Hexahydrofuro[2,3-b]benzofuran compounds and their preparation and application in the synthesis of aflatoxin B intermediates

Abstract

The present invention discloses a hexahydrofuro[2,3-b]benzofuran compound, its preparation, and its application in synthesizing an intermediate of aflatoxin B. The hexahydrofuro[2,3-b]benzofuran compound provided by the present invention adopts a one-step construction of a tricyclic structure with two consecutive chiral centers, and simultaneously has high enantioselectivity and diastereoselectivity. Using the hexahydrofuro[2,3-b]benzofuran compound as a raw material, a key intermediate can be obtained through 5-step transformation, and the chiral control step realizes the preparation on a gram scale. The synthetic route has the advantages of simple synthetic steps, cheap and easily available synthetic raw materials, good stereocontrol, high synthetic yield, synthesizing the key intermediate (V) with an overall yield of about 15%, mild reaction conditions, etc. The method has good repeatability, is easy to carry out industrial scale-up production, and has good application prospects.

Description

(1) Technical Field

[0001] The present invention belongs to the fields of food safety and chemical synthesis, and particularly relates to a hexahydrofuro[2,3-b]benzofuran compound, its preparation, and the development of a strategy in the total synthesis of aflatoxin B. (2) Background Art

[0002] Food safety is a hot topic of global concern, especially with the emergence of the concepts of green food and organic food, which has further increased people's attention to food safety. There are many influencing factors for food safety, and among them, the harm of aflatoxin (AF) is a prominent problem. Aflatoxin is a group of highly toxic secondary metabolites produced by the fungi Aspergillus flavus and Aspergillus parasiticus. This class of molecules is mainly composed of a bifuran ring and a coumarin, including dozens of types such as AFB1, AFB2, AFG1, AFG2, AFM1, AFM2, etc. Among them, AFB1 with the strongest toxicity and greatest harm is one of the most toxic and widely polluting mycotoxins found so far. AF is a highly toxic substance with extremely strong toxicity to humans, and it has obvious damage to the liver, which can cause lesions such as hepatic parenchymal necrosis, bile duct epithelial hyperplasia, hepatic lipid infiltration, and hepatic hemorrhage. AF is a class of strong carcinogens that can cause the loss of immune function in humans or animals. The poisoning symptoms are manifested as hepatitis symptoms such as vomiting, anorexia, fever, jaundice, and ascites, and it can induce the occurrence of deformities and cancers. Crops may be contaminated by toxin-producing fungi during various processes from harvesting, storage to transportation and processing, and the AF produced by them threatens the lives and health of humans and animals through the transmission of the food chain. Therefore, the research on aflatoxin is a hot topic of key concern at home and abroad.

[0003] Since the discovery of aflatoxin in the 1950s, the harm of AF has been widely reported. However, the low natural content is not sufficient to support various scientific studies on AF. Therefore, carrying out chemical synthesis to achieve its large-scale preparation is conducive to better studying the structure-activity relationship and reducing the harm of AF. In the past 60 years, scientists have developed multiple total synthesis routes to prepare various aflatoxins. However, there are only three asymmetric syntheses (J. Am. Chem. Soc., 2005, 127, 11958; Chem. Commun., 2019, 55, 5171 - 5174; J. Am. Chem. Soc., 2003, 10, 3095). But generally, they have the disadvantages of long synthesis routes, difficult-to-prepare raw materials, harsh reaction conditions, and low yields. The present invention aims to develop a simple and efficient synthesis scheme to provide a material basis for the research on AF. (3) Summary of the Invention

[0004] The object of the present invention is to provide a hexahydrofuro[2,3-b]benzofuran compound, a preparation method thereof and an application thereof in asymmetric synthesis of a key intermediate of aflatoxin B. The present invention provides a novel hexahydrofuro[2,3-b]benzofuran compound. The route for asymmetric synthesis of aflatoxin B using this compound is short, the raw materials are cheap and easily available, the stereoselectivity is good, the overall yield is relatively high, the reaction conditions are relatively mild, the repeatability is good, and it is easy to prepare on a large scale.

[0005] The technical solution adopted by the present invention is as follows:

[0006] In the first aspect, the present invention provides a hexahydrofuro[2,3-b]benzofuran compound represented by formula (I), where the two tetrahydrofuran groups face the same side and the two hydrogen atoms are located on the same side:

[0007]

[0008] In formula (I), R1 is mono-substituted or multi-substituted, and the multi-substitution includes ortho-position, para-position, and meta-position. R1 and R2 are each independently hydrogen, methoxy, o-methoxybenzyl, trifluoromethoxybenzyl, o-fluorobenzyl, o-chlorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-iodobenzyl, benzyl, o-trifluoromethylbenzyl, difluoromethylbenzyl, o-methylbenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl, 2,6-dimethylbenzyl, phenyl, methylphenyl, dimethylphenyl, p-methylphenyl, p-methoxyphenyl, p-methylphenyl, p-fluorophenyl, p-nitrophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, o-methoxyphenyl, o-methylphenyl, o-nitrophenyl, o-trifluoromethylphenyl, o-bromophenyl, o-fluorophenyl, o-chlorophenyl, o-iodophenyl, m-methylphenyl, m-methoxyphenyl, m-nitrophenyl, m-trifluoromethylphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-iodophenyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, ethynyl, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyridine-2-methyl, pyridine-3-methyl, pyridine-4-methyl, pyrimidine, benzofuran, indole, benzothiazole, quinoline, isoquinoline, purine, pterin, tetrahydrofuran, hexahydropyran.

[0009] Preferably, in formula (I), R1 is hydrogen, 3-methyl, 4-methyl, 4-methoxy, 4-methylphenyl, 4-phenyl, 4-fluorophenyl; R2 is methylphenyl, isopropyl, dimethylphenyl, 4-bromobenzyl, 3-bromobenzyl, o-bromobenzyl, o-methylbenzyl, o-methoxybenzyl, methyl, 2,6-dimethylbenzyl, o-trifluoromethylbenzyl, o-chlorobenzyl, o-iodobenzyl, o-fluorobenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl.

