Synthetic method of atractylenolide synthesis intermediate, atractylenolide and atractylenolide derivative

Abstract

The invention discloses a atractylenolide synthesis intermediate and a synthesis method of atractylenolide and a derivative thereof, and the method comprises the following steps: oxidizing methyl in a compound 17 to prepare a compound 18; preparing a compound 19 from the compound 18 under the action of a Grubbs catalyst; carrying out hydrogenation reduction on the compound 19 to prepare a compound 20; dehydrating and eliminating the compound 20 to obtain a compound 21; hydrolyzing the compound 21 to obtain a compound 22; according to the invention, asymmetric total synthesis of atractylone, 13 kinds of eudecane atractylenolides and lactam natural products is finally realized, the technical bottleneck of chiral control of the compounds is broken through for the first time, the convergent design has both step economy and derivative universality, and especially, the type of a nucleophilic reagent is changed by a system, so that the method is suitable for industrial production. And derivative libraries with various structures are successfully constructed.

Description

Technical Field

[0001] This invention relates to the field of natural product synthesis technology, specifically to a method for synthesizing atractylodes lactone synthesis intermediates, atractylodes lactone and its derivatives. Background Technology

[0002] The traditional Chinese medicine Atractylodes macrocephalae Rhizoma is the dried rhizome of the plant Atractylodes macrocephala Koidz, belonging to the Asteraceae family. The *Shennong Bencao Jing* (Shennong's Classic of Materia Medica) lists it as a superior-grade herb, stating that it has the effects of strengthening the spleen and replenishing qi, drying dampness and promoting diuresis, stopping sweating, and calming the fetus. It is suitable for symptoms such as poor appetite, loose stools, abdominal distension, fatigue, and edema caused by qi deficiency, spleen deficiency, and impaired digestion. Modern pharmacological studies have shown that Atractylodes macrocephala has various physiological activities, including diuresis, hypoglycemia, vasodilation, antibacterial, anti-inflammatory, and antitumor effects.

[0003] As is well known, chemical components are the material basis for the efficacy of traditional Chinese medicine. The main chemical component of Atractylodes macrocephala is its volatile oil, which accounts for 1.4% of its composition. It is yellow, viscous, and has an aroma. With the improvement of detection technology and the optimization of extraction processes, more and more components have been separated from the volatile oil of Atractylodes macrocephala. Among these, atractylone and atractylolactone series components have been the most discussed. Numerous studies have shown that atractylone has the highest content in the volatile oil of Atractylodes macrocephala, reaching over 50%, and is considered one of the main effective components. However, atractylone is unstable; its furan ring structure is highly susceptible to chemical transformation in air, mainly converting into atractylolactone compounds. This transformation process not only reduces its irritant effect but also increases its pharmacological efficacy. For a long time, there have been many reports on the chemical components of Atractylodes macrocephala both domestically and internationally. In addition to atractylone, many natural products have been identified, including more than thirty natural molecules such as atractylolactone and atractylamide natural products! Most sesquiterpenoids in Atractylodes macrocephala possess excellent biological activities. Among them, atractylodes lactones are the most studied compounds in this category, exhibiting various biological activities such as neuroprotection, anti-allergy, anti-inflammation, and anti-cancer effects. Regarding target research, in 2021, Professor Ji Guang of the Institute of Spleen and Stomach Diseases at Longhua Hospital affiliated with Shanghai University of Traditional Chinese Medicine and Professor Huang Cheng of the School of Traditional Chinese Medicine at Shanghai University of Traditional Chinese Medicine revealed the target and mechanism of atractylodes lactone I in treating colorectal cancer; in 2022, Professor Bai Gang's team at the School of Pharmacy, Nankai University, revealed the target and mechanism of atractylodes lactone I in treating hyperaldosteronism; also in 2022, the team of Zheng Shizhong / Zhang Feng at the School of Pharmacy, Nanjing University of Traditional Chinese Medicine, revealed the mechanism and direct target of atractylodes lactone III in improving liver fibrosis; and in 2023, the team of Li Ping / Yang Hua / Zheng Zuguo at China Pharmaceutical University revealed the mechanism and direct target of atractylodes lactone II in improving obesity-induced insulin resistance. In addition, the structurally unique dimeric taenialactam has a highly effective blood pressure lowering effect; Taenialactam A and Taenialactam B have anti-renal, anti-nerve, and anti-cardiovascular damage effects, and therefore both have the potential to be developed into drugs for anti-renal, anti-nerve, or anti-cardiovascular damage.

[0004] Despite the unique structures and broad bioactivities of these natural products extracted from Atractylodes macrocephala, there are few reports on their total synthesis. Therefore, there is an urgent need to achieve the total synthesis of atractylodes lactones (or lactams) through total synthesis, while simultaneously promoting a comprehensive exploration of the chemical space surrounding their parent nucleus. Surprisingly, although the first synthesis was completed nearly fifty years ago, research on the synthesis of atractylodes lactones (or lactams) has remained sporadic and limited. In 1966, Minato and Nagasaki's team first successfully synthesized atractylone and atractylodes lactone II using α-tetrahydronaphthone precursor as the starting material, with a total of 20 reaction steps. In 1985, Honan also completed the synthesis of atractylone using α-tetrahydronaphthone as the starting material, with a total of 14 reaction steps. In 2003, Baldwin's team followed a modified / simplified route of Minato's scheme and also achieved the synthesis of atractylodes lactone I–III using α-tetrahydronaphthone as the starting material, with a total of 12 reaction steps. In 2015, Ramesh and Mehta developed a "cluster-style" synthesis strategy using Hagemann's ester as the starting material, and achieved the total synthesis of seven atractylodes lactone natural products through key steps such as ring-closing metathesis (RCM), with reaction steps ranging from 9 to 12.

[0005] In summary, the synthetic strategies outlined above reveal that the α-tetrahydronaphthone route pioneered by Minato and Nagasaki (1966) and its subsequent improvements (Honan, 1985; Baldwin et al., 2003) did not involve chiral control, only yielding racemic products. Furthermore, they were limited by specific precursor structures, hindering the construction of diverse chiral analogs, and were characterized by long synthetic steps and low efficiency. While Ramesh and Mehta (2015) achieved breakthroughs in the "cluster-based" synthetic strategy in terms of step economy and diversity, their synthetic routes remain limited to racemic preparation, failing to address the fundamental issue of absolute stereochemical construction of this type of natural product. This, to some extent, restricts their application potential in chiral drug development and stereostructure-activity relationship studies.

[0006] Therefore, the efficient realization of divergent, stereoselective total synthesis of such natural products has great scientific and market value. Summary of the Invention

[0007] This application is made in view of the above-mentioned issues, and its purpose is to provide a method for synthesizing atractylodes lactone synthesis intermediates; the method can be used to stereoselectively synthesize atractylodes lactone.

[0008] Specifically, the first aspect of this application provides a method for synthesizing a synthetic intermediate of atractylodes lactone, comprising the following steps: Compound 18 was prepared by oxidizing and then reducing the methyl group in compound 17. Compound 18 was prepared into compound 19 under the action of Grubb catalyst; Compound 19 was reduced with hydrogen to obtain compound 20; Compound 20 was dehydrated to obtain compound 21; Compound 21 was hydrolyzed to obtain compound 22.

[0009] According to some embodiments of this application, the methyl oxidation employs a peroxide / selenium dioxide system.

[0010] According to some embodiments of this application, the peroxide includes at least one of hydrogen peroxide, m-chloroperoxybenzoic acid, and tert-butylhydrogen peroxide.

[0011] According to some embodiments of this application, the molar ratio of compound 17 to peroxide is 1:1.8~2.2.

[0012] According to some embodiments of this application, the molar ratio of compound 17 to tert-butyl hydroperoxide is 1:1.8~2.2.

[0013] According to some embodiments of this application, the molar ratio of compound 17 to selenium dioxide is 1:0.4~0.6.

[0014] According to some embodiments of this application, the tert-butyl hydroperoxide and selenium dioxide are added at -4°C to 0°C.

[0015] According to some embodiments of this application, the temperature for methyl oxidation is 20°C to 30°C.

[0016] According to some embodiments of this application, the methyl oxidation time is 2h to 10h.

[0017] According to some embodiments of this application, after the methyl oxidation is completed, the reaction is quenched with a saturated sodium thiosulfate aqueous solution, and the organic phase is collected after separation, extraction, and drying.

[0018] According to some embodiments of this application, the crude product is obtained after oxidation of the peroxide / selenium dioxide system.

[0019] According to some embodiments of this application, the crude product is obtained after oxidation of the tert-butyl hydrogen peroxide / selenium dioxide system.

[0020] According to some embodiments of this application, the crude product, cerium chloride, and borohydride are mixed and then subjected to a reduction reaction.

[0021] According to some embodiments of this application, the borohydride includes at least one of lithium borohydride, sodium borohydride, and potassium borohydride.

[0022] According to some embodiments of this application, the molar ratio of compound 17 to cerium chloride is 1:1.8~2.2.

[0023] According to some embodiments of this application, the molar ratio of compound 17 to borohydride is 1:1 to 2.

[0024] According to some embodiments of this application, the molar ratio of compound 17 to sodium borohydride is 1:1 to 2.

[0025] According to some embodiments of this application, the temperature of the reduction reaction of the crude product is -80℃ to -70℃.

[0026] According to some embodiments of this application, the reduction reaction time of the crude product is 0.5h to 1h.

[0027] According to some embodiments of this application, the reduction reaction is quenched with a saturated ammonium chloride aqueous solution after completion.

[0028] According to some embodiments of this application, the Grubbs catalyst is at least one of a first-generation Grubbs catalyst and a second-generation Grubbs catalyst.

