Synthesis method of gamma-substituted butene lactone compound

Abstract

The method comprises the following steps: adding an acrylic acid compound, ethyl glyoxylate, dichloro bis (4-methyl isopropyl phenyl) ruthenium (II) and cesium acetate into an organic solvent, heating under an air condition to react, after the reaction is completed, filtering, washing and drying to obtain the gamma-substituted butene lactone compound. And performing post-treatment to obtain the gamma-substituted butene lactone compound. According to the method, the gamma-substituted butene lactone compound is synthesized from simple and easily available raw materials through a one-pot method, the conversion efficiency is high, and the step economy is good; meanwhile, the synthesis method is simple to operate, high in reaction yield and wide in substrate universality.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing a gamma-substituted butene lactone compound. Background Art

[0002] γ-Substituted butenolides are a class of extremely useful and common oxygen-containing heterocyclic molecules, which have very wide applications in many fields such as pesticide chemistry, medicinal chemistry, and materials. For example, Aenolide is a highly effective antibiotic with a butenolide skeleton, and Strgol contains a γ-butenolide structure and has the effect of inhibiting plant growth. Asteriscunolide D is an anticancer drug with a γ-butenolide structure, which can effectively inhibit the division of pancreatic cancer cells and has a high reputation in medicinal chemistry. Due to the importance of the butenolide skeleton, chemists have developed a variety of reaction methodologies to construct this skeleton in recent years. In 2016, Zhu Chen's research group studied the synthesis of highly substituted butenolides through the cyclization reaction of α-keto acids with tertiary alcohols and alkynes. Prescher's group reported a method for synthesizing butenolides from functionalized cyclopropenones through ring-opening reactions. Novikov and his colleagues continued to develop a method for synthesizing butenolides through base-regulated regional differentiation of azide ring expansion. On the other hand, there is also an important class of methods that uses carbon monoxide to construct butenolides. Obviously, CO is a toxic gas that seriously pollutes the environment. The remaining methods all have certain defects such as poor atom and step economy, cumbersome operation, complex and harsh conditions, poor functional group tolerance, etc.

[0003] In recent years, the transition metal-catalyzed directing group-assisted carbon-hydrogen bond activation reaction strategy has become a powerful tool for the efficient synthesis of complex molecules. Carboxylic acids have three obvious characteristics as directing groups: First, carboxylic acids and their derivatives are cheap, easy to obtain, widely present in nature, and there are many types; Second, the carboxylic acid group (-COOH) itself has unique nucleophilic (electrophilic) properties. After successfully playing its directing role to activate the CH bond, it can quickly undergo intramolecular nucleophilic cyclization to construct the cyclized product; Third, many directing groups have pre-installation steps, which require tedious operations to remove later, while the carboxyl functional group can also remove a molecule of carbon dioxide (CO2) after directing the CH bond functionalization reaction, achieving traceless guidance. From this point of view, carboxyl is a very efficient and excellent directing group. In recent years, carboxyl-directed carbon-hydrogen bond activation reactions have also been a research hotspot in this field. Compared with the addition reactions assisted by nitrogen-containing groups that have been developed, reactions assisted by weak directing of carboxylic acids are developing. Summary of the invention

[0004] The present invention provides a method for synthesizing γ-substituted butenolide compounds, which uses cheap and readily available substrates, is easy to operate, has wide substrate universality, excellent functional group compatibility, and high reaction yield. The series of new compounds synthesized by the method of the present invention are expected to become key intermediates for synthesizing bioactive molecules-diol antifungal inhibitors.

[0005] A method for synthesizing a γ-substituted butenolide compound comprises the following steps: adding an acrylic acid compound, ethyl glyoxylate, a ruthenium catalyst and an additive into an organic solvent, heating under air conditions for reaction, and after the reaction is complete, post-processing to obtain the butenolide dimer compound;

[0006] The structure of the acrylic acid compound is shown in formula (II):

[0007]

[0008] The structure of ethyl glyoxylate is shown in formula (III):

[0009]

[0010] The structure of the butene lactone dimer compound is shown in formula (I):

[0011]

[0012] In formula (I) to (II), R 1 is selected from substituted or unsubstituted phenyl, wherein the substituent on the phenyl is selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, phenyl or naphthyl; preferably, R 1 is selected from substituted or unsubstituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methyl, tert-butyl, methoxy, phenyl or naphthyl.

