Application of a chiral oxazoline ligand in copper-catalyzed asymmetric radical reactions

Abstract

The present invention discloses the application of a chiral oxazoline ligand in the copper-catalyzed asymmetric lactonization reaction. Using carboxylic acid 1 linked with α,β-unsaturated ketone and hydrocarbon compound 2 as starting materials, copper trifluoromethanesulfonate as the metal catalyst, chiral oxazoline reagent Box-L* as the ligand, and peroxide as the oxidant, through a tandem reaction of radical addition / intramolecular asymmetric cyclization under the irradiation of blue light, the lactone compound 3 can be obtained with high enantioselectivity after separation and purification. The present invention applies a catalytic system of a copper catalyst and a chiral oxazoline ligand Box-L*, realizing a photo-promoted copper-catalyzed asymmetric radical tandem cyclization reaction. This catalytic system can rapidly synthesize chiral lactone compounds with high yield and high stereoselectivity. The present invention uses a chiral oxazoline ligand with large steric hindrance and a cheap and easily available metal copper catalyst, further expanding the application scope of this type of ligand in copper-catalyzed asymmetric synthesis reactions.

Description

Technical Field

[0001] The present invention belongs to the technical field of asymmetric organic synthesis, and particularly relates to the application of a chiral oxazoline ligand in a copper-catalyzed asymmetric radical reaction. Background Art

[0002] Chirality is one of the essential properties of nature. There are a large number of chiral molecules in nature and living organisms. Many biological macromolecules that are important bases for life activities, such as proteins, polysaccharides, and nucleic acids, are basically chiral. The study of chirality plays an important role in life science, pharmaceuticals, and food science. There are significant differences in the pharmacology and toxicity of chiral drugs. For example, Thalidomine (also known as Distaval) was widely used as a sedative in Europe. Many pregnant women who took this drug gave birth to deformed fetuses because only the R-isomer has a sedative effect while the S-isomer is teratogenic. The painful historical lesson tells us that chiral drugs must be investigated separately. Developing efficient enantioselective synthesis methods for enantiomers is of great significance for the pharmacological research of chiral drugs, the purity analysis of enantiomers, environmental monitoring, and the healthy life of humans. Therefore, developing more types of asymmetric reactions to achieve the highly enantioselective construction of stereocenters is a field with important scientific research value and high challenges.

[0003] At present, the organic synthesis strategy of transition metal asymmetric catalysis has been proven to be a simple and effective solution, and the key in this system lies in the selection of chiral ligands. In recent years, chemists have successively developed a variety of chiral ligands, including chiral oxazoline ligands, chiral P ligands, chiral N,P ligands, and chiral anion ligands, etc. Among them, chiral oxazoline ligands are one of the most widely used chiral ligands at present. Their complexation with metal copper precursors can achieve various types of asymmetric catalytic reactions, and this research field has gradually become the focus and hotspot in asymmetric organic synthesis chemistry. It includes: 1. Organic synthesis chemistry with carbene as the reactive intermediate (Angew. Chem. Int. Ed. 2008, 120, 946; Angew. Chem. Int. Ed. 2017, 56, 1864); 2. Organic synthesis chemistry with radical as the reactive intermediate (Angew. Chem. Int. Ed. 2013, 52, 12655; Science 2016, 353, 1014; Nature 2019, 574, 516); 3. Organic synthesis chemistry catalyzed by copper as a Lewis acid (J. Comb. Chem. 2004, 6, 301; J. Am. Chem. Soc. 2015, 137, 14594). The development of these different types of reactions provides an important guarantee for the efficient synthesis of natural products with important physiological activities and the study of structure-activity relationships. Therefore, the goal pursued by chemists is to achieve more types of asymmetric catalytic reactions through the design and development of new chiral oxazoline ligands. In 2013, Tsutomu et al. developed a class of sterically hindered chiral oxazoline ligands and applied them to the copper-catalyzed asymmetric cyclopropanation reaction with carbene participation, achieving good enantioselectivity and demonstrating the potential application value of this class of ligands. However, in the past decade, the application of this class of ligands in other types of copper-catalyzed reactions has not been reported. Therefore, there is an urgent need to develop a new reaction type catalyzed by this class of ligands to expand the application scope of this class of ligands in copper-catalyzed asymmetric synthesis reactions. Summary of the Invention

[0004] The purpose of the present invention is to provide an application of a chiral oxazoline ligand in a copper-catalyzed asymmetric radical reaction, so as to solve the above problems existing in the prior art.

