阅读说明：本技术 天然产物异猴头菌酮j的全合成方法 (Total synthesis method of natural product isoperidone J ) 是由 唐宇 曹伟 陈平 李�雨 田帅 于 2019-11-26 设计创作，主要内容包括：本发明公开了一种异苯并呋喃酮类天然化合物J的全合成方法。以3,5-二羟基-4-碘苯甲酸甲酯为起始原料,经过甲基化反应、傅克烷基化和酯交换后,得到异苯并呋喃酮中间体3,接着羟基经过保护后,被制成锡试剂中间体5,随后与乙酸香叶酯经过Stille偶联反应,脱保护后生成异猴头菌酮J。本发明中,原料简单易得,反应过程中各单元反应条件温和可控,反应收率较高,在天然产物异猴头菌酮J全合成和药物发现中具有重要的应用价值。(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.)

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.

Technical Field

The invention relates to an isobenzofuranone natural compound, in particular to a total synthesis method of isobavanone J, belonging to the technical field of natural product synthesis.

Background

Hericium erinaceus, as a medicine and food dual-purpose fungus, has the advantages of mild nature, sweet taste, stomach meridian entering, contribution to digestion, benefiting five internal organs, strengthening body resistance, consolidating constitution, and brain strengthening and refreshing effects. Polysaccharide compounds, fatty acids, diterpenoid compounds, alkaloids, sterol compounds and aromatic compounds such as isoperigerone J (isohericenone J), pseudoonidone A (hericenone) which are extracted in a related way attract people to pay attention in the aspects of treating digestive tract diseases, neurological dysfunction, diabetes, tumors and the like.

Isomonkey head fungus ketone J is an isobenzofuranone derivative separated from Hericium erinaceum, and has the following structural formula:

the structure was confirmed in 2015 by the Kim group, and the Kim group studies found that such compounds showed significant inhibition of the cellular activity of acute myeloid leukemia HL-60 and HEL-299 (Food chem.,2015,170, 336-342).

However, due to the relatively complex structure, the total synthesis research is few, and the further application of the isobenzofuranone compounds in the drug development is limited.

Disclosure of Invention

In order to overcome the technical defects, the invention provides a total synthesis method of isobenzofuranone natural compounds, in particular to isobacteoside J. Synthesizing an isobenzofuranone intermediate 3 by using commercially available 3, 5-dihydroxy-4-iodobenzoic acid methyl ester 1 as an initial raw material through methylation reaction, Friedel-crafts alkylation and ester exchange chain reaction; the hydroxyl of the intermediate 3 is protected and then prepared into a tin reagent intermediate 5; and then carrying out Stille coupling on the intermediate 5 and geranyl acetate, and carrying out deprotection to generate the isomonkey head fungus ketone J.

The total synthesis method of the isomonkey head fungus ketone J is finished by starting from 3, 5-dihydroxy-4-iodobenzoic acid methyl ester and sequentially carrying out six-step reactions such as monomethylation, Friedel-crafts alkylation/lactonization, hydroxyl protection, catalytic stannization, Stille coupling, deprotection and the like, and is expressed by a reaction equation as follows:

the reaction specifically comprises the following steps:

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).

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

Further, under the reaction conditions, 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; the preferred molar ratio is 1: 1-1.2: 1.5-2.

The typical operation of this step is as follows: sequentially adding 3, 5-dihydroxy-4-iodobenzoic acid methyl ester 1, alkali and a polar aprotic solvent into a reaction kettle, dropwise adding a methylating agent, and reacting at room temperature; after the reaction is finished, adding saturated solution of ammonium chloride for quenching, extracting and separating liquid, washing and drying an organic layer, then carrying out desolventizing and concentrating, adding ethers and alkane solvents for crystallization and purification, and obtaining the 3-hydroxy-4-iodine-5-methoxy methyl benzoate 2.

Second step, friedel-crafts alkylation/lactonization:

reacting methyl 3-hydroxy-4-iodo-5-methoxybenzoate (2) with paraformaldehyde in the presence of a mixed acid to produce 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one (3).

Wherein the mixed acid is a mixture of glacial acetic acid and hydrobromic acid, and the glacial acetic acid is a solvent. This reaction spontaneously undergoes transesterification to form lactones after the friedel-crafts reaction has ended.

