A process for the total synthesis of 17(15→16),18(4→3)-migrated abietane diterpenes

Abstract

The application provides a full synthesis method of 17(15->16), 18(4->3)-migrated abietane type diterpene, and particularly provides a preparation method of a compound of formula I, which comprises the following steps: in the presence of a solvent and an acid, a compound of formula II is subjected to rearrangement reaction to generate the compound of formula I; wherein, R 1 independently represents a hydroxyl protecting group. The application is the first asymmetric full synthesis of 17(15->16), 18(4->3)-migrated abietane type diterpene, and the first full synthesis of uncinatone (natural product 1), trichotomone F (natural product 6) and caryopterisoid C (natural product 8) is sequentially completed in 10-12 steps in a linear manner, thereby providing a reference for the synthesis of the diterpene. The synthesis method provided by the application has simple conditions, high reaction efficiency and high yield, and is more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a total synthesis method for 17(15→16),18(4→3)-migratory rosinane type diterpenes. Background Technology

[0002] 17(15→16),18(4→3)-migrating rosinane-type diterpenes have unique structures and are a class of lead compounds with great drug potential. Most of them have good pharmacological activities, such as anti-tumor, anti-inflammatory, and hypoglycemic effects. Uncinatone (1) has the effect of inhibiting cell proliferation and inducing G2 / M phase arrest, and has an effect on the IC50 of HEK-293 cells. 50 Reaching 1.2 μM; trichotomone D (2) IC50 against human oral epidermal carcinoma cells KB 50 The IC50 of teuvincenone E(4) against human T-lymphocytic leukemia cells Jurkat was 7.5 μM. 50 The concentration was 0.83 μM; trichotomone F (6) and caryopterisoid C (8) exhibited strong anti-inflammatory activity, with an IC50 concentration of 0.83 μM. 50 The concentrations were 1.12 μM and 3.49 μM, respectively. The inventors of this patent first reported the significant anti-acute kidney injury effect of compound 8 in Chinese invention patent application number 202111473664.6. However, to date, there have been no reports on the synthesis of such dimethyl migrating rosinane diterpenes. Therefore, the purpose of this invention is to provide a concise and efficient total synthesis method for such rosinane diterpenes, enabling the first total synthesis of compounds 1, 6, and 8, thus ensuring the drug-likeness study of compound 8.

[0003] .

[0004] There are currently no reports of total synthesis of 17(15→16) and 18(4→3)-migrating abirane diterpenes. The compound closest in structure to this type is the 17(15→16)-migrating abirane diterpenes. In 2024, Professor Wang Jie's group at the Shanghai Institute of Materia Medica reported the first total synthesis of villosin C and teuvincenone B. This synthesis constructed the complete ABC ring system and oxidation state in 5 steps, using Siegel-Tomkinson CH bond oxidation and Claisen rearrangement to complete the construction of the hexasubstituted benzene ring, and finally cyclizing with iodonium to obtain the D ring. However, this route can only synthesize the racemic forms of the two compounds mentioned above.

[0005] . Summary of the Invention

[0006] The technical problem this invention aims to solve is to overcome the shortcomings of existing technologies in synthesizing 17(15→16) and 18(4→3)-migrating abirane-type diterpenes with drug potential. This invention provides a synthetic method for 17(15→16) and 18(4→3)-migrating abirane-type diterpenes that features fewer reaction steps, milder and simpler conditions, higher reaction efficiency, and higher yield. It provides a synthetic method for a class of diterpenoid compounds, while also offering a stable source of compounds for drug development studies of diterpenoids and providing lead compounds for the development of drugs against acute kidney injury.

[0007] The present invention solves the above-mentioned technical problems through the following technical solution:

[0008] The present invention provides a method for preparing a compound of formula I, comprising the following steps: in the presence of a solvent and an acid, a compound of formula II undergoes a rearrangement reaction to generate a compound of formula I;

[0009] ;

[0010] Among them, R 1 Independently protected by a hydroxyl group;

[0011] The acid is trifluoromethanesulfonic acid.

[0012] R 1 These are conventional hydroxyl protecting groups for this type of reaction in the art; such as methyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl; for example, methyl.

[0013] In some embodiments, the solvent in the rearrangement reaction is an aromatic solvent, such as toluene.

[0014] In some embodiments, the molar ratio of the compound of formula II to the acid in the rearrangement reaction is 1:(15-25); for example, 1:20.

[0015] In some embodiments, the molar to volume ratio of the compound of formula II and the solvent in the rearrangement reaction is (0.05-0.15) mol / L; for example, 0.1 mol / L.

[0016] In some embodiments, the rearrangement reaction is carried out at a temperature of 15-35°C; for example, 25°C.

[0017] In some embodiments, the rearrangement reaction is carried out under a protective gas, such as nitrogen.

[0018] In some embodiments, the acid is added in the rearrangement reaction at 0°C; for example, by adding it dropwise at 0°C.

[0019] In some embodiments, the reactants of the rearrangement reaction consist of the following components: the compound of formula II, the acid, and the solvent.

[0020] The progress of the reaction can be monitored using conventional detection methods in the art (e.g., HPLC, TLC or NMR), generally ending when the compound of Formula II disappears or no longer transforms into the reaction endpoint.

