H), 2.68 (t, J = 11.6 Hz, 1H,), 2.37 (td, J = 11.6, 3.6 Hz, 1H), 1.79 - 1.64 (m, 1H), 1.63 - 1.56 (m, 3H), 1.54 (s, 3H), 1.18 (s, 3H);

[0100] 13 C NMR (100 MHz, CDCl3) δ: 158.2, 147.9, 147.0, 133.0, 129.3 (2C), 113.8 (2C), 112.1, 111.7, 78.9, 55.1, 50.9, 49.0, 41.7, 36.2, 27.3, 19.5, 15.2;

[0101] HRMS (ESI) m / z found 309.1826, calculated for C 18 H 24 O2[M+Na] + 309.1825;

[0102] Compound 8':

[0103] 11H NMR (400 MHz, CDCl3) δ: 7.15 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.88 (dd, J = 17.6, 10.8 Hz, 1H), 5.11 (dd, J = 4.4, 0.8 Hz, 1H), 5.08 (dd, J = 11.2, 1.2 Hz, 1H), 4.70 (brs, 1H), 4.63 (br s, 1H), 3.77 (s, 3H), 3.39 (br s, 1H), 3.45 (dd, J = 12.4, 2.0 Hz, 1H), 2.94 - 2.87 (m, 1H), 2.07 - 1.99 (m, 1H), 1.73 - 1.68 (m, 2H), 1.56 (s, 3H), 1.40 (dt, J = 13.2, 2.8 Hz, 1H), 1.20 (s, 3H);

[0104] 13 13C NMR (100 MHz, CDCl3) δ: 158.0, 147.9, 147.0, 134.1, 129.8 (2C), 113.4 (2C), 112.8, 111.9, 77.5, 55.1, 45.4, 42.0, 41.4, 28.5, 28.0, 22.4, 19.2;

[0105] HRMS (ESI) m / z found 309.1827, calculated for C 18 H 24 O2 [M + Na] + 309.1825;

[0106] Example 6: Preparation of Psoralen F (1a) and Compound 8α-hydroxy-Psoracorylifol F (9)

[0107] Compounds 8 and 8' (19.4 mg, 0.068 mmol) were separately dissolved in 1 mL of NMP. At room temperature, K2CO3 (3.7 mg, 0.027 mmol) and PhSH (28 μL, 0.27 mmol) were successively added. After the system was heated to 230 °C and refluxed for 12 h, upon completion of the reaction, it was cooled to room temperature, quenched with H2O respectively, and the resulting mixture was extracted with EtOAc (3 × 20 mL). Washed with saturated brine, dried over Na2SO4 and concentrated under reduced pressure. Psoralen F (1a) (as a white solid, 17.8 mg, 97% yield) and Compound 8α-hydroxy-Psoracorylifol F (9) (as a white solid, 17.5 mg, 95% yield) were obtained by silica gel column chromatography purification respectively.

[0108] Psoracorylifol F(1a):

[0109] 1 1H NMR(600MHz,Methanol-d4)δ:6.91(d,J = 8.4Hz,2H),6.57(d,J = 8.4Hz,2H),5.88(dd,J = 18.0,10.8Hz,1H),4.94(dd,J = 17.4,1.2Hz,1H),4.87(dd,J = 10.8,1.8Hz,1H),4.40(br s,1H),4.37(br s,1H),3.37(d,J = 10.8Hz,1H),2.54(t,J = 10.8Hz,1H),2.23(td,J = 12.0,3.6Hz,1H),1.69 - 1.59(m,1H),1.56 - 1.51(m,1H),1.48 - 1.45(m,1H),1.44 - 1.40(m,1H),1.41(s,3H),1.04(s,3H);

[0110] 13 13C NMR(150MHz,Methanol-d4)δ:156.8,150.1,149.1,134.7,131.0,116.1,112.3,111.9,80.6,53.4,51.0,43.3,37.6,28.9,20.1,16.6;

[0111] HRMS(ESI)m / z found 295.1669,calculated for C 18 H 24 O2[M + Na] + 295.1669;

[0112] 8α-hydroxy-Psoracorylifol F(9): 11H NMR (600 MHz, CDCl3) δ: 7.09 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 5.88 (dd, J = 17.4, 10.8 Hz, 1H), 5.11 (dd, J = 10.2, 1.2 Hz, 1H), 5.08 (dd, J = 16.8, 1.2 Hz, 1H), 4.72 (br s, 1H), 4.68 (br s, 1H), 4.62 (br s, 1H), 3.39 (s, 1H), 2.98 (dd, J = 12.6, 2.4 Hz, 1H), 2.90 - 2.86 (m, 1H), 2.04 - 1.99 (m, 1H), 1.72 - 1.68 (m, 2H), 1.54 (s, 3H), 1.40 (dt, J = 13.2, 3.0 Hz, 1H), 1.19 (s, 3H);

[0113] 13 13C NMR (150 MHz, CDCl3) δ: 153.9, 147.9, 147.0, 134.3, 130.1, 115.0, 112.9, 112.0, 77.6, 45.5, 42.1, 41.5, 28.5, 28.1, 22.4, 19.2;

[0114] HRMS (ESI) m / z found 295.1671, calculated for C 18 H 24 O2 [M + Na] + 295.1669.

