CN111233849A - Novel isoquinoline-oxazoline chiral ligand and preparation and application thereof - Google Patents

Abstract

通式中取代基R₁和R₂连接的碳原子的立体构型为R或者S；本发明涉及的异喹啉‑噁唑啉手性配体是一种用途十分广泛的化合物，可作为配体与金属形成络合物或者组合物用于不对称催化，特别是本发明的异喹啉‑噁唑啉配体与金属钯组合可以有效的催化硼酸与硝基烯烃的不对称迈克尔加成，具有优异的立体选择性。The present invention relates to a class of novel isoquinoline-oxazoline chiral ligands and their preparation and application. The chemical structural formula of the compound is shown in the following formula:

In the general formula, the stereoconfiguration of the carbon atom to which the substituents R ₁ and R ₂ are connected is R or S; the isoquinoline-oxazoline chiral ligand involved in the present invention is a compound with a wide range of uses, which can be used as a ligand. The compound or composition is used for asymmetric catalysis, especially the combination of the isoquinoline-oxazoline ligand and metal palladium of the present invention can effectively catalyze the asymmetric Michael addition of boronic acid and nitroalkene, Has excellent stereoselectivity.

Description

Novel isoquinoline-oxazoline chiral ligands and their preparation and application

technical field

The invention relates to a novel isoquinoline-oxazoline chiral ligand and its preparation and application, and belongs to the field of catalytic asymmetric organic synthesis.

Background technique

Catalytic asymmetric organic synthesis has always been a hotspot in the field of synthetic organic chemistry, in which asymmetric catalysis using metal complexes has long been considered to be a promising candidate for the preparation of pure compounds due to its high efficiency, good atom economy and low environmental impact. An efficient way of enantiomers (Vogel, P., et al., Springer Berlin Heidelberg: Berlin, Heidelberg, 2003; pp 3-44.). Since the discovery that organic ligands can affect the steric and electronic effects of metal catalysts, the development of novel and efficient chiral ligands has been at the heart of asymmetric catalysis (Desimoni, G., et ai., Chemical Reviews 2006, 106( 9), 3561-3651.), Metal-catalyzed organic reactions in the presence of chiral ligands improve reactivity, regioselectivity and enantioselectivity by lowering the temperature and reducing the generation of by-products. In 1986, Brunner's group discovered the first oxazoline-containing ligand - pyridineoxazoline ligand (PyoX) (Brunner, H., et al., Journal of Organometallic Chemistry 1987, 328(1), 71-80 .).) Since this pioneering work, many pyridineoxazoline ligands have been developed and exhibit excellent catalytic performance in many types of reactions. The availability and stability of starting materials are an important factor in asymmetric synthetic chemistry (Xi, T., et al., Organic Letters 2015, 17(24), 5939-5941.), oxazoline ligands can be easily The resulting aminoalcohols were synthesized in shorter steps and in higher yields (Hargaden, G.C., et al., Chemical Reviews 2009, 109(6), 2505-2550.). Therefore, pyridine-oxazoline-type chiral ligands have rapidly become popular in asymmetric catalysis, especially some novel and efficient asymmetric methodologies. Recent studies have found that pyridine-oxazoline-type ligands can catalyze some very challenging classical asymmetric reactions such as: Asymmetric Heck-type reactions, Asymmetric(aza)-Wacker-type, which shows its properties as ligands and Application potential for developing new catalytic methodologies (Yang, G., et al., Chemical Society Reviews 2018, 47(5), 1783-1810). The present invention designs and synthesizes a new type of isoquinoline-oxazoline chiral ligand, and finds that it can be used in catalytic asymmetric synthesis, and is added with high yield and ee value in Michael addition reaction product.

SUMMARY OF THE INVENTION

The invention provides a novel isoquinoline-oxazoline chiral ligand and its preparation and application. The isoquinoline-oxazoline is synthesized by cyclization through the condensation of isoquinoline-3-carboxylic acid and a chiral amino alcohol. Chiral ligands were used in the Michael addition reaction, and high catalytic activity and stereoselectivity were obtained.

