Phosphin oxazoline ligands, methods for their preparation and use in asymmetric reactions

Abstract

This invention belongs to the field of organic ligand technology, and specifically discloses a phosphoxazolin ligand having the structure shown in general formula I or general formula II, or its tautomers, enantiomers and diastereomers: , R 1 Selected from hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl; R 2 Selected from hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl; R 3 Selected from alkyl, cycloalkyl, alkenyl, and aryl; R 4 Selected from alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; R 5 Selected from hydrogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; R 6 The substituents are selected from hydrogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; n and m are the number of substituents, where n+m≤5. This invention also discloses a method for preparing phosphosoxazoline ligands and their application in catalytic allylation, bicyclization, intermolecular desymmetry, or intramolecular condensation reactions of nitrile derivatives.

Description

Technical Field

[0001] This invention belongs to the field of organic ligand technology, specifically relating to a phosphoxazolin ligand, its preparation method, and its application in asymmetric reactions. Background Technology

[0002] Phox ligands, as chiral N,P bidentate dominant ligands, have found wide application in transition metal-catalyzed asymmetric reactions. Examples include allylic alkylation and amination, Heck reaction, DA reaction, [3+2] dipolar cycloaddition, ruthenium-catalyzed transfer hydrogenation, and iridium-catalyzed hydrogenation (Kadunce, NT; Reisman, SE). J. Am. Chem. Soc. 2015, 137 (33), 10480 10483; Marchese, AD; Glorius, F.; et al. Lautens, M. ACS Catal. 2020, 10 (8), 4780 4785; Shao, W.; Besnard, C.; Guénée, L.; Mazet, C. Chem. Soc. 2020, 142 (38), 16486 16492. Jèssica, M.; Maria, B.; Montserrat, D.; et al. Coordination Chemistry Reviews 2021, 446 , 214120; Bae, J, Cho, EJ ACS Catal. 2023, 13 , 13540 13560.). Although reported for over 30 years, Phox ligands continue to be successfully applied in novel asymmetric catalytic reaction modes. Based on the oxazoline substituents, Phox ligands can be classified into three types: (1) monosubstituted; (2) trans-disubstituted; and (3) cis-disubstituted. Synthetic methods for common monosubstituted and trans-disubstituted chiral Phox ligands are well-developed (Dawson, GJ; Frost, CG; Williams, JM; Coote, SJ Tetrahedron Lett. 1993, 34, 3149). 3150; Frölander, A.;Lutsenko, S.; Privalov, T.; Moberg, C. J. Org. Chem. 2005, 70 , 9882 9891;Behenna, DC; Stoltz, BM The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126 , 15044 15045.). However, the synthesis of cis-disubstituted ligands remains difficult. There are two main types of cis-disubstituted ligands: one is a cis-cyclic disubstituted ligand derived from chiral indaninol, and the other is a cis-diaryl substituted ligand. There are two main challenges: (1) the indan ring or the diaryl substituent containing a sterically hindered substituent is on the same side, and the steric hindrance effect leads to a low yield of chiral oxazoline synthesis. Existing routes cannot efficiently modify the substituents on the aryl group; (2) since the H at the α-position of the imine and the benzylic position of the aryl group has a certain acidity and a repulsive effect on the diaryl group being on the same side, existing synthetic methods will cause H to undergo epimerization very easily in the CP formation reaction. Existing methods for synthesizing Phox ligands involve either coupling reactions, nucleophilic substitution of aryl fluorides with phosphine anions, or nucleophilic substitution of phosphine chlorides with metallization of the C-Br bond in CP bond formation reactions. These reactions typically occur in highly basic reaction systems, making it extremely difficult to prevent epimerization of the products. To date, efficient synthetic methods for cis-substituted Phox ligands remain lacking, necessitating the development of highly efficient synthetic routes to address the challenges in synthesizing these ligands. Summary of the Invention

[0003] The purpose of this invention is to address the aforementioned shortcomings of the prior art by providing a phosphoxazolin ligand, its preparation method, and its application in asymmetric reactions. Addressing the challenges of synthesizing cis-Phox ligands, this invention focuses on resolving the issues of sterically hindered indanamine alcohol condensation cyclization and the tendency for epimerization of cis-diaryl-substituted oxazolins during the CP bond construction step.

[0004] To achieve the above objectives, the present invention adopts the following technical solution: The first objective of this invention is to provide a phosphoxazolin ligand having the structure shown in general formula I or general formula II, or its chemical tautomers, enantiomers, and diastereomers: , , R 1 Selected from hydrogen, alkyl, perfluoroalkyl, alkoxy, and aryl; R 2 Selected from hydrogen, alkyl, perfluoroalkyl, alkoxy, and aryl; R 3 Selected from alkyl, cycloalkyl, alkenyl, and aryl groups; R 4 Selected from alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; R 5 Selected from hydrogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; R 6 Selected from hydrogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; n and m are the number of substituents, where n+m ≤ 5.

[0005] Furthermore, the compound represented by general formula I is selected from one of the following structures: , , , , , , , , , , , , , , , ; Where Me is methyl, OMe is methoxy, and Cy is cyclohexyl. i Pr is isopropyl. t Bu is tert-butyl, Ph is phenyl, and Ad is 1-adamantyl.

[0006] Furthermore, the compound represented by general formula II is selected from one of the following structures: , , , , , , , , , , , , , , ; Where Me stands for methyl and OMe stands for methoxy. t Bu is tert-butyl, and Ph is phenyl.

[0007] A second objective of this invention is to provide a method for preparing the phosphoxazolin ligand represented by general formula I, characterized by comprising the following steps: ; Compound S-1 and compound S-2 react to give intermediate S-3; Intermediate S-3 reacts with Meerwein salt to give compound S-4; Compound S-5 and compound S-6 react to give intermediate S-7; Intermediate S-7 hydrolyzes the lactam protecting group under alkaline conditions to give compound S-8; Compound S-4 and compound S-8 react to give intermediate S-9; Intermediate S-9 is coupled with phosphine hydrogen compounds with different substituents to obtain phosphoxazoline ligands represented by general formula I; R 1 R 2 R 3 R 4 As defined in claim 1, Pd is palladium, a catalyst precursor; Cu is copper, a catalyst precursor; Ligand is a ligand; solvent is an organic solvent; and additive is an additive.

[0008] Furthermore, with R 1 R 2 Starting from substituted o-bromo or o-iodobenzoic acid compounds (S-1), acyl chlorides (S-2) are prepared under the action of oxalyl chloride. These acyl chlorides then react with ammonia to give an amide compound (S-3), which is finally reacted with Meerwein salt to give imine tetrafluoroborate (S-4). Using compound S-5 as a starting material, it is coupled with S-6 to give compound S-7. Finally, the lactam protecting group is hydrolyzed under alkaline conditions to give a chiral indamine alcohol compound (S-8). The synthesized compound S-4 is reacted with compound S-8 to synthesize compound S-9, which is then coupled with phosphine hydrogen compounds with different substituents to obtain the phosphonoxazoline ligand represented by general formula I.

[0009] Furthermore, the catalyst precursor copper is a monovalent copper salt or its hydrate, wherein the monovalent copper salt is selected from at least one of CuOAc, CuBr, CuI, and CuOTf.

[0010] Furthermore, the catalyst precursor palladium is selected from at least one of Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(PPh3)4, or their hydrates.

[0011] Furthermore, the organic solvent is selected from at least one of toluene, diethyl ether, 1,4-dioxane, tetrahydrofuran, dichloromethane, ethanol, and water.

[0012] Furthermore, the additive is selected from at least one of N,N-dimethylformamide, cesium carbonate, potassium carbonate, and water.

[0013] A third objective of this invention is to provide a method for preparing the phosphoxazolin ligand represented by general formula II, characterized by comprising the following steps: ; Compound S-4 and compound S-11 react to give intermediate S-12; Intermediate S-12 and compound S-13 react to give the phosphonoxazoline ligand represented by general formula II; R 1 R 2 R 3 R 4 R 5 R 6 As defined in claim 1, n and m are the number of substituents, where n+m ≤ 5, Pd is the catalyst precursor palladium, Cu is the catalyst precursor copper, Ligand is the ligand, solvent is the organic solvent, and additive is the additive.

[0014] Further, S-4 reacts with the chiral amino alcohol S-11 to generate the chiral oxazoline S-12; under the catalysis of the catalyst precursor, the chiral oxazoline and phosphine hydrogen (S-10) or borane-protected phosphine hydrogen (S-13) undergo a reverse coupling reaction to obtain the phosphoxazoline ligand represented by general formula II.

[0015] The preparation method of compound S-11 includes the following steps: .

[0016] Furthermore, the catalyst precursor copper is a monovalent copper salt or its hydrate, wherein the monovalent copper salt is selected from at least one of CuOAc, CuBr, CuI, and CuOTf.

[0017] Furthermore, the catalyst precursor palladium is selected from at least one of Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(PPh3)4, or their hydrates.

[0018] Furthermore, the organic solvent is selected from at least one of toluene, diethyl ether, 1,4-dioxane, tetrahydrofuran, dichloromethane, ethanol, and water.

[0019] Furthermore, the reaction base includes DABCO, triethylamine, diisopropylethylamine, Cs2CO3, K2CO3, Na2CO3, KHCO3, and NaHCO3.