[0115] Example 7: Preparation of Compound 7α,8β-hydroxy-12β-Cyclobakuchiol C (1b)

[0116] At room temperature, NaHCO3 (21 mg, 0.25 mmol) and m-CPBA (13.4 mg, 80%, 0.06 mmol) were dissolved in CH2Cl2 (1 mL). At 0 °C, a solution of alkene 1a (14.8 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added to the system. The mixture was stirred at 5 °C for 4 h and the reaction was quenched by adding Me2S (5.3 μL, 0.07 mmol) and saturated NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give a residue for the next reaction.

[0117] At 0 °C, LiAlH4 (9.5 mg, 0.25 mmol) was slowly added to the above-mentioned epoxide in THF (2 mL). The resulting mixture was stirred under reflux for 3 h, cooled to room temperature, and diluted with THF and quenched with 1 mol / L HCl to quench the excess hydride. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined extracts were washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated to give a residual oil, which was purified by silica gel column chromatography to give 7α,8β-hydroxy-12β-Cyclobakuchiol C (1b) (11.0 mg, 76% yield in two steps from olefin 1a).

[0118] 7α,8β-hydroxy-12β-Cyclobakuchiol C (1b): 1 H NMR (600 MHz, Acetone-d6) δ: 8.13 (s, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 5.97 (dd, J = 17.4, 10.8 Hz, 1H), 4.96 (dd, J = 17.4, 1.8 Hz, 1H), 4.86 (dd, J = 10.8, 1.2 Hz, 1H), 3.40 (dd, J = 9.6, 4.2 Hz, 1H), 2.55 (t, J = 11.4 Hz, 1H), 2.44 (d, J = 4.2 Hz, 1H), 2.21 (s, 1H), 1.90 - 1.87 (m, 1H), 1.82 (td, J = 11.4, 4.2 Hz, 1H), 1.53 - 1.51 (m, 2H), 1.44 - 1.36 (m, 1H), 1.04 (s, 3H), 0.96 (s, 3H), 0.79 (s, 3H);

[0119] 13 C NMR (150 MHz, Acetone-d6) δ: 156.8, 149.9, 135.1, 131.1, 116.1, 110.9, 80.4, 73.2, 52.9, 49.4, 42.0, 36.0, 27.6, 23.5, 16.2;

[0120] HRMS (ESI) m / z found 313.1774, calculated for C 18 H 26 O3 [M+Na] + 313.1774;

[0121] Example 8: Preparation of Intermediate Compound 10

[0122] Compound 8 (70 mg, 0.24 mmol) was dissolved in THF (5 mL). At 0 °C, NaH (39 mg, 60%, 0.98 mmol) and MeI (62 μL, 0.98 mmol) were added successively. The reaction system was allowed to warm to room temperature naturally and reacted for 20 h. It was quenched with H2O. Extracted with EtOAc (3 × 20 mL), washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purified by silica gel column chromatography to obtain the product intermediate compound 10 (colorless oil, 65.2 mg, 95% yield).

[0123] Compound 10:

[0124] 1 H NMR (600 MHz, CDCl3) δ: 7.12 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.97 (dd, J = 17.4, 10.8 Hz, 1H), 5.04 (dd, J = 17.4, 1.2 Hz, 1H), 4.98 (dd, J = 10.8, 1.2 Hz, 1H), 4.55 (br s, 1H), 4.53 (br s, 1H), 3.77 (s, 3H), 2.89 (d, J = 10.2 Hz, 1H), 2.70 (t, J = 10.8 Hz, 1H), 2.70 (s, 3H), 2.38 (td, J = 11.4, 3.6 Hz, 1H), 1.69 - 1.55 (m, 4H), 1.53 (s, 3H), 1.13 (s, 3H);

[0125] 13 C NMR (150 MHz, CDCl3) δ: 157.8, 148.3, 147.1, 134.2, 129.5, 113.2, 111.7, 111.0, 90.8, 61.2, 55.0, 50.8, 48.5, 42.2, 35.9, 27.2, 19.3, 16.4;

[0126] HRMS (ESI) m / z found 323.1981, calculated for C 18 H 24 O2[M+Na] + 323.1982;

[0127] Example 9: Preparation of Intermediate Compound 11

[0128] Intermediate compound 10 (42 mg, 0.14 mmol) was dissolved in 2 mL of NMP. At room temperature, K2CO3 (7.7 mg, 0.056 mmol) and PhSH (72 μL, 0.7 mmol) were added successively. After the system was heated to 230 °C and refluxed for 12 h, upon completion of the reaction, it was cooled to room temperature, quenched with H2O, and the resulting mixture was extracted with EtOAc (3 × 20 mL). It was washed with saturated brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel column chromatography gave intermediate compound 11 (as a white solid, 36 mg, 90% yield).