The novel isoquinoline-oxazoline chiral ligand of the present invention has the following general formula:

In the general formula, the stereo configuration of the carbon atom connected to the substituents R ₁ and R ₂ is R or S;

Wherein the substituent R ₁ represents: a C ₁ -C ₈ hydrocarbon group, a phenyl group, a substituted phenyl group (the substituent on the phenyl group is a C ₁ -C ₆ hydrocarbon group, a hydrocarbon oxy group and a halogenated hydrocarbon group, and the number of the substituents is 1～5), benzyl, substituted benzyl (the substituents on the phenyl group are C ₁ ～C ₆ hydrocarbyl, hydrocarbyloxy and halogenated hydrocarbyl, the number of substituents is 1～5), hydroxymethylene, Carboxylic acid, carboxylic acid hydrocarbyl ester (C ₁ -C ₆ ), C ₁ -C ₆ hydrocarbyl carbonyl, phenyl carbonyl, substituted phenyl carbonyl (the substituent on the phenyl group is C ₁ -C ₆ hydrocarbyl, hydrocarbyloxy and halogenated hydrocarbon groups, the number of substituents is 1 to 5), substituted hydroxymethyl (the ortho position of the hydroxyl group is substituted by a C ₁ to C ₆ hydrocarbon group, a phenyl group, and a substituted phenyl group),

Substituents R ₂ respectively represent: methyl, ethyl, isopropyl, sec-butyl, isobutyl, hydroxymethylene, carboxylate hydrocarbyl ester (1-6 carbons), aryl and arylmethylene;

as well as

The compounds involved in the present invention can be chemically synthesized according to the following synthetic routes, including the following four-step reactions:

In step 1, L-phenylalanine, 37% formaldehyde and concentrated hydrochloric acid were added to the reaction system, heated to 95° C. and stirred for 5 hours, cooled to room temperature, and filtered to obtain tetrahydroisoquinoline-3-carboxylic acid.

Step 2, tetrahydroisoquinoline-3-carboxylic acid was dissolved in N,N-dimethylformamide (DMF), potassium permanganate (0.5 times the amount) was added under ice bath conditions, and stirred at room temperature for 72 hours, TLC tracking monitoring, after the reaction is complete, filter, the filtrate is concentrated under reduced pressure, and the obtained solid is washed three times with distilled water to obtain isoquinoline-3-carboxylic acid.

Step 3, isoquinoline-3-carboxylic acid (1 times the amount) and amino alcohol compounds (1 times the amount) were dissolved in dichloromethane, and 1-hydroxybenzotriazole (1.3 times the amount) was added under ice bath conditions, Subsequently, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 times the amount) was added, and the reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, water and saturated hydrogen carbonate were used respectively. Sodium solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and chromatographed on silica gel column to obtain isoquinoline amide alcohol.

Step 4, isoquinoline amide alcohol is dissolved in dichloromethane, thionyl chloride (3 times the amount) is added dropwise under an ice bath, the reaction is stirred at room temperature for 5 hours, concentrated under reduced pressure, then acetonitrile is added to dissolve, and triethylamine ( 2 times the amount), heated to 95 ° C with stirring and reaction TLC tracking monitoring, after the reaction was complete, the solvent was evaporated under reduced pressure, dissolved in dichloromethane, washed with water, saturated sodium bicarbonate solution, saturated sodium chloride solution, and anhydrous sulfuric acid. Dry over sodium, evaporate the solvent under reduced pressure, and perform silica gel column chromatography to obtain L as a white solid.

The synthesis of the isoquinoline-oxazoline chiral ligand provided by the invention has the characteristics of cheap and easy-to-obtain raw materials, easy operation and the like.

The isoquinoline oxazoline chiral ligands involved in the present invention are preferably the following compounds:

Specific implementation method

The implementation of the present invention is described in detail below: the present embodiment is implemented on the premise of the technical solution of the present invention, and a specific operation process is provided, but the protection scope of the present invention is not limited to the following reaction examples.

Example 1

L-phenylalanine (10 g, 60 mmol), 33 mL of 37% formaldehyde and 87 mL of concentrated hydrochloric acid were added to the reaction system, heated to 95° C. and stirred for 5 hours, cooled to room temperature, and filtered to obtain 8.3 g of white solid I with a yield of 83%.

The intermediate tetrahydroisoquinoline-3-carboxylic acid I (5.3g, 30mmol), 80mL of N,N-dimethylformamide (DMF) were added to the reaction system, and potassium permanganate (2.5g) was added under ice bath conditions. , 16 mmol), stirred at room temperature for 72 hours, filtered, the filtrate was concentrated under reduced pressure, and the obtained solid was washed three times with distilled water to obtain 3.1 g of yellow solid isoquinoline-3-carboxylic acid II with a yield of 62%.

The reaction system was added with intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol), S-2-aminopropanol (75mg, 1mmol), dissolved in 20ml of dichloromethane, HOBt (175mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride solution (10 mL×2) respectively. , dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} =4:1, 5% triethylamine), the product was obtained as a white solid III- 1. The yield is 76%.

