A method for synthesizing chiral dihydrocoumarins by palladium-catalyzed asymmetric hydrogenation of tetrasubstituted olefins

Abstract

This invention discloses a palladium-catalyzed asymmetric hydrogenation method for synthesizing chiral dihydrocoumarin from tetrasubstituted olefins. The method uses a chiral bisphosphine complex of palladium as a catalyst and a tetrasubstituted olefin as a substrate to synthesize chiral dihydrocoumarin via asymmetric hydrogenation. This invention employs a homogeneous palladium catalytic system to achieve asymmetric hydrogenation of tetrasubstituted olefins with high yield, high enantioselectivity (up to 99% enantiomeric excess), and high diastereoselectivity (diastereomer ratio >20:1), producing chiral dihydrocoumarin. The method is simple and practical, the catalyst is commercially available, the reaction conditions are mild, energy consumption is low, and it is environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric catalytic synthesis and relates to a method for the asymmetric hydrogenation synthesis of chiral dihydrocoumarin by palladium-catalyzed tetrasubstituted olefins. Technical Background

[0002] Dihydrocoumarins, chiral compounds, are an important class of structural units found in various natural products and pharmaceutically active molecules. Examples include natural products such as Populene E, Recedensolid, and Calomelanol A; as well as Soulamarin with antitrypanosome activity, Vismiaguianone D with cytotoxicity, and the Sirtuin inhibitor NSC 17364 with anticancer activity. Furthermore, they can serve as chiral starting materials for the synthesis of chiral drugs. For instance, they can be used in the asymmetric synthesis of the chiral drug tolterodine (an anti-urinary incontinence drug) and R-1065788 (a lipid-lowering drug). Therefore, the development of a simple, efficient, high-yield, highly enantioselective, and diastereoselective asymmetric synthetic method for the synthesis of chiral dihydrocoumarins has attracted widespread attention.

[0003] Currently developed asymmetric synthesis methods for chiral dihydrocoumarins mainly include transition metal-catalyzed asymmetric hydrogenation of coumarins, 1,4-conjugated reduction and addition reactions, and asymmetric hydrogenation esterification and cyclization reactions of alkenes. This patent utilizes a palladium / chiral phosphine ligand catalytic system to achieve the asymmetric hydrogenation of coumarins. It offers advantages such as a broad substrate range, high yield, and high enantioselectivity. Summary of the Invention

[0004] The purpose of this invention is to provide a palladium-catalyzed asymmetric hydrogenation method for synthesizing chiral dihydrocoumarins from tetrasubstituted olefins. This invention is simple and practical to operate, uses readily available raw materials, exhibits good enantioselectivity and diastereoselectivity, has high yield, and the reaction has the advantages of being green, atom-economical, and environmentally friendly.

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

[0006] This invention provides a palladium-catalyzed asymmetric hydrogenation synthesis of chiral dihydrocoumarin from tetrasubstituted olefins. The method uses a chiral bisphosphine complex of palladium as a catalyst and a tetrasubstituted olefin as a substrate to synthesize chiral dihydrocoumarin via asymmetric hydrogenation. The reaction formula of the method is as follows:

[0007]

[0008]

[0009] In the formula:

[0010] R is C1-C4 alkyl or benzyl;

[0011] R' is C1-C6 alkyl, benzyl, phenyl ring, naphthalene ring, thiophene ring or substituted aromatic ring containing substituents of methyl, ethyl, methoxy or halogen;

[0012] Ar is phenyl ring, naphthalene ring or substituted aromatic ring containing substituents of methyl or ethyl;

[0013] The catalyst is a complex of a metal palladium precursor and a chiral bisphosphine ligand.

[0014] Based on the above technical scheme, preferably, the asymmetric hydrogenation reaction solvent is an organic solvent, and the organic solvent is trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP), preferably trifluoroethanol.

[0015] Based on the above technical scheme, preferably, the asymmetric hydrogenation reaction temperature is 20-40°C, preferably 30°C; the reaction time is 15-36 hours, preferably 24 hours; and the hydrogen pressure is 300-500 psi, preferably 400 psi.

[0016] Based on the above technical scheme, preferably, the molar ratio of the tetra-substituted alkene, the metal palladium precursor and the chiral bisphosphine ligand in the asymmetric hydrogenation reaction is 1:0.03:0.05-1:0.005:0.005, preferably 1:0.01:0.012.

[0017] Based on the above technical scheme, preferably, the metal palladium precursor is palladium chloride, palladium acetate or palladium trifluoroacetate, preferably palladium trifluoroacetate.

[0018] Based on the above technical scheme, preferably, the chiral bisphosphine ligand is (R,R)-QuinoxP*, (R,R)-BenzP*, (1S,1S',2R,2R')-DuanPhos or (R,R)-Ph-BPE.