[0020] Furthermore, the reaction temperature is 25 ℃ to 110 ℃; the reaction time is 1 h to 48 h.

[0021] A fourth object of the present invention is to provide a chiral catalytic composition comprising a transition metal salt and the phosphoxazolin ligand.

[0022] Furthermore, the molar ratio of the transition metal salt to the phosphonoxazolin ligand is 1:1.1~3.3.

[0023] Furthermore, the transition metal salt is selected from at least one of Ni(OTs)2, Ni(OTf)2, Ni(cod)2, Pd(OAc)2, Pd2(dba)3, Pd(MeCN)2Cl2, Cu(MeCN)4OTf, and Cu(OTs)2.

[0024] A fourth objective of this invention is to provide the application of the chiral catalytic composition in catalyzing asymmetric reactions of nitrile derivatives, wherein the asymmetric reaction is any one of allylation, bicyclization, intermolecular desymmetry, or intramolecular condensation.

[0025] As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2... pentyl, isopentyl, neopentyl, hexyl, 2 Heji, 3 Heji, 3 Methylpentyl.

[0026] As used herein, "alkoxy group" refers to -O- (alkyl) and -O- (cycloalkyl), wherein alkyl and cycloalkyl are defined as described herein, wherein the alkyl group contains 1 to 20 carbon atoms, and the cycloalkyl group contains 3 to 8 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups typically have 1 to 7 carbon atoms connected by oxygen bridges.

[0027] As used in this article, "aryl" refers to a 6-membered carbon-ring aromatic ring, such as benzene; a bicyclic system in which at least one ring is both carbon-ringed and aromatic, such as naphthalene, indene, and 1,2,3,4-tetrahydronaphthalene; and a tricyclic system.

[0028] Compared with existing technologies, the beneficial effects of the technical solution provided by this invention are as follows: (1) The phosphoxazolin ligands provided by the present invention can effectively catalyze asymmetric reactions of nitrile derivatives to generate specific enantiomers or diastereomers, improve the enantiomeric excess (ee) or stereoselectivity of chiral products, thereby achieving precise chiral control.

[0029] (2) The phosphoxazolin ligands provided by the present invention are suitable for a variety of reactions such as allylation, bicyclization, intermolecular desymmetry and intramolecular condensation of nitrile derivatives. They can play a catalytic role in different substrate systems, which significantly broadens the application range of asymmetric reactions.

[0030] (3) This invention uses an imine salt intermediate to solve the problem of low condensation efficiency of o-bromobenzyl nitrile or o-bromobenzoic acid with cis-chiral amino alcohols in traditional methods. By regulating the base, the epimerization problem is solved by using palladium-catalyzed CP coupling reaction.

[0031] (4) The phosphoxazolin ligand provided by the present invention provides mild reaction conditions and simple operation in the catalytic asymmetric reaction of nitrile derivatives, which can significantly improve the yield and reaction rate, reduce the generation of side reactions, and improve the utilization rate of raw materials.

[0032] (5) The phosphoxazolin ligands provided by the present invention can be used to synthesize drug intermediates, functional material precursors, and provide an efficient preparation method for high-value-added chiral compounds for pharmaceuticals, materials chemistry and fine chemicals. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the specific embodiments of this invention are described in further detail below. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0034] The compounds in this invention are named systematically according to the "Nomenclature Principles of Organic Compounds" of the Chinese Chemical Society, maintaining the priority order of functional groups. Alkyne groups are expressed using the standard notation "prop-2-yn-1-yl". The positions of substituents on the benzene ring are indicated using the ortho / meta / para notation. Complex substituents are named by sequentially expanding the substituent chain priority. Methyl is abbreviated as Me, methoxy as OMe, ethyl as Et, ethoxy as Oet, and isopropyl as... i Pr, tert-butyl is abbreviated as t Bu, phenyl is abbreviated as Ph, 1-adamantyl is abbreviated as Ad, and cyclohexyl is abbreviated as Cy.

[0035] The enantiomeric excess (ee) in this invention was determined by high performance liquid chromatography (HPLC) using chiral columns AD-H or OD, with hexane / isopropanol = 95:5, 1.0 mL / min, wavelength = 254 nm, Chiralpak AD-H column (4.6 mm x 250 mm), tr (minor) = 12.0 min, tr (major) = 17.8 min; and with hexane / isopropanol = 95:5, 1.0 mL / min, wavelength = 254 nm, Chiralcel OD-H column (4.6 mm x 250 mm), tr (major) = 5.2 min, tr (minor) = 5.9 min.

[0036] The starting compound S-6 used in the preparation of general formula I in this embodiment of the invention includes: phenylboronic acid, , , , , All of them are commercially available.

[0037] The specific preparation method of the starting material compound S-11 used in the preparation of general formula II in this embodiment of the invention is as follows: ; In a reaction flask, substituted benzaldehyde 1 (10 mmol, 1.0 equiv), thiazole salt (15 mmol, 1.5 equiv), EtOH (30 mL), and triethylamine (1.5 mmol, 1.5 equiv) were added, and the reaction was carried out overnight at 80 °C. After the reaction was complete, an appropriate amount of water was added to the filtrate, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed from the filtrate using a rotary evaporator. The crude product was subjected to silica gel column chromatography to give a white solid 2.

[0038] Compound 2 obtained above was dissolved in DCM (20 mL), and DMP oxidant (1.5 equiv) was added at 0 °C. The reaction was carried out at room temperature for 2 h. After the reaction was completed, an appropriate amount of water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed from the filtrate using a rotary evaporator. The crude product was subjected to silica gel column chromatography to obtain a white solid 3.

[0039] Under an argon atmosphere, compound 3, Ru catalyst (20 mol%), triethylamine (2.0 equiv), and formic acid (0.2 M) were weighed into a dry, sealed tube and reacted at 45 °C for 48 h. After the reaction was complete, an appropriate amount of water was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed from the filtrate using a rotary evaporator. The crude product was purified by silica gel column chromatography to obtain a white solid 4.

[0040] Under an argon atmosphere, compound 4, triethylamine (1.5 equiv), and DCM (0.2 M) were placed in a dry, sealed tube, and SOCl2 (1.5 equiv) was slowly added dropwise at 0 °C for 2 h. After the reaction was complete, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed from the filtrate using a rotary evaporator. The crude product was purified by silica gel column chromatography to give a white solid 5.

[0041] Compound 4 was dissolved in THF (0.2 M) under an argon atmosphere. Lithium aluminum hydride (2 equiv) was slowly added at 0 °C, and the reaction was carried out at room temperature for 2 h. After adding an appropriate amount of water, the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The solvent in the filtrate was removed by rotary evaporation to obtain crude product 6. Crude product 6 was recrystallized to give compound S-11 with an enantioselectivity greater than 99%.

[0042] Example 1 Synthetic route of ligand Ia:

[0043] Under an argon atmosphere, 2.01 g (10 mmol) of o-bromobenzamide (S-3a, CAS: 4001-73-4) and 2.27 g (12 mmol) of boron triethoxytetrafluoroethylene were weighed into a 150 mL dry Schlenk tube. 20 mL of anhydrous dichloromethane was injected using a syringe, and the reaction was stirred at 40 °C for 10 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was washed with anhydrous diethyl ether (20 mL × 2) to give 2.99 g of white solid imine tetrafluoroborate (S-4a), with a yield of 95%.

[0044] Under an argon atmosphere, compounds S-5a (2.53 g, 10 mmol), phenylboronic acid (S-6a) (1.46 g, 12 mmol), Pd(PPh3)4 (0.23 g, 0.2 mmol), and cesium carbonate (4.89 g, 15 mmol) were weighed into a 200 mL Schlenk tube. Deoxygenated tetrahydrofuran (45 mL) and water (15 mL) were injected using a syringe, and the mixture was stirred at 90 °C for 12 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth. The filtrate was then extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed from the filtrate using a rotary evaporator. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 4:1~1:1) to give 2.18 g of a pale yellow solid S-7a, with a yield of 87%.

[0045] Under an argon atmosphere, the compound S-7a (2.18 g, 8.7 mmol) obtained above was dissolved in THF (15 mL), followed by the addition of ethanol (15 mL), water (15 mL), and potassium hydroxide (1.95 g, 35 mmol). The mixture was stirred at 80 °C for 24 hours. After the reaction was complete, an appropriate amount of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed from the filtrate using a rotary evaporator. The crude product S-8a was obtained, which was directly used in the next step without purification.

[0046] Under an argon atmosphere, compound S-8a (2.99 g, 9.5 mmol) was weighed into a 250 mL dry sealed tube. The crude product 1f obtained above was dissolved in dichloromethane (20 mL) and injected into the reaction system. The reaction was carried out at 70 °C for 36 hours. After the reaction was completed, an appropriate amount of water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed from the filtrate using a rotary evaporator. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 20:1~10:1) to give 2.50 g of white solid S-9a, with an overall yield of 74% for both steps.

