CN110669031A - Total synthesis method of natural product isoperidone J - Google Patents

Abstract

The invention discloses a total synthesis method of isobenzofuranone natural compounds J. Taking 3, 5-dihydroxy-4-iodobenzoic acid methyl ester as an initial raw material, obtaining an isobenzofuranone intermediate 3 after methylation reaction, Friedel-crafts alkylation and ester exchange, then protecting hydroxyl to prepare a tin reagent intermediate 5, and then carrying out Stille coupling reaction with geranyl acetate to generate the isomonkey head mycophenole J after deprotection. In the invention, the raw materials are simple and easy to obtain, the reaction conditions of each unit in the reaction process are mild and controllable, the reaction yield is high, and the method has important application value in the total synthesis of natural product isomonkey head mycophenole J and the discovery of medicaments.

Description

The total synthesis method of natural product isohericin J

technical field

The invention relates to an isobenzofuranone class natural compound, in particular to a total synthesis method of isohericium ketone J, and belongs to the technical field of natural product synthesis.

Background technique

Hericium erinaceus, as a medicinal and edible fungus, is mild in nature and sweet in taste. Related extracted polysaccharides, fatty acids, diterpenoids, alkaloids, sterols and aromatic compounds such as Isohericenone J and Hericenone A are used in the treatment of digestive tract diseases, Neurological dysfunction, diabetes, tumors, etc. have aroused widespread concern.

Hericium erinone J, is a kind of isobenzofuranone derivative isolated from Hericium erinaceus, the structural formula is as follows:

The structure was determined by Kim's group in 2015, and Kim's group's research found that this type of compound showed significant inhibition of acute myeloid leukemia HL-60 and HEL-299 cellular activity (Food Chem., 2015, 170, 336-342).

However, due to the relative complexity in the structure, there are few studies on total synthesis, which limits the further application of this class of isobenzofuranones in drug development.

SUMMARY OF THE INVENTION

In order to overcome the above-mentioned technical defects, the present invention provides a method for the total synthesis of isobenzofuranone natural compounds, especially isohericium ketone J. Using commercially available methyl 3,5-dihydroxy-4-iodobenzoate 1 as the starting material, through methylation reaction, Friedel-Crafts alkylation and transesterification chain reaction, isobenzofuranone intermediate 3 was synthesized; After the hydroxyl group of body 3 is protected, it is then made into tin reagent intermediate 5; then intermediate 5 is coupled with geranyl acetate through Stille, and then deprotected to generate isoericin J.

The total synthesis method of isohericin J according to the present invention starts from methyl 3,5-dihydroxy-4-iodobenzoate, and goes through successively monomethylation, Friedel-Crafts alkylation/lactonation, hydroxyl protection, Catalytic tinylation, Stille coupling, deprotection and other six-step reactions are completed, and the reaction equation is expressed as follows:

In the above reaction, the following steps are specifically included:

The first step, monomethylation:

Reaction of methyl 3,5-dihydroxy-4-iodobenzoate (1), a base and in a polar aprotic solvent affords methyl 3-hydroxy-4-iodo-5-methoxybenzoate (2 ).

Wherein, the methylating reagent is selected from dimethyl carbonate, dimethyl sulfate, methyl iodide and the like. The base is selected from inorganic bases (such as potassium carbonate, sodium carbonate, cesium carbonate, etc.) or organic bases (such as triethylamine, diisopropylethylamine, etc.), preferably potassium carbonate or cesium carbonate. The polar aprotic solvent is selected from DMF, DMSO, dioxane and the like.

Further, under the above reaction conditions, the molar ratio of the methyl 3,5-dihydroxy-4-iodobenzoate 1, the methylating reagent and the base is 1:0.8-1.5:1-3; the preferred molar ratio is 1:1-1.2:1.5-2.

The typical operation of this step is as follows: add methyl 3,5-dihydroxy-4-iodobenzoate 1, alkali and polar aprotic solvent to the reaction kettle in turn, add methylating reagent dropwise, and react at room temperature; after the reaction is completed, add Quenched with saturated ammonium chloride solution, extracted and separated, the organic layer was washed and dried with water, then desolvated and concentrated, added ether and alkane solvent for crystallization and purification to obtain methyl 3-hydroxy-4-iodo-5-methoxybenzoate 2.

