Synthesis method of active marine natural product gorgonian terpene (+)-Erologgiaene

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of an active marine natural product gorgoniaene (+)-Erogoniaene. According to the present invention, the cheap and easily available brominated naphthalene compound is adopted as the starting material for the first time, the palladium catalyst is adopted to catalyze to achieve the bifunctionalization of the hydronaphthalene, the homemade TADDOL type chiral ligand is adopted to achieve the expected asymmetric catalysis, and the green chemical synthesis technology such as the photoreaction is adopted to achieve the side chain installation and the functional group modification; and finally, the synthesis of the (+)-Erogongiaene is completed by nine steps. According to the synthesis method, other complex fragments do not need to be prepared in advance, related reagents are simple and easy to obtain, reaction conditions are mild, the reaction conversion rate is good, the overall route is simple and efficient, and the synthesis method is suitable for industrial kilogram-level preparation and production of the (+)-Erogongiaene.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology. More specifically, it relates to a method for synthesizing the active marine natural product gorgonianide (+)-Erogorgiaene. Background Technology

[0002] Erogorgiaene is a natural diterpenoid compound isolated from the marine coral *Erogorgia laurencia*. Its structure is based on decahydronaphthalene as a core skeleton and contains multiple oxygen-containing functional groups. Studies have shown that this compound possesses significant anti-inflammatory, cytotoxic, and antibacterial activities, particularly exhibiting selective inhibitory effects on cancer cell lines such as breast cancer and prostate cancer, possibly exerting its effects by regulating apoptosis or related signaling pathways. Furthermore, erogorgiaene also shows potential antimalarial activity, making it an important candidate molecule for drug development.

[0003] However, the natural sources of erogorgiaene are significantly limited. Due to the slow growth of gorgonians and their dependence on marine ecosystems, large-scale harvesting not only limits resources but also risks disrupting the marine ecological balance. Furthermore, the compound is present in extremely low concentrations in corals, making extraction and purification costly and unsuitable for drug development. Therefore, chemical synthesis has become the primary route for obtaining erogorgiaene, but existing chemical synthesis methods still face numerous challenges.

[0004] In 2004, Hoveyda's group first reported the asymmetric total synthesis of erogorgiaene. However, their synthetic route relied on two different chiral ligands to construct the hydraphthalene skeleton and bridgehead methyl group, resulting in numerous functional group transformations and a lengthy overall process (18 steps), making it impractical. In 2005, Davis's group developed a simpler 5-step synthetic route that achieved the construction of key intermediates through kinetic resolution. However, this approach relied on expensive Rh catalysts, failing to meet atom economy requirements. In 2011, Aggarwal's group efficiently constructed C4-C erogorgiaene using Li- and B-reaction reactions. 11 By introducing an alkenyl side chain, erogorgiaene can be synthesized in just 8 steps. However, the synthesis of chiral aromatic substrates via this route requires 7 steps, and key steps rely on strong bases such as sec-butyllithium, making the operation difficult and costly, which limits its practical application.

[0005]

[0006] In summary, despite the existence of various synthetic strategies, the efficient, economical, and scalable preparation of erogorgiaene remains a challenge. Future research needs to further optimize synthetic routes, reduce the use of expensive reagents, and improve yield and atom economy to advance in-depth research on this compound and its potential drug development. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of existing chemical synthesis methods for erogorgiaene, such as lengthy steps, dependence on expensive reagents, poor atom economy, complex operation and difficulty in chiral control. The primary objective is to provide a chiral ligand L.

[0008] A second objective of the present invention is to provide a method for preparing the chiral ligand L.

[0009] A third object of the present invention is to provide the use of the chiral ligand L in the preparation of (+)-Erogorgiaene.

[0010] A fourth objective of this invention is to provide a method for synthesizing (+)-Erogorgiaene.

[0011] The above-mentioned objective of this invention is achieved through the following technical solution:

[0012] This invention protects a chiral ligand L, which has the following structure:

[0013]

[0014] This invention also protects a method for preparing the chiral ligand L, comprising the following steps: mixing compounds sm1, sm2, and sm3 in the presence of an organic solvent and an organic amine, reacting thoroughly at room temperature until the reaction is complete, and then performing post-treatment to obtain the chiral ligand L.

[0015]

[0016] Preferably, the organic solvent is selected from one or more of tetrahydrofuran, toluene, trichloroethane, and dichloromethane, and more preferably tetrahydrofuran;

[0017] Preferably, the organic amine is selected from one or more of triethylamine (Et3N), 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, diisopropylethylamine, and pyridine, and more preferably triethylamine.

[0018] Preferably, the time for the full reaction is 10 to 48 hours, more preferably 10 to 24 hours.

[0019] Preferably, the molar ratio of compound sm1, compound sm2 and compound sm3 is 1:(0.8-2):(0.8-2), more preferably 1:1:1.

[0020] Preferably, the mass-to-volume ratio of the compound sm1 to the organic solvent is 1 g:(12-20) mL, more preferably 1 g:(15-17) mL.

[0021] Further, the post-processing includes dilution, filtration, concentration, and column chromatography purification, specifically including the following steps: Subsequently, the reactants are diluted with Et2O and filtered through a layer of diatomaceous earth. After the filtrate is concentrated under vacuum, the crude product is then purified by rapid silica gel column chromatography (PE / EA (petroleum ether / ethyl acetate) = 250:1 to 100:1) to obtain a white solid, yielding the chiral ligand L.

[0022] This invention protects the use of the chiral ligand L in the preparation of (+)-Erogorgiaene.

[0023] This invention protects a method for synthesizing (+)-Erogorgiaene, comprising the following steps:

[0024] S1. 6-Methyl-1-bromonaphthalene, diethylmethylmalonate, palladium catalyst, chiral ligand L as described in claim 1, first basic reagent and trimethylsilyl diazomethane are added to a first organic solvent and reacted fully at 40-70°C. After post-treatment, intermediate 1 is obtained.

[0025] S2. Dissolve intermediate 1 obtained in step S1 in a second organic solvent, add Crabtree catalyst, react fully under hydrogen atmosphere, and then perform post-treatment to obtain intermediate 2.

[0026] S3. Dissolve intermediate 2 obtained in step S2 in a third organic solvent, add fluorinating agent, react fully at 50-70°C, and then process to obtain intermediate 3.