[0129] Compound 11: White solid;

[0130] 1 1H NMR (400 MHz, CDCl3) δ: 7.07 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 5.96 (dd, J = 17.6, 10.8 Hz, 1H), 5.04 (dd, J = 17.6, 1.2 Hz, 1H), 4.99 (dd, J = 10.8, 1.2 Hz, 1H), 4.95 (s, 1H), 4.54 (br s, 1H), 4.53 (br s, 1H), 2.91 (d, J = 10.4 Hz, 1H), 2.73 (s, 3H), 2.75 - 2.67 (m, 1H), 2.37 (td, J = 11.6, 3.2 Hz, 1H), 1.71 - 1.56 (m, 4H), 1.53 (s, 3H), 1.13 (s, 3H);

[0131] 13 13C NMR (100 MHz, CDCl3) δ: 153.8, 148.2, 147.0, 134.3, 129.7, 114.8, 111.7, 111.2, 90.9, 61.2, 50.9, 48.5, 42.3, 36.0, 27.2, 19.3, 16.4;

[0132] HRMS (ESI) m / z found 309.1823, calculated for C 18 H 24 O2 [M + Na] + 309.1825;

[0133] Example 10: Preparation of Compound Corypsoriol J (1c)

[0134] Under an argon atmosphere, intermediate compound 11 (17 mg, 0.06 mmol) was dissolved in CHCl3 / MeOH (1.2 mL, (3:1 v / v)). At 0 °C, solid IBX (19.6 mg, 0.07 mmol) was added, and the system changed from yellow to orange. After reacting for 2 h, NaBH4 (20.5 mg, 0.54 mmol) was added, the color of the system disappeared, and the reaction was quenched with 1 M HCl and extracted with ethyl acetate (3 × 10 mL). Washed with brine, dried over Na2SO4, and filtered. After concentration under reduced pressure, the product Corypsoriol J (1c) (16.3 mg, 95% yield) was obtained by silica gel column chromatography.

[0135] Proposed Corypsoriol J(1c):White solid;

[0136] 1 H NMR(600MHz,Methanol-d4)δ:6.65(br s,1H),6.64(br s,1H),6.54(d,J=7.2Hz,1H),5.98,(dd,J=17.6,10.9Hz,1H),4.97(dd,J=10.8,1.2Hz,1H),4.55(br s,1H),4.50(br s,1H),3.00(d,J=10.4Hz,1H),2.58(t,J=10.8Hz,1H),2.38(td,J=12,3.6Hz,1H),1.71-1.64(m,2H),1.53(s,3H),1.52-1.49(m,2H),1.11(s,3H);

[0137] 13 C NMR(150MHz,Methanol-d4)δ:149.7(CH),148.5(C),143.0(C),143.0(C),135.0(C),122.9(CH),115.8(CH),115.8(CH),112,3(CH),111.7(CH),92.2(CH),61.7(CH3),52.4(CH),50.1(CH),43.4(C),37.3(CH2),28.4(CH2),19.7(CH3),16.7(CH3);

[0138] HRMS(ESI)m / z found 325.1772,calculated for C 18 H 24 O2[M+Na] +325.1774。

[0139] Example 11: Preparation of Intermediate Compound 12

[0140] Under an argon atmosphere, intermediate compound 2 (8.4 mg, 0.1 mmol) was dissolved in 2 mL of tetrahydrofuran. LHMDS (0.5 mL, 0.5 mmol) was slowly added dropwise at -78 °C. The mixture was allowed to warm to 0 °C naturally and reacted for 24 h, and then gradually heated to 20 °C and maintained for 6 h. The reaction was quenched by slowly adding a cold saturated aqueous solution of NH4Cl via a syringe. The mixture was extracted with EtOAc (3 × 30 mL), washed successively with water and brine, the organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography gave intermediate compound 12 (colorless oil, 14.2 mg, 50% yield).

[0141] Compound 12: Colorless oil;

[0142] 1 H NMR (400 MHz, CDCl3) δ: 7.41 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.10 (dd, J = 17.6, 10.8 Hz, 1H), 5.12 (d, J = 10.8 Hz, 1H), 5.07 - 5.03 (m, 3H), 4.95, (br s, 1H), 3.78 (s, 3H), 2.69 (t, J = 8.4 Hz, 1H), 2.45 - 2.19 (m, 2H), 1.95 - 1.90 (m, 1H), 1.87 (s, 3H), 1.85 - 1.81 (m, 1H), 0.91 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ: 215.0, 158.9, 145.7, 142.8, 132.2, 128.7, 113.7, 113.4, 112.9, 80.5, 55.2, 51.3, 49.8, 34.5, 25.0, 23.9, 23.3;

[0143] HRMS (ESI) m / z found 307.1668, calculated for C 18 H 24 O2 [M+Na] + 307.1669。

