R,r-naphthodianhydrofuran compounds, processes for their preparation and their use in the preparation of p-glycoprotein inhibitors

Abstract

This invention provides an R,R-naphthodihydrofuran compound, its preparation method, and its application in the preparation of P-glycoprotein inhibitors, belonging to the field of biomedical technology. The R,R-naphthodihydrofuran compound provided by this invention has the structure shown in Formula I, exhibiting a novel structure, good Pgp inhibitory activity, and low cytotoxicity. This R,R-naphthodihydrofuran compound can be used in the development of Pgp inhibitors, providing a potential option for reversing drug resistance in cancer cells.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to an R,R-naphthodihydrofuran compound, its preparation method, its application in the preparation of P-glycoprotein inhibitors, and P-glycoprotein inhibitors. Background Technology

[0002] For a long time, how to safely and effectively cure malignant tumors has been a focus of scientific research and social concern. Chemotherapy has broad-spectrum cytotoxicity and has always been regarded as the core therapy for treating malignant tumors (Arnold M, Rutherford M J, Bardot A, et al. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study [J]. The Lancet Oncology, 2019, 20(11), 1493-1505). However, malignant tumors often develop multidrug resistance (MDR), which ultimately leads to chemotherapy failure. There are many reasons for the development of multidrug resistance in malignant tumors, one of which is the drug efflux mechanism mediated by P-glycoprotein (Pgp). To address the drug efflux phenomenon of this glycoprotein, scientists have developed Pgp inhibitors, with the third-generation inhibitor, Tariquidar (Fox E, Bates S E. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor[J]. Expert Review of Anticancer Therapy, 2014, 7(4): 447-459), being a representative drug. The docking activity exhibited by the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ring in Tariquidar during molecular docking further confirms the important role of this structure in reversing tumor drug resistance. However, the third-generation inhibitor still faces many challenges in clinical trials, resulting in slow progress. Therefore, developing a safe and effective Pgp inhibitor is a key research focus in this field. Summary of the Invention

[0003] The purpose of this invention is to provide an R,R-naphthodihydrofuran compound, its preparation method, and its application in the preparation of P-glycoprotein inhibitors, as well as a P-glycoprotein inhibitor. The R,R-naphthodihydrofuran compound provided by this invention has a novel structure, exhibits good Pgp inhibitory activity, and shows low toxicity in cell assays, demonstrating great potential.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0005] This invention provides an R,R-naphthodihydrofuran compound having the structure shown in Formula I:

[0006]

[0007] In Formula I, Ar is selected from substituted or unsubstituted phenyl, naphthyl, pyridine, thiophene, furan, pyrrole, indole, benzofuran, or benzothiophene groups; substitution refers to the substitution of one or more hydrogen atoms in the group by a halogen, nitro, cyano, alkyl, alkoxy, or ester group.

[0008] Preferably, the number of carbon atoms in the alkyl or alkoxy group is 1 to 4; the number of carbon atoms in the ester group is 2 to 4.

[0009] Preferably, the R,R-naphthodihydrofuran compound is any one of the following compounds:

[0010]

[0011]

[0012] This invention provides a method for preparing the R,R-naphthodihydrofuran compounds described in the above technical solution, comprising the following steps:

[0013] An α-hydroxynaphthol derivative, a chloronitro olefin, a squaramide catalyst, a basic compound, and an organic solvent are mixed and subjected to a nucleophilic cyclization reaction to obtain the R,R-naphthodihydrofuran compound.

[0014] The structural formulas of the α-hydroxynaphthol derivative, the chloronitroolefin, and the squaramide catalyst are shown in Formula III, Formula IV, and Formula V, respectively:

[0015]

[0016] Ar in Formula IV is the same as in Formula I.

[0017] Preferably, the alkaline compound is an inorganic alkaline compound or an organic alkaline compound; the inorganic alkaline compound includes at least one of potassium carbonate, potassium phosphate, dipotassium hydrogen phosphate and cesium carbonate; the organic alkaline compound includes at least one of triethylamine, triethylenediamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 4-dimethylaminopyridine.

[0018] Preferably, the organic solvent includes at least one of halogenated hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents, and aromatic hydrocarbon solvents.

[0019] Preferably, the molar ratio of the α-hydroxynaphthol derivative to the chloronitroolefin is 1:1 to 2; and the molar ratio of the α-hydroxynaphthol derivative to the basic compound is 1:0.5 to 2.

[0020] Preferably, the nucleophilic cyclization reaction is carried out at a temperature of -20 to 25°C for 12 to 24 hours.

[0021] This invention provides the application of the R,R-naphthodihydrofuran compounds described in the above technical solution in the preparation of P-glycoprotein inhibitors.

[0022] This invention provides a P-glycoprotein inhibitor, comprising an active ingredient and excipients; the active ingredient is the R,R-naphthodihydrofuran compound described in the above technical solution.

[0023] This invention provides an R,R-naphthodihydrofuran compound having the structure shown in Formula I. The R,R-naphthodihydrofuran compound provided by this invention has a novel structure, exhibits good Pgp inhibitory activity, and low cytotoxicity. The R,R-naphthodihydrofuran compound provided by this invention can be used in the development of Pgp inhibitors, providing a potential option for reversing drug resistance in cancer cells. Bioactivity test results of the embodiments of this invention show that R,R-naphthodihydrofuran compounds having structures of Formulas I-9, I-11, I-14, I-15, and I-21 have good Pgp inhibitory activity, which is beneficial for developing safer and more effective Pgp inhibitors.

[0024] This invention provides a method for preparing R,R-naphthodihydrofuran compounds, wherein the R,R-naphthodihydrofuran compounds are prepared by nucleophilic cyclization reaction of α-hydroxynaphthol derivatives and chloronitroolefins in the presence of a squaramide catalyst. In this method, the raw materials are inexpensive and readily available, the reaction conditions are mild, and the resulting R,R-naphthodihydrofuran compounds exhibit high yields and excellent enantioselectivity. This invention achieves the asymmetric construction of naphthodihydrofuran Pgp inhibitors containing tetrahydroisoquinoline fragments, which is of great significance for promoting the application of small molecule catalytic products in the pharmaceutical field, especially in the preparation of novel Pgp inhibitors. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 The 1H NMR spectrum of R,R-naphthodihydrofuran compound I-1 is shown.

[0027] Figure 2 The image shows the carbon NMR spectrum of R,R-naphthodihydrofuran compound I-1.

[0028] Figure 3 The 1H NMR spectrum of R,R-naphthodihydrofuran compound I-4 is shown.

[0029] Figure 4 This is the carbon NMR spectrum of I-4, an R,R-naphthodihydrofuran compound. Detailed Implementation

[0030] This invention provides an R,R-naphthodihydrofuran compound having the structure shown in Formula I;

[0031]

[0032] In Formula I, Ar is selected from substituted or unsubstituted phenyl, naphthyl, pyridine, thiophene, furan, pyrrole, indole, benzofuran, or benzothiophene groups; substitution refers to the substitution of one or more hydrogen atoms in the group by a halogen, nitro, cyano, alkyl, alkoxy, or ester group.

