A method for preparing marine terpenoid natural products based on deoxygenative coupling reaction of carboxylate salt of sclareolide and benzoquinone compounds

Abstract

The patent relates to a method for preparing marine terpenoid natural products based on a decarboxylation coupling reaction of carboxylic acid salt of sclareolide or carboxylic acid of sclareolide and quinone compounds, and belongs to the field of chemical synthesis. The method takes sclareolide as raw material, and realizes, for the first time, a Minisci decarboxylation coupling reaction of carboxylic acid salt of bicyclic sesquiterpene or carboxylic acid of sclareolide and p-benzoquinone promoted by Selectfluor, so that the synthesis steps of yahazunone are shortened from the previous 6-18 steps to 2 steps, and asymmetric synthesis of multiple yahazunone natural products is realized. The method has the characteristics of good step economy, simple operation and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The application relates to a method for preparing marine terpenoid natural products based on a deacid coupling reaction of sclareolide carboxylate and a benzoquinone compound. BACKGROUND

[0002] Bioactivity detection of the marine natural product yahazunone shows that the yahazunone has good antibacterial activity on sclerotinia sclerotiorum, and the EC 50 value is 9.47 mg / L (Journal of Natural Product, 2018, 81 (9): 2010-2017). Based on the particularity of the structure of yahazunone, it can be used as a key intermediate to participate in the synthesis of various marine terpenoid natural products through subsequent functional group transformation or structural modification. The natural product puupehedione has excellent angiogenesis inhibition effect and is an important lead compound for drug research (International Journal of Cancer, 2004, 110 (1): 31-38). However, the pharmacological and pharmacodynamic research of the active marine terpenoid natural product is affected due to the low content of the active marine terpenoid natural product in the natural organisms and the difficulty in separation and taking. The chemical synthesis research can make up for the defect of insufficient raw material supply in subsequent drug research.

[0003] Therefore, it is particularly necessary to develop a chemical synthesis method of the yahazunone marine natural product. So far, the synthesis of the marine natural product yahazunone mostly adopts a convergent coupling strategy, and the synthesis route is as long as 18 steps, and the total yield is low. In 2012, Baran tried the direct coupling of various free radical donors and benzoquinone compounds, but failed (Journal of the American Chemical Society, 2012, 134 (20): 8432-8435). On the basis, the conditions are explored and optimized, and the direct coupling of sclareolide carboxylate and benzoquinone compounds is successfully realized, and the method has the advantages of few reaction steps, simple operation and suitability for industrial production. SUMMARY

[0004] The application aims to provide a method for preparing terpenoid natural products based on a deacid coupling reaction of sclareolide carboxylate and a benzoquinone compound, which has few reaction steps, good product selectivity and suitability for industrial production.

[0005] A method for preparing marine terpenoid natural products based on a deacid coupling reaction of sclareolide carboxylate and a benzoquinone compound, characterized by comprising the following steps:

[0006] Sclareolide carboxylate 1 or the peroxide of the serratene carboxylic acid 1 with benzoquinone 2 Minisci decarboxylation coupling reaction occurs under the action of Selectfluor oxidant and silver catalyst to generate coupling product 3 or the marine terpenoid natural product yahazunone

[0007] The coupling product 3 described in the application is prepared into a marine terpenoid natural product through subsequent functional group transformation and structural modification.

[0008] The serratene carboxylic acid salt described in the application selects potassium salt, sodium salt, ammonium salt.

[0009] The Selectfluor oxidant described in the application selects Selectfluor and Selectfluor II as the oxidant.

[0010] The silver catalyst described in the application selects silver nitrate, silver phosphate, silver carbonate and silver fluoride as the catalyst.

[0011] The decarboxylation coupling reaction process described in the application selects dichloroethane / water mixed solvent as the reaction solvent.

[0012] The decarboxylation coupling reaction process described in the application has a reaction temperature of 20-50 DEG C and a reaction time of 20-40 hours.

[0013] The application has the following characteristics:

[0014] 1. The Minisci decarboxylation coupling reaction of the Selectfluor promoted bicyclic sesquiterpene carboxylic acid salt and p-benzoquinone is realized for the first time, the synthesis steps of yahazunone are shortened from the previous 6-18 steps to 2 steps, and the yield is greatly improved;

[0015] 2. The application realizes the synthesis of multiple natural products by taking the Minisci reaction with a mild oxidant as the key reaction, and has the advantages of fewer reaction steps and suitability for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 is the structural formula of the marine natural product yahazunone.