[0021] In some embodiments, the rearrangement reaction further includes the following post-processing steps: after the reaction is completed, quenching is performed by adding a saturated sodium bicarbonate solution at 0°C, followed by extraction, drying, and filtration.

[0022] In some embodiments, the preparation of the compound of formula I further includes the following step: the compound of formula III undergoes an oxidation reaction to generate the compound of formula II;

[0023] ;

[0024] Among them, R 1 The definition is as described in any of the claims in this application.

[0025] In some embodiments, the preparation of the compound of formula I further includes the following step: the compound of formula IV undergoes a protecting group substitution reaction to generate the compound of formula III;

[0026] ;

[0027] Among them, R 1 The definition is as described in any of the claims in this application.

[0028] In some embodiments, the preparation of the compound of formula I further includes the following step: the compound of formula V undergoes a cyclization reaction to generate the compound of formula IV;

[0029] ;

[0030] Among them, R 1 The definition is as described in any of the claims in this application.

[0031] In some embodiments, the preparation of the compound of formula I further includes the following step: a coupling reaction between the compound of formula VI and the compound of formula VII to generate the compound of formula V;

[0032] ;

[0033] Among them, R 1 The definition is as described in any of the claims in this application.

[0034] The present invention also provides a method for preparing natural product 6, which includes the following steps: in the presence of a solvent, natural product 1 and peroxytrifluoroacetic acid undergo an epoxidation reaction to generate natural product 6;

[0035] .

[0036] In some embodiments, the solvent in the epoxidation reaction is a halocarbon solvent, such as dichloromethane.

[0037] In some embodiments, the epoxidation reaction is carried out at a temperature of -78 to -30°C; for example, -50°C.

[0038] In some embodiments, the molar ratio of the natural product 1 to the peroxytrifluoroacetic acid in the epoxidation reaction is 1:(5-25); for example, 1:10 or 1:20.

[0039] In some embodiments, the peroxytrifluoroacetic acid in the epoxidation reaction is prepared by a method for preparing peroxytrifluoroacetic acid by reacting hydrogen peroxide and trifluoroacetic anhydride.

[0040] In some embodiments, the hydrogen peroxide participates in the reaction in the form of a 30% aqueous solution of hydrogen peroxide.

[0041] In some embodiments, the trifluoroacetic anhydride participates in the reaction in the form of a dichloromethane solution of trifluoroacetic anhydride.

[0042] In some embodiments, the molar ratio of the hydrogen peroxide to the trifluoroacetic anhydride is 1:(1.5-2.5); for example, 1:2.

[0043] The progress of the epoxidation reaction can be monitored using conventional detection methods in the art (e.g., HPLC, TLC, or NMR), generally ending when natural product 1 disappears or no longer transforms into the reaction endpoint.

[0044] In some embodiments, the reactants for the epoxidation reaction consist of the following components: the solvent, the natural product 1, the hydrogen peroxide, and the trifluoroacetic anhydride.

[0045] In some embodiments, the epoxidation reaction further includes the following post-treatment steps: after the reaction is completed, the reaction is quenched with an aqueous sodium thiosulfate solution, adjusted to a weakly acidic state, extracted, dried, and filtered.

[0046] In some embodiments, the preparation of natural product 6 further includes the preparation of natural product 1, which comprises the following steps:

[0047] ;

[0048] The compound of formula VIII was subjected to a deprotection reaction, and the non-corresponding isomers were resolved to give natural product 1.

[0049] In some embodiments, the preparation of natural product 6 further includes the preparation of compound VIII, which comprises the following steps:

[0050] ;

[0051] Compound IX undergoes a ring-closure reaction to form compound VIII;

[0052] Among them, R 1 The definition is as described in any of the claims in this application.

[0053] In some embodiments, the preparation of natural product 6 further includes the preparation of compound of formula IX, which comprises the following steps:

[0054] ;

[0055] Compound X undergoes a Claisen rearrangement to generate compound IX;

[0056] Among them, R 1 The definition is as described in any of the claims in this application.

[0057] In some embodiments, the preparation of natural product 6 further includes the preparation of compound X, which comprises the following steps:

[0058] ;

[0059] Compound XI undergoes an O-allylation reaction to generate compound X;

[0060] Among them, R 1 The definition is as described in any of the claims in this application.

[0061] In some embodiments, the preparation of natural product 6 further includes the preparation of compound XI, which comprises the following steps:

[0062] ;

[0063] Compound I undergoes an oxidation reaction to yield compound XI;

[0064] Among them, R 1 The definition is as described in any of the claims in this application.

[0065] In some embodiments, the preparation of the natural product 6 further includes preparing the compound of formula I using the method for preparing the compound of formula I as described in any one of the present applications.

[0066] The present invention also provides a method for preparing natural product 8, which includes the following steps: in the presence of a solvent, natural product 6 undergoes an epoxide isomerization reaction in the presence of dimethylaluminum-2,2,6,6-tetramethylpiperidine to generate natural product 8;

[0067] .

[0068] In some embodiments, the method for preparing the natural product 8 further includes preparing the natural product 6 using the method for preparing the natural product 6 described in any one of the present applications.