[0033] In this invention, the number of substituents on the substituted phenyl group can be one or two; when the number of substituents on the substituted phenyl group is one, the substitution site on the phenyl group can be ortho, para, or meta; when the number of substituents on the substituted phenyl group is two, the substitution site on the phenyl group can be meta. In a specific embodiment of this invention, when the number of substituents on the substituted phenyl group is one, the substituent can be halogen, nitro, cyano, alkyl, alkoxy, or ester; when the number of substituents on the substituted phenyl group is one, the substituent can be halogen or alkyl.

[0034] In this invention, when the substituent on the substituted phenyl group is a halogen, the halogen can be -F, -Cl, or -Br.

[0035] In this invention, when the substituent on the substituted phenyl group is an alkyl group, the number of carbon atoms in the alkyl group can be 1 to 4, specifically 1, 2, 3, or 4. In a specific embodiment of this invention, the alkyl group on the substituted phenyl group can be methyl or tert-butyl.

[0036] In this invention, when the substituent on the substituted phenyl group is an alkoxy group, the number of carbon atoms in the alkoxy group can be 1 to 4, specifically 1, 2, 3, or 4. In a specific embodiment of this invention, the alkyl group on the substituted phenyl group can be methyl or tert-butyl.

[0037] In this invention, when the substituent on the substituted phenyl group is an ester group, the number of carbon atoms in the ester group can be 2 to 4, specifically 2, 3, or 4. In a specific embodiment of this invention, the alkoxy group on the substituted phenyl group can be a methoxy group.

[0038] In this invention, the R,R-naphthodihydrofuran compound can be any one of the following compounds:

[0039]

[0040]

[0041] The R,R-naphthodihydrofuran compounds described in this invention have two chiral carbon atoms and are dextrorotatory compounds.

[0042] The R,R-naphthodihydrofuran compounds provided by this invention have novel structures, exhibit good Pgp inhibitory activity, and show low toxicity in cell experiments. These R,R-naphthodihydrofuran compounds can be used in the development of Pgp inhibitors, providing a potential option for reversing drug resistance in cancer cells.

[0043] This invention also provides a method for preparing the R,R-naphthodihydrofuran compounds described in the above technical solution, comprising the following steps:

[0044] An α-hydroxynaphthol derivative, a chloronitro olefin, a squaramide catalyst, a basic compound, and an organic solvent are mixed and subjected to a nucleophilic cyclization reaction to obtain the R,R-naphthodihydrofuran compound.

[0045] The structural formulas of the α-hydroxynaphthol derivative, the chloronitroolefin, and the squaramide catalyst are shown in Formula III, Formula IV, and Formula V, respectively:

[0046]

[0047] Ar in Formula IV is the same as in Formula I.

[0048] In this invention, unless otherwise specified, all raw materials used are commercially available products well known to those skilled in the art or prepared using methods well known to those skilled in the art.

[0049] In this invention, the molar ratio of the α-hydroxynaphthol derivative to the chloronitro olefin can be 1:1 to 2; in specific embodiments, the molar ratio of the α-hydroxynaphthol derivative to the chloronitro olefin can be 1:1.1, 1:1.2, 1:1.5, 1:1.8 or 1:2.

[0050] In this invention, the basic compound may include an inorganic basic compound or an organic basic compound; the inorganic basic compound may include at least one of potassium carbonate, potassium phosphate, dipotassium hydrogen phosphate, and cesium carbonate; the dipotassium hydrogen phosphate may be dipotassium hydrogen phosphate trihydrate; the organic basic compound may include at least one of triethylamine, triethylenediamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 4-dimethylaminopyridine; in specific embodiments, the basic compound may be dipotassium hydrogen phosphate trihydrate, triethylamine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In this invention, the molar ratio of the α-hydroxynaphthol derivative to the basic compound may be 1:0.5 to 2; in specific embodiments, the molar ratio of the α-hydroxynaphthol derivative to the basic compound may be 1:0.5, 1:1, 1:1.5, or 1:2.

[0051] In this invention, the organic solvent may include at least one selected from halogenated hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents, and aromatic hydrocarbon solvents; the halogenated hydrocarbon solvent may include at least one selected from dichloromethane, 1,2-dichloroethane, and chloroform; the nitrile solvent may be acetonitrile; the ether solvent may include at least one selected from tetrahydrofuran and 1,4-dioxane; the ester solvent may be ethyl acetate; the aromatic hydrocarbon solvent may be toluene; in specific embodiments, the organic solvent may be dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, or 1,4-dioxane. In this invention, based on the molar amount of the α-hydroxynaphthol derivative, the volume of the organic solvent may be 5–20 mL / mmol; in specific embodiments, the volume of the organic solvent may be 5 mL / mmol, 10 mL / mmol, 15 mL / mmol, or 20 mL / mmol.

[0052] In this invention, the molar ratio of the α-hydroxynaphthol derivative to the squaring amide catalyst can be 1:0.05 to 1; in a specific embodiment, the molar ratio of the α-hydroxynaphthol derivative to the squaring amide catalyst can be 1:0.1.

[0053] This invention involves mixing an α-hydroxynaphthol derivative, a chloronitroolefin, a squaramide catalyst, a basic compound, and an organic solvent to perform a nucleophilic cyclization reaction, yielding the R,R-naphthodihydrofuran compound. In specific embodiments, the α-hydroxynaphthol derivative, the squaramide catalyst, and the basic compound are added to an organic solvent and stirred to obtain a mixed solution. A chloronitroolefin is then added to the mixed solution, and the nucleophilic cyclization reaction is carried out under a second stirring condition. In embodiments, the first stirring time can be 4 min, 5 min, or 6 min. In this invention, the temperature of the nucleophilic cyclization reaction can be -20 to 25°C, and the time can be 12 to 24 h. In specific embodiments, the temperature of the nucleophilic cyclization reaction can be -20°C, -10°C, 0°C, 10°C, or 25°C, and the time can be 12 h, 16 h, 20 h, or 24 h. During the nucleophilic cyclization reaction, a reaction detection process can be performed using petroleum ether and ethyl acetate at a volume ratio of 2:1. After the nucleophilic cyclization reaction described in this invention is completed, the resulting reaction solution can be subjected to silica gel column chromatography. In this invention, the eluent used for silica gel column chromatography can be a petroleum ether-ethyl acetate mixture, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixture can be 2:1. In this invention, the volume of the eluent can be 5 to 10 column volumes; in specific embodiments, the volume of the eluent can be 5, 6, 7, 8, 9, or 10 column volumes. In this invention, the flow rate of the eluent can be 5 to 15 mL / min; in specific embodiments, the flow rate of the eluent can be 5 mL / min, 10 mL / min, or 15 mL / min. During the silica gel column chromatography process, thin-layer chromatography (TCL) monitoring can be performed using a 2:1 volume ratio of petroleum ether and ethyl acetate as the developing solvent. The eluent with a specific gravity shift (Rf value) of 0.3–0.4 is collected and dried to obtain the R,R-naphthodihydrofuran compounds. In this invention, the drying can be performed by rotary evaporation under reduced pressure.

[0054] In the preparation of R,R-naphthodihydrofuran compounds described in this invention, the raw materials are inexpensive and readily available, the reaction conditions are mild, and the resulting R,R-naphthodihydrofuran compounds exhibit high yields and excellent enantioselectivity. This invention achieves the asymmetric construction of naphthodihydrofuran Pgp inhibitors containing tetrahydroisoquinoline fragments, which is of great significance for promoting the application of small molecule catalytic products in the pharmaceutical field, especially in the preparation of novel Pgp inhibitors.