[0013] Preferably, the γ-substituted butenolide compound is one of the compounds represented by formula (I-1) to formula (I-12):

[0014]

[0015]

[0016] Preferably, the ruthenium catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II).

[0017] Preferably, the organic solvent is hexafluoroisopropanol (HFIP).

[0018] Preferably, the reaction temperature is 50 to 70° C., and the reaction time is 5 to 15 hours in an air atmosphere. More preferably, the reaction temperature is 60° C., and the reaction time is 10 hours.

[0019] Preferably, the additive for the reaction is cesium acetate.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] (1) The present invention uses a one-pot method to synthesize γ-substituted butenolide compounds in high yield using very simple and readily available raw materials, with high conversion efficiency and good step economy;

[0022] (2) The synthesis method of the present invention is simple to operate, has a high reaction yield, and has good substrate universality and functional group compatibility.

[0023] (3) The series of new compounds synthesized by the method of the present invention are expected to become key intermediates for synthesizing bioactive molecules - diol antifungal inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The hydrogen and carbon spectra of the compound obtained in Example 1;

[0025] Figure 2 The hydrogen and carbon spectra of the compound obtained in Example 2;

[0026] Figure 3 The hydrogen and carbon spectra of the compound obtained in Example 3;

[0027] Figure 4 The hydrogen and carbon spectra of the compound obtained in Example 4;

[0028] Figure 5 The hydrogen and carbon spectra of the compound obtained in Example 5;

[0029] Figure 6 The hydrogen and carbon spectra of the compound obtained in Example 6;

[0030] Figure 7 The hydrogen and carbon spectra of the compound obtained in Example 7;

[0031] Figure 8 The hydrogen and carbon spectra of the compound obtained in Example 8;

[0032] Fig. 9 The hydrogen and carbon spectra of the compound obtained in Example 9;

[0033] Fig.10 The hydrogen and carbon spectra of the compound obtained in Example 10;

[0034] Fig.11 The hydrogen and carbon spectra of the compound obtained in Example 11;

[0035] Fig.12 The hydrogen and carbon spectra of the compound obtained in Example 12;

[0036] The hydrogen spectrum was tested on a 400MHz nuclear magnetic resonance instrument. The carbon spectrum was tested on a 100MHz nuclear magnetic resonance instrument. The test conditions were all room temperature with tetramethylsilane as the internal standard and the samples were dissolved in deuterated chloroform. DETAILED DESCRIPTION

[0037] The present invention is further described below in conjunction with specific embodiments, and the following specific embodiments are all optimal implementation modes of the present invention.

[0038] Examples 1 to 12

[0039] According to the raw material ratio in Table 1, acrylic acid compound (0.2 mmol), ethyl glyoxylate (0.5 mmol), dichlorobis(4-methylisopropylphenyl)ruthenium (II) (0.05 mmol), cesium acetate (0.4 mmol) and 1.5 mL of organic solvent were added into a test tube, mixed and stirred evenly, and after the reaction was completed according to the reaction conditions in Table 2, the mixture was cooled, filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding γ-substituted butene lactone compound (I). The reaction process is shown in the following formula:

[0040]

[0041] Table 1 Raw material ratios of Examples 1 to 10

[0042]

[0043] Table 2 Reaction conditions and reaction results of Examples 1 to 10

[0044]

[0045] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, 2,3,4-OMe is 2,3,4-trisubstituted methoxy, 1-naphthyl is 1-substituted naphthyl, and 2-naphthyl is 2-substituted naphthyl.