[0069] In some embodiments, the solvent in the epoxy isomerization reaction is an aromatic solvent, such as toluene.

[0070] In some embodiments, the reaction temperature of the epoxy isomerization reaction is -20 to -5°C; for example, -10°C.

[0071] In some embodiments, in the epoxy isomerization reaction, the molar ratio of dimethylaluminum-2,2,6,6-tetramethylpiperidine to the natural product 6 is (6-10):1; for example, 8:1.

[0072] The progress of the epoxide isomerization reaction can be monitored using conventional detection methods in the art (e.g., HPLC, TLC or NMR). The reaction endpoint is generally reached when natural product 6 disappears or no longer transforms into the product. The reaction time is generally 20 to 50 minutes, for example, 30 minutes.

[0073] In some embodiments, in the epoxy isomerization reaction, the dimethylaluminum-2,2,6,6-tetramethylpiperidine is prepared by the following method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine: in a solvent, tetramethylpiperidine reacts with n-butyllithium to obtain intermediate 1, and intermediate 1 reacts with dimethylaluminum chloride to obtain dimethylaluminum-2,2,6,6-tetramethylpiperidine.

[0074] In some embodiments, in the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the solvent is an aromatic solvent, such as toluene.

[0075] In some embodiments, in the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the molar ratio of tetramethylpiperidine to n-butyllithium is 1:(1-2); for example, 1:1.

[0076] In some embodiments, in the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the reaction temperature of the tetramethylpiperidine and the n-butyllithium is -10°C to 10°C; for example, 0°C.

[0077] In some embodiments, in the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the reaction between the tetramethylpiperidine and the n-butyllithium is carried out under a protective gas atmosphere, such as under a nitrogen atmosphere.

[0078] In some embodiments, in the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the reaction temperature of the intermediate 1 and the dimethylaluminum chloride is -10°C to 10°C; for example, 0°C.

[0079] In some embodiments, in the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the molar ratio of tetramethylpiperidine to dimethylaluminum chloride is 1:(1-2); for example, 1:1.

[0080] The present invention also provides a compound as shown in Formula II: Among them, R 1 The definition is as described in any of the claims in this application.

[0081] This invention also provides compounds with the following structures:

[0082] , , , , , , , , .

[0083] The present invention also provides the use of the aforementioned compounds as intermediates in the preparation of natural product 1, natural product 6 or natural product 8.

[0084] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0085] The reagents and raw materials used in this invention are all commercially available.

[0086] The significant advantages of this invention are as follows: This invention represents the first asymmetric total synthesis of 17(15→16), 18(4→3)-migrating abirane-type diterpenes. It achieves the first total synthesis of uncinatone (natural product 1), trichotomone F (natural product 6), and caryopterisoid C (natural product 8) in a linear 10-12 steps, providing a reference for the synthesis of this type of diterpenes. Furthermore, caryopterisoid C possesses anti-acute kidney injury efficacy, and this synthesis provides a stable source of compounds for drug development studies and offers lead compounds for the development of anti-acute kidney injury drugs. The synthetic method provided by this invention features simple conditions, high reaction efficiency, and high yield, making it more suitable for industrial production. Detailed Implementation

[0087] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0088]

[0089] This invention uses chiral epoxide 13 and 2,5-dimethoxytoluene 14 as starting materials. Through their coupling reaction, chiral epoxide 15 can be prepared in 70% yield, and the ee value of this compound reaches 96% according to chiral HPLC analysis. At room temperature, intermediate 15 undergoes a cyclization reaction under acidic conditions to give tricyclic product 16 in 64% yield. Subsequently, the hydroxyl group is protected and the oxidation state of the B ring is adjusted to give rearranged product 18. Under strongly acidic conditions, the key rearrangement reaction yields 91% to give intermediate 19. Siegel-Tomkinson oxidation of the CH bond using peroxide 20 as an oxidant yields the target aromatic ring oxidation product in 40% yield. Then, O-allylation and Claisen rearrangement complete the construction of a hexasubstituted benzene ring. A catalytic amount of silver trifluoromethanesulfonate reacts in situ with 1,2-dichloroethane to form a Brønsted acid-catalyzed furan ring closure, yielding a tetracyclic intermediate 24 in a 1:1 dr ratio and a total yield of 60%. Under hydrochloric acid / acetic acid solution, the methoxy group protection was successfully removed to synthesize natural product 1, and the epimers could be separated using a normal silica gel. Under ultra-low temperature conditions, peroxytrifluoroacetic acid epoxidized the γ,δ-position in 49% yield to give product 6; subsequently, under Lewis acid-base action on dimethylaluminum-2,2,6,6-tetramethylpiperidine, epoxidation was achieved to give the target natural product 8 in 56% yield.