[0017] Figure 2 is the specific synthesis route of the Minisci decarboxylation coupling in the application.

[0018] Figure 3 is the specific synthesis route of the 8-epi-puupehenol natural product in the application.

[0019] Figure 4 is a specific synthetic route of puupehenol natural product in the present application. DETAILED DESCRIPTION

[0020] The present application is further illustrated below with reference to the accompanying drawings:

[0021] A method for preparing marine terpenoid natural product based on decarboxylation coupling reaction of sclareolide carboxylate and benzoquinone compounds, characterized in that the method steps are as follows:

[0022] Sclareolide carboxylate 1 or Sclareolide carboxylic acid 1' and benzoquinone compounds 2 Under the action of Selectfluor oxidant and silver catalyst, Minisci decarboxylation coupling reaction occurs to generate coupling product 3 or marine terpenoid natural product yahazunone

[0023] Further, the coupling product 3 is prepared into marine terpenoid natural product through subsequent functional group transformation and structural modification.

[0024] Further, the sclareolide carboxylate is selected from potassium salt, sodium salt, and ammonium salt (M in the structural formula).

[0025] Further, the Selectfluor oxidant is selected from Selectfluor and Selectfluor II as the oxidant.

[0026] Further, the silver catalyst is selected from silver nitrate, silver phosphate, silver carbonate, and silver fluoride as the catalyst.

[0027] Further, the decarboxylation coupling reaction process selects dichloroethane / water mixed solvent as the reaction solvent.

[0028] Further, the reaction temperature of the decarboxylation coupling reaction process is 20-50°C, and the reaction time is 20-40 hours.

[0029] Example 1: Synthesis of natural product yahazunone (see attached Figure 2 )

[0030] A round bottom flask was charged with yahazunone carboxylate (0.2 mmol, 1.0 equiv.), 1,4-benzoquinone (0.4 mmol, 43 mg) and Selectfluor (142 mg, 0.4 mmol, 2.0 equiv.) at room temperature. DCE ((1 mL) and deionized water (0.9 mL) were added and stirred for about 1 minute at room temperature. Aqueous AgN03(0.1 mL, 0.4 M in H20, 0.04 mmol) was added under nitrogen protection. Stirring was continued for 24 hours. Ethyl acetate (3 x 3 mL) was used for extraction and the crude product after drying was purified by column chromatography to yield the desired product (+)-yahazunone 41 mg in 62% yield. 1 H NMR (400 MHz, CDC13): δ 6.72 (d, J = 10.0 Hz, 1H), 6.67 (d, J = 10.2, 2.8 Hz, 1H), 6.59 (s, 1H), 2.62 (dd, J = 15.1, 6.0 Hz, 1H), 2.47 (dd, J = 15.2, 5.1 Hz, 1H), 1.87 (dt, J = 12.2, 3.0 Hz, 1H), 1.29-1.24 (m, 1H), 1.20 (s, 3H), 0.87 (s, 3H), 0.86 (s, 3H), 0.79 (s, 3H); 13 C NMR (100 MHz, CDC13): δ 188.1, 187.6, 152.7, 136.9, 136.2, 132.8, 74.0, 61.6, 55.9, 44.8, 41.8, 40.5, 39.4, 33.2 (2C), 24.6, 23.8, 21.5, 20.3, 18.4, 15.1 ppm.

[0031] Example 2: Synthesis of natural product yahazunone

[0032] A round bottom flask was charged with yahazunone carboxylate 1' (0.2 mmol, 1.0 equiv.), 1,4-benzoquinone (0.4 mmol, 43 mg) and Selectfluor (142 mg, 0.4 mmol, 2.0 equiv.) at room temperature. DCE ((1 mL) and deionized water (0.9 mL) were added and stirred for about 1 minute at room temperature. Aqueous AgN03(0.1 mL, 0.4 M in H20, 0.04 mmol) was added under nitrogen protection. Stirring was continued for 24 hours. Ethyl acetate (3 x 3 mL) was used for extraction and the crude product after drying was purified by column chromatography to yield the desired product (+)-yahazunone 41 mg in 62% yield.

