A multi-substituted axial chiral biphenol compound and its preparation method and application

Abstract

The present invention discloses a multi-substituted axial chiral biphenol compound and a preparation method and application thereof. The structural formula of the multi-substituted axial chiral biphenol compound is as shown in Formula I or Formula II, R 1 , R 2 and R 3 R is independently selected from hydrogen, alkyl having 1 to 4 carbon atoms, aryl, halogen, nitro, ether, sulfonyl, phosphine (phosphorus) acyl, amine, amide and ester; 4 The present invention provides a multi-substituted axial chiral biphenol parent structure, which can provide a variety of adjustable axial chiral ligands and catalysts, and has a wide range of application prospects in asymmetric synthesis.

Description

Technical Field

[0001] The invention relates to a multi-substituted axial chiral biphenol compound and a preparation method and application thereof, belonging to the field of axial chiral compounds. Background Art

[0002] Chiral organic compounds are widely present in biomolecules, natural products and drugs. Their chemical synthesis is mainly through catalytic asymmetric synthesis, and their catalytic efficiency is highly dependent on chiral ligands and chiral catalysts. Therefore, the development of chiral catalysts, especially chiral ligands, is of vital importance. In the past few decades, a variety of chiral ligands have been developed and successfully applied in academia and industry. Many of these ligands are axially chiral ligands. It is well known that among the existing axially chiral ligands, axially chiral biphenylphenols are the most commonly used core structures. The most prominent axially chiral core structures should be binaphthol (BINOL) and spirobihydroindole (SPINOL) ( Figure 1 ). Derivatives of BINOL and SPINOL have been widely used as chiral ligands and catalysts for asymmetric synthesis. However, the reactivity and enantioselectivity of these catalytic reactions are closely related to the structure of the substrate. To date, there is no universal ligand in asymmetric catalytic synthesis. The main reason is that slight changes in the geometry, stereostructure and / or electronic effects of chiral ligands and substrates can lead to huge differences in reactivity and enantioselectivity. However, due to the structural limitations of BINOL and SPINOL, the modification of their parent structures is limited. For example Figure 2 As shown in the figure, the axial chiral ligands or catalysts derived from the parent structures of BINOL and SPINOL are usually transformed and modified from two sites (here only the (R)-type is taken as an example): when BINOL is used as the parent structure, the type of ligand or catalyst is determined by changing the structure of 2,2'-OH, and the spatial effect and electronic effect of the ligand or catalyst are adjusted by changing the structure of 3,3'-R ( Figure 2 A); when SPINOL is used as the parent structure, the type of ligand or catalyst is determined by changing the structure of 7,7'-OH, and the spatial effect and electronic effect of the ligand or catalyst are adjusted by changing the structure of 6,6'-R ( Figure 2 Therefore, it is necessary to provide an axial chiral compound with a completely new structure. Summary of the invention

[0003] The purpose of the present invention is to provide a new structure of multi-substituted axial chiral biphenyl diphenol (BIPHNOL) compound, such as Figure 2 As shown in C, the axial chiral biphenol can be modified by changing the 3,3'-R 1 and 5,5'-R 3 The structure of ligands or catalysts can be used to adjust the steric and electronic effects of the catalyst by changing the 6,6'-R4 The dihedral angle, steric effect and electronic effect of the ligand or catalyst are adjusted, and the defects of the existing axial chiral diphenol BINOL and SPINOL structures are overcome. The present invention provides a diverse and adjustable axial chiral ligand for asymmetric synthesis.

[0004] The multi-substituted axial chiral biphenol compound provided by the present invention has a structural formula as shown in Formula I or Formula II.

[0005]

[0006] In the formula, R 1 , R 2 and R 3 Independently selected from hydrogen, alkyl groups having 1 to 4 carbon atoms, aryl groups, halogen groups, nitro groups, ether groups, sulfonyl groups, phosphinoyl groups, amine groups, amide groups and ester groups;

[0007] R 4 It is selected from an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 2 carbon atoms substituted with a halogen, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 3 to 8 carbon atoms, an aryl group, a halogen group, a nitro group, an ether group, a sulfonyl group, a phosphinoyl group, an amine group, an amide group and an ester group.

[0008] The structural formula of the multi-substituted axial chiral biphenol compound is specifically shown in Formula I-1 or Formula II-1.

[0009]

[0010] In the formula, R 4 It is selected from an alkyl group having 1 to 4 carbon atoms or an alkyl group substituted with halogen; preferably an alkyl group having 1 to 3 carbon atoms or a fluoroalkyl group, specifically methyl, ethyl, isopropyl or difluoromethyl.

[0011] The structural formula of the multi-substituted axial chiral biphenol compound is specifically shown in Formula I-2 or Formula II-2.

[0012]

[0013] In the formula, R 3 is selected from halogen; R 4 The halogen is preferably fluorine or chlorine, and the alkyl is preferably methyl, ethyl or isopropyl.

[0014] The structural formula of the multi-substituted axial chiral biphenol compound is specifically shown in Formula I-3 or Formula II-3,

[0015]

[0016] In the formula, R 3is selected from an alkyl group having 1 to 4 carbon atoms and an aryl group, the alkyl group is preferably an alkyl group having 1 to 3 carbon atoms, more preferably a methyl group, and the aryl group is preferably a phenyl group; R 4 It is an alkyl group having 1 to 4 carbon atoms, preferably an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group.

[0017] The structural formula of the multi-substituted axial chiral biphenol compound is specifically shown in Formula I-4 or Formula II-4,

[0018]

[0019] In the formula, R 4 It is an ester group.

[0020] The structural formula of the multi-substituted axial chiral biphenol compound is specifically shown in Formula I-5 or Formula II-5,

[0021]

[0022] In the formula, R 1 is halogen, preferably fluorine, bromine or iodine; R 3 is an aryl group, preferably a phenyl group; R 4 It is an alkyl group having 1 to 4 carbon atoms, and is preferably an ethyl group.

[0023] The multi-substituted axial chiral biphenol compound provided by the present invention can be used as a chiral ligand and in combination with a catalyst for an asymmetric addition reaction.

[0024] The multi-substituted axial chiral biphenol compound of the present invention can be used as a ligand of tetraisopropyl titanate to catalyze the asymmetric addition reaction of aldehyde compounds and alkyl zinc.