[0055] This invention provides the application of the R,R-naphthodihydrofuran compounds described in the above technical solution in the preparation of P-glycoprotein inhibitors.

[0056] This invention provides a P-glycoprotein inhibitor, comprising an active ingredient and excipients; the active ingredient is the R,R-naphthodihydrofuran compound described in the above technical solution.

[0057] Compared with the prior art, the advantages of this invention are as follows: R,R-naphthodihydrofuran compounds with structures of formulas I-9, I-11, I-14, I-15 and I-21 have significant Pgp inhibitory activity against human breast cancer cells, which is beneficial for the development of safer and more effective Pgp inhibitors.

[0058] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0059] The α-hydroxynaphthol derivatives with the structure shown in Formula III used in the examples are known compounds reported in the literature. They were prepared by amide condensation of commercially available 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and commercially available α-hydroxynaphthoic acid. For specific procedures, please refer to the following literature: New coupling reagents in peptide chemistry. Tetrahedron Lett. 1989, 30, 1927;

[0060] The chloronitroolefins with the structure shown in Formula IV used in the examples are known compounds reported in the literature. The synthetic method is based on the following literature: Rodriguez J, Bonne D, Becerra D, et al. Enantioselective Organocatalyzed Consecutive Synthesis of Alkyl 4,5-Dihydrofuran-2-carboxylates from α-Keto Esters and (Z)-β-Chloro-β-nitrostyrenes. Synthesis, 2016, 49(01):195-201;

[0061] The synthesis method of the square amide catalyst with the structure shown in Formula IV used in the examples is referred to the following literature: Enantioselective syntheses of furan atropisomers by an oxidative central-to-axial chirality conversion strategy. Journal of the American Chemical Society, 2017, 139(6):2140-2143;

[0062] The “room temperature” mentioned in the examples is 25–30°C.

[0063] Example 1

[0064] The preparation process of (6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)((1S,2S)-2-nitro-1-phenyl-1,2-dihydronaphtho[2,1-b]furan-7-yl) methyl ketone (i.e., R,R-naphthodihydrofuran compounds having the structure shown in Formula I-1) is as follows:

[0065]

[0066] 72.6 mg of (6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)(6-hydroxynaphth-2-yl) methyl ketone (III), 8.4 g of catalyst (squamamide catalyst), and 91.3 mg of dipotassium hydrogen phosphate trihydrate were added to 2 mL of 1,2-dichloroethane. The resulting mixture was placed in a 0°C cryogenic reactor and magnetically stirred for 5 min. After stirring, 43.9 g of (Z)-2-chloro-2-nitrobenzene (IV-1) was added to the mixture. The mixture was reacted in the 0°C cryogenic reactor for 24 h. During the reaction, petroleum ether and ethyl acetate at a volume ratio of 2:1 were used as the developing solvent to monitor the reaction. After the reaction was completed, the magnetic ball was removed, and the resulting reaction solution was subjected to silica gel column chromatography using a petroleum ether-ethyl acetate mixture (volume ratio of petroleum ether to ethyl acetate was 2:1) as the eluent. The eluent flow rate was 10 mL / min, and 10 column volumes were eluted. TLC monitoring was performed using petroleum ether and ethyl acetate in a volume ratio of 2:1 as the developing solvent. The eluent with an Rf value of 0.3 was collected and evaporated to dryness under reduced pressure to obtain a white solid, which was R,R-naphthodihydrofuran compound I-1 (93.8 mg), with a yield of 92% and an ee of 95%.

[0067] The 1H NMR spectrum of R,R-naphthodihydrofuran compound I-1 is shown below. Figure 1 As shown, the carbon spectrum is as follows Figure 2 As shown. Specific characterization data are as follows: 1 H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.98(d,J=8.7Hz,1H),7.52(d,J=8.8Hz,1H),7.49-7.40(m,2H),7.40-7.32(m,3H),7.20(dd,J=7. 0,2.1Hz,2H),6.79-6.23(m,2H),6.15(d,J=1.6Hz,1H),5.35(d,J=1.7Hz,1H),4.70(d,J=145.1Hz,2H),3.87(m,8H),2.87(d,J=56.9Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.5,157.2,147.9,137.6,132.2,132.1,130.1,130.1,129.5,128.6,128.0 ,127.5,126.3,124.8,123.5,118.6,112.8,112.5,111.5,109.4,108.8,56.0,55.2.HRMS(ESI)m / z Calcd.for C 30 H 27 N2O6 + ([M + H] + )511.1864, Found511.1863. Enantiomeric excess was determined to be 95% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =40.2min,t minor =30.0min).

[0068] Example 2

[0069] R,R-naphthodihydrofuran compound I-2 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-chloro-4-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-2 is shown below:

[0070]

[0071] Characterization data for R,R-naphthodihydrofuran compound I-2 are as follows: white solid, yield 65%, 96% ee. 1 H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.98(d,J=9.0Hz,1H),7.52(d,J=9.0Hz,1H),7.48(dd,J=8.3,1.7Hz,1H),7.39(d,J=8.5Hz,1H),7.36-7.31 (m,2H),7.16-7.10(m,2H),6.74-6.30(m,2H),6.10(d,J=1.8Hz,1H),5.33- 5.31(m,1H),4.70(d,J=147.8Hz,2H),3.87(m,8H),2.87(d,J=54.6Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.3,157.2,148.0,136.0,134.7,132.4,132.4,130.2,129.9,129.7,128 .9,128.1,126.4,124.7,123.3,118.1,112.8,112.1,111.6,56.0,54.6.HRMS(ESI)m / zCalcd.for C 30 H 26 ClN2O6 + ([M + H] + )545.1474, Found 545.1466. Enantiomeric excess was determined to be 96% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =39.4min,t minor =30.1min).

[0072] Example 3

[0073] R,R-naphthodihydrofuran compound I-3 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrobenzene was replaced with (Z)-1-bromo-4-(2-chloro-2-nitrobenzene). The structural formula of R,R-naphthodihydrofuran compound I-3 is shown below:

[0074]

[0075] Characterization data for R,R-naphthodihydrofuran compound I-3 are as follows: white solid, yield 82%, 92% ee. 1 H NMR(500MHz,Chloroform-d)δ8.08-7.92(m,2H),7.58-7.41(m,4H),7.38(d,J=8.5Hz,1H),7.07(d,J=8.3Hz,2H),6 .74-6.28(m,2H),6.10(d,J=1.8Hz,1H),5.31(s,1H),4.70(d,J=147.9Hz,2H),3.87(m,8H),2.87(d,J=55.8Hz,2H). 13 CNMR (126MHz, CDCl3) δ170.5,157.2,148.0,136.5,132.7,132.4,130.2,129.9,129.2,128.2, 126.4,124.7,123.3,122.8,118.0,112.8,112.0,111.4,56.0,54.6.HRMS(ESI)m / zCalcd.for C 30 H 26 BrN2O6 + ([M + H] + )589.0969, Found 589.0959. Enantiomeric excess was determined to be 92% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =52.0min,t minor =33.0min).

