A method for preparing the natural product mycenolide A

Abstract

This invention discloses a method for preparing the natural product mycenolide A, comprising the following steps: mixing compound 2, IBX oxidant, and solvent to carry out an oxidation reaction to obtain the natural product mycenolide A; the structural formulas of compound 2 and the natural product mycenolide A are as follows: This invention proposes and realizes for the first time an efficient total synthesis strategy for all possible chiral isomers of mycenolide A, not only solving the scientific problem of the scarcity of natural mycenolide A and its unknown absolute configuration, but also providing solid technical support and material guarantee for subsequent evaluation of neuroprotective activity and development of related original drugs due to its excellent synthetic efficiency and comprehensive coverage of chiral isomers.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing the natural product mycenolide A. Background Technology

[0002] Mycenolide A, a novel natural product, was first isolated from the marine sediment-derived Streptomyces sp. 4054. It possesses a unique γ-butenoic acid lactone ring skeleton. Activity studies from the isolation literature indicate that mycenolide A exhibits significant neuroprotective activity in in vitro cell models by selectively activating the TrkB receptor: at a concentration of 1 µM, it effectively reduces serum deprivation-induced death of TrkB-expressing cells. Therefore, mycenolide A is a highly promising lead compound for the development of treatments for neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease) and neuropsychiatric disorders (such as depression and anxiety).

[0003]

[0004] However, the extremely low natural abundance of this compound and the fact that the absolute configuration of its chiral center has not been confirmed by total synthesis or crystallography have seriously hindered in-depth research on its structure-activity relationship and multiple biological activities.

[0005] Therefore, it is necessary to develop a method for preparing the natural product mycenolide A. Summary of the Invention

[0006] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present invention proposes a method for preparing the natural product mycenolide A, providing for the first time a total synthesis method for the natural product mycenolide A, with a good yield.

[0007] According to a first aspect of the present invention, a method for preparing the natural product mycenolide A is provided, comprising the following steps: Compound 2, IBX oxidant, and solvent were mixed and subjected to an oxidation reaction to obtain the natural product mycenolide A. The structural formulas of compound 2 and the natural product mycenolide A are as follows: .

[0008] Understandably, "*" indicates a chiral carbon atom; for example, the structural formula of compound 2 includes... and .

[0009] For example, the structural formula of the natural product mycenolide A includes and .

[0010] According to a preferred embodiment of the present invention, the solvent includes at least one selected from dimethyl sulfoxide, 2-methyl-2-propanol, ethyl acetate, or 1,2-dichloroethane.

[0011] According to a preferred embodiment of the present invention, the oxidation reaction takes 1 to 3 hours.

[0012] According to a preferred embodiment of the present invention, the molar ratio of compound 2 to IBX oxidant is 1:(2.0~2.2).

[0013] According to a preferred embodiment of the present invention, compound 2 is prepared by the following method: Compound 12 and pyridine hydrogen fluoride are mixed to remove the TES silicon protecting group, and a lactone reaction occurs simultaneously to obtain the product. The structure of compound 12 is as follows: .

[0014] According to a preferred embodiment of the present invention, the reaction temperature for removing the TES silicon-based protective group is 0~5℃.

[0015] According to a preferred embodiment of the present invention, the reaction time for removing the TES silicon-based protective group is 0.5 to 2 hours.

[0016] According to a preferred embodiment of the present invention, the molar ratio of compound 12 and pyridine hydrogen fluoride is 1:(15~15.5).

[0017] According to a preferred embodiment of the present invention, compound 12 is prepared by the following method: Compound 10 was first reduced to an aldehyde by diisobutylaluminum hydride at low temperature, and then reacted with compound 11 in a Horner-Wadsworth-Emmons olefination reaction to obtain compound 12. The structures of compounds 10 and 11 are as follows: .

[0018] According to a preferred embodiment of the present invention, the molar ratio of compound 10 to diisobutylaluminum hydride is 1:(2.0~2.2).