[0047] Under an argon atmosphere, cuprous iodide (70 mg, 0.37 mmol), N,N'-dimethylethylenediamine (163 mg, 1.85 mmol), and diphenylphosphine hydrogen (1.65 g, 8.88 mmol) were weighed into a 100 mL dry sealed tube, and 5 mL of toluene was added. The mixture was stirred at room temperature for 30 minutes. Finally, compound S-9a (2.50 g, 7.4 mmol), cesium carbonate (3.62 g, 11.1 mmol), and 30 mL of toluene were added to the reaction system, and the reaction was carried out at 110 °C for 24 hours. After the reaction was completed and cooled to room temperature, the reaction solution was directly loaded onto the sample using a wet method and rapidly separated by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1~10:1) to give 2.79 g of white solid Ia, with a yield of 76%.

[0048] Ia (3a S ,8a R )-2-(2-(diphenylphosphino)phenyl)-5-phenyl-3a,8a-dihydro-8H-inden[1,2- d Oxazole (Ia): White solid (2.79 g, 76% yield) R f = 0.5 (PE : EA = 10 : 1). [α]25 D = –290.0( c 1.0, CHCl3). 1 H NMR(400 MHz, CDCl3) δ 7.99 – 7.90 (m, 1H), 7.64 – 7.56 (m,2H), 7.52 – 7.44 (m, 4H), 7.42 – 7.26 (m, 9H), 7.25 – 7.20 (m, 2H), 7.20 –7.14 (m, 2H), 7.12 – 7.05 (m, 1H), 6.94 – 6.82 (m, 1H), 5.65 (d, J = 7.9 Hz,1H), 5.34 – 5.19 (m, 1H), 3.43 – 3.30 (m, 1H), 3.23 – 3.11 (m, 1H). 13C NMR(100MHz, CDCl3) δ 163.80, 163.77, 142.4, 141.1, 140.4, 138.9, 138.8, 138.3,138.2, 137.7, 137.6, 134.5, 134.3, 133.8, 133.7, 133.6, 133.4, 131.9, 131.7,130.5, 130.00, 129.97, 128.7, 128.5, 128.4, 128.3, 128.23, 128.15, 128.0,127.2, 127.1, 125.4, 124.2, 83.3, 77.0, 39.1. 31 P NMR(162 MHz, CDCl3) δ –5.3.HRMS(ESI + ) m / z calc'd for C 34 H 27 NOP [M+H] + : 496.1825, found 496.1823. Example 2 The difference from Example 1 is that S-6a in Example 1 is replaced with an equimolar amount of S-6b, while the rest of the process and conditions are the same as in Example 1.

[0049] S-6b Ib (3a S ,8a R )-5-(3,5-di-tert-butylphenyl)-2-(2-(diphenylphosphino)phenyl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (Ib): White solid (2.72 g, 84% yield) R f = 0.7 (PE : EA = 10 : 1).[α]25 D = –233.1 ( c 1.0, CHCl3). 11H NMR (400 MHz, CDCl3) δ 7.96 – 7.90 (m, 1H), 7.54 – 7.51 (m, 1H), 7.51 – 7.47 (m, 2H), 7.46 – 7.42 (m, 2H), 7.37 – 7.22 (m, 10H), 7.19 – 7.12 (m, 2H), 7.08 – 7.02 (m, 1H), 6.90 – 6.85 (m, 1H), 5.64 (d, J = 7.9 Hz, 1H), 5.31 – 5.24 (m, 1H), 3.44 – 3.33 (m, 1H), 3.23 – 3.13 (m, 1H), 1.45 (s, 18H). 13 13C NMR (100 MHz, CDCl3) δ 164.03, 164.00, 151.1, 142.2, 141.8, 140.7, 138.9, 138.6, 138.4, 138.1, 138.0, 137.6, 137.5, 134.5, 134.3, 133.68, 133.65, 133.4, 132.0, 131.8, 130.5, 130.10, 130.07, 128.7, 128.5, 128.41, 128.36, 128.25, 128.17, 128.0, 127.6, 125.3, 124.6, 121.8, 121.2, 83.4, 77.0, 39.1, 35.0, 31.6. HRMS (ESI + ) m / z calc’d for C 42 H 43 NOP [M+H] + : 608.3077, found 608.3073. Example 3 The difference from Example 1 is that S-6a in Example 1 is replaced with an equimolar amount of S-6c, and the remaining processes and conditions are the same as those in Example 1.

[0050] S-6c I-c (3a S ,8a R )-5-(3,5-bis((3 S ,5 S ,7 S(-adamantane-1-yl)-4-methoxyphenyl)-2-(2-(diphenylphosphino)phenyl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (IC): White solid (3.95 g, 76% yield) R f =0.4 (PE : EA = 10 : 1). [α]25 D = –290.1 ​​( c 1.0, CHCl3). 1 H NMR(400 MHz, CDCl3)δ 7.94 – 7.88 (m, 1H), 7.47 – 7.41 (m, 4H), 7.38 – 7.29 (m, 6H), 7.28 – 7.27(m, 1H), 7.24 – 7.18 (m, 3H), 7.16 – 7.10 (m, 2H), 7.06 – 7.00 (m, 1H), 6.88– 6.82 (m, 1H), 5.61 (d, J = 7.9 Hz, 1H), 5.29 – 5.22 (m, 1H), 3.77 (s, 3H), 3.36 (dd, J = 18.0, 6.8 Hz, 1H), 3.16 (d, J = 17.9 Hz, 1H), 2.27 – 2.19 (m,12H), 2.16 – 2.10 (m, 6H), 1.89 – 1.76 (m, 12H). 13 C NMR (100 MHz, CDCl3) δ163.9, 160.0, 143.8, 142.1, 141.3, 138.9, 138.0, 135.5, 134.5, 134.3, 133.7,133.6, 133.4, 131.7, 130.48, 130.45, 130.0, 128.7, 128.5, 128.4, 128.3,128.2, 128.1, 128.0, 127.2, 125.3, 125.2, 124.2, 83.4, 77.0, 65.8, 42.8,39.1, 38.7, 37.0, 29.4. 31 P NMR(162 MHz, CDCl3) δ –5.3.HRMS(ESI + ) m / z calc'd forC 55 H 57NO2P [M+H] + : 794.4121, found 794.4119. Example 4 The difference from Example 1 is that S-6a in Example 1 is replaced with an equimolar amount of S-6d, while the rest of the process and conditions are the same as in Example 1.

[0051] S-6d Id (3a S ,8a R )-2-(2-(diphenylphosphino)phenyl)-5-(2,4,6-triisopropylphenyl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (Id): White solid (3.30 g, 95% yield) R f = 0.6 (PE : EA = 10 : 1).[α]25 D = –250.1 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 7.77 – 7.68 (m, 1H), 7.25 – 7.15 (m, 13H), 7.06 (d, J = 7.7 Hz, 1H), 6.98 – 6.93 (m, 3H), 6.82 –6.75 (m, 1H), 5.42 (d, J = 7.9 Hz, 1H), 5.13 – 5.05 (m, 1H), 3.24 (dd, J =17.9, 7.0 Hz, 1H), 3.02 – 2.94 (m, 1H), 2.91 – 2.80 (m, 1H), 2.67 – 2.56 (m,1H), 2.53 – 2.45 (m, 1H), 1.25 – 1.21 (m, 6H), 1.03 – 0.97 (m, 12H). 13C NMR(100 MHz, CDCl3) δ 164.3, 147.7, 146.7, 146.5, 141.6, 139.9, 138.9, 138.7,138.0, 137.9, 137.8, 137.0, 134.20, 134.15, 134.0, 133.9, 133.7, 130.4,130.1, 130.0, 128.64, 128.58, 128.5, 128.4, 128.0, 126.9, 124.6, 120.6,120.5, 120.4, 83.6, 77.3, 39.2, 34.3, 30.3, 24.41, 24.35, 24.33, 24.26, 24.15, 24.11. 31 P NMR(162 MHz, CDCl3) δ –6.2.HRMS(ESI + ) m / z calc'd for C 43 H 45 NOP[M+H] + : 622.3233, found 622.3232. Example 5 The difference from Example 1 is that S-6a in Example 1 is replaced with an equimolar amount of S-6e, while the rest of the process and conditions are the same as in Example 1.

[0052] S-6e Ie (3a S ,8a R )-2-(2-(diphenylphosphino)phenyl)-5-(3,3'',5,5''-tetratert-butyl-[1,1':3',1''-terphenyl]-5'-yl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (Ie): White solid (3.27 g, 84% yield) R f = 0.5 (PE : EA = 10 : 1). [α]25 D = –151.4 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.01 – 7.95 (m, 1H), 7.86 (t, J= 1.6 Hz, 1H), 7.82 – 7.76 (m, 2H), 7.65 – 7.58 (m, 7H), 7.56 (d, J = 1.7 Hz, 1H), 7.42 – 7.37 (m, 1H), 7.36 –7.28 (m, 7H), 7.28 – 7.25 (m, 2H), 7.19 – 7.12 (m, 2H), 7.00 – 6.94 (m, 1H),6.94 – 6.87 (m, 1H), 5.73 (d, J = 7.9 Hz, 1H), 5.39 – 5.28 (m, 1H), 3.52 –3.39 (m, 1H), 3.32 – 3.20 (m, 1H), 1.49 (s, 36H). 13 C NMR(100 MHz, CDCl3) δ163.9, 163.8, 151.4, 143.7, 142.5, 142.2, 141.2, 140.9, 139.1, 139.0, 138.8,138.4, 138.3, 137.7, 137.6, 134.7, 134.5, 133.87, 133.85, 133.5, 133.3,131.8, 131.6, 130.6, 130.1, 130.1, 128.7, 128.53, 128.46, 128.4, 128.24,128.17, 128.0, 127.7, 126.1, 125.6, 124.7, 122.1, 121.8, 83.3, 77.4, 39.3, 35.1, 31.7. 31 P NMR(162 MHz, CDCl3) δ –5.0.HRMS(ESI + ) m / z calc'd for C 62 H 67 NOP [M+H] + : 872.4955, found 872.4949. Example 6 The difference from Example 1 is that S-6a in Example 1 is replaced with an equimolar amount of S-6f, while the rest of the process and conditions are the same as in Example 1.