The intermediate amido alcohol III-1 (115 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 mL of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 mL of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated chlorine After washing with sodium chloride solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 2:1, 5% triethyl acetate amine) to obtain a white solid L1 with a yield of 90%.

The structural identification data of compound L1 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.42 (s, 1H), 8.02 (d, J=8.44 Hz, 1H), 7.90 (d, J=8.19 Hz, 1H), 7.78 -7.65(m, 2H), 4.62-4.68(m, 1H), 4.44-4.54(m, 1H), 4.08(td, J1 ₌ 1.23Hz, J2= _8.06Hz , 1H), 1.43(d, J ₁ = 1.08 Hz, J ₂ = 6.62 Hz, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.05, 152.68, 140.30, 135.57, 130.95, 129.30, 128.77, 127.70, 127.51, 121.58, 74.65, 62.34, 21.41.

ESI-HRMS, calcd for C ₁₃ H ₁₃ N ₂ O[M+H] ⁺ 213.0950, found 213.1098.

Embodiment 2

Intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol), S-2-aminobutanol (89 mg, 1 mmol) were added to the reaction system, dissolved in 20 ml of dichloromethane, and HOBt (175 mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride solution (10 mL×2) respectively. , dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} =4:1, 5% triethylamine), white solid III-2 was obtained, Yield 68%.

The intermediate amide alcohol III-2 (122 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 ml of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated chlorine After washing with sodium chloride solution (10ml×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L2 with a yield of 87%.

The structural identification data of compound L2 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.42 (s, 1H), 8.02 (d, J=8.51 Hz, 1H), 7.90 (d, J=8.33 Hz, 1H), 7.64 -7.78(m, 2H), 4.62(dd, J1 ₌ 8.21Hz, J2= _9.58Hz , 1H), 4.31-4.40(m, 1H), 4.17(t, J=8.13Hz, 1H), 1.87( m, 1H), 1.64-1.74 (m, 1H), 1.05 (t, J=7.40Hz, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.34, 152.70, 142.03, 140.13, 135.58, 131.05, 129.44, 128.95, 128.77, 127.73, 127.68, 127.59, 126.88, 122.14, 75.31, 70.4

ESI-HRMS, calcd for C ₁₄ H ₁₅ N ₂ O[M+H] ⁺ 227.1106, found 227.1264.

Embodiment 3

The reaction system was added with intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol), R-2-aminobutanol (89 mg, 1 mmol), dissolved in 20 mL of dichloromethane, and HOBt (175 mg, 1.3mmol), EDCi (250mg, 1.3mmol), stirred overnight at room temperature, the reaction system was washed with water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated sodium chloride solution (10ml×2) respectively , dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} =4:1, 5% triethylamine), white solid III-3 was obtained, Yield 68%.

The intermediate amido alcohol III-3 (122 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 ml of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated chlorine After washing with sodium chloride solution (10ml×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L3 with a yield of 87%.

The structural identification data of compound L3 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 8.41 (s, 1H), 8.01 (d, J=8.62 Hz, 1H), 7.89 (d, J=8.05 Hz, 1H), 7.70 (m, 2H), 4.60 (dd, J1 ₌ 8.12Hz, J2= _9.57Hz , 1H), 4.34 (m, 1H), 4.16 (t, J=8.19Hz, 1H), 1.85 (m, 1H) , 1.67(m, 1H), 1.04(t, J=7.50Hz, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.08, 152.69, 140.30, 135.57, 130.96, 129.28, 128.77, 127.71, 127.52, 121.61, 72.75, 68.40, 28.61, 10.23.

ESI-HRMS, calcd for C ₁₄ H ₁₅ N ₂ O[M+H] ⁺ 227.1106, found 227.1264.

Embodiment 4

In the reaction system, add intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol), S-valinol was dissolved in 20ml of dichloromethane, HoBt (175mg, 1.3mmol), EDCi (250mg, 1.3 mmol), stirred at room temperature overnight, the reaction system was washed with water (10 ml × 2), saturated sodium bicarbonate solution (10 ml × 2), and saturated sodium chloride solution (10 ml × 2), dried over anhydrous sodium sulfate, reduced The solvent was evaporated under pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 4:1, 5% triethylamine), the product was obtained as white solid III-4 with a yield of 73%.

The intermediate amido alcohol III-4 (129 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 ml of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated chlorine After washing with sodium chloride solution (10ml×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L4 with a yield of 85%.