[0019] According to a preferred embodiment of the present invention, the low temperature refers to ≤-78°C.

[0020] According to a preferred embodiment of the present invention, compound 10 is prepared by the following method: Compound 9 was subjected to a silicon-based protection reaction under the action of TESOTf and a base to obtain the product. The structural formula of compound 9 is as follows: .

[0021] According to a preferred embodiment of the present invention, the base includes at least one of triethylamine, N,N-diisopropylethylamine, 2,6-dimethylpyridine, or pyridine.

[0022] According to a preferred embodiment of the present invention, the reaction temperature of the silicon-based protection reaction is -30℃ to -78℃.

[0023] According to a preferred embodiment of the present invention, the reaction time of the silicon-based protection reaction is 30 to 50 minutes.

[0024] According to a preferred embodiment of the present invention, the molar ratio of compound 9, TESOTf and base is 1:(3.0~3.2):(6.0~6.2).

[0025] According to a preferred embodiment of the present invention, compound 9 is prepared by the following method: Compound 8, palladium-on-carbon catalyst, and hydrogen are mixed and reduced to obtain the product. The structural formula of compound 8 is as follows: .

[0026] According to a preferred embodiment of the present invention, the palladium-on-carbon catalyst accounts for 1% to 12% of the total mass of compound 8.

[0027] According to a preferred embodiment of the present invention, the temperature of the reduction reaction is 20~25°C.

[0028] According to a preferred embodiment of the present invention, the reduction reaction takes 12 to 24 hours.

[0029] According to a preferred embodiment of the present invention, compound 8 is prepared by the following method: The compound 7 and compound 4 were subjected to an olefin cross-metathesis reaction in the presence of Grubbs II catalyst to obtain the compound 7. The structural formulas of compounds 7 and 4 are as follows: .

[0030] According to a preferred embodiment of the present invention, the molar ratio of compound 7, compound 4 and Grubbs II catalyst is 1:(3.0~3.2):(0.1~0.15).

[0031] According to a preferred embodiment of the present invention, the reaction temperature of the olefin cross metathesis reaction is 20~50°C.

[0032] According to a preferred embodiment of the present invention, the reaction time of the olefin cross metathesis reaction is 12-24 hours.

[0033] According to a preferred embodiment of the present invention, compound 7 is prepared by the following method: Compound 5 is reacted with a Grignard reagent via an asymmetric Grignard addition reaction to obtain the product; The structural formula of compound 5 is as follows: .

[0034] According to a preferred embodiment of the present invention, the Grignard reagent includes at least one of methylmagnesium bromide, methyllithium, or methylmagnesium chloride.

[0035] According to a preferred embodiment of the present invention, the reaction temperature of the asymmetric Grignard addition reaction is 0~5℃.

[0036] According to a preferred embodiment of the present invention, the reaction time of the asymmetric Grignard addition reaction is 2-3 hours.

[0037] According to a preferred embodiment of the present invention, the molar ratio of compound 5 to magnesium methyl bromide is 1:(2~3).

[0038] According to a preferred embodiment of the present invention, compound 4 is prepared by the following method: Under the action of sulfuric acid and sodium nitrite, L-α-allylglycine undergoes a diazotization and deamination reaction to give compound 3; Subsequently, compound 3 under the conditions of condensing agent and DIPEA as base, undergoes an amide condensation reaction with N,O-dimethylhydroxylamine hydrochloride to give compound 4; The structural formulas of L-α-allylglycine and compound 3 are as follows: .

[0039] According to a preferred embodiment of the present invention, the molar ratio of L-α-allylglycine, sulfuric acid and sodium nitrite is 1:(1.0~1.2):(3.0~3.5).

[0040] According to a preferred embodiment of the present invention, the condensing agent comprises PyBOP (CAS No.: 128625-52-5) and / or PyAOP (CAS No.: 156311-83-0).