[0010] Preferably, the compound represented by the formula (I) is one of the following: when R1 is hydrogen, R2 is one of benzyl, isopropyl, diphenylmethyl, 4-bromobenzyl, 3-bromobenzyl, o-bromobenzyl, o-methylbenzyl, o-methoxybenzyl, methyl, 2,6-dimethylbenzyl, o-trifluoromethylbenzyl, o-chlorobenzyl, o-iodobenzyl, o-fluorobenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl; when R2 is o-bromobenzyl, R1 is one of 3-methyl, 4-methyl, 4-methoxy, 4-methylphenyl, 4-phenyl or 4-fluorophenyl.

[0011] In a second aspect, the present invention provides a method for preparing a hexahydrofuro[2,3-b]benzofuran compound represented by the formula (I), and the reaction formula of the method is as follows:

[0012]

[0013] In the formula (II), R1 is mono-substituted or multi-substituted, and the multi-substitution includes ortho, para, and meta positions. R1 and R2 are each independently hydrogen, methoxy, o-methoxybenzyl, trifluoromethoxybenzyl, o-fluorobenzyl, o-chlorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-iodobenzyl, benzyl, o-trifluoromethylbenzyl, difluoromethylbenzyl, o-methylbenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl, 2,6-dimethylbenzyl, phenyl, methylphenyl, dimethylphenyl, p-methylphenyl, p-methoxyphenyl, p-methylphenyl, p-fluorophenyl, p-nitrophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, o-methoxyphenyl, o-methylphenyl, o-nitrophenyl, o-trifluoromethylphenyl, o-bromophenyl, o-fluorophenyl, o-chlorophenyl, o-iodophenyl, m-methylphenyl, m-methoxyphenyl, m-nitrophenyl, m-trifluoromethylphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-iodophenyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, ethynyl, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidine, benzofuran, indole, benzothiazole, quinoline, isoquinoline, purine, pterin, tetrahydrofuran, hexahydropyran.

[0014] In the formula (I), R1 is the same as R1 in the formula (II), and R2 in the formula (I) is the same as R2 in the formula (II).

[0015] In the formula (III), R3 is isopropyl, tert-butyl, phenyl or benzyl, preferably phenyl.

[0016] Preferably, the method for preparing the hexahydrofuro[2,3-b]benzofuran compound is as follows: under an argon atmosphere, in the presence of a Lewis acid and a diluent, the compound shown in formula (II) is reacted with 2,3-dihydrofuran and the compound shown in formula (III) at -80 to 25 °C for 12 to 48 hours to prepare the hexahydrofuro[2,3-b]benzofuran compound shown in formula (I). The Lewis acid includes copper chloride, copper bromide, copper iodide, copper trifluoromethanesulfonate, copper bis(trifluoromethylsulfonyl)imide, copper perchlorate, copper acetate, cuprous chloride, cuprous bromide, cuprous iodide, copper sulfate, cuprous trifluoromethanesulfonate, cobalt trifluoromethanesulfonate, iron trifluoromethanesulfonate, nickel trifluoromethanesulfonate, zinc trifluoromethanesulfonate, scandium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, erbium trifluoromethanesulfonate, copper hexafluoroantimonate, preferably copper trifluoromethanesulfonate. The diluent is water or an inert organic solvent, and the inert organic solvent includes benzene, toluene, p-xylene, m-xylene, o-xylene, mesitylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether, preferably toluene and mesitylene.

[0017] Preferably, the method for preparing the hexahydrofuro[2,3-b]benzofuran compound is carried out according to the following steps: under an argon atmosphere, the Lewis acid and the compound shown in formula (III) are added to a diluent, stirred at room temperature for 30 minutes, cooled to -80 °C, and the compound shown in formula (II) and 2,3-dihydrofuran are added. Stir at -80 to 25 °C for 12 - 48 h. After the reaction is completed, the reaction solution is extracted with 3 volumes of ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid; the oily liquid is subjected to silica gel column chromatography using a petroleum ether and ethyl acetate eluent with a volume ratio of 20:1, eluting 5 - 10 (preferably 7) column volumes, with an elution rate of 5 - 15 mL / min (preferably 10 mL / min). TLC monitoring is carried out using a petroleum ether and ethyl acetate developing agent with a volume ratio of 3:1, and the effluent with an Rf value of 0.2 - 0.4 is collected and rotary evaporated to dryness under reduced pressure to obtain the hexahydrofuro[2,3-b]benzofuran compound shown in formula (I).

[0018] Preferably, the molar ratio of the compound represented by formula (II) to the Lewis acid is 1:0.05 - 1, preferably 1:0.1; the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:0.05 - 1, preferably 1:0.1; the volume dosage of the diluent is 10 - 20 mL / mmol based on the amount of substance of the compound represented by formula (II), preferably 13 - 14 mL / mmol; the molar ratio of the compound represented by formula (II) to 2,3-dihydrofuran is 1:1 - 2, preferably 1:2.

[0019] Preferably, the diluent is a mixture of tetrahydrofuran, water, mesitylene and toluene in a volume ratio of 1.5:0.0062:6.15:40.

[0020] In the third aspect, the present invention also provides an application of a hexahydrofuran[2,3-b]benzofuran compound in the synthesis of aflatoxin B intermediate (V), and the application process is as follows:

[0021]

[0022]

[0023] In formula (I), R1 is mono-substituted or multi-substituted, the multi-substitutions include ortho, para, and meta positions, and R1 and R2 are each independently hydrogen, methoxy, o-methoxybenzyl, trifluoromethoxybenzyl, o-fluorobenzyl, o-chlorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-iodobenzyl, benzyl, o-trifluoromethylbenzyl, difluoromethylbenzyl, o-methylbenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl, 2,6-dimethylbenzyl, phenyl, methylphenyl, dimethylphenyl, p-methylphenyl, p-methoxyphenyl, p-methylphenyl, p-fluorophenyl, p-nitrophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, o-methoxyphenyl, o-methylphenyl, o-nitrophenyl, o-trifluoromethylphenyl, o-bromophenyl, o-fluorophenyl, o-chlorophenyl, o-iodophenyl, m-methylphenyl, m-methoxyphenyl, m-nitrophenyl, m-trifluoromethylphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-iodophenyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, ethynyl, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyridine-2-methyl, pyridine-3-methyl, pyridine-4-methyl, pyrimidine, benzofuran, indole, benzothiazole, quinoline, isoquinoline, purine, pterin, tetrahydrofuran, hexahydropyran;

[0024] In formulas (VI), (VII), (VIII), and (IX), R2 is the same as R2 in formula (I).

