A diphenylamine-linked chiral bis(oxazoline) ligand without C2-symmetry, synthesis method and application thereof

Abstract

The present invention discloses a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of formula 3 and its synthesis method and application in an asymmetric catalytic reaction, wherein C.sub.2-symmetry is lost by introducing different groups into the diphenylamine backbone to realize precise control of “electronic effect” of the ligand backbone. An anthranilic acid derivative and an orthochlorobenzoic acid derivative are used as starting materials to prepare a compound of formula 1, and then the compound of formula 1 is reacted with a chiral amino alcohol compound to prepare a β-bishydroxy amide compound of formula 2, and the compound of formula 2 is further subjected to condensation to obtain the diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of formula 3. The present invention also provides an application of a catalyst formed by coordination of the diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry with copper salt, zinc salt, nickel salt, iron salt or rhodium salt, in an asymmetric catalytic reaction.

##STR00001##

Claims

1. A diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of formula 3: ##STR00027## wherein R.sub.1 and R.sub.2 are each independently hydrogen, C.sub.1˜4 alkyl, phenyl, benzyl, 1-naphthyl, 2-naphthyl or substituted phenyl, or R.sub.1 and R.sub.2 are both 2,3-dihydroindenyl; wherein the substituted phenyl is a phenyl of which H atoms on the benzene ring are mono- or di-substituted with C.sub.1˜4 alkyl, halogen or trifluoromethyl; R.sub.3 and R.sub.4 are each independently hydrogen, C.sub.1˜4 alkyl, C.sub.1˜4 alkoxy, halogen, trifluoromethyl, nitro, sulfo, hydroxyl, amino or N,N-di(C.sub.1˜4) alkylamino.

2. A synthesis method of the diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry as claimed in claim 1, wherein the method is carried out as follows: (1) In an organic solvent A, under a temperature condition of 80˜200° C., an anthranilic acid derivative of formula I and an orthochlorobenzoic acid derivative of formula II are taken as raw materials, and then a carbonate, copper and cuprous iodide are added, the coupling reaction is carried out for 1-24 h to obtain a reaction solution A, after cooling and filtration, diluted hydrochloric acid is added to the filtrate until the pH of the solution reaches 1˜4, the solution is stirred and filtered to obtain the compound of formula 1; wherein the molar ratio of the anthranilic acid derivative of formula I to the orthochlorobenzoic acid derivative of formula II, the carbonate, the copper and the cuprous iodide is 1:1:1-2:0.01-0.5:0.01-0.5; (2) the compound of formula 1 obtained in step (1) is mixed with thionyl chloride and heated to reflux temperature for 4 h, excess SOCl.sub.2 is removed by evaporation, thereby obtaining diacid chloride, the diacid chloride is added into an organic solvent B, thereby obtaining a diacid chloride solution, chiral amino alcohol and an alkaline substance A are added into another organic solvent B to obtain a mixture solution, the diacid chloride solution is added into the mixture solution dropwise at −20-20° C., and the reaction is carried out at room temperature for 1-24 h, thereby obtaining a reaction solution B; the reaction solution B is quenched with an ammonium chloride aqueous solution, extracted three times with water, saturated NaHCO.sub.3 solution, and saturated brine, respectively, the resulting organic phase is dried over anhydrous sodium sulfate, the solvent is removed, and then column chromatography is carried out to obtain the intermediate of formula 2, i.e. β-bishydroxy amide; wherein the molar ratio of the compound of formula 1 to the thionyl chloride is 1:5-10; the molar ratio of the diacid chloride to the chiral amino alcohol and the alkaline substance A is 1:2-3:1-6, in which the amount of substance of the diacid chloride is calculated by the amount of substance of the compound of formula 1; (3) in an organic solvent C, under a temperature condition of 0-30° C., a mixture of the β-bishydroxy amide of formula 2 in step (2), methanesulfonyl chloride and an alkaline substance B are reacted for 1-24 h, the resulting reaction solution C is evaporated to remove the solvent to obtain a crude product, and column chromatography is further used for separation to obtain the diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of formula 3; wherein the molar ratio of the β-bishydroxy amide of formula 2 to the methanesulfonyl chloride and the alkaline substance B is 1:2-3:1-6. ##STR00028##

3. The synthesis method as claimed in claim 2, wherein in step (1), the carbonate is sodium carbonate, potassium carbonate or cesium carbonate.

4. The synthesis method as claimed in claim 2, wherein in step (1), the organic solvent A is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, toluene, chlorobenzene, tetrahydrofuran, chloroform, carbon tetrachloride, dichloromethane, 1,4-dioxane or pyridine; and the additive amount of the organic solvent A calculated by the amount of substance of the anthranilic acid derivative of formula I is 1-20 mL/mmol.

5. The synthesis method as claimed in claim 2, wherein in step (2), the organic solvent B is toluene, xylene, chlorobenzene, tetrahydrofuran, chloroform, carbon tetrachloride, methylene chloride, 1,4-dioxane or pyridine; and the additive amount of the organic solvent B calculated by the amount of substance of the compound of formula 1 is 1-10 mL/mmol.

6. The synthesis method as claimed in claim 2, wherein in step (2) or (3), the alkaline substance A and the alkaline substance B are each independently triethylamine, tripropylamine, tributylamine, N,N-diisopropylmethylamine, N,N-diisopropylethylamine, tetramethyldiethylamine, sodium carbonate or potassium carbonate.

7. The synthesis method as claimed in claim 2, wherein in step (3), the organic solvent C is toluene, xylene, chlorobenzene, tetrahydrofuran, chloroform, carbon tetrachloride or methylene chloride; and the additive amount of the organic solvent C calculated by the amount of substance of the β-bishydroxy amide of formula 2 is 1-10 mL/mmol.

8. The synthesis method as claimed in claim 2, wherein the preparation method of the intermediate of formula 2, i.e. β-bishydroxy amide in step (2) is as follows: at room temperature, chiral amino alcohol, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole are dissolved in an organic solvent D, and then the compound of formula 1 obtained in step (1) is added and reacted at room temperature for 1-24 h to obtain a reaction solution D; the reaction solution D is quenched with an ammonium chloride aqueous solution, washed with water and extracted, the resulting organic phase is dried over anhydrous sodium sulfate, the solvent is removed, and then column chromatography is carried out to for separation, a mixing solution of PE/EA in a volume ratio ranging from 2:1 to 5:1 is used as the eluting reagent to collect an eluate containing the target product, the eluate is evaporated to remove the solvent, thereby obtaining the intermediate of formula 2, i.e. β-bishydroxy amide; wherein the molar ratio of the compound of formula 1 to the chiral amino alcohol, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole is 1:2-3:2-3:2-3.