[0144] Example 12: Preparation of Compound 13

[0145] Under an argon atmosphere, intermediate compound 12 (25 mg, 0.09 mmol) was dissolved in 2 mL of methanol solution. The system was cooled to -60 °C, and sodium borohydride (34.2 mg, 0.9 mmol) was added. The mixture was stirred for 2 hours. 10 mL of water was added, and then methanol was removed under reduced pressure. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic phases were combined, washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 13 (22 mg, 85% yield). Compound 13: Colorless oil;

[0146] 1 H NMR (400 MHz, CDCl3) δ: 7.67 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 5.85 (dd, J = 17.6, 10.8 Hz, 1H), 5.04 (dd, J = 10.8, 0.8 Hz, 1H), 4.99 (dd, J = 17.6, 0.8 Hz, 1H), 4.93 (br s, 1H), 4.92 (br s, 1H), 3.79 (s, 3H), 3.66 (s, 1H), 2.88 (br s, 1H), 2.55 (dd, J = 12.4, 3.2 Hz, 1H), 2.26 - 2.15 (m, 1H), 2.09 - 2.03 (m, 1H), 1.75 (s, 3H), 1.70 - 1.66 (m, 2H), 0.65 (s, 3H);

[0147] 13 C NMR (125 MHz, CDCl3) δ: 158.5, 148.2, 146.1, 132.8, 130.3, 113.8, 112.33, 112.25, 83.4, 77.6, 55.0, 53.8, 42.4, 36.1, 25.4, 25.0, 15.5;

[0148] HRMS (ESI) m / z found 309.1824, calculated for C 18 H 24 O2 [M + Na] + 309.1825.

[0149] Example 13: Preparation of compound 7β,8α-hydroxy-12β-Psoracorylifol F (1d)

[0150] Compound 13 (7.0 mg, 0.025 mmol) was dissolved in 1 mL of NMP. At room temperature, K2CO3 (1.38 mg, 0.01 mmol) and PhSH (12.6 μL, 0.12 mmol) were added successively. After the reaction system was refluxed for 12 h, upon completion of the reaction, it was cooled to room temperature, quenched with H2O, and the resulting mixture was extracted with EtOAc (3 × 20 mL). It was washed with saturated brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel column chromatography gave compound 7β,8α-hydroxy-12β-Psoracorylifol F (1d) (as a white solid, 6.3 mg, 93% yield).

[0151] 7β,8α-hydroxy-12β-Psoracorylifol F (1d): White solid;

[0152] 1 H NMR (600 MHz, acetone-d6) δ: 8.02 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 6.33 (dd, J = 18.0, 11.4 Hz, 1H), 5.18 (dd, J = 5.4, 1.2 Hz, 1H), 5.15 (dd, J = 12.0, 1.2 Hz, 1H), 4.49 (br s, 1H), 4.42 (br s, 1H), 3.43 (dd, J = 10.2, 4.8 Hz, 1H), 2.94 (s, 1H), 2.78 (s, 1H), 2.73 (d, J = 4.2 Hz, 1H), 2.55 (t, J = 11.4 Hz, 1H), 2.44 (td, J = 12.0, 4.2 Hz, 1H), 1.94 - 1.92 (m, 1H), 1.78 - 1.75 (m, 1H), 1.55 - 1.53 (m, 1H), 1.46 (s, 3H), 1.43 - 1.41 (m, 1H), 1.13 (s, 3H);

[0153] 13 C NMR (150 MHz, acetone-d6) δ: 156.6, 148.7, 142.8, 133.7, 130.6, 115.8, 113.9, 111.8, 81.6, 52.4, 51.7, 43.1, 36.9, 28.9, 28.8, 19.8;

[0154] HRMS (ESI) m / z found 295.1671, calculated for C 18 H 24 O2[M+Na]+ 295.1669。

[0155] Example 14: Preparation of Intermediate Compounds 14 and 14'

[0156] Under an argon atmosphere, intermediate compound 2' (167 mg, 4.4 mmol) was dissolved in 4 mL of methanol solution. The system was cooled to -60 °C, sodium borohydride (167 mg, 4.4 mmol) was added, and the mixture was stirred for 2 hours. 10 mL of water was added, and then methanol was removed under reduced pressure. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic phases were combined, washed with brine, dried over Na2SO4, and filtered. After drying over Na2SO4 and concentrating under reduced pressure, the residue was purified by silica gel column chromatography to obtain intermediate compound 14 (colorless needles, 99.4 mg, 79% yield), and a small amount of diastereomer 14' (colorless needles, 13.8 mg, 11% yield).