[0005] The present invention discloses the application of a chiral oxazoline ligand in copper-catalyzed asymmetric radical reactions. Different from the previously reported cyclopropanation reactions of alkenes based on carbene intermediates, this reaction involves radical reactive intermediates and represents a completely new reaction type. This reaction uses carboxylic acid 1 linked with α,β-unsaturated ketone and hydrocarbon compound 2 as starting materials, copper trifluoromethanesulfonate as the metal catalyst, bulky chiral oxazoline reagent Box-L* as the ligand, and peroxide as the oxidant. Under blue light irradiation, through a tandem reaction of radical addition / intramolecular asymmetric cyclization, the chiral lactone product 3 is obtained after separation and purification.

[0006] The reaction route of the present invention is as follows:

[0007]

[0008] In the formula: * represents a chiral carbon atom; Ar is an aromatic ring, a substituted aromatic ring, or an aromatic heterocycle; R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, ester group, acyl group, an alkyl or oxyalkyl group of C 1-4 ; R 6 , R 7 , R 8 are each independently selected from hydrogen, halogen, benzyl, cycloalkyl, oxyalkyl group.

[0009] The target product 3 is an optically active compound with the structure shown in the above formula, including its stereoisomers with the same chemical general formula.

[0010] The present invention applies a bulky oxazoline ligand to a photo-promoted copper-catalyzed asymmetric radical reaction, which specifically includes the following steps:

[0011] Under a nitrogen atmosphere, a copper trifluoromethanesulfonate metal catalyst, a bulky chiral oxazoline ligand Box-L * , carboxylic acid 1 linked with α,β-unsaturated ketone and a magnetic stir bar are added to a reaction flask. Subsequently, under nitrogen protection, hydrocarbon compound 2, peroxide, and an organic solvent are added to the mixed system. The reaction is carried out at 10 - 60 °C for 4 - 72 hours under blue light irradiation, and the reaction end point is determined by thin-layer chromatography spotting. Then, the reaction system is diluted with ethyl acetate and extracted with water, and then the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1, V / V) to obtain the chiral lactone compound 3.

[0012] The molar ratio of the copper trifluoromethanesulfonate metal catalyst to carboxylic acid 1 linked with α,β-unsaturated ketone is 0.002:1 - 0.5:1; the molar ratio of the chiral oxazoline ligand to carboxylic acid 1 linked with α,β-unsaturated ketone is 0.002:1 - 0.5:1; the molar equivalent ratio of carboxylic acid 1 linked with α,β-unsaturated ketone to hydrocarbon compound 2 is 1:5 - 1:100; the molar ratio of carboxylic acid 1 linked with α,β-unsaturated ketone to peroxide is 1:1 - 1:5.

[0013] Furthermore, the molar ratio of the copper trifluoromethanesulfonate metal catalyst to the chiral oxazoline ligand is 1:1 - 1:4.

[0014] The wavelength range of the blue light is 415 - 495 nm; the power of the blue light lamp is 1 - 100 W.

[0015] In the preparation process of the present invention, the peroxide is di-tert-butyl peroxide, benzoyl peroxide, lauroyl peroxide, 2,5-bis(tert-butyl)-2,5-dimethylhexane, N-fluorobis(phenylsulfonamide), tert-butyl peroxybenzoate, dicumyl peroxide, 1,4-di-tert-butylperoxyisopropylbenzene, tert-butyl cumyl peroxide or di-tert-butyl peroxide isopropylbenzene.

[0016] In the preparation process of the present invention, the organic solvent is 1,4-dioxane, dichloromethane, dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, acetone, 1,2-dichloroethane, acetonitrile, benzene, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, trifluorotoluene, xylene, mesitylene, 1,2-dichlorobenzene, 1,2-difluorobenzene, 1,3-difluorobenzene, 1,4-difluorobenzene, 1,3,5-trifluorobenzene, 2,4-difluorochlorobenzene, 3,5-difluorochlorobenzene, 1-chloro-4-fluorobenzene, 1,2,4-trifluorobenzene, 1,2,3-trifluorobenzene, 1,2,4,5-tetrafluorobenzene, 1,2,3,5-tetrafluorobenzene, 1,2,3,4-tetrafluorobenzene, hexafluorobenzene or cyclohexane.