[0090] Example 1: Preparation of Epoxy Compound 15

[0091]

[0092] Weigh 28 g (184 mmol) of 2,5-dimethoxytoluene into a round-bottom flask and purge with nitrogen. Add 650 mL of anhydrous tetrahydrofuran, cool to -78 °C, and add 91 mL (210 mmol) of 2.3 M n-butyllithium hexane solution. Heat to 0 °C and stir for 4 h. The reaction system turns yellow. Cool again to -78 °C, and add the brominated chiral epoxy compound dropwise to the reaction system. 30.6 g (131.4 mmol) was added dropwise, and the mixture was heated to 0°C and stirred for 5 h. After the reaction was complete, 250 mL of saturated ammonium chloride solution was added at low temperature to quench the reaction. The reaction system was then heated to room temperature and 100 mL of water was added. The organic phase was separated, and the aqueous phase was extracted three times with 200 mL of ethyl acetate. The combined organic phases were washed successively with 200 mL of water and 200 mL of saturated NaCl. Then, anhydrous sodium sulfate powder was added and dried. The crude product was obtained by filtration, and 28 g of a pale yellow oily compound 15 was obtained by column chromatography, with a yield of 70% and an ee value of 96%.

[0093] 1 H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 3.0Hz, 1H), 6.68 (dd, J = 8.7, 3.1 Hz, 1H), 5.26 (td, J = 7.1, 1.3 Hz, 1H), 3.78(s, 3H), 3.75 (s, 3H), 2.70 (t, J = 6.2 Hz, 1H), 2.62 (d, J = 7.4 Hz, 1H), 2.27 (q, J = 7.5 Hz, 2H), 2.20 – 2.02 (m, 2H), 1.67 – 1.60 (m, 2H), 1.59 (d,J = 1.3 Hz, 3H), 1.30 (s, 3H), 1.26 (s, 3H).

[0094] Example 2 Preparation of Compound 16

[0095]

[0096] 9.0 g (0.03 mol) of the product obtained in Example 1 was dissolved in 600 mL of hexafluoroisopropanol under nitrogen protection. 0.28 g (2.96 mmol) of methanesulfonic acid was added dropwise at 0°C. After the addition was complete, the mixture was allowed to rise to room temperature, and the reaction system turned black. After the reaction was monitored by thin-layer chromatography (TLC) to confirm complete conversion of the starting material, 2 g of potassium carbonate was added to quench the reaction. The reaction system was concentrated under reduced pressure, reconstituted with EA, filtered through a short silica gel column, and the concentrated filtrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain 11.5 g of the product as a white powder (yield: 64%).

[0097] 1 H NMR (400 MHz, CDCl3) δ 6.68 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 8.8Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.34 – 3.25 (m, 1H), 3.18 (dt, J = 13.6, 3.7 Hz, 1H), 2.90 (ddd, J = 17.8, 5.5, 1.5 Hz, 1H), 2.62 – 2.43 (m, 1H), 1.88 (dd, J = 13.1, 7.0 Hz, 1H), 1.78 – 1.69 (m, 2H), 1.55 (qd, J = 12.5, 5.5 Hz,1H), 1.31 (s, 3H), 1.33 – 1.26 (m, 1H), 1.23 (dd, J = 12.0, 1.4 Hz, 1H), 1.08(s, 3H), 0.90 (s, 3H).

[0098] Example 3

[0099]

[0100] 6.5 g (21.3 mmol) of the product obtained in Example 2 was dissolved in 195 mL of dichloromethane under nitrogen protection. 6.9 mL (49.6 mmol) of triethylamine and 4.3 mL (55.5 mmol) of methanesulfonyl chloride were added dropwise at 0 °C, and the reaction was maintained at 0 °C for 1 h. The reaction was quenched by adding 100 mL of saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted three times with 100 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. 17.6.7 g of the product was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 10:1), as a white powder, yield: 82%.

[0101] 1H NMR (400 MHz, CDCl3) δ 6.68 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 8.8Hz, 1H), 4.45 – 4.36 (m, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.25 (dt, J = 13.9,3.7 Hz, 1H), 3.03 (s, 3H), 2.90 (ddd, J = 18.0, 5.5, 1.5 Hz, 1H), 2.59 – 2.44(m, 1H), 2.10 – 2.00 (m, 2H), 1.88 (dd, J = 13.1, 7.0 Hz, 1H), 1.63 – 1.50(m, 1H), 1.37 – 1.28 (m, 1H), 1.33 (s, 3H), 1.12 (s, 3H), 0.98 (s, 3H).

[0102] Example 4

[0103]

[0104] 7 g (18.3 mmol) of the product obtained in Example 3 was dissolved in 125 mL of dichloromethane under nitrogen protection. 31.5 g (146.4 mmol) of pyridinium chlorochromate was added at -10 °C, and the mixture was allowed to rise to room temperature for 48 h. 50 g of diatomaceous earth was added to the reaction mixture, and the mixture was filtered through a short silica gel column. The filtrate was concentrated and then subjected to silica gel column chromatography (petroleum ether:acetone volume ratio = 4:1) to obtain 18.455 g of the product as a pale yellow powder, yield: 63%.

[0105] 1 H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 9.1 Hz, 1H), 6.90 (d, J = 9.1Hz, 1H), 6.46 (s, 1H), 4.40 (dd, J = 11.6, 4.9 Hz, 1H), 3.88 (s, 3H), 3.84(s, 3H), 3.41 (dt, J = 14.2, 3.9 Hz, 1H), 3.05 (s, 3H), 2.32 – 2.23 (m, 1H), 2.21 – 2.08 (m, 1H), 1.63 (s, 3H), 1.41 – 1.31 (m, 1H), 1.36 (s, 4H), 1.35(s, 3H).