[0029] According to some embodiments of this application, the molar ratio of compound 18 to the Grubb catalyst is 1:0.05~0.15.

[0030] According to some embodiments of this application, the reaction is carried out under the action of the Grubb catalyst.

[0031] According to some embodiments of this application, the reflux reaction time is 30°C to 50°C.

[0032] According to some embodiments of this application, the reaction time of the Grubb catalyst is 2h to 10h.

[0033] According to some embodiments of this application, the methyl oxidation, reduction, Grubb catalysis, hydrogenation reduction, dehydration elimination, and hydrolysis are carried out in the liquid phase.

[0034] According to some embodiments of this application, the liquid phase includes at least one of an aqueous phase and an organic phase.

[0035] According to some embodiments of this application, the methyl oxidation is carried out in an organic phase.

[0036] According to some embodiments of this application, the Grubb catalyst acts in an organic phase.

[0037] According to some embodiments of this application, the hydrogenation reduction is carried out in an organic phase.

[0038] According to some embodiments of this application, the dehydration is carried out in the organic phase.

[0039] According to some embodiments of this application, the hydrolysis is carried out in an organic phase.

[0040] According to some embodiments of this application, the organic phase includes at least one selected from dichloromethane, methanol, ethanol, N,N-dimethylformamide, and acetone.

[0041] According to some embodiments of this application, the catalyst for hydrogenation reduction is a noble metal oxide and a Pt / C catalyst.

[0042] According to some embodiments of this application, the noble metal oxide includes platinum oxide.

[0043] According to some embodiments of this application, the platinum oxide is platinum dioxide.

[0044] According to some embodiments of this application, the Pt loading in the Pt / C catalyst is 0.5wt% to 60wt%.

[0045] According to some embodiments of this application, the molar ratio of compound 19 to noble metal oxide is 1:0.05~0.15.

[0046] According to some embodiments of this application, the temperature of the hydrogenation reduction is 20°C to 30°C.

[0047] According to some embodiments of this application, the pressure of the hydrogenation reduction is 100 kPa to 120 kPa.

[0048] According to some embodiments of this application, the hydrogenation reduction time is 10h to 100h.

[0049] According to some embodiments of this application, the dehydration elimination includes a first step reaction and a second step reaction.

[0050] According to some embodiments of this application, the first step reaction involves the addition of a base, a sulfonating agent, and a pyridine catalyst.

[0051] According to some embodiments of this application, the base includes triethylamine.

[0052] According to some embodiments of this application, the sulfonating agent includes p-toluenesulfonyl chloride.

[0053] According to some embodiments of this application, the pyridine catalyst includes at least one of 4-dimethylaminopyridine and 4-(3-methylpyrrole)-pyridine.

[0054] According to some embodiments of this application, the addition temperature of the alkali, sulfonating agent and pyridine catalyst is -4℃ to 0℃.

[0055] According to some embodiments of this application, the molar ratio of compound 20 to base is 1:5 to 15.

[0056] According to some embodiments of this application, the molar ratio of compound 20 to the sulfonating agent is 1:2~5.

[0057] According to some embodiments of this application, the molar ratio of compound 20 to pyridine catalyst is 1:0.2~0.8.

[0058] According to some embodiments of this application, the temperature of the first step reaction is 20°C to 30°C.

[0059] According to some embodiments of this application, the reaction time of the first step is 1 hour to 10 hours.

[0060] According to some embodiments of this application, the first step reaction is quenched with a saturated sodium bicarbonate aqueous solution.

[0061] According to some embodiments of this application, the solid phase is collected after the first step reaction.

[0062] According to some embodiments of this application, the second step reaction involves the addition of iodine salt and 1,8-dioctyl-1,3,6,8-tetraazacyclododecane.

[0063] According to some embodiments of this application, the iodized salt includes sodium iodide or potassium iodide.

[0064] According to some embodiments of this application, the molar ratio of the solid phase to the iodine salt is 1:4~10.

[0065] According to some embodiments of this application, the molar ratio of the solid phase to 1,8-dioctyl-1,3,6,8-tetraazacyclododecane is 1:2~5.

[0066] According to some embodiments of this application, the temperature of the second step reaction is 80°C to 100°C.

[0067] According to some embodiments of this application, the reaction time for the second step is 10h to 30h.

[0068] According to some embodiments of this application, the reaction is quenched with a saturated sodium bicarbonate solution after the second step reaction.

[0069] According to some embodiments of this application, the hydrolysis involves the addition of a protic acid.

[0070] According to some embodiments of this application, the molar ratio of compound 21 to protic acid is 1:0.4~0.6.

[0071] According to some embodiments of this application, the protic acid includes at least one of p-toluenesulfonic acid, sulfuric acid, and hydrogen halide.

[0072] According to some embodiments of this application, the hydrogen halide includes at least one of hydrogen chloride, hydrogen bromide, and hydrogen iodide.

[0073] According to some embodiments of this application, the hydrolysis temperature is 20°C to 30°C.

[0074] According to some embodiments of this application, the hydrolysis time is 3h to 5h.

[0075] According to some embodiments of this application, the reaction is quenched with a saturated sodium bicarbonate solution after hydrolysis.

[0076] According to some embodiments of this application, the method for synthesizing compound 17 includes the following steps: , According to some embodiments of this application, compound 15 undergoes addition reaction after treatment with Grignard reagent and cuprous iodide to obtain compound 16.

[0077] According to some embodiments of this application, the Grignard reagent is 3-butenyl magnesium bromide.

[0078] According to some embodiments of this application, compound 16, acetic anhydride, and boron trifluoride diethyl ether are mixed and reacted to obtain an oily compound.

[0079] According to some embodiments of this application, the oily compound, ethylene glycol, trimethyl orthoformate and p-toluenesulfonic acid are mixed and reacted to obtain compound 17.

[0080] A second aspect of this application provides a method for synthesizing atractylodes lactone, comprising at least one of the following reactions (a) to (b): (a) ; (b) ; Atractylodes lactone was prepared using compound 22 as a raw material; The atractylodes lactones include atractylodes lactone (I) and atractylodes lactone (II); Compound 22 was prepared using the synthetic method described in the first aspect of this application.

[0081] According to some embodiments of this application, compound 22 is subjected to γ-lactoneation to obtain atractylodes lactone.

[0082] According to some embodiments of this application, the γ-lactoneation is carried out in the form of titanium tetrachloride.

[0083] According to some embodiments of this application, the preparation method of the atractylodes lactone (I) includes the following steps: The compound 22, base, titanium tetrachloride, methyl pyruvate, and organic solvent are mixed and reacted.

[0084] According to some embodiments of this application, the preparation method of the atractylodes lactone (II) includes the following steps: The compound 22, base, titanium tetrachloride, 1,1-dimethoxyacetone and organic solvent are mixed and reacted.

[0085] According to some embodiments of this application, the molar ratio of compound 22 to base is 1:2~5.

[0086] According to some embodiments of this application, the molar ratio of compound 22 to titanium tetrachloride is 1:1 to 2.

[0087] According to some embodiments of this application, the molar ratio of compound 22 to methyl pyruvate is 1:1.8~2.2.

[0088] According to some embodiments of this application, the initial temperature of the reaction is -80°C to -70°C.

[0089] According to some embodiments of this application, the reaction is carried out by raising the initial temperature to 20°C~30°C and then reacting for 20h~30h.

[0090] According to some embodiments of this application, the base includes triethylamine.

[0091] According to some embodiments of this application, the reaction is quenched with water after completion.

[0092] A third aspect of this application provides a method for preparing atractylodes lactone derivatives, comprising at least one of the following reactions (a) to (k): (a) ; (b) ; (c) ; (d) ; (e) ; (f) ; (g) ; (h) ; (i) ; (j) ; (k) ; Atractylodes lactone (I) and atractylodes lactone (II) were both prepared independently using the synthesis method of the second method of this application.

[0093] According to some embodiments of this application, reaction (a) includes the following steps: Compound 4 was prepared by reacting atractylodes lactone (I), ammonia, and an organic solvent.

[0094] According to some embodiments of this application, the temperature of reaction (a) is 110°C to 130°C.

[0095] According to some embodiments of this application, the reaction (a) takes 20h to 30h.

[0096] According to some embodiments of this application, the molar volume ratio of atractylodes lactone (I) to ammonia is 1 mmol: 6 mL to 15 mL.

[0097] According to some embodiments of this application, the mass fraction of the ammonia water is 20% to 30%.

[0098] According to some embodiments of this application, reaction (b) includes the following steps: Compound 5 was prepared by reacting a mixture of compound 4, a protic acid, and an organic solvent.

[0099] According to some embodiments of this application, the temperature of reaction (b) is 20°C to 30°C.

[0100] According to some embodiments of this application, the reaction (b) takes 10h to 20h.

[0101] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to protic acid is 1:0.3~1.

[0102] According to some embodiments of this application, reaction (c) includes the following steps: Compound 7 was prepared by mixing atractylodes lactone (I) with an organic solvent and then reacting it under light.

[0103] According to some embodiments of this application, the temperature of the reaction (c) is 20°C to 30°C.

[0104] According to some embodiments of this application, the reaction (c) takes 20h to 30h.

[0105] According to some embodiments of this application, the photoreaction is carried out under mercury lamp irradiation.

[0106] According to some embodiments of this application, the power of the mercury lamp is 100W~150W.

[0107] According to some embodiments of this application, reaction (d) includes the following steps: Compound 3 was prepared by reacting atractylodes lactone (I), 1,8-dioctyl-1,3,6,8-tetraazacyclododecane (DBU), water, and an organic solvent.