Further, under the reaction conditions, the molar ratio of the methyl 3-hydroxy-4-iodo-5-methoxybenzoate 2 to the paraformaldehyde to the 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: sequentially adding 3-hydroxy-4-iodo-5-methoxybenzoic acid methyl ester 2, paraformaldehyde and glacial acetic acid into a reaction kettle, dropwise adding a mixed solution of hydrobromic acid and glacial acetic acid at 0 ℃, and reacting at room temperature after dropwise adding; and after the reaction is finished, adding a saturated sodium bicarbonate solution for quenching, extracting and separating liquid, washing and drying an organic layer, removing the solvent, concentrating, adding an ether and alkane mixed solvent for crystallization and purification, and obtaining the 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).

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

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

the typical operation of this step is as follows: sequentially adding 4-hydroxy-5-iodo-6-methoxy-3H-isobenzofuran-1-one 3, alkali and chloralkane solvent into a reaction kettle, dropwise adding bromomethyl ether at 0 ℃, and reacting at room temperature after dropwise adding; after the reaction is finished, adding water for quenching, extracting, separating liquid, washing and drying an organic layer, then carrying out desolventizing and concentrating, adding a mixed solvent of ethers and alkanes for crystallization and purification, and obtaining the 5-iodine-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4.

Step four, catalyzing tin-based reaction:

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

Wherein the palladium catalyst is selected from Pd (PPh)₃)₄、Pd₂(dba)₃Or Pd (t-Bu)₃P)₂At least one of them. The reaction solvent is selected from toluene, dioxane, DMF or THF.

Further, under the reaction conditions, the molar ratio of 5-iodine-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-one 4 to palladium catalyst to hexamethyltin is 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: adding 5-iodine-6-methoxy-4-methoxymethoxy-3H-isobenzofuran-1-ketone 4, a palladium catalyst, hexamethyltin and a reaction solvent into a reaction kettle in sequence, and carrying out reflux reaction under the protection of nitrogen; and after the reaction is finished, adding water for quenching, extracting, separating liquid, washing and drying an organic layer, removing solution, concentrating, adding an alkane solvent for crystallization and purification, and obtaining the 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one 5.

Step five, Stille coupling:

6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one (5), palladium catalyst geranyl acetate (6) and lithium chloride are reacted in a solvent to generate MOM protected isocoumarone J (7).

Wherein the palladium catalyst is selected from Pd₂(dba)₃、Pd(PPh₃)₄And Pd (t-Bu)₃P)₂At least one of (1). The reaction solvent is selected from the common solvents such as toluene, dioxane, DMF and THF.

Further preferably: when the fourth step and the fifth step are continuously carried out, the fifth step does not need a palladium catalyst;

further, under the above reaction conditions, the molar ratio of 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-one 5, palladium catalyst, geranyl acetate 6 and lithium chloride was 1: 0.001-0.02: 1-3: 1-3, preferably in a molar ratio of 1: 0.05-0.10: 1.1-1.5: 1-1.5.

The typical operation of this step is as follows: sequentially adding 6-methoxy-4-methoxymethoxy-5-trimethyltin-3H-isobenzofuran-1-ketone 5, a palladium catalyst, geranyl acetate 6, lithium chloride and a reaction solvent into a reaction kettle, and heating for reaction under the protection of nitrogen; after the reaction is finished, water is added for quenching, extraction and liquid separation are carried out, an organic layer is washed and dried, then exsolution and concentration are carried out, and silica gel column chromatography is carried out, so as to obtain MOM protected isocouptolone J-7.

Sixthly, deprotection:

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

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

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

The typical operation of this step is as follows: adding MOM protected isocoupiolactone J-7, an acid catalyst and a reaction solvent into a reaction kettle in sequence, and stirring the mixture at room temperature for reaction; and adding triethylamine to quench after the reaction is finished, extracting and separating liquid, washing and drying an organic layer, desolventizing and concentrating, and separating a product mixture by a reversed-phase medium-pressure column chromatography to obtain the isomonkey head bacteria ketone J.

Advantageous effects of the invention

The invention provides a total synthesis method of the isomonkey head fungus ketone J for the first time, the synthesis method has the advantages of simple and easily obtained raw materials, mild and controllable reaction conditions of each unit in the reaction process and higher reaction yield. Has important application value in natural product total synthesis and drug discovery.

Detailed Description

The technical solution of the present invention will be described in further detail with reference to specific examples.