[0106] Example 5

[0107]

[0108] 4.0 g (10.1 mmol) of the product obtained in Example 4 was dissolved in 100 mL of toluene under nitrogen protection. 18 mL (203.5 mmol) of trifluoromethanesulfonic acid was added dropwise at 0 °C. After the addition was complete, the mixture was allowed to rise to room temperature, and the reaction system turned bright red. After complete conversion of the starting material as monitored by TLC, the reaction system was cooled to 0 °C, and the reaction was quenched by adding 200 mL of saturated sodium bicarbonate solution in batches. The reaction system was extracted three times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then subjected to silica gel column chromatography (petroleum ether:acetone volume ratio = 4:1) to obtain 19 g (2.75 g) of product as a yellow gel, yield: 91%.

[0109] 1 H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 9.1 Hz, 1H), 6.91 (d, J = 9.1Hz, 1H), 6.30 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.12 (ddd, J = 13.1, 5.6,1.6 Hz, 1H), 2.46 (m, 1H), 2.17 (dd, J = 18.9, 5.7 Hz, 1H), 1.90 (s, 3H),1.86 (s, 3H), 1.51 – 1.41 (m, 1H), 1.46 (s, 3H).

[0110] Example 6

[0111]

[0112] 300 mg (1.01 mmol) of the product obtained in Example 5 was dissolved in 10 mL of trifluoroethanol under nitrogen protection, and peroxide was added at -20°C. 188 mg (1.20 mmol) was added, and the reaction was continued at -20 °C. After complete conversion of the starting material as monitored by TLC, 1.5 mL of saturated sodium thiosulfate aqueous solution, 1.5 mL of saturated potassium carbonate aqueous solution, and 11 mL of anhydrous methanol were added to the reaction system. The reaction was then brought to room temperature for hydrolysis. After complete conversion of the ester intermediate as monitored by TLC, the reaction system was concentrated. 10 mL of water was added, and the reaction system was extracted three times with 10 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (dichloromethane:acetone volume ratio = 2:1) to give 21,128 mg of product as a yellow solid, yield: 40%.

[0113] 1 H NMR (400 MHz, CDCl3) δ 6.76 (s, 1H), 6.27 (s, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.01 (dd, J = 12.9, 5.4 Hz, 1H), 2.51 (d, J = 14.2 Hz, 1H), 2.21 (dd, J = 19.7, 5.9 Hz, 1H), 1.89 (s, 3H), 1.88 (s, 3H), 1.57 (td, J =12.4, 5.9 Hz, 1H), 1.47 (s, 3H).

[0114] Example 7

[0115]

[0116] 170 mg (0.54 mmol) of the product obtained in Example 6 was dissolved in 5 mL of anhydrous acetone under nitrogen protection. 112 mg (0.81 mmol) of potassium carbonate was added at room temperature, followed by 47 μL of allyl bromide. The reaction system was heated to 50 °C. After complete conversion of the starting material was monitored by TLC, the crude product was obtained by filtration. The filtrate was concentrated and subjected to silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 1:1) to obtain 22,173 mg of the product as a yellow solid, yield: 90%.

[0117] 1 H NMR (400 MHz, CDCl3) δ 6.56 (s, 1H), 6.23 (s, 1H), 6.11 (ddt, J =17.3, 10.5, 5.3 Hz, 1H), 5.48 (dd, J = 17.2, 1.6 Hz, 1H), 5.35 (dd, J = 10.5,1.4 Hz, 1H), 4.67 (dd, J = 4.3, 2.7 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.01(ddd, J = 13.0, 5.7, 1.6 Hz, 1H), 2.48 (m, 1H), 2.18 (dd, J = 18.7, 4.2 Hz,1H), 1.89 (s, 3H), 1.86 (s, 3H), 1.53 – 1.41 (m, 1H), 1.47 (s, 3H).

[0118] Example 8

[0119]

[0120] 65 mg (0.18 mmol) of the product obtained in Example 7 was dissolved in 2 mL of N,N-diethylaniline, and the reaction system was heated to 200 °C. After the starting material was completely converted by TLC, the mixture was diluted with 10 mL of ethyl acetate, and 15 mL of 1M dilute hydrochloric acid was added to separate the organic phase. The aqueous phase was extracted three times with 10 mL of ethyl acetate. The organic phases were combined and washed successively with 5 mL of 1M dilute hydrochloric acid and 5 mL of saturated brine. The mixture was then dried over anhydrous sodium sulfate and filtered to obtain the crude product. The filtrate was concentrated and subjected to silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 10:1) to obtain 23.55 mg of the product as a yellow solid, with a yield of 85%.

[0121] 1 H NMR (400 MHz, CDCl3) δ 6.26 (s, 1H), 6.03 (ddt, J = 17.2, 10.1, 6.2Hz, 1H), 5.75 (s, 1H), 5.15 (dd, J = 17.2, 1.8 Hz, 1H), 5.10 (dd, J = 10.1,1.6 Hz, 1H), 2.20 (dd, J =19.0, 5.9 Hz, 1H), 1.90 (s, 3H), 1.87 (s, 3H), 1.58 (m, 1H), 1.48 (s, 3H).