[0108] According to some embodiments of this application, the temperature of the reaction (d) is 20°C to 30°C.

[0109] According to some embodiments of this application, the reaction (d) time is 20h~30h.

[0110] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to 1,8-dioctyl-1,3,6,8-tetraazacyclododecane is 1:4~10.

[0111] According to some embodiments of this application, the mass-to-volume ratio of atractylodes lactone (I) to water is 1g:20mL~30mL.

[0112] According to some embodiments of this application, reaction (e) includes the following steps: Compound 8 was prepared by reacting atractylodes lactone (I), 1,8-dioctyl-1,3,6,8-tetraazacyclododecane, and an organic solvent.

[0113] According to some embodiments of this application, the temperature of the reaction (e) is 20°C to 30°C.

[0114] According to some embodiments of this application, the reaction (e) takes 20h to 30h.

[0115] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to 1,8-dioctyl-1,3,6,8-tetraazacyclododecane is 1:4~10.

[0116] According to some embodiments of this application, reaction (f) includes the following steps: Atractylodes lactone (I), ethanolamine and organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product. The intermediate product, protic acid, and organic solvent were mixed and then reacted in the second step to obtain compound 9.

[0117] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to ethanolamine is 1:9~11.

[0118] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to protic acid is 1:0.4~0.6.

[0119] According to some embodiments of this application, the temperature of the first step reaction in reaction (f) is 110°C to 130°C.

[0120] According to some embodiments of this application, the reaction time of the first step in reaction (f) is 20h~30h.

[0121] According to some embodiments of this application, the temperature of the second step reaction in reaction (f) is 20°C to 30°C.

[0122] According to some embodiments of this application, the reaction time of the second step in reaction (f) is 10h to 20h.

[0123] According to some embodiments of this application, reaction (g) includes the following steps: Atractylodes lactone (I), ethylamine and organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product. The intermediate product, protic acid, and organic solvent were mixed and reacted in the second step to obtain compound 10.

[0124] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to ethylamine is 1:9~11.

[0125] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to protic acid is 1:0.4~0.6.

[0126] According to some embodiments of this application, the temperature of the first step reaction in the reaction (g) is 110°C to 130°C.

[0127] According to some embodiments of this application, the reaction time of the first step in reaction (g) is 20h to 30h.

[0128] According to some embodiments of this application, the temperature of the second step reaction in reaction (g) is 20°C to 30°C.

[0129] According to some embodiments of this application, the reaction time of the second step in reaction (g) is 10h to 20h.

[0130] According to some embodiments of this application, reaction (h) includes the following steps: Atractylodes lactone (I), phenylethylamine and organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product; The intermediate product, protic acid, and organic solvent were mixed and reacted in the second step to obtain compound 11.

[0131] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to phenylethylamine is 1:4~11.

[0132] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to protic acid is 1:0.4~0.6.

[0133] According to some embodiments of this application, the temperature of the first step reaction in the reaction (h) is 110°C to 130°C.

[0134] According to some embodiments of this application, the reaction time of the first step in the reaction (h) is 20h~30h.

[0135] According to some embodiments of this application, the temperature of the second step reaction in reaction (h) is 20°C to 30°C.

[0136] According to some embodiments of this application, the reaction time of the second step in the reaction (h) is 10h to 20h.

[0137] According to some embodiments of this application, reaction (h) includes the following steps: Atractylodes lactone (I), 4-hydroxyphenylethylamine and an organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product. The intermediate product, protic acid, and organic solvent were mixed and reacted in the second step to obtain compound 12.

[0138] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to 4-hydroxyphenylethylamine is 1:4~11.

[0139] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to protic acid is 1:0.4~0.6.

[0140] According to some embodiments of this application, the temperature of the first step reaction in the reaction (h) is 110°C to 130°C.

[0141] According to some embodiments of this application, the reaction time of the first step in the reaction (h) is 20h~30h.

[0142] According to some embodiments of this application, the temperature of the second step reaction in reaction (h) is 20°C to 30°C.

[0143] According to some embodiments of this application, the reaction time of the second step in the reaction (h) is 10h to 20h.

[0144] According to some embodiments of this application, reaction (i) includes the following steps: Compound 13 was prepared by reacting atractylodes lactone (I), 4-aminobutyric acid, 1,8-dioctyl-1,3,6,8-tetraazacyclododecane and an organic solvent.

[0145] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to 4-aminobutyric acid is 1:4~11.

[0146] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to 1,8-dioctyl-1,3,6,8-tetraazacyclododecane is 1:5~10.

[0147] According to some embodiments of this application, the temperature of the reaction (i) is 110°C to 130°C.

[0148] According to some embodiments of this application, the reaction (i) takes 20h to 30h.

[0149] According to some embodiments of this application, reaction (j) includes the following steps: Atractylodes lactone (I), tryptophan and organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product. The intermediate product, protic acid, and organic solvent were mixed and then reacted in the second step to obtain compound 14.

[0150] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to tryptophan is 1:4~11.

[0151] According to some embodiments of this application, the molar ratio of atractylodes lactone (I) to protic acid is 1:0.4~0.6.

[0152] According to some embodiments of this application, the temperature of the first step reaction in reaction (j) is 110°C to 130°C.

[0153] According to some embodiments of this application, the reaction time of the first step in reaction (j) is 20h~30h.

[0154] According to some embodiments of this application, the temperature of the second step reaction in reaction (j) is 20°C to 30°C.

[0155] According to some embodiments of this application, the reaction time of the second step in reaction (j) is 10h to 20h.

[0156] According to some embodiments of this application, reaction (k) includes the following steps: Compound 6 was prepared by reacting atractylodes lactone (II), diisobutylaluminum hydride, dilute sulfuric acid, and an organic solvent.

[0157] According to some embodiments of this application, the temperature of the reaction (k) is -5°C to 5°C.

[0158] According to some embodiments of this application, the reaction (k) time is 0.2h to 1h.

[0159] According to some embodiments of this application, the molar ratio of atractylodes lactone (II) and diisobutylaluminum hydride is 1:1.8~2.2.

[0160] According to some embodiments of this application, the mass fraction of the dilute sulfuric acid is 8% to 12%.

[0161] According to some embodiments of this application, the molar volume ratio of atractylodes lactone (II) to dilute sulfuric acid is 1 mmol: 5 mL to 10 mL.

[0162] According to some embodiments of this application, the reaction is quenched with a saturated sodium bicarbonate aqueous solution or water after completion.

[0163] According to some embodiments of this application, the organic solvent in the reaction includes at least one of tetrahydrofuran, n-hexane, and methanol.

[0164] According to some embodiments of this application, the protic acid includes at least one of p-toluenesulfonic acid, sulfuric acid, and hydrogen halide.

[0165] According to some embodiments of this application, the hydrogen halide includes at least one of hydrogen chloride, hydrogen bromide, and hydrogen iodide.

[0166] According to some embodiments of this application, the reaction is purified after completion.

[0167] According to some embodiments of this application, the purification process includes at least one of extraction, liquid-liquid separation, drying, solid-liquid separation, concentration, and chromatography.

[0168] According to one of the technical solutions of the synthesis method in this application, at least the following beneficial effects are achieved: This application provides a novel asymmetric total synthesis method for eucalyptane-type natural products and their derivatives. The method uses a natural chiral source (+)-verbenone as the starting material, constructs a quaternary carbon chiral center through stereoselective 1,4-conjugated addition, constructs a bicyclic [4.4.0]decane core skeleton via boron trifluoride-mediated ring-opening acetylation, and then efficiently constructs a universal chiral intermediate 22 through key steps such as a Grubbs II-catalyzed ring-closure olefin metathesis reaction (RCM).

[0169] Based on this, a regioselective γ-lactone synthesis strategy mediated by TiCl4 was first employed to synthesize atractylodes lactone (I) and atractylodes lactone (II). Then, using atractylodes lactone (I) and atractylodes lactone (II) as key substrates, through diverse functional group transformations, changes in nucleophilic reagents (such as ammonia, various amines, amino acids, etc.) or the use of biomimetic strategies such as photocatalysis [2+2], 12 target natural products, including lactams, photochemical products, and reduction products, were efficiently constructed. This fully demonstrates the powerful ability of this method to achieve "functional group transformation of such natural products" and is of great value for understanding the biotransformation relationships among such natural products.

[0170] This application finally achieved the asymmetric total synthesis of atractylone and 13 eucalyptane-type atractylodes lactones and lactams, breaking through the technical bottleneck of chiral control of this type of compound for the first time. Its convergent design combines step economy and derivatization versatility. In particular, by systematically changing the type of nucleophile, a library of structurally diverse derivatives was successfully constructed.

[0171] This application provides an important material basis and technical platform for the development of chiral drugs based on eucalyptane-type natural products and the study of their structure-activity relationships. Attached Figure Description

[0172] To more clearly illustrate the technical solutions in the embodiments of this drawing or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this drawing. For those skilled in the art, other drawings can be obtained based on the structures shown in these drawings without creative effort.

[0173] Figure 1 Synthetic route for trans-6 / 6 cyclic key intermediate 22.

[0174] Figure 2 This provides a synthetic route for some atractylodes lactone (or lactam) natural products.

[0175] Figure 3 This is another route for the synthesis of atractylodes lactones (or lactams) and other natural products.

[0176] The purpose, features, and advantages of this accompanying drawing will be further explained in conjunction with the embodiments and with reference to the accompanying drawing. Detailed Implementation

[0177] To make the objectives, technical solutions, and advantages of this application clearer, the following description and illustration are provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application. All other embodiments obtained by those skilled in the art based on the embodiments provided in this application without inventive effort are within the scope of protection of this application.