[0025] The solvent used in the asymmetric addition reaction may be dichloromethane;

[0026] The temperature of the asymmetric addition reaction is 0 to -3°C and the time is 10 to 15 hours;

[0027] The alkyl zinc is preferably diethyl zinc;

[0028] The structural formulas of the aldehyde compounds are shown in Formula 1 to Formula 4;

[0029]

[0030] In the formula, R1 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl having 1 to 2 carbon atoms or halogen-substituted alkyl, or alkoxy having 1 to 2 carbon atoms;

[0031] R2 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl or halogen-substituted alkyl having 1 to 2 carbon atoms, or alkoxy having 1 to 2 carbon atoms;

[0032] R3 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl having 1 to 2 carbon atoms or halogen-substituted alkyl, or alkoxy having 1 to 2 carbon atoms.

[0033] The multi-substituted axial chiral biphenol compound of the present invention can also be used as a ligand of tetraisopropyl titanate to catalyze the asymmetric addition reaction of aldehyde compounds and terminal alkynes;

[0034] The solvent used in the asymmetric addition reaction can be dichloromethane or toluene;

[0035] The temperature of the asymmetric addition reaction is 25 to 0°C and the time is 11 to 48 hours;

[0036] The terminal alkyne is phenylacetylene or substituted phenylacetylene, and the substituent is halogen, alkoxy with 1 to 2 carbon atoms, alkyl with 1 to 2 carbon atoms or alkyl substituted with halogen, preferably chlorine, methoxy or trifluoromethyl;

[0037] The structural formula of the aldehyde compound is shown in Formula 1, Formula 2, Formula 4 or Formula 5;

[0038]

[0039] In the formula, R1 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl having 1 to 2 carbon atoms or halogen-substituted alkyl, alkoxy having 1 to 2 carbon atoms, wherein the alkoxy is preferably methoxy, and the halogen is preferably fluorine, chlorine or bromine;

[0040] R3 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl or halogen-substituted alkyl having 1 to 2 carbon atoms, or alkoxy having 1 to 2 carbon atoms;

[0041] R4 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl having 1 to 2 carbon atoms or halogen-substituted alkyl, or alkoxy having 1 to 2 carbon atoms.

[0042] like Figure 2 As shown in C, the parent structure of the multi-substituted axial chiral biphenol (BIPHNOL) provided by the present invention can be determined by changing the structure of 2,2'-OH to determine the type of ligand or catalyst, by changing the structure of 3,3'-R 1 In addition to adjusting the spatial and electronic effects of ligands or catalysts, the structure of 5,5'-R 3The structure of ligands or catalysts can be used to adjust the steric and electronic effects of the catalyst by changing the 6,6'-R 4 To adjust the dihedral angle, steric effect and electronic effect of the ligand or catalyst. Therefore, the multi-substituted axial chiral biphenol parent structure provided by the present invention can provide diverse and adjustable axial chiral ligands and catalysts, and has a wide range of application prospects in asymmetric synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 It is the structure of the axial chiral compound in the prior art.

[0044] Figure 2 The ligands or catalysts derived from BINOL and SPINOL and the ligands and catalysts derived from BIPHNOL.

[0045] Figure 3 This is the reaction result in Example 16 of the present invention. DETAILED DESCRIPTION

[0046] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0047] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0048] Example 1. Preparation of Compound (S)-L1

[0049] The reaction equation is as follows:

[0050]

[0051] 13.5g of compound (S)-1 and a stirrer were added to a 500mL round-bottom flask and dissolved in 200mL of anhydrous ethanol. The round-bottom flask was then placed in an ice bath, stirred and cooled for 10 minutes, 4.7g of sodium borohydride was added to the above system in batches, and the ice bath was removed when no bubbles were generated after the addition was completed, and stirring was continued at room temperature for 8 hours. After the reaction was detected by thin layer chromatography, an ice bath was added again, and a saturated aqueous solution of ammonium chloride was slowly added dropwise until no bubbles were generated. Most of the ethanol was concentrated with a rotary evaporator, water was added, and it was extracted three times with ethyl acetate. The organic phase was combined, and the organic phase was washed with water and a saturated sodium chloride solution once each, dried over anhydrous sodium sulfate, filtered and evaporated to obtain 13.4g of compound (S)-2, with a yield of 99%.

[0052] 8.2 g of compound (S)-2 and a stirring bar were added to a 250 mL round-bottom flask, 80 mL of dichloromethane was poured in, stirred to completely dissolve it and cooled in an ice bath for 10 minutes, 50 mL of the prepared 1.5 M phosphorus tribromide dichloromethane solution was slowly added dropwise to the above system, and the temperature naturally rose to room temperature after the addition and continued to stir for 5 hours. After the reaction was completed by thin layer chromatography, the system was poured into 200 mL of ice water, stirred and 100 mL of saturated sodium carbonate solution was slowly added dropwise, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, the organic phases were washed once with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain compound (S)-3, which was directly used in the next reaction without purification.

[0053] 12 g of compound (S)-3 was dissolved in a mixed solution of 93 mL of ethyl acetate and methanol (volume ratio of 1:30), a stirring bar and 1 g of palladium carbon were added, and a three-way valve with a hydrogen balloon was installed. The mixture was degassed under reduced pressure and hydrogen was replaced five times. The mixture was stirred at room temperature for 48 hours, the palladium carbon was filtered out, the filtrate was collected, and the compound (S)-4 was evaporated to dryness, which was directly used in the next reaction without purification.

[0054] 7.3 g of compound (S)-4 was added to a 250 mL round-bottom flask, and 50 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 50 mL of the prepared 2M dichloromethane solution of boron tribromide was slowly added dropwise to the above system. After the addition, stirring was continued at 0°C for 1.5 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 6.0 g of compound (S)-1 with a yield of 95%.

[0055] (S)-L1 structural characterization data:

[0056] 1 H NMR: (400MHz, Chloroform-d) δ7.22 (t, J = 7.9 Hz, 2H), 6.89 (t, J = 8.0 Hz, 4H), 4.81 (s, 2H), 2.00 (s, 6H) ppm.

[0057] 13 C NMR: (101MHz, Chloroform-d) δ154.0,139.1,130.1,122.6,119.8,113.3,19.6ppm.

[0058] HRMS(ESI)m / z calcd for C 14 H 14 O2[MH] -:m / z 213.0916,found:213.0914

[0059] Mp:125-126℃.