[0017] In the preparation process of the present invention, the bulky chiral oxazoline ligand Box-L* is preferably:

[0018]

[0019] In the formula: R is independently selected from hydrogen, or the following groups which are substituted or unsubstituted: C 1-10 alkyl, benzyl, C 3-10 cycloalkyl or C 6-20 aryl, R' is independently selected from hydrogen, or the following groups which are substituted or unsubstituted: C 1-10 alkyl, benzyl, silyl. The preparation method refers to the patent of Tsutomu et al.: JP2013103904, AN: 2013:829684, CAN: 159:26539.

[0020] The present invention provides an application of a bulky chiral oxazoline ligand Box-L* in a copper-catalyzed asymmetric radical reaction. In this reaction, carboxylic acid 1 linked with α,β-unsaturated ketone and hydrocarbon compound 2 are used as starting materials, copper trifluoromethanesulfonate is used as a metal catalyst, a bulky chiral oxazoline reagent is used as a ligand, and di-tert-butyl peroxide is used as an oxidant. Under the irradiation of blue light, through a tandem reaction of radical addition / intramolecular asymmetric cyclization, chiral lactone compound 3 is rapidly synthesized with high yield and high stereoselectivity. The present invention successfully develops an application of a bulky chiral oxazoline ligand Box-L* in a copper-catalyzed asymmetric lactonization reaction, further expanding the application scope of this type of ligand in the field of copper-catalyzed asymmetric synthesis. Specific Embodiments

[0021] The technical solution of the present invention is further analyzed and illustrated through specific embodiments as follows.

[0022] Example 1: Investigation of various bulky chiral oxazoline ligands

[0023]

[0024] Compared with the commercial ligands L1-L8, the bulky oxazoline ligands L9-L20 also showed good catalytic activity. Among them, when the R group is methyl and the R' group is a TBS protecting group, ligand L16 can obtain a 80% NMR yield and a 91% enantioselectivity. Due to its best catalytic activity, we used L16 as the optimal ligand to demonstrate the application of this bulky oxazoline ligand in copper-catalyzed asymmetric radical chemistry.

[0025] Example 2: Application of the bulky chiral oxazoline ligand L16 in the reported copper-catalyzed asymmetric radical reaction

[0026]

[0027] In the reported copper-catalyzed asymmetric radical reaction (Chem. Sci. 2019, 10, 9265), using ligand L16 can significantly improve the yield and enantioselectivity of the reaction.

[0028] Example 3: Preparation of chiral lactone compound 3a

[0029]

[0030] At 25 °C and under a nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube. *(3.1 mg, 0.006 mmol, 6 mol%)、carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 h, and the reaction end point was determined by thin layer chromatography (TLC) spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3a (24.8 mg, 75% yield, 91% e.e.), which was a yellow oily liquid.

[0031] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.23 - 8.12 (m, 2H), 7.15 (t, J = 8.6 Hz, 2H), 7.05 (dd, J = 8.5, 5.4 Hz, 2H), 6.93 (t, J = 8.7 Hz, 2H), 2.99 - 2.86 (m, 1H), 2.76 - 2.55 (m, 3H), 2.54 - 2.38 (m, 2H), 2.34 - 2.20 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 197.4, 175.4, 165.9 (d, J = 256.8 Hz), 161.5 (d, J = 244.6 Hz), 135.5 (d, J = 3.3 Hz), 133.1 (d, J = 9.5 Hz, 2C), 130.6 (d, J = 3.1 Hz), 129.7 (d, J = 7.9 Hz, 2C), 115.9 (d, J = 21.7 Hz, 2C), 115.4 (d, J = 21.3 Hz, 2C), 92.3, 40.9, 30.9, 29.1, 27.9 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.4 (s, 1F), -116.6 (s, 1F) ppm. [α] D 20=-20.8 (c = 0.72, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 254 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 14.0 min, t R (minor) = 15.9 min. HRMS (ESI): m / z calculated for C 19 H 17 F2O3 + [M + H + : 331.1140, found: 331.1139.