[0178] Obviously, the following description is merely some examples or embodiments of this application. Those skilled in the art can apply this application to other similar scenarios without any inventive effort. Furthermore, it is understood that although the effort involved in such development may be complex and lengthy, for those skilled in the art related to the content disclosed in this application, any changes to design, manufacturing, or production based on the technical content disclosed in this application are merely conventional technical means and should not be construed as insufficient disclosure of the content of this application.

[0179] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0180] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0181] Example 1 This embodiment describes a method for preparing an intermediate in the synthesis of atractylodes lactone, which consists of the following steps: Synthetic descriptions of compounds 15, 16, and 17 Figure 1 Compound 15 is a commercially available reagent, and compounds 16 and 17 can be synthesized according to known literature (Chin. Org. Chem., 2015, 35, 2157~2161).

[0182] Synthetic description of compound 16 ( Figure 1 3-Butylmagnesium bromide (1.0 M in THF, 66.57 mL, 66.57 mmol) was added dropwise to 34 mL of a dry tetrahydrofuran suspension of cuprous iodide (3.17 g, 16.64 mmol) at -50 °C. The mixture was stirred at this temperature for 0.5 h, followed by the addition of 34 mL of a dry tetrahydrofuran solution of (+)-verbenone (15, 5.0 g, 33.28 mmol). The reaction was stirred continuously (TLC monitoring). After 2.5 h, the reaction was quenched by adding 25 mL of saturated ammonium chloride aqueous solution in an ice-water bath. The mixture was then concentrated under reduced pressure, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The mixture was extracted with ethyl acetate (3 x 25 mL) in aqueous phase. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 30:1] to give 6.66 g of yellow oily compound 16, yield 97%.

[0183] Synthetic description of compound 17 ( Figure 1 Compound 16 (20 g, 96.9 mmol) was dissolved in 138 mL of acetic anhydride and stirred at -20 °C for 0.5 h. Then, boron trifluoride diethyl ether (2.75 g, 2.4 mL, 19.4 mmol) was added dropwise at this temperature, and the reaction was naturally heated to room temperature with stirring (TLC monitoring). After 3 h, the reaction was quenched by adding saturated sodium bicarbonate aqueous solution in an ice-water bath. The aqueous phase was extracted with ethyl acetate (3 x 300 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 30:1] to give 23.1 g of a pale yellow oily compound, with a yield of 75%.

[0184] The above-mentioned pale yellow oily compound (22.3 g, 89.8 mmol) was dissolved in a mixed solution of ethylene glycol (27.5 g, 24.7 mL, 442.9 mol) and trimethyl orthoformate (47.0 g, 51.6 mL, 442.9 mol), cooled to 0 °C, and p-toluenesulfonic acid (7.7 g, 44.7 mmol) was weighed and added to the reaction system. The reaction was allowed to proceed naturally to room temperature (TLC monitoring). After 15 h, the reaction was quenched with 100 mL of saturated sodium carbonate aqueous solution in an ice-water bath. The aqueous phase was extracted with ethyl acetate (3 x 100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 50:1] to give 19.3 g of pale yellow oily compound 17, yield 86%.

[0185] The spectra of compounds 16 and 17 are consistent with those in reference Yu, Tianzi; Liu, Bo. Chin. J. Org. Chem. 2015, 35, 2157~2161.

[0186] Synthetic description of compound 18 ( Figure 1 Compound 17 (4.2 g, 16.8 mmol) was dissolved in dichloromethane (DCM, 120 mL). Tert-butyl hydroperoxide (6.47 M in CH2Cl2, 5.2 mL, 33.6 mmol) and selenium dioxide (930 mg, 8.4 mmol) were added at 0 °C. The reaction was stirred at room temperature (approximately 25 °C) (TLC monitoring). After 3 h, the reaction was quenched with 100 mL of saturated sodium thiosulfate aqueous solution in an ice-water bath. The mixture was separated, and the aqueous phase was extracted with dichloromethane (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5.4 g of crude reddish-brown oil.

[0187] The crude product was dissolved in a mixed solution of 60 mL dichloromethane and 60 mL methanol. Anhydrous cerium chloride (8.3 g, 33.6 mmol) was added at room temperature. The mixture was cooled to -78 °C, and sodium borohydride (955 mg, 25.2 mmol) was slowly added. After stirring for 40 min, the reaction was quenched with 60 mL of saturated ammonium chloride aqueous solution in an ice-water bath. The mixture was concentrated under reduced pressure, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The mixture was extracted with ethyl acetate (3 x 100 mL) in aqueous phase. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 5:1] to give 3.21 g of oily compound 18, yield 72%.

[0188] 1H NMR (600 MHz, CDCl3) δ 5.80~5.73 (m, 1H), 5.22 (d, J = 1.8 Hz 1H), 4.98 (dd, J = 25.2, 2.4 Hz, 1H), 4.93~4.90 (m, 2H), 4.11 (q, J = 22.2 Hz,2H), 3.99~3.96 (m, 2H), 3.91~3.87 (m, 2H), 2.05~1.98 (m, 2H), 1.94~1.88 (m,2H), 1.83~1.79 (m, 1H), 1.68~1.64 (m, 1H), 1.57~1.44 (m, 3H), 1.37~1.30 (m,1H), 1.26~1.16 (m, 1H), 1.01 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 150.7, 139.3, 114.2, 111.5, 109.1, 67.2,64.6, 63.6, 48.4, 45.3, 43.3, 37.7, 35.7, 27.8, 26.9, 19.8; HRMS (EI): m / z calcd for C 16 H 27 O3 + [M + H] + 267.1955 found 267.1958. Synthetic description of compound 19 ( Figure 1 Compound 18 (2.87 g, 10.77 mmol) was dissolved in 120 mL of anhydrous dichloromethane. A second-generation Grubbs catalyst (91 mg, 0.11 mmol) was added at room temperature. The mixture was heated to 40 °C and refluxed for 2 h. Heating was stopped and the mixture was cooled to room temperature. The mixture was filtered through diatomaceous earth. The filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 3:1] to give 2.81 g of yellow oily compound 19, with a yield of 98%.

[0189] 1H NMR (600 MHz, CDCl3) δ 5.63 (s, 1H), 4.10 (d, J = 12.6 Hz 1H), 4.00~3.97 (m, 3H), 3.89~3.86 (m, 2H), 2.16~2.05 (m, 3H), 1.92~1.89 (m, 2H), 1.66~1.64 (m, 1H), 1.57~1.55 (m, 1H), 1.48~1.46 (m, 1H), 1.44~1.42 (m, 1H), 1.40~1.37 (m, 2H), 0.94 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 137.8, 124.2, 109.1, 65.7, 64.5, 63.4, 47.9, 44.4, 37.9, 36.3, 33.5, 22.6, 21.2, 15.9; HRMS (EI): m / z calcd for C 14 H 23 O3 + [M + H] + 239.1642 found 239.1643. Synthetic description of compound 20 ( Figure 1 Compound 19 (2.32 g, 9.73 mmol) was dissolved in 200 mL of ethanol, and PtO2 (232 mg, 1.02 mmol) was added. The reaction was carried out at room temperature and atmospheric pressure under hydrogenation and bubbling conditions (TLC monitoring). After 72 h, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 3:1] to give 2.20 g of colorless viscous oil 20, with a yield of 94%.

[0190] 1 H NMR (600 MHz, CDCl3) δ 3.97~3.95 (m, 2H), 3.90~3.84 (m, 2H), 3.67~3.59 (m, 2H), 1.95~1.91 (m, 1H), 1.88~1.83 (m, 1H), 1.79~1.76 (m, 1H), 1.73~1.66 (m, 1H), 1.60~1.50 (m, 4H), 1.43~1.39 (m, 5H), 1.13~1.05 (m, 1H), 0.90(s, 3H); 13C NMR (150 MHz, CDCl3) δ 109.3, 64.5, 63.5, 61.5, 51.1, 46.9, 43.0,42.0, 36.6, 34.7, 28.0, 25.2, 19.7, 16.9; HRMS (EI): m / z calcd for C 14 H 25 O3 + [M + H] + 241.1798 found 241.1795. Synthetic description of compound 21 ( Figure 1 Compound 20 (3.0 g, 12.48 mmol) was dissolved in 45 mL of anhydrous dichloromethane. Triethylamine (12.60 g, 17.3 mL, 124.52 mmol), p-toluenesulfonyl chloride (TsCl, 7.14 g, 37.45 mmol), and 4-dimethylaminopyridine (762 mg, 6.24 mmol) were added at 0 °C. The reaction was stirred at room temperature (TLC monitoring). After 2 h, the reaction was quenched with 100 mL of saturated sodium bicarbonate solution in an ice-water bath. The mixture was extracted with dichloromethane (3 x 30 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 10:1] to give 4.18 g of white solid, yield 85%.

[0191] The above-mentioned white solid (4.12 g, 10.14 mmol) was dissolved in 80 mL of anhydrous N,N-dimethylformamide, and sodium iodide (7.60 g, 50.70 mmol) and 1,8-dioctyl-1,3,6,8-tetraazacyclododecane (4.63 g, 4.6 mL, 30.41 mmol) were added. The reaction was stirred in an oil bath at 90 °C (TLC monitoring). After 20 h, the mixture was cooled to room temperature, and the reaction was quenched with 100 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (3 x 100 mL) in the aqueous phase. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 10:1] to give 2.28 g of light brown oily substance 21, with a yield of 98%.

