Method for preparing chiral furanone ester derivative

Abstract

The invention discloses a method for preparing a chiral furanone ester derivative, which comprises the following steps: adding a metal catalyst into a solvent, sequentially adding a carboxylic acid compound I or a carboxylic acid compound II and a butene lactone compound III, introducing inert gas, stirring, post-treating and purifying to obtain a chiral furanone ester compound IV; the palladium catalysis system is composed of palladium salt and a chiral ligand V, and the chiral ligand has a structure shown in a formula V.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis and relates to a method for preparing chiral furanone ester derivatives. Background Art

[0002] Furanone ester compounds have been shown to have the potential as chiral synthons; natural and synthetic furanone derivatives as well as unsaturated lactones have been shown to have a wide range of biological activities, including anticonvulsant, anti-inflammatory, analgesic, antitumor, antiviral and anticancer activities. However, it is very difficult to obtain such compounds only through natural separation and biosynthesis, and they have the disadvantages of low content and high cost. For example, the 2(5H)-furan-2-one structure (also known as γ-butenolide) is the core unit of the strigolactone (SL) series of compounds. Since the content of SL in plants is extremely low, it is difficult to obtain it by separation and extraction. In addition, its total synthesis is difficult and the overall yield is low; another example is that natural and synthetic furanone compounds, pyrrolidone compounds, diketopiperazine compounds, etc. can be used as quorum sensing inhibitors (QSIs) to prevent the formation of biofilms of antibacterial bacteria, reduce the pathogenicity of bacteria without causing bacteria to develop drug resistance.

[0003] In recent decades, transition metal-catalyzed asymmetric carbon-carbon (C-C) bond and carbon-heteroatom bond activation have been powerful tools for realizing the construction and transformation of novel complex molecules, with the advantage of high step economy, and have become a general method for constructing various cyclic compounds. And through the combination of chiral ligands and metals, the control of multiple chiral centers can be completed in one-step reaction, and the asymmetric and efficient construction of the core skeletons of natural products can be completed.

[0004] Therefore, it is of potential application value and important methodological significance to develop an intermolecular coupling reaction based on C-heteroatom bond activation realized by inexpensive metals to achieve the efficient and highly selective construction of complex molecules, but it is also full of challenges. Summary of the Invention

[0005] In order to overcome the deficiencies of the prior art, one of the purposes of the present invention is to provide a method for chiral 2(5H)-furan-2-one ester derivatives. The present invention uses a transition metal catalyst with a simple structure and a chiral ligand that is simple and easy to synthesize as a catalytic system to achieve the efficient asymmetric synthesis of chiral furanone esters.

[0006] The technical solution of the present invention is as follows:

[0007] 1. A method for preparing chiral furanone ester derivatives, comprising the following steps:

[0008] A metal catalyst is added to a solvent, and a carboxylic acid compound I or a carboxylic acid compound II and a butenolide compound III are added in sequence. An inert gas is introduced, and through stirring, post-treatment, and purification steps, a chiral furanone ester compound IV is obtained; the palladium catalyst system is composed of a palladium salt and a chiral ligand V, and the chiral ligand has the structure shown in formula V; wherein, the structures of each formula are as follows:

[0009]

[0010] Among them, in compound I, when R 2 and R 3 are hydrogen, R 1 is a monosubstituted phenyl, a disubstituted phenyl, a biphenyl, a naphthalene ring, a furan ring, a thiophene ring, an indole, a phenyltetrahydrofuran, or a piperonyl ring; compound I is diclofenac, tilactol, isoxepac, or Vadimezan;

[0011] Among them, in compound I, when R 2 is methyl and R 3 is hydrogen, R 1 is a phenyl or a monosubstituted phenyl; compound I is ketoprofen, ibuprofen, flurbiprofen, loxoprofen, naproxen, fenoprofen, pranoprofen, or indoprofen;

[0012] Among them, in compound I, when R 2 is a phenyl and R 3 is hydrogen, R 1 is a phenyl;

[0013] Among them, in compound I, when R 2 is a phenyl and R 3 is a phenyl, R 1 is methyl;

[0014] Among them, in compound I, when R 2 is methyl and R 3 is methyl, R 1 is a substituted phenyl;

[0015] Among them, in compound II, R 4 is methyl, phenyl, or a substituted phenyl; compound II is febuxostat, repaglinide, tamibarotene, phenylpropionic acid, sorbic acid, retinoic acid, or oxaprozin;

[0016] Among them, in compound II, compound II is an amino acid, a dipeptide, or a tripeptide.