9. The synthesis method as claimed in claim 8, wherein the organic solvent D is toluene, xylene, chlorobenzene, tetrahydrofuran, chloroform, carbon tetrachloride or methylene chloride; the additive amount of the organic solvent D calculated by the amount of substance of the compound of formula 1 is 1-10 mL/mmol.

10. A catalyst formed by coordination of the diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry as claimed in claim 1 with copper salt, zinc salt, nickel salt, iron salt or rhodium salt.

11. The catalyst as claimed in claim 10, wherein the copper salt is copper chloride, copper sulfate, copper bromide, copper acetate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper acetylacetonate or copper perchlorate; the zinc salt is zinc chloride, zinc sulfate, zinc bromide, zinc acetate, zinc trifluoroacetate, zinc trifluoromethanesulfonate, zinc acetylacetonate or zinc perchlorate; the nickel salt is nickel chloride, nickel sulfate, nickel bromide, nickel acetate, nickel trifluoromethanesulfonate, nickel trifluoroacetate, nickel acetylacetonate or nickel perchlorate; the iron salt is ferrous chloride, ferrous sulfate, ferrous bromide, ferrous acetate, ferrous trifluoroacetate, ferrous trifluoromethanesulfonate, ferrous acetylacetonate or ferrous perchlorate; the rhodium salt is rhodium chloride, rhodium trifluoroacetate, rhodium carbonyl chloride, bis(triphenylphosphine) rhodium carbonyl chloride, tris(triphenylphosphine)rhodium carbonyl hydride or chlorotris(triphenylphosphine)rhodium.

12. An application of the catalyst as claimed in claim 10 in an asymmetric catalytic reaction.

13. The application as claimed in claim 12, wherein the asymmetric catalytic reaction is asymmetric chlorination or bromination dearomatization of β-naphthol derivatives, asymmetric fluorination, chlorination, bromination, oxidation, thiocyanation or trifluoromethylthiolation of 1,3-dicarbonyl compound, asymmetric Michael addition reaction of 1,3-dicarbonyl compound, or asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes.

Description

SPECIFIC EMBODIMENTS

[0037] The present invention will be further described in conjunction with the specific examples, but the scope of protection of the present invention is not limited thereto:

Example 1

[0038] ##STR00005##

[0039] 5.48 g of anthranilic acid, 7.44 g of 2-chloro-5-methoxybenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-5-methoxybenzoic acid.

[0040] 1.35 g of (R)-(−)-2-phenylglycinol, 2.20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.55 g of 1-hydroxybenzotriazole were dissolved in THF, and then 1.44 g of 2-((2-carboxyphenyl)amino)-5-methoxybenzoic acid was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with an ammonium chloride solution, the solvent was removed under reduced pressure, and the crude product was dissolved in ethyl acetate, washed with water, and extracted three times. The organic phase was dried over sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0041] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1-5:1), thereby obtaining 1.96 g of a yellow solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-methoxy-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro oxazol-2-yl)phenyl)aniline.

[0042] 3-a: [α]D.sup.20=−261 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 10.78 (s, 1H), 7.91-7.86 (m, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.42 (d, J=3.1 Hz, 1H), 7.31-7.20 (m, 11H), 7.13 (dd, J=7.3, 2.0 Hz, 2H), 7.01 (dd, J=9.0, 3.1 Hz, 1H), 6.84 (ddd, J=8.1, 5.5, 2.8 Hz, 1H), 5.26 (dd, J=9.9, 8.1 Hz, 1H), 5.17 (dd, J=10.0, 8.3 Hz, 1H), 4.55 (dd, J=10.0, 8.3 Hz, 1H), 4.45 (dd, J=10.1, 8.4 Hz, 1H), 4.07 (t, J=8.1 Hz, 1H), 3.94 (t, J=8.3 Hz, 1H), 3.85 (s, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 164.35, 164.14, 145.36, 142.39, 131.83, 130.39, 128.51, 127.29, 126.66, 123.35, 118.75, 117.85, 115.13, 114.09, 112.60, 74.22, 73.32, 70.10, 69.89, 55.74; melting point: 70-72° C.; HRMS: m/z calculated for C.sub.31H.sub.27N.sub.3O.sub.3Na ([M+Na].sup.+): 512.1945; found: 512.1939.

Example 2

[0043] ##STR00006##

[0044] 5.48 g of anthranilic acid, 6.98 g of 2-chloro-5-fluorobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-5-fluorobenzoic acid.

[0045] 1.35 g of (R)-(−)-2-phenylglycinol, 2.20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.55 g of 1-hydroxybenzotriazole were dissolved in THF, and then 1.10 g of 2-((2-carboxyphenyl)amino)-5-fluorobenzoic acid was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with ammonium chloride solution, the solvent was removed under reduced pressure, and the crude product was dissolved in ethyl acetate, washed with water, and extracted three times. The organic phase was dried over sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0046] On ice bath 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 1.55 g of a yellow solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-fluoro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0047] 3-b: [α]D.sup.20=−260 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 10.93 (s, 1H), 7.87 (dd, J=7.9, 1.4 Hz, 1H), 7.53 (ddd, J=33.1, 9.2, 3.9 Hz, 2H), 7.42-7.00 (m, 13H), 6.89 (t, J=7.5 Hz, 1H), 5.16 (q, J=10.3 Hz, 2H), 4.47 (ddd, J=13.3, 10.0, 8.4 Hz, 2H), 4.04-3.93 (m, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 142.53, 131.68, 128.50, 128.48, 127.29, 126.59, 126.57, 119.28, 118.49, 116.67, 116.65, 73.98, 73.54, 70.00; .sup.19F NMR (376 MHZ, CDCl.sub.3) δ −122.66; melting point: 55-58° C.; HRMS: m/z calculated for C.sub.30H.sub.24FN.sub.3O.sub.2Na ([M+Na].sup.+): 500.1745; found: 500.1742.

Example 3

[0048] ##STR00007##

[0049] 5.48 g of anthranilic acid, 9.42 g of 2-chloro-5-bromobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-5-bromobenzoic acid.