[0053] S-6f If (3a S,8a R )-5-(3',5'-di-tert-butyl-[1,1'-biphenyl]-4-yl)-2-(2-(diphenylphosphino)phenyl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (If): White solid (3.36 g, 80% yield) R f = 0.5 (PE : EA= 10 : 1). [α]25 D = –299.6 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 7.85 –7.78 (m, 1H), 7.62 – 7.54 (m, 4H), 7.43 – 7.37 (m, 5H), 7.25 (td, J = 7.6, 1.4Hz, 1H), 7.22 – 7.16 (m, 6H), 7.15 – 7.10 (m, 3H), 7.09 – 7.04 (m, 2H), 7.03– 6.97 (m, 1H), 6.75 (ddd, J = 7.7, 4.1, 1.4 Hz, 1H), 5.54 (d, J = 7.9 Hz, 1H), 5.22 – 5.15 (m, 1H), 3.32 – 3.23 (m, 1H), 3.11 – 3.02 (m, 1H), 1.33 (s, 18H). 13 C NMR(100 MHz, CDCl3) δ 163.94, 163.80, 153.61, 151.36, 142.4, 141.1,140.6, 138.9, 138.6, 138.3, 138.1, 137.7, 137.6, 134.5, 134.2, 133.8, 133.7,133.6, 133.4, 131.7, 130.5, 130.00, 129.9, 128.5, 128.4, 128.3, 128.23,128.17, 128.0, 127.4, 127.0, 125.6, 124.1, 83.66, 77.2, 39.3, 19.6, 19.3. 31 PNMR(162 MHz, CDCl3) δ –5.3.HRMS(ESI + ) m / z calc'd for C 36H 31 NOP [M+H] + : 524.2138, found 524.2128. Example 7 The difference from Example 1 is that S-8a in Example 1 is replaced with an equimolar amount of S-8g, while the rest of the process and conditions are the same as in Example 1.

[0054] S-8g Ig (3a S ,8a R )-5-((3 S 5 S 7 S )-adamantane-1-yl)-2-(2-(diphenylphosphino)phenyl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (Ig): White solid (2.39 g, 77% yield) R f = 0.5 (PE : EA = 10 :1). [α]25 D = –160.1 ( c 1.0, CHCl3). 1 H NMR(400 MHz, CDCl3) δ 7.80 – 7.71 (m,1H), 7.31 – 7.27 (m, 1H), 7.25 – 7.18 (m, 7H), 7.17 – 7.13 (m, 6H), 6.99 (d, J = 8.0 Hz, 1H), 6.78 – 6.73 (m, 1H), 5.43 (d, J = 8.1 Hz, 1H), 5.14 – 5.07 (m,1H), 3.17 (dd, J = 17.8, 7.1 Hz, 1H), 2.97 – 2.89 (m, 1H), 2.03 – 1.99 (m,3H), 1.84 – 1.81 (m, 6H), 1.72 – 1.67 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 163.9,150.8, 141.5, 138.8, 138.5, 138.1, 138.0, 137.6, 137.5, 136.8, 134.3, 134.1,134.0, 133.8, 133.6, 132.3, 132.1, 130.4, 130.0, 128.6, 128.42, 128.35,128.3, 128.2, 127.9, 125.1, 124.8, 122.0, 83.5, 77.2, 43.4, 39.1, 36.8, 36.2, 29.0. 31 P NMR(162 MHz, CDCl3) δ –6.0.HRMS(ESI + ) m / z calc'd for C 38 H 37 NOP [M+H] + :554.2607, found 554.2609. Example 8 The difference from Example 1 is that S-8a in Example 1 is replaced with an equimolar amount of S-8h, while the rest of the process and conditions are the same as in Example 1.

[0055] S-8h Ih (3a R ,8a S )-5-((3R,5R,7R)-adamantane-1-yl)-2-(2-(diphenylphosphino)phenyl)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole (Ih): white solid (1.92 g, 70% yield). HRMS (ESI) + ) m / z calc'd forC 38 H 37 NOP [M+H] + : 554.2607, found 554.2601. Example 9 The difference from Example 1 is that S-6a in Example 1 is replaced with an equimolar amount of S-6i, and S-7i' is obtained through the following reaction route, while the rest of the process and conditions are the same as in Example 1.

[0056]

[0057] The specific synthetic steps of S-7i' are as follows: Under an argon atmosphere, compound S-7i' (2.17 g, 8.5 mmol) was weighed into a 250 mL dry Schlenk flask, and a palladium / carbon catalyst (0.9 g, 0.85 mmol) was slowly added. The Schlenk flask was connected to a hydrogen balloon via a three-way valve. After purging the flask three times, 30 mL of ethyl acetate was added, and the reaction was carried out at room temperature for 4 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The mixture was then rapidly separated by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1~2:1) to obtain 1.88 g of white solid S-7i', with a yield of 86%.

[0058] Ii (3a S ,8a R )-5-cyclohexyl-2-(2-(diphenylphosphino)phenyl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (Ii): White solid (1.48 g, 65% yield) R f = 0.5 (PE : EA = 10 : 1). [α]25 D = –160.6( c 0.5, CHCl3). 1 H NMR(400 MHz, CDCl3) δ 7.78 – 7.70 (m, 1H), 7.25 – 7.10 (m,12H), 7.06 – 7.01 (m, 1H), 6.99 – 6.90 (m, 2H), 6.78 – 6.69 (m, 1H), 5.45 –5.35 (m, 1H), 5.13 – 5.03 (m, 1H), 3.24 – 3.08 (m, 1H), 2.93 (d, J = 17.8 Hz,1H), 2.44 – 2.28 (m, 1H), 1.83 – 1.70 (m, 4H), 1.69 – 1.62 (m, 1H), 1.36 –1.25 (m, 4H), 1.20 – 1.13 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 163.84, 163.81,147.3, 141.7, 138.8, 138.6, 138.2, 138.1, 137.8, 137.7, 137.0, 134.4, 134.2,133.9, 133.73, 133.66, 132.2, 132.0, 130.4, 130.02, 129.99, 128.6, 128.44,128.37, 128.3, 128.2, 127.9, 127.0, 125.0, 123.9, 83.5, 44.5, 39.1, 34.9, 34.4, 27.0, 26.2. 31 P NMR(162 MHz, CDCl3) δ –5.7.HRMS(ESI + ) m / z calc'd forC 34 H 33 NOP [M+H] + : 502.2294, found 502.2291. Example 10 The difference from Example 1 is that S-3a in Example 1 is replaced with an equimolar amount of S-3j, while the rest of the process and conditions are the same as in Example 1.

[0059] S-3j Ij (3a S ,8a R )-2-(2-(diphenylphosphino)-4,5-dimethylphenyl)-5-phenyl-3a,8a-dihydro-8H-inden[1,2- d Oxazole (Ij): White solid (3.01 g, 80% yield). HRMS (ESI) + ) m / z calc'd for C 36 H 31 NOP[M+H] + : 524.2138, found 524.2128. Example 11 The difference from Example 1 is that S-3a in Example 1 is replaced with an equimolar amount of S-3k, while the rest of the process and conditions are the same as in Example 1.

[0060] S-3k Ik (3aS ,8a R 2-(2-(diphenylphosphino)-4,5-dimethoxyphenyl)-5-phenyl-3a,8a-dihydro-8H-indeno[1,2-d]oxazole (Ik): White solid (2.87 g, 78% yield). HRMS (ESI) + ) m / z calc'd forC 36 H 31 NO3P [M+H] + : 556.2036, found 556.2043. Example 12 The difference from Example 1 is that S-3a in Example 1 is replaced with an equimolar amount of S-3l, and S-6a in Example 1 is replaced with an equimolar amount of S-6b. The rest of the process and conditions are the same as in Example 1.

[0061] S-3l S-6b Il (3a S ,8a R )-5-(3,5-di-tert-butylphenyl)-2-(2-(diphenylphosphino)-4,5-bis(trifluoromethyl)phenyl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (Il): White solid (2.69 g, 71% yield). HRMS (ESI) + ) m / z calc'd for C 44 H 41 F6NOP [M+H] + : 744.2824, found 744.2819. Example 13 The difference from Example 12 is that S-8a in Example 12 is replaced with an equimolar amount of S-8m, and S-6a in Example 1 is replaced with an equimolar amount of S-6b. The rest of the process and conditions are the same as in Example 12.