[0019] Based on the above technical scheme, preferably, the concentration of the tetra-substituted alkene substrate is 0.067 mmol / mL.

[0020] Based on the above technical scheme, preferably, the preparation method of the catalyst is: under nitrogen protection, the metal palladium precursor and the chiral bisphosphine ligand are stirred in acetone at room temperature for 30-60 minutes, and then the acetone is removed by vacuum concentration.

[0021] Based on the above technical scheme, preferably, the specific steps of the asymmetric hydrogenation reaction are:

[0022] The tetra-substituted alkene substrate, the catalyst and the solvent are added to a reaction bottle, the reaction bottle is placed in a high-pressure kettle, hydrogen is introduced for reaction to obtain a hydrogenated product, and the pure product is obtained after purification.

[0023] Based on the above technical scheme, preferably, when R' is C1-C6 alkyl or benzyl, the asymmetric hydrogenation reaction still needs to take the method of allyl protection, which is convenient for the determination of the enantioselectivity of the product.

[0024] Based on the above technical scheme, preferably, the method further comprises the following steps: taking tetrabutylammonium iodide as a catalyst, potassium carbonate as a base, and the above chiral dihydrocoumarin as a raw material, and carrying out allylation reaction with an allyl reagent to obtain an allyl-protected dihydrocoumarin.

[0025] The reaction formula is as follows:

[0026]

[0027] Based on the above technical scheme, preferably, the allyl compound is one of allyl bromide and allyl iodide.

[0028] Based on the above technical scheme, preferably, the solvent in the allylation reaction is an organic solvent, and the organic solvent is acetone.

[0029] Based on the above technical scheme, preferably, the reaction temperature in the allylation reaction is room temperature, and the reaction time is 4 hours.

[0030] Based on the above technical scheme, preferably, the molar ratio of the tetra-substituted alkene, potassium carbonate, tetrabutylammonium iodide and the allyl reagent in the allylation reaction is 1:1:1:1-1:4:4:4, and preferably 1:2:2:1.5.

[0031] Based on the above technical scheme, preferably, the specific reaction steps of the allylation reaction are as follows:

[0032] After the asymmetric hydrogenation reaction is completed, the solvent in the reaction system is removed, and then an allyl compound, tetrabutylammonium iodide, potassium carbonate and a solvent are added to react at a required temperature to obtain an allyl-protected product.

[0033] The present application adopts a homogeneous palladium catalytic system to realize asymmetric hydrogenation of a tetra-substituted alkene, and high yield, high enantioselectivity (the enantiomer excess can reach 99%) and high diastereoselectivity (the diastereomer ratio can reach >20:1) are achieved to generate a chiral dihydrocoumarin.

[0034] Advantages

[0035] 1. The raw material is simple and easy to obtain, the catalyst is commercially available and easy to prepare, and the reaction operation is simple and practical.

[0036] 2. The reaction activity is high, the raw material conversion is complete, the separation is convenient, and high-purity products can be obtained.

[0037] 3. Good stereoselectivity, high enantioselectivity of enantiomers can be obtained.

[0038] 4. Mild reaction conditions, low energy consumption, environmentally friendly and green. DETAILED DESCRIPTION

[0039] The present application is described in detail below by examples, but the present application is not limited to the following examples.

[0040] In the following examples, the synthesis of tetra-substituted olefins is referred to the following references:

[0041] 1. Hahn-Weinheimer, P.; Borsche, W. Zur Kenntnis der Benzisoxazole. VI. Die Acylierung von Benzisoxazolen nach Friedel-Crafts. Justus Liebigs Annalen der Chemie. 1950, 570, 155-159.

[0042] 2. Zhao, Q. K.; Wu, X.; Yang, F.; Yan, P. C.; Xie, J.-H.; Zhou, Q. L. Catalytic Asymmetric Hydrogenation of 3-Ethoxycarbonyl Quinolin-2-ones and Coumarins. Org. Lett. 2021, 23, 3593-3598.

[0043] 3. Yang S.-M.; Tang, Y.; Zhang, R.; Lu, H.; Kuo, G.-H.; Gaul, M. D.; Li, Y. 4-Bicyclic Heter-oaryl-Piperidine Derivatives as Potent, Orally Bioavailable Stearoyl-CoA Desaturase-1 (SCD1) Inhibitors. Part 1: Urea-Based Analogs. Bioorg. Med. Chem. Lett. 2013, 23, 6773-6776.

[0044] Examples 1-13

[0045] Condition optimization

[0046] Into a reaction flask was placed palladium trifluoroacetate (0.002 mmol) and chiral ligand L (0.0024 mmol), after purging with nitrogen, 1 mL of acetone was added, stirred at room temperature for 1 hour, then concentrated under vacuum to remove acetone to obtain catalyst. In a glove box, substrate 1a (0.20 mmol), catalyst prepared in situ and 3 mL of organic solvent were placed into a high pressure reaction vessel, hydrogen was introduced (600 psi), and the reaction was carried out at 30 °C for 24 hours. After the reaction was completed, hydrogen was slowly released, and the solvent was removed by rotary evaporation. The product was separated by column chromatography.