[0157] Compound 14: Colorless needles;

[0158] 1 H NMR (600 MHz, CDCl3) δ: 7.09 (d, J = 7.2 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.30 (dd, J = 18.0, 10.8 Hz, 1H), 5.26 (dd, J = 11.4, 1.2 Hz, 1H), 5.19 (dd, J = 17.4, 1.2 Hz, 1H), 4.51 (br s, 1H), 4.50 (br s, 1H), 3.78 (s, 3H), 3.40 (d, J = 10.8 Hz, 1H), 2.60 (t, J = 11.4 Hz, 1H), 2.39 (td, J = 12.0, 3.6 Hz, 1H), 1.92 - 1.88 (m, 1H), 1.80 - 1.73 (m, 1H), 1.54 - 1.50 (m, 2H), 1.49 (s, 3H), 1.18 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ: 158.3, 147.1, 140.6, 132.7, 129.4, 114.5, 113.9, 111.6, 81.2, 55.1, 51.2, 50.5, 41.7, 36.6, 27.7, 27.4, 19.4;

[0159] HRMS (ESI) m / z found 309.1826, calculated for C 18 H 24 O2 [M + Na] +309.1825;

[0160] MS (EI) m / z (%) : 286 (26), 150 (65), 121 (100), 91 (12), 81 (10), 68 (15), 57 (14);

[0161] IR (KBr plate) ν max (cm -1 ): 3532, 2928, 2892, 2851, 1637, 1611, 1511, 1446, 1243, 1182, 1012, 918, 892, 829, 812, 568.

[0162] Compound 14': Colorless needles;

[0163] 1 1H NMR (400 MHz, CDCl3) δ: 7.11 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.95 (dd, J = 17.6, 11.2 Hz, 1H), 5.20 (dd, J = 10.8, 0.8 Hz, 1H), 5.15 (dd, J = 18.0, 1.2 Hz, 1H), 4.67 (br s, 1H), 4.60 (br s, 1H), 3.78 (s, 3H), 3.46 (br s, 1H), 2.97 (dd, J = 12.0, 1.6 Hz, 1H), 2.86 (td, J = 11.6, 3.6 Hz, 1H), 1.86 - 1.78 (m, 1H), 1.74 - 1.66 (m, 1H), 1.64 - 1.56 (m, 2H), 1.49 (s, 3H), 1.07 (s, 3H);

[0164] 13 13C NMR (125 MHz, CDCl3) δ: 158.0, 148.1, 144.9, 134.5, 129.5, 113.7, 113.2, 111.8, 78.7, 55.1, 46.5, 41.6, 41.4, 30.5, 28.5, 27.0, 19.1;

[0165] HRMS (ESI) m / z found 309.1824, calculated for C 18 H 24 O2 [M+Na] + 309.1825.

[0166] Example 15: Preparation of Corypsoriol H (1e) and psoracorylifol G (1f)

[0167] Intermediate compounds 14 and 14' (28.6 mg, 0.1 mmol) were separately dissolved in 1 mL of NMP. At room temperature, K2CO3 (5.5 mg, 0.04 mmol) and PhSH (52 μL, 0.5 mmol) were successively added. After the system was heated to 230 °C and refluxed for 12 h, upon completion of the reaction, it was cooled to room temperature, quenched with H2O respectively, and the resulting mixture was extracted with EtOAc (3 × 20 mL). Washed with saturated brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel column chromatography gave Corypsoriol H (1e) (as a white solid, 24.5 mg, 90% yield) and compound psoracorylifol G (1f) (as a white solid, 25.5 mg, 94% yield) respectively.

[0168] Corypsoriol H (1e): Colorless needles;

[0169] 1 H NMR (600 MHz, Methanol-d4) δ: 7.01 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H), 6.30 (dd, J = 17.4, 10.8 Hz, 1H), 5.24 (dd, J = 10.8, 1.2 Hz, 1H), 5.18 (dd, J = 17.4, 1.2 Hz, 1H), 4.49 (br s, 1H), 4.46 (br s, 1H), 3.43 (d, J = 10.2 Hz, 1H), 2.58 (t, J = 10.8 Hz, 1H), 2.39 (td, J = 12.6, 4.2 Hz, 1H), 1.93 (dt, J = 13.8, 3.0 Hz, 1H), 1.80 (ddd, J = 25.8, 13.2, 3.0 Hz,, 1H), 1.55 (td, J = 13.8, 4.2 Hz, 1H), 1.48 (s, 3H), 1.47 - 1.43 (m, 1H), 1.15 (s, 3H);

[0170] 13 C NMR (150 MHz, Methanol-d4) δ: 156.7, 149.0, 142.5, 134.5, 130.8, 116.0, 114.8, 112.2, 82.4, 53.6, 51.9, 43.6, 37.9, 29.1, 28.7, 20.0;

[0171] HRMS(ESI) m / z found 295.1670, calculated for C 18 H 24 O2[M+Na] + 295.1669;

[0172] Psoracorylifol G (1f): Colorless needles;