[0046] Application Example 1:

[0047] The series of products synthesized by the method can be easily synthesized into a class of biologically active molecules - antifungal agents through a few simple transformation steps including hydrogenation, reduction, substitution, etc.

[0048]

[0049] Specific steps:

[0050] 1) In a dry 25mL Schlenk tube, compound I (1mmol) was dissolved in methanol (5.0mL), and Pd / C (0.1mmol) was added. The reaction mixture was placed in a H2 atmosphere at room temperature and stirred overnight (using a balloon). After the reaction was completed, the organic solvent was removed by decompression on a rotary evaporator, and the crude reaction mixture was purified by silica gel chromatography (petroleum ether / ethyl acetate) to obtain a hydrogenated product II.

[0051] 2) Compound II was dissolved in THF, LiBH4 (10 equiv) was added at 0°C, and stirred for 2 hours. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude diol product. The crude product was dissolved in dichloromethane, triethylamine Et3N (2 equiv) and 4-dimethylaminopyridine DMAP (0.2 equiv) were added at 0°C, and the mixed solution was stirred at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the crude reaction mixture was purified by silica gel chromatography (petroleum ether / ethyl acetate) to obtain product III.

[0052] 3) Compound III was dissolved in ultra-dry THF, LiAlH4 (6 equiv) was slowly added at 0°C, and stirred for 6 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, the mixture was extracted with ethyl acetate, the organic layer was concentrated, and the crude reaction mixture was purified by silica gel chromatography (petroleum ether / ethyl acetate) to obtain product IV.

[0053] 4) The product IV is dissolved in dichloromethane, triethylamine Et3N (3 equiv) and MsCl (2 equiv) are added at 0°C, and the mixed solution is stirred at room temperature for 1 hour. After the reaction is completed, the solvent is removed by reduced pressure to obtain a crude product with a protective group. The product is dissolved in methanol, and 1,2,4-triazole (3 equiv) and sodium carbonate (10 equiv) are added, and the reaction solution is refluxed for 12 hours. After the reaction is completed, it is cooled to room temperature, filtered with diatomaceous earth, and washed with 10 mL of ethyl acetate. The filtrate is concentrated and then the crude reaction mixture is purified by silica gel chromatography (petroleum ether / ethyl acetate) to obtain the product triazole-substituted diol derivative. The diol derivative is dissolved in ether, 1 mL of formic acid is added at 0°C and stirred for 15 minutes, the solvent is removed by reduced pressure, and the mixture is purified by silica gel chromatography (petroleum ether / ethyl acetate) to obtain the final antifungal inhibitor V.

[0054] The structural confirmation data of some compounds prepared in Examples 1 to 12 are as follows:

[0055]

[0056] Ethyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-oxo-4-phenyl-2,5-dihydrofuran-2-carboxylate (I-1): Purified by column chromatography (petroleum ether:EtOAc=3:1) to obtain a mixture of diastereomers (54.8 mg, 82% yield, 2:1dr) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.85-7.84(m,2H),7.60(s,0.33H,minor),7.55(s,0.65H,major),7.40-7.39(m,3H),4.92(s,0.65H,major), 4.87(s,0.33H,minor),4.39-4.10(m,4H),3.74(s,0.30H,minor),3.53(s,0.62H,major),1.34-1.28(m,5H),1.11(t,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3) δ170.0,169.8,169.6,169.0,166.0,165.8,142.8,142.6,133.2,132.4,130.2, 130.0,128.8,128.7,128.5,128.4,127.4,127.2,87.9,73.7,71.8,63.3(2C),63.1,62.7,14.0(2C).