[0060] The raw material compound (S)-1 is replaced with its enantiomer compound (R)-1, and the enantiomer (R)-L1 is obtained according to the above steps.

[0061] Example 2. Preparation of Compound (S)-L2

[0062] The reaction equation is as follows:

[0063]

[0064] 29.3 g of methyl triphenylphosphonium bromide and 300 mL of anhydrous tetrahydrofuran were added to a 500 mL three-necked flask, and the mixture was cooled in an ice bath and stirred for 10 minutes under argon protection. 9 g of potassium tert-butoxide was added to the above system in batches, and stirring was continued at 0°C for 0.5 hours. 5.4 g of (S)-1 was dissolved in 50 mL of anhydrous tetrahydrofuran, and the solution was slowly added dropwise to the above system. After the addition, stirring was continued at room temperature for 8 hours. Hydrated ethyl acetate was added, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phases were washed with water and saturated sodium chloride solution once each, dried over anhydrous sodium sulfate, filtered and evaporated to obtain the residue, which was separated by column chromatography to obtain 5 g of compound (S)-5 with a yield of 95%.

[0065] 5 g of compound (S)-5 was dissolved in a mixed solution of 62 mL of ethyl acetate and methanol (volume ratio of 1:30), a stirring bar and 0.5 g of palladium carbon were added, and a three-way valve with a hydrogen balloon was installed. The mixture was degassed under reduced pressure and hydrogen was replaced five times. The mixture was stirred at room temperature for 48 hours, the palladium carbon was filtered out, the filtrate was collected, and the compound (S)-6 was evaporated to dryness, which was directly used in the next reaction without purification.

[0066] 4 g of compound (S)-6 was added to a 250 mL round-bottom flask, and 50 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 25 mL of the prepared 2M dichloromethane solution of boron tribromide was slowly added dropwise to the above system. After the addition, stirring was continued at 0°C for 1.5 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 3.4 g of compound (S)-L2 with a yield of 94%.

[0067] Results characterization data:

[0068] 1H NMR: (400MHz, Chloroform-d) δ7.30 (t, J=7.9Hz, 2H), 6.96 (d, J=7.6Hz, 2H), 6.9 0(d,J=8.2Hz,2H),4.72(s,2H),2.29(q,J=7.4Hz,4H),1.06(t,J=7.6Hz,6H)ppm.

[0069] 13 C NMR: (101MHz, Chloroform-d) δ153.9,145.1,130.4,120.9,118.8,113.2,26.2,14.7ppm.

[0070] HRMS(ESI)m / z calcd for C 16 H 18 O2[MH] - :m / z 241.1229, found:241.1234.

[0071] Mp:135-136℃.

[0072] The enantiomer (R)-L2 was obtained by replacing the starting compound (S)-1 with its enantiomer (R)-1 according to the above steps.

[0073] Example 3. Preparation of Compound (S)-L3

[0074] The reaction equation is as follows:

[0075]

[0076] To a 500 mL three-necked flask, 13.5 g of compound (S)-1, 4.1 g of sodium dihydrogen phosphate, 200 mL of acetonitrile and 100 mL of water were added, and the mixture was placed in an oil bath preheated to 50° C. and stirred for 10 min. 15 g of sodium chlorite was added at one time, and 11 mL of 30% aqueous hydrogen peroxide solution was injected into the above system in batches, and stirring was continued at 50° C. for 1 hour. The mixture was cooled to room temperature, and 1 N hydrochloric acid was added to adjust the pH to 7. Most of the acetonitrile was concentrated, and ethyl acetate was added for extraction three times. The organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain compound (S)-7, which was directly used in the next step without purification.

[0077] To a 250 mL round-bottom flask, 15.1 g of compound (S)-7, 100 mL of methanol and 1 mL of concentrated sulfuric acid were added, the temperature was raised to 70 ° C and stirred for 24 hours. After cooling to room temperature, most of the methanol was concentrated, water and ethyl acetate were added, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to dryness to obtain a crude product, and recrystallized from a dichloromethane / petroleum ether system to obtain 16.2 g of compound (S)-8, with a yield of 98%.

[0078] To a 500mL three-necked flask, 6.6g of compound (S)-8 and 200mL of anhydrous tetrahydrofuran were added, and the mixture was cooled in an ice bath under argon protection. 200mL of 1M methylmagnesium bromide THF solution was added dropwise. After the addition, stirring was continued at 0°C for 0.5 hours, and then the temperature was raised to reflux for 24 hours. The mixture was ice-bathed again, and a saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 5.8g of compound (S)-9 in a yield of 89%.

[0079] 600 mg of compound (S)-9 was dissolved in anhydrous acetonitrile, 435 μL of thionyl chloride was added dropwise at 0°C, stirring was continued at 0°C for 15 minutes, 646 μL of pyridine was added dropwise, the mixture was restored to room temperature and stirring was continued for 12 hours, water was added to quench, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 666 mg of compound (S)-10, with a yield of 91%.

[0080] 1.5 g of compound (S)-10 was dissolved in 16 mL of a mixed solution of ethyl acetate and methanol (volume ratio of 1:30), a stirring bar and 0.15 g of palladium carbon were added, and a three-way valve with a hydrogen balloon was installed. The mixture was degassed under reduced pressure and hydrogen was replaced five times. The mixture was stirred at room temperature for 48 hours, the palladium carbon was filtered out, the filtrate was collected, and the compound (S)-11 was evaporated to dryness and used directly in the next reaction without purification.

[0081] 1.5 g of compound (S)-6 was added to a 100 mL round-bottom flask, and 50 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 10 mL of the prepared 1.8 M dichloromethane solution of boron tribromide was slowly added dropwise to the above system. After the addition, stirring was continued at 0°C for 1.5 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 1.2 g of compound (S)-L3 with a yield of 90%.

[0082] Results Characterization Data:

[0083] 1 H NMR: (400MHz, Chloroform-d) δ7.36 (t, J = 8.0 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H), 6. 90(d,J=8.0Hz,2H),4.65(s,2H),2.54(p,J=6.8Hz,2H),1.20–1.00(m,12H)ppm.

[0084] 13 C NMR: (101MHz, Chloroform-d) δ153.8,150.4,130.6,118.3,118.0,113.0,30.5,24.9,23.5ppm.

[0085] HRMS(ESI)m / z calcd for C 18 H 22 O2[MH] - :m / z 269.1542,found:269.1553.