[0033] Example 3: Preparation of compound 3a (3a, see attached scheme)Figure 3

[0034] To a round bottom flask was added the carboxylate salt (0.2 mmol, 1.0 equiv.), 2-methoxy-1,4-benzoquinone (0.4 mmol, 2.0 equiv.) and Selectfluor (142 mg, 0.4 mmol, 2.0 equiv.) at room temperature. DCE (1 mL) and deionized water (0.9 mL) were then added and stirred at room temperature for about 1 minute. Aqueous AgN03(0.1 mL, 0.4 M in H20, 0.04 mmol) was added in one portion. The reaction was sealed with a cap and stirred at 50 °C for 24 hours. The reaction was diluted with ethyl acetate (1 mL) and to this was added saturated NaHC03(3 mL). The crude product after rotary evaporation was column chromatography purified to yield the desired product 3a (21 mg, 27%) as a brown oil. 1 H NMR (400 MHz, CDC13): δ 6.56 (s, 1H), 5.89 (s, 1H), 3.80 (s, 3H), 2.64 (ddd, J = 15.2, 5.6, 1.2 Hz, 1H), 2.45 (ddd, J = 14.8, 5.2, 1.2 Hz, 1H), 1.39 (d, J = 10.8 Hz, 2H), 1.19 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.78 (s, 3H) ppm; 13 C NMR (100 MHz, CDC13): δ 188.3, 182.4, 158.6, 153.6, 131.2, 108.0, 73.9, 62.1, 56.3 (2C), 44.8, 41.8, 40.6, 39.6, 33.5, 33.4, 25.0, 24.0, 21.6, 20.5, 18.6, 15.4 ppm.

[0035] Example 4: Preparation of compound 4 (4, see Figure 1) Figure 3

[0036] pTsOH (21 mg, 0.12 mmol) was added to a solution of 3a (29 mg, 0.08 mmol) in DCM (3 mL) and the mixture was stirred at room temperature for 15 minutes before being quenched with saturated aqueous NaHC03, and the crude product after rotary evaporation was column chromatography purified to yield compound 4 (26 mg, 93%) as an orange oil. 1 ​​H NMR (400 MHz, CDC13): δ 6.17 (s, 1 H), 5.75 (s, 1 H), 2.63 (d, J = 9.2 Hz, 2 H), 2.09 (d, J = 11.1 Hz, 1 H), 1.80 (d, J = 13.8 Hz, 1 H), 1.74-1.69 (m, 2 H), 1.64-1.60 (m, 3 H), 1.51-1.37 (m, 3 H), 1.33 (s, 3 H), 1.18 (d, J = 13.8 Hz, 1 H), 1.02 (d, J = 12.0 Hz, 1 H), 0.90 (s, 3 H), 0.86 (s, 3 H), 0.82 (s, 3 H) ppm; 13 C NMR (100 MHz, CDC13): δ 180.3, 178.7, 165.2, 145.2, 128.3, 107.8, 82.0, 55.7, 51.5, 41.5, 40.5, 38.5, 37.0, 33.2, 33.1, 23.5, 21.9, 21.3, 19.5, 18.1, 14.6 ppm.

[0037] Example 5: Synthesis of (+)-8-epi-puupehenol (see Figure 1) Figure 3 )

[0038] Compound 4 (26 mg, 0.08 mmol) was dissolved in EtOH (2 mL) and NaBH4(6 mg, 0.16 mmol) was added. After the mixture was stirred at room temperature for 20 minutes, it was placed in a 0 °C cold trap and quenched with dilute hydrochloric acid (2 Naq.) added slowly dropwise until gas evolution ceased. It was then diluted with EtOAc (15 mL) and spun dry to give the crude compound (+)-8-epi-puupehenol.