[0057]

[0058] Ethyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-oxo-4-(p-tolyl)-2,5-dihydrofuran-2-carboxylate (I-2): Purified by column chromatography (petroleum ether:EtOAc=3:1) to obtain a mixture of diastereomers (56.4 mg, 81% yield, 1.9:1 dr) as a colorless oil. 1H NMR(400MHz, CDCl3)δ7.77-7.73(m,2H),7.54(s,0.33H,minor),7.48(s,0.63H, major),7.23-7.20(m,2H),4.91(d,J=6.4Hz,0.63H,major),4.85(d,J=9.2Hz,0 .33H, minor), 4.40-4.11 (m, 4H), 3.63 (d, J=8.8Hz, 0.33H, minor), 3.43 (d, J=6. 4Hz,0.62H,major),2.37-2.36(m,3H),1.34-1.29(m,5H),1.12(t,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3) δ170.1,169.9,169.7,169.0,166.1,165.9,141.6,141.5,140.5,140.3,133.1,132.3,129.5,129.4 ,127.2,127.1,125.7,125.6,87.8,73.8,71.8,63.3,63.2,63.0,62.6,21.4,14.1,14.0(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 18 H 20 O7Na:371.1101; measured value 371.1103.

[0059]

[0060] Ethyl

[0061] 4-(4-(tert-butyl)phenyl)-2-(-2-ethoxy-1-hydroxy-2-oxoethyl)-5-oxo-2,5-dihydrofuran-2-carb oxylate (I-3): Purified by column chromatography (petroleum ether:EtOAc=3:1) to obtain a mixture of diastereomers (58.6 mg, 75% yield, 2:1 dr) in the form of a colorless oil. 1H NMR (400MHz, CDCl3) δ7.81-7.76(m,2H),7.54(s,0.32H,minor),7.49(s,0.65H,major),7.45-7.42(m,2H),4.91(d,J=6.0Hz,0.65H,major),4.85(d, J=8.4Hz,0.33H,minor),4.41-4.13(m,2H),3.58(d,J=8.8Hz,0.32H,minor),3.38-3.37(m,0.63H,major),1.34-1.30(m,14H),1.15(t,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3) δ170.2,169.9,169.7,169.0,166.1,166.0,153.6,153.4,141.8,141.6,133.0,132.3,127.1,127.0,125.8 ,125.7(2C),125.6,87.9,87.8,73.8,71.8,63.3(2C),63.0,62.6,34.8(2C),31.2,14.1,14.0(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 21 H 26 O7Na:413.1571; measured value 413.1569.

[0062]

[0063] Ethyl2-(2-ethoxy-1-hydroxy-2-oxoethyl)-4-(4-methoxyphenyl)-5-oxo-2,5-dihydrofuran-2-carboxylate (I-4): Purified by column chromatography (petroleum ether:EtOAc=3:1) to obtain a mixture of diastereomers (58.3 mg, 80% yield, 2:1dr) as a colorless oil. 1H NMR(400MHz, CDCl3)δ7.85-7.80(m,2H),7.45(s,0.32H,minor),7.40(s,0.64H, major),6.95-6.90(m,2H),4.90(d,J=6.0Hz,0.65H,major),4.84(d,J=8.8Hz,0 .32H,minor),4.40-4.11(m,4H),3.84-3.83(m,3H),3.58(d,J=8.8Hz,0.33H,mi nor),3.38(d,J=6.4Hz,0.65H,major),1.35-1.29(m,5H),1.12(t,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3) δ170.3,169.9,169.8,169.0,166.2,166.0,161.1,161.0,140.1,140.0,132.6,131.8,128.8,128.7 ,121.1,120.9,114.2,114.1,87.8,87.7,73.8,71.8,63.3,63.0,62.6,55.4,14.1,14.0(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 18 H 20 O8Na:387.1050; measured value 387.1048.