[0086] Mp:151-152℃.

[0087] The enantiomer (R)-L3 was obtained by replacing the starting compound (S)-1 with its enantiomer (R)-1 according to the above steps.

[0088] Example 4. Preparation of Compound (S)-L4

[0089] The reaction equation is as follows:

[0090]

[0091] 1.35 g of compound (S)-1 was added to a 100 mL round-bottom flask, and 50 mL of anhydrous dichloromethane was added. The liquid nitrogen-acetone system was cooled to -78 ° C, and 10 mL of the prepared 1.8 M boron tribromide dichloromethane solution was slowly added dropwise to the above system. After the addition, stirring was continued at -78 ° C for 2 hours. Saturated ammonium chloride solution was added dropwise to quench the reaction, and the organic phase was separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed with water and saturated sodium chloride solution once, dried over anhydrous sodium sulfate, filtered and evaporated to obtain compound (S)-12, which was directly used in the next step without separation.

[0092] The product of the previous step was dissolved in anhydrous acetonitrile, ice-bathed, 1.7 g of anhydrous potassium carbonate was added, 1 mL of chloromethyl methyl ether was added dropwise, and the reaction was carried out at room temperature for 5 hours. Ethyl acetate and water were added to dilute, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 1.5 g of compound (S)-13, with a yield of 90%.

[0093] 264 mg of compound (S)-13 and 5 mL of anhydrous dichloromethane were added to a 50 mL sealed tube, iced, and 2.4 mL of bis(2-methoxyethyl)aminosulfur trifluoride was slowly added dropwise. After adding, the mixture was stirred at 0°C for 5 minutes, and a drop of anhydrous ethanol was added. The lid was tightened and the reaction was continued at 50°C for 36 hours. Ice-bathed again, saturated sodium carbonate solution was slowly added dropwise to quench the reaction and neutralize the hydrofluoric acid. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the organic phases were washed with water and saturated sodium chloride solution once each, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and separated by column chromatography to obtain 215 mg of compound (S)-14 with a yield of 72%.

[0094] 187 mg of compound (S)-14 was dissolved in 10 mL of 1,4-dioxane, 0.1 mL of concentrated hydrochloric acid was added, and the mixture was stirred at 60 ° C for 3 hours. Ethyl acetate and water were added to dilute the mixture, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 136 mg of compound (S)-14 with a yield of 95%.

[0095] Results Characterization Data:

[0096] 1 H NMR: (400MHz, DMSO-d6)δ9.78(s,2H),7.37(t,J=7.9Hz,2H),7.20–7.00(m,4H),6.27(t,J=55.5Hz,2H)ppm.

[0097] 13 C NMR: (101MHz, DMSO-d6) δ 155.3, 134.61 (t, J = 21.8Hz), 130.0, 120.82 (t, J = 5.9Hz), 118.1, 114.02 (t, J = 235.9Hz), 115.9ppm.

[0098] HRMS(ESI)m / z calcd for C 14 H 10 F4O2[MH] - :m / z 285.0539,found:285.0546.

[0099] Mp:172-173℃.

[0100] The enantiomer (R)-L4 was obtained by replacing the starting compound (S)-1 with its enantiomer (R)-1 according to the above steps.

[0101] Example 5. Preparation of Compound (S)-L5

[0102] The reaction equation is as follows:

[0103]

[0104] 363 mg of compound (S)-4 was dissolved in 10 mL of N,N-dimethylformamide, and 561 mg of N-bromosuccinimide was added at one time. The mixture was stirred at room temperature for 12 hours. After the reaction was completed by thin layer chromatography, water was added to quench the mixture, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 570 mg of compound (S)-15 with a yield of 95%.

[0105] 2 g of compound (S)-15 was added to a 100 mL round-bottom flask, and 30 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 2.9 mL of boron tribromide was dissolved in 15 mL of dichloromethane and slowly added dropwise to the above system. After the addition, the temperature was naturally raised and stirring was continued at room temperature for 12 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 51.7 g of compound (S)-L with a yield of 94%.

[0106] Results Characterization Data:

[0107] 1 H NMR: (400MHz, Chloroform-d) δ7.53 (d, J = 8.7Hz, 2H), 6.81 (d, J = 8.7Hz, 2H), 4.67 (s, 2H), 2.06 (s, 6H) ppm.

[0108] 13 C NMR: (101MHz, Chloroform-d) δ153.0,138.2,134.3,121.6,116.6,115.3,20.2ppm.

[0109] HRMS(ESI)m / z calcd for C 14 H 12 Br2O2[MH] -:m / z 370.9105, found:370.9112.

[0110] Mp:201-202℃.

[0111] The enantiomer (R)-L5 was obtained by replacing the starting compound (S)-4 with its enantiomer (R)-4 according to the above steps.

[0112] Example 6. Preparation of Compound (S)-L6

[0113] The reaction equation is as follows:

[0114]

[0115] 405 mg of compound (S)-6 was dissolved in 10 mL of N,N-dimethylformamide, and 561 mg of N-bromosuccinimide was added at one time. The mixture was stirred at room temperature for 12 hours. After the reaction was completed by thin layer chromatography, water was added to quench the mixture, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 603 mg of compound (S)-16 with a yield of 94%.

[0116] 2.1 g of compound (S)-16 was added to a 100 mL round-bottom flask, and 30 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 2.9 mL of boron tribromide was dissolved in 15 mL of dichloromethane and slowly added dropwise to the above system. After the addition, the temperature was naturally raised and stirring was continued at room temperature for 12 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 1.8 g of compound (S)-L6 with a yield of 94%.

[0117] Results Characterization Data:

[0118] 1 H NMR: (400MHz, Chloroform-d) δ7.56(d,J=8.8Hz,2H),6.84(d,J=8.7Hz,2H),4.64(s,2H),2.63–2.51(m,2H),2.39–2.25(m,2H),0.99(t,J=7.5Hz,6H)ppm.

[0119] 13 C NMR: (101MHz, Chloroform-d) δ153.3,143.8,135.0,120.8,116.1,115.5,27.8,13.2ppm.

[0120] HRMS(ESI)m / z calcd for C 16 H 16 Br2O2[MH] - :m / z 398.9418, found:398.9451.

[0121] Mp:215-216℃.