[0122] Example 9

[0123]

[0124] Under nitrogen protection, 10 mL of ultra-dry dichloroethane was added to a reaction flask containing 2.6 mg of silver trifluoromethanesulfonate, and the mixture was heated to 90 °C for 3 h. Then, 10 mg (28.21 μmol) of the product obtained in Example 8 was added to the same flask, and the reaction was continued at 90 °C for 1 h. After complete conversion of the starting material as monitored by TLC, the crude product was concentrated under reduced pressure, and then subjected to silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1) to obtain 24.6.0 mg of a pair of diastereomers in a 1:1 ratio, as a yellow solid, yield: 60%.

[0125] 1 H NMR (400 MHz, CDCl3) δ 6.22 (s, 2H), 5.07 (m, 2H), 3.92 (s, 6H), 3.83 (s, 6H), 3.43 (m, 1H), 3.39 (m, 1H), 2.97 (dd, J = 12.9, 5.7 Hz, 2H), 2.88 (ddd, J = 15.6, 11.2, 7.4 Hz, 2H), 2.47 (m, 2H), 2.18 (d, J = 18.1 Hz,2H), 1.90 (s, 6H), 1.86 (s, 6H), 1.53 (d, J = 2.0 Hz, 3H), 1.51 (d, J = 2.0Hz, 3H), 1.45 (s, 3H), 1.44 (s, 3H).

[0126] Example 10: Synthesis of Natural Product 1

[0127]

[0128] 20 mg (28.21 μmol) of the product obtained in Example 9 was dissolved in 1 mL of ultra-dry dichloromethane, cooled to -5°C, and 0.28 mL of 1 M boron tribromide dichloromethane solution (0.28 mmol) was added. The reaction was then brought to room temperature. After complete conversion of the starting material as monitored by TLC, the reaction was quenched with 5 mL of water, extracted three times with 5 mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. The filtrate was concentrated and subjected to silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain a pair of diastereomers of the product, 14.8 mg, as a yellow solid, with a yield of 80%. The single target product of 7.4 mg was obtained again by silica gel column chromatography (dichloromethane:acetone volume ratio = 50:1).

[0129] 1 H NMR (400 MHz, CDCl3) δ 13.72 (s, 1H), 6.22 (s, 1H), 5.11 (m, 1H), 4.87 (s, 1H), 3.40 (dd, J = 15.3, 8.9 Hz, 1H), 3.23 (ddd, J = 13.3, 5.7, 1.5Hz, 1H), 2.88 (dd, J = 15.3, 7.4 Hz, 1H), 2.51 (s, 1H), 2.20 (dd, J = 19.1,5.8 Hz, 1H), 1.90 (s, 2H), 1.88 (s, 3H), 1.57 (dd, J = 11.9, 5.9 Hz, 1H),1.52 (d, J = 6.3 Hz, 3H), 1.50 (s, 3H), consistent with literature data on the isolated natural products.

[0130] Example 11: Synthesis of Natural Product 6

[0131]

[0132] Peroxytrifluoroacetic acid was prepared by adding 1.9 mL of 30% hydrogen peroxide solution dropwise to a 60 mL solution of trifluoroacetic anhydride (5.2 mL, 36.7 mmol) in dichloromethane at 0 °C and reacting for 1 h at 0 °C. 600 mg (1.84 mmol) of the product obtained in Example 10 was mixed with 11.2 g (81 mmol) of potassium carbonate and dissolved in 60 mL of dichloromethane. The solution was cooled to -78 °C, and then the peroxytrifluoroacetic acid was added to the solution. The solution was then slowly heated to -50 °C and reacted overnight. After the raw material was completely converted by TLC, the reaction was quenched with 20 mL of sodium thiosulfate aqueous solution, and the reaction system was adjusted to weak acidity with 1M hydrochloric acid aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with 60 mL of dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, and filtered to obtain the crude product. The filtrate was concentrated and subjected to silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 8:1) to obtain 306 mg of product as a yellow solid, with a yield of 49%.

[0133] 1 H NMR (400 MHz, CDCl3) δ 13.31 (s, 1H), 6.57 (s, 1H), 5.12 (dt, J =8.5, 6.4 Hz, 1H), 4.86 (s, 1H), 3.39 (dd, J = 15.4, 9.0 Hz, 1H), 2.86 (dd, J= 15.3, 7.3 Hz, 1H), 2.82 (ddd, J = 13.5, 5.3, 2.4 Hz, 1H), 2.14 – 2.05 (m,2H), 1.58 (s, 3H), 1.52 (d, J = 6.2 Hz, 3H), 1.51 (s, 3H), 1.44 (s, 3H), 1.29(ddd, J = 13.5, (10.8, 7.0, 1H), consistent with literature data on isolated natural products.