[0027] S4. Under ice bath conditions, intermediate 3 obtained in step S3 is dissolved in a mixture of organic solvent and water, a second alkaline reagent is added, and after thorough mixing, m-chloroperoxybenzoic acid is added, and the mixture is allowed to react fully. After post-treatment, intermediate 4 is obtained.

[0028] S5. Dissolve intermediate 4 obtained in step S4 in a fourth organic solvent, add palladium catalyst and organic amine, react fully under hydrogen atmosphere, and then process to obtain intermediate 5.

[0029] S6. Dissolve intermediate 5 obtained in step S5 in the fifth organic solvent, add sodium hydride, carbon disulfide and iodomethane in sequence, react fully at room temperature, and then process to obtain intermediate 6.

[0030] S7. Dissolve intermediate 6, 10-phenylphenthiazide (PTH), Zn(CHO2)2, and sodium 2-mercaptoethanesulfonate (mesna) obtained in step S6 in dimethyl sulfoxide, add formic acid, mix evenly under a protective gas atmosphere, react fully under 365-450 nm light irradiation, and then perform post-treatment to obtain intermediate 7.

[0031] S8. Dissolve intermediate 7 obtained in step S7 in an alcohol reagent, add a third basic reagent, react fully under reflux conditions, and then process to obtain crude product 8'; dissolve the obtained crude product 8', tetrabutylammonium tetrachloroferrate, copper hexafluorophosphate, 1,4-diazidobicyclo[2.2.2]octane and acrolein in dichloromethane, react fully under a protective gas atmosphere and 365-450nm light, and then process to obtain intermediate 8;

[0032] S9. Dissolve diisopropyltriphenylphosphine iodide in the sixth organic solvent, add the fourth basic reagent, mix well, and then add the sixth organic solvent solution containing intermediate 8 obtained in step S8. React fully at room temperature, and then perform post-treatment to obtain the target compound:

[0033]

[0034] Preferably, in step S1, the first alkaline reagent is selected from one or two of sodium tert-butoxide and sodium hydride;

[0035] Preferably, in step S1 or S5, the palladium catalyst is selected from divalent palladium catalysts, zero-valent palladium catalysts, and supported palladium catalysts; preferably, the divalent palladium catalyst is selected from one or more of palladium acetate, palladium chloride, and palladium trifluoroacetate; preferably, the zero-valent palladium catalyst is selected from one or more of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, tris(dibenzylacetone)dipalladium, and bis(tri-tert-butylphosphine)palladium; preferably, the supported palladium catalyst is selected from one or two of palladium on carbon (Pd / C) and palladium hydroxide on carbon.

[0036] More preferably, in step S1, the palladium catalyst is selected from divalent palladium catalysts, and the divalent palladium catalyst is preferably palladium acetate;

[0037] More preferably, in step S5, the palladium catalyst is selected from supported palladium catalysts, and the supported palladium catalyst is preferably Pd / C.

[0038] Preferably, in step S3, the fluorinating agent is selected from one or more of 30 vol% to 50 vol% hydrofluoric acid, tetrabutylammonium fluoride, and potassium fluoride, more preferably 30 vol% to 50 vol% hydrofluoric acid;

[0039] Preferably, in step S4, the second alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide, and more preferably sodium carbonate;

[0040] Preferably, in step S5, the organic amine is selected from one or more of 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane, and triethylamine, more preferably DBU.

[0041] Preferably, in step S8, the third alkaline reagent is selected from one or more of potassium hydroxide, sodium hydroxide, and lithium hydroxide, and more preferably potassium hydroxide;

[0042] Preferably, in step S9, the fourth alkaline reagent is selected from one or more of bis(trimethylsilyl)aminopotassium (KHMDS), potassium hydroxide, and sodium hydroxide, and more preferably KHMDS.

[0043] Preferably, in step S1, the first organic solvent is selected from one or more of trifluorotoluene, toluene, chlorobenzene, and n-hexane, and more preferably trifluorotoluene.

[0044] Preferably, in step S2, the second organic solvent is selected from one or more of dichloromethane, methanol, and ethyl acetate, and more preferably dichloromethane.

[0045] Preferably, in steps S3, S5, S6, and S9, the third organic solvent, the fifth organic solvent, and the sixth organic solvent are each independently selected from one or more of tetrahydrofuran, diethyl ether, toluene, n-hexane, and anisole, more preferably tetrahydrofuran.

[0046] Preferably, in step S4, the organic solvent in the organic solvent-water mixture is selected from one or more of dichloromethane, toluene, or diethyl ether, and more preferably dichloromethane.

[0047] Preferably, in step S4, the volume ratio of organic solvent to water in the organic solvent-water mixture is (2-3):1, more preferably 2:1.

[0048] Preferably, in step S4, the fourth organic solvent is selected from one or more of ethanol, dichloromethane, tetrahydrofuran, and toluene, and more preferably ethanol.

[0049] Preferably, in step S8, the alcohol reagent is selected from one or more of methanol, ethanol, propanol, and butanol, and more preferably ethanol.

[0050] Preferably, in step S1, the temperature at which the reaction is fully completed is 50–70°C.

[0051] Preferably, in step S1, the molar ratio of 6-methyl-1-bromonaphthalene to chiral ligand L is 1:(0.05-0.5), more preferably 1:(0.1-0.15).

[0052] Preferably, in step S1, the molar ratio of 6-methyl-1-bromonaphthalene, diethylmethylmalonate and trimethylsilyldiazomethane is 1:(0.4-1):(0.8-2), more preferably 1:(0.6-0.7):(1.2-1.5).

[0053] Preferably, in step S1, the molar ratio of 6-methyl-1-bromonaphthalene to palladium catalyst is 1:(0.01-0.1), more preferably 1:(0.01-0.05).

[0054] Preferably, in step S1, the molar ratio of 6-methyl-1-bromonaphthalene to the first basic reagent is 1:(0.01 to 0.1), more preferably 1:(0.8 to 1.5).

[0055] Preferably, in step S1, the mass-to-volume ratio of 6-methyl-1-bromonaphthalene to the first organic solvent is 1 g:(50-80) mL, more preferably 1 g:(60-70) mL.

[0056] Preferably, in step S2, the molar ratio of intermediate 1 to Crabtree catalyst is 1:(0.08-0.5), more preferably 1:(0.08-0.15).

[0057] Preferably, in step S2, the mass-to-volume ratio of intermediate 1 and the second organic solvent is 1 g:(5-20) mL, more preferably 1 g:(8-12) mL.