[0062] S-8m Im (3a R ,8a S )-5-(3,5-di-tert-butylphenyl)-2-(2-(diphenylphosphino)-4,5-bis(trifluoromethyl)phenyl)-3a,8a-dihydro-8H-inden[1,2- dOxazole (Im): White solid (3.17 g, 81% yield). HRMS (ESI) + ) m / z calc'd for C 44 H 41 F6NOP [M+H] + : 744.2824, found 744.2830. Example 14 The difference from Example 12 is that S-10a in Example 12 is replaced with an equimolar amount of S-10e, while the rest of the process and conditions are the same as in Example 12.

[0063] S-10e In (3a S ,8a R )-2-(2-(bis(3,5-dimethylphenyl)phosphino)-4,5-bis(trifluoromethyl)phenyl)-5-(3,5-di-tert-butylphenyl)-3a,8a-dihydro-8H-inden[1,2- d Oxazole (In): White solid (2.03 g, 82% yield). HRMS (ESI) + ) m / z calc'd for C 48 H 49 F6NOP [M+H] + : 800.3450, found 800.3441. Example 15 Synthetic route of ligand II-a:

[0064] Under an argon atmosphere, o-bromophenylimine tetrafluoroborate (S-4a) (1.73 g, 5.0 mmol, 1.0 equiv), S-11a (2.18 g, 5.0 mmol, 1.0 equiv), and 10.0 mL of dichloromethane were added sequentially to a 25 mL sealed tube. The reaction system was sealed and incubated at 70 °C for 24 hours. After the reaction system cooled naturally to ambient temperature, the solvent was removed by vacuum distillation. The crude product was then subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 20:1~10:1) to give 2.56 g of white solid S-12a, with a yield of 85%.

[0065] Under an argon atmosphere, palladium acetate (43.2 mg, 0.18 mmol, 5 mol%), dppf (182.0 mg, 0.26 mmol, 6 mol%), S-12a (2.56 g, 4.25 mmol, 1.0 equiv), diphenylphosphine hydrogen (0.95 g, 5.1 mmol, 1.2 equiv), DABCO (0.95 g, 8.5 mmol, 2.0 equiv), and 0.2 mL of toluene were added sequentially to a 15 mL sealed tube. The reaction system was sealed and incubated at 120 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate (10 mL × 3), and the filtrate was collected. The solvent was removed under reduced pressure, and the target product II-a was obtained by column chromatography.

[0066] II-a (4 S 5 R 4,5-Bis(3,5-di-tert-butylphenyl)-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole (II-a): White solid (2.26 g, 87% yield) R f = 0.4 (PE : EA = 10 : 1). [α]25 D = –61.2( c 0.6, CHCl3). 1 H NMR(400 MHz, CDCl3) δ 8.14 – 8.07 (m, 1H), 7.47 – 7.41 (m,1H), 7.40 – 7.28 (m, 12H), 7.09 – 7.07 (m, 1H), 7.04 – 7.02 (m, 1H), 6.80 –6.76 (m, 2H), 6.71 – 6.68 (m, 2H), 5.64 (d, J = 10.0 Hz, 1H), 5.50 (d, J = 10.0Hz, 1H), 1.11 (s, 36H). 13 C NMR (100 MHz, CDCl3) δ 164.6 (d, J = 1.4 Hz), 149.8 (d, J = 28.3 Hz), 139.5 (d, J = 25.7 Hz), 138.8 (d, J= 13.4 Hz), 138.5 (d, J =11.4 Hz), 137.4, 135.8, 134.6, 134.3 (d, J = 2.0 Hz), 134.0 (d, J = 2.0 Hz), 133.0 (d, J = 22.1 Hz), 130.7, 130.2 (d, J = 3.8 Hz), 128.6, 128.51, 128.48,128.4 (d, J = 1.9 Hz), 122.4 (d, J = 2.2 Hz), 121.5, 121.4, 120.6, 86.5, 74.9, 34.72, 34.70, 31.62, 31.55. 31 P NMR(162 MHz, CDCl3) δ –8.1.HRMS(ESI + ) m / z calc'dfor C 49 H 58 NOP [M+H] + : 708.4329, found: 708.4332. Example 16 The difference from Example 15 is that S-11a in Example 1 is replaced with an equimolar amount of S-11b, while the rest of the process and conditions are the same as in Example 15.

[0067] S-11b II-b (4 R 5 S 4,5-Bis(3,5-di-tert-butylphenyl)-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole (II-b): White solid (2.26 g, 87% yield). HRMS (ESI) + ) m / z calc'd for C 49 H 58 NOP [M+H] + :708.4329, found: 708.4340. Example 17 The difference from Example 15 is that S-11a in Example 1 is replaced with an equimolar amount of S-11c, while the rest of the process and conditions are the same as in Example 15.

[0068] S-11c II-c (4 S 5 R 2-(2-(diphenylphosphino)phenyl)-4,5-di-p-methylphenyl-4,5-dihydrooxazole (II-c): White solid (1.22 g, 63% yield) R f = 0.4 (PE : EA = 5 : 1). [α]25 D = –71.9 ( c 0.4,CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.15 (ddd, J = 7.7, 3.6, 1.5 Hz, 1H), 7.46 –7.30 (m, 12H), 6.97 (ddd, J = 7.8, 4.0, 1.4 Hz, 1H), 6.85 – 6.76 (m, 2H), 6.74– 6.67 (m, 4H), 6.55 – 6.48 (m, 2H), 5.64 (d, J = 10.2 Hz, 1H), 5.53 (d, J =10.2 Hz, 1H), 2.17 (s, 3H), 2.14 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 164.3,137.2, 136.5, 134.6, 134.3, 133.3, 132.0, 131.9, 129.8, 128.53, 128.50,128.0, 127.3, 126.8, 122.2, 86.0, 74.4, 21.22, 21.19.HRMS(ESI + ) m / z calc'd forC 23 H 21 NOBr [M+H] + : 406.0801, found 406.0800. Example 18 The difference from Example 15 is that S-11a in Example 15 is replaced with an equimolar amount of S-11d, while the rest of the process and conditions are the same as in Example 15.

[0069] S-11d II-d (4 S 5 R 2-(2-(diphenylphosphino)phenyl)-4,5-bis(naphthyl-2-yl)-4,5-dihydrooxazole (II-c): White solid (1.94 g, 83% yield) R f = 0.3 (PE : EA = 5 : 1). [α]25 D = –88.7 ( c 0.5, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.22 (ddd, J = 7.7, 3.7, 1.5 Hz, 1H), 7.66 –7.28 (m, 24H), 7.05 (ddd, J = 7.8, 3.9, 1.4 Hz, 1H), 6.87 – 6.78 (m, 1H), 6.72– 6.65 (m, 1H), 5.97 (d, J = 10.2 Hz, 1H), 5.85 (d, J = 10.2 Hz, 1H). 13 C NMR (200MHz, CDCl3) δ 164.6 (d, J = 2.8 Hz), 139.7 (d, J = 26.5 Hz), 138.5 (d, J = 12.9Hz), 138.4 (d, J = 9.6 Hz), 135.5, 134.7, 134.6, 134.2, 133.9 (d, J = 20.2 Hz),132.9, 132.71, 132.70, 132.4, 131.8 (d, J = 20.1 Hz), 131.1, 130.5 (d, J = 3.1Hz), 128.8, 128.68, 128.65, 128.6, 128.5, 128.0 (d, J = 20.5 Hz), 127.6,127.5, 127.1, 126.9, 126.14, 126.05, 125.91, 125.87, 125.5, 125.4, 124.6,85.4, 74.7.31 P NMR(162 MHz, CDCl3) δ –8.4.HRMS(ESI + ) m / z calc'd for C 41 H 31 NOP [M+H] + : 584.2138, found 584.2127. Example 19 The difference from Example 15 is that S-10a in Example 15 is replaced with an equimolar amount of S-10e, and S-11a in Example 15 is replaced with an equimolar amount of S-11e. The rest of the process and conditions are the same as in Example 13.

[0070] S-11e S-10e II-e (4 S 5 R 2-(2-(bis(3,5-dimethylphenyl)phosphino)phenyl)-4,5-diphenyl-4,5-dihydrooxazole (II-e): White solid (2.00 g, 93% yield) R f = 0.2 (PE : EA = 10 : 1). [α]25 D = –80.3( c 0.7, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.17 (ddd, J = 7.6, 3.6, 1.7 Hz, 1H),7.48 – 7.35 (m, 2H), 7.05 – 6.84 (m, 13H), 6.81 – 6.76 (m, 2H), 6.64 – 6.57(m, 2H), 5.69 (d, J = 10.2 Hz, 1H), 5.59 (d, J = 10.2 Hz, 1H), 2.25 (s, 6H), 2.23 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 164.8 (d, J = 3.2 Hz), 140.0 (d, J = 27.2Hz), 138.0, 137.9, 137.8 (d, J= 2.4 Hz), 137.71, 137.67, 137.64, 136.6,134.3, 132.4 (d, J = 21.4 Hz), 131.43 (d, J = 19.3 Hz), 131.39 (d, J = 20.3 Hz),130.8, 130.5, 130.3 (d, J = 2.9 Hz), 130.2, 128.0, 127.9, 127.4 (d, J = 16.3Hz), 127.2, 126.6, 126.5, 85.0, 74.6, 21.4 (d, J = 1.2 Hz). 31 P NMR (162 MHz, CDCl3) δ –5.6.HRMS (ESI + ) m / z calc'd for C 37 H 34 NOP [M+H] + : 540.2451, found540.2467. Example 20 The difference from Example 15 is that S-10a in Example 15 is replaced with an equimolar amount of S-10f, while the rest of the process and conditions are the same as in Example 15.