The second step, Friedel-Crafts alkylation/lactonation:

Reaction of methyl 3-hydroxy-4-iodo-5-methoxybenzoate (2) and paraformaldehyde in the presence of mixed acid to generate 4-hydroxy-5-iodo-6-methoxy-3H-isophenyl and furan-1-one (3).

Wherein, the mixed acid is a mixture of glacial acetic acid and hydrobromic acid, wherein glacial acetic acid is a solvent. After the Friedel-Crafts reaction, the reaction spontaneously undergoes transesterification to form lactones.

Further, under the above reaction conditions, the molar ratio of the methyl 3-hydroxy-4-iodo-5-methoxybenzoate 2, paraformaldehyde and hydrobromic acid is 1:0.8-2:1-3; The preferred molar ratio is 1:2:1.1.

The typical operation of this step is as follows: add methyl 3-hydroxy-4-iodo-5-methoxybenzoate 2, paraformaldehyde and glacial acetic acid successively to the reaction kettle, and dropwise add a mixed solution of hydrobromic acid and glacial acetic acid at 0°C , after the dropwise addition was completed, the reaction was carried out at room temperature; after the reaction was completed, a saturated sodium bicarbonate solution was added to quench, and the liquid was extracted and separated. 5-iodo-6-methoxy-3H-isobenzofuran-1-one 3.

The third step, hydroxyl protection:

4-Hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one (3), base and halomethyl methyl ether were reacted in a chlorinated alkane solvent to give 5-iodo-6- Methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one (4).

Wherein, the base is selected from inorganic bases (such as potassium carbonate, sodium carbonate, cesium carbonate) or organic bases (such as triethylamine, diisopropylethylamine, etc.), preferably diisopropylethylamine. The halomethyl methyl ether is selected from chloromethyl methyl ether or bromomethyl methyl ether. The chlorinated alkane solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, etc., preferably dichloromethane.

Further, under the above reaction conditions, the molar ratio of 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one 3, halomethyl methyl ether and alkali is 1:1-3 : 1-3; the preferred molar ratio is 1:1.5:2.

The typical operation of this step is as follows: successively add 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one 3, alkali and chlorinated alkane solvent to the reactor, dropwise at 0 °C Add bromomethyl methyl ether, and react at room temperature after the dropwise addition is completed; after the reaction is completed, add water to quench, extract and separate the organic layer, wash and dry the organic layer, remove and concentrate, add ether and alkane mixed solvent for crystallization and purification to obtain 5-iodine -6-Methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4.

The fourth step, catalytic tin-based:

5-Iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one (4), palladium catalyst and hexamethyltin were reacted in solvent to form 6-methoxy -4-Methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one (5).

Wherein, the palladium catalyst is selected from at least one of Pd(PPh ₃ ) ₄ , Pd ₂ (dba) ₃ or Pd(t-Bu ₃ P) ₂ . The reaction solvent is selected from common solvents such as toluene, dioxane, DMF or THF.

Further, under above-mentioned reaction conditions, 5-iodo-6-methoxyl group-4-methoxymethoxyl group-3H-isobenzofuran-1-one 4, palladium catalyst and hexamethyltin mol ratio are 1 : 0.001-0.020: 1-3; the preferred molar ratio is 1: 0.05-0.10: 1.2-1.5.

The typical operation of this step is as follows: 5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4, palladium catalyst and hexamethyltin and The reaction solvent is refluxed under the protection of nitrogen; after the reaction is completed, water is added to quench, extract and liquid separation, the organic layer is washed and dried with water, then desolvated and concentrated, and an alkane solvent is added for crystallization and purification to obtain 6-methoxy-4-methoxymethoxy yl-5-trimethyltin-3H-isobenzofuran-1-one 5.

The fifth step, Stille coupling:

6-Methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one (5), palladium catalyst geranyl acetate (6) and lithium chloride The reaction in the solvent generates MOM-protected ericin J(7).

Wherein, the palladium catalyst is selected from at least one of Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ and Pd(t-Bu ₃ P) ₂ . The reaction solvent is selected from common solvents such as toluene, dioxane, DMF and THF.

Further preferably: when the 4th step and the 5th step are carried out continuously, the 5th step does not need a palladium catalyst;

Further, under the above reaction conditions, 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one 5, palladium catalyst, geranyl acetate 6 The molar ratio with lithium chloride is 1:0.001-0.02:1-3:1-3, preferably the molar ratio is 1:0.05-0.10:1.1-1.5:1-1.5.