[0076] Example 4

[0077] The preparation process of (6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)((1S,2S)-2-nitro-1-(p-tolyl)-1,2-dihydronaphtho[2,1-b]furan-7-yl) methyl ketone (i.e., R,R-naphthodihydrofuran compounds having the structure shown in Formula I-4) is as follows:

[0078]

[0079] 72.6 mg of (6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)(6-hydroxynaphth-2-yl) methyl ketone (III), 8.4 g of catalyst (squamamide catalyst), and 91.3 mg of dipotassium hydrogen phosphate trihydrate were added to 2 mL of 1,2-dichloroethane. The resulting mixture was placed in a 0°C cryogenic reactor and magnetically stirred for 5 min. After stirring, 47.7 g of (Z)-2-chloro-2-nitrovinyl-2-toluene (IV-4) was added to the mixture. The mixture was reacted in the 0°C cryogenic reactor for 24 h. During the reaction, petroleum ether and ethyl acetate were used as the developing solvent in a volume ratio of 2:1 for monitoring. After the reaction was completed, the magnetic ball was removed, and the resulting reaction solution was subjected to silica gel column chromatography using a petroleum ether-ethyl acetate mixture (volume ratio of petroleum ether to ethyl acetate was 2:1) as the eluent. The eluent flow rate was 10 mL / min, and 10 column volumes were eluted. TLC monitoring was performed using petroleum ether and ethyl acetate in a volume ratio of 2:1 as the developing solvent. The eluent with an Rf value of 0.3 was collected and evaporated to dryness under reduced pressure to obtain a white solid, which was R,R-naphthodihydrofuran compound I-4 (74.4 mg), with a yield of 71% and 95% ee.

[0080] The 1H NMR spectrum of R,R-naphthodihydrofuran compound I-4 is shown below. Figure 3 As shown, the carbon spectrum is as follows Figure 4 As shown. Specific characterization data are as follows: 1 H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.96(d,J=8.9Hz,1H),7.51(d,J=9.0Hz,1H),7.47-7.38(m,2H),7.16(d,J=7.9Hz,2H),7.07(d,J=8.0H z,2H),6.76-6.31(m,2H),6.12(d,J=1.8Hz,1H),5.31(d,J=1.7Hz,1H),4 .70(d,J=143.7Hz,2H),3.87(m,8H),2.84(d,J=55.0Hz,2H),2.34(s,3H). 13 CNMR (126MHz, CDCl3) δ170.1,157.1,147.9,138.5,134.6,132.2,132.0,130.1,128.0,127.4,126.2 ,124.8,123.5,118.8,112.8,112.6,111.6,109.5,108.7,56.0,55.0,21.1.HRMS(ESI)m / zCalcd.for C 31 H 29 N2O6+ ([M + H] + )525.2020, Found525.2024. Enantiomeric excess was determined to be 95% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =29.8min,t minor =21.9min).

[0081] Example 5

[0082] R,R-naphthodihydrofuran compound I-5 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-nitro-4-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-5 is shown below:

[0083]

[0084] Characterization data for R,R-naphthodihydrofuran compound I-5 are as follows: white solid, yield 64%, 97% ee. 1 H NMR(500MHz,Chloroform-d)δ8.22(d,J=8.4Hz,2H),8.00(d,J=9.0Hz,2H),7.53(d,J=8.9Hz,1H),7.47(dd,J=8.3,1.5Hz,1H),7.40(d,J=8.4Hz,2H ),7.33(d,J=8.6Hz,1H),6.80-6.21(m,2H),6.14(d,J=1.7Hz,1H),5.56-5 .39(m,1H),4.69(d,J=148.6Hz,2H),3.86(m,8H),2.86(d,J=58.9Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.1,157.3,148.1,148.0,144.4,132.8,132.6,130.2,129.7,128.7,128 .2,126.7,124.7,123.0,117.3,112.9,111.3,109.4,108.8,56.0,54.6.HRMS(ESI)m / zCalcd.for C 30 H 26N3O8 + ([M + H] + )556.1714, Found 556.1733. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =91.8min,t minor =58.3min).

[0085] Example 6

[0086] R,R-naphthodihydrofuran compound I-6 was prepared according to the conditions of the examples, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-methoxy-4-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-6 is shown below:

[0087]

[0088] Characterization data for R,R-naphthodihydrofuran compound I-6 are as follows: white solid, yield 74%, 88% ee. 1 H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.95(d,J=8.9Hz,1H),7.55-7.40(m,3H),7.13-7.06(m,2H),6.92-6.83(m,2H),6. 76-6.30(m,2H),6.11(d,J=1.8Hz,1H),5.29(d,J=1.8Hz,1H),4.70(d,J=142.3Hz,2H),3.82(m,11H),2.86(d,J=55.0Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.2,159.7,157.0,147.9,132.2,132.0,130.1,129.7,128.7,128.0,126. 2,124.6,123.5,118.9,114.8,112.8,112.7,111.6,109.4,108.8,56.0,55.3,54.6.HRMS(ESI)m / z Calcd.for C 31 H 29 N2O7 + ([M+ H] + )541.1969, Found 541.1971. Enantiomeric excess was determined to be 88% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =48.6min,t minor =35.5min).

[0089] Example 7

[0090] R,R-naphthodihydrofuran compound I-7 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-methoxycarbonyl-4-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-7 is shown below:

[0091]

[0092] Characterization data for R,R-naphthodihydrofuran compound I-7 are as follows: white solid, yield 73%, 93% ee. 1 H NMR(500MHz,Chloroform-d)δ8.03(d,J=1.9Hz,1H),8.01(d,J=3.8Hz,2H),7.98( d,J=8.8Hz,1H),7.52(d,J=8.8Hz,1H),7.45(d,J=8.6,1.7Hz,1H),7.37(d,J=8.6 Hz,1H),7.29(s,1H),7.27(s,1H),6.80-6.26(m,2H),6.14(d,J=2.0Hz,1H),5.40 (d,J=1.8Hz,1H),4.69(d,J=144.7Hz,2H),3.88(m,11H),2.86(d,J=55.0Hz,2H). 13C NMR (126MHz, CDCl3) δ170.2,166.3,157.3,147.9,142.4,132.5,132.4,130.7,130.6,130.2,129.9,128.1,1 27.7,126.3,125.5,124.7,123.3,118.0,112.8,111.9,111.6,109.4,108.7,56.0,55.0,52.3.HRMS(ESI)m / z Calcd.for C 32 H 29 N2O8 + ([M + H] + )569.1918, Found 569.1926. Enantiomeric excess was determined to be 93% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =73.7min,t minor =44.0min).

[0093] Example 8

[0094] R,R-naphthodihydrofuran compound I-8 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-fluoro-3-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-8 is shown below:

[0095]

[0096] Characterization data for R,R-naphthodihydrofuran compound I-8 are as follows: white solid, yield 85%, 96% ee. 1 H NMR(500MHz,Chloroform-d)δ8.06-7.94(m,2H),7.55-7.44(m,2H),7.44-7.31(m,2H),7.09-7.01(m,2H),6.91-6.81(m,1H), 6.75-6.30(m,2H),6.13(d,J=1.8Hz,1H),5.34(d,J=1.8Hz,1H),4.71(d,J=143.7Hz,2H),3.87(m,8H),2.87(d,J=53.7Hz,2H). 13C NMR (126MHz, CDCl3) δ170.3,163.3(d,J C-F =248.2Hz),157.3,148.0,140.0,139.9,132.4,131.2,131.2,130.2,130.0,128.1,12 6.4,124.7,123.3,123.3,118.0,115.8,115.7,114.7,114.5,112.8,112.0,109.1(d,J C-F =110.9Hz),56.0,54.8.HRMS(ESI)m / z Calcd.for C 30 H 26 FN2O6 + ([M + H] + )529.1769, Found529.1776. Enantiomeric excess was determined to be 96% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =38.2min,t minor =30.6min).