[0064]

[0065] Ethyl4-([1,1'-biphenyl]-4-yl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-oxo-2,5-dihydrofuran-2-carb oxylate (I-5): Purified by column chromatography (petroleum ether:EtOAc=3:1) to obtain a mixture of diastereomers (50.9 mg, 62% yield, 2:1 dr) in the form of a yellow oil. 1H NMR (400MHz, CDCl3) δ7.97-7.94(m,2H),7.68-7.60(m,4.35H),7.58(s,0.65H ),7.48-7.44(m,2H),7.40-7.36(m,1H),4.95(d,J=6.4Hz,0.65H,major),4.88 (d,J=8.8Hz,0.33H,minor),4.43-4.15(m,4H),3.60(d,J=8.8Hz,0.32H,minor r),3.41(d,J=6.4Hz,0.64H,major),1.37-1.31(m,5H),1.16(t,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3) δ170.0,169.8,169.6,169.0,166.0,165.8,142.9,142.8,142.3,142.2,140.1,140.0,132.8,132.0,129.0,128.9,128.0 ,127.9,127.8,127.7,127.5,127.4,127.3,127.1,88.0,87.9,73.8,71.8,63.4,63.3,63.1,62.7,14.1(2C),14.0.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 23 H 22 O7Na:433.1258; measured value 433.1259.

[0066]

[0067] Ethyl

[0068] 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-4-(4-fluorophenyl)-5-oxo-2,5-dihydrofuran-2-carboxylate (I-6): Purified by column chromatography (petroleum ether:EtOAc=3:1) to obtain a mixture of diastereomers (58.5 mg, 83% yield, 2:1 dr) as a colorless oil. 11H NMR (400 MHz, CDCl3) δ 7.89 - 7.85 (m, 2H), 7.56 (s, 0.33H, minor), 7.49 (s, 0.65H, major), 7.14 - 7.08 (m, 2H), 4.92 (d, J = 6.0 Hz, 0.65H, major), 4.84 (d, J = 9.2 Hz, 0.33H, minor), 4.41 - 4.11 (m, 4H), 3.58 (d, J = 8.8 Hz, 0.33H, minor), 3.40 (d, J = 6.4 Hz, 0.65H, major), 1.35 - 1.29 (m, 5H), 1.13 (t, J = 7.2 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 169.9, 169.8, 169.5, 168.9, 165.9, 165.7, 163.8 (d, J C-F = 250.0 Hz), 163.7 (d, J C-F = 249.6 Hz), 142.2 (d, J C-F = 1.6 Hz), 142.1 (d, J C-F = 1.6 Hz), 132.2, 131.4, 129.4 (d, J C-F = 8.4 Hz), 129.3 (d, J C-F = 8.4 Hz), 124.7 (d, J C-F = 3.4 Hz), 124.6 (d, J C-F = 3.3 Hz), 116.0 (d, J C-F = 21.7 Hz), 115.9 (d, J C-F = 21.6 Hz), 87.9, 87.8, 73.7, 71.6, 63.4, 63.4, 63.1, 62.7, 14.1, 14.0 (2C). 19 19F NMR (300 MHz, CDCl3) δ -109.5, -109.8. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 17 H 17 FO7Na: 375.0851; Found 375.0851.

[0069]

[0070] Ethyl4-(4-chlorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-oxo-2,5-dihydrofuran-2-carboxylate (I-7): Purified by column chromatography (petroleum ether:EtOAc=3:1) to obtain a mixture of diastereomers (56.8 mg, 77% yield, 2:1dr) in the form of a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.83-7.80(m,2H),7.61(s,0.32H,minor),7.54(s,0.64H,major),7.41-7.36(m,2H),4.92(s,0.64H,major), 4.84(s,0.32H,minor),4.40-4.10(m,4H),3.63(s,0.30H,minor),3.44(s,0.62H,major),1.35-1.29(m,5H),1.12(t,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3) δ169.7,169.3,168.9,165.8,165.6,142.9,142.8,136.3,136.2,132.1,131.3,129.1,129.0,12 8.7,128.5,126.9,126.8,88.0,87.9,73.7,71.6,63.4(2C),63.1,62.7,14.1,14.0(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 17 H 17 ClO7Na:391.0555; measured value 391.0557.