[0058] Preferably, in step S3, the molar ratio of intermediate 2 to fluorinating agent is 1:(10-30), more preferably 1:(15-25).

[0059] Furthermore, the purity of the m-chloroperoxybenzoic acid is ≥85%.

[0060] Preferably, in step S4, the molar ratio of intermediate 3 to m-chloroperoxybenzoic acid is 1:(1-2), more preferably 1:(1.2-1.6).

[0061] Preferably, in step S4, the molar ratio of intermediate 3 to the second alkaline reagent is 1:(1-3), more preferably 1:(1.5-2.5).

[0062] Preferably, in step S4, the mass-volume ratio of the intermediate 3 and the organic solvent-water mixture is 1g:(70-110)mL, more preferably 1g:(80-100)mL.

[0063] Preferably, in step S5, the molar ratio of intermediate 4 to palladium catalyst is 1:(0.1-0.4), more preferably 1:(0.15-0.25).

[0064] Preferably, in step S5, the molar ratio of intermediate 4 to organic amine is 1:(0.1-0.4), more preferably 1:(0.15-0.25).

[0065] Preferably, in step S6, the molar ratio of intermediate 5 to sodium hydride is 1:(4-6), more preferably 1:(4.5-5.5).

[0066] Preferably, in step S6, the molar ratio of intermediate 5 to carbon disulfide is 1:(4-6), more preferably 1:(4.5-5.5).

[0067] Preferably, in step S6, the molar ratio of intermediate 5 to potassium iodide is 1:(4-6), more preferably 1:(4.5-5.5).

[0068] Preferably, in step S6, the mass-to-volume ratio of the intermediate 5 and the fifth organic solvent is 1 g:(40-60) mL, more preferably 1 g:(45-55) mL.

[0069] Preferably, in step S7, the molar ratio of intermediate 6, PTH, Zn(CHO2)2 and mesna is 1:(0.01~0.1):(0.5~1.5):(0.01~0.1), more preferably 1:(0.03~0.007):(0.8~1.2):(0.03~0.007).

[0070] Preferably, in step S7, the molar ratio of intermediate 6 to formic acid is 1:(1-3), more preferably 1:(1.5-2.5).

[0071] Preferably, in step S7, the wavelength of the illumination is 380–400 nm.

[0072] Preferably, in step S7, the mass-to-volume ratio of intermediate 6 and dimethyl sulfoxide is 1 g:(20-40) mL, more preferably 1 g:(25-35) mL.

[0073] Preferably, in step S8, the molar ratio of the intermediate 7 and the third alkaline reagent is 1:(6-15), more preferably 1:(8-12).

[0074] Preferably, in step S8, the mass-to-volume ratio of intermediate 7 and alcohol reagent is 1g:(20-40)mL, more preferably 1g:(25-35)mL.

[0075] Preferably, in step S8, the molar ratio of intermediate 8', tetrabutylammonium tetrachloroferrate, copper hexafluorophosphate, 1,4-diazidobicyclo[2.2.2]octane and acrolein is 1:(0.1-0.4):(0.1-0.3):(0.1-0.6):(8-15), more preferably 1:(0.15-0.25):(0.1-0.2):(0.2-0.4):(8-12).

[0076] Preferably, in step S8, the wavelength of the illumination is 380–400 nm.

[0077] Preferably, in step S9, the molar ratio of intermediate 8 to diisopropyltriphenylphosphine iodide is 1:(3-5), more preferably 1:(3.5-4.5).

[0078] Preferably, in step S9, the molar ratio of the intermediate 8 and the fourth basic reagent is 1:(3-5), more preferably 1:(3.5-4.5).

[0079] Preferably, in step S9, diisopropyltriphenylphosphine is used. Iodide dissolved in the sixth organic solvent, the diisopropyltriphenylphosphine The mass-to-volume ratio of iodide to the sixth organic solvent is 1 g:(200-250) mL, more preferably 1 g:(220-240) mL.

[0080] Preferably, in step S9, the mass-to-volume ratio of intermediate 8 to the sixth organic solvent in the sixth organic solvent solution containing intermediate 8 obtained in step S8 is 1 g: (800-1500) mL, more preferably 1 g: (900-1200) mL.

[0081] Furthermore, in step S7 or step S8, the protective gas is independently selected from any one of argon, nitrogen, neon, argon, and helium.

[0082] Furthermore, in step S1, the time for the full reaction is 10 to 24 hours, preferably 12 to 18 hours.

[0083] Furthermore, in step S2, the time for the full reaction is 10 to 20 hours, preferably 15 to 17 hours.

[0084] Furthermore, in step S3, the time for the full reaction is 8 to 15 hours, preferably 11 to 13 hours.

[0085] Furthermore, in step S4, the time for the full reaction is 0.5 to 2 hours, preferably 0.8 to 1.2 hours.

[0086] Furthermore, in step S5, the time for the full reaction is 12 to 20 hours, preferably 15 to 17 hours.

[0087] Furthermore, in step S6, the time for the full reaction is 2 to 6 hours, preferably 3 to 5 hours.

[0088] Furthermore, in step S7, the time for the full reaction is 8 to 15 hours, preferably 11 to 13 hours.

[0089] Furthermore, in step S8, during the generation of crude product 8', the time for the full reaction is 8 to 15 hours, preferably 11 to 13 hours.

[0090] Furthermore, in step S8, during the generation of intermediate 8, the time for the full reaction is 12 to 20 hours, preferably 15 to 17 hours.

[0091] Furthermore, in step S9, the time for the full reaction is 10 to 48 hours, more preferably 10 to 24 hours.

[0092] Further, in step S1, the post-processing includes cooling, filtration, concentration, and column chromatography purification, specifically including the following steps: After the reaction is complete, the reaction mixture is cooled to room temperature and filtered through alumina (using hexane / ethyl acetate = 1:1 as the eluent). The filtrate is concentrated under reduced pressure, and the resulting residue is purified by alkaline alumina column chromatography (petroleum ether / ethyl acetate (PE / EA) = 50 / 1) to obtain intermediate 1.

[0093] Further, in step S2, the post-processing includes concentration and column chromatography purification, specifically including the following steps: after the reaction is completed, the solvent is concentrated under reduced pressure, and the crude product is purified by column chromatography (PE / EA: 100 / 1-50 / 1) to obtain intermediate 2.

[0094] Further, in step S3, the post-processing includes cooling, quenching, extraction, washing, drying, vacuum concentration, and column chromatography purification, specifically including the following steps: after the reaction is completed, the mixture is cooled to 0°C, quenched by adding saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, the organic layer is washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product obtained by concentration is purified by rapid column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain intermediate 3.