[0097] Example 9

[0098] R,R-naphthodihydrofuran compound I-9 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-chloro-3-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-9 is shown below:

[0099]

[0100] Characterization data for R,R-naphthodihydrofuran compound I-9 are as follows: white solid, yield 86%, 94% ee. 1H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.99(d,J=9.0Hz,1H),7.56-7.44(m,2H),7.40(d,J=8.6Hz,1H),7.36-7.28(m,2H),7.18(d,J=2.0Hz,1H ),7.12-7.04(m,1H),6.82-6.21(m,2H),6.12(d,J=1.8Hz,1H),5.32(d,J= 1.8Hz,1H),4.71(d,J=144.3Hz,2H),3.87(m,8H),2.87(d,J=53.4Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.1,157.3,147.9,139.5,135.5,132.5,132.4,130.8,130.2,129.9,129.0,128.2 ,127.7,126.4,125.8,124.8,123.3,117.9,112.8,111.9,111.6,109.4,108.7,56.0,54.7.HRMS(ESI)m / z Calcd.for C 30 H 26 ClN2O6 + ([M + H] + )545.1474, Found545.1480. Enantiomeric excess was determined to be 94% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =37.6min,t minor =31.6min).

[0101] Example 10

[0102] R,R-naphthodihydrofuran compound I-10 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrobenzene was replaced with (Z)-1-bromo-3-(2-chloro-2-nitrobenzene). The structural formula of R,R-naphthodihydrofuran compound I-10 is shown below:

[0103]

[0104] Characterization data for R,R-naphthodihydrofuran compound I-10 are as follows: white solid, yield 74%, 94% ee. 1 H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.97(d,J=8.8Hz,1H),7.54-7.44(m,3H),7.43-7.33(m,2H),7.26-7.20(m,1H),7.11(d, J=7.7Hz,1H),6.76-6.26(m,2H),6.11(d,J=1.7Hz,1H),5.31(s,1H),4.70(d,J=143.8Hz,2H),3.86(m,8H),2.86(m,J=55.0Hz,2H). 13 CNMR (126MHz, CDCl3) δ170.4,157.2,147.9,139.8,132.5,132.4,131.9,131.1,130.5,130.2,129.9,128. 1,126.4,126.3,124.7,123.6,123.3,117.9,112.8,111.9,111.6,109.4,108.7,56.0,54.7.HRMS(ESI)m / z Calcd.forC 30 H 26 BrN2O6 + ([M + H] + )589.0969, Found 589.0957. Enantiomeric excess was determined to be 94% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =40.2min,t minor =32.6min).

[0105] Example 11

[0106] R,R-naphthodihydrofuran compound I-11 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-methyl-3-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-11 is shown below:

[0107]

[0108] Characterization data for R,R-naphthodihydrofuran compound I-11 are as follows: white solid, yield 74%, 92% ee. 1 H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.97(d,J=9.0Hz,1H),7.52(d,J=8.8Hz,1H),7.45(d,J=2.4Hz,2H),7.26-7.18(m,1H),7.15(d,J=7 .6Hz,1H),7.05-6.89(m,2H),6.79-5.95(m,3H),5.41-5.10(m,1H),4.7 0(d,J=143.9Hz,2H),3.87(m,8H),2.87(d,J=52.6Hz,2H),2.32(s,3H). 13 C NMR (126MHz, CDCl3) δ170.5,157.2,147.9,139.4,137.6,132.2,132.0,130.1,129.4,129.3,128.1,128. 0,126.1,124.7,124.6,123.6,118.8,112.8,112.6,111.5,109.4,108.7,56.0,55.2,21.4.HRMS(ESI)m / z Calcd.for C 31 H 29 N2O6 + ([M + H] + )525.2020,Found 525.2035.Enantiomericexcess was determined to be 92%(determined by HPLC using chiral AD-H column,hexane / 2-propanol=60 / 40,λ=254nm,25℃,1mL / min,t major =31.0min,t minor =25.1min).

[0109] Example 12

[0110] R,R-naphthodihydrofuran compound I-12 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-nitro-3-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-12 is shown below:

[0111]

[0112] Characterization data for R,R-naphthodihydrofuran compound I-12 are as follows: white solid, yield 86%, 97% ee. 1 H NMR(500MHz,Chloroform-d)δ8.26-8.15(m,1H),8.08(m,1H),8.05-7.97(m,2H),7.66-7.50(m,3H),7.48(dd,J=8.5,1.6Hz,1H) ,7.35(d,J=8.4Hz,1H),6.78-6.05(m,3H),5.48(d,J=1.7Hz,1H),4.69(d,J=146.0Hz,2H),3.86(m,8H),2.86(d,J=55.0Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.3,157.4,149.0,148.0,139.6,133.7,132.9,132.6,130.7,130.3,129.7,128.2 ,126.7,124.6,123.8,123.0,122.6,117.3,112.9,111.6,111.5,109.4,108.7,56.0,54.5.HRMS(ESI)m / z Calcd.for C 30 H 26 N3O8 + ([M + H] + )556.1714, Found 556.1732. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =62.0min,t minor =45.9min).

[0113] Example 13

[0114] R,R-naphthodihydrofuran compound I-13 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-methoxy-3-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-13 is shown below:

[0115]

[0116] Characterization data for R,R-naphthodihydrofuran compound I-13 are as follows: white solid, yield 92%, 97% ee. 1 H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.96(d,J=8.8Hz,1H),7.56-7.41(m,3H),7.29(s,1H),6.87(dd,J=8.3,2.6Hz,1H),6.82-6.7 5(m,1H),6.75-6.30(m,3H),6.14(d,J=1.8Hz,1H),5.30(d,J=1.8Hz,1H),4.70(d,J=141.7Hz,2H),3.82(m,11H),2.86(d,J=56.0Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.5,160.4,157.2,147.9,139.2,132.2,132.1,130.6,130.1,128.0,126.2,124. 7,123.5,119.7,118.5,113.6,113.5,112.8,112.4,111.6,109.5,108.8,56.0,55.3,55.2.HRMS(ESI)m / z Calcd.for C 31 H 29 N2O7 + ([M + H] + )541.1969, Found 541.1984.Enantiomericexcess was determined to be 97% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =41.1min,t minor =34.3min).

[0117] Example 14

[0118] R,R-naphthodihydrofuran compound I-14 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-fluoro-2-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-14 is shown below:

[0119]

[0120] Characterization data for R,R-naphthodihydrofuran compound I-14 are as follows: white solid, yield 92%, 96% ee. 1 H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.98(d,J=8.9Hz,1H),7.55-7.39(m,3H),7.37-7.31(m,1H),7.25-7.19(m,1H), 7.07-6.99(m,1H),6.81-6.14(m,4H),5.67(d,J=1.6Hz,1H),4.70(d,J=144.7Hz,2H),3.87(m,8H),2.87(d,J=53.1Hz,2H). 13 C NMR (126MHz, CDCl3) δ 170.5, 160.2 (d, JC-F = 249.5Hz), 157.3, 147.9, 132.3, 132.3, 130.5, 130.5, 130.1, 130.0, 128.9, 128.1, 126.5, 126. 4,125.1,125.0,124.6,124.5,123.2,117.8,116.3,116.1,112.8,111.6,111.5,109.4,108.7,56.0,47.9,47.9.HRMS(ESI)m / zCalcd.for C 30 H 26 FN2O6 + ([M + H] + )529.1769, Found529.1793. Enantiomeric excess was determined to be 92% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =40.8min,t minor =27.0min).