The structural identification data of compound L4 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (s, 1H), 8.44 (s, 1H), 8.02 (d, J=7.85 Hz, 1H), 7.91 (d, J=8.19 Hz, 1H), 7.71 (m, 2H), 4.55 (td, J1 ₌ 1.20Hz, J2= _7.40Hz , 1H), 4.16-4.30 (m, 2H), 1.95 (m, 1H), 1.09 (d, J=6.70Hz, 3H), 0.97 (d, J=6.71Hz, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.61, 152.71, 140.23, 137.95, 135.57, 131.00, 129.35, 129.24, 128.85, 128.62, 127.73, 127.56, 126.55, 121.74, 41.79.51, 68.20

ESI-HRMS, calcd for C ₁₅ H ₁₇ N ₂ O[M+H] ⁺ 241.1263, found 241.1427.

Embodiment 5

The intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol) and S-phenylglycinol (137 mg, 1 mmol) were added to the reaction system, dissolved in 20 mL of dichloromethane, and HOBt (175 mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride solution (10 mL×2), respectively, It was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 4:1, 5% triethylamine), the product was obtained as white solid III-5 , the yield is 72%.

The intermediate amido alcohol III-5 (146 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 mL of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 mL of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir for 6 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated chlorine After washing with sodium chloride solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L5 with a yield of 89%.

The structural identification data of compound L5 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35 (s, 1H), 8.57 (s, 1H), 8.04 (d, J=8.05 Hz, 1H), 7.92 (d, J=8.17 Hz, 1H), 7.67 -7.80 (m, 2H), 7.28-7.42 (m, 5H), 5.51 (dd, J=8.54Hz, J= _10.33Hz , 1H), 4.95 (dd, J1 ₌ 8.55, J2=10.30Hz, 1H ), 4.44(t, J=8.55Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.05, 152.68, 140.30, 135.57, 130.95, 129.30, 128.77, 127.70, 127.51, 121.58, 74.65, 62.34, 21.41.

ESI-HRMS, calcd for C ₁₈ H ₁₅ N ₂ O[M+H] ⁺ 275.1106, found 275.1270.

Embodiment 6

The reaction system was added with intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol), S-phenylalaninol (151 mg, 1 mmol), dissolved in 20 mL of dichloromethane, and HOBt (175 mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride solution (10 mL×2), respectively, It was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 4:1, 5% triethylamine), the product was obtained as white solid III-6 , the yield is 73%.

The intermediate amido alcohol III-6 (153 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 mL of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir for 6 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated chlorine After washing with sodium chloride solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L6 in a yield of 85%.

The structural identification data of compound L6 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (s, 1H), 8.43 (s, 1H), 8.03 (d, J=8.14 Hz, 1H), 7.92 (d, J=8.03 Hz, 1H), 7.72 (m, 2H), 7.19-7.38 (m, 5H), 4.71 (m, 1H), 4.48 (t, J=9.01Hz, 1H), 4.27 (t, J=8.17Hz, 1H), 3.38 (dd, J ₁ =4.91Hz, J ₂ =13.83Hz, 1H), 2.80 (dd, J ₁ =9.30Hz, J ₂ =13.91Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.01, 152.67, 140.37, 135.60, 130.94, 129.30, 128.74, 127.70, 127.52, 121.64, 73.05, 70.69, 32.79, 19.20, 18.19.

ESI-HRMS, calcd for C ₁₉ H ₁₇ N ₂ O[M+H] ⁺ 289.1263, found 289.1439.

Embodiment 7

Intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) was added to the reaction system, S-tert-leucinol was dissolved in 20ml of dichloromethane, HoBt (175mg, 1.3mmol), EDCi (250mg) were added under ice bath conditions , 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 ml × 2), saturated sodium bicarbonate solution (10 ml × 2), saturated sodium chloride solution (10 ml × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 4:1, 5% triethylamine), the product was obtained as white solid III-7 with a yield of 76%.

Intermediate amido alcohol III-7 (136 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 ml of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated chlorine After washing with sodium chloride solution (10ml×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 2:1, 5% triethyl acetate amine) to obtain the product L7 as a white solid with a yield of 81%.