[0050] 1.68 g of 2-((2-carboxyphenyl)amino)-5-bromobenzoic acid and 10 mL of SOCl.sub.2 were added to a round-bottom flask and heated to reflux temperature for 4 h, excess SOCl.sub.2 was removed by evaporation, thereby obtaining diacid chloride, the diacid chloride was added to dichloromethane. On ice bath, the dichloromethane solution of the diacid chloride was added dropwise to a dichloromethane solution containing 1.35 g of (R)-(−)-2-phenylglycinol and 3.8 mL of trimethylamine. The resulting solution was stirred for 20 h. The reaction was quenched with ammonium chloride solution, extracted by water, saturated sodium bicarbonate solution and saturated brine three times, respectively. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0051] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1-5:1), thereby obtaining 2.15 g of a yellow solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-bromo-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0052] 3-c: [α]D.sup.20=−223 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, Chloroform-d) δ 11.13 (s, 1H), 8.04-7.99 (m, 1H), 7.90 (dd, J=7.8, 1.5 Hz, 1H), 7.52 (dd, J=8.4, 1.1 Hz, 1H), 7.41 (d, J=2.0 Hz, 2H), 7.28-7.23 (m, 8H), 7.16-7.14 (m, 4H), 7.01-6.97 (m, 1H), 5.18 (ddd, J=10.5, 8.2, 2.8 Hz, 2H), 4.50 (dd, J=9.9, 8.5 Hz, 2H), 4.01 (dt, J=10.0, 8.2 Hz, 2H). .sup.13C NMR (126 MHz, Chloroform-d) δ 163.00, 142.46, 142.40, 134.27, 132.95, 131.59, 130.71, 128.56, 128.53, 127.40, 127.35, 126.62, 120.66, 119.14, 118.72, 116.73, 111.08, 73.79, 70.10; melting point: 75-78° C., HRMS: m/z calculated for C.sub.30H.sub.24BrN.sub.3O.sub.2Na ([M+Na].sup.+): 538.1125; found: 538.1126.

Example 4

[0053] ##STR00008##

[0054] 5.48 g of anthranilic acid, 8.98 g of 2-chloro-5-bromobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-5-trifluoromethylbenzoic acid.

[0055] 1.63 g of 2-((2-carboxyphenyl)amino)-5-trifluoromethylbenzoic acid and 10 mL of SOCl.sub.2 were added to a round-bottom flask and heated to reflux temperature for 4 h, excess SOCl.sub.2 was removed by evaporation, thereby obtaining diacid chloride, the diacid chloride was added to dichloromethane. On ice bath, the dichloromethane solution of the diacid chloride was added dropwise to a dichloromethane solution containing 1.35 g of (R)-(−)-2-phenylglycinol and 3.8 mL of trimethylamine. The resulting solution was stirred for 20 h. The reaction was quenched with ammonium chloride solution, extracted by water, saturated sodium bicarbonate solution and saturated brine three times, respectively. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0056] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1-5:1), thereby obtaining 2.29 g of a pale yellow solid. The product of the reaction was adiphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-trifluoromethyl-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0057] 3-d: [α]D.sup.20=−259 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 11.42 (s, 1H), 8.18 (s, 1H), 7.93 (dd, J=7.8, 1.6 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.9 Hz, 2H), 7.43 (td, J=8.4, 7.9, 1.6 Hz, 1H), 7.31-7.17 (m, 9H), 7.15-7.09 (m, 3H), 5.20 (ddd, J=25.4, 10.0, 8.3 Hz, 2H), 4.52 (ddd, J=39.1, 10.1, 8.3 Hz, 2H), 4.10 (t, J=8.2 Hz, 1H), 3.98 (t, J=8.3 Hz, 1H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 163.77, 163.21, 146.99, 142.35, 142.21, 140.92, 131.48, 130.83, 128.60, 128.51, 128.37, 128.35, 128.03, 128.00, 127.47, 127.36, 126.61, 126.58, 122.36, 121.13, 118.94, 115.43, 112.78, 74.08, 73.57, 70.23, 69.98; .sup.19F NMR (376 MHZ, CDCl.sub.3) δ −61.64; melting point: 66-68° C., HRMS: m/z calculated for C.sub.31H.sub.24F.sub.3N.sub.3O.sub.2Na ([M+Na].sup.+): 550.1713; found: 550.1712.

Example 5

[0058] ##STR00009##

[0059] 5.48 g of anthranilic acid, 8.06 g of 2-chloro-5-nitrobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-5-nitrobenzoic acid.

[0060] 1.51 g of 2-((2-carboxyphenyl)amino)-5-nitrobenzoic acid and 10 mL of SOCl.sub.2 were added to a round-bottom flask and heated to reflux temperature for 4 h, excess SOCl.sub.2 was removed by evaporation, thereby obtaining diacid chloride, the diacid chloride was added to dichloromethane. On ice bath, the dichloromethane solution of the diacid chloride was added dropwise to a dichloromethane solution containing 1.35 g of (R)-(−)-2-phenylglycinol and 3.8 mL of trimethylamine. The resulting solution was stirred for 20 h. The reaction was quenched with ammonium chloride solution, extracted by water, saturated sodium bicarbonate solution and saturated brine three times, respectively. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0061] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 2.32 g of a yellow solid. The product of the reaction was adiphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0062] 3-e: [α]D.sup.20=−139 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 11.80 (s, 1H), 8.83 (d, J=2.8 Hz, 1H), 8.14 (dd, J=9.4, 2.8 Hz, 1H), 7.96 (dd, J=7.8, 1.5 Hz, 1H), 7.61-7.55 (m, 1H), 7.50 (td, J=8.2, 7.8, 1.6 Hz, 1H), 7.32 (d, J=9.4 Hz, 1H), 7.28-7.25 (m, 8H), 7.20 (dd, J=7.6, 1.7 Hz, 2H), 7.10 (dd, J=6.5, 3.0 Hz, 2H), 5.19 (ddd, J=27.0, 10.0, 8.3 Hz, 2H), 4.60 (dd, J=10.1, 8.4 Hz, 1H), 4.48 (dd, J=10.2, 8.4 Hz, 1H), 4.17 (t, J=8.3 Hz, 1H), 3.97 (t, J=8.3 Hz, 1H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 162.75, 144.95, 141.89, 141.07, 131.94, 131.62, 130.91, 128.65, 128.54, 127.56, 127.40, 126.58, 122.26, 119.76; melting point: 153-156° C., HRMS: m/z calculated for C.sub.30H.sub.24N.sub.4O.sub.4Na ([M+Na].sup.+): 527.1690; found: 527.1691.