[0071] S-10f II-f (4 S 5 R 2-(2-(di-p-tolylphosphino)phenyl)-4,5-bis(3,5-dimethylphenyl)-4,5-dihydrooxazole (II-f): white solid (1.79 g, 83% yield) R f = 0.3 (PE : EA = 20 : 1). [α]25 D = –72.9 ( c 0.4, CHCl3). 11H NMR (400 MHz, CDCl3) δ 8.12–8.05 (m, 1H), 7.45–7.32 (m, 2H), 7.28–7.18 (m, 4H), 7.17–7.05 (m, 6H), 7.03 (s, 1H), 6.77 (s, 2H), 6.69 (s, 2H), 5.65 (d, J J = 10.0 Hz, 1H), 5.52 (d, J J = 10.0 Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 1.11 (s, 36H). 13 13C NMR (100 MHz, CDCl3) δ 164.6, 149.7 (d, J J = 28.2 Hz), 140.0 (d, J J = 25.8 Hz), 138.2 (d, J J = 2.0 Hz), 137.3, 135.7, 135.3 (d, J J = 11.7 Hz), 135.1 (d, J J = 10.5 Hz), 134.4, 134.2, 134.1, 134.0, 133.9, 132.8 (d, J J = 22.4 Hz), 130.5, 130.0 (d, J J = 3.7 Hz), 129.23 (d, J J = 5.2 Hz), 129.16 (d, J J = 5.7 Hz), 128.1, 122.3 (d, J J = 2.1 Hz), 121.34, 121.29, 120.4, 86.3, 74.8, 34.60, 34.59, 31.5, 31.4, 21.4. 31 31P NMR (162 MHz, CDCl3) δ –10.0. HRMS (ESI + ) m / z calc’d for C 51 H 62 NOP [M+H] + : 736.4642, found 736.4642. Example 21 The difference from Example 15 is that S-10a in Example 1 is replaced with an equimolar amount of S-10e, while the rest of the process and conditions are the same as in Example 13.

[0072] S-10e II-g (4 S 5 R 2-(2-(bis(3,5-dimethylphenyl)phosphino)phenyl)-4,5-bis(3,5-di-tert-butylphenyl)-4,5-dihydrooxazole (II-g): White solid (2.66 g, 93% yield) R f = 0.2 (PE : EA = 20 : 1).[α]25 D = –105.4 ( c 1.1, CHCl3). 1 H NMR(400 MHz, CDCl3) δ 8.15 – 8.06 (m, 1H),7.48 – 7.35 (m, 2H), 7.13 – 7.07 (m, 2H), 7.06 – 7.02 (m, 1H), 6.99 – 6.93(m, 5H), 6.93 – 6.91 (m, 1H), 6.75 – 6.71 (m, 2H), 6.69 – 6.65 (m, 2H), 5.50(d, J = 10.0 Hz, 1H), 5.42 (d, J = 10.0 Hz, 1H), 2.25 (s, 6H), 2.21 (s, 6H), 1.11 (s, 36H). 13 C NMR (100 MHz, CDCl3) δ 165.3, 149.8 (d, J = 26.1 Hz), 140.0(d, J = 25.8 Hz), 138.2 (d, J = 12.1 Hz), 138.0 (d, J = 11.3 Hz), 137.74, 137.67 (d, J = 1.6 Hz), 137.6, 137.4, 135.7, 134.6, 133.2 (d, J = 22.4 Hz), 132.0 (d, J = 20.9 Hz), 131.8 (d, J= 20.7 Hz), 130.6, 130.4, 130.1 (d, J = 3.9 Hz), 128.2,122.3, 121.5, 121.3, 120.6, 86.6, 74.6, 34.69, 34.68, 31.61, 31.56, 21.5 (d, J = 5.4 Hz). 31 P NMR(162 MHz, CDCl3) δ –7.5.HRMS(ESI + ) m / z calc'd for C 53 H 66 NOP [M+H] + : 764.4955, found 764.4965. Example 22 The difference from Example 15 is that S-10a in Example 15 is replaced with an equimolar amount of S-10h, while the rest of the process and conditions are the same as in Example 15.

[0073] S-10h II-h (4 S 5 R )-2-(2-(bis(3,5-di-tert-butylphenyl)phosphino)phenyl)-4,5-bis(3,5-di-tert-butylphenyl)-4,5-dihydrooxazole (II-h): white solid (3.43 g, 92% yield) R f = 0.5 (PE : EA = 20 : 1).[α]25 D = –88 ( c 0.7, CHCl3). 1 H NMR(400 MHz, CDCl3) δ 8.14 – 8.03 (m, 1H),7.47 – 7.40 (m, 1H), 7.39 – 7.32 (m, 3H), 7.29 – 7.19 (m, 4H), 7.09 – 6.98(m, 3H), 6.70 – 6.61 (m, 4H), 5.33 (d, J = 9.9 Hz, 1H), 5.24 (d, J = 9.9 Hz,1H), 1.24 (s, 18H), 1.21 (s, 18H), 1.10 (s, 36H). 13C NMR (100 MHz, CDCl3) δ165.7 (d, J = 1.4 Hz), 150.3 (d, J = 6.9 Hz), 150.2 (d, J = 7.3 Hz), 149.6 (d, J = 24.0 Hz), 141.2 (d, J = 25.8 Hz), 137.2, 137.10, 137.06, 136.9, 135.6, 133.8(d, J = 2.2 Hz), 132.8 (d, J = 20.0 Hz), 130.2, 129.7 (d, J = 3.3 Hz), 128.8, 128.6 (d, J = 3.2 Hz), 128.4, 127.8, 122.3 (d, J = 5.2 Hz), 122.1, 121.2,120.9, 120.6, 86.2, 74.3, 34.90, 34.88, 34.5 (d, J = 2.7 Hz), 31.49, 31.46, 31.4. 31 P NMR(162 MHz, CDCl3) δ –3.7.HRMS(ESI + ) m / z calc'd for C 65 H 90 NOP [M+H] + :932.6833, found 932.6854. Example 23 The difference from Example 15 is that S-10a in Example 1 is replaced with an equimolar amount of S-10i, while the rest of the process and conditions are the same as in Example 13.

[0074] S-10i II-i (4 S 5 R )-2-(2-(bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino)phenyl)-4,5-bis(3,5-di-tert-butylphenyl)-4,5-dihydrooxazole (II-i): white solid (3.75 g, 89% yield) R f = 0.6 (PE : EA = 20: 1). [α]25 D = –82.7 ( c 0.4, CHCl3). 1 H NMR(400 MHz, CDCl3) δ 8.14 – 8.07 (m,1H), 7.46 – 7.36 (m, 2H), 7.25 – 7.19 (m, 4H), 7.08 – 7.05 (m, 1H), 7.05 –6.99 (m, 2H), 6.72 – 6.63 (m, 4H), 5.38 (d, J = 9.9 Hz, 1H), 5.26 (d, J = 9.9Hz, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 1.33 (s, 18H), 1.30 (s, 18H), 1.10 (s,36H). 13 C NMR(100 MHz, CDCl3) δ 165.7, 160.1 (d, J = 2.9 Hz), 149.6 (d, J = 25.0Hz), 143.2 (d, J = 7.1 Hz), 143.1 (d, J = 7.4 Hz), 141.5 (d, J = 25.6 Hz),137.0, 135.5, 133.5 (d, J = 2.2 Hz), 133.0, 132.8, 132.7, 132.6, 131.6 (d, J =8.4 Hz), 131.5 (d, J = 9.3 Hz), 130.2, 129.8 (d, J = 2.2 Hz), 127.7, 122.1,121.3, 120.8, 120.6, 86.3, 74.4, 64.3 (d, J = 5.9 Hz), 35.8 (d, J = 2.7 Hz),34.6, 34.5, 32.1 (d, J = 3.8 Hz), 31.5, 31.4. 31 P NMR(162 MHz, CDCl3) δ –5.8.HRMS(ESI + ) m / z calc'd for C 67 H 94 NO3P [M+H] + : 992.7044, found 992.7067. Example 24 The difference from Example 22 is that S-3a in Example 22 is replaced with an equimolar amount of S-3j, while the rest of the process and conditions are the same as in Example 22.

[0075] S-3j II-j (4 S 5 R 2-(2-(bis(3,5-di-tert-butylphenyl)phosphino)-4,5-dimethylphenyl)-4,5-bis(3,5-di-tert-butylphenyl)-4,5-dihydrooxazole (II-j): white solid (3.77 g, 81% yield). HRMS (ESI) + ) m / z calc'd for C 67 H 95 NOP [M+H] + : 960.7146, found 960.7159. Example 25 The difference from Example 24 is that S-11a in Example 24 is replaced with an equimolar amount of S-11b, while the rest of the process and conditions are the same as in Example 24.