[0122] The raw material compound (S)-6 is replaced by its enantiomer compound (R)-6, and the enantiomer (R)-L6 is obtained according to the above steps.

[0123] Example 7. Preparation of Compound (S)-L7

[0124] The reaction equation is as follows:

[0125]

[0126] 447 mg of compound (S)-11 was dissolved in 10 mL of N,N-dimethylformamide, and 561 mg of N-bromosuccinimide was added at one time. The mixture was stirred at room temperature for 12 hours. After the reaction was completed by thin layer chromatography, water was added to quench the mixture, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 609 mg of compound (S)-17 with a yield of 89%.

[0127] 2.2 g of compound (S)-17 was added to a 100 mL round-bottom flask, and 30 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 2.9 mL of boron tribromide was dissolved in 15 mL of dichloromethane and slowly added dropwise to the above system. After the addition, the temperature was naturally raised and stirring was continued at room temperature for 12 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 1.9 g of compound (S)-L7 with a yield of 90%.

[0128] Results characterization data:

[0129] 1 H NMR: (400MHz, Chloroform-d) δ7.53(d,J=8.7Hz,2H),6.79(d,J=8.7Hz,2H),4.67(s,2H),2.82(s,2H),1.4–1.2(m,12H)ppm.

[0130] 13C NMR: (101MHz, Chloroform-d) δ153.2,146.3,137.1,122.0,115.5,113.8,33.0,27.0,20.2,19.9ppm.

[0131] HRMS(ESI)m / z calcd for C 18 H 20 Br2O2[MH] - :m / z 426.9731,found:426.9728.

[0132] Mp:233-234℃.

[0133] The enantiomer (R)-L7 was obtained by replacing the starting compound (S)-11 with its enantiomer (R)-11 according to the above steps.

[0134] Example 8. Preparation of Compound (S)-L8

[0135] The reaction equation is as follows:

[0136]

[0137] 484 mg of compound (S)-4 was dissolved in chloroform, and 1.1 g of N-chlorosuccinimide and 28 μL of dimethyl sulfoxide were added at one time. The mixture was stirred at room temperature for 24 hours, quenched with water, and extracted with dichloromethane three times. The organic phases were combined, washed with water and saturated sodium chloride solution once, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 564 mg of compound (S)-19 with a yield of 91%.

[0138] 1.55 g of compound (S)-18 ​​was added to a 100 mL round-bottom flask, and 30 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 2.9 mL of boron tribromide was dissolved in 15 mL of dichloromethane and slowly added dropwise to the above system. After the addition, the temperature was naturally raised and stirring was continued at room temperature for 12 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 1.3 g of compound (S)-L8 with a yield of 95%.

[0139] Results Characterization Data:

[0140] 1H NMR: (400MHz, Chloroform-d) δ7.35 (d, J = 8.7Hz, 2H), 6.86 (d, J = 8.7Hz, 2H), 4.62 (s, 2H), 2.03 (s, 6H) ppm.

[0141] 13 C NMR: (101MHz, Chloroform-d) δ152.4,136.6,131.1,126.9,121.2,114.8,17.3ppm.

[0142] HRMS(ESI)m / z calcd for C 14 H 12 Cl2O2[MH] - :m / z 281.0136,found:281.0129.

[0143] Mp:216-217℃.

[0144] The enantiomer (R)-L8 was obtained by replacing the starting compound (S)-8 with its enantiomer (R)-8 according to the above steps.

[0145] Example 9. Preparation of Compound (S)-L9

[0146] The reaction equation is as follows:

[0147]

[0148] To a 100mL three-necked flask, 800mg of compound (S)-15, 210mg of bis(triphenylphosphine)palladium dichloride, 839mg of methylboric acid, and 15mL of ethylene glycol dimethyl ether were added under argon protection. 1.06g of sodium carbonate was dissolved in 5mL of water and injected into the above system. After addition, the mixture was refluxed for 24 hours, cooled to room temperature, diluted with ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 432mg of compound (S)-19 with a yield of 80%.

[0149] 1.97 g of compound (S)-20 was added to a 100 mL round-bottom flask, and 30 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 2.9 mL of boron tribromide was dissolved in 15 mL of dichloromethane and slowly added dropwise to the above system. After the addition, the temperature was naturally raised and stirring was continued at room temperature for 12 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 1.1 g of compound (S)-L9 with a yield of 91%.

[0150] Results characterization data:

[0151] 1 H NMR: (400MHz, Chloroform-d) δ7.13 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 4.54 (s, 2H), 2.26 (s, 6H), 1.90 (s, 6H) ppm.

[0152] 13 C NMR: (101MHz, Chloroform-d) δ151.9,137.0,131.4,129.3,120.3,112.7,19.9,16.4ppm.

[0153] HRMS(ESI)m / z calcd for C 16 H 18 O2[MH] - :m / z 241.1229 found:241.1235.

[0154] Mp:195-196℃.

[0155] The enantiomer (R)-L9 was obtained by replacing the starting compound (S)-15 with its enantiomer (R)-15 according to the above steps.

[0156] Example 10. Preparation of Compound (S)-10

[0157] The reaction equation is as follows:

[0158]

[0159] To a 100mL three-necked flask, 800mg of compound (S)-15, 210mg of bis(triphenylphosphine)palladium dichloride, 1.2g of phenylboric acid, and 15mL of ethylene glycol dimethyl ether were added. Under argon protection, 1.06g of sodium carbonate was dissolved in 5mL of water and injected into the above system. After addition, the mixture was refluxed for 24 hours, cooled to room temperature, diluted with ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 701mg of compound (S)-20 with a yield of 89%.

[0160] 1.97 g of compound (S)-20 was added to a 100 mL round-bottom flask, and 30 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 2.9 mL of boron tribromide was dissolved in 15 mL of dichloromethane and slowly added dropwise to the above system. After the addition, the temperature was naturally raised and stirring was continued at room temperature for 12 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 1.57 g of compound (S)-L10 with a yield of 86%.

[0161] Results Characterization Data:

[0162] 1 H NMR: (400MHz, Chloroform-d) δ7.44–7.35(m,4H),7.36–7.28(m,1H),7.25–7.22(m,2H),7.02–6.88(m,2H),4.80(s,2H),1.94(s,6H)ppm.

[0163] 13 C NMR: (101MHz, Chloroform-d) δ153.0,141.8,136.1,135.9,132.0,129.6,128.2,126.8,120.5,113.2,17.8ppm.