[0025] Preferably, in formula (I), R1 is hydrogen, 3-methyl, 4-methyl, 4-methoxy, 4-methylphenyl, 4-phenyl, 4-fluorophenyl; R2 is methylphenyl, isopropyl, dimethylphenyl, 4-bromobenzyl, 3-bromobenzyl, o-bromobenzyl, o-methylbenzyl, o-methoxybenzyl, methyl, 2,6-dimethylbenzyl, o-trifluoromethylbenzyl, o-chlorobenzyl, o-iodobenzyl, o-fluorobenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl.

[0026] The method for synthesizing the intermediate of aflatoxin B using the hexahydrofuro[2,3-b]benzofuran compound in the present invention is as follows:

[0027] (1) Under stirring at room temperature, the compound shown in formula (I), trifluoromethanesulfonic acid, and hexamethylenetetramine are mixed and reacted at 90 °C. Using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent for TLC monitoring. After the reaction is completed, the reaction solution is cooled to room temperature, 1M HCl is added, and the mixture is stirred at room temperature for 1 h. Then ethyl acetate is added for extraction. The organic phase is successively washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid. The oily liquid is loaded onto a silica gel column (silica gel 300 - 400 mesh, column height 15 cm, diameter 20 mm), using petroleum ether and ethyl acetate with a volume ratio of 15:1 as the eluent, the elution volume is 5 - 10 (preferably 8) column volumes, the elution speed is 5 - 15 mL / min (preferably 10 mL / min), and TLC spotting is carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent. According to the Rf value and UV color development, the effluent with an Rf value of 0.2 - 0.4 is collected and rotary evaporated under reduced pressure until no liquid flows out and dried (preferably dried at 60 °C for 6 h) to obtain the compound shown in formula (VI); the molar ratio of the compound shown in formula (I) to hexamethylenetetramine in the feed is 1:1.0 - 3.0, preferably 1:1.5; the volume of trifluoromethanesulfonic acid used is 5 - 15 ml / mmol based on the amount of substance of the compound shown in formula (I), preferably 10 ml / mmol;

[0028] (2) Under argon protection, the compound shown in formula (VI) was stirred and mixed with tetrahydrofuran, and then an aqueous solution of sodium hydroxide at 6 mg / ml was added at 0 °C, and an aqueous hydrogen peroxide solution with a mass concentration of 6% was added dropwise. The temperature was raised to 40 °C and stirred for reaction. TLC monitoring was carried out using petroleum ether / ethyl acetate / dichloromethane with a volume ratio of 3:1:0.5 as the developing agent. After the reaction was completed, the reaction solution was cooled to room temperature, 1M HCl was added and extracted with ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain a pale yellow solid; all the pale yellow solid was dissolved in dichloromethane and loaded onto a silica gel column (silica gel 300-400 mesh, column height 6 cm, diameter 15 mm), using petroleum ether / ethyl acetate with a volume ratio of 5:1 as the eluent, the elution volume was 1-5 (preferably 3) column volumes, and the elution rate was 5-20 mL / min (preferably 15 mL / min). TLC spotting plate monitoring was carried out using petroleum ether / ethyl acetate with a volume ratio of 2:1 as the developing agent. According to the Rf value and UV color development, the effluent with an Rf value of 0.2-0.4 was collected and rotary evaporated under reduced pressure until no liquid flowed out and dried (preferably dried at 40 °C for 0.5 h) to obtain the compound shown in formula (VII); the volume of tetrahydrofuran used was 1-5 mL / mmol based on the amount of substance of the compound shown in formula (VI), preferably 3.3 mL / mmol; the volume of the aqueous sodium hydroxide solution and the aqueous hydrogen peroxide solution used were both 5-15 mL / mmol based on the amount of substance of the compound shown in formula (VI), and both were preferably 10 mL / mmol;

[0029] (3) Under argon protection and in an ice-water bath, sodium hydride solid and dimethyl sulfoxide a were stirred at 0 °C for 10 minutes. The compound shown in formula (VII) was added, and the mixture was stirred at room temperature for 30 minutes. Methyl iodide and dimethyl sulfoxide b were slowly added dropwise, and then the mixture was stirred at room temperature. TLC monitoring was carried out using petroleum ether / ethyl acetate with a volume ratio of 3:1 as the developing agent. After the reaction was completed, the reaction solution was cooled to room temperature; 1M HCl was added and the mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain an oily liquid; all the oily liquid was loaded onto a silica gel column (silica gel 300 - 400 mesh, column height 15 cm, diameter 15 mm), and the eluent was V petroleum ether / V ethyl acetate = 15 / 1. The elution volume was 5 - 10 (preferably 7) column volumes, and the elution rate was 5 - 15 mL / min (preferably 10 mL / min). TLC spotting plate monitoring was carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent. According to the Rf value and UV color development, the effluent with an Rf value of 0.2 - 0.5 was collected and rotary evaporated under reduced pressure until no liquid flowed out and dried (preferably dried at 60 °C for 6 h) to obtain the compound shown in formula (VIII); the sodium hydride was added in the form of sodium hydride mineral oil with a mass concentration of 60%. The molar ratio of the compound shown in formula (VII) to sodium hydride in the feed was 1:1.0 - 5.0, preferably 1:1.5; the volume of dimethyl sulfoxide a used was 5 - 15 mL / mmol based on the amount of substance of the compound shown in formula (VII), preferably 10 mL / mmol; the molar ratio of the compound shown in formula (VII) to methyl iodide in the feed was 1:1 - 5, preferably 1:1; the volume of dimethyl sulfoxide b used was 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula (VII), preferably 1 mL / mmol; both dimethyl sulfoxide a and dimethyl sulfoxide b are dimethyl sulfoxide, and the letters themselves have no meaning;