[0017] 2. The method for synthesizing a chiral furanone ester compound according to claim 1, wherein in compound I, when R 2 and R 3 are hydrogen, R 1It is 4-fluorophenyl, 2-naphthyl, 4-boronic acid pinacol ester phenyl, 4-methoxyphenyl, 4-methylphenyl, 3-cyanophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-(N,N-dimethyl)phenyl, 4-biphenyl, 2-thienyl 2-indolyl;

[0018] Among them, in compound I, R 2 is methyl, R 3 is hydrogen, R 1 is 4-methylphenyl, 4-nitrophenyl;

[0019] Among them, in compound I, R 2 is methyl, R 3 is methyl, R 1 is 4-bromophenyl, 4-nitrophenyl;

[0020] Among them, in compound II, R 4 is methyl, phenyl, 4-methylphenyl, 4-formylphenyl;

[0021] Among them, in compound II, compound II is phenylalanine, leucine, alanine, valine, isoleucine, methionine, tyrosine.

[0022] 3. The method for synthesizing chiral furanone esters according to claim 1, characterized in that the solvent is one of dichloromethane, toluene, tetrahydrofuran, ethyl acetate, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, dichloroethane.

[0023] 4. The method for synthesizing chiral furanone esters according to claim 1, characterized in that the palladium catalyst is one of tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium.

[0024] 5. The method for synthesizing chiral furanone esters according to claim 1, characterized in that the temperature of the asymmetric esterification reaction is 0 °C to 50 °C, and the optimal temperature is 25 °C; the time of the cycloaddition reaction is 3 to 24 hours.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] The present invention uses carboxylic acid compound I or carboxylic acid compound II substituted with different substituents and butenolide compound III substituted with different substituents as raw materials, and uses a catalyst and a chiral ligand that are simple, easy to obtain and have a novel structure as a catalytic system, and prepares chiral furanone esters through an asymmetric esterification reaction. The method of the present invention can generate furanone esters with high stereoselectivity and regioselectivity, and perform efficient asymmetric synthesis of furanone esters.

[0027] The catalyst used in the method of the present invention is a palladium catalyst and a chiral ligand V that are simple to obtain and inexpensive, and a palladium catalyst and a Trost-type chiral ligand with novel structures; it has the advantages of low catalyst cost and high efficiency; the method for preparing chiral furanone ester compounds by the asymmetric esterification reaction of a metal catalyst of the present invention has the advantages of convenient operation, wide substrate applicability, and inexpensive and easily available reaction raw materials. Detailed implementation manners

[0028] The present invention will be further described below in conjunction with specific implementation manners, but not limited thereto.

[0029] Meanwhile, in the following examples, the experimental methods are conventional methods unless otherwise specified; the reagents, materials and equipment can be obtained from commercial channels unless otherwise specified.

[0030] The yield mentioned in the examples is the molar yield.

[0031] The reaction route is as follows:

[0032] Example 1

[0033] The synthesis steps of 1c are as follows:

[0034]

[0035] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for thirty minutes. 1a (27.2 mg, 0.2 mmol) and 1b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 3 h. The reaction solution was rotary evaporated and separated by silica gel column chromatography to obtain the target product 1c. The eluent was ethyl acetate and petroleum ether (volume ratio 0.1:1), and the yield was 91%.

[0036] The characterization data of the obtained product 1c are as follows:

[0037] White solid (39.7 mg, 90% ee)

[0038] 1 H NMR (400 MHz, CDCl 3 ) δ 7.38–7.26 (m, 6H), 7.00 (q, J = 1.3 Hz, 1H), 6.31 (dt, J = 5.7, 1.4 Hz, 1H), 3.72 (d, J = 1.4 Hz, 2H) ppm.