[0041] The method for preparing the natural product mycenolide A according to embodiments of the present invention has at least the following beneficial effects: This invention is the first to propose and realize a highly efficient total synthesis strategy for all possible chiral isomers of mycenolide A. Starting from the chiral source L-allylglycine, this strategy precisely constructs the skeleton using key reactions such as chelation-induced asymmetric addition, olefin metathesis, and Still-Gennari-modified HWE reaction. The longest linear step is only 9 steps, and the overall yield is as high as 19.3%. This invention not only solves the scientific problem of the scarcity of natural mycenolide A sources and the unknown absolute configuration, but also provides solid technical support and material guarantee for subsequent evaluation of neuroprotective activity and development of related original drugs due to its excellent synthetic efficiency and comprehensive coverage of chiral isomers.

[0042] Definitions and general terms "*" indicates a chiral carbon atom.

[0043] In embodiments of the present invention, the product after synthesis further includes a purification step, and the purification methods include, but are not limited to, extraction, washing, concentration and drying.

[0044] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Detailed Implementation

[0045] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0046] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0047] Example This example provides a method for preparing the natural product mycenolide A. The reaction equation and preparation method are as follows: Compound 4

[0048] L-α-allylglycine (5.0 g, 43.4 mmol, 1.0 eq.) was dissolved in sulfuric acid solution (0.5 M, 87 mL, 43.4 mmol, 1.0 eq.) at 0 °C, and sodium nitrite solution (9.0 g, 130.2 mmol, 3 M, 43.4 mL, 3.0 eq.) was slowly added dropwise at 0 °C. The mixture was stirred at 0 °C for 3 h, then heated to room temperature and stirred for another 36 h. The reaction mixture was extracted with ethyl acetate (100 mL x 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude α-hydroxy acid 3 (5.0 g, 43.0 mmol, 1.0 eq.), which could be used in the next step without further purification.

[0049] The crude product acid 3 (5.0 g, 43.0 mmol, 1.0 eq.) and N , O Dimethylhydroxylamine hydrochloride (DMHH) (8.4 g, 86.0 mmol, 2.0 eq.) was dissolved in anhydrous dichloromethane (215 mL), and TEA (19.2 mL, 137.6 mmol, 3.2 eq.) and PyBOP (22.4 g, 43.0 mmol, 1.0 eq.) were added at –20 °C. The mixture was stirred at –20 °C for 30 min, then brought to room temperature and stirred overnight. The reaction was quenched with water and extracted with dichloromethane (240 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give Weinreb amide 4 (4.7 g, 68% overall yield from both steps) as a colorless oil. 1 H NMR(500 MHz, CDCl3) δ 5.85 – 5.74 (m, 1H), 5.17 – 5.03 (m, 2H), 4.44 (s, 1H), 3.68 (s, 3H), 3.43 (s, 1H), 3.19 (s, 3H), 2.50 – 2.43 (m, 1H),2.34 – 2.27 (m, 1H); 13 C NMR(126 MHz, CDCl3) δ 174.2, 133.3, 117.9, 68.3, 61.4,38.9, 32.3. Compounds 7a / 7b

[0050] At 0 °C, ketone 5 (100.0 mg, 0.46 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (2.3 mL), and methylmagnesium bromide (3.0 M in THF, 0.4 mL, 1.2 mmol, 2.6 eq.) was added dropwise under a nitrogen atmosphere. The mixture was stirred at 0 °C for 2 hours. The reaction was quenched with saturated ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate (4.0 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give a colorless oily alcohol 7a (102.4 mg, 95%). 1 H NMR (500 MHz, CDCl3) δ 7.41 – 7.35 (m, 4H), 7.35 – 7.30 (m, 1H), 5.88 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.06 (dd, J = 17.1, 1.8 Hz, 1H), 4.97(dd, J = 10.2, 1.8 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz, 1H), 3.43 (q, J = 6.3 Hz, 1H), 2.41 (s, 1H), 2.32 – 2.21 (m, 1H), 2.19 – 2.05 (m,1H), 1.71 (ddd, J = 13.8, 11.9, 4.8 Hz, 1H), 1.51 (ddd, J = 13.8, 11.9, 5.1 Hz,1H), 1.22 (d, J = 6.3 Hz, 3H), 1.19 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 139.4,138.5, 128.4, 127.7, 114.2, 81.8, 74.2, 71.4, 35.5, 27.7, 23.2, 13.6.