[0076] S-11b II-k (4 R 5 S 2-(2-(bis(3,5-di-tert-butylphenyl)phosphino)-4,5-dimethylphenyl)-4,5-bis(3,5-di-tert-butylphenyl)-4,5-dihydrooxazole (II-k): white solid (3.12 g, 74% yield). HRMS (ESI) + ) m / z calc'd for C 67 H 95 NOP [M+H] + : 960.7146, found 960.7150. Example 26 The difference from Example 15 is that S-11a in Example 15 is replaced with an equimolar amount of S-11l, while the rest of the process and conditions are the same as in Example 15.

[0077] S-11l II-l (4 S 5 R 4,5-Di(3-(tert-butyl)-5-methylphenyl)-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole (II-l): White solid (2.11 g, 69% yield). HRMS (ESI) + ) m / z calc'd for C 43 H 47 NOP [M+H] + : 624.3390, found 624.3378. Example 27 The difference from Example 15 is that S-11a in Example 15 is replaced with an equimolar amount of S-11m, while the rest of the process and conditions are the same as in Example 15.

[0078] S-11m II-m (4 S 5 R 2-(2-(diphenylphosphino)phenyl)-4,5-bis(2,3,4,5,6-pentamethylphenyl)-4,5-dihydrooxazole (II-m): white solid (2.79 g, 65% yield). HRMS (ESI) + ) m / z calc'd for C 43 H 47 NOP [M+H] + :624.3390, found 624.3393. Example 28 The difference from Example 15 is that Pd(OAc)2 in Example 15 is replaced with an equimolar amount of CuI, and DABCO in Example 15 is replaced with an equimolar amount of CsCO3. The rest of the process and conditions are the same as in Example 15.

[0079] II-n (4 R 5 R )-2-(2-(bis(3,5-di-tert-butylphenyl)phosphino)-4,5-dimethylphenyl)-4,5-bis(3,5-di-tert-butylphenyl)-4,5-dihydrooxazole (II-n): white solid (3.77 g, 81% yield) R f = 0.7 (PE : EA = 20 : 1). 1 H NMR (400 MHz, CDCl3) δ 8.00 – 7.89 (m, 1H), 7.38 – 7.25 (m, 4H), 7.24 – 7.17 (m, 12H), 7.16 – 7.13 (m, 2H), 7.04 – 6.96 (m, 1H), 5.23 (d, J =8.6 Hz, 1H), 5.18 (d, J = 8.6 Hz, 1H), 1.25 (s, 18H), 1.24 (s, 18H). 13 C NMR (100MHz, CDCl3) δ 166.7 (d, J = 1.4 Hz), 150.4 (d, J = 28.3 Hz), 139.5 (d, J = 11.0Hz), 136.8 (d, J = 7.4 Hz), 138.5 (d, J = 11.4 Hz), 129.04, 129.0, 128.98,128.93 128.8, 128.76, 128.73, 128.69, 127.7, 127.3, 127.0, 126.8, 125.2,124.8 (d, J = 2.3 Hz), 123.9, 122.7, 122.4, 121.3, 121.2, 121.1, 86.5, 77.4,35.2, 34.8, 31.8, 31.5. 31 P NMR (162 MHz, CDCl3) δ -12.8.HRMS (ESI + ) m / z calc'dfor C 49 H 59 NOP [M+H] + : 708.4329, found 708.4339. Example 29 The difference from Example 28 is that S-11a in Example 28 is replaced with an equimolar amount of S-11b, while the rest of the process and conditions are the same as in Example 28.

[0080] S-11b II-o (4S 5 S 2-(2-(bis(3,5-di-tert-butylphenyl)phosphino)-4,5-dimethylphenyl)-4,5-bis(3,5-di-tert-butylphenyl)-4,5-dihydrooxazole (II-o): white solid (2.67 g, 71% yield). HRMS (ESI) + ) m / z calc'd for C 49 H 59 NOP [M+H] + : 708.4329, found 708.4325. The ligands of this invention are used to catalyze asymmetric reactions of nitrile derivatives: (1) Intermolecular desymmetry and intramolecular condensation reaction of nitrile derivatives Example 30

[0081] In a glove box, Ni(OTf)₂ (3.7 mg, 0.01 mmol, 10 mol%), Ia (5.9 mg, 0.012 mmol, 12 mol%), and 0.5 mL of toluene were added to a 10 mL sealed tube. The resulting solution was stirred at room temperature for 20 minutes, and then substrate 1a (26.4 mg, 0.1 mmol, 1.0 equivalent), PhB(OH)₂ (2a) (25.3 mg, 0.2 mmol, 2.0 equivalent), and toluene (1.5 mL) were added. After sealing the tube, the glove box was removed and connected to a Schlenk line. Under positive argon pressure, the sealed tube was opened, and H₂O (4.0 μL, 0.2 mmol, 2.0 equivalent) was rapidly added using a microsyringe. After sealing the tube, the mixture was stirred at 50 °C for 48 hours. After cooling the mixture to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (…). R )-3aa, 62% yield, 95% enantioselectivity of ee.

[0082] Example 31 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 was replaced with Ib, while the rest was the same as in Example 30, and the reaction yielded ( R )-3aa, 78% yield, 97% enantioselectivity of ee.

[0083] Example 32 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with Ic, while the rest is the same as in Example 30, and the reaction yields ( R)-3aa, 84% yield, 98% enantioselectivity of ee.

[0084] Example 33 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with Id, while the rest is the same as in Example 30, and the reaction yields ( R )-3aa, 60% yield, 95% enantioselectivity of ee.

[0085] Example 34 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with Ie, while the rest is the same as in Example 30, and the reaction yields ( R )-3aa, 80% yield, 95% enantioselectivity of ee.

[0086] Example 35 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with If, while the rest is the same as in Example 30. The reaction yields ( R )-3aa, 72% yield, 96% enantioselectivity of ee.

[0087] Example 36 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 was replaced with Ig, while the rest was the same as in Example 30, and the reaction yielded ( R )-3aa, 75% yield, 95% ee enantioselectivity.

[0088] Example 37 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 was replaced with Ih, while the rest was the same as in Example 30, and the reaction yielded ( S )-3aa, 75% yield, 95% ee enantioselectivity.

[0089] Example 38 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with Ii, while the rest is the same as in Example 30, and the reaction yields ( R )-3aa, 80% yield, 90% enantioselectivity of ee.

[0090] Example 39 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with Ij, while the rest is the same as in Example 30, and the reaction yields ( R )-3aa, 60% yield, 94% enantioselectivity of ee.

[0091] Example 40 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with Ik, while the rest is the same as in Example 30. The reaction yields ( R )-3aa, 72% yield, 95% enantioselectivity of ee.

[0092] Example 41 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 was replaced with 1l, while the rest was the same as in Example 30, and the reaction yielded ( R )-3aa, 70% yield, 95% enantioselectivity of ee.

[0093] Example 42 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with Im, while the rest is the same as in Example 30. The reaction yields ( S )-3aa, 77% yield, 96% enantioselectivity of ee.

[0094] Example 43 The difference from Example 30 is that the equimolar amount of chiral ligand Ia in Example 30 is replaced with In, while the rest is the same as in Example 30. The reaction yields ( R )-3aa, 75% yield, 95% ee enantioselectivity.

[0095] Example 44 The difference from Example 32 is that the equimolar amount of Ni(OTf)2 in Example 32 was replaced with Pd(dba)2, while the rest was the same as in Example 32, and the reaction yielded ( R )-3aa, 62% yield, 97% enantioselectivity of ee.

[0096] Example 45 The difference from Example 32 is that the equimolar amount of Ni(OTf)2 in Example 32 was replaced with CuBr2, while the rest was the same as in Example 32, and the reaction yielded ( R )-3aa, 55% yield, 95% enantioselectivity of ee.

[0097] (2) Nickel-catalyzed bicyclization reaction of nitrile derivatives Example 46

[0098] In a glove box, Ni(OTf)₂ (3.7 mg, 0.01 mmol, 10 mol%), II-a (8.5 mg, 0.012 mmol, 12 mol%), and 0.5 mL of toluene were added to a 10 mL sealed tube. The resulting solution was stirred at room temperature for 20 minutes, and then substrate 4a (32.2 mg, 0.1 mmol, 1.0 equivalent), 4-F-C₆H₄(OH)₂(5a) (28.0 mg, 0.2 mmol, 2.0 equivalent), and toluene (1.5 mL) were added. After sealing the tube, the glove box was removed and connected to an argon line. Under positive argon pressure, the sealed tube was opened, and H₂O (90 μL, 0.5 mmol, 5.0 equivalent) was rapidly added using a microsyringe. After sealing the tube, the mixture was stirred at 100 °C for 48 hours. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ( S -6aa, 62% yield, 96% enantioselectivity of ee.

[0099] Example 47 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-b, while the rest was the same as in Example 46, and the reaction yielded ( R )-6aa, 60% yield, 90% enantioselectivity of ee.

[0100] Example 48 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-c, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 56% yield, 90% enantioselectivity of ee.

[0101] Example 49 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-d, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 50% yield, 92% enantioselectivity of ee.

[0102] Example 50 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-e, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 80% yield, 96% enantioselectivity of ee.

[0103] Example 51 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-f, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 71% yield, 95% enantioselectivity of ee.

[0104] Example 52 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-g, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 69% yield, 94% enantioselectivity of ee.