[0095] Further, in step S4, the post-processing includes quenching, extraction, washing, drying, vacuum concentration, and column chromatography purification, specifically including the following steps: quenching with saturated Na2S2O3 aqueous solution in an ice bath, DCM extraction, washing with saturated brine, drying with anhydrous Na2SO4, vacuum concentration, and purification of the crude product obtained by rapid column chromatography (PE:EA:Et3N=10:1:0.01) to obtain a white solid compound, namely intermediate 4.

[0096] Further, in step S5, the post-processing includes filtration, washing, vacuum concentration and column chromatography purification, specifically including the following steps: the reaction solution is filtered through diatomaceous earth, the filter cake is washed three times with EA, the filtrate is concentrated under vacuum, and the crude product obtained by concentration is purified by rapid column chromatography (PE / EA = 20 / 1) to obtain a pale yellow oily substance, namely intermediate 5.

[0097] Further, in step S6, the post-processing includes quenching, extraction, washing, drying, vacuum concentration and column chromatography purification, specifically including the following steps: adding saturated ammonium chloride aqueous solution to quench the reaction, extracting with ethyl acetate, washing with saturated NaCl, drying with anhydrous Na2SO4, concentrating under reduced pressure, and purifying the crude product obtained by rapid column chromatography (PE:EA = 50:1) to obtain a yellow oily substance, i.e., intermediate 6.

[0098] Further, in step S7, the post-processing includes vacuum concentration and column chromatography purification, specifically including the following steps: after the reaction is completed, the reaction solution is concentrated under reduced pressure and purified by rapid column chromatography (PE / EA = 50 / 1) to obtain a colorless oily substance, namely intermediate 7.

[0099] Further, in step S8, during the generation of crude product 8', the post-processing includes pH adjustment, extraction, washing, drying, and vacuum concentration, specifically including the following steps: acidifying the reaction mixture to pH=2 with concentrated hydrochloric acid, followed by extraction with ethyl acetate, washing the organic layer sequentially with saturated brine, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude product 8'.

[0100] Further, in step S8, during the generation of intermediate 8, the post-processing includes column chromatography purification, specifically including the following steps: after the reaction is completed, the reaction mixture is purified by rapid column chromatography (PE / EA = 50:1) to obtain a colorless oily substance, i.e., intermediate 8.

[0101] Further, in step S9, the post-processing includes quenching, extraction, washing, drying, vacuum concentration, and column chromatography purification, specifically including the following steps: After the reaction is completed, the reaction system is quenched with saturated ammonium chloride aqueous solution, then extracted with ethyl acetate, the organic layer is washed sequentially with saturated brine, dried with anhydrous sodium sulfate, and then concentrated under vacuum. The residual oily substance after vacuum concentration is purified by rapid column chromatography (PE / EA = 200:1) to obtain a colorless oily substance, i.e., the target compound.

[0102] Compared with the prior art, the present invention has the following beneficial effects:

[0103] This invention is the first to use readily available and inexpensive naphthalene bromide as a starting material. It utilizes a palladium catalyst to achieve the bifunctionalization of hydraphthalene, employs a self-made TADDOL-type chiral ligand to achieve the desired asymmetric catalysis, and utilizes green chemical synthesis techniques such as photoreaction to install side chains and modify functional groups. Finally, the synthesis of (+)-Erogorgiaene is completed in 9 steps. The above synthetic method does not require the prior preparation of other complex fragments, uses simple and readily available reagents, employs mild reaction conditions, and achieves good reaction conversion rates. The overall route is concise and efficient, suitable for industrial-scale kilogram-scale production of (+)-Erogorgiaene. Attached Figure Description

[0104] Figure 1 This is the HPLC chromatogram of intermediate 1 obtained in Example 2. Detailed Implementation

[0105] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0106] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0107] Example 1: Preparation of TADDOL ligands

[0108] The synthetic pathway for TADDOL ligands is shown below:

[0109]

[0110] The specific preparation includes the following steps:

[0111] Compound Sm1 (933 mg, 2 mmol, 1.0 eq) was added to a 25 mL round-bottom flask equipped with a magnetic stir bar. THF (15 mL) was added via syringe, followed by Et3N (1.4 mL, 10 mmol, 5.0 eq). The resulting solution was cooled to 0 °C, and then phosphorus trichloride Sm2 (175 μL, 2 mmol, 1.0 eq) was added dropwise. The reaction mixture was stirred for 1 hour, and then compound sm3 (2.0 mmol, 1.0 eq) was slowly added at 0 °C. The mixture was heated to room temperature and stirred overnight (12 h). Subsequently, the reactants were diluted with Et2O (60 mL) and filtered through a layer of diatomaceous earth. The filtrate was concentrated under vacuum, and the crude product was then purified by rapid silica gel column chromatography (PE / EA (petroleum ether / ethyl acetate) = 250:1 to 100:1) to give a white solid (815.1 mg, yield 67%), namely the TADDOL ligand (L ligand). Its NMR and mass spectrometry data are shown below:

[0112] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.82 (d, J = 7.6Hz, 2H), 7.66 (d, J = 7.6Hz, 2H), 7.53 (d, J = 7.6H) z,2H),7.48(d,J=7.2Hz,2H),7.35–7.28(m,10H),7.24–7.20(m,2H),5.22(dd,J=8.4,3. 2Hz,1H),4.81(d,J=8.0Hz,1H),3.60–3.21(m,1H),2.82(d,J=7.2Hz,3H),1.84–1.74(m, 4H),1.66–1.52(m,3H),1.37(s,3H),1.32–1.26(m,2H),1.14–1.04(m,1H),0.33(s,3H).

[0113] 13 C NMR (101MHz, CDCl3) δ (ppm) 147.4,146.9,142.7,142.2,129.2,129.0,128.9,128.1,127.7,127.6,127.5,127.4,127.33,127.28,127.2,1 27.11,127.06,111.6,82.84,82.80,82.6,82.4,81.6,81.3,81.2,57 .5,57.2,32.5(t,J=4.0Hz),27.8,27.3,27.2,26.4,26.3,25.9,25.4.

[0114] 31P NMR (202MHz, CDCl3) δ (ppm) 140.41.

[0115] HRMS-ESI: calculated[M+H] + :608.2924,found:608.2913.