[0051] From the enantiomers of compound 5 entStarting from -5, compound 7b can be prepared using the same synthetic method described above, with a yield of 93%.

[0052] Compounds 9a / 9b

[0053] In a sealed tube, compound 7a (100.0 mg, 0.43 mmol, 1.0 eq.), compound 4 (205 mg, 1.29 mmol, 3.0 eq.), and Grubbs II catalyst (37 mg, 0.043 mmol, 0.1 eq.) were dissolved in anhydrous dichloromethane (4.0 mL) and purged with nitrogen for 30 min. The reaction mixture was then heated to 35 °C and stirred overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 8a (108.4 mg, 69%) as a colorless oil.

[0054] Compound 8a (100.0 mg, 0.27 mmol, 1.0 eq.) was dissolved in ethyl acetate (1.4 mL), and Pd / C (30 mg, 10 wt%) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a layer of diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give compound 9a (68.4 mg, 90%) as a colorless oil. 1 H NMR (500 MHz, CDCl3) δ 4.45 – 4.30 (m,1H), 3.72 (s, 3H), 3.65 – 3.60 (m, 1H), 3.34 – 3.16 (m, 1H), 3.25 (s, 3H), 2.19 (brs, 2H), 1.83 – 1.67 (m, 1H), 1.59 – 1.26 (m, 9H), 1.19 – 1.09 (m, 6H); 13 C NMR (126 MHz, CDCl3) δ 175.2, 74.6, 74.1, 68.6, 61.3, 35.6, 34.6, 32.4, 30.0, 24.9, 23.5, 23.1, 17.4.

[0055] Starting from 7b, compound 9b can be prepared using the same synthetic method described above, with a yield of 92%. 1H NMR (500MHz, CDCl3) δ 4.41 (s, 1H), 3.73 (s, 3H), 3.64 (q, J = 6.4 Hz, 1H), 3.32 – 3.20(m, 1H), 3.26 (s, 3H), 1.96 (s, 2H), 1.79 – 1.68 (m, 1H), 1.59 – 1.33 (m,9H), 1.21 – 1.01 (m, 6H); 13 C NMR (126 MHz, CDCl3) δ 175.2, 74.7, 74.2, 68.6, 61.3, 35.6, 34.5, 32.4, 30.0, 24.9, 23.5, 23.1, 17.4. Compounds 10a / 10b

[0056] Compound 9a (500.0 mg, 1.8 mmol, 1.0 eq.) was dissolved in anhydrous dichloromethane (9.0 mL) under a nitrogen atmosphere. TEA (1.5 mL, 10.8 mmol, 6.0 eq.) and TESOTf (1.2 mL, 5.4 mmol, 3.0 eq.) were slowly added at –78 °C. The mixture was stirred at –78 °C for 30 min. The reaction was quenched with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (12 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 10a (1.06 g, 95%) as a colorless oil. 1 H NMR(500 MHz, CDCl3) δ 4.54 (s, 1H), 3.71 (s,3H), 3.64 (q, J = 6.2 Hz, 1H), 3.21 (s, 3H), 1.66 (q, J = 7.0, 6.4 Hz, 2H), 1.63– 1.55 (m, 1H), 1.48 (dt, J = 14.7, 6.3 Hz, 1H), 1.37 – 1.24 (m, 6H), 1.17 –1.03 (m, 6H), 0.95 (dt, J = 13.6, 8.0 Hz, 27H), 0.70 – 0.51 (m, 18H);13 C NMR(126MHz, CDCl3) δ 174.9, 77.7, 72.2, 69.6, 61.2, 40.6, 34.9, 32.6, 30.2, 25.7,23.3, 22.3, 17.8, 7.2, 7.0, 6.9, 6.7, 5.3, 4.7.