[0039] 13 C NMR (100 MHz, CDCl 3) δ 169.69, 149.75, 132.54, 129.37, 128.83, 127.62, 125.26, 94.14, 40.77 ppm.

[0040] Example 2

[0041]

[0042] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for thirty minutes. 2a (30.8 mg, 0.2 mmol) and 2b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 3 h. The reaction solution was evaporated to dryness and separated by silica gel column chromatography to obtain the target product 2c. The eluent was ethyl acetate and petroleum ether (volume ratio 0.2:1), and the yield was 57%.

[0043] The characterization data of the obtained product 2c are as follows:

[0044] White solid (27 mg, 91% ee)

[0045] 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (dd, J = 5.7, 1.3 Hz, 1H), 7.23 (m, 2H), 7.06–6.99 (m, 2H), 6.98 (d, J = 1.3 Hz, 1H), 6.30 (m, 1H), 3.68 (s, 2H) ppm.

[0046] 13 C NMR (100 MHz, CDCl 3 ) δ 169.60, 163.55, 161.11, 149.64, 131.09, 131.01, 128.27, 125.40, 115.87, 115.66, 94.17, 39.93 ppm.

[0047] Example 3

[0048]

[0049] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for 30 minutes. 3a (37.2 mg, 0.2 mmol) and 3b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 3 h. The reaction solution was evaporated to dryness, and the target product 3c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 0.2:1), and the yield was 61%.

[0050] The characterization data of the obtained product 3c are as follows:

[0051] White solid (32.7 mg, 92% ee)

[0052] 1 H NMR (400 MHz, CDCl 3 ) δ 7.86–7.77 (m, 3H), 7.73 (s, 1H), 7.52–7.46 (m, 2H), 7.40 (dd, J = 8.4, 1.8 Hz, 1H), 7.28 (dd, J = 5.6, 1.3 Hz, 1H), 7.01 (t, J = 1.2 Hz, 1H), 6.29 (dd, J = 5.6, 1.2 Hz, 1H), 3.88 (d, J = 1.8 Hz, 2H) ppm.

[0053] 13 C NMR (100 MHz, CDCl 3 ) δ 169.74, 169.64, 149.66, 133.52, 132.75, 130.01, 128.65, 128.37, 127.82, 127.19, 126.50, 126.26, 125.40, 94.24, 41.06 ppm.

[0054] Example 4

[0055]

[0056] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for 30 minutes. 4a (27 mg, 0.2 mmol) and 4b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 3 h. The reaction solution was evaporated to dryness, and the target product 4c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 0.2:1), and the yield was 81%.

[0057] The characterization data of the obtained product 4c are as follows:

[0058] White solid (35.2 mg, 90% ee)

[0059] 1 H NMR (400 MHz, CDCl 3 ) δ 7.82–7.74 (m, 2H), 7.30–7.26 (m, 3H), 6.98 (t, J = 1.2 Hz, 1H), 6.30 (dd, J = 5.6, 1.2 Hz, 1H), 3.74–3.69 (s, 2H), 1.34 (s, 12H) ppm.

[0060] 13 C NMR (100 MHz, CDCl 3 ) δ 169.62, 169.47, 149.65, 135.58, 135.35, 128.79, 125.42, 94.22, 84.01, 41.11, 24.99 ppm.

[0061] Example 5

[0062]

[0063] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for 30 minutes. 5a (32.4 mg, 0.2 mmol) and 5b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 9 h. The reaction solution was concentrated by rotary evaporation and the target product 5c was obtained by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio 0.1:1), and the yield was 94%.

[0064] The characterization data of the obtained product 5c are as follows:

[0065] White solid (45.9 mg, 80% ee)

[0066] 1 H NMR (400 MHz, CDCl 3 ) δ 7.43–7.38 (m, 2H), 7.35 (m, 3H), 7.31–7.27 (m, 1H), 7.05 (d, J = 1.4 Hz, 1H), 6.61–6.51 (m, 1H), 6.38–6.22 (m, 2H), 3.37 (dd, J = 7.1, 1.4 Hz, 2H) ppm.