[0116] [α] 25 D =-122.4 (c=0.5,EA).

[0117] The structure of the TADDOL ligand is shown below:

[0118]

[0119] Example 2: Synthesis of (+)-Erogorgiaene

[0120] The synthetic pathway for (+)-Erogorgiaene is shown below:

[0121]

[0122] The specific preparation includes the following steps:

[0123] S1. Synthesis of Intermediate 1

[0124] 6-Methyl-1-bromonaphthalene (31.1 mg, 0.15 mmol, 1 eq), diethylmethylmalonate (17.4 mg, 0.10 mmol, 0.67 eq), palladium acetate (1.1 mg, 0.005 mmol), TADDOL ligand (L) (12.2 mg, 0.02 mmol), sodium tert-butoxide (11.5 mg, 0.12 mmol, 0.8 eq), and trimethylsilyldiazomethane (2.0 M hexane solution: 100 μL, 0.20 mmol, indicating 0.2 mmol of trimethylsilyldiazomethane in 100 μL of hexane) were added to PhCF3 (2.0 mL), and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered through alumina (using hexane / ethyl acetate = 1:1 as the eluent). The filtrate was concentrated under reduced pressure, and the residue was purified by alkaline alumina column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give a colorless oil (yield 61%, Ee 85%, 26.3 mg), i.e., intermediate 1. Its NMR data are shown below, and its HPLC data are shown below. Figure 1 As shown in the figure.

[0125] 1H NMR (400MHz, CDCl3) δ (ppm) 7.61 (d, J = 8.0Hz, 1H), 7.07 (dd, J = 8.0, 2.0Hz, 1H), 6.94 (s, 1H), 6.81 (d, J = 10.4Hz, 1H), 6 .27–6.22(m,2H),4.55(d,J=4.8Hz,1H),4.29-4.11(m,4H),2.29(s,3H),1.30-1.23(m,6H),1.04(s,3H),0.22(s,9H). 13 C NMR (101MHz, CDCl3) δ (ppm) 171.0,145.5,136.8,134.3,133.6,132.2,129.1 ,128.4,128.0,124.2,124.0,61.6,61.5,45.1,21.2,14.5,14.1,14.0,0.4.

[0126] HRMS-ESI: Calculated [M+Na] + :423.1962,found:423.1957.

[0127] [α] 25 D = -155.0 (c = 0.2, n - Hexane).

[0128] Chiral HPLC analysis of the corresponding mixture(IF-3,Hexane / isopropanol99 / 01,flow rate=0.6mL / min,254nm):indicate 85%ee for the majordiastereomer:t R (major) = 10.4 min, t R (minor) = 11.5 min.

[0129] The structure of intermediate 1 is shown below:

[0130]

[0131] S2. Synthesis of Intermediate 2

[0132] In a 25 mL round-bottom flask, intermediate 1 (745 mg, 1.86 mmol, 1.0 eq) obtained in step S1 was dissolved in anhydrous DCM (8 mL), and Crabtree catalyst (150 mg, 0.186 mmol, 0.1 eq) was added. The system was purged with hydrogen three times and reacted under a hydrogen atmosphere for 16 h. After the reaction was completed, the solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE / EA100 / 1-50 / 1) to obtain a colorless oil, i.e., intermediate 2. Its NMR and mass spectrometry data are shown below:

[0133] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.09 (d, J = 7.8Hz, 1H), 7.00 (d, J = 8.6Hz, 1H), 6.90 (s, 1H), 5.4 5(dd,J=6.6,2.8Hz,1H),4.19(q,J=7.0Hz,2H),4.15–4.03(m,2H),3.79(d,J=6.6Hz,1H), 2.69(dd,J=18.2,8.4Hz,1H),2.42(dd,J=19.2,5.2Hz,1H),2.27(s,3H),1.90(d,J=14.4H z,1H),1.76(d,J=14.4Hz,1H),1.35(s,3H),1.26(t,J=7.0Hz,3H),1.18(t,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ (ppm) 171.8, 171.4, 135.9, 134.0, 133.7, 133.2, 130.2, 127. 8,123.7,121.3,61.4,61.2,60.3,40.2,26.6,22.4,21.2,17.5,14.1,14.0,-0.6.

[0134] HRMS-ESI: Calculated [M+Na] + :403.2119,found:403.2128.

[0135] The structure of intermediate 2 is shown below:

[0136]

[0137] S3. Synthesis of Intermediate 3

[0138] In a 25 mL round-bottom flask, intermediate 2 obtained in step S2 was dissolved in 8 mL of THF solution, followed by slow addition of 40 vol% HF (4 mL, 4.8 mol, 20 eq). The flask was placed in an oil bath and heated to 65 °C for 12 h. After the reaction was completed, the mixture was cooled to 0 °C, quenched with 30 mL of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (3 × 20 mL), washed with 2 × 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 50:1) to give a pale yellow oil (655 mg, 66% yield of steps S2 and S3), which is intermediate 3.

[0139] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.11 (d, J = 7.8Hz, 1H), 7.04 (d, J = 7.8Hz, 1H), 6.92 (s, 1H), 5.58 (d, J = 6.2Hz, 1H), 4.24–4.04 (m, 4H), 3.73 (d ,J=10.0Hz,1H),2.71–2.59(m,1H),2.51(dd,J=18.0,6.4Hz,1H),2.29(s,3H),1.98(s,3H),1.29(s,3H),1.23(dt,J=15.4,7.0Hz,6H). 13 C NMR (101MHz, CDCl3) δ (ppm) 171.7, 136.0, 134.1, 133.4, 131.6, 130.4, 128. 2,123.6,122.9,61.4,61.2,59.3,40.6,26.5,21.3,19.1,18.2,14.1,14.0.

[0140] HRMS-ESI: Calculated [M+Na] + :353.1722,found:353.1723.

[0141] [α] 25 D = -18.4 (c = 2.5, CHCl3).