Example 6

[0063] ##STR00010##

[0064] 0.18 g of 10% Pd/C, 0.50 g of 4-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline and anhydrous ethanol were added to a reaction kettle, the air in the kettle was replaced with N.sub.2 for three times, and then the N.sub.2 in the kettle was replaced with H.sub.2 for three times, and H.sub.2 (2.5 MPa) was pumped into to start the reaction. After the end of the reaction, the reaction solution was taken out, filtered with diatomaceous earth, and the solvent was removed. Column chromatography separation (PE/EA=20:1-10:1) was carried out, thereby obtaining 0.39 g of yellow product. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-amino-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0065] 3-f: [α]D.sup.20=−233 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, Chloroform-d) δ 10.60 (s, 1H), 7.86 (dd, J=7.9, 1.5 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.28 (s, 7H), 7.26 (d, J=2.9 Hz, 2H), 7.24 (d, J=3.0 Hz, 3H), 7.23 (s, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.10 (dd, J=7.3, 1.9 Hz, 2H), 6.83-6.75 (m, 2H), 5.29 (dd, J=9.9, 8.0 Hz, 1H), 5.13 (dd, J=9.9, 8.4 Hz, 1H), 4.57 (dd, J=10.0, 8.3 Hz, 1H), 4.41 (dd, J=10.1, 8.4 Hz, 1H), 4.09 (t, J=8.1 Hz, 1H), 3.90 (t, J=8.3 Hz, 1H). .sup.13C NMR (126 MHz, Chloroform-d) δ 163.28, 162.82, 150.61, 146.29, 142.82, 142.24, 141.48, 131.94, 130.31, 128.54, 128.51, 127.33, 127.30, 126.70, 124.65, 119.80, 118.93, 117.71, 114.42, 110.56, 73.22, 70.14; melting point: 85-89° C., HRMS: m/z calculated for C.sub.30H.sub.26N.sub.4O.sub.2Na ([M+Na].sup.+): 475.2129; found: 475.2128.

Example 7

[0066] ##STR00011##

[0067] 5.48 g of anthranilic acid, 9.42 g of 2-chloro-5-bromobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-5-bromobenzoic acid.

[0068] 1.68 g of 2-((2-carboxyphenyl)amino)-5-bromobenzoic acid and 10 mL of SOCl.sub.2 were added to a round-bottom flask and heated to reflux temperature for 4 h, excess SOCl.sub.2 was removed by evaporation, thereby obtaining diacid chloride, the diacid chloride was added to dichloromethane. On ice bath, the dichloromethane solution of the diacid chloride was added dropwise to a dichloromethane solution containing 2.13 g of (1R,2S)-2-amino-1,2-diphenylethanol and 3.8 mL of trimethylamine. The resulting solution was stirred for 20 h. The reaction was quenched with ammonium chloride solution, extracted by water, saturated sodium bicarbonate solution and saturated brine three times, respectively. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0069] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 2.15 g of a yellow solid. The product of the reaction was adiphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-bromo-2-((4R,5R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((4R,5R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0070] 3-g: [α]D.sup.20=−73 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 11.34 (s, 1H), 8.09 (dd, J=1.8, 0.8 Hz, 1H), 8.01 (d, J=7.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.47 (d, J=1.8 Hz, 2H), 7.45-7.41 (m, 1H), 7.33 (td, J=4.6, 1.4 Hz, 6H), 7.18 (qd, J=6.8, 3.0 Hz, 11H), 7.05 (ddd, J=7.7, 5.4, 1.8 Hz, 5H), 5.14-5.11 (m, 2H), 4.94 (dd, J=12.9, 7.7 Hz, 2H). .sup.13C NMR (126 MHz, Chloroform-d) δ 162.19, 143.05, 140.30, 132.96, 131.79, 130.89, 128.79, 128.76, 128.57, 128.38, 128.30, 127.40, 126.41, 126.38, 125.87, 125.77, 119.37, 119.28, 111.10, 88.00, 78.71; melting point: 86-89° C., HRMS: m/z calculated for C.sub.42H.sub.32BrN.sub.3O.sub.2Na ([M+Na].sup.+): 690.1750; found: 690.1749.

Example 8

[0071] ##STR00012##

[0072] 5.48 g of anthranilic acid, 8.06 g of 2-chloro-4-nitrobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-4-nitrobenzoic acid.

[0073] 1.51 g of 2-((2-carboxyphenyl)amino)-4-nitrobenzoic acid and 10 mL of SOCl.sub.2 were added to a round-bottom flask and heated to reflux temperature for 4 h, excess SOCl.sub.2 was removed by evaporation, thereby obtaining diacid chloride, the diacid chloride was added to dichloromethane. On ice bath, the dichloromethane solution of the diacid chloride was added dropwise to a dichloromethane solution containing 1.35 g of (R)-(−)-2-phenylglycinol and 3.8 mL of trimethylamine. The resulting solution was stirred for 20 h. The reaction was quenched with ammonium chloride solution, extracted by water, saturated sodium bicarbonate solution and saturated brine three times, respectively. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0074] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 2.07 g of an orange solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 5-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0075] 3-h: [α]D.sup.20=−358 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 11.48 (s, 1H), 8.34 (s, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.95 (dd, J=7.9, 1.6 Hz, 1H), 7.65 (dd, J=8.6, 2.2 Hz, 1H), 7.63-7.58 (m, 1H), 7.47 (ddd, J=8.4, 7.4, 1.6 Hz, 1H), 7.29-7.23 (m, 8H), 7.18-7.12 (m, 4H), 5.18 (ddd, J=10.1, 8.2, 5.2 Hz, 2H), 4.52 (dt, J=10.1, 8.3 Hz, 2H), 4.05 (dt, J=38.5, 8.3 Hz, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 163.68, 141.05, 131.92, 131.61, 130.89, 128.65, 128.53, 127.56, 127.39, 126.58, 122.24, 119.75, 118.65, 112.62, 110.75, 73.97, 73.77, 70.28, 70.03; melting point: 76-78° C., HRMS: m/z calculated for C.sub.30H.sub.24N.sub.4O.sub.4Na ([M+Na].sup.+): 527.1690; found: 527.1684.

Example 9

[0076] ##STR00013##

[0077] 5.48 g of anthranilic acid, 8.06 g of 2-chloro-3-nitrobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-3-nitrobenzoic acid.