The typical operation of this step is as follows: successively add 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one 5, palladium catalyst, acetic acid into the reactor Leaf ester 6, lithium chloride and reaction solvent were heated and reacted under the protection of nitrogen; after the reaction was completed, water was added to quench, extract and liquid separation, the organic layer was washed and dried, desolvated and concentrated, and subjected to silica gel column chromatography to obtain MOM-protected Hericium erinaceus Mycoketone J-7.

The sixth step, deprotection:

Deprotection of MOM-protected ericin J (7) in the presence of an acid catalyst yields ericin J.

Wherein, the acid catalyst is selected from p-toluenesulfonic acid, camphorsulfonic acid, acetic acid, etc., preferably camphorsulfonic acid. The reaction solvent is selected from common alcohol solvents such as methanol, ethanol and isopropanol.

Further, under the above reaction conditions, the molar ratio of MOM-protected isohericin J-7 to the acid catalyst is 1:1-3; the preferred molar ratio is 1:2-2.5.

The typical operation of this step is as follows: add MOM-protected isohericium ketone J-7, acid catalyst and reaction solvent to the reaction kettle in turn, and the mixture is stirred at room temperature for reaction; after the reaction is completed, add triethylamine to quench, extract and separate liquids, and the organic layer After washing and drying, desolventizing and concentrating, the product mixture was separated by reversed-phase medium pressure column chromatography to obtain isohericium ketone J.

Invention Beneficial Effects

The present invention provides a total synthesis method of isohericium ketone J for the first time. The synthesis method has simple and easy-to-obtain raw materials, mild and controllable reaction conditions of each unit in the reaction process, and high reaction yield. It has important application value in the total synthesis of natural products and drug discovery.

Detailed ways

The technical solutions of the present invention will be described in further detail below with reference to specific embodiments.

Example 1

1) the synthesis of 3-hydroxy-4-iodo-5-methoxybenzoic acid methyl ester 2, concrete process is as follows:

29.4g (0.1mol, 99%) of methyl 3,5-dihydroxy-4-iodobenzoate, 27.6g (0.2mol, 98%, 2eq) of potassium carbonate and 200g DMF were successively put into a dry 1L four-necked flask, 17.03 g of methyl iodide (0.12 mol, 99%, 1.2 eq.) was slowly added dropwise at room temperature. After the addition was completed, the reaction was stirred at room temperature for 24 h. TLC detected the reaction raw material, methyl 3,5-dihydroxy-4-iodobenzoate. complete conversion.

After the reaction was completed, it was lowered to room temperature, 500 g of saturated ammonium chloride solution was added to quench the reaction, stirred for 0.5 h, ethyl acetate was added to extract the layers, and the organic phase was retained; the organic phase was washed twice with 2*250 g of water; anhydrous sulfuric acid was added to the organic phase Sodium was dried, filtered and concentrated; a light yellow viscous liquid was obtained, which was recrystallized by adding isopropyl ether and n-hexane to obtain 19.1 g of a white solid, which was the target intermediate 2,3-hydroxy-4-iodo-5-methoxybenzene Methyl formate, yield 62.0%.

Melting point 128-130℃; 1H NMR(400MHz, CD ₃ OD): 7.13-7.11(m, 1H), 7.03-6.99(m, 1H), 3.88(s, 6H). ¹³ C NMR(100MHz, CD ₃ OD) ): 168.1, 161.2, 159.6, 132.8, 109.4, 103.4, 83.3, 57.0, 52.8. HRMS-ESI(m/z): calcd for C ₉ H ₈ IO ₄ (MH) ^- 306.9473, found 306.9476.

2) the synthesis of 4-hydroxyl-5-iodo-6-methoxyl group-3H-isobenzofuran-1-one 3, the concrete process is as follows:

Into a dry 250mL four-necked flask, successively put into intermediate 2 (methyl 3-hydroxy-4-iodo-5-methoxybenzoate) 15.4g (0.05mol, 99%), paraformaldehyde 3.0g (0.1mol, 98%, 2eq) and 100g glacial acetic acid, cooled to 0°C, slowly added dropwise 18.4g of hydrobromic acid solution (0.075mol, 33% acetic acid solution, 1.5eq), after the addition was completed, the reaction was stirred at room temperature for 24h, TLC detected, The reaction raw material 3-hydroxy-4-iodo-5-methoxybenzoic acid methyl ester was converted completely.