[0134] Example 12: Synthesis of Natural Product 8

[0135]

[0136] 1.66 mL (9.81 mmol) of tetramethylpiperidine was dissolved in 21 mL of ultra-dry toluene, cooled to 0 °C, and 3.93 mL (9.81 mmol) of a 2.5 M n-butyllithium solution was added dropwise under a nitrogen atmosphere. The reaction was then carried out at 0 °C for 30 min. 9.81 mL of a 1 M dimethylaluminum chloride solution was added, and the reaction was continued at 0 °C for 1 h, followed by cooling to -10 °C. 420 mg (1.23 mmol) of the product obtained in Example 11 was dissolved in 20 mL of ultra-dry toluene and slowly added dropwise to the above reaction system, which was then reacted at -10 °C for 30 min. After the raw material was completely converted by TLC, the reaction was quenched with 20 mL of sodium thiosulfate aqueous solution to separate the organic phase. The aqueous phase was further extracted three times with 20 mL of diethyl ether. The organic phases were combined, dried with anhydrous sodium sulfate, and filtered to obtain the crude product. The filtrate was concentrated and then subjected to silica gel column chromatography (dichloromethane:acetone volume ratio = 5:1) to obtain 236 mg of product as a yellow solid, with a yield of 56%.

[0137] 1 H NMR (600 MHz, CDCl3) δ 13.45 (s, 1H), 6.22 (s, 1H), 5.28 (s, 1H), 5.20 (s, 1H), 5.14 (m, 1H), 4.76 (s, 1H), 3.41 (dd, J = 15.3, 8.9 Hz, 1H), 3.09 (m, 1H), 2.88 (dd, J = 15.3, 7.3 Hz, 1H), 1.95 (m, 1H), 1.87 (m, 2H), 1.52 (d, J = 7.0 Hz, 3H), 1.51 (s, 3H), 1.50 (s, 3H);

[0138] 13 C NMR (150 MHz, CDCl3) δ 189.8, 167.6, 154.7, 154.2, 151.7, 136.2,131.2, 123.6, 112.4, 111.4, 109.5, 83.4, 77.2, 72.7, 42.5, 35.2, 34.6, 29.3,26.9, 22.1, 21.6.

[0139] It matches the literature data of the isolated natural products.

Claims

1. A method for preparing a compound of formula I, characterized in that, It includes the following steps: In the presence of solvent and acid, compound II undergoes a rearrangement reaction to generate compound I; ； Among them, R 1 Independently protected by a hydroxyl group; The acid is trifluoromethanesulfonic acid.

2. The method for preparing the compound of formula I as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) R 1 It can be methyl, benzyl, trimethylsilyl, or tert-butyldimethylsilyl; for example, methyl. (2) In the rearrangement reaction, the solvent is an aromatic solvent; for example, toluene; (3) In the rearrangement reaction, the molar ratio of the compound of formula II to the acid is 1:(15-25); for example, 1:20; (4) In the rearrangement reaction, the molar to volume ratio of the compound of formula II and the solvent is (0.05-0.15) mol / L; for example, 0.1 mol / L; (5) The reaction temperature of the rearrangement reaction is 15-35℃; for example, 25℃; (6) The rearrangement reaction is carried out under a protective gas, for example under nitrogen protection; (7) In the rearrangement reaction, the acid is added at 0°C; for example, by adding dropwise at 0°C. (8) The reactants for the rearrangement reaction consist of the following components: the compound of formula II, the acid, and the solvent; and (9) The rearrangement reaction further includes the following post-processing steps: after the reaction is completed, saturated sodium bicarbonate solution is added at 0°C to quench the reaction, followed by extraction, drying, and filtration.

3. The method for preparing the compound of formula I as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The preparation of the compound of formula I further includes the following steps: the compound of formula III undergoes an oxidation reaction to generate the compound of formula II; ； Among them, R 1 The definition is as described in claim 1 or 2; (2) The preparation of the compound of formula I further includes the following steps: the compound of formula IV undergoes a protecting group substitution reaction to generate the compound of formula III; ； Among them, R 1 The definition is as described in claim 1 or 2; (3) The preparation of the compound of formula I further includes the following steps: the compound of formula V undergoes a cyclization reaction to generate the compound of formula IV; ； Among them, R 1 The definition is as described in claim 1 or 2; and (4) The preparation of the compound of formula I further includes the following steps: the compound of formula VI and the compound of formula VII undergo a coupling reaction to generate the compound of formula V; ； Among them, R 1 The definition is as described in claim 1 or 2.

4. A method for preparing natural product 6, characterized in that, It includes the following steps: In the presence of a solvent, natural product 1 and peroxytrifluoroacetic acid undergo an epoxidation reaction to generate natural product 6; 。 5. The method for preparing natural product 6 as described in claim 4, characterized in that, It meets one or more of the following conditions: (1) In the epoxidation reaction, the solvent is a halocarbon solvent; for example, dichloromethane; (2) In the epoxidation reaction, the reaction temperature is -78~-30℃; for example, -50℃; (3) In the epoxidation reaction, the molar ratio of the natural product 1 to the peroxytrifluoroacetic acid is 1:(5-25); for example, 1:10 or 1:20; (4) In the epoxidation reaction, the mass-to-volume ratio of the natural product 1 and the solvent is 1g:(50-150)ml; for example, 1g:100ml; (5) In the epoxidation reaction, the peroxytrifluoroacetic acid is prepared by the following method: reacting hydrogen peroxide and trifluoroacetic anhydride to obtain peroxytrifluoroacetic acid; and (6) The epoxidation reaction further includes the following post-treatment steps: after the reaction is completed, the reaction is quenched with sodium thiosulfate aqueous solution, adjusted to weak acidity, extracted, dried, and filtered; Preferably, the method for preparing peroxytrifluoroacetic acid satisfies one or more of the following conditions: (1) The hydrogen peroxide participates in the reaction in the form of a 30% hydrogen peroxide aqueous solution; (2) The trifluoroacetic anhydride participates in the reaction in the form of a dichloromethane solution of trifluoroacetic anhydride; and (3) The molar ratio of the hydrogen peroxide and the trifluoroacetic anhydride is 1:(1.5-2.5); for example, 1:2; More preferably, the reactants for the epoxidation reaction consist of the following components: the solvent, the natural product 1, the hydrogen peroxide, and the trifluoroacetic anhydride.