[0030] (4) Under argon protection and at room temperature, the compound shown in formula (VIII) and dichloromethane a were added to pyridine, and the mixture was stirred for 5 minutes. A dichloromethane b solution of trifluoromethanesulfonic anhydride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature. After the reaction was monitored by TLC (the developing agent was V petroleum ether / V ethyl acetate = 3 / 1) and completed, it was cooled to room temperature; 1M HCl was added, and the mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain an oily liquid; the oily liquid was loaded onto a silica gel column (silica gel 300 - 400 mesh, column height 15 cm, diameter 15 mm), and the eluent was V petroleum ether / V ethyl acetate = 20 / 1. The elution volume was 5 - 10 (preferably 7) column volumes, and the elution rate was 5 - 15 mL / min (preferably 10 mL / min). TLC plate monitoring was carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent. According to the Rf value and UV color development, the effluent with an Rf value of 0.2 - 0.5 was collected and rotary evaporated under reduced pressure until no liquid flowed out, and then dried (preferably dried at 60 °C for 5 h) to obtain the compound shown in formula (IX); the molar ratio of the compound shown in formula (VIII) to pyridine in the feed was 1:1 - 5, preferably 1:3; the volume of dichloromethane a used was 10 - 30 mL / mmol based on the amount of substance of the compound shown in formula (VIII), preferably 20 mL / mmol; the molar ratio of the compound shown in formula (VIII) to trifluoromethanesulfonic anhydride in the feed was 1:5 - 15, preferably 1:10; the volume of dichloromethane b used was 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula (VIII), preferably 4 mL / mmol; both dichloromethane a and dichloromethane b are dichloromethane, and the letters themselves have no meaning;

[0031] (5) Under argon protection, the compound shown in formula (IX) is mixed with toluene, and a hexane solution of diisobutylaluminum hydride is added dropwise at 0 °C, stirred at 0 °C, monitored by TLC (the developing agent is V petroleum ether / V ethyl acetate = 2 / 1). After the reaction is completed, it is cooled to room temperature; ethyl acetate is added for extraction, and the organic phase is washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid (no purification is required and it can be directly used for the next reaction); the oily liquid is dissolved in dichloromethane c, pyridinium chlorochromate is added, and stirred at room temperature for 20 minutes, monitored by TLC (the developing agent is V petroleum ether / V ethyl acetate = 3 / 1). After the reaction is completed, dichloromethane d is added for extraction, and the organic phase is washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid; the oily liquid is loaded onto a silica gel column (silica gel 300 - 400 mesh, column height 15 cm, diameter 15 mm), the eluent is V petroleum ether / V ethyl acetate = 20 / 1, the elution volume is 5 - 10 (preferably 7) column volumes, the elution rate is 5 - 15 mL / min (preferably 10 mL / min), TLC plate monitoring is carried out with petroleum ether and ethyl acetate in a volume ratio of 3:1 as the developing agent, and the effluent with an Rf value of 0.2 - 0.5 is collected according to the Rf value and UV color development, rotary evaporated under reduced pressure until no liquid flows out, and dried (preferably dried at 40 °C for 2 h) to obtain the intermediate compound shown in formula (V); the volume of toluene used is 5 - 15 mL / mmol based on the compound shown in formula (IX), preferably 10 mL / mmol; the molar ratio of the compound shown in formula (IX) to diisobutylaluminum hydride is 1:1 - 10, preferably 1:5.5; the volume of hexane used is 1 - 5 mL / mmol based on the compound shown in formula (IX), preferably 1.1 mL / mmol; the volume of dichloromethane c used is 1 - 10 mL / mmol based on the compound shown in formula (IX), preferably 10 mL / mmol; the volume of dichloromethane d used is 30 - 70 mL / mmol based on the compound shown in formula (IX), preferably 50 mL / mmol; the molar ratio of the compound shown in formula (IX) to pyridinium chlorochromate is 1:1 - 5, preferably 1:2.

[0032] The method for synthesizing aflatoxin B shown in formula (IV) using the aflatoxin B intermediate shown in formula (V) in the present invention refers to the literature Gang Zhou and E.J.Corey, J.Am.Chem.Soc.2005, 127, 11958 - 11959.

[0033] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in that: the hexahydrofuro[2,3-b]benzofuran compounds provided by the present invention adopt a one-step construction of a tricyclic structure with two consecutive chiral centers, and at the same time have high enantioselectivity (94% ee) and diastereoselectivity (dr greater than 20:1). Compared with the raw materials for synthesizing aflatoxin currently, they are simpler, more readily available, and have better stability, which can improve the final yield and enantioselectivity of the synthesis.

[0034] The present invention discloses an asymmetric synthesis route of aflatoxin. Using hexahydrofuro[2,3-b]benzofuran compounds as raw materials, a key intermediate can be obtained through 5-step transformation, and the chiral control step realizes the preparation on a gram scale. The synthesis route has the advantages of simple synthesis steps, cheap and readily available synthesis raw materials, good stereocontrol, high enantioselectivity (94% ee) and diastereoselectivity (dr greater than 20:1), high synthesis yield, synthesizing the key intermediate (V) with a total yield of about 15%, mild reaction conditions, etc. The method has good repeatability, is easy to carry out industrial scale-up production, and has good application prospects. (IV) BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 1H nuclear magnetic resonance spectrum of the compound shown in Formula I.

[0036] Figure 2 1H nuclear magnetic resonance spectrum of the compound shown in Formula V. (V) SPECIFIC EMBODIMENTS

[0037] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0038] Example 1: Preparation of benzyl (3aS,8aR)-5-hydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (I-1)

[0039]

[0040] Under an argon atmosphere, copper trifluoromethanesulfonate (0.31 mmol), tetrahydrofuran (1.5 mL), water (6.2 μL) and the compound of formula (Ⅲ) (0.37 mmol) were added to a 150 mL two-necked flask in 40 mL of toluene and 6.15 mL of mesitylene, and stirred at room temperature for 30 minutes. The temperature was lowered to -80 °C, and the compound of formula (Ⅱ) (3.1 mmol) and 2,3-dihydrofuran (6.2 mmol) were added. After the addition was complete, the temperature of the system was maintained at -80 °C and stirred for 30 h. After the reaction was completed, the reaction solution was extracted with 3 volumes of ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain an oily liquid. The oily liquid was subjected to silica gel column chromatography (silica gel particle size 200 - 300 mesh, column height 15 cm, diameter 15 mm) using petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent. The eluent was V petroleum ether / V ethyl acetate = 20 / 1, the elution volume was 7 column volumes, and the elution rate was 10 mL / min. TLC plate monitoring was carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent, and the effluent with an Rf value of 0.3 was collected. The effluent was detected by high performance liquid chromatography for the contents of benzyl (3aS,8aR)-5-hydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate and benzyl (3aR,8aS)-5-hydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate, and the enantiomeric excess value was calculated. Then the remaining effluent was rotary evaporated under reduced pressure until no liquid flowed out and dried at 40 °C for 2 h to obtain 982 mg of a white solid, namely benzyl (3aS,8aR)-5-hydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅰ-1), with a yield of 81% and an enantiomeric excess value of 94%.