After the reaction was completed, 200 g of saturated sodium bicarbonate solution was added to quench the reaction, ethyl acetate was added to extract the layers, and the organic phase was retained; the organic phase was washed twice with 2*50 g of saturated brine; the organic phase was dried by adding anhydrous sodium sulfate, filtered, and concentrated. to obtain a light yellow solid, which was recrystallized by adding isopropyl ether and n-hexane to obtain 11.2 g of a white solid, which was the target intermediate 3,4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1 -ketone, yield 73.2%.

Melting point 180-182℃, ¹ H NMR (400MHz, CDCl ₃ ): 6.89(s, 1H), 5.89(s, 1H), 5.27(s, 2H), 3.96(s, 3H). ¹³ C NMR(100MHz, CDCl ₃ ): 170.8, 160.1, 150.8, 128.6, 125.3, 98.4, 85.9, 68.0, 57.3. HRMS-ESI (m/z): calcd for C ₉ H ₆ IO ₄ (MH) ^- 304.9316, found 304.9322.

3) Synthesis of 5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4, the concrete process is as follows:

Into a dry 250mL four-necked flask, put intermediate 3 (4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one) 9.2g (0.03mol, 98%), diiso 7.8g of propylethylamine (0.06mol, 99%, 4eq) and 100g of dichloromethane, cooled to 0°C, slowly added dropwise 28.1g of bromomethyl methyl ether solution (0.045mol, 20% solution of dichloromethane, 1.5eq ), and the reaction was stirred at room temperature for 24 h after the dropwise addition. TLC detected that the reaction raw material 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one was completely converted.

After the reaction was completed, 100 g of water was added to quench the reaction, extracted and separated, and the organic phase was retained; the organic phase was washed twice with 2*50 g of saturated brine; the organic phase was dried by adding anhydrous sodium sulfate, filtered, and concentrated; Recrystallization from propyl ether and n-hexane gave 9.1 g of white solid, which was the target intermediate 4 (5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one), Yield 86.2%.

Melting point 163-165℃, ¹ H NMR (400MHz, CDCl ₃ ): 7.07(s, 1H), 5.40(s, 2H), 5.17(s, 2H), 3.97(s, 3H), 3.58(s, 3H) . ¹³ C NMR (100 MHz, CDCl ₃ ): 170.6, 160.8, 152.7, 128.7, 101.4, 97.6, 91.7, 77.4, 68.6, 57.4, 57.3. HRMS-ESI (m/z): calcd for C ₁₁ H _{12 10 5} (M+H) ⁺ 350.9724,found350.9722.

4) Synthesis of 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-ketone 5, the concrete process is as follows:

Into a dry 250mL four-necked flask, put into the intermediate 4 (5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one) 8.8g (0.025mol, 97 %), Pd(t- _Bu3P ) ₂ catalyst 0.64g (0.00125mol, 99%, 0.05eq), Sn( _CH3 ) ₆ 12.3g (0.0375mol, 99%, 1.0eq) and 100g toluene, nitrogen replacement And heated to 100 ℃ under nitrogen protection for 24 hours, TLC detection, the reaction raw material 5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one was completely converted.

After the reaction is completed, add 100 g of water to quench the reaction, extract and separate, and retain the organic phase; the organic phase is washed twice with an aqueous ammonia solution of 2*50 g saturated potassium fluoride; the organic phase is dried by adding anhydrous sodium sulfate, filtered, and concentrated; The yellow solid was recrystallized by adding isopropyl ether and n-hexane to obtain 6.0 g of white solid, which was the target intermediate 5(6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isophenylene) and furan-1-one), yield 61.5%.

Melting point 93-94℃, ¹ H NMR (400MHz, CDCl ₃ ): 7.05(s, 1H), 5.38(s, 2H), 5.04(s, 2H), 3.82(s, 3H), 3.50(s, 3H) , 0.33(s, 9H). ¹³ C NMR (100MHz, CDCl ₃ ): 171.3, 166.1, 156.9, 130.3, 129.4, 127.0, 100.5, 96.2, 69.6, 56.8, 55.9, -6.8.HRMS-ESI (m/z ):calcd for C ₁₄ H ₂₁ O ₅ Sn(M+H) ⁺ 389.0406, found 389.0402.