[0078] 1.51 g of 2-((2-carboxyphenyl)amino)-3-nitrobenzoic acid and 10 mL of SOCl.sub.2 were added to a round-bottom flask and heated to reflux temperature for 4 h, excess SOCl.sub.2 was removed by evaporation, thereby obtaining diacid chloride, the diacid chloride was added to dichloromethane. On ice bath, the dichloromethane solution of the diacid chloride was added dropwise to a dichloromethane solution containing 1.35 g of (R)-(−)-2-phenylglycinol and 3.8 mL of trimethylamine. The resulting solution was stirred for 20 h. The reaction was quenched with ammonium chloride solution, extracted by water, saturated sodium bicarbonate solution and saturated brine three times, respectively. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0079] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 1.69 g of an orange solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 2-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0080] 3-i: [α]D.sup.20=−142 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, Chloroform-d) δ 11.55 (d, J=72.1 Hz, 1H), 8.13-8.10 (m, 1H), 7.92 (d, J=7.4 Hz, 1H), 7.47-7.34 (m, 2H), 7.28 (s, 8H), 7.18-7.07 (m, 3H), 6.98-6.84 (m, 2H), 5.47 (s, 1H), 5.07 (s, 1H), 4.69 (d, J=44.5 Hz, 1H), 4.47 (s, 1H), 4.18 (t, J=8.1 Hz, 1H), 3.97 (s, 1H), 3.68 (s, 1H). .sup.13C NMR (126 MHz, Chloroform-d) 6164.11, 164.08, 143.58, 139.90, 136.10, 131.87, 130.17, 128.60, 128.57, 127.52, 127.37, 126.58, 126.53, 124.37, 124.33, 123.26, 121.26, 120.12, 114.16, 113.71, 74.47, 74.46, 70.06, 70.03; melting point: 115-118° C., HRMS: m/z calculated for C.sub.30H.sub.24N.sub.4O.sub.4Na ([M+Na].sup.+): 527.1690; found: 527.1684.

Example 10

[0081] ##STR00014##

[0082] 5.48 g of anthranilic acid, 6.98 g of 2-chloro-6-fluorobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxyphenyl)amino)-6-fluorobenzoic acid.

[0083] 1.35 g of (R)-(−)-2-phenylglycinol, 2.20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.55 g of 1-hydroxybenzotriazole were dissolved in THF, and then 1.10 g of 2-((2-carboxyphenyl)amino)-6-fluorobenzoic acid was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with ammonium chloride solution, the solvent was removed under reduced pressure, and the crude product was dissolved in ethyl acetate, washed with water, and extracted three times. The organic phase was dried over sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0084] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 1.29 g of a pale yellow solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 3-fluoro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline.

[0085] 3-j: [α]D.sup.20=−298 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 10.92 (s, 1H), 7.86 (d, J=6.8 Hz, 1H), 7.52 (ddd, J=32.5, 9.2, 3.9 Hz, 2H), 7.42-6.99 (m, 14H), 6.88 (t, J=7.3 Hz, 1H), 5.16 (q, J=10.3 Hz, 2H), 4.47 (ddd, J=13.3, 10.0, 8.5 Hz, 2H), 3.98 (dt, J=17.0, 8.2 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ 164.10, 163.16, 142.52, 142.19, 131.68, 130.53, 128.48, 127.29, 126.56, 121.02, 120.94, 119.27, 118.71, 118.49, 116.67, 116.43, 113.84, 73.98, 73.54, 70.00; .sup.19F NMR (376 MHZ, CDCl.sub.3) δ −122.68; melting point: 68-71° C.; HRMS: m/z calculated for C.sub.30H.sub.24FN.sub.3O.sub.2Na ([M+Na].sup.+): 500.1745; found:500.1739.

Example 11

[0086] ##STR00015##

[0087] 7.28 g of 2-amino-5-nitrobenzoic acid, 6.82 g of 2-chloro-5-methylbenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxy-4-methylphenyl)amino)-5-nitrobenzoic acid.

[0088] 1.35 g of (R)-(−)-2-phenylglycinol, 2.20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.55 g of 1-hydroxybenzotriazole were dissolved in THF, and then 1.58 g of 2-((2-carboxy-4-methylphenyl)amino)-5-nitrobenzoic acid was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with ammonium chloride solution, the solvent was removed under reduced pressure, and the crude product was dissolved in ethyl acetate, washed with water, and extracted three times. The organic phase was dried over sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0089] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 2.07 g of a yellow solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-methyl-N-(4-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)aniline.

[0090] 3-k: [α]D.sup.20=−169 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, Chloroform-d) δ 11.63 (s, 1H), 8.82 (d, J=2.6 Hz, 1H), 8.11 (dd, J=9.4, 2.6 Hz, 1H), 7.79 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.31-7.20 (m, 11H), 7.12-7.08 (m, 2H), 5.26 (t, J=9.1 Hz, 1H), 5.16 (t, J=9.2 Hz, 1H), 4.66-4.59 (m, 1H), 4.49-4.42 (m, 1H), 4.18 (t, J=8.2 Hz, 1H), 3.95 (t, J=8.3 Hz, 1H), 2.40 (s, 3H). .sup.13C NMR (126 MHz, Chloroform-d) δ 163.56, 162.97, 150.73, 142.12, 141.95, 137.75, 136.40, 132.44, 132.44, 131.40, 128.71, 128.56, 127.65, 127.52, 127.48, 127.40, 126.59, 126.52, 124.31, 121.61, 113.22, 110.31, 74.42, 73.45, 70.36, 69.87, 20.76; melting point: 85-86° C.; HRMS: m/z calculated for C.sub.31H.sub.26N.sub.4O.sub.4Na ([M+Na].sup.+): 541.1846; found: 541.1847.

Example 12

[0091] ##STR00016##

[0092] 7.28 g of 2-amino-5-nitrobenzoic acid, 7.46 g of 2-chloro-5-methoxybenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxy-4-methoxyphenyl)amino)-5-nitrobenzoic acid.

[0093] 1.35 g of (R)-(−)-2-phenylglycinol, 2.20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.55 g of 1-hydroxybenzotriazole were dissolved in THF, and then 1.66 g of 2-((2-carboxy-4-methoxyphenyl)amino)-5-nitrobenzoic acid was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with ammonium chloride solution, the solvent was removed under reduced pressure, and the crude product was dissolved in ethyl acetate, washed with water, and extracted three times. The organic phase was dried over sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0094] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 1.98 g of an orange solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-methoxy-N-(4-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)aniline.