[0041] High performance liquid chromatography was performed using waters HPLC (OD-H chiral column), mobile phase: V n-hexane / V isopropanol = 99 / 1, flow rate: 1 mL / min, detection wavelength: 254 nm.

[0042] According to a method similar to Example 1, only the R in the compound shown in formula Ⅰ was replaced as shown in Table 1, and the effluent with an Rf value of 0.2 - 0.5 was collected to obtain the corresponding compound shown in formula Ⅰ. The appearance, yield and high resolution mass spectrometry data of the above compounds are listed in Table 1, and the 1H NMR results are listed in Table 2. As can be seen from the above, the structures of the above compounds are correct and are all compounds shown in formula Ⅰ.

[0043] Table 1 Physical and chemical constants and high resolution mass spectrometry data of the compound shown in formula Ⅰ

[0044]

[0045] Table 2 1H NMR data of the compound shown in formula Ⅰ

[0046]

[0047]

[0048]

[0049] Example 2: Preparation of (3aS,8aR)-6-formyl-5-hydroxy-2-bromobenzyl 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅵ-6)

[0050]

[0051] (1) Under stirring at 25 °C, 780 mg (2 mmol) of (3aS,8aR)-5-hydroxy-2-bromobenzyl 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate of formula (Ⅰ-6) and 20 mL of trifluoromethanesulfonic acid were added to a 50 mL round-bottom flask. Subsequently, 420 mg of hexamethylenetetramine (HMTA) was added, and the mixture was heated to 90 °C and stirred for 4 h. After the reaction was monitored by TLC (the developing agent was V petroleum ether / V ethyl acetate = 3 / 1, v / v) and completed, it was cooled to room temperature, and 1 M HCl (20 mL) was added and stirred at room temperature for 1 h. After the reaction was completed, ethyl acetate (40 mL) was added for extraction. The organic phase was successively washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain an oily liquid. The oily liquid was loaded onto a silica gel column (silica gel 300 - 400 mesh, column height 15 cm, diameter 20 mm), and the eluent was V petroleum ether / V ethyl acetate = 15 / 1. The elution volume was 8 column volumes, and the elution rate was 10 mL / min. TLC plate monitoring was carried out using petroleum ether and ethyl acetate in a volume ratio of 3:1 as the developing agent, and the effluent with an Rf value of 0.3 was collected and rotary evaporated under reduced pressure until no liquid flowed out, and dried at 60 °C for 6 h to obtain 610 mg of a pale yellow solid, which was the product (3aS,8aR)-6-formyl-5-hydroxy-2-bromobenzyl 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅵ-6). The 1H NMR data are shown in Table 3, and the yield was 73%.

[0052] (2) Under argon protection, add 586.5 mg (1.5 mmol) of 2-bromobenzyl (3aS, 8aR)-6-formyl-5-hydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅵ-6) prepared by the method of step (1) and 4.95 mL of tetrahydrofuran into a 100 mL round-bottom flask, stir, and then add 15 mL of an aqueous solution of sodium hydroxide at 6 mg / mL at 0 °C. Then slowly dropwise add 15 mL of a 6% hydrogen peroxide aqueous solution at 0 °C. After the addition is complete, raise the temperature to 40 °C and stir for 4 h. Monitor the reaction by TLC (the developing agent is V petroleum ether / V ethyl acetate / V dichloromethane = 3 / 1 / 0.5). After the reaction is completed, cool to room temperature. Then add 1 M HCl (10 mL), extract with ethyl acetate (30 mL × 3). The organic phase is washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain a pale yellow solid. All the pale yellow solid is dissolved in 4 mL of dichloromethane and loaded onto a silica gel column (silica gel 300 - 400 mesh, column height 6 cm, diameter 15 mm). The eluent is V petroleum ether / V ethyl acetate = 5 / 1, the elution volume is 3 column volumes, the elution speed is 15 mL / min, and TLC plate monitoring is carried out using petroleum ether and ethyl acetate with a volume ratio of 2:1 as the developing agent. Collect the effluent with an Rf value of 0.3, rotary evaporate under reduced pressure until no liquid flows out, and dry at 40 °C for 0.5 h to obtain 410 mg of a white solid, which is the product 2-bromobenzyl (3aS, 8aR)-5,6-dihydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅶ-6). The nuclear magnetic resonance hydrogen spectrum data is shown in Table 3, and the yield is 66%.

[0053] (3) Under argon protection, in an ice-water bath, add 100 mg of sodium hydride (added in the form of 60% sodium hydride mineral oil by mass concentration) and 10 mL of dry dimethyl sulfoxide to a 50 mL round-bottom flask, and stir at 0 °C for 10 minutes. Add 407 mg (1 mmol) of (3aS,8aR)-5,6-dihydroxy-2,3,3a,8a-hexahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅶ-6) prepared by the method in step (2), stir at room temperature for 30 minutes, slowly dropwise add 62 μL (1 mmol) of methyl iodide and 1 mL of dry dimethyl sulfoxide, then stir at room temperature for 12 hours, monitor by TLC (the developing agent is V petroleum ether / V ethyl acetate = 3 / 1), after the reaction is completed, cool to room temperature; add 1 M HCl (10 mL), extract with ethyl acetate (20 mL × 3), the organic phase is washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid. Load all the oily liquid onto a silica gel column (silica gel 300 - 400 mesh, column height 15 cm, diameter 15 mm), the eluent is V petroleum ether / V ethyl acetate = 15 / 1, the elution volume is 7 column volumes, the elution speed is 10 mL / min, monitor by TLC spotting plate with petroleum ether and ethyl acetate in a volume ratio of 3:1 as the developing agent, collect the effluent with an Rf value of 0.3, rotary evaporate under reduced pressure until no liquid flows out, and dry at 60 °C for 6 h to obtain 258 mg of a white solid, which is the product (3aS,8aR)-5-hydroxy-6-methoxy-2,3,3a,8a-hexahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅷ-6), and the yield is 62%.