5) MOM protects the synthesis of heterohericin J-7, and the concrete process is as follows:

Into a dry 250mL four-necked flask, 5.8g (0.015mol, 97%) of 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one, 5.8g (0.015mol, 97%), Geranyl acetate 3.2g (0.0165mol, 99%, 1.1eq.), Pd ₂ (dba) ₃ catalyst 0.69g (0.75mmol, 97%, 0.05eq), Anhydrous lithium chloride 0.7g (0.0165mol, 99 %, 1.1 eq.) and DMF 50g, replaced with nitrogen three times and heated to 50°C under nitrogen protection for 24h.

After the reaction was completed, it was lowered to room temperature, quenched by adding 200 g of ice water, stirred for 0.5 h, and extracted with dichloromethane, and the organic phase was retained; the organic phase was washed twice with 2*50 g saturated potassium fluoride aqueous ammonia solution, *50g brine was washed twice; the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated; a brown-red viscous liquid was obtained, and silica gel column chromatography gave 3.1g of a light yellow oily liquid, which was confirmed by NMR as MOM-protected Hericium erinaceus Ketone J-7, yield 57.4%.

6) Synthesis of isohericium ketone J, the concrete process is as follows:

Into a dry 250mL four-necked flask, put MOM-protected ericine J-7 (2.9g, 0.008mol), 3.7g (0.016mol, 99%, 2.0eq) of camphorsulfonic acid and 50g of methanol in turn, and the reaction mixture was at room temperature The reaction was continued for 24 h, and the deprotection conversion was complete as detected by TLC.

After the reaction is completed, add triethylamine to quench, stir for 0.5h, add dichloromethane and water to extract and separate, and retain the organic phase; the organic phase is washed twice with 2*50g brine; the organic phase is dried by adding anhydrous sodium sulfate, filtered, Concentrated; light yellow viscous liquid was obtained, the ratio of E:Z configuration in the mixture was increased from about 1.1:1 to 8:1 by silica gel column chromatography, isopropyl ether and n-hexane (1/5 volume ratio) were added to weigh Crystallized to obtain E-configuration ericin J, white solid 1.1 g, yield 44.6%.

Melting point: 95-97°C, ¹ H NMR (400MHz, CDCl ₃ ): 6.97(s, 1H), 6.04(s, 1H), 5.25(t, J=7.1Hz, 1H), 5.21(s, 2H), 5.03-4.99(m, 1H), 3.87(s, 3H), 3.48(d, J=7.1Hz, 1H), 2.17-2.07(m, 4H), 1.82(s, 3H), 1.67(s, 3H) , 1.60(s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): 171.8, 159.2, 150.6, 141.1, 132.7, 127.4, 125.3, 123.6, 121.1, 120.4, 98.6, 68.1, 56.4, 39.8, 26.3, 25.8, 23.1, 17.9, 16.4. HRMS-ESI(m/z): calcd for C ₁₉ H ₂₃ O ₄ (M+H) ^- 315.1602, found315.1602.

Example 2

1) the synthesis of 3-hydroxy-4-iodo-5-methoxybenzoic acid methyl ester 2, concrete process is as follows:

29.4g (0.1mol, 99%) of methyl 3,5-dihydroxy-4-iodobenzoate, 27.6g (0.2mol, 98%, 2eq) of potassium carbonate and 200g DMF were successively put into a dry 1L four-necked flask, 17.03 g of methyl iodide (0.12 mol, 99%, 1.2 eq) was slowly added dropwise at room temperature. After the addition was completed, the reaction was stirred at room temperature for 24 h. TLC detected that the reaction raw material, methyl 3,5-dihydroxy-4-iodobenzoate, was converted into completely.

After the reaction was completed, it was lowered to room temperature, 500 g of saturated ammonium chloride solution was added to quench the reaction, stirred for 0.5 h, ethyl acetate was added to extract the layers, and the organic phase was retained; the organic phase was washed twice with 2*250 g of water; anhydrous sulfuric acid was added to the organic phase Sodium was dried, filtered and concentrated; a light yellow viscous liquid was obtained, which was recrystallized by adding isopropyl ether and n-hexane to obtain 19.1 g of a white solid, which was the target intermediate 2,3-hydroxy-4-iodo-5-methoxybenzene Methyl formate, yield 62.0%.