[0039] Example 6: Synthesis of (+)-8-epi-puupehedione (see Figure 1) Figure 4 )

[0040] The crude product (+)-8-epi-puupehenol was dissolved in tert-butanol (2 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 36 mg, 0.16 mmol) was added. After the resulting mixture was refluxed for 2 hours, the solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and the crude product after being spun dry was purified by column chromatography to give the red solid (+)-8-epi-puupehedione (13 mg, 48% overall yield for two steps). 1H NMR (400 MHz, CDC13): δ 6.26 (s, 1H), 6.12 (s, 1H), 5.92 (s, 1H), 2.20 (dd, J = 9.6, 5.8 Hz, 1H), 1.92-1.89 (m, 2H), 1.82-1.72 (m, 2H), 1.68-1.62 (m, 2H), 1.58 (s, 3H), 1.56-1.25 (m, 1H), 1.47-1.40 (m, 2H), 1.18 (s, 3H), 1.10 (d, J = 12.2 Hz, 1H), 0.92 (s, 3H), 0.89 (s, 3H) ppm; 13 C NMR (100 MHz, CDC13): δ 181.0, 179.5, 166.2, 164.1, 137.7, 122.1, 114.3, 107.9, 82.9, 53.0, 41.1, 41.0, 40.2, 37.6, 34.0, 33.1, 30.6, 21.8, 21.6, 19.1, 18.5 ppm

[0041] Example 7: Preparation of compound 3b (3b, see Scheme 1) Figure 4 )

[0042] To a round bottom flask was added the carboxylate salt (0.2 mmol, 1.0 equiv.), 2-methoxy-1,4-benzoquinone (0.4 mmol, 2.0 equiv.) and Selectfluor (142 mg, 0.4 mmol, 2.0 equiv.) at room temperature. Then DCE (1 mL) and deionized water (0.9 mL) were added and stirred at room temperature for about 1 min. Aqueous AgN03(0.1 mL, 0.4 M in H20, 0.04 mmol) was added in one portion. The reaction was sealed with a cap and stirred at 50 °C for 24 h. The reaction was diluted with ethyl acetate (1 mL) and to this saturated NaHC03(3 mL) was added. The crude product after rotary evaporation was washed with ethyl acetate (3 x 3 mL) and column chromatography purification to give the desired product 3a (17 mg, 21%) as a brown oil. 1 H NMR (400 MHz, CDC13): δ 6.56 (s, 1H), 5.89 (s, 1H), 3.80 (s, 3H), 2.64 (ddd, J = 15.2, 5.6, 1.2 Hz, 1H), 2.45 (ddd, J = 14.8, 5.2, 1.2 Hz, 1H), 1.39 (d, J = 10.8 Hz, 2H), 1.19 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.78 (s, 3H) ppm; 13C NMR (100 MHz, CDC13): δ 188.3, 182.4, 158.6, 153.6, 131.2, 108.0, 73.9, 62.1, 56.3 (2C), 44.8, 41.8, 40.6, 39.6, 33.5, 33.4, 25.0, 24.0, 21.6, 20.5, 18.6, 15.4 ppm.

[0043] Example 8: Preparation of compound 6 (6, see attached scheme 2) Figure 4 )

[0044] pTsOH (31 mg, 0.18 mmol) was added to a solution of compound 3b (43 mg, 0.12 mmol) in DCM (3 mL) at room temperature and the solvent was evaporated under vacuum after stirring for 15 min. The residue was purified by column chromatography to give compound 6 (37 mg, 94%) as an orange oil. 1 H NMR (400 MHz, CDC13): δ 6.55 (s, 1H), 5.93 (s, 1H), 3.81 (s, 3H), 2.78 (ddd, J = 18.7, 6.1, 1.3 Hz, 1H), 2.40-2.38 (m, 1H), 2.04 (d, J = 18.9 Hz, 1H), 1.76 (dd, J = 11.2, 3.4 Hz, 2H), 1.55-1.51 (m, 3H), 1.39-1.33 (m, 2H), 1.30 (dd, J = 6.0, 3.1 Hz, 1H), 1.15-1.07 (m, 1H), 1.02 (s, 3H), 0.97 (s, 3H), 0.91-0.89 (m, 2H), 0.87 (s, 3H) 0.83 (s, 3H) ppm; 13 C NMR (100 MHz, CDC13): δ 188.3, 182.4, 158.6, 153.6, 131.2, 108.0, 73.9, 62.1, 56.3 (2C), 44.8, 41.8, 40.6, 39.6, 33.5, 33.4, 25.0, 24.0, 21.6, 20.5, 18.6, 15.4 ppm.