[0192] 1H NMR (600 MHz, CDCl3) δ 4.73~4.72 (m, 1H), 4.47~4.46 (m, 1H), 3.99~3.96 (m, 2H), 3.89~3.86 (m, 2H), 2.32~2.28 (m, 1H), 2.05~1.96 (m, 1H), 1.90~1.85 (m, 1H), 1.81~1.77 (m, 1H), 1.65~1.54 (m, 6H), 1.45~1.42 (m, 2H), 1.34~1.25 (m, 1H), 0.86 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 150.1, 109.1, 105.8, 64.54, 63.4, 49.6, 48.4, 42.2, 37.0, 36.7, 35.5, 22.8, 22.4, 16.7; HRMS (EI): m / z calcd for C 14 H 23 O2 + [M + H] + 223.1693 found 223.1695. Synthetic description of compound 22 ( Figure 1 ): Compound 21 (1.08 g, 4.86 mmol) was dissolved in 35 mL of acetone, and p-toluenesulfonic acid (418 mg, 2.43 mmol) was added under ice-water bath. The mixture was heated to room temperature and stirred (TLC monitoring). After 4 h, the reaction was quenched with 20 mL of saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (3 x 50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 20:1] to give 0.89 g of pale yellow oil 22, yield 100%.

[0193] 1H NMR (600 MHz, CDCl3) δ 4.83 (d, J = 2.4 Hz, 1H), 4.52 (d, J = 2.4Hz, 1H), 2.46~2.42 (m, 1H), 2.41~2.36 (m, 2H), 2.30~2.25 (m, 2H), 2.18~2.14(m, 1H), 2.11~2.06 (m, 1H), 2.03~1.96 (m, 1H), 1.83~1.73 (m, 1H), 1.68~1.65(m, 1H), 1.57~1.48 (m, 3H), 0.71 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 211.5, 148.8, 107.3, 56.0, 48.2, 41.7,41.3, 40.2, 36.7, 25.3, 23.1, 17.3; HRMS (EI): m / z calcd for C 12 H 19 O + [M + H] + 179.1430 found 179.1427. Example 2 This embodiment describes a method for synthesizing atractylodes lactone, including methods for synthesizing atractylodes lactone I and atractylodes lactone II.

[0194] The synthesis method of atractylenolide-I (1) is as follows ( Figure 2 ): Compound 22 (200 mg, 1.12 mmol) was dissolved in 6.5 mL of dry dichloromethane. Dry triethylamine (340 mg, 0.47 mL, 3.37 mmol) and titanium tetrachloride (1.0 M in CH2Cl2, 1.7 mL, 1.7 mmol) were added sequentially to the solution at -78 °C. The mixture was stirred for 30 min, then methyl pyruvate (230 mg, 0.2 mL, 2.24 mmol) was added. The reaction was allowed to proceed naturally to room temperature for 24 h (TLC monitoring). The reaction was quenched with 50 mL of distilled water, diluted with 30 mL of ethyl acetate, and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 30:1] to give 185 mg of white solid atractylenolide-I(1), yield 72%.

[0195] 1 H NMR (600 MHz, CDCl3) δ 5.62 (s, 1H), 4.91 (d, J = 1.2 Hz, 1H), 4.63 (d, J = 1.2 Hz, 1H), 4.91 (dd, J = 3.6, 16.8 Hz, 1H), 2.56~2.50 (m, 1H), 2.39~2.33 (m, 2H), 2.08~2.23 (m, 1H), 1.91 (m, 3H), 1.74~1.70 (m, 2H), 1.66~1.59 (m, 2H), 0.94 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 171.5, 148.5, 148.2, 148.1, 120.6, 119.3,107.6, 48.5, 39.2, 38.3, 36.3, 23.1, 22.8, 18.7, 8.6. HRMS (EI): m / z calcd for C 15 H 19 O2 + [M + H] + 230.1380 found 230.1383. The synthesis method of atractylenolide-II (2) is as follows ( Figure 2 ): Compound 22 (200 mg, 1.12 mmol) was dissolved in 6.5 mL of dry dichloromethane. Dry tri-n-butylamine (624 mg, 0.8 mL, 3.37 mmol) and titanium tetrachloride (1.0 M in CH2Cl2, 1.7 mL, 1.7 mmol) were added sequentially to the solution at -78 °C. The mixture was stirred for 30 min, and 1,1-dimethoxyacetone (265 mg, 0.27 mL, 2.24 mmol) was added. The reaction was then allowed to warm naturally to room temperature and allowed to proceed for 24 h (TLC monitoring). The reaction was quenched with 50 mL of distilled water and diluted with 30 mL of ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 30:1] to give 194.2 mg of white solid atractylenolide-II (2), yield 74%.

[0196] 1 H NMR (600 MHz, CDCl3) δ 4.88~4.82 (m, 2H), 4.61 (d, J = 1.8 Hz, 1H), 2.73 (dd, J = 5.4, 21.0 Hz, 1H), 2.41~2.28 (m, 3H), 2.02~1.94 (m, 1H), 1.85~1.83 (m, 1H), 1.82 (m, 3H), 1.66~1.57 (m, 3H), 1.36~1.25 (m, 1H), 1.14 (t, J= 17.4 Hz, 1H), 0.90 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 174.9, 162.6, 148.5, 120.2, 107.0, 78.1,50.0, 47.5, 40.9, 37.0, 36.3, 25.8, 22.4, 16.5, 8.3; HRMS (EI): m / z calcd for C 15 H 21 O2 + [M + H] + 233.1536 found 233.1532. Example 3 This embodiment describes a method for synthesizing atractylodes lactone derivatives, as detailed below: The synthesis method of taenialactams B (4) is as follows ( Figure 2 ): Atractylodes lactone I (165 mg, 0.69 mmol) was dissolved in 15 mL of tetrahydrofuran, and 8 mL of 25% ammonia was added. The mixture was stirred at 120 °C for 24 h in a sealed tube. After concentration under reduced pressure, the crude product was subjected to column chromatography [V (dichloromethane):V (methanol) = 50:1] to obtain 96 mg of light yellow solid taenialactams B (4), with a yield of 56%.

[0197] 1H NMR (600 MHz, CDCl3) δ 7.62 (s, 1H), 4.84 (s, 1H), 4.60 (s, 1H), 4.18 (s, 1H), 2.51 (d, J = 12.6 Hz, 1H), 2.42~2.33 (m, 2H), 2.24 (d, J = 13.8Hz, 1H), 1.98~1.93 (m, 1H), 1.76~1.72 (m, 2H), 1.69 (s, 3H), 1.61 (m, 1H), 1.52 (d, J = 12.6 Hz, 1H), 1.37 (d, J = 13.2 Hz, 1H), 1.19~1.53 (m, 1H), 1.03 (s, 3H); 13 C NMR (151 MHz, CDCl3) δ 173.9, 157.4, 149.5, 124.5, 106.5, 86.2, 52.1, 51.9, 41.6, 36.5, 36.3, 23.9, 22.6, 16.9, 8.0. HRMS (EI): m / z calcd for C 15 H 22 NO2 + [M + H] + 248.1645 found. The synthesis method of atractylenolactam (5) is as follows ( Figure 2 ): Atractylenolactam I (165 mg, 0.69 mmol) was dissolved in 15 mL of tetrahydrofuran, and 8 mL of 25% ammonia was added. The mixture was stirred at 120 °C for 24 h in a sealed tube, and the crude product was obtained by concentration under reduced pressure. The crude product was dissolved in 20 mL of tetrahydrofuran solution, and p-toluenesulfonic acid (60 mg, 0.35 mmol) was added under ice-water bath. The mixture was heated to room temperature and stirred (TLC monitoring) for 12 h. The reaction was quenched with 30 mL of saturated sodium bicarbonate aqueous solution, and the phases were separated with 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(dichloromethane):V(methanol) = 50:1] to give 146 mg of pale yellow solid atractylenolactam (5), with a yield of 84%.

[0198] 1H NMR (600 MHz, CDCl3) δ 8.13 (s, 1H), 5.50 (s, 1H), 4.88 (d, J = 2.4Hz, 1H), 4.63 (d, J = 3.6 Hz, 1H), 2.63 (dd, J =5.4, 25.2 Hz, 1H), 2.51~2.43(m, 1H), 2.39~2.29 (m, 2H), 2.09~2.01 (m, 1H), 1.88 (m, 3H), 1.74~1.72 (m,1H), 1.71~1.66 (m, 1H), 1.65~1.63 (m, 1H), 1.61~1.56 (m, 1H), 0.90 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 173.3, 148.8, 141.6, 135.4, 124.9, 121.0,107.1, 49.0, 39.3, 38.1, 36.3, 23.2, 22.4, 18.5, 8.3; HRMS (EI): m / z calcd for C 15 H 20 NO + [M + H] + 230.1539 found 230.1537. The synthetic method of atractylon (6) is as follows ( Figure 2 ): Atractylodes lactone II (150 mg, 0.65 mmol) was dissolved in 8.0 mL of dry tetrahydrofuran. Diisobutylaluminum hydride (1.5 M in toluene, 0.86 mL, 1.29 mmol) was slowly added to the reaction solution at -30 °C. After the addition was completed, the reaction solution was slowly raised to -10 °C, and then a mixed solution of 5.6 mL tetrahydrofuran and 5.4 mL 10% sulfuric acid was added. The reaction was then stirred at 0 °C for 30 min. The reaction was quenched by adding 30 mL of distilled water, and 30 mL of ethyl acetate was added for phase separation. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography (petroleum ether) to obtain 110 mg of colorless oily atractylon (6), with a yield of 79%.