[0121] Example 15

[0122] R,R-naphthodihydrofuran compound I-15 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-chloro-2-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-15 is shown below:

[0123]

[0124] Characterization data for R,R-naphthodihydrofuran compound I-15 are as follows: white solid, yield 61%, 97% ee. 1 H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.99(d,J=8.9Hz,1H),7.63-7.43(m,3H),7.41(d,J=8.4Hz,1H),7.29(dd,J=7.7, 1.6Hz,1H),7.15-7.07(m,1H),6.87-6.08(m,4H),5.89(s,1H),4.70(d,J=145.2Hz,2H),3.87(m,8H),2.87(d,J=53.4Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.3,157.5,147.9,134.7,133.6,132.4,132.3,130.3,130.2,130.0,129.1,12 8.1,127.8,126.4,125.5,124.7,123.5,118.5,112.8,111.8,111.6,109.4,108.7,56.0.HRMS(ESI)m / z Calcd.for C 30 H 26 ClN2O6 + ([M + H] + )545.1474, Found545.1480. Enantiomeric excess was determined to be 97% (determined by HPLC using chiralAD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =31.5min,t minor =26.2min).

[0125] Example 16

[0126] R,R-naphthodihydrofuran compound I-16 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-bromo-2-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-16 is shown below:

[0127]

[0128] Characterization data for R,R-naphthodihydrofuran compound I-16 are as follows: white solid, yield 71%, 97% ee. 1 H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.98(d,J=8.9Hz,1H),7.74(d,J=8.0Hz,1H),7.55-7.45(m,2H),7.42(d,J=8.6Hz,1H),7.22 -7.19(m,1.7Hz,1H),7.16-7.09(m,1H),6.83-6.06(m,4H),5.91(s,1H),4.70(d,J=144.1Hz,2H),3.86(m,8H),2.87(d,J=60.0Hz,2H). 13 CNMR (126MHz, CDCl3) δ170.4,157.5,147.9,136.5,133.6,132.4,132.3,130.2,129.9,129.2,128.5,12 8.1,126.4,125.6,124.7,123.9,123.6,119.0,112.8,111.9,111.6,109.4,108.7,56.0.HRMS(ESI)m / z Calcd.forC 30 H 26 BrN2O6 + ([M + H] + )589.0969, Found 589.0969. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =32.0min,t minor =29.6min).

[0129] Example 17

[0130] R,R-naphthodihydrofuran compound I-17 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-methyl-2-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-17 is shown below:

[0131]

[0132] Characterization data for R,R-naphthodihydrofuran compound I-17 are as follows: white solid, yield 74%, 84% ee. 1 H NMR(500MHz,Chloroform-d)δ8.02(s,1H),7.98(d,J=9.0Hz,1H),7.53(d,J=9.0Hz ,1H),7.44(dd,J=8.3,1.7Hz,1H),7.35(d,J=7.6Hz,1H),7.29(d,J=8.5Hz,1H),7. 25-7.19(m,1H),7.14-6.96(m,1H),6.74-6.28(m,3H),6.07(d,J=1.7Hz,1H),5.55 (s,1H),4.70(d,J=143.4Hz,2H),3.87(m,8H),2.86(d,J=55.1Hz,2H),2.76(s,3H). 13 C NMR (126MHz, CDCl3) δ170.5,157.5,148.0,136.0,135.4,132.2,132.0,131.3,130.2,130.0,128.5,128.1 ,127.4,127.0,126.2,124.7,123.5,119.2,112.7,112.2,111.6,109.5,108.8,56.0,20.1.HRMS(ESI)m / z Calcd.for C 31 H 29 N2O6 + ([M + H] + )525.2020, Found525.2042. Enantiomeric excess was determined to be 84% (determined by HPLC using chiralAD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =67.3min,tminor =55.8min).

[0133] Example 18

[0134] R,R-naphthodihydrofuran compound I-18 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-nitro-2-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-18 is shown below:

[0135]

[0136] Characterization data for R,R-naphthodihydrofuran compound I-18 are as follows: white solid, yield 71%, 96% ee. 1 H NMR(500MHz,Chloroform-d)δ8.12(d,J=8.1Hz,1H),8.07-7.97(m,2H),7.56-7.43(m,4H),7.38(d,J=8.6Hz, 1H),6.84-6.31(m,3H),6.17(d,J=81.5Hz,2H),4.70(d,J=150.4Hz,2H),3.87(m,8H),2.87(d,J=56.7Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.0,157.9,148.7,148.0,134.1,132.7,132.6,131.5,130.3,130.1,129.8 ,129.8,128.0,126.5,125.5,124.5,123.3,112.7,112.3,111.6,109.4,108.7,56.0.HRMS(ESI)m / z Calcd.for C 30 H 26 N3O8 + ([M + H] + )556.1714, Found556.1740. Enantiomeric excess was determined to be 96% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =56.7min,t minor =45.9min).

[0137] Example 19

[0138] R,R-naphthodihydrofuran compound I-19 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-methoxy-2-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-19 is shown below:

[0139]

[0140] Characterization data for R,R-naphthodihydrofuran compound I-19 are as follows: white solid, yield 76%, 94% ee. 1 H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.95(d,J=8.8Hz,1H),7.56-7.40(m,3H),7.34-7.28(m,1H),7.02(d,J=8.2Hz,1H),6.84- 6.29(m,4H),6.18(d,J=1.9Hz,1H),5.71(d,J=1.9Hz,1H),4.72(d,J=139.6Hz,2H),4.00(s,3H),3.87(m,8H),2.87(d,J=53.0Hz,2H). 13 CNMR(126MHz, CDCl3)δ170.6,157.5,156.7,147.9,132.0,131.7,130.4,130.0,129.8,128.4,128.0,126.1,125.4,12 4.8,123.8,121.0,118.5,112.8,111.6,110.9,109.4,108.7,77.4,77.3,77.1,76.8,56.0,55.7,48.7.HRMS(ESI)m / z Calcd.for C 31 H 29 N2O7 + ([M + H] + )541.1969, Found 541.1987. Enantiomericexcess was determined to be 94% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =30.0min,tminor =23.2min).

[0141] Example 20

[0142] R,R-naphthodihydrofuran compound I-20 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-methoxycarbonyl-2-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-20 is shown below:

[0143]

[0144] Characterization data for R,R-naphthodihydrofuran compound I-20 are as follows: white solid, yield 66%, 95% ee. 1 H NMR(400MHz,Chloroform-d)δ8.10(d,J=7.8Hz,1H),8.03(s,1H),7.98(d,J=8.9Hz,1H),7.52-7.39(m,4H),7.38-7.31(m,1H) ,6.68(d,J=15.4Hz,2H),6.45(s,1H),6.17(s,1H),4.71(d,J=117.6Hz,2H),4.04(m,3H),3.88(m,8H),2.88(d,J=45.7Hz,2H). 13 C NMR (101MHz, CDCl3) δ167.9,157.7,147.9,135.8,135.3,133.1,132.2,132.2,132.0,132.0,131. 5,130.2,128.5,128.5,126.4,123.9,122.2,115.8,113.5,112.7,56.0,52.8,49.8.HRMS(ESI)m / z Calcd.for C 32 H 29 N2O8 + ([M + H] + )569.1918, Found 569.1941. Enantiomeric excess was determined to be 95% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =32.1min,t minor=25.4min).