[0057] Starting from 9b, compound 10b can be prepared using the same synthetic method described above, with a yield of 96%. 1 H NMR (400MHz, CDCl3) δ 4.55 (s, 1H), 3.72 (s, 3H), 3.65 (q, J = 6.2 Hz, 1H), 3.22 (s,3H), 1.72 – 1.56 (m, 3H), 1.54 – 1.42 (m, 1H), 1.39 – 1.23 (m, 6H), 1.15 –1.07 (m, 6H), 1.02 – 0.89 (m, 27H), 0.69 – 0.53 (m, 18H); 13 C NMR (126 MHz, CDCl3) δ 174.9, 77.7, 72.2, 69.5, 61.2, 40.6, 35.0, 32.7, 30.2, 25.8, 23.3,22.3, 17.8, 7.2, 7.0, 6.9, 6.8, 5.3, 4.7. Compounds 12a / 12b

[0058] Compound 10a (100.0 mg, 0.16 mmol, 1.0 eq.) was dissolved in anhydrous dichloromethane (1.0 mL) under a nitrogen atmosphere. DIBAL-H (1.0 M in hexane, 0.32 mL, 0.32 mmol, 2.0 eq.) was slowly added at –78 °C. The mixture was stirred at –78 °C for 2 hours. The reaction was quenched with methanol and a saturated aqueous solution of potassium sodium tartrate. The resulting mixture was stirred for 3 hours until the organic and aqueous layers separated. The aqueous phase was extracted with dichloromethane (3.0 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give the intermediate aldehyde (83.0 mg) as a colorless oil.

[0059] Phosphonate 11 (104.4 mg, 0.32 mmol, 2.0 eq.) was dissolved in tetrahydrofuran and slowly added to a tetrahydrofuran solution of NaH (60 wt%, 13.2 mg, 0.32 mmol, 2.0 eq.) at 0 °C under nitrogen protection. The mixture was stirred at 0 °C for 30 min and then cooled to –78 °C. The aforementioned intermediate aldehyde (83.0 mg) was dissolved in tetrahydrofuran and added dropwise to the reaction mixture over 10 min. The resulting mixture was stirred at –78 °C for 30 min. The reaction was quenched with a saturated ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate (12 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give compound 12a (57.3 mg, total yield of 57% in both steps) as a colorless oil. 1 H NMR(400 MHz, CDCl3) δ 6.20(dd, J = 11.7, 8.3 Hz, 1H), 5.72 (dd, J = 11.7, 1.3 Hz, 1H), 5.39 – 5.24 (m, 1H), 3.74 (s, 3H), 3.65 (q, J 0.69 –0.51 (m, 18H); 13 C NMR(101 MHz, CDCl3) δ 166.3, 154.1, 117.0, 77.7, 72.2, 68.5,51.2, 40.6, 37.6, 30.4, 25.3, 23.3, 22.3, 17.8, 7.2, 7.0, 6.9, 6.8, 5.3, 4.8.