[0095] 3-l: [α]D.sup.20=−121 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, Chloroform-d) δ 11.47 (s, 1H), 8.82 (s, 1H), 8.10 (d, J=12.2 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.29-7.23 (m, 9H), 7.10-7.07 (m, 3H), 7.02 (d, J=9.4 Hz, 1H), 5.28 (dd, J=9.9, 8.3 Hz, 1H), 5.18 (dd, J=10.0, 8.4 Hz, 1H), 4.63 (dd, J=10.0, 8.4 Hz, 1H), 4.48 (dd, J=10.1, 8.5 Hz, 1H), 4.19 (t, J=8.2 Hz, 1H), 3.95 (t, J=8.4 Hz, 1H), 3.88 (s, 3H). .sup.13C NMR (126 MHz, Chloroform-d) δ 163.28, 163.14, 156.99, 151.50, 141.97, 137.41, 131.65, 128.72, 128.58, 127.67, 127.53, 127.44, 127.02, 126.59, 126.51, 123.91, 118.44, 114.96, 112.62, 109.54, 74.55, 73.39, 70.34, 69.95, 55.79; melting point: 80-81° C.; HRMS: m/z calculated for C.sub.31H.sub.26N.sub.4O.sub.5Na ([M+Na].sup.+): 557.1795; found: 557.1793.

Example 13

[0096] ##STR00017##

[0097] 7.28 g of 2-amino-5-nitrobenzoic acid, 6.98 g of 2-chloro-5-fluorobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxy-4-fluorophenyl)amino)-5-nitrobenzoic acid.

[0098] 1.35 g of (R)-(−)-2-phenylglycinol, 2.20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.55 g of 1-hydroxybenzotriazole were dissolved in THF, and then 1.66 g of 2-((2-carboxy-4-fluorophenyl)amino)-5-nitrobenzoic acid was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with ammonium chloride solution, the solvent was removed under reduced pressure, and the crude product was dissolved in ethyl acetate, washed with water, and extracted three times. The organic phase was dried over sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0099] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 1.85 g of a yellow solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-fluoro-N-(4-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)aniline.

[0100] 3-m: [α]D.sup.20=−149 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, Chloroform-d) δ 11.65 (s, 1H), 8.83 (d, J=2.7 Hz, 1H), 8.13 (dd, J=9.4, 2.7 Hz, 1H), 7.67 (dd, J=8.9, 3.0 Hz, 1H), 7.52 (dd, J=8.9, 4.9 Hz, 1H), 7.27 (dt, J=6.3, 4.0 Hz, 7H), 7.23-7.18 (m, 3H), 7.15 (d, J=9.4 Hz, 1H), 7.10-7.06 (m, 2H), 5.21 (ddd, J=27.6, 10.0, 8.4 Hz, 2H), 4.62 (dd, J=10.0, 8.4 Hz, 1H), 4.50 (dd, J=10.2, 8.5 Hz, 1H), 4.18 (t, J=8.2 Hz, 1H), 3.98 (t, J=8.4 Hz, 1H). .sup.13C NMR (126 MHz, Chloroform-d) δ 162.87, 162.24, 160.09, 156.14, 150.57, 141.82, 138.02, 135.17, 128.71, 128.59, 127.68, 127.58, 127.56, 127.37, 126.56, 126.44, 126.22, 126.16, 123.49, 123.43, 118.86, 118.68, 117.63, 117.43, 112.98, 110.55, 74.48, 73.49, 70.32, 70.05. .sup.19F NMR (376 MHZ, CDCl.sub.3) δ −122.69; melting point: 85-86° C.; HRMS: m/z calculated for C.sub.30H.sub.23FN.sub.4O.sub.4Na ([M+Na].sup.+): 545.1596; found: 545.1598.

Example 14

[0101] ##STR00018##

[0102] 7.28 g of 2-amino-5-nitrobenzoic acid, 9.42 g of 2-chloro-5-bromobenzoic acid, 5.52 g of K.sub.2CO.sub.3, 0.378 g of copper powder and 1.14 g of CuI were added to a round-bottom flask and mixed, then DMF was added, and the reaction was carried out at reflux temperature for 3 hours. After cooling and filtration, diluted hydrochloric acid was added to the filtrate until the solution was weakly acidic, the resulting solution was stirred and filtered by suction to obtain a solid product 2-((2-carboxy-4-bromophenyl)amino)-5-nitrobenzoic acid.

[0103] 1.35 g of (R)-(−)-2-phenylglycinol, 2.20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.55 g of 1-hydroxybenzotriazole were dissolved in THF, and then 1.66 g of 2-((2-carboxy-4-bromophenyl)amino)-5-nitrobenzoic acid was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with ammonium chloride solution, the solvent was removed under reduced pressure, and the crude product was dissolved in ethyl acetate, washed with water, and extracted three times. The organic phase was dried over sodium sulfate, the solvent was removed, and after purification by column chromatography, the product was used directly in the next reaction.

[0104] 0.9 mL of methanesulfonyl chloride and 3.3 mL of triethylamine were added to a dichloromethane solution containing the product obtained in the previous step on ice bath. After the system was stable, the reaction was carried out at room temperature for 10 hours. The reaction was quenched by a saturated ammonium chloride solution, the resulting solution was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed, thereby obtaining a crude product. The crude product was purified by column chromatography (PE/EA=10:1˜5:1), thereby obtaining 2.47 g of a yellow solid. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-bromo-N-(4-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)aniline.

[0105] 3-n: [α]D.sup.20=−149 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, Chloroform-d) δ 11.82 (s, 1H), 8.82 (d, J=2.7 Hz, 1H), 8.15 (dd, J=9.4, 2.8 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.58 (dd, J=8.7, 2.4 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.32 (d, J=9.4 Hz, 1H), 7.27 (dt, J=7.0, 2.9 Hz, 7H), 7.18 (dd, J=7.5, 1.7 Hz, 2H), 7.09 (dd, J=6.5, 3.0 Hz, 2H), 5.18 (ddd, J=26.5, 10.0, 8.4 Hz, 2H), 4.61 (dd, J=10.0, 8.4 Hz, 1H), 4.49 (dd, J=10.1, 8.4 Hz, 1H), 4.16 (t, J=8.3 Hz, 1H), 3.99 (t, J=8.4 Hz, 1H). .sup.13C NMR (126 MHz, Chloroform-d) δ 162.65, 162.12, 149.47, 141.85, 138.64, 134.46, 133.64, 128.71, 128.61, 127.67, 127.56, 127.39, 127.30, 126.55, 126.46, 124.35, 122.18, 116.44, 114.01, 111.81, 74.38, 73.61, 70.35, 70.06; melting point: 87-89° C.; HRMS: m/z calculated for C.sub.30H.sub.23BrN.sub.4O.sub.4Na ([M+Na].sup.+): 605.0795; found: 605.0794.