2) the synthesis of 4-hydroxyl-5-iodo-6-methoxyl group-3H-isobenzofuran-1-one 3, the concrete process is as follows:

Into a dry 250mL four-necked flask, successively put into intermediate 2 (methyl 3-hydroxy-4-iodo-5-methoxybenzoate) 15.4g (0.05mol, 99%), paraformaldehyde 3.0g (0.1mol, 98%, 2eq) and 100g glacial acetic acid, cooled to 0°C, slowly added dropwise 18.4g of hydrobromic acid solution (0.075mol, 33% acetic acid solution, 1.5eq), after the addition was completed, the reaction was stirred at room temperature for 24h, TLC detected, The reaction raw material 3-hydroxy-4-iodo-5-methoxybenzoic acid methyl ester was converted completely.

After the reaction was completed, 200 g of saturated sodium bicarbonate solution was added to quench the reaction, ethyl acetate was added to extract the layers, and the organic phase was retained; the organic phase was washed twice with 2*50 g of saturated brine; the organic phase was dried by adding anhydrous sodium sulfate, filtered, and concentrated. to obtain a light yellow solid, which was recrystallized by adding isopropyl ether and n-hexane to obtain 11.2 g of a white solid, which was the target intermediate 3,4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1 -ketone, yield 73.2%.

3) Synthesis of 5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4, the concrete process is as follows:

Into a dry 250mL four-necked flask, put intermediate 3 (4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one) 9.2g (0.03mol, 98%), diiso 7.8g of propylethylamine (0.06mol, 99%, 4eq) and 100g of dichloromethane, cooled to 0°C, slowly added dropwise 28.1g of bromomethyl methyl ether solution (0.045mol, 20% solution of dichloromethane, 1.5eq ), and the reaction was stirred at room temperature for 24 h after the dropwise addition. TLC detected that the reaction raw material 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one was completely converted.

After the reaction was completed, 100 g of water was added to quench the reaction, extracted and separated, and the organic phase was retained; the organic phase was washed twice with 2*50 g of saturated brine; the organic phase was dried by adding anhydrous sodium sulfate, filtered, and concentrated; Recrystallization from propyl ether and n-hexane gave 9.1 g of white solid, which was the target intermediate 4 (5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one), Yield 86.2%.

4) the synthesis of isohericium ketone J, the concrete process is as follows:

Into a dry 10mL there-necked flask, successively put intermediate 4 (5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one) 0.176g (0.5mmol, 97%) , Pd(t-Bu ₃ P) ₂ catalyst 0.0128g (0.025mmol, 99%, 0.05eq), Sn(CH ₃ ) ₆ 0.246g (0.75mmol, 99%, 1.0eq) and 3g toluene, replaced with nitrogen and replaced with nitrogen The reaction was heated to 100 °C for 24 h under nitrogen protection. TLC detection showed that the reaction raw material 5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one was completely converted.

After the reaction was cooled down, geranyl acetate 0.107g (0.55mmol, 99%, 1.1eq) and anhydrous lithium chloride 0.023g (0.55mmol, 99%, 1.1eq.) were then added, replaced with nitrogen and heated under nitrogen protection Reaction at 100°C for 24h.

After the reaction was completed, it was lowered to room temperature, quenched by adding 2 g of ice water, stirred for 0.5 h, and extracted with ethyl acetate, and the organic phase was retained; the organic phase was washed twice with 2*3 g saturated potassium fluoride ammonia solution, and then 2 *3g brine was washed twice; the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated; a brown-red viscous liquid was obtained, and silica gel column chromatography gave 0.058g of a light yellow oily liquid, which was confirmed by NMR as MOM-protected Hericium erinaceus Ketone J-7, yield 32.6%.

Then, to the above yellow oily liquid, camphorsulfonic acid (2.0 eq) and 10 g of methanol were added, the reaction mixture was reacted at room temperature for 24 h, and TLC detected that the deprotection conversion was complete. After the reaction is completed, add triethylamine to quench, stir for 0.5h, add dichloromethane and water to extract and separate, and keep the organic phase; the organic phase is washed twice with 2*10g brine; the organic phase is dried by adding anhydrous sodium sulfate, filtered, Concentrated; a pale yellow viscous liquid was obtained, and the ratio of E:Z configuration in the mixture was increased from about 1.1:1 to 8:1 by silica gel column chromatography, and isopropyl ether and n-hexane (1/5 volume ratio) were added. After recrystallization, the E-configuration isoericine J was obtained in a yield of 45.5%.