[0142] The structure of intermediate 3 is shown below:

[0143]

[0144] Synthesis of S4 intermediate 4

[0145] Intermediate 3 (33 mg, 0.1 mmol, 1.0 equivalent) obtained in step S3 was dissolved in a solution of DCM / H2O = 2 / 1 (3 mL), and Na2CO3 (22 mg, 0.2 mmol, 2.0 equivalent) was added. The mixture was stirred at 0 °C for 10 minutes. Then, m-CPBA (m-chloroperoxybenzoic acid, 85% purity, 31 mg, 0.15 mmol, 1.5 equivalent) was added to the reaction mixture, and stirring was continued for 1 hour in an ice bath. The mixture was quenched with saturated Na2S2O3 aqueous solution (1 mL) in an ice bath, extracted with DCM (3 × 5 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (PE:EA:Et3N = 10:1:0.01) to give a white solid compound, namely intermediate 4. Its NMR and mass spectrometry data are shown below:

[0146] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.48 (d, J = 7.8Hz, 1H), 7.07 (d, J = 6.0Hz, 1H), 6.86 (s, 1H), 4.29–4.18 (m, 2H), 4.18–4.09 (m, 2H), 3.72 (dd, J = 6.4, 4.4Hz,1H),3.37–3.31(m,1H),2.36–2.26(m,4H),2.23–2.09(m,1H),1.72(s,3H),1.41(s,3H),1.28(t,J=7.0Hz,3H),1.22(t,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ (ppm) 171.4, 171.3, 137.5, 134.9, 133.9, 130.1, 128.2, 127.8,61.8,61.6,59.8,58.8,55.1,40.2,28.1,21.4,20.6,17.3,14.1,14.1.

[0147] HRMS-ESI: Calculated [M+Na] + :369.1672,found:369.1669.

[0148] The structure of intermediate 4 is as follows:

[0149]

[0150] S5. Synthesis of Intermediate 5

[0151] In a 5 mL round-bottom flask, intermediate 4 (1.0 equivalent) obtained in step 4 was dissolved in ethanol (2.0 mL). Pd / C (21 mg, 0.02 mmol, 0.2 equivalent) and DBU (3 μL, 0.02 mmol, 0.2 equivalent) were added sequentially. The mixture was purged with hydrogen three times and stirred for 16 h under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth and the filter cake was washed three times with EA. The filtrate was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (PE / EA = 20 / 1) to give a pale yellow oil (25.7 mg, 74% yield in steps S4 and S5, dr = 3.5:1), i.e., intermediate 5.

[0152] 1 H NMR(400MHz, CDCl3)δ(ppm)7.12(d,J=7.8Hz,1H),7.02(d,J=6.2Hz,1H),6.93(s,1H),4.29–4.11(m,5H),4.08(s,1 H),2.92–2.86(m,1H),2.32–2.22(m,4H),1.81–1.70(m,1H),1.35(d,J=7.0Hz,3H),1.31–1.22(m,6H),1.21(s,3H). 13 C NMR (101MHz, CDCl3) δ (ppm) 171.9, 171.4, 136.7, 135.5, 134.9, 129.4, 128.1, 127.5,71.0,61.6,61.6,60.7,39.4,37.5,33.5,21.2,16.7,16.5,14.2,14.1.

[0153] HRMS-ESI: Calculated [M+Na] + :371.1829,found:371.1826.

[0154] [α] 25 D ＝ 15.4 (c=1.1, CHCl3).

[0155] The structure of intermediate 5 is shown below:

[0156]

[0157] Synthesis of S6 intermediate 6

[0158] In a dry 5 mL round-bottom flask, intermediate 5 (38 mg, 0.11 mmol, 1.0 equivalent) obtained in step S5 was dissolved in anhydrous tetrahydrofuran (2.0 mL). Sodium hydride (22 mg, 0.55 mmol, 5.0 equivalent) was added at 0 °C and stirred for about 30 minutes. Then carbon disulfide (41.8 mg, 0.55 mmol, 5.0 equivalent) was added, and the reaction was continued at room temperature for 30 minutes. Iodomethane (34 μL, 0.55 mmol, 5.0 equivalent) was then added, and the reaction was continued at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (1 mL), extracted with ethyl acetate (3 × 5 mL), washed with saturated NaCl (2 × 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (PE:EA = 50:1) to obtain a yellow oily substance, intermediate 6. Its NMR and mass spectrometry data are shown below:

[0159] 1H NMR(400MHz, CDCl3)δ(ppm)7.09(d,J=8.0Hz,1H),7.01(d,J=7.8Hz,1H),6.89(s,1H),6.11–6.04(m,1H),4.26–4.15(m,4H),4 .11(t,J=7.4Hz,1H),3.27–3.20(m,1H),2.58–2.43(m,1H),2.28(s,3H),2.26(s,3H),1.97–1.86(m,1H),1.32–1.22(m,12H). 13 CNMR(101MHz,CDCl3)δ(ppm)215.1,171.8,171.3,137.3,135.3,134.6,129.1,127.9 ,127.3,82.7,61.8,61.7,60.3,40.0,36.1,29.1,21.3,18.3,17.3,17.0,14.1,14.1.

[0160] HRMS-ESI: Calculated [M+Na] + :461.1427,found:461.1429.

[0161] The structure of intermediate 6 is shown below:

[0162]

[0163] S7. Synthesis of Intermediate 7

[0164] In a dry 5 mL round-bottom flask, intermediate 6 (47 mg, 0.14 mmol, 1.0 equivalent) obtained in step S6, PTH (2.0 mg, 0.007 mmol, 0.05 equivalent), Zn(CHO2)2 (22.4 mg, 0.14 mmol, 1.0 equivalent), and mesna (sodium 2-mercaptoethanesulfonate, 1.2 mg, 0.007 mmol, 0.05 equivalent) were added sequentially, and the reactants were dissolved in 1.4 mL of DMSO. Finally, formic acid (13.2 mg, 0.28 mmol, 2.0 equivalent) was added to the reaction system. The reaction flask was sealed, and the mixture was stirred for 5 min under an argon atmosphere until homogeneous, followed by reaction under 390 nm light for 12 h. The reaction solution was concentrated under reduced pressure and purified by rapid column chromatography (PE / EA = 50 / 1) to obtain a colorless oil (33.5 mg, yield 66%), namely intermediate 7. Its NMR and mass spectrometry data are shown below:

[0165] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.13 (d, J = 8.0Hz, 1H), 6.97 (d, J = 6.2Hz, 1H), 6.90 (s, 1H), 4.21 (m, 4.25–4.17, 4H), 4.04 (t, J = 7.6Hz ,1H),2.78–2.65(m,1H),2.24(s,3H),2.06–1.97(m,1H),1.96–1.88(m,1H),1.65–1.46(m,2H),1.28–1.23(m,9H),1.21(s,3H). 13 CNMR(101MHz,CDCl3)δ(ppm)172.4,171.7,141.6,135.9,134.7,129.5,127 .2,126.7,61.5,60.5,41.8,32.6,31.6,25.4,22.0,21.2,16.6,14.2,14.1.