[0032] Example 4: Preparation of Chiral Lactone Compound 3b

[0033]

[0034] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%), chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1b linked with α-β unsaturated ketone (20.4 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 h, and the reaction end point was determined by thin layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3b (18.7 mg, 60% yield, 89% e.e.), which was a colorless oily liquid.

[0035] 11H-NMR: (400 MHz, Chloroform-d) δ = 8.09 (d, J = 7.3 Hz, 2H), 7.65 - 7.55 (m, 1H), 7.48 (dd, J = 8.4, 7.1 Hz, 2H), 7.11 - 7.00 (m, 2H), 6.93 (t, J = 8.7 Hz, 2H), 2.99 - 2.85 (m, 1H), 2.76 - 2.41 (m, 5H), 2.36 - 2.21 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 199.1, 175.5, 161.5 (d, J = 244.5 Hz), 135.7 (d, J = 3.3 Hz), 134.4, 133.6, 130.0 (2C), 129.7 (d, J = 7.9 Hz, 2C), 128.6 (2C), 115.4 (d, J = 21.3 Hz, 2C), 92.3, 40.9, 31.0, 29.2, 28.0 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -116.7 ppm. [α] D 20 = -8.2 (c = 0.29, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 254 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 14.3 min, t R (minor) = 15.4 min. HRMS (ESI): m / z calculated for C 19 H 18 FO3 + [M + H + : 313.1234, found: 313.1239.

[0036] Example 5: Preparation of chiral lactone compound 3c

[0037]

[0038] Under 25 °C and nitrogen atmosphere, copper (I) trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%)、carboxylic acid 1c linked with α-β unsaturated ketone (23.4 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 h, and the reaction end point was determined by TLC spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3c (17.5 mg, 51% yield, 92% e.e.), which was a colorless oily liquid.

[0039] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.15 (d, J = 9.1 Hz, 2H), 7.14 - 7.01 (m, 2H), 6.99 - 6.84 (m, 4H), 3.88 (s, 3H), 3.02 - 2.87 (m, 1H), 2.72 - 2.39 (m, 5H), 2.35 - 2.16 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 197.1, 175.6, 163.9, 161.5 (d, J = 244.4 Hz), 135.9 (d, J = 3.2 Hz), 132.8 (2C), 129.6 (d, J = 7.8 Hz, 2C), 127.2, 115.3 (d, J = 21.3 Hz, 2C), 113.9 (2C), 92.5, 55.5, 41.1, 31.1, 29.2, 28.1 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -116.8 ppm. [α] D 20 = -14.1 (c = 0.38, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 254 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 14.8 min, t R(minor) = 16.5 min. HRMS (ESI): m / z calculated for C 20 H 20 FO4 + [M + H + : 343.1340, found: 343.1344.

[0040] Example 6: Preparation of Chiral Lactone Compound 3d

[0041]

[0042] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%), chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1d linked with α-β unsaturated ketone (27.2 mg, 0.1 mmol, 1.0 equivalent) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction end point was determined by thin layer chromatography (TLC) spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3d (27.8 mg, 73% yield, 88% e.e.), which was a yellow oily liquid.

[0043] 1 H-NMR: (400 MHz, Chloroform-d) δ = 8.19 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.11 - 7.02 (m, 2H), 6.99 - 6.88 (m, 2H), 2.98 - 2.83 (m, 1H), 2.73 - 2.41 (m, 5H), 2.36 - 2.23 (m, 2H) ppm. 1313C-NMR(101MHz,Chloroform-d):δ=198.5,175.1,161.6(d,J=244.8Hz),137.2,135.3(d,J=3.3Hz),134.8(q,J=32.9Hz),130.4(2C),129.7(d,J=8.0Hz,2C),125.6(q,J=3.8Hz,2C),123.4(q,J=272.8Hz),115.4(d,J=21.3Hz,2C),92.1,40.6,30.8,29.1,27.9ppm. 19 19F NMR(376MHz,CDCl3)δ=-63.4(s,3F),-116.5(s,1F)ppm.[α] D 20 =-14.4(c=0.72,chloroform);The e.e.was determined by HPLC analysis(Chiralpak IA column,λ=242nm,n-hexane / isopropanol=95 / 5,flow rate=1.0mL / min):t R (major)=12.2min,t R (minor)=14.2min.HRMS(ESI):m / z calculated for C 20 H 17 F4O3 + [M+H + :381.1108,found:381.1113.