The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above-mentioned embodiments, and the descriptions in the above-mentioned embodiments and the description are only to illustrate the principles of the present invention, and the present invention will have various changes without departing from the scope of the principles of the present invention. and improvements, these changes and improvements all fall within the scope of protection of the present invention.

Claims (10)

1. The total synthesis method of the isoprotudone J is characterized by comprising the following steps: starting from 3, 5-dihydroxy-4-iodomethyl benzoate, the method is completed by monomethylation, Friedel-crafts alkylation/lactonization, hydroxyl protection, catalytic tin alkylation, Stille coupling and deprotection reaction in sequence, and the reaction equation is expressed as follows:

2. the total synthesis process of isoperigeron J as claimed in claim 1, characterized in that:

first step, monomethylation:

reacting 3, 5-dihydroxy-4-iodobenzoic acid methyl ester 1 with alkali in a polar aprotic solvent to obtain 3-hydroxy-4-iodo-5-methoxybenzoic acid methyl ester 2;

second step, friedel-crafts alkylation/lactonization:

reacting 3-hydroxy-4-iodo-5-methoxybenzoic acid methyl ester 2 with paraformaldehyde in the presence of mixed acid to generate 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one 3;

step three, hydroxyl protection:

reacting 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one 3, alkali and halomethyl methyl ether in chloroalkane solvent to generate 5-iodo-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4;

step four, catalyzing tin-based reaction:

reacting 5-iodine-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4, a palladium catalyst and hexamethyltin in a solvent to generate 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one 5;

step five, Stille coupling:

reacting 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one 5, palladium catalyst geranyl acetate 6 and lithium chloride in a solvent to generate MOM protected isocoumarone J-7; wherein, when the fourth step and the fifth step are continuously carried out, the fifth step does not need a palladium catalyst;

sixthly, deprotection:

and deprotecting MOM protected isocoupanone J-7 in an alcohol solvent in the presence of an acid catalyst to obtain isocoupanone J.

3. The total synthesis process of isoperigeron J as claimed in claim 2, characterized in that: in the first step, the methylating agent is selected from dimethyl carbonate, dimethyl sulfate or methyl iodide; the base is selected from potassium carbonate, sodium carbonate or cesium carbonate; the polar aprotic solvent is selected from DMF, DMSO or dioxane.

4. The total synthesis process of isoperigeron J as claimed in claim 3, characterized in that: in the first step, the molar ratio of the methyl 3, 5-dihydroxy-4-iodobenzoate 1 to the methylating agent to the base is 1: 0.8-1.5: 1-3.

5. The total synthesis process of isoperigeron J as claimed in claim 2, characterized in that: in the second step, the mixed acid is a mixture of glacial acetic acid and hydrobromic acid, wherein the glacial acetic acid is a solvent; the molar ratio of the 3-hydroxy-4-iodo-5-methoxybenzoic acid methyl ester 2 to the paraformaldehyde to the hydrobromic acid is 1: 0.8-2: 1-3.

6. The total synthesis process of isoperigeron J as claimed in claim 2, characterized in that: in the third step, the base is selected from triethylamine or diisopropylethylamine; the halomethyl methyl ether is selected from chloromethyl methyl ether or bromomethyl methyl ether; the chloralkane solvent is selected from dichloromethane, 1, 2-dichloroethane or chloroform.

7. The total synthesis process of isoperigeron J as claimed in claim 6, characterized in that: in the third step, the molar ratio of the 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one 3, bromomethyl methyl ether and alkali is 1: 1-3: 1-3.

8. The total synthesis process of isoperigeron J as claimed in claim 2, characterized in that: in the fourth and fifth steps, the palladium catalyst is selected from Pd (PPh)₃)₄、Pd₂(dba)₃Or Pd (t-Bu)₃P)₂At least one of them.

9. The total synthesis process of isoperigeron J as claimed in claim 2, characterized in that: in the fourth step, the molar ratio of the 5-iodine-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4 to the palladium catalyst to the hexamethyltin is 1: 0.001-0.020: 1-3; in the fifth step, the molar ratio of the 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one 5, the palladium catalyst, geranyl acetate 6 and lithium chloride is 1: 0.001-0.02: 1-3: 1-3.

10. The total synthesis process of isoperigeron J as claimed in claim 2, characterized in that: in the sixth step, the acid catalyst is selected from p-toluenesulfonic acid, camphorsulfonic acid or acetic acid; the mol ratio of MOM protected isoprotudone J-7 to acid catalyst is 1: 1-3.