[0054] (4) Under argon protection, add 210 mg (0.5 mmol) of 2-bromobenzyl (3aS, 8aR)-5-hydroxy-6-methoxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅷ-6) prepared by the method of step (3) and 10 mL of dry dichloromethane into a 50 mL round-bottom flask. Add 121 μL of pyridine (1.5 mmol) at room temperature and stir for 5 minutes. Slowly add dropwise a 2 mL dichloromethane solution of 840 μL of trifluoromethanesulfonic anhydride (5 mmol) at 0 °C and stir at room temperature for 3 hours. Monitor the reaction by TLC (the developing agent is V petroleum ether / V ethyl acetate = 3 / 1). After the reaction is completed, cool to room temperature; add 1 M HCl (10 mL), extract with ethyl acetate (20 mL × 3). The organic phase is washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid. The oily liquid is loaded onto a silica gel column (silica gel 300-400 mesh, column height 15 cm, diameter 15 mm), the eluent is V petroleum ether / V ethyl acetate = 20 / 1, the elution volume is 7 column volumes, the elution speed is 10 mL / min, and TLC plate monitoring is carried out with petroleum ether and ethyl acetate in a volume ratio of 3:1 as the developing agent. Collect the effluent with an Rf value of 0.3, rotary evaporate under reduced pressure until no liquid flows out, and dry at 60 °C for 5 h to obtain 220 mg of a white solid, which is the product 2-bromobenzyl (3aS, 8aR)-6-methoxy-5-((trifluoromethyl)sulfonyloxy)-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅸ-6), and the yield is 78%.

[0055] (5) Under argon protection, 110 mg (0.2 mmol) of 2-bromobenzyl (3aS,8aR)-6-methoxy-5-((trifluoromethyl)sulfonyloxy)-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-4-carboxylate (Ⅸ-6) prepared by the method of step (4) and 2 mL of dry toluene were added to a 10 mL round-bottom flask. A solution of 220 μL of diisobutylaluminum hydride (1.1 mmol) in n-hexane was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 hour. After the reaction was monitored by TLC (the developing agent was V petroleum ether / V ethyl acetate = 2 / 1) and completed, it was cooled to room temperature; ethyl acetate (20 mL × 3) was added for extraction. The organic phase was washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain an oily liquid (which was directly used for the next reaction without purification). The oily liquid was dissolved in 2 mL of dichloromethane, 86 mg (0.4 mmol) of pyridinium chlorochromate was added, and the mixture was stirred at room temperature for 20 minutes. After the reaction was monitored by TLC (the developing agent was V petroleum ether / V ethyl acetate = 3 / 1) and completed, dichloromethane (10 mL) was added for extraction. The organic phase was washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain an oily liquid. The oily liquid was loaded onto a silica gel column (silica gel 300 - 400 mesh, column height 15 cm, diameter 15 mm), the eluent was V petroleum ether / V ethyl acetate = 20 / 1, the elution volume was 7 column volumes, the elution rate was 10 mL / min, TLC plate monitoring was carried out with petroleum ether and ethyl acetate in a volume ratio of 3:1 as the developing agent, the effluent with an Rf value of 0.3 was collected, rotary evaporated under reduced pressure until no liquid flowed out, and dried at 40 °C for 2 h to obtain 55 mg of a white solid, which was the product (3AS,8aR)-4-formyl-6-methoxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran-5-yl trifluoromethanesulfonate (Ⅴ-6), with a yield of 76%.

[0056] (6) According to the literature report (Gang Zhou and E.J.Corey, J.Am.Chem.Soc.2005, 127, 11958 - 11959.), aflatoxin B shown in formula (Ⅳ-6) can be obtained from the compound shown in formula (V-6) through several steps of transformation. The specific operation is as follows:

[0057]

[0058] Compound (Ⅴ-6) (184 mg, 0.5 mmol) was dissolved in anhydrous tetrahydrofuran. MeMgBr (3.0 M in diethyl ether, 0.33 mL, 1.0 mmol) was added dropwise at -20 °C. After reacting for 2 h, the reaction was quenched with saturated ammonium chloride. The mixture was extracted with diethyl ether (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure until no liquid flowed out. The obtained intermediate was dissolved in 30 mL of dichloromethane. Dess-Martin periodinane (0.43 g, 1 mmol) was added at 0 °C. The reaction was carried out at room temperature for 3 h, diluted with diethyl ether (30 mL), and the reaction solution was poured into 10 mL of saturated aqueous NaHCO3 solution and 10 mL of saturated aqueous Na2S2O3 solution, stirred for 30 minutes, extracted with diethyl ether (3×50 mL), the organic phase was washed with saturated aqueous NaHCO3 solution (2×10 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure until no liquid flowed out. The oily liquid was loaded onto a silica gel column (silica gel 300-400 mesh, column height 15 cm, diameter 15 mm). The eluent was V hexane / V diethyl ether = 10 / 1, the elution volume was 7 column volumes, the elution rate was 10 mL / min, TLC plate monitoring was carried out using hexane and diethyl ether with a volume ratio of 2:1 as the developing agent, the effluent with an Rf value of 0.3 was collected, evaporated under reduced pressure until no liquid flowed out, and dried at 50 °C for 5 h to obtain colorless oily compound 11 (162 mg, 85%).

[0059] Urea-hydrogen peroxide complex was dissolved in 30 mL of dichloromethane. Trifluoroacetic anhydride (0.17 mL, 1.2 mmol) was added dropwise slowly with strong stirring at room temperature for 1 h. Compound 11 (150 mg, 0.40 mmol) was added, and trifluoroacetic anhydride (0.17 mL, 1.2 mmol) was added dropwise slowly within 10 h. After the reaction was completed, it was extracted with CH2Cl2 (3×30 mL). The organic phase was washed with 5% Na2SO3 / 5% Na2HPO4 aqueous solution (3×10 mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure until no liquid flowed out. The oily liquid was loaded onto a silica gel column (silica gel 300-400 mesh, column height 15 cm, diameter 15 mm). The eluent was V hexane / V diethyl ether = 10 / 1, the elution volume was 7 column volumes, the elution rate was 10 mL / min, TLC plate monitoring was carried out using hexane and diethyl ether with a volume ratio of 2:1 as the developing agent, the effluent with an Rf value of 0.3 was collected, evaporated under reduced pressure until no liquid flowed out, and dried at 50 °C for 5 h to obtain yellow oily compound 12 (99.5 mg, 62.5%).