[0044] Example 7: Preparation of chiral lactone compound 3e

[0045]

[0046] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1e linked with α-β unsaturated ketone (21.8 mg, 0.1 mmol, 1.0 equivalent), and a magnetic stir bar. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation with a 3W 455 nm blue light lamp at 20 °C for 72 hours. The reaction endpoint was determined by thin-layer chromatography (TLC). Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3e (18.9 mg, 58% yield, 86% e.e.), which is a colorless oily liquid.

[0047] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 7.90 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.44 - 7.31 (m, 2H), 7.05 (dd, J = 8.5, 5.5 Hz, 2H), 6.93 (t, J = 8.7 Hz, 2H), 2.97 - 2.85 (m, 1H), 2.76 - 2.43 (m, 5H), 2.42 (s, 3H), 2.34 - 2.20 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 199.3, 175.5, 161.5 (d, J = 244.4 Hz), 138.5, 135.8 (d, J = 3.3 Hz), 134.5, 134.4, 130.4, 129.7 (d, J = 7.9 Hz, 2C), 128.5, 127.2, 115.3 (d, J = 21.3 Hz, 2C), 92.3, 40.9, 31.1, 29.2, 28.1, 21.4 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -116.8 ppm. [α] D 20 = -11.1 (c = 0.24, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 245 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 12.0 min, t R(minor) = 13.1 min. HRMS(ESI): m / z calculated for C 20 H 20 FO3 + [M + H + : 327.1391, found: 327.1393.

[0048] Example 8: Preparation of Chiral Lactone Compound 3f

[0049]

[0050] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1f linked with α-β unsaturated ketone (21.8 mg, 0.1 mmol, 1.0 equiv.) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equiv.), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv.) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction end point was determined by TLC spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3f (20.2 mg, 62% yield, 58% e.e.), which was a colorless oily liquid.

[0051] 1 H-NMR: (400 MHz, Chloroform-d) δ = 7.61 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.33 - 7.23 (m, 2H), 7.15 - 7.05 (m, 2H), 7.00 - 6.93 (m, 2H), 2.79 (td, J = 13.0, 4.8 Hz, 1H), 2.71 - 2.45 (m, 5H), 2.39 (s, 3H), 2.35 - 2.25 (m, 1H), 2.21 - 2.10 (m, 1H) ppm. 1313C-NMR (101 MHz, Chloroform-d): δ = 204.2, 175.5, 161.5 (d, J = 244.3 Hz), 137.4, 136.1 (d, J = 3.3 Hz), 135.7, 131.7, 131.3, 129.7 (d, J = 7.9 Hz, 2C), 128.2, 125.4, 115.4 (d, J = 21.2 Hz, 2C), 91.9, 40.3, 31.4, 29.4, 28.2, 20.6 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -116.8 ppm. [α] D 20 = 5.5 (c = 0.25, chloroform); The e.e. was determined by HPLC analysis (Chiralpak OD-H column, λ = 303 nm, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min): t R (major) = 12.9 min, t R (minor) = 16.2 min. HRMS (ESI): m / z calculated for C 20 H 20 FO3 + [M + H + : 327.1391, found: 327.1395.

[0052] Example 9: Preparation of chiral lactone compound 3g

[0053]

[0054] Under 25 °C and nitrogen atmosphere, copper (I) trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%)、carboxylic acid linked with α-β unsaturated ketone 1 g (25.4 mg, 0.1 mmol, 1.0 equivalent) and a magnetic stir bar. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the end point of the reaction was determined by thin layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3g (16.7 mg, 46% yield, 90% e.e.), which was a colorless oily liquid.