[0071]

[0072] Ethyl 4-(4-bromophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-oxo-2,5-dihydrofuran-2-carboxyl ate (I-8): Purified by column chromatography (petroleum ether:EtOAc=3:1) to give a mixture of diastereomers (57.0 mg, 69% yield, 2:1 dr) as a yellow oil. 1H NMR (400MHz, CDCl3) δ7.75-7.73(m,2H),7.62(s,0.32H,minor),7.56-7.52(m,2.64H,major),4.92(d,J=5.2Hz,0.64H,major),4.85(d,J=8.0Hz ,0.32H,minor),4.40-4.10(m,4H),3.63(d,J=8.4Hz,0.32H,minor),3.45(d,J=6.0Hz,0.64H,major),1.35-1.29(m,5H),1.12(t,J=7.2Hz,1H); 13 C NMR(100MHz, CDCl3)δ169.7(2C),169.2,168.9,165.7,165.6,143.0,142.9,132.2,132.1,132.0,131.4,128.9,128.7, 127.4,127.2,124.7,124.5,88.0,87.9,73.7,71.6,63.4(2C),63.2,62.7,14.1,14.0(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcdfor C 17 H 17 BrO7Na:435.0050; measured value 435.0048.

[0073]

[0074] Ethyl2-(2-ethoxy-1-hydroxy-2-oxoethyl)-4-(4-iodophenyl)-5-oxo-2,5-dihydrofuran-2-carboxylate (I-9): Purified by column chromatography (petroleum ether:EtOAc=3:1) to give a mixture of diastereomers (58.9 mg, 64% yield, 2:1 dr) as a yellow oil. 1H NMR (400MHz, CDCl3) δ7.77-7.73(m,2H),7.63-7.56(m,3H),4.91(d,J=5.2Hz,0.66H,major),4.84(d,J=8.0Hz,0.33H,minor), 4.40-4.10(m,4H),3.62(d,J=8.4Hz,0.33H,minor),3.43(d,J=6.0Hz,0.66H,major),1.35-1.28(m,5H),1.12(t,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3) δ169.7,169.6,169.2,168.9,165.7,165.5,143.1,143.0,138.1,137.9,132.3,131.5,128.9,128 .8,127.9,127.8,96.7,96.5,88.0(2C),73.7,71.6,63.4(2C),63.2,62.7,14.1,14.0(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 17 H 17 IO7Na:482.9911; measured value 482.9913.

[0075]

[0076] Ethyl2-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-oxo-4-(3,4,5-trimethoxyphenyl)-2,5-dihydrofuran-2-carbooxylate (I-10): Purified by column chromatography (petroleum ether:EtOAc=2:1) ​​to obtain a mixture of diastereomers (67.9 mg, 80% yield, 2:1 dr) as a colorless oil. 1H NMR(400MHz, CDCl3)δ7.53(s,0.33H,minor),7.47(s,0.66H,major),7.13-7.12(m,2H) ,4.92(d,J=5.6Hz,0.66H,major),4.83(d,J=8.4Hz,0.33H,minor),4.40-4.11(m,4H), 3.89-3.88(m,6H),3.86(s,1.01H,minor),3.85(s,1.98H,major),3.60(d,J=8.8Hz,0. 33H, minor), 3.41 (d, J=5.2Hz, 0.66H, major), 1.35-1.29 (m, 5H), 1.16 (t, J=7.2Hz, 1H); 13 C NMR (100MHz, CDCl3) δ169.9,169.8,169.5,169.0,166.0,165.9,153.4,153.3,141.8,141.7,139.8(2C),132.7,131.9,123.9,1 23.7,104.6,104.5,87.7,87.6,73.8,71.7,63.4,63.3,63.1,62.7,61.0,56.3(2C),14.1,14.0(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 20 H 24 O 10 Na:447.1262; measured value 447.1261.