[0199] 1H NMR (600 MHz, CDCl3) δ 7.05 (s, 1H), 4.86 (s, 1H), 4.70 (s, 1H), 2.43~2.37 (m, 4H), 2.31~2.27 (m, 1H), 2.12~2.11 (m, 1H), 2.07~2.01 (m, 1H), 1.95 (s, 3H), 1.71~1.70 (m, 1H), 1.67~1.65 (m, 1H), 1.58~1.55 (m, 1H), 1.53~1.49 (m, 1H), 0.76 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 149.9, 149.4, 136.9, 119.6, 116.2, 107.3, 45.7, 41.9, 39.3, 37.3, 36.7, 23.6, 20.9, 17.6, 8.2. HRMS (EI): m / z calcd for C 15 H 20 O + [M] + 216.1509 was found. The synthesis method of biepiasreorlid II (7) is as follows ( Figure 2 ): Atractylodes lactone I (65 mg, 0.28 mmol) was dissolved in 25 mL of n-hexane and reacted at room temperature under the irradiation of a 125 W mercury lamp in a quartz reaction tube (TLC monitoring). After 24 h, the mixture was concentrated under reduced pressure, and the crude product was subjected to column chromatography [V (petroleum ether):V (ethyl acetate) = 10:1] to give 35 mg of white solid biepiasreorlid II (7), yield 54%.

[0200] 1H NMR (600 MHz, CDCl3) δ 4.96 (s, 2H), 4.76 (s, 2H), 2.89~2.85 (m,4H), 2.71~2.66 (m, 2H), 2.53 (s, 2H), 2.42 (d, J = 13.2 Hz, 2H), 2.02~1.98(m, 2H), 1.81 (s, 6H), 1.69 (d, J = 12.6 Hz, 2H), 1.57~1.50 (m, 4H), 1.26 (d,J = 11.4 Hz, 2H), 0.66 (s, 6H); 13 C NMR (150 MHz, CDCl3) δ 172.9, 160.2, 147.8, 123.2, 108.6, 88.4, 48.8, 39.2, 38.4, 36.6, 35.6, 25.4, 22.5, 19.6, 8.8. HRMS (EI): m / z calcd for C 30 H 37 O4 + [M + H] + 461.2686 found 461.2681. The synthesis method of atractylenolide-III (3) is as follows ( Figure 3 ): Atractylodes lactone I (200 mg, 0.87 mmol) was dissolved in a mixture of 5 mL water and 5 mL tetrahydrofuran. 1,8-dioctyl-1,3,6,8-tetraazacyclododecane (660 mg, 0.65 mL, 4.36 mmol) was added at 0 °C. The mixture was heated to room temperature (TLC monitoring). After 24 h, the reaction was quenched with 30 mL distilled water. The mixture was separated into phases by 30 mL ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 5:1] to give 157 mg of white solid atractylodes lactone III (3), yield 73%.

[0201] 1H NMR (600 MHz, CDCl3) δ 4.87 (d, J = 1.2 Hz, 1H), 4.60 (d, J = 1.2Hz, 1H), 2.63 (dd, J = 3.0, 13.2 Hz, 1H), 2.46~2.36 (m, 2H), 2.26 (d, J =13.8 Hz, 1H), 1.99~1.94 (m, 1H), 1.85~1.83 (m, 4H), 1.67~1.62 (m, 2H), 1.58~1.55 (m, 2H), 1.27~1.22 (m, 1H), 1.03 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 172.5, 161.1, 148.7, 122.3, 107.0, 103.8,51.8, 51.4, 41.4, 36.9, 36.2, 24.7, 22.5, 16.7, 8.4. HRMS (EI): m / z calcd for C 15 H 21 O3 + [M + H] + 249.1485 found 249.1481. The synthesis method of taenialactone A (8) is as follows ( Figure 3 ): Atractylodes lactone I (160 mg, 0.69 mmol) was dissolved in 15 mL of methanol, and 1,8-dioctyl-1,3,6,8-tetraazacyclododecane (528 mg, 0.52 mL, 3.46 mmol) was added at 0 °C. The reaction was heated to room temperature (TLC monitoring). After 24 h, the reaction was quenched with 30 mL of distilled water, and the phases were separated by 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(petroleum ether):V(ethyl acetate) = 20:1] to give 136 mg of white solid taenialactone A (8), yield 75%.

[0202] 1H NMR (600 MHz, CDCl3) δ 4.85 (s, 1H), 4.57 (1H,s), 3.15 (s, 3H), 2.61 (dd, J =3.0, 13.2 Hz, 1H), 2.36~2.31 (m, 2H), 2.23 (t, J = 13.2 Hz, 1H),1.98~1.92 (m, 1H), 1.86 (s, 3H), 1.81 (d, J = 12.6 Hz, 1H), 1.64~1.60 (m,2H), 1.55 (d, J = 13.2 Hz, 1H), 1.41 (m, 1H), 1.23~1.19 (m, 1H), 0.95 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 171.8, 159.4, 148.6, 124.2, 106.8, 106.4, 51.8, 50.4, 50.0, 41.3, 36.7, 36.0, 24.9, 22.3, 16.4, 8.4; HRMS (EI): m / z calcd for C 16 H 23 O3 + [M + H] + 263.1642 found 263.1638. The synthesis method of cespilactam A (9) is as follows ( Figure 3 ): Atractylodes lactone I (185 mg, 0.80 mmol) was dissolved in 15 mL of tetrahydrofuran, and ethanolamine (490 mg, 0.48 mL, 8.02 mmol) was added. The mixture was stirred at 120 °C for 24 h in a sealed tube, and then concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the intermediate product. The intermediate obtained was dissolved in 20 mL of tetrahydrofuran, and p-toluenesulfonic acid (64 mg, 0.37 mmol) was added under ice-water bath. The mixture was heated to room temperature and stirred (TLC monitoring) for 12 h. The reaction was quenched with 30 mL of saturated sodium bicarbonate aqueous solution, and the phases were separated with 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(dichloromethane):V(methanol) = 50:1] to give 185 mg of colorless oily cespilactam A (9), yield 86%.

[0203] 1 H NMR (600 MHz, CDCl3) δ 5.42 (s, 1H), 4.87 (s, 1H), 4.62 (s, 1H), 3.77 (m, 2H), 3.70~3.68 (m, 2H), 3.36 (Br, 1H), 2.62 (dd, J = 3.6, 16.8 Hz, 1H), 2.44 (t, J = 13.8 Hz, 1H), 2.36~2.34 (m, 1H), 2.28 (dd, J = 2.4, 13.2Hz, 1H), 2.05~2.01 (m, 1H), 1.86 (s, 3H), 1.70 (m, 1H), 1.68 (m, 1H), 1.66(m, 1H), 1.58~1.55 (m, 1H), 0.90 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 172.6, 148.7, 140.5, 137.6, 124.3, 119.9,107.3, 68.1, 61.9, 49.0, 42.8, 39.6, 38.1, 36.3, 23.3, 22.4, 18.7, 8.5. HRMS (EI): m / z calcd for C 17 H 24 NO2 + [M + H] + 274.1802 found. The synthesis method of atramacronoid E (10) is as follows ( Figure 3 ): Atractylodes lactone I (170 mg, 0.74 mmol) was dissolved in 15 mL of tetrahydrofuran, and ethylamine (2 M intoluene, 3.7 mL, 7.40 mmol) was added. The mixture was stirred at 120 °C for 24 h in a sealed tube, and then concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the intermediate product. The obtained intermediate was dissolved in 20 mL of tetrahydrofuran, and p-toluenesulfonic acid (64 mg, 0.37 mmol) was added under ice-water bath. The mixture was heated to room temperature and stirred (TLC monitoring) for 12 h. The reaction was quenched with 30 mL of saturated sodium bicarbonate aqueous solution, and the phases were separated with 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(dichloromethane):V(methanol) = 50:1] to give 190 mg of colorless oily atramacronoid E (10), with a yield of 100%.

[0204] 1 H NMR (600 MHz, CD3OD) δ 5.64 (s, 1H), 4.90 (s, 1H), 4.68 (s, 1H), 3.62~3.58 (m, 2H), 2.68 (dd, J = 3.6, 16.2 Hz, 1H), 2.55~2.50 (m, 1H), 2.39~2.32 (m, 2H), 2.12~2.07 (m, 1H), 1.84 (m, 3H), 1.78~1.68 (m, 3H), 1.65~1.61(m, 1H), 1.12 (t, J = 7.2 Hz, 3H), 0.94 (s, 3H); 13 C NMR (150 MHz, CD3OD) δ 171.3, 148.8, 140.4, 136.6, 123.5, 120.9,106.28, 49.0, 39.0, 37.8, 36.0, 33.5, 23.0, 21.8, 17.3, 13.0, 6.9; HRMS (EI): m / z calcd for C 17 H 24 NO + [M + H] + 258.1852 found. The synthesis method of cespilamide C (11) is as follows ( Figure 3 ): Atractylodes lactone I (200 mg, 0.87 mmol) was dissolved in 8 mL of tetrahydrofuran solution, and phenethylamine (528 mg, 0.55 mL, 4.35 mmol) was added. The mixture was stirred at 120 °C for 24 h in a sealed tube, and then concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the intermediate product. The obtained intermediate was dissolved in 20 mL of tetrahydrofuran, and p-toluenesulfonic acid (75 mg, 0.43 mmol) was added under ice-water bath. The mixture was heated to room temperature and stirred (TLC monitoring) for 12 h. The reaction was quenched with 30 mL of saturated sodium bicarbonate aqueous solution, and the phases were separated with 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(dichloromethane):V(methanol) = 30:1] to give 268 mg of a pale yellow oil, cespilamide C, in 93% yield.