[0166] HRMS-ESI: Calculated [M+Na] + :355.1880,found:355.1876.

[0167] [α] 25 D = +27 (c = 1.0, CHCl3).

[0168] The structure of intermediate 7 is shown below:

[0169]

[0170] Synthesis of S8 intermediate 8

[0171] Intermediate 7 (35 mg, 0.105 mmol, 1.0 equivalent) obtained in step S7 was dissolved in ethanol (1.0 mL), and KOH (59.0 mg, 1.05 mmol, 10.0 equivalent) was added. The reaction mixture was heated to 80 °C and stirred under reflux for 12 h. The pH of the reaction mixture was acidified to 2 with concentrated hydrochloric acid, followed by extraction with ethyl acetate (3 × 5 mL). The organic layer was washed successively with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 8'. Crude product 8' was used directly in the next reaction without column chromatography purification.

[0172] The crude product 8' (1.0 equivalent), tetrabutylammonium tetrachloroferrate (TBAFeCl4, 8.9 mg, 0.02 mmol, 0.2 equivalent), copper hexafluorophosphate (Cu(MeCN)4PF6, 5.6 mg, 0.015 mmol, 0.15 equivalent), DABCO (1,4-diazabicyclo[2.2.2]octane, 3.4 mg, 0.03 mmol, 0.3 equivalent), and acrolein (58.9 mg, 1.05 mmol, 10 equivalent) were added sequentially to a 10 mL reaction flask and dissolved in anhydrous dichloromethane (DCM, 2.2 mL). The reaction system was irradiated with 390 nm (30 W) under an argon atmosphere and stirred at room temperature for 16 h. Finally, the reaction mixture was purified by rapid column chromatography (PE / EA = 50:1) to obtain a colorless oil, intermediate 8, whose NMR and mass spectrometry data are shown below:

[0173] 1 H NMR (400MHz, CDCl3) δ (ppm) 9.83 (s, 1H), 7.14 (d, J = 7.8Hz, 1H), 7.06–6.92 (m, 2H),2.90–2.84(m,1H),2.80–2.69(m,1H),2.61–2.33(m,2H),2.30(s,3H),2.2 0–2.02(m,1H),1.98–1.89(m,1H),1.87–1.72(m,2H),1.70–1.61(m,1H),1.60 –1.50(m,1H),1.38–1.30(m,1H),1.27(d,J=6.8Hz,3H),0.67(d,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ (ppm) 202.7, 140.4, 139.1, 134.8, 128.0, 126.6, 126.3, 42.5, 41.7, 36.9, 32.7, 31.5, 27.2, 21.9, 21.6, 21.1, 14.4.

[0174] HRMS-ESI: Calculated [M+Na] + :267.1719,found:267.1716.

[0175] [α] 25 D = +16 (c = 0.5, CHCl3).

[0176] The structure of intermediate 8 is shown below:

[0177]

[0178] S9. Synthesis of the target compound

[0179] In a dry 5 mL round-bottom flask, diisopropyltriphenylphosphine was added... Iodide (43 mg, 0.01 mmol, 4.0 equivalent) was dissolved in anhydrous THF (10 mL), and KHMDS (88 μL, 0.01 mmol, 4.0 equivalent, 1.0 M toluene solution) was slowly added. After stirring for 5 min, a THF solution (7 mL) of intermediate 8 (6 mg, 0.025 mmol, 1.0 equivalent) obtained in step S8 was added, followed by stirring overnight (12 h) at room temperature. The reaction system was quenched with saturated ammonium chloride aqueous solution (4 mL) and then extracted with ethyl acetate (3 × 5 mL). The organic layer was washed successively with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil was purified by rapid column chromatography (PE / EA = 200:1) to give a colorless oil, namely the target compound (+)-erogorgiaene (2.0 mg, 30% yield of steps S8 and S9).

[0180] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.13 (d, J = 7.8Hz, 1H), 7.02 (s, 1H), 6.94 (d, J = 7.6Hz, 1H), 5.17(t,J=6.5Hz,1H),2.91–2.84(m,1H),2.77–2.68(m,1H),2.30(s,3H),2.20–1.98(m ,2H),1.97–1.87(m,1H),1.86–1.76(m,1H),1.72(s,3H),1.64(s,3H),1.59–1.50(m,1 H),1.50–1.40(m,1H),1.38–1.29(m,2H),1.26(d,J=6.8Hz,3H),0.64(d,J=6.8Hz,3H). 13C NMR (151MHz, CDCl3) δ (ppm) 140.4, 139.9, 134.7, 131.3, 128.1, 126.4, 126.0, 124.9,41.5,37.0,35.2,32.8,31.8,26.3,25.8,21.9,21.5,21.2,17.7,14.5.

[0181] HRMS-ESI: Calculated [M+Na] + :293.2240,found:293.2237.

[0182] [α] 25 D =+9(c=2.0,CHCl3).

[0183] The chemical name of the target compound is as follows: (1S,4R)-1,6-dimethyl-4-(6-methylhept-5-en-2-yl)-1,2,3,4-tetrahydronaphthalene,(+)-erogorgiaene, and its structure is shown below:

[0184]

[0185] Example 3: Effect of different basic reagents on the synthesis of intermediate 1

[0186] The only difference from step S1 in Example 2 is that the type and / or amount of sodium tert-butoxide (11.5 mg, 0.12 mmol, 0.8 eq) is changed (see Table 1), the stirring reaction time is 12 h, and other parameters and conditions are the same as in step S1.

[0187] Table 1 Effects of different basic reagents on the synthesis of intermediate 1

[0188]

[0189] Note: Yield passed 1 H NMR was performed, with CH2Br2 used as an internal standard.

[0190] As shown in Table 1, intermediate 1 can be synthesized using basic reagents, including sodium tert-butoxide and sodium hydride, with high yields (≥56%) and Ee (≥89%).

[0191] Example 4: Effect of different solvents on the synthesis of intermediate 1

[0192] The only difference from step S1 in Example 2 is that the type and / or amount of PhCF3 is changed (see Table 2), the stirring reaction time is 12h, and other parameters and conditions are the same as in step S1.

[0193] Table 2 Effects of different solvents on the synthesis of intermediate 1

[0194]

[0195] As shown in Table 2, intermediate 1 can be synthesized using organic solvents including toluene, trifluorotoluene, chlorobenzene and n-hexane, with high yields (≥15%) and Ee (≥67%). Trifluorotoluene, in particular, has the best yield and Ee.