The structural identification data of compound L7 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (s, 1H), 8.48 (s, 1H), 8.04 (d, J=8.04 Hz, 1H), 7.94 (d, J=8.15 Hz, 1H), 7.68 -7.79(m, 2H), 4.50(dd, J1 ₌ 8.60Hz, J2= _10.21Hz , 1H), 4.37(t, J=8.51Hz, 1H), 4.19(dd, J1 ₌ 8.24Hz, J ₂ = 10.09Hz, 1H), 1.03(s, 9H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.08, 152.69, 140.36, 135.59, 130.95, 129.30, 128.75, 127.71, 127.52, 121.60, 72.75, 68.42, 28.61, 10.21.

ESI-HRMS, calcd for C ₁₆ H ₁₉ N ₂ O[M+H] ⁺ 254.1419, found 255.1585.

Embodiment 8

Intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) was added to the reaction system, S-isoleucinol was dissolved in 20mL of dichloromethane, HOBt (175mg, 1.3mmol), EDCi (250mg) were added under ice bath conditions , 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated sodium chloride solution (10 mL×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 4:1, 5% triethylamine), the product was obtained as white solid III-8 with a yield of 74%.

The intermediate amido alcohol III-8 (136 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 mL of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 mL of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir for 6 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated chlorine After washing with sodium chloride solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 2:1, 5% triethyl acetate amine) to obtain the product L8 as a white solid with a yield of 83%.

The structural identification data of compound L8 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (s, 1H), 8.44 (s, 1H), 8.02 (d, J=8.11 Hz, 1H), 7.91 (d, J=8.08 Hz, 1H), 7.72 (m, 2H), 4.53 (dd, J1 ₌ 7.91Hz, J2= _9.48Hz , 1H), 4.29-4.39 (m, 1H), 4.26 (d, J=8.25Hz, 1H), 1.77-1.87 ( m, 1H), 1.66-1.74 (m, 1H), 1.23-1.36 (m, 1H), 0.98 (t, J=7.43Hz, 3H), 0.92 (d, J=6.84Hz, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 161.78, 152.63, 140.14, 135.59, 130.92, 129.29, 128.73, 127.71, 127.52, 121.60, 72.60, 71.03, 38.86, 26.45, 12.89, 11.66.

ESI-HRMS, calcd for C ₁₆ H ₁₉ N ₂ O[M+H] ⁺ 255.1419, found 255.1585.

Embodiment 9

The reaction system was added with intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol), S-leucinol was dissolved in 20mL of dichloromethane, HOBt (175mg, 1.3mmol), EDCi (250mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, and then reduced The solvent was evaporated under pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 4:1, 5% triethylamine), white solid III-9 was obtained with a yield of 72%.

Intermediate III-9 (136 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then dissolved by adding 10 mL of acetonitrile, 277 μL of triethylamine was added dropwise, heated to 95°C and stirred for 6 hours, the solvent was evaporated under reduced pressure, dissolved in dichloromethane, water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride were added dropwise. The solution (10 mL×2) was washed, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and subjected to silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} =2:1, 5% triethylamine) , the product was white solid L9, the yield was 82%.

The structural identification data of compound L9 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.41 (s, 1H), 8.01 (d, J=8.09 Hz, 1H), 7.90 (d, J=8.18 Hz, 1H), 7.65 -7.80(m, 2H), 4.64(dd, J1 ₌ 8.08Hz, J2= _9.36Hz , 1H), 4.44(m, 1H), 4.10(t, J=8.28Hz, 1H), 1.87-1.95( m, 1H), 1.79-1.86 (m, 1H), 1.43 (dt, J1 ₌ 7.72Hz, J2= _13.38Hz , 1H), 0.99 (dd, J1 ₌ 6.53Hz, J2= _8.97Hz , 6H ).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.92, 152.68, 140.40, 135.59, 130.94, 129.28, 128.74, 127.71, 127.52, 121.59, 73.71, 65.46, 45.56, 25.45, 22.80, 22.76.

ESI-HRMS, calcd for C ₁₆ H ₁₉ N ₂ O[M+H] ⁺ 255.1419, found 255.1580.

Embodiment ten

Intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol), (1S, 2R)-(-)-1-2-indanol (150 mg, 1 mmol) were added to the reaction system, dissolved in 20 mL of dichloromethane, HOBt (175 mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature overnight. After washing with sodium solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} = 4:1, 5% triethylamine ) to obtain white solid III-10 with a yield of 72%.

Intermediate III-10 (152 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 6 hours, concentrated under reduced pressure, and then dissolved by adding 10 mL of acetonitrile, 277 μL of triethylamine was added dropwise, heated to 95°C and stirred for 6 hours, the solvent was evaporated under reduced pressure, dissolved in dichloromethane, water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride were added dropwise. The solution (10 mL×2) was washed, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and subjected to silica gel column chromatography (eluent: V _{petroleum ether} /V _{ethyl acetate} =2:1, 5% triethylamine) , the product was white solid L10, the yield was 82%.