[0060] Starting from 10b, compound 12b can be prepared using the same synthetic method described above, with a yield of 56%. 1 H NMR (500 MHz, CDCl3) δ 6.20 (dd, J = 11.7, 8.2 Hz, 1H), 5.72 (dd,J = 11.7, 1.3 Hz,1H), 5.44 – 5.21 (m, 1H), 3.74 (s, 3H), 3.65 (q, J = 6.1 Hz, 1H), 1.61 – 1.52(m, 2H), 1.48 (s, 2H), 1.30 (tdd, J = 19.8, 8.8, 4.1 Hz, 6H), 1.14 – 1.09 (m,6H), 0.96 (tt, J = 7.8, 2.3 Hz, 27H), 0.60 (pd, J = 7.7, 2.3 Hz, 18H); 13 C NMR(126MHz, CDCl3) δ 166.3, 154.2, 117.0, 77.7, 72.1, 68.5, 51.2, 40.6, 37.6, 30.4,25.3, 23.3, 22.3, 17.8, 7.2, 7.0, 6.9, 6.8, 5.3, 4.8. Compounds 2a / 2b

[0061] Lactone 12a (200.0 mg, 0.32 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (2.0 mL) at 0 °C, and HF·Py (6.9 mL, 4.8 mmol, 15.0 eq.) was slowly added under a nitrogen atmosphere. The mixture was stirred at 0 °C for 1 h, then heated to room temperature and stirred for another 48 h. The reaction mixture was quenched with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (12 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to give compound 2a (68.5 mg, 88%) as a colorless oil. 1 H NMR (500 MHz, Methanol-) d 4) δ 7.72 (dd, J = 5.7, 1.5 Hz, 1H), 6.13 (dd, J = 5.7, 2.0 Hz, 1H), 5.15 (ddt, J = 7.1, 5.1, 1.8 Hz, 1H), 3.55(q, J= 6.4 Hz, 1H), 1.87 – 1.78 (m, 1H), 1.70 – 1.60 (m, 1H), 1.54 – 1.35 (m,8H), 1.14 (d, J = 6.4 Hz, 3H), 1.09 (s, 3H); 13 C NMR (126 MHz, Methanol-) d 4) δ175.8, 159.6, 121.6, 85.6, 75.4, 74.2, 38.8, 34.1, 31.2, 26.1, 24.0, 21.7,17.4.

[0062] Starting from 12b, compound 2b can be prepared using the same synthetic method described above, with a yield of 90%. 1 H NMR (500MHz, Methanol-) d 4) δ 7.71 (dd, J = 5.7, 1.5 Hz, 1H), 6.12 (dd, J = 5.7, 2.0 Hz, 1H), 5.14 (ddt, J = 7.1, 5.0, 1.8 Hz, 1H), 3.54 (q, J = 6.5 Hz, 1H), 1.87 – 1.77(m, 1H), 1.69 – 1.59 (m, 1H), 1.55 – 1.32 (m, 8H), 1.14 (d, J = 6.4 Hz, 3H), 1.08 (s, 3H); 13 C NMR (126 MHz, Methanol-) d 4) δ 175.8, 159.7, 121.6, 85.6, 75.4,74.2, 38.8, 34.1, 31.2, 26.1, 24.0, 21.7, 17.4. 10-( S )-mycenolide A (1a) / 10-( R )-mycenolide A (1b)

[0063] Compound 2a (20.0 mg, 0.08 mmol, 1.0 eq.) was dissolved in anhydrous dimethyl sulfoxide (0.4 mL) at room temperature, and IBX (45.0 mg, 0.16 mmol, 2.0 eq.) was added under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (12 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 1a (18.6 mg, 97%) as a colorless oil. 1 H NMR (500 MHz, DMSO- d 6) δ 7.83 (dd, J = 5.8, 1.5 Hz, 1H), 6.20 (dd, J = 5.8, 2.0 Hz, 1H), 5.13(ddt, J = 7.2, 5.2, 1.8 Hz, 1H), 5.07 (s, 1H), 2.13 (s, 3H), 1.75 – 1.64 (m,1H), 1.61 – 1.46 (m, 2H), 1.46 – 1.37 (m, 1H), 1.36 – 1.17 (m, 5H), 1.13 (s,3H), 1.11 – 1.03 (m, 1H); 13 C NMR (126 MHz, DMSO-) d 6) δ 214.1, 173.0, 158.8,120.2, 83.1, 78.2, 39.0, 32.3, 29.1, 25.1, 24.6, 24.3, 22.9.