[0205] 1 H NMR (600 MHz, CDCl3) δ 7.29~7.26 (m, 2H), 7.22~7.17 (m, 3H), 5.05(s, 1H), 4.87 (s, 1H), 4.61 (s, 1H), 3.76~3.73 (m, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.60 (dd, J = 3.6, 16.8 Hz, 1H), 2.43~2.33 (m, 2H), 2.21~1.19 (m, 1H), 2.04~1.99 (m, 1H), 1.88 (m, 3H), 1.71 (m, 1H), 1.61 (m, 1H), 1.56 (m, 1H),1.46~1.41 (m, 1H), 0.80 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 170.9, 148.8, 139.7, 139.2, 137.2, 129.0,128.5, 126.4, 124.2, 119.1, 107.1, 48.9, 41.0, 39.5, 37.8, 36.3, 35.4, 23.2,22.3, 18.6, 8.5; HRMS (EI): m / z calcd for C 23 H 28 NO + [M + H] +334.2165 found 334.2165. The synthesis method of cespilamide D (12) is as follows ( Figure 3 ): Atractylodes lactone I (175 mg, 0.76 mmol) was dissolved in 15 mL of tetrahydrofuran, and 4-hydroxyphenylethylamine (520 mg, 3.79 mmol) was added. The mixture was stirred at 120 °C for 24 h in a sealed tube, and then concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the intermediate product. The intermediate obtained was dissolved in 20 mL of tetrahydrofuran, and p-toluenesulfonic acid (54 mg, 0.31 mmol) was added under ice-water bath. The mixture was heated to room temperature and stirred (TLC monitoring) for 12 h. The reaction was quenched with 30 mL of saturated sodium bicarbonate aqueous solution, and the phases were separated with 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(dichloromethane):V(methanol) = 30:1] to give 245 mg of a pale yellow oily substance cespilamide D (12), with a yield of 92%.

[0206] 1 H NMR (600 MHz, CDCl3) δ 7.01 (br s, 1H), 6.99 (d, J = 7.8 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 5.21 (s, 1H), 4.87 (s, 1H), 4.61 (s, 1H), 3.75~3.72(m, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.60 (dd, J = 3.0, 16.2 Hz, 1H), 2.44~2.34(m, 2H), 2.23 (d, J = 13.2 Hz, 1H), 2.03~2.01 (m, 1H), 1.87 (m, 3H), 1.70~1.48 (m, 1H), 1.64~1.61 (m, 2H), 1.53~1.50 (m, 1H), 0.85 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 171.5, 155.2, 148.8, 140.1, 137.2, 130.2,130.0, 124.2, 120.5, 115.6, 107.2, 49.0, 41.3, 39.5, 38.1, 36.4, 34.5, 23.3,22.4, 18.7, 8.6; HRMS (EI): m / z calcd for C 23 H 28 NO2 + [M + H] + 350.2115 found. The synthesis method of Atrchiterpene A (13) is as follows ( Figure 3 ): Atractylodes lactone I (175 mg, 0.76 mmol) was dissolved in 15 mL of tetrahydrofuran, and 4-aminobutyric acid (392 mg, 3.80 mmol) and 1,8-dioctyl-1,3,6,8-tetraazacyclododecane (694 mg, 0.69 mL, 4.56 mmol) were added. The mixture was stirred at 120 °C for 24 h in a sealed tube, cooled to room temperature, and the reaction was quenched with saturated ammonium chloride solution. The pH was adjusted to 1-2 with 1M HCl aqueous solution. The phases were separated by 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(dichloromethane):V(methanol) = 20:1] to give 110 mg of a pale yellow solid atrchiterpene A (13), with a yield of 48%.

[0207] 1 H NMR (600 MHz, CDCl3) δ 5.42 (s, 1H), 4.88 (s, 1H), 4.63 (s, 1H), 3.64~3.61 (m, 2H), 2.65~2.61 (m, 1H), 2.47~2.42 (m, 1H), 2.37 (m, 2H), 2.29(d, J = 13.2 Hz, 1H), 2.06~1.99 (m, 1H), 1.87 (s, 3H), 1.71~1.64 (m, 4H), 1.58~1.57 (m, 1H), 0.74 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 177.2, 171.8, 148.8, 140.3, 137.3, 124.2,120.1, 107.3, 49.1, 39.6, 38.3, 38.2, 36.4, 31.5, 24.5, 23.3, 22.4, 18.7,8.6. HRMS (EI): m / z calcd for C 19 H 26 NO3 + [M + H] + 316.1907 found 316.1911. The synthesis method of cespilamide E (14) is as follows ( Figure 3 ): Atractylodes lactone I (210 mg, 0.91 mmol) was dissolved in 20 mL of tetrahydrofuran, and tryptophan (729 mg, 4.55 mmol) was added. The mixture was stirred at 120 °C for 24 h in a sealed tube, and then concentrated under reduced pressure to obtain crude product. The crude product was then subjected to column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the intermediate product. The intermediate obtained was dissolved in 20 mL of tetrahydrofuran, and p-toluenesulfonic acid (78 mg, 0.45 mmol) was added under ice-water bath. The mixture was heated to room temperature and stirred (TLC monitoring) for 12 h. The reaction was quenched with 30 mL of saturated sodium bicarbonate aqueous solution, and the phases were separated with 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography [V(dichloromethane):V(methanol) = 30:1] to give 295 mg of pale yellow solid cespilamide E (14), yield 87%.

[0208] 1H NMR (600 MHz, CDCl3) δ 8.24 (br s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.17 (t, J =7.2 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H),7.00 (m, 1H), 5.07 (s, 1H), 4.85 (s, 1H), 4.59 (s, 1H), 3.88~3.79 (m, 2H),3.03 (t, J = 7.2 Hz, 2H), 2.57 (dd, J = 3.0, 16.8 Hz, 1H), 2.39~2.31 (m, 2H),2.11 (d, J = 13.2 Hz, 1H), 2.00~1.95 (m, 1H), 1.89 (s, 3H), 1.61~1.56 (m,1H), 1.46~1.42 (m, 1H), 1.35~1.31 (m, 1H), 1.29~1.25 (m, 1H), 0.74 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 171.2, 149.0, 139.8, 137.4, 136.3, 127.7,124.2, 122.2, 122.0, 119.4, 119.4, 118.8, 113.3, 111.3, 107.1, 48.9, 40.1,39.4, 37.8, 36.4, 25.0, 23.3, 22.3, 18.5, 8.6; HRMS (EI): m / z calcd for C 25 H 29 N2O + [M + H] + 373.2274 was found. In summary, the embodiments of this application have at least the following beneficial effects: 1. Innovation in source chirality control: For the first time, the asymmetric total synthesis of eucalyptane-type natural products was achieved using the natural chiral source (+)-verbenone as the starting material, fundamentally solving the technical bottleneck that related synthetic routes can only obtain racemic mixtures.

[0209] 2. Breakthrough in Synthetic Strategy: Adopting the concept of "convergent synthesis", the key chiral intermediate 22 was constructed in just 9 steps through innovative reaction strategies such as Grubbs II catalyst-catalyzed cyclic olefin metathesis (RCM) reaction and TiCl4-mediated regioselective γ-lactone cyclization and biomimetic synthesis, demonstrating excellent step economy.

[0210] 3. Excellent derivatization ability: Based on the biotransformation relationship between butenolactone and butenolactam, by systematically changing the type of nucleophile, 14 structurally diverse eucalyptane-type terpenoid natural products, including lactones, lactams, photochemical products and reduction products, were successfully constructed, demonstrating a strong ability to explore the "chemical space".

[0211] 4. Broad application prospects: For the first time, a series of high optical purity eucalyptane-type natural products and their derivatives have been prepared on a large scale, providing an important material basis and technical platform for the discovery of chiral drug lead compounds, structure-activity relationship studies and subsequent drug development.

[0212] 5. High versatility of the method: The established synthetic strategy has good universality. It is not only applicable to the total synthesis of natural products, but can also be extended to the construction of other chiral molecules with similar skeletons. It has important value in the fields of organic synthesis methods and medicinal chemistry.

[0213] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments, and various changes can be made within the scope of knowledge possessed by those skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. A method for synthesizing an intermediate of atractylodes lactone, characterized in that, Includes the following steps: Compound 18 was prepared by oxidizing and then reducing the methyl group in compound 17. Compound 18 was prepared into compound 19 under the action of Grubb catalyst; Compound 19 was reduced with hydrogen to obtain compound 20; Compound 20 was dehydrated to obtain compound 21; Compound 21 was hydrolyzed to obtain compound 22.

2. The synthesis method according to claim 1, characterized in that, The methyl oxidation employs a peroxide / selenium dioxide system; And / or, the peroxide includes at least one of hydrogen peroxide, m-chloroperoxybenzoic acid, and tert-butylhydrogen peroxide; And / or, the temperature for methyl oxidation is 20°C to 30°C; And / or, the methyl oxidation time is 2h~10h; And / or, the crude product is obtained by oxidation of the methyl group; And / or, the crude product, cerium chloride, and borohydride are mixed and then subjected to a reduction reaction; And / or, the borohydride includes at least one of lithium borohydride, sodium borohydride and potassium borohydride; And / or, the reduction reaction temperature of the crude product is -80℃ to -70℃; And / or, the reduction reaction time of the crude product is 0.5h~1h; And / or, the Grubb catalyst is at least one of a first-generation Grubb catalyst and a second-generation Grubb catalyst; And / or, a reflux reaction under the action of the Grubb catalyst; And / or, the reflux reaction time is 30°C to 50°C; And / or, the reaction time of the Grubb catalyst is 2h to 10h; And / or, the methyl oxidation, reduction, Grubb catalysis, hydrogenation reduction, dehydration elimination, and hydrolysis are carried out in the liquid phase; And / or, the liquid phase includes at least one of an aqueous phase and an organic phase; And / or, the oxidation takes place in an organic phase; And / or, the Grubb catalyst acts in an organic phase; And / or, the hydrogenation reduction is carried out in an organic phase; And / or, the dehydration elimination is carried out in the organic phase; And / or, the hydrolysis takes place in an organic phase.