[0173] 1 H NMR (600 MHz, CDCl3) δ: 7.05 (d, J = 7.8 Hz, 2H), 6.74 (d, J = 7.2 Hz, 2H), 5.94 (dd, J = 18.0, 11.4 Hz, 1H), 5.20 (d, J = 10.8 Hz, 1H), 5.15 (d, J = 18.0 Hz, 1H), 5.07 (br s, 1H), 4.66 (br s, 1H), 4.59 (br s, 1H), 3.47 (br s, 1H), 2.95 (d, J = 12.6 Hz, 1H), 2.83 (td, J = 10.8 Hz, 1H), 1.80 (t, J = 13.2 Hz, 1H), 1.70 - 1.56 (m, 4H), 1.48 (s, 3H), 1.07 (s, 3H);

[0174] 13 C NMR (150 MHz, CDCl3) δ: 154.0, 148.0, 144.9, 134.5, 129.7, 115.2, 113.3, 111.9, 78.8, 46.4, 41.6, 41.4, 30.5, 28.5, 27.1, 19.0;

[0175] HRMS(ESI) m / z found 295.1670, calculated for C 18 H 24 O2[M+Na] + 295.1669.

[0176] Example 16: Preparation of compound 8α-hydroxy-Cyclobakuchiol C (1g)

[0177] At room temperature, NaHCO3 (21 mg, 0.25 mmol) and m-CPBA (16.1 mg, 80%, 0.75 mmol) were dissolved in CH2Cl2 (1 mL). At 0 °C, a solution of alkene 1a (13.6 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added to the system. The mixture was stirred at 5 °C for 4 h and the reaction was quenched by adding Me2S (5.3 μL, 0.07 mmol) and saturated NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined extracts were washed with brine, dried over Na2SO4, and concentrated to give a residue for the next reaction.

[0178] At 0 °C, LiAlH4 (9.5 mg, 0.25 mmol) was slowly added to the above epoxide in THF (2 mL). The resulting mixture was stirred under reflux for 3 h, cooled to room temperature, and diluted with THF and quenched with 1 mol / L HCl to quench the excess hydride. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined extracts were washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated to give a residual oil. The residual oil was purified by silica gel column chromatography to give 8α-hydroxy-Cyclobakuchiol C (1 g) (11.3 mg, 78% yield in two steps from alkene 1a).

[0179] 8α-hydroxy-Cyclobakuchiol C (1 g): Colorless needles;

[0180] 1 H NMR (600 MHz, acetone-d6) δ: 8.16 (s, 1H), 7.08 (br s, 2H), 6.74 (d, J = 7.8 Hz, 2H), 6.23 (dd J = 17.4, 10.8 Hz, 1H), 5.11 (dd, J = 10.8, 1.2 Hz, 1H), 5.09 (dd, J = 10.2, 1.8 Hz, 1H), 3.38 (dd, J = 10.2, 4.2 Hz, 1H), 2.48 (s, 1H), 2.46 (t, J = 10.8 Hz, 1H), 2.12 (s, 1H), 1.88 - 1.83 (m, 2H), 1.79 - 1.76 (m, 1H), 1.46 - 1.38 (m, 2H), 1.07 (s, 3H), 0.93 (s, 3H), 0.75 (s, 3H);

[0181] 1313C NMR (150 MHz, acetone-d6) δ: 156.8, 142.5, 134.7, 130.5, 116.1, 113.7, 82.1, 73.2, 53.3, 50.5, 42.4, 36.5, 29.3, 28.6, 27.5, 24.0;

[0182] HRMS (ESI) m / z found 313.1775, calculated for C 18 H 24 O2[M+Na] + 313.1774.

[0183] Example 17: Preparation of Compound 15

[0184] The intermediate compound 14 (70 mg, 0.24 mmol) was dissolved in THF (5 mL). At 0 °C, NaH (39 mg, 60%, 0.98 mmol) and MeI (62 μL, 0.98 mmol) were added successively. The reaction system was allowed to warm to room temperature naturally and reacted for 20 h. It was quenched with H2O. Extracted with EtOAc (3 × 20 mL), washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purified by silica gel column chromatography to obtain the product compound 15 (colorless oil, 71.7 mg, 95% yield).

[0185] Compound 15: Colorless oil;

[0186] 1 1H NMR (400 MHz, CDCl3) δ: 7.11 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.23 (dd, J = 18.0, 11.2 Hz, 1H), 5.21 (dd, J = 11.2, 1.6 Hz, 1H), 5.13 (dd, J = 18.0, 1.6 Hz, 1H), 4.54 (br s, 1H), 4.51 (br s, 1H), 3.78 (s, 3H), 2.83 (d, J = 10.4 Hz, 1H), 2.74 (s, 3H), 2.64 (t, J = 11.6 Hz, 1H), 2.45 (td, J = 12.0, 3.6 Hz, 1H), 1.91 - 1.87 (m, 1H), 1.77 - 1.65 (m, 1H), 1.52 - 1.43 (m, 2H), 1.49 (s, 3H), 1.13 (s, 3H);

[0187] 1313C NMR (125 MHz, CDCl3) δ: 157.7, 147.2, 141.4, 134.1, 129.8, 113.9, 113.1, 111.7, 92.7, 61.4, 55.0, 51.0, 49.4, 43.1, 36.7, 27.9, 27.6, 19.2;