6. The method for preparing natural product 6 as described in claim 4, characterized in that, It meets one or more of the following conditions: (1) The preparation of natural product 6 also includes the preparation of natural product 1, which includes the following steps: ； The compound of formula VIII was subjected to a deprotection reaction, and the non-corresponding isomers were resolved to give natural product 1. Among them, R 1 The definition is as described in claim 1 or 2; (2) The preparation of the natural product 6 also includes the preparation of compound VIII, which includes the following steps: ； Compound IX undergoes a ring-closure reaction to form compound VIII; Among them, R 1 The definition is as described in claim 1 or 2; (3) The preparation of the natural product 6 also includes the preparation of compound IX, which includes the following steps: ； Compound X undergoes a Claisen rearrangement to generate compound IX; Among them, R 1 The definition is as described in claim 1 or 2; (4) The preparation of the natural product 6 also includes the preparation of compound X, which includes the following steps: ； Compound XI undergoes an O-allylation reaction to generate compound X; Among them, R 1 The definition is as described in claim 1 or 2; and (5) The preparation of the natural product 6 also includes the preparation of the compound of formula XI, which includes the following steps: ； Compound I undergoes an oxidation reaction to yield compound XI; Among them, R 1 The definition is as described in claim 1 or 2; Preferably, the method for preparing the natural product 6 further includes preparing the compound of formula I using the method for preparing the compound of formula I as described in any one of claims 1-3.

7. A method for preparing natural product 8, characterized in that, It includes the following steps: In the presence of a solvent, natural product 6 undergoes an epoxide isomerization reaction in the presence of dimethylaluminum-2,2,6,6-tetramethylpiperidine to generate natural product 8. ； Preferably, the epoxy isomerization reaction satisfies one or more of the following conditions: (1) In the epoxy isomerization reaction, the solvent is an aromatic solvent; for example, toluene; (2) The reaction temperature of the epoxy isomerization reaction is -20~-5℃; for example, -10℃; (3) In the epoxy isomerization reaction, the molar ratio of dimethylaluminum-2,2,6,6-tetramethylpiperidine to natural product 6 is (6-10):1; for example, 8:1; (4) In the epoxy isomerization reaction, the mass-to-volume ratio of the natural product 6 and the solvent is 1g:(30-80)ml; for example, 1g:50ml; (5) The reaction time of the epoxy isomerization reaction is 20 to 50 minutes, for example, 30 minutes; (6) In the epoxy isomerization reaction, the dimethylaluminum-2,2,6,6-tetramethylpiperidine is prepared by the following method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine: in a solvent, tetramethylpiperidine reacts with n-butyllithium to obtain intermediate 1, and intermediate 1 reacts with dimethylaluminum chloride to obtain dimethylaluminum-2,2,6,6-tetramethylpiperidine; and (7) The materials for the epoxy isomerization reaction consist of the following components Composition: the dimethylaluminum-2,2,6,6-tetramethylpiperidine, the solvent, and the natural product 6; (8) The method for preparing the natural product 8 further includes preparing the natural product 6 using the method for preparing the natural product 6 as described in any one of claims 4-6; More preferably, the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine satisfies one or more of the following conditions: (1) In the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the solvent is an aromatic solvent; for example, toluene; (2) In the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the molar ratio of tetramethylpiperidine to n-butyllithium is 1:(1-2); for example, 1:1; (3) In the preparation method of dimethylaluminum-2,2,6,6-tetramethylpiperidine, the reaction temperature of the tetramethylpiperidine and the n-butyllithium is -10℃ to 10℃; for example, 0℃; (4) In the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the reaction between the tetramethylpiperidine and the n-butyllithium is carried out under a protective gas, for example under a nitrogen gas; (5) In the method for preparing dimethylaluminum-2,2,6,6-tetramethylpiperidine, the reaction temperature of the intermediate 1 and the dimethylaluminum chloride is -10℃ to 10℃; for example, 0℃; and (6) In the preparation method of dimethylaluminum-2,2,6,6-tetramethylpiperidine, the molar ratio of tetramethylpiperidine to dimethylaluminum chloride is 1:(1-2); for example, 1:

1.

8. A compound as shown in Formula II: ;in, R 1 The definition is as described in claim 1 or 2.

9. Compounds with the following structures: 、 、 、 、 、 、 、 。 10. The compound of claim 8 or the compound of claim 9 as an intermediate in the preparation of natural product 1 6 natural products Or natural products 8 Applications.

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