[0164] HRMS(ESI)m / z calcd for C 26 H 22 O2[MH] - :m / z 365.1542 found:365.1549.

[0165] Mp:218-219℃.

[0166] The enantiomer (R)-L10 was obtained by replacing the starting compound (S)-15 with its enantiomer (R)-15 according to the above steps.

[0167] Example 11. Preparation of Compound (S)-L11

[0168] The reaction equation is as follows:

[0169]

[0170] To a 100mL three-necked flask, 800mg of compound (S)-16, 210mg of bis(triphenylphosphine)palladium dichloride, 1.2g of phenylboric acid, and 15mL of ethylene glycol dimethyl ether were added under argon protection. 1.06g of sodium carbonate was dissolved in 5mL of water and injected into the above system. After addition, the mixture was refluxed for 24 hours, cooled to room temperature, diluted with ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated, and separated by column chromatography to obtain 743mg of compound (S)-21 with a yield of 88%.

[0171] 2.1 g of compound (S)-21 was added to a 100 mL round-bottom flask, and 30 mL of anhydrous dichloromethane was added. The mixture was cooled in an ice bath and stirred for 10 minutes. 2.9 mL of boron tribromide was dissolved in 15 mL of dichloromethane and slowly added dropwise to the above system. After the addition, the temperature was naturally raised and stirring was continued at room temperature for 12 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 1.7 g of compound (S)-L11 with a yield of 86%.

[0172] Results Characterization Data:

[0173] 1 H NMR: (400MHz, Chloroform-d) δ7.48–7.30 (m, 10H), 7.23 (d, J = 8.3Hz, 2H), 6.98 (d, J = 8. 3Hz,2H),4.84(s,2H),2.62–2.37(m,2H),2.38–2.16(m,2H),0.76(t,J=7.5Hz,6H)ppm.

[0174] 13 C NMR: (101MHz, Chloroform-d) δ153.3,142.8,142.0,135.9,132.6,129.6,128.2,126.8,119.5,113.2,24.4,14.7ppm.

[0175] HRMS(ESI)m / z calcd for C 28 H 26 O2[MH] - :m / z 393.1855 found:393.1860.

[0176] Mp:226-227℃.

[0177] The enantiomer (R)-L11 was obtained by replacing the starting compound (S)-16 with its enantiomer (R)-16 according to the above steps.

[0178] Example 12. Preparation of Compound (S)-L12

[0179] The reaction equation is as follows:

[0180]

[0181] 3.3 g of compound (S)-8 was added to a 500 mL three-necked flask, and 100 mL of anhydrous dichloromethane was added. The liquid nitrogen and acetone system was cooled to -78 ° C, 30 mmol of boron tribromide was dissolved in 100 mL of dichloromethane solution, and slowly added dropwise to the above system. After the addition, the temperature was naturally raised to -30 ° C at -78 ° C and stirred for 3 hours. A saturated ammonium chloride solution was added dropwise to quench the reaction, and the organic phase was separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated, and separated by column chromatography to obtain 2.7 g of compound (S)-L12 with a yield of 90%.

[0182] Results Characterization Data:

[0183] 1 H NMR: (400MHz, Chloroform-d) δ7.75–7.55(m,1H),7.44–7.39(m,2H),7.32–7.03(m,1H),5.04(s,2H),3.63(s,6H)ppm.

[0184] 13 C NMR: (101MHz, Chloroform-d) δ167.0,154.1,131.8,130.0,123.2,121.6,120.1,52.3ppm.

[0185] HRMS(ESI)m / z calcd for C 16 H 14 O6[MH] -:m / z 301.0712 found:301.0703.

[0186] Mp:268-269℃.

[0187] The enantiomer (R)-L12 was obtained by replacing the starting compound (S)-8 with its enantiomer (R)-8 according to the above steps.

[0188] Example 13. Preparation of Compound (S)-L13

[0189] The reaction equation is as follows:

[0190]

[0191] 5.9 g of compound (S)-L11 was dissolved in 50 mL of dichloromethane, 7.8 mL of morpholine was added, and 9.5 g of iodine was added, and stirred at room temperature for 10 hours. 50 mL of 2M hydrochloric acid was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, the organic phases were washed once with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated, and separated by column chromatography to obtain 8.7 g of compound (S)-L13, with a yield of 90%.

[0192] Results characterization data:

[0193] 1 H NMR: (400MHz, Chloroform-d) δ7.66(s,2H),7.48–7.29(m,10H),5.23(s,2H),2.4 3(dq,J=15.0,7.5Hz,2H),2.24(dq,J=14.9,7.5Hz,2H),0.74(t,J=7.5Hz,6H)ppm.

[0194] 13 C NMR: (101MHz, Chloroform-d) δ151.9,143.2,140.6,140.4,137.7,129.4,128.3,127.2,121.7,81.4,24.4,14.3ppm.

[0195] HRMS(ESI)m / z calcd for C 28 H 24 I2O2[MH] - :m / z 644.9787 found:644.9780.

[0196] Mp:305-306℃.

[0197] The enantiomer (R)-L13 was obtained by replacing the raw material compound (S)-L11 with its enantiomer compound (R)-L11 according to the above steps.

[0198] Example 14. Preparation of Compound (S)-L14

[0199] The reaction equation is as follows:

[0200]

[0201] 5.9g of compound (S)-L11 was dissolved in 50mL of dichloromethane, 7.8mL of morpholine was added, and 2mL of bromine was added, and stirred at room temperature for 10 hours. 50mL of 2M hydrochloric acid was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, the organic phases were washed once with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated, and separated by column chromatography to obtain 7g of compound (S)-L14, with a yield of 85%.

[0202] Results characterization data:

[0203] 1 H NMR: (400MHz, Chloroform-d) δ7.66(s,2H),7.48–7.29(m,10H),5.23(s,2H),2.4 3(dq,J=15.0,7.5Hz,2H),2.24(dq,J=14.9,7.5Hz,2H),0.74(t,J=7.5Hz,6H)ppm.

[0204] 13 C NMR: (101MHz, Chloroform-d) δ151.9,143.2,140.6,140.4,137.7,129.4,128.3,127.2,121.7,81.4,24.4,14.3ppm.

[0205] HRMS(ESI)m / z calcd for C 28 H 24 Br2O2[MH] - :m / z 551.0044 found:551.0049.