[0188] HRMS (ESI) m / z found 323.1981, calculated for C 18 H 24 O2 [M+Na] + 323.1982;

[0189] Example 18: Preparation of Compound 16

[0190] Compound 15 (42 mg, 0.14 mmol) was dissolved in 2 mL of NMP. At room temperature, K2CO3 (7.7 mg, 0.056 mmol) and PhSH (72 μL, 0.7 mmol) were added successively. The reaction system was heated to 230 °C and refluxed for 12 h. After the reaction was completed, it was cooled to room temperature, quenched with H2O, and the resulting mixture was extracted with EtOAc (3 × 20 mL). It was washed with saturated brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel column chromatography gave Compound 16 (colorless oil, 38 mg, 95% yield).

[0191] Compound 16: Colorless oil;

[0192] 1 1H NMR (400 MHz, CDCl3) δ: 7.06 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.22 (dd, J = 18.0, 11.2 Hz, 1H), 5.20 (dd, J = 11.2, 0.8 Hz, 1H), 5.12 (dd, J = 18.0, 1.2 Hz, 1H), 4.82 (s, 1H), 4.54 (br s, 1H), 4.51 (br s, 1H), 2.84 (d, J = 10.4 Hz, 1H), 2.76 (s, 3H), 2.64 (t, J = 11.6 Hz, 1H), 2.43 (td, J = 12.0, 4.0 Hz, 1H), 1.90 - 1.85 (m, 1H), 1.77 - 1.65 (m, 1H), 1.51 - 1.43 (m, 2H), 1.49 (s, 3H), 1.13 (s, 3H);

[0193] 1313C NMR(150MHz,CDCl3)δ:153.7,147.2,141.3,134.3,130.0,114.8,113.9,111.7,92.8,61.4,51.1,49.4,43.1,36.8,27.8,27.6,19.2;

[0194] HRMS(ESI)m / z found 309.1822, calculated for C 18 H 24 O2[M+Na] + 309.1825;

[0195] Example 19: Preparation of Compound Corypsoriol I(1h)

[0196] Under an argon atmosphere, compound 16(18mg, 0.06mmol) was dissolved in CHCl3 / MeOH(1.2mL, (3:1 v / v)). At 0 °C, solid IBX(120mg, 0.07mmol) was added, and the system changed from yellow to orange. After reacting for 2h, NaBH4(21mg, 0.54mmol) was added, the color of the system disappeared, and the reaction was quenched with 1M HCl and extracted with ethyl acetate(3×10mL). Washed with brine, dried over Na2SO4, and filtered. After concentration under reduced pressure, the product Corypsoriol I(1h) was purified by silica gel column chromatography(obtained as a white solid, 16.7mg, 93% yield).

[0197] Corypsoriol I: White solid;

[0198] 11H NMR (600 MHz, Methanol-d4) δ: 6.65 (J = 8.4 Hz, 2H), 6.53 ((br s, 1H), 6.19, (dd, J = 18.0, 11.4 Hz, 1H), 5.17 (dd, J = 10.8, 1.8 Hz, 1H), 5.12 (dd, J = 18.0, 1.2 Hz, 1H), 4.52 (br s, 1H), 4.48 (br s, 1H), 2.95 (d, J = 10.2 Hz, 1H), 2.82 (s, 3H), 2.51 (t, J = 11.4 Hz, 1H), 2.44 (td, J = 12.0, 4.2 Hz, 1H), 1.89 (dt, J = 13.8, 3.0 Hz, 1H), 1.75 - 1.68 (m, 1H), 1.54 - 1.49 (m, 1H), 1.48 (s, 3H), 1.43 - 1.39 (m, 1H), 1.11 (s, 3H);

[0199] 13 13C NMR (150 MHz, Methanol-d4) δ: 148.6, 145.7, 144.4, 142.9, 135.0, 115.8, 114.2, 112.2, 94.0, 61.8, 52.6, 51.2, 44.3, 37.5, 28.9, 28.6, 19.6;

[0200] HRMS (ESI) m / z found 325.1773, calculated for C 18 H 24 O2 [M+Na] + 325.1774;

[0201] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a monoterpene phenol heteroterpene compound, characterized in that, The method described above comprises the following steps: (1) Using 2-methylcyclohexanone as the starting material, synthesize the intermediate compound 3: (2) The intermediate compound 3 obtained in step (1) selectively constructs the intermediate compound 2 or 2' with two stereocenters in one step through a copper-mediated "one-pot" Michael addition / arylation reaction: (3) The intermediate compound 2 or 2' is subjected to stereoselective reduction, regioselective oxidation, and demethylation transformation to obtain the monoterpene phenol heteroterpenoid compound represented by formula (V): Among them, R 1 is R 2 is H or OMe, and R3 is H or OH; The method described in step (1) is specifically as follows: ① First, 2-methylcyclohexanone and methyl acrylate are subjected to Michael addition to obtain intermediate compound 5, and the reaction is as follows: ② Intermediate compound 5 is oxidized by IBX and hydrolyzed under alkaline conditions to obtain intermediate compound 4, and the reaction is as follows: ③ Intermediate compound 4 is decarboxylated under the catalysis of a palladium catalyst to generate intermediate compound 3, and the reaction is as follows: The said Cat.1 is a thiourea catalyst 2. The synthesis method of the monoterpene phenol heteroterpene compound according to claim 1, characterized in that, The base used for hydrolysis under the alkaline conditions in step ② is sodium hydroxide, the palladium catalyst in step ③ is dichlorobis(triphenylphosphine)palladium, and the reaction temperature for decarboxylation is 130 °C.