[0067] 13 C NMR (100 MHz, CDCl 3) δ 169.70, 149.74, 136.49, 134.63, 128.68, 127.95, 126.44, 125.31, 119.95, 94.07, 37.88 ppm.

[0068] Example 6

[0069]

[0070] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for 30 minutes. 6a (32.4 mg, 0.2 mmol) and 6b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 9 h. The reaction solution was rotary evaporated to dryness and separated by silica gel column chromatography to obtain the target product 6c. The eluent was ethyl acetate and petroleum ether (volume ratio 0.1:1), and the yield was 72%.

[0071] The characterization data of the obtained product 6c are as follows:

[0072] White solid (35.1 mg, 90% ee)

[0073] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.40–7.27 (m, 5H), 7.21 (dd, J = 5.7, 1.4 Hz, 1H), 6.95 (t, J = 1.4 Hz, 1H), 6.23 (dd, J = 5.7, 1.2 Hz, 1H), 1.70 (m, 2H), 1.33 (m, 2H) ppm.

[0074] 13 13C NMR (100 MHz, CDCl 3 ) δ 172.88, 169.77, 149.81, 138.15, 130.60, 128.42, 127.71, 125.27, 94.34, 29.04, 17.71, 17.55 ppm.

[0075] Example 7

[0076]

[0077] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for thirty minutes. 7a (33.2 mg, 0.2 mmol) and 7b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 3 h. The reaction solution was concentrated by rotary evaporation and separated by silica gel column chromatography to obtain the target product 7c. The eluent was ethyl acetate and petroleum ether (volume ratio 0.1:1), and the yield was 89%.

[0078] The characterization data of the obtained product 7c are as follows:

[0079] White solid (44.2 mg, 72% ee)

[0080] 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (dd, J = 5.7, 1.4 Hz, 1H), 7.23–7.14 (m, 2H), 6.98 (t, J = 1.3 Hz, 1H), 6.91–6.82 (m, 2H), 6.29 (dd, J = 5.6, 1.2 Hz, 1H), 3.79 (s, 3H), 3.65 (s, 2H) ppm.

[0081] 13 C NMR (100 MHz, CDCl 3 ) δ 170.03, 169.69, 159.12, 149.76, 130.46, 125.32, 124.54, 114.29, 94.17, 55.38, 39.96 ppm.

[0082] Example 8

[0083]

[0084] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for thirty minutes. 8a (53 mg, 0.2 mmol) and 8b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 3 h. The reaction solution was concentrated by rotary evaporation and separated by silica gel column chromatography to obtain the target product 8c. The eluent was ethyl acetate and petroleum ether (volume ratio 0.1:1), and the yield was 62%.

[0085] The characterization data of the obtained product 8c are as follows:

[0086] White solid (43 mg, 17:1 dr)

[0087] 11H NMR (400 MHz, CDCl 3 ) δ 7.35–7.27 (m, 3H), 7.18–7.13 (d, J = 6.7 Hz, 2H), 7.11 (d, J = 5.6 Hz, 1H), 6.89 (s, 1H), 6.27 (d, J = 5.6 Hz, 1H), 4.99 (d, J = 8.2 Hz, 1H), 4.61 (m, 1H), 3.09 (d, J = 6.5 Hz, 2H), 1.41 (s, 9H) ppm.

[0088] 13 13C NMR (100 MHz, CDCl 3 ) δ 170.43, 169.39, 155.04, 149.35, 135.52, 129.34, 128.84, 127.41, 125.34, 94.39, 54.75, 38.28, 28.31 ppm.

[0089] Example 9

[0090]

[0091] Under a nitrogen atmosphere, a dichloromethane solution of tris(dibenzylideneacetone)dipalladium and (R,R)-L1 was stirred at room temperature for thirty minutes. 9a (27.2 mg, 0.2 mmol) and 9b (80 mg, 0.4 mmol) were successively added to a 4 ml reaction flask, and then the pre-complexed copper catalyst was added to the reaction flask. The mixture was reacted at room temperature for 3 h. The reaction solution was rotary evaporated to dryness and separated by silica gel column chromatography to obtain the target product 9c. The eluent was ethyl acetate and petroleum ether (volume ratio 0.1:1), and the yield was 87%.