[0064] Starting from 2b, compound 1b can be prepared using the same synthetic method described above, with a yield of 95%. 1 H NMR (500MHz, DMSO-) d 6) δ 7.83 (dd, J = 5.7, 1.5 Hz, 1H), 6.20 (dd, J = 5.8, 2.0 Hz, 1H), 5.14 (ddt, J= 7.2, 4.3, 2.5 Hz, 1H), 5.07 (s, 1H), 2.13 (s, 3H), 1.75 – 1.64(m, 1H), 1.61 – 1.48 (m, 2H), 1.46 – 1.37 (m, 1H), 1.34 – 1.20 (m, 5H), 1.13(s, 3H), 1.11 – 1.02 (m, 1H); 13 C NMR (126 MHz, DMSO-) d 6) δ 214.2, 173.0, 158.8,120.2, 83.1, 78.2, 39.0, 32.3, 29.1, 25.1, 24.6, 24.3, 22.9. The present invention has been described in detail above with reference to the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A method for preparing the natural product mycenolide A, characterized in that, Includes the following steps: Compound 2, IBX oxidant, and solvent were mixed and subjected to an oxidation reaction to obtain the natural product mycenolide A. The structural formulas of compound 2 and the natural product mycenolide A are as follows: 。 2. The preparation method according to claim 1, characterized in that, Compound 2 was prepared by the following method: Compound 12 and pyridine hydrogen fluoride are mixed to remove the TES silicon protecting group, and a lactone reaction occurs simultaneously to obtain the product. The structure of compound 12 is as follows: 。 3. The preparation method according to claim 2, characterized in that, Compound 12 was prepared by the following method: Compound 10 was first reduced to an aldehyde by diisobutylaluminum hydride at low temperature, and then reacted with compound 11 in a Horner-Wadsworth-Emmons olefination reaction to obtain compound 12. The structures of compounds 10 and 11 are as follows: 。 4. The preparation method according to claim 3, characterized in that, Compound 10 was prepared by the following method: Compound 9 was subjected to a silicon-based protection reaction under the action of TESOTf and a base to obtain the product. The structural formula of compound 9 is as follows: 。 5. The preparation method according to claim 4, characterized in that, Compound 9 was prepared by the following method: Compound 8, palladium-on-carbon catalyst, and hydrogen are mixed and reduced to obtain the product. The structural formula of compound 8 is as follows: 。 6. The preparation method according to claim 1, characterized in that, Compound 8 was prepared by the following method: The compound 7 and compound 4 were subjected to an olefin cross-metathesis reaction in the presence of Grubbs II catalyst to obtain the compound 7. The structural formulas of compounds 7 and 4 are as follows: 。 7. The preparation method according to claim 6, characterized in that, Compound 7 was prepared by the following method: Compound 5 is reacted with a Grignard reagent via an asymmetric Grignard addition reaction to obtain the product; The structural formula of compound 5 is as follows: 。 8. The preparation method according to claim 6, characterized in that, Compound 4 was prepared by the following method: Under the action of sulfuric acid and sodium nitrite, L-α-allylglycine undergoes a diazotization and deamination reaction to give compound 3; Subsequently, compound 3 under the conditions of condensing agent and DIPEA as base, undergoes an amide condensation reaction with N,O-dimethylhydroxylamine hydrochloride to give compound 4; The structural formulas of L-α-allylglycine and compound 3 are as follows: 。 9. The preparation method according to claim 1, characterized in that, The molar ratio of compound 2 to IBX oxidant is 1:(2.0~2.2).

10. The preparation method according to claim 2, characterized in that, The molar ratio of compound 12 to the pyridine hydrogen fluoride is 1:(15~15.5).

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