3. The synthesis method according to claim 1, characterized in that, The catalyst for the hydrogenation reduction is a noble metal oxide; And / or, the noble metal oxide includes platinum oxide and Pt / C catalyst; And / or, the platinum oxide is platinum dioxide; And / or, the Pt loading in the Pt / C catalyst is 0.5wt%~60wt%; And / or, the temperature of the hydrogenation reduction is 20°C to 30°C; And / or, the pressure of the hydrogenation reduction is 100 kPa to 120 kPa; And / or, the hydrogenation reduction time is 10h~100h.

4. The synthesis method according to claim 1, characterized in that, The dehydration elimination includes a first step reaction and a second step reaction; And / or, the first step reaction is carried out with a base, a sulfonating agent and a pyridine catalyst; And / or, the base includes triethylamine; And / or, the sulfonating agent includes p-toluenesulfonyl chloride and methanesulfonyl chloride; And / or, the pyridine catalyst includes at least one of 4-dimethylaminopyridine and 4-(3-methylpyrrole)-pyridine; And / or, the molar ratio of compound 20 to base is 1:5 to 15; And / or, the molar ratio of compound 20 to the sulfonating agent is 1:2~5; And / or, the molar ratio of compound 20 to the pyridine catalyst is 1:0.2~0.8; And / or, the temperature of the first step reaction is 20°C to 30°C; And / or, the reaction time of the first step is 1h to 10h; And / or, the solid phase is collected after the first step reaction; And / or, in the second step of the reaction, iodide salt and 1,8-dioctyl-1,3,6,8-tetraazacyclododecane are added; And / or, the molar ratio of the solid phase to the iodide salt is 1:4~10; And / or, the molar ratio of the solid phase to 1,8-dioctyl-1,3,6,8-tetraazacyclododecane is 1:2~5; And / or, the temperature of the second step reaction is 80℃~100℃; And / or, the reaction time in the second step is 10h~30h.

5. The synthesis method according to claim 1, characterized in that, The hydrolysis involves the addition of protic acids; And / or, the protic acid includes at least one of p-toluenesulfonic acid, sulfuric acid, and hydrogen halide; And / or, the hydrogen halide includes at least one of hydrogen chloride, hydrogen bromide and hydrogen iodide; And / or, the hydrolysis temperature is 20℃~30℃; And / or, the hydrolysis time is 3h~5h.

6. The synthesis method according to claim 1, characterized in that, It also includes the following steps: 。 7. A method for synthesizing atractylodes lactone, characterized in that, Includes at least one of the following reactions (a) to (b): （a）、 ； （b）、 ； Atractylodes lactone was prepared using compound 22 as a raw material; The atractylodes lactones include atractylodes lactone (I) and atractylodes lactone (II); Compound 22 was prepared by the synthetic method according to any one of claims 1 to 6.

8. The synthesis method according to claim 7, characterized in that, Compound 22 was subjected to γ-lactoneation to obtain the atractylodes lactone; And / or, the γ-lactoneation is carried out in the form of titanium tetrachloride; And / or, the method for preparing the atractylodes lactone (I) includes the following steps: The compound 22, base, titanium tetrachloride, methyl pyruvate and organic solvent are mixed and reacted; And / or, the method for preparing the atractylodes lactone (II) includes the following steps: The mixture of compound 22, base, titanium tetrachloride, 1,1-dimethoxyacetone and organic solvent was reacted. And / or, the molar ratio of compound 22 to base is 1:2~5; And / or, the molar ratio of compound 22 to titanium tetrachloride is 1:1~2; And / or, the molar ratio of compound 22 to methyl pyruvate is 1:1.8~2.2; And / or, the initial temperature of the reaction is -80℃ to -70℃; And / or, the reaction is carried out by heating the initial temperature to 20℃~30℃ and then reacting for 20h~30h.

9. A method for preparing atracentronin derivative, characterized in that, Includes at least one of the following reactions (a) to (k): （a）、 ； （b）、 ； （c）、 ； （d）、 ； （e）、 ； （f）、 ； （g）、 ； （h）、 ； （i）、 ； （j）、 ； （k）、 ； Atractylodes lactone (I) and atractylodes lactone (II) were both prepared independently using the synthetic method described in claim 7 or 8.

10. The synthesis method according to claim 9, characterized in that, Reaction (a) includes the following steps: Compound 4 was prepared by reacting atractylodes lactone (I), ammonia, and an organic solvent. And / or, the temperature of reaction (a) is 110°C to 130°C; And / or, the reaction (a) takes place over a period of 20 to 30 hours; And / or, reaction (b) includes the following steps: Compound 4, a protic acid, and an organic solvent were mixed and reacted to prepare compound 5. And / or, the temperature of reaction (b) is 20°C to 30°C; And / or, the reaction (b) takes place over a period of 10 to 20 hours; And / or, reaction (c) includes the following steps: Compound 7 was prepared by mixing atractylodes lactone (I) with an organic solvent and then reacting it under light. And / or, the temperature of the reaction (c) is 20°C to 30°C; And / or, the reaction (c) takes place over a period of 20 to 30 hours; And / or, reaction (d) includes the following steps: Compound 3 was prepared by reacting atractylodes lactone (I), 1,8-dioctyl-1,3,6,8-tetraazacyclododecane, water, and an organic solvent. And / or, the temperature of the reaction (d) is 20°C to 30°C; And / or, the reaction (d) takes place over a period of 20 to 30 hours; And / or, reaction (e) includes the following steps: Compound 8 was prepared by reacting atractylodes lactone (I), 1,8-dioctyl-1,3,6,8-tetraazacyclododecane and an organic solvent; And / or, the temperature of the reaction (e) is 20°C to 30°C; And / or, the reaction (e) takes place over a period of 20 to 30 hours; And / or, reaction (f) includes the following steps: Atractylodes lactone (I), ethanolamine and organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product. The intermediate product, protic acid and organic solvent were mixed and then reacted in the second step to obtain compound 9. And / or, the temperature of the first step reaction in reaction (f) is 110°C to 130°C; And / or, the reaction time of the first step in reaction (f) is 20h~30h; And / or, the temperature of the second step reaction in reaction (f) is 20°C to 30°C; And / or, the reaction time of the second step in reaction (f) is 10h to 20h; And / or, reaction (g) includes the following steps: Atractylodes lactone (I), ethylamine and organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product. The intermediate product, protic acid and organic solvent were mixed and then reacted in the second step to obtain compound 10. And / or, the temperature of the first step reaction in the reaction (g) is 110°C to 130°C; And / or, the reaction time of the first step in the reaction (g) is 20h~30h; And / or, the temperature of the second step reaction in the reaction (g) is 20°C to 30°C; And / or, the reaction time of the second step in the reaction (g) is 10h to 20h; And / or, reaction (h) includes the following steps: Atractylodes lactone (I), phenylethylamine and organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product; The intermediate product, protic acid and organic solvent were mixed and then reacted in the second step to obtain compound 11. And / or, the temperature of the first step reaction in the reaction (h) is 110°C to 130°C; And / or, the reaction time of the first step in the reaction (h) is 20h~30h; And / or, the temperature of the second step reaction in the reaction (h) is 20°C to 30°C; And / or, the reaction time of the second step in the reaction (h) is 10h~20h; And / or, reaction (h) includes the following steps: Atractylodes lactone (I), 4-hydroxyphenylethylamine and an organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product. The intermediate product, protic acid and organic solvent were mixed and then reacted in the second step to obtain compound 12. And / or, the temperature of the first step reaction in the reaction (h) is 110°C to 130°C; And / or, the reaction time of the first step in the reaction (h) is 20h~30h; And / or, the temperature of the second step reaction in the reaction (h) is 20°C to 30°C; And / or, the reaction time of the second step in the reaction (h) is 10h~20h; And / or, reaction (i) includes the following steps: Compound 13 was prepared by reacting atractylodes lactone (I), 4-aminobutyric acid, 1,8-dioctyl-1,3,6,8-tetraazacyclododecane and an organic solvent. And / or, the temperature of reaction (i) is 110°C to 130°C; And / or, the reaction (i) takes 20 h to 30 h; And / or, reaction (j) includes the following steps: Atractylodes lactone (I), tryptophan and organic solvent were mixed and carried out in the first step of the reaction to obtain the intermediate product. The intermediate product, protic acid and organic solvent were mixed and then reacted in the second step to obtain compound 14. And / or, the temperature of the first step reaction in reaction (j) is 110°C to 130°C; And / or, the reaction time of the first step in reaction (j) is 20h~30h; And / or, the temperature of the second step reaction in reaction (j) is 20°C to 30°C; And / or, the reaction time of the second step in reaction (j) is 10h~20h; And / or, reaction (k) includes the following steps: Compound 6 was prepared by reacting atractylodes lactone (II), diisobutylaluminum hydride, dilute sulfuric acid and organic solvent. And / or, the temperature of the reaction (k) is -5°C to 5°C; And / or, the reaction (k) takes place for 0.2 h to 1 h; And / or, the protic acid includes at least one of p-toluenesulfonic acid, sulfuric acid, and hydrogen halide; And / or, the hydrogen halide includes at least one of hydrogen chloride, hydrogen bromide, and hydrogen iodide.

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