The structural identification data of compound L9 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 8.43 (s, 1H), 8.00 (d, J=8.15 Hz, 1H), 7.89 (d, J=8.03 Hz, 1H), 7.60 -7.77 (m, 3H), 7.26-7.29 (m, 3H), 5.86 (d, J=7.76Hz, 1H), 5.66-5.57 (m, 1H), 3.53 (dd, J1 _{= 4.03Hz} , J2 =10.00Hz, 2H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.64, 152.62, 141.76, 140.34, 139.82, 135.51, 130.96, 129.28, 128.81, 128.56, 127.69, 127.51, 125.84, 125.93, 12.3.90, 83

ESI-HRMS, calcd for C ₁₉ H ₁₅ N ₂ O[M+H] ⁺ 287.1184, found 287.1290.

Embodiment 11

Asymmetric Michael addition reaction

Pd(TFA) ₂ (3.4 mg, 0.01 mmol), L7 (3.8 mg, 0.015 mmol), 2 mL of methanol were added to a 10 mL reaction flask, and the mixture was stirred at 40° C. for half an hour. Nitrostyrene (38 mg, 0.25 mmol), p-methoxyphenylboronic acid (76 mg, 0.5 mmol) were then added. The completion of the reaction was monitored by TLC tracking, concentrated under reduced pressure, and subjected to column chromatography (V _{petroleum ether} :V _{ethyl acetate} =30:1). The ee of the addition product was 93%.

The structural identification data are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (m, 1H), 7.23 (m, 2H), 7.15 (m, 1H), 6.85 (m, 1H), 4.96 (d, J=2.43Hz, 1H) , 4.94(s, 1H), 4.86(t, J=8.05Hz, 1H), 3.78(s, 1H).

¹³ C NMR (100MHz, CDCl3) δ 158.92, 139.65, 131.27, 129.04, 128.71, 127.62, 127.52, 114.40, 79.55, 55.36, 48.35.

Claims (6)

1. a novel isoquinoline-oxazoline chiral ligand, characterized by having the following structural formula:

wherein the substituent R₁Represents: c₁～C₈A phenyl group, a substituted phenyl group (the substituent on the phenyl group is C)₁～C₆The number of the substituent groups is 1-5), benzyl, substituted alkyl, alkoxy and halogenated alkylBenzyl (substituent on phenyl is C₁～C₆The number of the substituents is 1 to 5), hydroxymethylene, carboxylic acid, and carboxylic acid alkyl ester (C)₁～C₆)，C₁～C₆Hydrocarbyl carbonyl, phenylcarbonyl, substituted phenylcarbonyl (substituent on phenyl is C)₁～C₆The number of the substituent is 1-5), and substituted hydroxymethyl (the ortho position of the hydroxyl is substituted by C)₁～C₆Phenyl, and substituted phenyl substitution),

the substituents R2 represent respectively: methyl, ethyl, isopropyl, sec-butyl, isobutyl, hydroxymethylene, hydrocarbyl carboxylate (1-6 carbons), aryl and arylmethylene;

and

substituent R in the general formula₁And R₂The steric configuration of the attached carbon atom is R or S.

2. The compound of formula (I) according to claim 1, characterized in that it is selected from the following compounds:

3. the method for synthesizing the chiral isoquinoline oxazoline ligand of claim 1, which is derived from phenylalanine through the following four-step reaction:

and (3) preparing an isoquinoline oxazoline chiral ligand.

4. The method for synthesizing isoquinoline-oxazoline chiral ligand according to claim 1, wherein phenylalanine is used as a starting material, tetrahydroisoquinoline-3-carboxylic acid is obtained through Pictet-Spengler reaction, isoquinoline-3-carboxylic acid is obtained through oxidative dehydrogenation, chiral amidol is obtained through condensation with chiral β -amino alcohol, and finally the isoquinoline-oxazoline ligand is obtained through cyclization of the chiral amidol.

5. The metal complex of isoquinoline-oxazoline chiral ligand of claim 1 with metallic palladium (Pd), copper (Cu) and nickel (Ni).

6. The isoquinoline-oxazoline chiral ligand of claim 1 and the metal complex of claim 5 for use in asymmetric catalytic reactions, including Michael addition reactions, [2+3] cycloaddition reactions of imines and olefins, and asymmetric oxidation reactions.