[0060] NaHCO3 (1.0 g) and ZnCO3 (0.6 g) were dissolved in 10 mL of dichloromethane. 2-Bromo-5-oxocyclopentane-1-carboxylic acid ethyl ester (40 mg, 0.17 mmol) and compound 12 (18 mg, 0.086 mmol) were added. The reaction was carried out at room temperature for 20 hours. The reaction mixture was transferred to a Soxhlet thimble and extracted with 2% MeOH-CH2Cl2 for 24 hours. The solid was dissolved in 10% HCl and extracted with chloroform. The organic phase was washed with water, saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out. Purification was carried out by silica gel column chromatography (silica gel 200 - 300 mesh, column height 15 cm, diameter 15 mm). The elution solvent (5% MeOH in CH2Cl2) was eluted at a volume of 5 column volumes at a flow rate of 10 mL / min. TLC plate monitoring was carried out using CH2Cl2 and MeOH in a volume ratio of 10:1 as the developing agent. The effluent with an Rf value of 0.3 was collected, rotary evaporated under reduced pressure until no liquid flowed out, and dried at 50 °C for 5 h to obtain white solid Ⅳ-6 (9.7 mg, 36%).

[0061] 1H NMR results of the above compounds are listed in Table 3. As can be seen from the above, the structures of the above compounds are correct and are all the compounds shown in the synthetic route.

[0062] Meanwhile, according to the method of Example 2, compound Ⅰ-6 was replaced with Ⅰ-1~Ⅰ-5 and Ⅰ-7~Ⅰ-23 prepared in Example 1 respectively. The effluent with an Rf value of 0.2 - 0.5 was collected in each step, and the corresponding compound Ⅴ was obtained by 1H NMR detection. Compound Ⅳ was prepared by the literature method. The yields of compound Ⅴ are shown in Table 4. Due to the de-esterification in step (6), the substituents of compound Ⅴ do not affect the preparation of compound Ⅳ.

[0063] Table 3 1H NMR data of the compounds shown in the synthetic route

[0064]

[0065] Table 4 Yields of compound Ⅴ

[0066]

[0067]

[0068] Note: Compound Ⅰ-18 in Table 4 cannot synthesize compound Ⅶ in step (2) and subsequent compounds.

Claims

1. A hexahydrofuro[2,3-b]benzofuran compound represented by formula (I): Ⅰ The compound represented by formula (I) is one of the following: when R1 is hydrogen, R2 is one of benzyl, isopropyl, diphenylmethyl, 4-bromobenzyl, 3-bromobenzyl, o-methylbenzyl, o-methoxybenzyl, methyl, 2,6-dimethylbenzyl, o-trifluoromethylbenzyl, o-chlorobenzyl, o-iodobenzyl, o-fluorobenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl; when R2 is o-bromobenzyl, R1 is one of 4-methyl, 4-methoxy, 4-methylphenyl, 4-phenyl or 4-fluorophenyl.

2. A method for preparing the hexahydrofuro[2,3-b]benzofuran compound according to claim 1, characterized in that, The method is carried out according to the following steps: under an argon atmosphere, a Lewis acid and the compound represented by formula (III) are added to a diluent, stirred at room temperature for 30 minutes, cooled to -80 °C, and the compound represented by formula (II) and 2,3-dihydrofuran are added, stirred at -80~25 °C for 12-48 h. After the reaction is completed, the reaction solution is extracted with 3 volumes of ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid; the oily liquid is subjected to silica gel column chromatography using petroleum ether and ethyl acetate with a volume ratio of 20:1 as the eluent, the elution rate is 5-15 mL / min, TLC monitoring is carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent, the effluent with an Rf value of 0.2-0.4 is collected, and rotary evaporated to dryness under reduced pressure to obtain the hexahydrofuro[2,3-b]benzofuran compound represented by formula (I); the diluent is water or an inert organic solvent, and the inert organic solvent includes benzene, toluene, p-xylene, m-xylene, o-xylene, mesitylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether; Ⅱ Ⅲ Ⅰ In formula (II), R1 and R2 are the same as those described in claim 1; In formula (I), R1 is the same as R1 in formula (II), and R2 in formula (I) is the same as R2 in formula (II); In formula (III), R3 is isopropyl, tert-butyl, phenyl or benzyl.

3. The preparation method according to claim 2, characterized in that, The Lewis acid includes copper chloride, copper bromide, copper iodide, copper trifluoromethanesulfonate, copper bis(trifluoromethylsulfonyl)imide, copper perchlorate, copper acetate, cuprous chloride, cuprous bromide, cuprous iodide, copper sulfate, cuprous trifluoromethanesulfonate, cobalt trifluoromethanesulfonate, iron trifluoromethanesulfonate, nickel trifluoromethanesulfonate, zinc trifluoromethanesulfonate, scandium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, erbium trifluoromethanesulfonate, copper hexafluoroantimonate.

4. The preparation method according to claim 2, characterized in that, The molar ratio of the compound shown by the formula (II) to the Lewis acid is 1:0.05 - 1; the molar ratio of the compound shown by the formula (II) to the compound shown by the formula (III) is 1:0.05 - 1; the molar ratio of the compound shown by the formula (II) to 2,3 - dihydrofuran is 1:1 - 2; the volume dosage of the diluent is 10 - 20 mL / mmol based on the amount of the compound shown by the formula (II).