Example 15

[0106] ##STR00019##

[0107] Under N.sub.2, 0.53 g of 4-methoxy-N-(4-nitro-2-((R)-4-phenyl-4,5-dihydrooxazole-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)aniline and dichloromethane were added to a round-bottom flask with three outlets, the system was put at −78° C. and added dropwise a dichloromethane solution of 4M BBr.sub.3 slowly. After the dropping, the system was placed at room temperature to react for 12 hours. The reaction solution was slowly added dropwise to ice water, extracted with dichloromethane three times, and the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was removed. Column chromatography separation (PE/EA=20:1˜10:1) was carried out, thereby obtaining 0.34 g of orange product. The product of the reaction was a diphenylamine-linked chiral bis(oxazoline) ligand without C.sub.2-symmetry of the present invention 4-hydroxy-N-(4-nitro-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)aniline.

[0108] 3-o: [α]D.sup.20=−52 (c=1.0, CH.sub.2Cl.sub.2); .sup.1H NMR (500 MHz, Chloroform-d) δ 11.25 (s, 1H), 8.81 (s, 1H), 8.08 (d, J=11.6 Hz, 1H), 7.36-7.33 (m, 1H), 7.32-7.17 (m, 11H), 7.05 (d, J=5.0 Hz, 2H), 6.90-6.84 (m, 2H), 5.36 (t, J=9.0 Hz, 1H), 5.15 (t, J=9.1 Hz, 1H), 4.69 (t, J=9.2 Hz, 1H), 4.42 (t, J=9.4 Hz, 1H), 4.23 (t, J=8.2 Hz, 1H), 3.89 (t, J=8.3 Hz, 1H). .sup.13C NMR (126 MHz, Chloroform-d) δ 165.12, 163.36, 151.77, 141.91, 137.28, 130.37, 128.78, 128.72, 127.85, 127.83, 127.79, 127.71, 127.38, 126.61, 126.45, 123.98, 119.84, 117.54, 112.42, 108.92, 75.14, 73.39, 70.31, 69.04; melting point: 119-122° C.; HRMS: m/z calculated for C.sub.30H.sub.24N.sub.4O.sub.5Na ([M+Na].sup.+): 521.1819; found: 521.1815.

Example 16

[0109] The reaction formula was as follows:

##STR00020##

0.02 mmol of complex of the oxazoline ligand 3-e and copper acetate and 2-hydroxy-1-naphthoate (0.2 mmol) were added to 10 mL tube, 2 mL of toluene was added and dissolved, the resulting solution was stirred for 10 min at 0° C., 1,3-dichloro-5,5-dimethylhydantoin of formula (II) (1.2 equiv.) was added, the system was stirred for 18 h at 0° C. The reaction solution was concentrated under reduced pressure and separated on a silica gel chromatography column, wherein a solution of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 was used as the eluent for gradient elution, and the elution solution was collected and evaporated to remove the solvent, thereby obtaining a pale yellow solid product (yield 98%), [α]D.sup.20=79° (c=1.0, CH.sub.2Cl.sub.2). 1H NMR (500 MHz, Chloroform-d) δ 7.55-7.50 (m, 2H), 7.49-7.43 (m, 2H), 7.39 (dd, J=7.3, 1.7 Hz, 1H), 6.29 (d, J=10.0 Hz, 1H), 3.78 (s, 3H); .sup.13C NMR (126 MHz, Chloroform-d) δ 189.81, 166.77, 145.59, 137.44, 131.01, 130.03, 129.94, 128.96, 128.39, 123.28, 67.35, 54.21 ppm. The product was analyzed by chiral HPLC, the specific conditions were as follows: Daicel Chiralpak OJ-H, N-hexane/isopropanol=70:30, flow speed 1.0 mL/min, detection wavelength 320 nm, t.sub.R1=14.679 min (major), t.sub.R2=20.812 min (minor). 90% ee. HRMS: m/z=259.0132 [M+Na].sup.+.

[0110] The reactants above were taken, the ligand 3-e was replaced by 0.02 mmol of one of the following ligands, the asymmetric chlorination dearomatization was carried out with the same conditions and operations as above, and the results were gathered in the following table:

##STR00021##

TABLE-US-00001 TABLE 1 experimental results of different ligands Number Ligand yield[%] ee[%]  1 3-a 95 76  2 4-a 78 59  3 3-b 89 80  4 4-b 96 70  5 3-c 92 70  6 4-c 94 68  7 3-d 98 84  8 4-d 98 73  9 3-e 98 90 10 4-e 97 80 11 5 92 70

Example 17

[0111] The reaction formula was as follows:

##STR00022##

[0112] 0.02 mmol of complex of the oxazoline ligand 3-a and copper trifluoromethanesulfonate was added to 2 mL of dichloromethane to dissolve and stirred at room temperature for 0.5 h, cooled to −45° C., then 2-hydroxy-1-naphthoate (0.2 mmol) was added, 1,3-dibromo-5,5-dimethylhydantoin of formula (II) (1.2 equiv.) was added and stirred for 0.5 h. The reaction solution was concentrated under reduced pressure and separated on a silica gel chromatography column, wherein a solution of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 was used as the eluent for gradient elution, and the elution solution was collected and evaporated to remove the solvent, thereby obtaining a pale yellow solid product (yield 90%), .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.50 (d, J=10.0 Hz, 1H), 7.48-7.46 (m, 1H), 7.46-7.41 (m, 2H), 7.41-7.38 (m, 1H), 6.32 (d, J=10.1 Hz, 1H), 3.82 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ=189.87, 166.67, 144.99, 138.05, 131.05, 130.12, 129.97, 129.17, 127.95, 123.26, 60.22, 54.46 ppm. The product was analyzed by chiral HPLC, the specific conditions were as follows: Daicel Chiralpak OD-H, 2-propanol:hexane=10:90, flow rate 1.0 mL/min, 254 nm); t.sub.R=15.11 min, 20.37 min. 97% ee. ° HRMS: m/z=280.9811 [M+Na].sup.+