[0145] Example 21

[0146] R,R-naphthodihydrofuran compound I-21 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-2-(2-chloro-2-nitrovinyl)thiophene. The structural formula of R,R-naphthodihydrofuran compound I-21 is shown below:

[0147]

[0148] Characterization data for R,R-naphthodihydrofuran compound I-21 are as follows: white solid, yield 53%, 75% ee. 1 H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.98(d,J=8.9Hz,1H),7.60-7.43(m,3H),7.29(d,J=5.1Hz,1H),6.98(dd,J=5.1,3.6Hz,1H),6 .90(d,J=3.6Hz,1H),6.77-6.24(m,2H),6.20(d,J=1.7Hz,1H),5.63(s,1H),4.71(d,J=142.3Hz,2H),3.87(m,8H),2.87(d,J=53.5Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.4,156.8,147.9,140.3,132.5,132.3,130.2,130.0,128.0,127.6,126.6 ,126.4,126.4,124.7,123.4,118.3,112.8,112.1,111.5,109.5,108.8,56.0,50.2.HRMS(ESI)m / z Calcd.forC 28 H 25 N2O6S + ([M + H] + )517.1428, Found 517.1415. Enantiomeric excess was determined to be 75% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =48.8min,t minor=33.5min).

[0149] Example 22

[0150] R,R-naphthodihydrofuran compound I-22 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-2-(2-chloro-2-nitrovinyl)furan. The structural formula of R,R-naphthodihydrofuran compound I-22 is shown below:

[0151]

[0152] Characterization data for R,R-naphthodihydrofuran compound I-22 are as follows: white solid, yield 66%, 93% ee. 1 H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.95(d,J=9.0Hz,1H),7.62(d,J=8.4Hz,1H),7.55(dd,J=8.7,1.7Hz,1H),7.50-7.39(m,2H),6.76-6.34 (m,2H),6.32(dd,J=3.8,1.9Hz,2H),6.05(d,d,J=3.4Hz,1H),5.46(d,J= 1.5Hz,1H),4.72(d,J=142.3Hz,2H),3.87(m,8H),2.88(d,J=55.0Hz,2H). 13 C NMR (126MHz, CDCl3) δ170.5,157.0,149.5,147.9,143.5,132.4,132.3,130.1,130.0,128.0,126.4 ,124.7,123.3,116.1,112.9,111.5,110.8,109.7,109.5,108.8,108.6,56.0,48.7.HRMS(ESI)m / z Calcd.for C 28 H 25 N2O7 + ([M + H] + )501.1656,Found 501.1634.Enantiomericexcess was determined to be 93%(determined by HPLC using chiral AD-H column,hexane / 2-propanol=60 / 40,λ=254nm,25℃,1mL / min,t major=45.6min,t minor =28.2min).

[0153] Example 23

[0154] R,R-naphthodihydrofuran compound I-23 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-1-fluoro-4-(2-chloro-2-nitrovinyl)benzene. The structural formula of R,R-naphthodihydrofuran compound I-23 is shown below:

[0155]

[0156] Characterization data for naphthodihydrofuran compound I-23 are as follows: white solid, yield 83%, 92% ee. 1 H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.95(d,J=8.8Hz,1H),7.49(d,J=8.9Hz,1H),7.45(dd,J=8.7,1.7Hz,1H),7.37(d,J=8.6Hz,1H),7.17-7.12( m,2H),7.05-7.00(m,2H),6.75-6.23(m,2H),6.09(d,J=1.8Hz,1H),5.32(d ,J=1.8Hz,1H),4.68(d,J=143.3Hz,2H),3.84(m,8H),2.84d,J=56.2Hz,2H). 13 C NMR(101MHz,CDCl3)δ170.5,162.7(d,J C-F =242.4Hz),157.1,147.8,133.4,133.4,132.3,132.3,130.1(d,J C-F =23.2Hz),129.4,129.3,128.0,126.2,125.5,124.7,123.4,118.4,116.6,116.4,112.8,112.2,111.3,108.9(d,J C-F =63.2Hz), 56.0, 54.4. 19 F NMR(376MHz,CDCl3)δ-112.8.HRMS(ESI)m / z Calcd.for C 30 H 26 FN2O6 + ([M + H] +)529.1769, Found529.1758. Enantiomeric excess was determined to be 92% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =37.1min,t minor =28.2min).

[0157] Example 24

[0158] R,R-naphthodihydrofuran compound I-24 was prepared according to the conditions of Example 1, except that (Z)-2-chloro-2-nitrovinylbenzene was replaced with (Z)-3-(2-chloro-2-nitrovinyl)benzo[b]thiophene. The structural formula of R,R-naphthodihydrofuran compound I-24 is shown below:

[0159]

[0160] Characterization data for R,R-naphthodihydrofuran compound I-24 are as follows: white solid, yield 69%, 95% ee. 1 H NMR(500MHz,Chloroform-d)δ8.34(d,J=8.1Hz,1H),8.11-7.98(m,2H),7.93(d,J=8.0Hz,1H),7.67-7.43(m ,5H),6.65(s,3H),6.22(d,J=1.4Hz,1H),5.73(s,1H),4.72(d,J=138.2Hz,2H),3.87(m,8H),2.88(d,J50.6 Hz,2H). 13 CNMR (126MHz, CDCl3) δ170.4,157.2,147.9,141.2,137.0,132.4,132.4,131.2,130.2,128.1,126.3,126.2,1 25.3,125.1,124.8,123.7,123.4,121.7,117.4,113.0,111.6,110.5,109.4,108.7,56.0,49.3.HRMS(ESI)m / z Calcd.for C 32 H 27 N2O6S + ([M + H] +)567.1584, Found 567.1609. Enantiomeric excess was determined to be 95% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=60 / 40, λ=254nm, 25℃, 1mL / min, t major =61.9min,t minor =39.8min).

[0161] Test Example 1

[0162] Determination of Pgp inhibitory activity of R,R-naphthodihydrofuran compounds (I-1-24) obtained in Examples 1-24.

[0163] Pgp inhibition activity was tested using a human breast cancer cell line resistant to drugs (MCF-7 / ADR). The culture medium consisted of 90% RPMI 1640 medium, 1% penicillin antibiotics and 10% serum. The culture conditions were 95% air, 5% CO2, and constant temperature culture at 37℃.

[0164] The general procedures for cell culture are as follows:

[0165] Resuscitation: Remove the cell cryopreservation tubes and place them in a 37°C constant temperature water bath to accelerate thawing; after thawing, transfer the cell suspension to a centrifuge tube; add 3 mL of culture medium and centrifuge at 1000 rpm for 5 minutes; discard the supernatant and resuspend the cells in a culture dish containing complete culture medium; place the culture dish in a cell culture incubator at 37°C and 5% CO2; observe the cells overnight using a microscope to see if they adhere to the wall and grow.