[0105] Example 53 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-h, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 75% yield, 98% enantioselectivity of ee.

[0106] Example 54 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-i, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 70% yield, 98% enantioselectivity of ee.

[0107] Example 55 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-j, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 60% yield, 97% enantioselectivity of ee.

[0108] Example 56 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-k, while the rest was the same as in Example 46, and the reaction yielded ( R )-6aa, 58% yield, 97% enantioselectivity of ee.

[0109] Example 57 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 39 was replaced with II-l, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 60% yield, 95% enantioselectivity of ee.

[0110] Example 58 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-m, while the rest was the same as in Example 46, and the reaction yielded (S )-6aa, 71% yield, 93% enantioselectivity of ee.

[0111] Example 59 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-n, while the rest was the same as in Example 46, and the reaction yielded ( S -6aa, 68% yield, 91% enantioselectivity of ee.

[0112] Example 60 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with II-o, while the rest was the same as in Example 46, and the reaction yielded ( R -6aa, 69% yield, 91% enantioselectivity of ee.

[0113] Example 61 The difference from Example 53 is that the equimolar amount of Ni(OTf)2 in Example 53 was replaced with Pd(dba)2, while the rest was the same as in Example 53, and the reaction yielded ( S )-6aa, 75% yield, 92% enantioselectivity of ee.

[0114] Example 62 The difference from Example 53 is that the equimolar amount of Ni(OTf)2 in Example 53 was replaced with Cu(MeCN)BF4, while the rest was the same as in Example 53, and the reaction yielded ( S )-6aa, 70% yield, 90% enantioselectivity of ee.

[0115] Example 63 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with Ib, while the rest was the same as in Example 43, and the reaction yielded ( S )-6aa, 50% yield, 93% ee enantioselectivity.

[0116] Example 64 The difference from Example 46 is that the equimolar amount of chiral ligand II-a in Example 46 was replaced with Ic, while the rest was the same as in Example 46, and the reaction yielded ( S )-6aa, 63% yield, 95% enantioselectivity of ee.

[0117] (3) Palladium-catalyzed allylation of nitrile derivatives Example 65

[0118] In a glove box, Pd2(dba)3 (18.3 mg, 0.02 mmol, 10 mol%), Ia (11.8 mg, 0.024 mmol, 12 mol%), and 0.5 mL of toluene were added to a 10 mL sealed tube. The resulting solution was stirred at room temperature for 20 minutes, and then substrate 7a (51.3 mg, 0.2 mmol, 1.0 equivalent) and toluene (1.5 mL) were added. After sealing the tube, the glove box was removed. The mixture was stirred at 60 °C for 24 hours. After cooling the mixture to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (…). S )-8a, 65% yield, 91% enantioselectivity of ee.

[0119] Example 66 The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with Ib, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 80% yield, 94% enantioselectivity of ee.

[0120] Example 67 The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with Ic, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 78% yield, 98% enantioselectivity.

[0121] Example 68 The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with Id, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 74% yield, 95% enantioselectivity.

[0122] Example 69 The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with In, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 69% yield, 93% enantioselectivity.

[0123] Example 70 The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with II-a, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 76% yield, 95% enantioselectivity.

[0124] Example 71 The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with II-d, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 73% yield, 95% enantioselectivity.

[0125] Example 72 The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with II-i, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 82% yield, 97% enantioselectivity.

[0126] Example 73 The difference from Example 1 is that S-3a in Example 1 is replaced with an equimolar amount of S-3o, and S-10a in Example 1 is replaced with an equimolar amount of S-10o. The rest of the process and conditions are the same as in Example 1.

[0127] S-3o S-10o Io (3a S ,8a R )-2-(5'-(diphenylphosphino)-[1,1':2',1''-terphenyl]-4'-yl)-5-phenyl-3a,8a-dihydro-8H-indenzo[1,2- d Oxazole (Io). White solid (1.98 g, 80% yield). HRMS (ESI+) m / z calc'd for C 58 H 42 NOP [M+H]+: 799.3004, found 799.3000. The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with Io, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 71% yield, 95% enantioselectivity.

[0128] Example 74 The difference from Example 1 is that S-10a in Example 1 is replaced with an equimolar amount of S-10p, while the rest of the process and conditions are the same as in Example 1.

[0129] S-10p Ip (3a S ,8a R )-2-(2-(dicyclohexylphosphino)phenyl)-5-phenyl-3a,8a-dihydro-8H-inden[1,2-d Oxazole (Ip). White solid (1.77 g, 84% yield). HRMS (ESI+) m / z calc'd for C 34 H 38 NOP [M+H]+:507.2691, found 507.2698. The difference from Example 65 is that the equimolar amount of chiral ligand Ia in Example 65 was replaced with Ip, while the rest was the same as in Example 65, and the reaction yielded ( S )-8a, 77% yield, 95% enantioselectivity.

[0130] Where there is no conflict, the above embodiments and features described herein can be combined with each other.

[0131] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A phosphonoxazolin ligand having the structure shown in general formula I or general formula II, or its chemical tautomers, enantiomers, and diastereomers: 、 ， R 1 Selected from hydrogen, alkyl, perfluoroalkyl, alkoxy, and aryl; R 2 Selected from hydrogen, alkyl, perfluoroalkyl, alkoxy, and aryl; R 3 Selected from alkyl, cycloalkyl, alkenyl, and aryl groups; R 4 Selected from alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; R 5 Selected from hydrogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; R 6 Selected from hydrogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, aryl, and fluorine atoms; n and m are the number of substituents, where n+m ≤ 5.

2. A phosphonoxazolin ligand according to claim 1, characterized in that, The compound represented by general formula I is selected from one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Where Me is methyl, OMe is methoxy, and Cy is cyclohexyl. i Pr is isopropyl. t Bu is tert-butyl, Ph is phenyl, and Ad is 1-adamantyl.

3. A phosphonoxazolin ligand according to claim 1, characterized in that, The compound represented by general formula II is selected from one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Where Me stands for methyl and OMe stands for methoxy. t Bu is tert-butyl, and Ph is phenyl.

4. A method for preparing the phosphonoxazolin ligand represented by general formula I according to claim 1, characterized in that, Includes the following steps: ； Compound S-1 and compound S-2 react to give intermediate S-3; Intermediate S-3 reacts with Meerwein salt to give compound S-4; Compound S-5 and compound S-6 react to give intermediate S-7; Intermediate S-7 hydrolyzes the lactam protecting group under alkaline conditions to give compound S-8; Compound S-4 and compound S-8 react to give intermediate S-9; Intermediate S-9 is coupled with phosphine hydrogen compounds with different substituents to obtain phosphoxazoline ligands represented by general formula I; R 1 R 2 R 3 R 4 As defined in claim 1, Pd is palladium, a catalyst precursor; Cu is copper, a catalyst precursor; Ligand is a ligand; solvent is an organic solvent; and additive is an additive.

5. The preparation method according to claim 4, characterized in that, The catalyst precursor copper is a monovalent copper salt or its hydrate, wherein the monovalent copper salt is selected from at least one of CuOAc, CuBr, CuI, and CuOTf; The catalyst precursor palladium is selected from at least one of Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(PPh3)4 or their hydrates; The organic solvent is selected from at least one of toluene, diethyl ether, 1,4-dioxane, tetrahydrofuran, dichloromethane, ethanol, and water; The additive is selected from at least one of N,N-dimethylformamide, cesium carbonate, potassium carbonate, and water.

6. A method for preparing the phosphonoxazolin ligand of general formula II as described in claim 1, characterized in that, Includes the following steps: ； Compound S-4 and compound S-11 react to give intermediate S-12; Intermediate S-12 and compound S-13 react to give the phosphonoxazoline ligand represented by general formula II; R 1 R 2 R 3 R 4 R 5 R 6 As defined in claim 1, n and m are the number of substituents, where n+m ≤ 5, Pd is the catalyst precursor palladium, Cu is the catalyst precursor copper, Ligand is the ligand, solvent is the organic solvent, and additive is the additive.

7. The preparation method according to claim 6, characterized in that, The catalyst precursor copper is a monovalent copper salt or its hydrate, wherein the monovalent copper salt is selected from at least one of CuOAc, CuBr, CuI, and CuOTf; The catalyst precursor palladium is selected from at least one of Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(PPh3)4 or their hydrates; The organic solvent is selected from at least one of toluene, diethyl ether, 1,4-dioxane, tetrahydrofuran, dichloromethane, ethanol, and water.

8. A chiral catalytic composition, characterized in that, It contains a transition metal salt and the phosphonoxazoline ligand as described in claim 1.

9. The chiral catalytic composition according to claim 8, characterized in that, The molar ratio of the transition metal salt to the phosphonoxazolin ligand is 1:1.1 to 3.3, and the transition metal salt is selected from at least one of Ni(OTs)2, Ni(OTf)2, Ni(cod)2, Pd(OAc)2, Pd2(dba)3, Pd(MeCN)2Cl2, Cu(MeCN)4OTf, and Cu(OTs)2.

10. The use of the chiral catalytic composition of claim 8 in catalyzing asymmetric reactions of nitrile derivatives, wherein the asymmetric reaction is any one of allylation, bicyclization, intermolecular desymmetry, or intramolecular condensation.

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