[0206] Mp:286-287℃.

[0207] The enantiomer (R)-L15 was obtained by replacing the raw material compound (S)-L11 with its enantiomer compound (R)-L11 according to the above steps.

[0208] Example 15. Preparation of Compound (S)-L15

[0209] The reaction equation is as follows:

[0210]

[0211] To a 250mL three-necked flask, 4.2g of compound (S)-21 and 50mL of anhydrous tetrahydrofuran were added. Under argon protection, the liquid nitrogen-acetone system was cooled to -78°C, naturally warmed to room temperature and maintained for 1 hour, and then cooled to -78°C again. 7.6g of N-fluorobisbenzenesulfonamide was dissolved in 50mL of anhydrous tetrahydrofuran and added dropwise to the above system at -78°C. After the addition, the temperature naturally rose to room temperature and the stirring was continued for 12 hours. Water was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product.

[0212] The crude product of the previous step was dissolved in 30 mL of anhydrous dichloromethane, cooled in an ice bath and stirred for 10 minutes. 2.9 mL of boron tribromide was dissolved in 15 mL of dichloromethane and slowly added dropwise to the above system. After the addition, the temperature was naturally raised and continued to stir at room temperature for 12 hours. Saturated ammonium chloride solution was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the organic phases were washed once with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue, which was separated by column chromatography to obtain 3.5 g of compound (S)-L15 with a total yield of 81% in three steps.

[0213] Results characterization data:

[0214] 1 H NMR: (400MHz, Chloroform-d) δ7.66(s,2H),7.48–7.29(m,10H),5.23(s,2H),2.4 3(dq,J=15.0,7.5Hz,2H),2.24(dq,J=14.9,7.5Hz,2H),0.74(t,J=7.5Hz,6H)ppm.

[0215] 13 C NMR: (101MHz, Chloroform-d) δ151.9,143.2,140.6,140.4,137.7,129.4,128.3,127.2,121.7,81.4,24.4,14.3ppm.

[0216] 19 F NMR: (282MHz, Chloroform-d) δ-113.49ppm.

[0217] HRMS(ESI)m / z calcd for C 28 H24 F2O2[MH] - :m / z 429.1666 found:429.1660.

[0218] Mp:211-212℃.

[0219] The enantiomer (R)-L15 was obtained by replacing the starting compound (S)-21 with its enantiomer (R)-21 according to the above steps.

[0220] Example 16: Application of the axially chiral biphenol of the present invention as a chiral ligand

[0221] The axial chiral biphenol of the present invention is used as a ligand of tetraisopropyl titanate to study the asymmetric addition reaction of aldehyde and diethyl zinc.

[0222] The reaction equation is as follows:

[0223]

[0224] The dry 10mL Schlenk tube equipped with a magnetic stirring bar is cooled to room temperature. (S)-L2 (0.02mmol, 4.8mg) is added to the flask, vacuumized and backfilled with argon five times. Then dry toluene (1mL) and Ti (O-iPr) 4 (0.32mmol, 95μL) are added by syringe subsequently. The mixture is stirred at room temperature for about 10 minutes. Then, ZnEt2 hexane solution (0.6mL, 1M) is added dropwise by syringe at room temperature. After the addition is completed, the mixture is stirred at room temperature for about 10 minutes. The mixture is cooled to -3 ° C and the toluene (1mL) solution of aldehyde (0.2mmol) is added dropwise by syringe. The reaction is stirred at -3 ° C for 10 hours, then the 1N HCl aqueous solution (2mL) is added to quench the reaction and the mixture is stirred at room temperature for 0.5 hour. The mixture is extracted with EtOAc, and the combined organic layer is washed with water, brine, through Na2SO4 drying, filtered and concentrated. The residue was purified by column chromatography (eluent: PE:EtOAc=10:1) to give the desired chiral alcohol.

[0225] The reaction data of using (S)-L1~(S)-L11 and (S)-BINOL as chiral ligands in the asymmetric addition reaction of benzaldehyde and diethylzinc are shown in Table 1.

[0226] Table 1 Data of the asymmetric addition reaction of benzaldehyde with diethylzinc in the presence of axially chiral biphenyl diphenol ligands

[0227]

[0228] It can be seen from the data in Table 1 that the above asymmetric addition reaction shows high reactivity and enantioselectivity in the presence of axial chiral diphenol ligands, among which (S)-L2, (S)-L5, and (S)-L8 have good reaction effects (numbers 5, 8, and 13 in the table). Among them, (S)-L2 (number 13) has the best effect. And compared with (S)-BINOL under the same conditions, it is found that the effect is better than (S)-BINOL. The catalytic effect of the R-configuration compound is basically the same as that of the S-configuration.

[0229] In the asymmetric addition reaction of aldehyde and diethylzinc, the present invention replaces benzaldehyde with an aldehyde compound shown in Formula 22, and examines its reaction effect with diethylzinc. The reaction equation is as follows:

[0230]

[0231] Reaction effect Figure 3 shown.

[0232] Depend on Figure 3 The data in the figure show that the overall yield of the reaction is high, between 84% and 99%, and it can maintain a high enantioselectivity, with the ee value up to 95%. The reaction system shows a high tolerance for functional groups, and a variety of substrates containing substituents can proceed smoothly. Moreover, when the reaction conditions are not ideal, the ligand can be adjusted to achieve the purpose of regulating the reaction effect, demonstrating the controllability of such ligands.

[0233] Example 17: Application of the axially chiral biphenol of the present invention as a chiral ligand

[0234] The axial chiral biphenol of the present invention is used as a ligand of tetraisopropyl titanate to study the asymmetric addition reaction of aldehydes and terminal alkynes.

[0235] The reaction equation is as follows:

[0236]

[0237] A dry 10mL Schlenk tube equipped with a magnetic stirring bar was cooled to room temperature. (S)-L5 (0.1mmol, 37mg) was added to the flask and vacuumed and backfilled with argon five times. Then dry DCM (1mL) and Ti (O-iPr) 4 (0.125mmol, 37μL) were added by syringe. The mixture was stirred at room temperature for about 15 minutes to prepare a titanium complex. Alkynes (1.25mmol) were added to another dry Schlenk tube, vacuumed and backfilled with argon five times. Then a toluene solution of 1M ZnMe2 (1mmol, 1mL) was added by syringe at 0°C while continuing to stir for 15 minutes. The titanium complex was added by syringe and the homogeneous solution was stirred at 0°C for 15 minutes. A solution of aldehydes (0.5mmol) in DCM (1mL) was added, the mixture was stirred at 0°C for 36 hours, and then 1N HCl aqueous solution (2mL) was added to quench the reaction and the stirred mixture was placed at room temperature for 0.5 hours. The mixture was extracted with DCM, and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent: PE:EtOAc=10:1) to give the desired chiral propargyl alcohol.