[0055] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.74 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 8.7, 1.8 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.93 - 7.84 (m, 2H), 7.67 - 7.53 (m, 2H), 7.11 - 7.00 (m, 2H), 6.91 (t, J = 8.7 Hz, 2H), 3.09 - 2.92 (m, 1H), 2.79 - 2.48 (m, 5H), 2.43 - 2.26 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 198.8, 175.5, 161.5 (d, J = 244.5 Hz), 135.7 (d, J = 3.2 Hz), 135.6, 132.4, 132.3, 131.6, 130.1, 129.7 (d, J = 7.8 Hz, 2C), 129.1, 128.4, 127.7, 126.9, 125.2, 115.4 (d, J = 21.3 Hz, 2C), 92.5, 41.1, 31.1, 29.2, 28.1 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -116.7 ppm. [α] D 20=-25.0 (c = 0.21, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 278 nm, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min): t R (major) = 12.7 min, t R (minor) = 14.9 min. HRMS (ESI): m / z calculated for C 23 H 20 FO3 + [M + H + : 363.1391, found: 363.1395.

[0056] Example 10: Preparation of Chiral Lactone Compound 3h

[0057]

[0058] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%), chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1h linked with α-β unsaturated ketone (21.0 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out for 72 hours under irradiation with a 3W 455 nm blue light lamp at 20 °C, and the reaction end point was determined by thin layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3h (14.6 mg, 46% yield, 91% e.e.), which was a yellow oily liquid.

[0059] 11H-NMR: (400 MHz, Chloroform-d) δ = 8.16 (dd, J = 3.9, 1.1 Hz, 1H), 7.75 (dd, J = 5.0, 1.2 Hz, 1H), 7.18 (dd, J = 5.0, 3.9 Hz, 1H), 7.12 - 7.04 (m, 2H), 6.99 - 6.88 (m, 2H), 2.90 - 2.79 (m, 1H), 2.74 (td, J = 13.0, 4.9 Hz, 1H), 2.68 - 2.41 (m, 4H), 2.32 - 2.14 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 192.2, 175.4, 161.5 (d, J = 244.3 Hz), 140.3, 136.1, 135.8, 135.8, 129.7 (d, J = 7.9 Hz, 2C), 128.8, 115.3 (d, J = 21.2 Hz, 2C), 91.9, 41.1, 31.3, 29.3, 28.0 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -116.9 ppm. [α] D 20 = -14.4 (c = 0.21, chloroform); The e.e. was determined by HPLC analysis (Chiralpak OD-H column, λ = 258 nm, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min): t R (major) = 13.8 min, t R (minor) = 17.3 min. HRMS (ESI): m / z calculated for C 17 H 16 FO3S + [M + H + : 319.0799, found: 319.0800.

[0060] Example 11: Preparation of Chiral Lactone Compound 3i

[0061]

[0062] At 25 °C under a nitrogen atmosphere, copper (I) trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1i linked with α-β unsaturated ketone (21.8 mg, 0.1 mmol, 1.0 equiv), and a magnetic stir bar. Subsequently, under nitrogen protection, 4-fluorotoluene 2a (550.7 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation with a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction endpoint was determined by thin-layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3i (13.4 mg, 41% yield, 58% e.e.), which was a colorless oily liquid.

[0063] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.14 - 8.02 (m, 2H), 7.63 - 7.55 (m, 1H), 7.48 (dd, J = 8.4, 7.0 Hz, 2H), 7.13 - 7.03 (m, 2H), 6.98 - 6.88 (m, 2H), 2.85 (td, J = 13.0, 5.0 Hz, 1H), 2.70 - 2.58 (m, 2H), 2.56 - 2.32 (m, 3H), 2.24 (ddd, J = 14.1, 12.4, 5.0 Hz, 1H), 1.96 - 1.69 (m, 3H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 200.8, 170.1, 161.4 (d, J = 244.3 Hz), 136.2 (d, J = 3.1 Hz), 135.1, 133.4, 129.8 (2C), 129.7 (d, J = 7.8 Hz, 2C), 128.7 (2C), 115.3 (d, J = 21.3 Hz, 2C), 91.9, 42.0, 30.4, 29.2, 28.9, 16.6 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -116.99 ppm. [α] D 20 = -14.1 (c = 0.17, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 258 nm, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min): tR (major)=10.2 min, t R (minor)=11.6 min. HRMS(ESI): m / z calculated for C 20 H 20 FO3 + [M + H + : 327.1391, found: 327.1396.