[0077]

[0078] Ethyl

[0079] 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-4-(naphthalen-2-yl)-5-oxo-2,5-dihydrofuran-2-carboxyl ate (I-11): Purified by column chromatography (petroleum ether:EtOAc=3:1) to obtain a mixture of diastereomers (52.3 mg, 68% yield, 1.8:1 dr) in the form of a colorless oil. 1H NMR (400MHz, CDCl3) δ8.60(s,1H),7.91-7.81(m,3H),7.77-7.75(m,1H),7.72(s,0. 34H, minor),7.66(s,0.65H,major),7.56-7.49(m,2H),4.97(d,J=5.6Hz,0.63H,ma jor),4.91(d,J=8.4Hz,0.34H,minor),4.42-4.10(m,4H),3.64(d,J=8.8Hz,0.34H, minor),3.46(d,J=6.0Hz,0.63H,major),1.37-1.31(m,5H),1.11(t,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3) δ170.1,169.9,169.6,169.0,166.0,165.9,142.6,142.5,1 33.8,133.8,133.1,133.0(2C),132.1,129.0,128.7,128.5,127.7(2C),127.6,1 27.5,127.4,127.3,126.8,126.7,125.7,125.6,124.1,123.9,88.0,77.4,77.1 ,76.8,73.8,71.8,63.4(2C),63.1,62.7,14.1,14.0.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 21 H 20 O7Na:407.1101; measured value 407.1103.

[0080]

[0081] Ethyl

[0082] 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-4-(naphthalen-1-yl)-5-oxo-2,5-dihydrofuran-2-carboxyl ate (I-12): Purified by column chromatography (petroleum ether:EtOAc=3:1) to give a mixture of diastereomers (43.1 mg, 56% yield, 2.2:1 dr) as a yellow oil. 11H NMR (400 MHz, CDCl3) δ 7.97 - 7.87 (m, 3H), 7.66 - 7.49 (m, 5H), 5.03 (d, J = 5.6 Hz, 0.65H, major), 4.99 (d, J = 8.0 Hz, 0.29H, minor), 4.46 - 4.24 (m, 4H), 3.63 (d, J = 8.0 Hz, 0.29H, minor), 3.55 (d, J = 5.6 Hz, 0.65H, major), 1.39 - 1.33 (m, 5H), 1.22 (t, J = 7.2 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 170.7, 170.3, 169.9, 169.0, 165.9, 165.8, 147.4, 147.0, 133.8 (2C), 133.7, 133.1, 131.2, 131.0, 130.3, 130.0, 128.9, 128.7, 127.8, 127.7, 127.0, 126.3 (2C), 126.1, 125.1 (2C), 124.5, 124.2, 88.6, 73.7, 71.6, 63.4 (2C), 63.1, 63.0, 14.2, 14.1, 14.0. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 21 H 20 O7Na: 407.1101; found 407.1102.

Claims

1. A method for synthesizing a γ-substituted butenolide compound, characterized in that: The method comprises the following steps: adding an acrylic acid compound, ethyl glyoxylate, a ruthenium catalyst and an additive into an organic solvent, heating under air conditions to react, and after the reaction is complete, post-treating to obtain the γ-substituted butene lactone compound; The structure of the γ-substituted butenolide compound is shown in formula (II): The structure of ethyl glyoxylate is shown in formula (III): The structure of the γ-substituted butenolide compound is shown in formula (I): In formula (I) to (II), R 1 is selected from substituted or unsubstituted phenyl groups, wherein the substituents on the phenyl group are selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, phenyl or naphthyl.

2. The method for synthesizing a γ-substituted butenolide compound according to claim 1, characterized in that: R 1 is selected from substituted or unsubstituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, I, methyl, tert-butyl, methoxy, phenyl or naphthyl.

3. The method for synthesizing a γ-substituted butenolide compound according to claim 1, characterized in that: The organic solvent is hexafluoroisopropanol (HFIP).

4. The method for synthesizing a γ-substituted butenolide compound according to claim 1, characterized in that: All additives were cesium acetate.

5. The method for synthesizing a γ-substituted butenolide compound according to claim 1, characterized in that: The ruthenium catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II).

6. The method for synthesizing a γ-substituted butenolide compound according to claim 1, characterized in that: The reaction temperature is 50 to 70° C., and the reaction time is 5 to 15 hours under air atmosphere.

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