[0238] The reaction data using (S)-L1~(S)-L11 and (R)-BINOL as chiral ligands in the asymmetric addition reaction of benzaldehyde and phenylacetylene are shown in Table 2.

[0239] Table 2 Data of asymmetric addition reaction of benzaldehyde and phenylacetylene in the presence of axially chiral biphenyl diphenol ligand

[0240]

[0241]

[0242] It can be seen from the data in Table 2 that the above asymmetric addition reaction showed high reactivity and enantioselectivity in the presence of axial chiral diphenol ligands, among which (S)-L2, (S)-L5, and (S)-L8 had good reaction effects (numbers 2, 5, and 8 in the table), and (S)-L5 (number 5) had the best effect. And compared with (S)-BINOL under the same conditions, it was found that the effect was better than (S)-BINOL. The catalytic effect of the R-configuration compound is basically the same as that of the S-configuration.

[0243] In the asymmetric addition reaction of aldehyde and terminal alkyne, the present invention replaces benzaldehyde with an aldehyde compound shown in Formula 22, and replaces the terminal alkyne with an alkyne shown in Formula 24, and investigates their reaction effects. The reaction equation, various raw materials and reaction results are shown below:

[0244] The reaction results show that the overall yield of the reaction is high, between 79% and 96%, and it can maintain a high enantioselectivity, with the ee value reaching more than 99%. The reaction system shows a high tolerance for functional groups, and a variety of substrates containing substituents can proceed smoothly. Moreover, when the reaction conditions are not ideal, the ligand can be adjusted to achieve the purpose of regulating the reaction effect, demonstrating the controllability of such ligands.

[0245]

Claims

1. Application of multi-substituted axial chiral biphenol compounds as chiral ligands in asymmetric addition reactions; The asymmetric addition reaction is an asymmetric reaction between an aldehyde compound and an alkyl zinc or an asymmetric reaction between an aldehyde compound and a terminal alkyne; The structural formula of the multi-substituted axial chiral biphenol compound is as shown in Formula I or Formula II. In the formula, R 1 , R 2 and R 3 Independently selected from hydrogen, alkyl groups having 1 to 4 carbon atoms, aryl groups, halogen groups, nitro groups, ether groups, sulfonyl groups, phosphinoyl groups, amine groups, amide groups and ester groups; R 4 It is selected from an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 2 carbon atoms substituted with a halogen, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 3 to 8 carbon atoms, an aryl group, a halogen group, a nitro group, an ether group, a sulfonyl group, a phosphinoyl group, an amine group, an amide group and an ester group.

2. The use according to claim 1, characterized in that: The structural formula of the multi-substituted axial chiral biphenol compound is as shown in Formula Ⅰ-1 or Formula Ⅱ-1, In the formula, R 4 It is selected from an alkyl group having 1 to 4 carbon atoms or an alkyl group substituted with a halogen.

3. The use according to claim 1, characterized in that: The structural formula of the multi-substituted axial chiral biphenol compound is as shown in Formula I-2 or Formula II-2. In the formula, R 3 is selected from halogen; R 4 It is selected from alkyl groups having 1 to 4 carbon atoms.

4. The use according to claim 1, characterized in that: The structural formula of the multi-substituted axial chiral biphenol compound is as shown in Formula I-3 or Formula II-3, In the formula, R 3 is selected from alkyl and aryl groups having 1 to 4 carbon atoms; R 4 It is an alkyl group having 1 to 4 carbon atoms.

5. The use according to claim 1, characterized in that: The structural formula of the multi-substituted axial chiral biphenol compound is as shown in Formula I-4 or Formula II-4, In the formula, R 4 It is an ester group.

6. The use according to claim 1, characterized in that: The structural formula of the multi-substituted axial chiral biphenol compound is as shown in Formula I-5 or Formula II-5, In the formula, R 1 is halogen; R 3 is an aryl group; R 4 It is an alkyl group having 1 to 4 carbon atoms.

7. The use according to any one of claims 1 to 6, characterized in that: The catalyst used in the asymmetric reaction between the aldehyde compound and the alkyl zinc is tetraisopropyl titanate; In the asymmetric reaction, the alkyl zinc is diethyl zinc; The structural formulas of the aldehyde compounds are shown in Formula 1 to Formula 4; In the formula, R1 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl having 1 to 2 carbon atoms or halogen-substituted alkyl, or alkoxy having 1 to 2 carbon atoms; R2 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl or halogen-substituted alkyl having 1 to 2 carbon atoms, or alkoxy having 1 to 2 carbon atoms; R3 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl having 1 to 2 carbon atoms or halogen-substituted alkyl, or alkoxy having 1 to 2 carbon atoms.

8. The use according to claim 7, characterized in that: The catalyst used in the asymmetric reaction between the aldehyde compound and the terminal alkyne is tetraisopropyl titanate; In the asymmetric reaction, the terminal alkyne is phenylacetylene or substituted phenylacetylene, and the substituent is a halogen, an aryl, an alkoxy group having 1 to 2 carbon atoms, an alkyl group having 1 to 2 carbon atoms, or a halogen-substituted alkyl group; The structural formula of the aldehyde compound is shown in Formula 1, Formula 2, Formula 4 or Formula 5; In the formula, R1 represents one or more substituents on the benzene ring, which are hydrogen, halogen, cyano, nitro, alkyl having 1 to 2 carbon atoms or halogen-substituted alkyl, or alkoxy having 1 to 2 carbon atoms; R3 represents one or more substituents on the benzene ring, which are hydrogen, cyano, nitro, an alkyl group having 1 carbon atom or a halogen-substituted alkyl group, or an alkoxy group having 1 carbon atom; R4 represents one or more substituents on the benzene ring, which are hydrogen, cyano, nitro, an alkyl group having 1 carbon atom or a halogen-substituted alkyl group, or an alkoxy group having 1 carbon atom.

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