3. The synthesis method of the monoterpene phenol heteroterpenoid compound according to claim 1, characterized in that, The copper salts mediated by copper in step (2) are cuprous cyanide and copper acetate.

4. The synthesis method of the monoterpene phenol heteroterpenoid compound according to claim 1, characterized in that, In step (2), the Michael addition reagent is an organolithium copper reagent, the arylation reagent is a diaryliodonium salt, the temperature of the Michael addition reaction is -78 °C and 25 °C, and the time is 2 to 12 hours.

5. The synthesis method of the monoterpene phenol heteroterpene compound according to claim 1, wherein, The synthesis of the monoterpene phenol heteroterpenoid compound described in step (3) specifically comprises the following steps: S1: Intermediate compound 2 is stereoselectively reduced to obtain intermediate compounds 8 and 8', and the reaction is as follows: S2: Intermediate compounds 8 and 8' are respectively deprotected from the methyl group under the action of boron tribromide to obtain the natural product Psoracorylifol F (1a) and intermediate compound 9, and the reaction is as follows: S3: Psoracorylifol F (1a) is selectively epoxidized and reduced to obtain compound 1b, and the reaction is as follows: S4: Compound 8 is methyl-protected for the alcohol under alkaline conditions to obtain intermediate compound 10, and the reaction is as follows: S5: Intermediate compound 10 is selectively demethylated under alkaline conditions to obtain intermediate compound 11, and the reaction is as follows: S6: Intermediate compound 11 is selectively oxidized and reduced on the aromatic ring to obtain the natural product Corypsoriol J (1c), and the reaction is as follows: S7: Intermediate compound 2 is enolized under alkaline conditions to obtain intermediate compound 12, and the reaction is as follows: S8: Intermediate compound 12 is stereoselectively reduced and demethylated to obtain compound 1d, and the reaction is as follows: S9: Intermediate compound 2' is stereoselectively reduced by sodium borohydride to obtain intermediate compounds 14 and 14', and the reaction is as follows: S10: Intermediate compounds 14 and 14' are respectively subjected to demethylation reactions under alkaline conditions to obtain the natural product Corypsoriol H (1e) and psoracorylifol G (1h), and the reaction is as follows: S11: Compound Corypsoriol H (1e) is selectively epoxidized and reduced to obtain compound (1g), and the reaction is as follows: S12: The methyl group of the alcohol in intermediate compound 14 is protected under basic conditions, the methyl group is selectively removed, and finally compound 1h is obtained through the selective redox of the aromatic ring. The reaction is as follows:

6. The method for synthesizing the monoterpenoid phenol heteroterpenoid compound according to claim 5, wherein in S1, the reducing agent for the stereoselective reduction is sodium borohydride, and the reaction temperature is -60 °C; in S2, the demethylating reagent is boron tribromide or potassium carbonate and benzenethiol, and the reaction temperature is -78 to 0 °C or 230 °C; in S3, the oxidizing agent for the selective epoxidation is m-chloroperbenzoic acid, the reducing reagent is lithium aluminum hydride, the oxidation temperature is 5 °C, and the reduction temperature is 70 °C; in S4, the basic condition is provided by sodium hydride; in S5, the reagent for the selective demethylation is potassium carbonate and benzenethiol, and the reaction temperature is 230 °C; in S6, the oxidizing agent for the selective oxidation on the aromatic ring is IBX, the reducing reagent is sodium borohydride, and the temperature is 0 °C; in S7, the base is lithium hexamethyldisilazide, and the reaction temperature is -78 to 20 °C; in S8, the reducing agent for the stereoselective reduction is sodium borohydride, and the demethylating reagent is potassium carbonate and benzenethiol; in S9, the reducing agent for the stereoselective reduction is sodium borohydride, and the reaction temperature is -60 °C; in S10, the demethylating reagent is potassium carbonate and benzenethiol, and the reaction temperature is 230 °C; in S11, the oxidizing agent for the selective epoxidation is m-chloroperbenzoic acid, the reducing reagent is lithium aluminum hydride, the oxidation temperature is 5 °C, and the reduction temperature is 70 °C; in S12, the oxidizing agent for the selective oxidation of the aromatic ring is IBX, the reducing reagent is sodium borohydride, and the temperature is 0 °C.

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