[0166] Medium change: If cell growth is slow and the density is below 70%, a medium change can be performed. Discard the old culture medium; wash the cells twice with sterile phosphate-buffered saline (PBS) to remove cell metabolites and residual culture medium; add preheated fresh culture medium.

[0167] Subculturing: Before subculturing, discard the original culture medium and wash the bottom of the culture dish twice with sterile PBS. Next, add 1 mL of trypsin and gently agitate the dish to ensure the trypsin covers the bottom. Incubate at room temperature for 3 minutes. When the cells become rounded and a small number float, add 2–3 mL of complete culture medium to stop digestion. Gently pipette the bottom of the culture dish to detach all cells. Transfer the detached cell suspension to a centrifuge tube and centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, add 2 mL of fresh complete culture medium, gently pipette the cells to suspend them evenly in the medium, and then transfer to a suitable culture flask and incubate in a constant temperature incubator.

[0168] Cryopreservation: First, discard the original culture medium and wash the bottom of the culture dish twice with sterile PBS to ensure thorough cleaning. Add 1-2 mL of trypsin solution and incubate the culture dish in a 37°C incubator for 2 minutes. When the cells become rounded and a small number of cells float, add an appropriate amount of complete culture medium to stop digestion. Gently pipette the cells to transfer the detached cell suspension to a centrifuge tube and centrifuge at 1000 rpm for 5 minutes, discarding the supernatant. Then resuspend the cells in 2 mL of cryopreservation solution and transfer 1 mL to cryovials. Freeze overnight at -80°C and then transfer to a liquid nitrogen tank for storage.

[0169] The experimental method is as follows: The cytotoxicity of phenylfuran derivatives to MCF-7 and MCF-7 / ADR was determined using the MTT assay. The procedure consists of the following steps.

[0170] Cell Plating: According to experimental requirements, each well requires 5000 MCF-7 cells and 8000 MCF-7 / ADR cells. Use 100 μL of cell-containing culture medium per well. Add 100 μL of cell suspension to each 96-well plate using a pipette. Add 100 μL of PBS to the outermost layer of the 96-well plate. After completing these steps, gently shake the 96-well plate to ensure even cell distribution in each well. Finally, incubate the 96-well plate overnight in an incubator. Once the cells have adhered and grown normally, subsequent experimental procedures can be performed.

[0171] Drug addition: Dilute the prepared 10 mol / L dimethyl sulfoxide (DMSO) stock solution of the candidate compound to concentration gradients (10 mmol, 1 mmol, 0.1 mmol, 0.01 mmol, 0.001 mmol) with complete culture medium. Use PBS buffer for the blank control group and DMSO containing an equal volume for the negative control group. Perform triplet incubation. After removing the original culture medium, replace it with drug-containing medium or medium containing an equal volume of DMSO. Gently shake the 96-well plate after each step. Finally, incubate the 96-well plate in an incubator.

[0172] Assay: After 48 hours of incubation with the drug, add 10 μL of MTT (5 mg / mL) aqueous solution to each well, return to the incubator for 2 hours, and then remove. Measure the absorbance (OD value) of the 96-well plate at 450 nm using a full-wavelength microplate reader. The formulas for calculating cell viability and growth inhibition rate are:

[0173] Cell viability (%) = (OD drug-treated group - OD blank group) / (OD control group - OD blank group) × 100%

[0174] Cell growth inhibition rate (%) = 100% - cell survival rate (%)

[0175] The growth inhibition rates under different concentration gradients were imported into GraphPadPrism 6 software to calculate IC. 50 The values ​​are shown in Table 1.

[0176] Table 1. Evaluation of the drug resistance reversal activity of R,R-naphthodihydrofuran compounds against MCF-7 / ADR.

[0177]

[0178]

[0179] Wherein: [a]: The combined drug concentration of the R,R-naphthodihydrofuran compounds is 5 μmol / L.

[0180] [b]: Each set of data represents the average of three parallel experiments. The combined drug used was doxorubicin, and the IC50 value was... 50 The values ​​were calculated from the cell growth inhibition rates at five concentration gradients (10 mmol, 1 mmol, 0.1 mmol, 0.01 mmol, and 0.001 mmol).

[0181] [c]: IC50 when no candidate compound is added 50 (Doxorubicin) = 54.4 μmol / L. RF = IC 50 (Combined medication) / IC 50 (Multiple rhymes and metaphors)

[0182] As shown in Table 3, the R,R-naphthodihydrofuran compounds prepared in Examples 1 to 24 have low toxicity and different degrees of Pgp inhibitory activity. Among them, the R,R-naphthodihydrofuran compounds with structures of formulas I-9, I-11, I-14, I-15 and I-21 have good Pgp inhibitory activity, which is beneficial for the development of safer and more effective Pgp inhibitors.

[0183] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An R,R-naphthodihydrofuran compound, characterized in that, The R,R-naphthodihydrofuran compounds have the structure shown in Formula I; In Formula I, Ar is selected from substituted or unsubstituted phenyl, naphthyl, pyridine, thiophene, furan, pyrrole, indole, benzofuran, or benzothiophene groups; substitution refers to the substitution of one or more hydrogen atoms in the group by a halogen, nitro, cyano, alkyl, alkoxy, or ester group.

2. The R,R-naphthodihydrofuran compound according to claim 1, characterized in that, The alkyl or alkoxy group has 1 to 4 carbon atoms; the ester group has 2 to 4 carbon atoms.

3. The R,R-naphthodihydrofuran compound according to claim 1 or 2, characterized in that, The R,R-naphthodihydrofuran compound is any one of the following compounds:

4. A method for preparing the R,R-naphthodihydrofuran compound according to any one of claims 1 to 3, comprising the following steps: An α-hydroxynaphthol derivative, a chloronitro olefin, a squaramide catalyst, a basic compound, and an organic solvent are mixed and subjected to a nucleophilic cyclization reaction to obtain the R,R-naphthodihydrofuran compound. The structural formulas of the α-hydroxynaphthol derivative, the chloronitroolefin, and the squaramide catalyst are shown in Formula III, Formula IV, and Formula V, respectively: Ar in Formula IV is the same as in Formula I.

5. The preparation method according to claim 4, characterized in that, The alkaline compound is an inorganic alkaline compound or an organic alkaline compound; the inorganic alkaline compound includes at least one of potassium carbonate, potassium phosphate, dipotassium hydrogen phosphate and cesium carbonate; the organic alkaline compound includes at least one of triethylamine, triethylenediamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 4-dimethylaminopyridine.

6. The preparation method according to claim 4, characterized in that, The organic solvent includes at least one of halogenated hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents, and aromatic hydrocarbon solvents.

7. The preparation method according to claim 4 or 5, characterized in that, The molar ratio of the α-hydroxynaphthol derivative to the chloronitroolefin is 1:1 to 2; the molar ratio of the α-hydroxynaphthol derivative to the basic compound is 1:0.5 to 2.

8. The preparation method according to claim 4, characterized in that, The nucleophilic cyclization reaction is carried out at a temperature of -20 to 25°C for 12 to 24 hours.

9. The use of the R,R-naphthodihydrofuran compound according to any one of claims 1 to 3 in the preparation of P-glycoprotein inhibitors.

10. A P-glycoprotein inhibitor, comprising an active ingredient and excipients; wherein the active ingredient is an R,R-naphthodihydrofuran compound as described in any one of claims 1 to 3.

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