[0047] The type of organic solvent and chiral ligand was changed, and the reaction temperature was changed, and the specific results are shown in Table 1; ee is enantioselectivity.

[0048]

[0049] Table 1. Optimization of reaction conditions for asymmetric hydrogenation of tetra-substituted olefins

[0050]

[0051]

[0052] Examples 14-37

[0053] Asymmetric hydrogenation of tetra-substituted olefins:

[0054] Into a reaction flask was placed palladium trifluoroacetate (0.002 mmol) and chiral ligand (R,R)-QuinoxP* (0.0024 mmol), after purging with nitrogen, 1 mL of acetone was added, stirred at room temperature for 1 hour, then concentrated under vacuum to remove acetone to obtain catalyst. In a glove box, substrate 1 (0.20 mmol), catalyst prepared in situ and 3 mL of trifluoroethanol were placed into a high pressure reaction vessel, hydrogen was introduced (400 psi), and the reaction was carried out at 30 °C for 24 hours. After the reaction was completed, hydrogen was slowly released, and the solvent was removed by rotary evaporation. The product was separated by column chromatography.

[0055] When R' is C1-C6 alkyl or benzyl, after the asymmetric hydrogenation reaction, the method of allyl protection needs to be taken to facilitate the determination of the enantioselectivity of the product. Specifically: after the asymmetric hydrogenation reaction is completed, hydrogen is slowly released, and the solvent is removed by rotary evaporation. Then allyl bromide (0.4 mmol), tetrabutylammonium iodide (0.6 mmol) and potassium carbonate (0.6 mmol) were added to the reaction flask, 2 mL of acetone was added, and the reaction was carried out at room temperature for 4 hours. The solvent was removed by rotary evaporation, and the product was separated by column chromatography.

[0056] The type of tetra-substituted olefin is 1, and different examples are obtained by changing the type of 1 in the reaction, and the changed types are as follows:

[0057]

[0058] Example 38

[0059]

[0060] Into a reaction vial was placed palladium trifluoroacetate (0.002 mmol) and chiral ligand (R,R)-QuinoxP* (0.0024 mmol), after purging with nitrogen 1 mL of acetone was added, stirred at room temperature for 1 hour, then concentrated in vacuo to remove the acetone to give the catalyst. In a glove box, substrate 3 (0.20 mmol), in situ prepared catalyst and 3 mL of trifluoroethanol were placed into a high pressure reaction vessel, hydrogen was introduced (400 psi), and the reaction was stirred at 30 °C for 24 hours. After the reaction was complete, the hydrogen was slowly released, the solvent was removed by rotary evaporation, and the pure product was isolated by column chromatography.

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

Claims

1. A method for the synthesis of chiral dihydrocoumarins by palladium catalyzed asymmetric hydrogenation of tetra-substituted olefins, characterized in that, The method uses chiral diphosphine palladium complex as catalyst, tetra-substituted olefin as substrate to synthesize chiral dihydrocoumarin through asymmetric hydrogenation; The reaction formula is as follows: In the formula, R is C1-C4 alkyl or benzyl; R′ is C1-C6 alkyl, benzyl, benzene ring, naphthalene ring, thiophene ring or aromatic ring containing substituent, and the substituent is methyl, ethyl, methoxy or halogen; Ar is benzene ring, naphthalene ring or aromatic ring containing substituent, and the substituent is methyl or ethyl; The catalyst is a complex of metal palladium precursor and chiral diphosphine ligand; The metal palladium precursor is palladium trifluoroacetate; The chiral diphosphine ligand is L1 or L3, and the structures are as follows: The preparation method of the catalyst is as follows: under nitrogen protection, the metal palladium precursor and the chiral diphosphine ligand are stirred in acetone at room temperature for 30-60 minutes, and then acetone is removed by vacuum concentration; The reaction solvent is trifluoroethanol; The reaction temperature is 20-40℃, the time is 15-36 hours, and the hydrogen pressure is 300-500 psi.

2. The method of claim 1, wherein, The molar ratio of tetra-substituted olefin, metal palladium precursor and chiral diphosphine ligand is 1:0.005:0.005-1:0.03:0.

05.

3. The method of claim 1, wherein, The specific steps of the asymmetric hydrogenation reaction are as follows: The tetra-substituted olefin substrate, the catalyst and the solvent are added into a reaction bottle, the reaction bottle is placed into an autoclave, hydrogen is introduced for reaction to obtain hydrogenated product, and the pure product is obtained after purification.

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