[0045] Example 9: Preparation of natural product puupehedione (see attached scheme 3) Figure 4 )

[0046] Compound 6 (37 mg, 0.12 mmol) was dissolved in EtOH (2 mL) and to this was added sodium borohydride (9 mg, 0.24 mmol) slowly at room temperature. The resulting mixture was stirred further and the reaction was quenched by the dropwise addition of dilute hydrochloric acid (2 Naq.) until no gas was evolved. The mixture was then diluted with ethyl acetate (15 mL) and the crude compound puupehenol was obtained upon drying.

[0047] The crude product puupehenol was dissolved in 1,4-dioxane (2 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 54 mg, 0.24 mmol) was added. The resulting mixture was stirred at reflux for 2 h and then concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography to give puupehedione as a red solid (17 mg, 43% overall yield for two steps). 1 H NMR (400 MHz, CDC13): δ 6.31 (s, 1H), 6.12 (s, 1H), 5.95 (s, 1H), 2.09-2.06 (m, 1H), 2.03-2.00 (m, 1H), 1.88 (d, J = 9.0 Hz, 1H), 1.69 (d, J = 14.4 Hz, 1H), 1.60 (d, J = 14.2 Hz, 1H), 1.54 (s, 3H), 1.47-1.46 (m, 1H), 1.46-1.42 (m, 1H), 1.32-1.29 (m, 1H), 1.24 (s, 3H), 1.13 (d, J = 12.4 Hz, 1H), 0.96 (s, 3H), 0.89 (s, 3H) ppm; 13 C NMR (100 MHz, CDC13): δ 180.9, 179.5, 169.4, 164.5, 138.3, 122.1, 115.3, 109.1, 81.8, 43.4, 41.6, 40.8, 38.6, 33.8, 32.7, 30.8, 29.5, 25.1, 21.1, 18.7, 16.7 ppm

[0048] Example 10: Preparation of natural product puupehenone (see attached Figure 4 )

[0049] The crude product 6 was dissolved in CH3CN (2 mL) and K2CO3 (10 mg, 0.075 mmol) was added to it. After stirring at room temperature for 1 h, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The crude product was purified by silica gel flash column chromatography to give puupehenone as a yellow oil (45 mg, 92%). 1H NMR (400 MHz, CDC13): δ 6.88 (s, br, 1H), 6.66 (d, J = 6.9 Hz, 1H), 6.20 (s, 1H), 5.86 (s, 1H), 2.17 (dd, J = 2.4, 11.4 Hz, 1H), 2.04 (d, J = 6.9 Hz, 1H), 1.68 (d, J = 6.9 Hz, 1H), 1.23 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H) ppm; 13 C NMR (100 MHz, CDC13): δ 182.1, 162.8, 147.5, 140.4, 129.4, 106.1, 105.1, 78.9, 54.9, 53.9, 41.7, 40.8, 40.1, 39.3, 33.7, 33.3, 28.1, 21.9, 18.5, 18.1, 15.0 ppm

[0050] The present application relates to the decarboxylation coupling reaction of natural product yahazunone class active natural product by mild oxidant and silver catalyst, and the above specific embodiment is the preferred example of the present application, and is not the limitation of the present application to other forms.

Claims

1. A method for preparing a marine terpenoid natural product based on a deoxygenative coupling reaction of a carboxylate salt of sclareolide with a benzoquinone compound, characterized in that The method steps are as follows: Sclareolide carboxylate 1 or Sclareolide carboxylic acid 1' with benzoquinone compounds 2 Minisci decarboxylation coupling reaction occurs under the action of Selectfluor oxidant and silver catalyst to generate coupling product 3 , M is potassium, sodium, ammonium, R is hydrogen or methoxy, the Selectfluor oxidant is selected from Selectfluor and Selectfluor II, the silver catalyst is selected from silver nitrate, and the decarboxylation coupling reaction process selects dichloroethane / water mixed solvent as the reaction solvent.

2. The method for preparing marine terpenoid natural products based on the deoxygenative coupling reaction of carboxylate salt of sclareolide with benzoquinone compounds according to claim 1, characterized in that The coupling product 3 is prepared into marine terpenoid natural products through subsequent functional group transformation and structural modification.

3. The method for preparing marine terpenoid natural products based on the deoxygenative coupling reaction of carboxylate salt of sclareolide with benzoquinone compounds according to claim 1, characterized in that The reaction temperature of the decarboxylation coupling reaction process is 20-50 DEG C, and the reaction time is 20-40 hours.

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