[0064] Example 12: Preparation of chiral lactone compound 3j

[0065]

[0066] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%), chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, 2-methyltoluene 2b (531.0 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction end point was determined by thin layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the asymmetric lactone product 3j (17.9 mg, 55% yield, 86% e.e.), which was a colorless oily liquid.

[0067] 1 H-NMR: (400 MHz, Chloroform-d) δ = 8.27 - 8.13 (m, 2H), 7.20 - 7.07 (m, 5H), 7.05 - 6.99 (m, 1H), 3.05 - 2.89 (m, 1H), 2.69 - 2.46 (m, 4H), 2.43 - 2.21 (m, 3H), 2.17 (s, 3H) ppm. 1313C-NMR(101MHz,Chloroform-d):δ=197.3,175.4,165.9(d,J=256.8Hz),138.1,135.7,133.1(d,J=9.3Hz,2C),130.7(d,J=3.2Hz),130.4,128.7,126.6,126.3,115.9(d,J=21.7Hz,2C),92.4,39.6,30.6,28.0,27.3,19.0ppm. 19 19F NMR(376MHz,CDCl3)δ=-103.5ppm.[α] D 20 =-31.3(c=0.20,chloroform); The e.e. was determined by HPLC analysis(Chiralpak IA column,λ=259nm,n-hexane / isopropanol=95 / 5,flow rate=1.0mL / min):t R (major)=9.7min,t R (minor)=10.7min.HRMS(ESI):m / z calculated for C 20 H 20 FO3 + [M+H + :327.1391,found:327.1394.

[0068] Example 13: Preparation of chiral lactone compound 3k

[0069]

[0070] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equivalent), and a magnetic stir bar. Subsequently, under nitrogen protection, 3-methyltoluene 2c (531.0 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation with a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction endpoint was determined by thin-layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the asymmetric lactone product 3k (24.5 mg, 75% yield, 91% e.e.), which was a colorless oily liquid.

[0071] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.25 - 8.13 (m, 2H), 7.19 - 7.10 (m, 3H), 6.99 (d, J = 7.7 Hz, 1H), 6.93 - 6.81 (m, 2H), 3.00 - 2.89 (m, 1H), 2.68 - 2.39 (m, 5H), 2.36 - 2.22 (m, 2H), 2.29 (s, 3H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 197.4, 175.4, 165.9 (d, J = 256.8 Hz), 139.9, 138.3, 133.1 (d, J = 9.4 Hz, 2C), 130.7 (d, J = 3.2 Hz), 129.0, 128.5, 127.2, 125.2, 115.8 (d, J = 21.7 Hz, 2C), 92.4, 40.7, 30.7, 29.7, 28.0, 21.3 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.6 ppm. [α] D 20 = -17.9 (c = 0.29, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 242 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 9.4 min, t R(minor) = 10.5 min. HRMS(ESI): m / z calculated for C 20 H 19 FNaO3 + [M + H + : 349.1210, found: 349.1211.

[0072] Example 14: Preparation of chiral lactone compound 3l

[0073]

[0074] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%), chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, 4-methyltoluene 2d (531.0 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction end point was determined by thin layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the asymmetric lactone product 3l (15.3 mg, 47% yield, 91% e.e.), which was a colorless oily liquid.

[0075] 1 H-NMR: (400 MHz, Chloroform-d) δ = 8.28 - 8.11 (m, 2H), 7.14 (t, J = 8.7 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 7.9 Hz, 2H), 3.00 - 2.88 (m, 1H), 2.67 - 2.38 (m, 5H), 2.36 - 2.21 (m, 2H), 2.29 (s, 3H) ppm. 1313C-NMR(101MHz,Chloroform-d):δ=197.4,175.4,165.9(d,J=256.9Hz),136.8,136.0,133.1(d,J=9.3Hz,2C),130.7(d,J=3.2Hz),129.3(2C),128.1(2C),115.8(d,J=21.8Hz,2C),92.4,40.9,30.7,29.8,28.0,21.0ppm. 19 19F NMR(376MHz,CDCl3)δ=-103.6ppm.[α] D 20 =-15.6(c=0.19,chloroform); The e.e. was determined by HPLC analysis(Chiralpak IA column,λ=255nm,n-hexane / isopropanol=95 / 5,flow rate=1.0mL / min):t R (major)=11.1min,t R (minor)=12.8min.HRMS(ESI):m / z calculated for C 20 H 20 FO3 + [M+H + :327.1391,found:327.1387.