Example 18

[0113] The reaction formula was as follows:

##STR00023##

[0114] 0.02 mmol of complex of the oxazoline ligand 3-n and copper trifluoromethanesulfonate and methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate (0.2 mmol) were added to a 10 mL tube, 4 mL of toluene was added to dissolve and stirred at room temperature for 10 min, α,β-unsaturated enone (1.2 mmol) was added by injection needle and stirred at room temperature for 8 h. The reaction solution was concentrated under reduced pressure and separated on a silica gel chromatography column, wherein a solution of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 was used as the eluent for gradient elution, and the elution solution was collected and evaporated to remove the solvent, thereby obtaining a yellow liquid product (yield 75%), .sup.1H NMR (500 MHz, Chloroform-d) δ=7.70-7.64 (m, 2H), 7.20 (d, J=8.7 Hz, 1H), 7.15 (t, J=7.4 Hz, 1H), 3.77 (s, 3H), 2.64-2.58 (m, 1H), 2.52-2.49 (m, 2H), 2.42-2.34 (m, 3H), 1.03 (t, J=7.3 Hz, 3H) ppm. .sup.13C NMR (125 MHz, Chloroform-d) δ=208.88, 195.53, 172.04, 166.06, 138.67, 125.02, 122.83, 119.41, 113.50, 90.28, 53.36, 35.83, 35.73, 27.90, 7.68 ppm. The product was analyzed by chiral HPLC, the specific conditions were as follows: Daicel Chiralpak OD-H, 2-propanol:hexane=10:90, flow rate 1.0 mL/min, 254 nm); t.sub.R=18.2 min (minor), 20.5 min (major). 96% ee.

Example 19

[0115] The reaction formula was as follows:

##STR00024##

[0116] 0.01 mmol of complex of the oxazoline ligand 3-d and copper trifluoroacetate as the chiral catalyst, methyl 1-oxo-2,3-indanone-2-carboxylate (1 mmol), N-fluorobisbenzenesulfonamide (1.2 mmol) were added to a 10 mL tube, 4 mL of dichloromethane was added to dissolve and stirred at room temperature for 8 h. The reaction solution was concentrated under reduced pressure and separated on a silica gel chromatography column, wherein a solution of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 was used as the eluent for gradient elution, and the elution solution was collected and evaporated to remove the solvent, thereby obtaining a white solid product (yield 97%), .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.85 (d, J=7.7 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.53-7.46 (m, 2H), 3.82 (s, 3H), 3.81 (dd, J=11.7, 17.7 Hz, 1H), 3.80 (d, J=11.3 Hz, 1H), 3.45 (dd, J=23.3, 17.6 Hz, 3H); .sup.13C NMR (125 MHz, CDCl.sub.3): δ 195.02 (d, J.sub.CF=18.2 Hz), 167.74 (d, J.sub.CF=27.9 Hz), 150.80 (d, J.sub.CF=3.6 Hz), 136.72, 133.32, 128.67, 126.61, 125.68, 94.64 (d, J.sub.CF=201.8 Hz), 38.29 (d, J.sub.CF=24.0 Hz). The product was analyzed by chiral HPLC, the specific conditions were as follows: Daicel Chiralpak OD-H, Hexane:iPrOH=90:10, flow rate 1.0 ml/min, 254 nm:t.sub.R (major)=12.2 min, t.sub.R (minor)=14.1 min, 99% ee.

Example 20

[0117] The reaction formula was as follows:

##STR00025##

[0118] 0.02 mmol of complex of the oxazoline ligand 3-a and copper trifluoromethanesulfonate and tert-butyl indanonate (0.2 mmol) were added to 10 mL tube, 2 mL of dichloromethane was added and dissolved, the resulting solution was stirred for 10 min at 0° C., N-thiocyanophthalimide of formula (II) (1.5 equiv.) was added, the reaction was carried out for 12 h at 0° C. The reaction solution was concentrated under reduced pressure and separated on a silica gel chromatography column, wherein a solution of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 was used as the eluent for gradient elution, and the elution solution was collected and evaporated to remove the solvent, thereby obtaining a white solid product (yield 90%), [α]D.sup.20=60° (c=1.0, CH.sub.2Cl.sub.2). 1H NMR (500 MHz, CDCl.sub.3) δ=7.88 (d, J=7.7 Hz, 1H), 7.73 (td, J=7.7, 1.0 Hz, 1H), 7.55-7.47 (m, 2H), 4.06 (d, J=18.0 Hz, 1H), 3.63 (d, J=18.0 Hz, 1H), 1.45 (s, 9H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ=194.97, 150.98, 136.74, 133.11, 128.80, 126.18, 125.80, 86.07, 64.19, 40.38, 27.65 ppm. The product was analyzed by chiral HPLC, the specific conditions were as follows: Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate 1.0 mL/min, 285 nm; t.sub.R=14.759 min, 15.852 min. 96% ee. HRMS: m/z=312.0663 [M+Na]*.

Example 21

[0119] The reaction formula was as follows:

##STR00026##

[0120] 0.02 mmol of complex of the oxazoline ligand 3-e and zinc triflate, indole (0.2 mmol) and β-nitrostyrene (0.2 mmol) were added to 10 mL tube, 4 mL of toluene was added to dissolve and stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure and separated on a silica gel chromatography column, wherein a solution of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 was used as the eluent for gradient elution, and the elution solution was collected and evaporated to remove the solvent, thereby obtaining an oily liquid product (yield 93%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.43 (d, J=7.8 Hz, 1H) 7.31-7.15 (m, 7H), 7.06 (t, J=7.6 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 5.17 (t, J=8.1 Hz, 1H), 5.02 (dd, J=12.4, 7.6 Hz, 1H), 4.90 (dd, J=12.4, 8.6 Hz, 1H); .sup.13C NMR (75 MHz, Chloroform-d) δ 139.1, 136.4, 128.9, 127.7, 127.5, 126.0, 122.7, 121.6, 119.9, 118.8, 114.3, 111.4, 79.5, 41.6. The product was analyzed by chiral HPLC, the specific conditions were as follows: Daicel Chiralpak OD-H, N-hexane/isopropanol=70:30, the flow speed is 1.0 mL/min, the detecting wavelength is 254 nm, t.sub.R1=24.8 min (major), t.sub.R2=20.4 min (minor), 98% ee.