[0196] In summary, this invention is the first to use readily available and inexpensive naphthalene bromide as a starting material, utilizes palladium catalyst to achieve bifunctionalization of naphthalene, employs a self-made TADDOL-type chiral ligand to achieve the desired asymmetric catalysis, and utilizes modern chemistry such as photoreaction to achieve side chain mounting and functional group modification. Finally, the synthesis of (+)-Erogorgiaene was completed in 9 steps. The above synthetic method does not require the prior preparation of other complex fragments, the reagents involved are simple and readily available, the reaction conditions are mild, the reaction conversion rate is good, and the overall route is concise and efficient, suitable for industrial-scale kilogram-scale production of (+)-Erogorgiaene.

[0197] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A chiral ligand L, characterized in that, The chiral ligand L has the following structure:

2. The method for preparing the chiral ligand L according to claim 1, characterized in that, The process includes the following steps: Compounds sm1, sm2, and sm3 are mixed in the presence of an organic solvent and an organic amine, and then reacted thoroughly at room temperature until the reaction is complete. After post-treatment, the chiral ligand L is obtained. Preferably, the organic solvent is selected from one or more of tetrahydrofuran, toluene, trichloroethane, and dichloromethane; Preferably, the organic amine is selected from one or more of triethylamine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, diisopropylethylamine, and pyridine.

3. The use of the chiral ligand L of claim 1 in the preparation of (+)-Erogorgiaene.

4. A method for synthesizing (+)-Erogorgiaene, characterized in that, Includes the following steps: S1. 6-Methyl-1-bromonaphthalene, diethylmethylmalonate, palladium catalyst, chiral ligand L as described in claim 1, first basic reagent and trimethylsilyl diazomethane are added to a first organic solvent and reacted fully at 40-70°C. After post-treatment, intermediate 1 is obtained. S2. Dissolve intermediate 1 obtained in step S1 in a second organic solvent, add Crabtree catalyst, react fully under hydrogen atmosphere, and then perform post-treatment to obtain intermediate 2. S3. Dissolve intermediate 2 obtained in step S2 in a third organic solvent, add fluorinating agent, react fully at 50-70°C, and then process to obtain intermediate 3. S4. Under ice bath conditions, intermediate 3 obtained in step S3 is dissolved in a mixture of organic solvent and water, a second alkaline reagent is added, and after thorough mixing, m-chloroperoxybenzoic acid is added, and the mixture is allowed to react fully. After post-treatment, intermediate 4 is obtained. S5. Dissolve intermediate 4 obtained in step S4 in a fourth organic solvent, add palladium catalyst and organic amine, react fully under hydrogen atmosphere, and then process to obtain intermediate 5. S6. Dissolve intermediate 5 obtained in step S5 in the fifth organic solvent, add sodium hydride, carbon disulfide and iodomethane in sequence, react fully at room temperature, and then process to obtain intermediate 6. S7. Dissolve intermediate 6, 10-phenylphenthiazide, Zn(CHO2)2, and sodium 2-mercaptoethanesulfonate obtained in step S6 in dimethyl sulfoxide, add formic acid, mix evenly under a protective gas atmosphere, react fully under 365-450 nm light irradiation, and then perform post-treatment to obtain intermediate 7. S8. Dissolve intermediate 7 obtained in step S7 in an alcohol reagent, add a third basic reagent, react fully under reflux conditions, and then process to obtain crude product 8'; dissolve the obtained crude product 8', tetrabutylammonium tetrachloroferrate, copper hexafluorophosphate, 1,4-diazidobicyclo[2.2.2]octane and acrolein in dichloromethane, react fully under a protective gas atmosphere and irradiation at 365-450 nm, and then process to obtain intermediate 8; S9, diisopropyltriphenylphosphine The iodide was dissolved in the sixth organic solvent, and the fourth basic reagent was added. After mixing, the sixth organic solvent solution containing intermediate 8 obtained in step S8 was added. The mixture was allowed to react completely at room temperature, followed by post-treatment to obtain the target compound. Preferably, in step S1, the first alkaline reagent is selected from one or two of sodium tert-butoxide and sodium hydride; Preferably, in step S1 or S5, the palladium catalyst is selected from divalent palladium catalysts, zero-valent palladium catalysts, or supported palladium catalysts; preferably, the divalent palladium catalyst is selected from one or more of palladium acetate, palladium chloride, and palladium trifluoroacetate; preferably, the zero-valent palladium catalyst is selected from one or more of tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, tris(dibenzylacetone)dipalladium, and bis(tri-tert-butylphosphine)palladium; preferably, the supported palladium catalyst is selected from one or two of palladium on carbon and palladium hydroxide on carbon. Preferably, in step S3, the fluorinating agent is selected from one or more of 30% to 50% hydrofluoric acid, tetrabutylammonium fluoride, and potassium fluoride; Preferably, in step S4, the second alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide; Preferably, in step S5, the organic amine is selected from one or more of 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and triethylamine; Preferably, in step S8, the third alkaline reagent is selected from one or more of potassium hydroxide, sodium hydroxide, and lithium hydroxide; Preferably, in step S9, the fourth alkaline reagent is selected from one or more of bis(trimethylsilyl)aminopotassium, potassium hydroxide, and sodium hydroxide.

5. The preparation method according to claim 4, characterized in that, In step S1, the first organic solvent is selected from one or more of trifluorotoluene, toluene, chlorobenzene, and n-hexane.

6. The preparation method according to claim 4, characterized in that, In step S2, the second organic solvent is selected from one or more of dichloromethane, methanol, and ethyl acetate.

7. The preparation method according to claim 4, characterized in that, In steps S3, S5, S6, and S9, the third organic solvent, the fifth organic solvent, and the sixth organic solvent are each independently selected from one or more of tetrahydrofuran, diethyl ether, toluene, n-hexane, and anisole.

8. The preparation method according to claim 4, characterized in that, In step S4, the organic solvent in the organic solvent-water mixture is selected from one or more of dichloromethane, toluene, or diethyl ether.

9. The preparation method according to claim 4, characterized in that, In step S4, the fourth organic solvent is selected from one or more of ethanol, dichloromethane, tetrahydrofuran, and toluene.

10. The preparation method according to claim 4, characterized in that, In step S8, the alcohol reagent is selected from one or more of methanol, ethanol, propanol, and butanol.

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