[0092] The characterization data of the obtained product 9c are as follows:

[0093] White solid (38 mg, 89% ee)

[0094] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.92 (d, J = 8.0 Hz, 2H), 7.45 (dd, J = 5.7, 1.4 Hz, 1H), 7.25–7.20 (m, 2H), 6.36 (dd, J = 5.7, 1.2 Hz, 1H), 2.41 (s, 3H) ppm.

[0095] 13 13C NMR (100 MHz, CDCl 3)δ 169.85, 164.67, 150.09, 149.28, 145.29, 130.30, 129.50, 125.40, 94.51, 21.89 ppm.

[0096] The above are only some embodiments of the present invention, and do not impose any form of limitation on the present invention. Any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the invention all fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing a chiral furanone ester derivative, comprising the following steps: A metal catalyst is added to a solvent, and a carboxylic acid compound I or a carboxylic acid compound II and a butene lactone compound III are added in sequence, and an inert gas is introduced, and a chiral furanone ester compound IV is obtained after stirring, post-treatment and purification steps; the palladium catalytic system is composed of a palladium salt and a chiral ligand V, and the chiral ligand has a structure shown in formula V; wherein, The various structures are as follows: In compound I, R 2 , R 3 When it is hydrogen, R 1 is a monosubstituted phenyl, a disubstituted phenyl, a biphenyl, a naphthalene ring, a furan ring, a thiophene ring, an indole, a phenylpropane tetrahydrofuran, a piperonyl ring; compound I is diclofenac, tirlatrexol, isoxacic acid, and vadimezan; In compound I, R 2 Methyl, R 3 When it is hydrogen, R 1 is phenyl or monosubstituted phenyl; compound I is ketoprofen, ibuprofen, flurbiprofen, loxoprofen, naproxen, fenoprofen, pranoprofen, indoprofen; In compound I, R 2 Phenyl, R 3 When it is hydrogen, R 1 is phenyl; In compound I, R 2 Phenyl, R 3 When it is phenyl, R 1 is methyl; In compound I, R 2 Methyl, R 3 When it is methyl, R 1 is a substituted phenyl group; Among the compounds II, R 4 is methyl, phenyl, substituted phenyl; compound II is febuxostat, repaglinide, tamibarotene, phenylpropionic acid, sorbic acid, retinoic acid, oxaprozin; Among the compound II, compound II is an amino acid, a dipeptide or a tripeptide.

2. The method for synthesizing chiral furanone ester compounds according to claim 1, characterized in that: In compound I, R 2 , R 3 When it is hydrogen, R 1 4-fluorophenyl, 2-naphthyl, 4-boronic acid pinacol ester phenyl, 4-methoxyphenyl, 4-methylphenyl, 3-cyanophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-(N,N-dimethyl)phenyl, 4-biphenyl, 2-thienyl 2-indolyl; In compound I, R 2 Methyl, R 3 When it is hydrogen, R 1 4-methylphenyl, 4-nitrophenyl; In compound I, R 2 Methyl, R 3 When it is methyl, R 1 4-bromophenyl, 4-nitrophenyl; Among the compounds II, R 4 is methyl, phenyl, 4-methylphenyl, 4-formylphenyl; Among the compound II, compound II is phenylalanine, leucine, alanine, valine, isoleucine, methionine, and tyrosine.

3. The method for synthesizing chiral furanone ester compounds according to claim 1, characterized in that: The solvent is one of dichloromethane, toluene, tetrahydrofuran, ethyl acetate, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether and dichloroethane.

4. The method for synthesizing chiral furanone ester compounds according to claim 1, characterized in that: The palladium catalyst is one of tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium and tetrakistriphenylphosphine palladium.

5. The method for synthesizing chiral furanone ester compounds according to claim 1, characterized in that: The temperature of the asymmetric esterification reaction is 0°C to 50°C, with the optimal temperature being 25°C; the time of the cycloaddition reaction is 3 to 24 hours.

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