5. Use of the hexahydrofuro[2,3-b]benzofuran compound according to claim 1 in the synthesis of aflatoxin B intermediate (V), characterized in that, The application is carried out as follows: Ⅰ Ⅵ Ⅶ Ⅷ Ⅸ Ⅴ R1 and R2 in the formula (I) are the same as those described in claim 1; R2 in the formulas (VI), (VII), (VIII), and (IX) is the same as R2 in the formula (I); (1) Under stirring at room temperature, the compound shown by the formula (I), trifluoromethanesulfonic acid, and hexamethylenetetramine are mixed and reacted at 90 °C. Using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent for TLC monitoring. After the reaction ends, the reaction solution is cooled to room temperature, 1M HCl is added and stirred at room temperature for 1 h, then ethyl acetate is added for extraction. The organic phase is successively washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid; The oily liquid is loaded onto a silica gel column, using petroleum ether and ethyl acetate with a volume ratio of 15:1 as the eluent, eluting for 5 - 10 column volumes, with an elution rate of 5 - 15 mL / min. Using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent for TLC spotting monitoring, collecting the effluent with an Rf value of 0.2 - 0.4, rotary evaporating under reduced pressure until no liquid flows out, and drying to obtain the compound shown by the formula (VI); (2) Under argon protection, the compound shown by the formula (VI) and tetrahydrofuran are stirred and mixed, and an aqueous solution of sodium hydroxide with a concentration of 6 mg / mL is added dropwise at 0 °C, and a hydrogen peroxide aqueous solution with a mass concentration of 6% is added dropwise. The temperature is raised to 40 °C and stirred for reaction. Using petroleum ether, ethyl acetate, and dichloromethane with a volume ratio of 3:1:0.5 as the developing agent for TLC monitoring. After the reaction ends, the reaction solution is cooled to room temperature, 1M HCl is added and extracted with ethyl acetate. The organic phase is successively washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain a pale yellow solid; all the pale yellow solid is dissolved in dichloromethane and loaded onto a silica gel column, using petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent, eluting for 1 - 5 column volumes, with an elution rate of 5 - 20 mL / min. Using petroleum ether and ethyl acetate with a volume ratio of 2:1 as the developing agent for TLC spotting monitoring, collecting the effluent with an Rf value of 0.2 - 0.4, rotary evaporating under reduced pressure until no liquid flows out, and drying to obtain the compound shown by the formula (VII); (3) Under argon protection and in an ice-water bath, sodium hydride solid and dimethyl sulfoxide a were stirred at 0 °C for 10 minutes. The compound shown in formula (VII) was added, and the mixture was stirred at room temperature for 30 minutes. Methyl iodide and dimethyl sulfoxide b were slowly added dropwise, and then the mixture was stirred at room temperature. TLC monitoring was carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent. After the reaction was completed, the reaction solution was cooled to room temperature; 1M HCl was added and the mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain an oily liquid; all the oily liquid was loaded onto a silica gel column, and the eluent was petroleum ether and ethyl acetate with a volume ratio of 15:

1. Elution was carried out for 5 - 10 column volumes at an elution rate of 5 - 15 mL / min. TLC spotting plate monitoring was carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent, and the effluent with an Rf value of 0.2 - 0.5 was collected, rotary evaporated under reduced pressure until no liquid flowed out, and dried to obtain the compound shown in formula (VIII); (4) Under argon protection and at room temperature, the compound shown in formula (VIII) and dichloromethane a were added to pyridine and stirred for 5 minutes. A dichloromethane b solution of trifluoromethanesulfonic anhydride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature. TLC monitoring was carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent. After the reaction was completed, it was cooled to room temperature; 1M HCl was added and the mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure until no liquid flowed out to obtain an oily liquid; the oily liquid was loaded onto a silica gel column, and the eluent was petroleum ether and ethyl acetate with a volume ratio of 20:

1. Elution was carried out for 5 - 10 column volumes at an elution rate of 5 - 15 mL / min. TLC spotting plate monitoring was carried out using petroleum ether and ethyl acetate with a volume ratio of 3:1 as the developing agent, and the effluent with an Rf value of 0.2 - 0.5 was collected, rotary evaporated under reduced pressure until no liquid flowed out, and dried to obtain the compound shown in formula (IX); Under argon protection, the compound shown in formula (IX) is mixed with toluene, and a n - hexane solution of diisobutylaluminum hydride is added dropwise at 0 °C, stirred at 0 °C, and monitored by TLC using a developing agent of petroleum ether and ethyl acetate with a volume ratio of 2:

1. After the reaction is completed, it is cooled to room temperature; ethyl acetate is added for extraction, and the organic phase is washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid; the oily liquid is dissolved in dichloromethane c, pyridinium chlorochromate is added, and stirred at room temperature for 20 minutes, and monitored by TLC using a developing agent of petroleum ether and ethyl acetate with a volume ratio of 3:

1. After the reaction is completed, dichloromethane d is added for extraction, and the organic phase is washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated under reduced pressure until no liquid flows out to obtain an oily liquid; the oily liquid is loaded onto a silica gel column, and the eluent is petroleum ether and ethyl acetate with a volume ratio of 20:1, eluting 5 - 10 column volumes, with an elution rate of 5 - 15 mL / min, and monitored by TLC spotting using a developing agent of petroleum ether and ethyl acetate with a volume ratio of 3:

1. The effluent with an Rf value of 0.2 - 0.5 is collected, rotary evaporated under reduced pressure until no liquid flows out, and dried to obtain the intermediate compound shown in formula (V); the volume of toluene used is 5 - 15 mL / mmol based on the compound shown in formula (IX); the molar ratio of the compound shown in formula (IX) to diisobutylaluminum hydride is 1:1 - 10; the volume of n - hexane used is 1 - 5 mL / mmol based on the compound shown in formula (IX); the volume of dichloromethane c used is 1 - 10 mL / mmol based on the compound shown in formula (IX); the molar ratio of the compound shown in formula (IX) to pyridinium chlorochromate is 1:1 - 5.

6. The application according to claim 5, characterized in that, In step (1), the molar ratio of the compound shown in formula (I) to hexamethylenetetramine is 1:1.0 - 3.0; the volume of trifluoromethanesulfonic acid used is 5 - 15 mL / mmol based on the amount of substance of the compound shown in formula (I).

7. The application according to claim 5, wherein In step (2), the volume of tetrahydrofuran used is 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula (VI); the volumes of the aqueous sodium hydroxide solution and hydrogen peroxide solution used are both 5 - 15 mL / mmol based on the amount of substance of the compound shown in formula (VI).

8. The application according to claim 5, characterized in that In step (3), sodium hydride is added in the form of a 60% sodium hydride mineral oil by mass concentration, the molar ratio of the compound shown in formula (VII) to sodium hydride is 1:1.0 - 5.0; the volume of dimethyl sulfoxide a used is 5 - 15 mL / mmol based on the amount of substance of the compound shown in formula (VII); the molar ratio of the compound shown in formula (VII) to methyl iodide is 1:1 - 5; the volume of dimethyl sulfoxide b used is 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula (VII).

9. The application according to claim 5, characterized in that, The molar ratio of the compound shown in formula (VIII) described in step (4) to pyridine is 1:1 - 5; the volume of dichloromethane a used is 10 - 30 mL / mmol based on the amount of the compound shown in formula (VIII); the molar ratio of the compound shown in formula (VIII) to trifluoromethanesulfonic anhydride is 1:5 - 15; the volume of dichloromethane b used is 1 - 5 mL / mmol based on the amount of the compound shown in formula (VIII).

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