[0076] Example 15: Preparation of chiral lactone compound 3m

[0077]

[0078] At 25 °C and under a nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equivalent), and a magnetic stir bar. Subsequently, under nitrogen protection, mesitylene 2e (601.0 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation with a 3W 455 nm blue light lamp at 20 °C for 72 hours. The reaction endpoint was determined by thin-layer chromatography (TLC) spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3m (27.2 mg, 80% yield, 92% e.e.), which was a colorless oily liquid.

[0079] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.19 (dd, J = 8.9, 5.5 Hz, 2H), 7.14 (d, J = 17.3 Hz, 2H), 6.82 (s, 1H), 6.71 (s, 2H), 3.00 - 2.86 (m, 1H), 2.65 - 2.38 (m, 5H), 2.35 - 2.27 (m, 2H), 2.25 (s, 6H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 197.4, 175.4, 165.9 (d, J = 256.6 Hz), 139.8, 138.2, 133.1 (d, J = 9.4 Hz, 2C), 130.7 (d, J = 3.0 Hz), 128.0 (2C), 126.0 (2C), 115.8 (d, J = 21.7 Hz, 2C), 92.4, 40.8, 30.7, 29.6, 28.0, 21.2 (2C) ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.7 ppm. [α] D 20 = -19.8 (c = 0.36, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 259 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 7.8 min, t R(minor) = 8.8 min. HRMS(ESI): m / z calculated for C 21 H 22 FO3 + [M + H + : 341.1547, found: 341.1552.

[0080] Example 16: Preparation of Chiral Lactone Compound 3n

[0081]

[0082] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a (22.2 mg, 0.1 mmol, 1.0 equiv) linked with α-β unsaturated ketone and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, 1,2,4,5-tetramethylbenzene 2f (671.0 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction end point was determined by TLC spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the asymmetric lactone product 3n (18.4 mg, 52% yield, 91% e.e.), which was a colorless oily liquid.

[0083] 1 H-NMR: (400 MHz, Chloroform-d) δ = 8.19 (dd, J = 9.0, 5.4 Hz, 2H), 7.14 (dd, J = 9.0, 8.3 Hz, 2H), 6.87 (s, 1H), 6.79 (s, 1H), 3.04 - 2.92 (m, 1H), 2.67 - 2.46 (m, 4H), 2.40 - 2.19 (m, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 2.09 (s, 3H) ppm. 1313C-NMR(101MHz, Chloroform-d): δ=197.3, 175.5, 165.9(d, J=256.6Hz), 135.3, 134.7, 134.2, 133.1(d, J=9.4Hz, 2C), 132.8, 131.8, 130.7(d, J=3.2Hz), 130.1, 115.8(d, J=21.8Hz, 2C), 92.4, 39.9, 30.6, 28.0, 26.8, 19.1(2C), 18.3ppm. 19 19F NMR(376MHz, CDCl3) δ=-103.6ppm. [α] D 20 =-23.7 (c=0.19, chloroform). The e.e. was determined by HPLC analysis (Chiralpak IA column, λ=274nm, n-hexane / isopropanol=95 / 5, flow rate=1.0mL / min): t R (major)=8.1min, t R (minor)=9.4min. HRMS(ESI): m / z calculated for C 22 H 24 FO3 + [M+H + : 355.1704, found: 355.1707.

[0084] Example 17: Preparation of chiral lactone compound 3o

[0085]

[0086] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equivalent), and a magnetic stir bar. Subsequently, under nitrogen protection, 2-methylthiophene 2a (491.0 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction endpoint was determined by thin layer chromatography spotting; subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the asymmetric lactone product 3o (11.5 mg, 36% yield, 91% e.e.), which was a colorless oily liquid.

[0087] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.18 (dd, J = 9.0, 5.4 Hz, 2H), 7.23 (dd, J = 4.9, 2.9 Hz, 1H), 7.14 (dd, J = 9.0, 8.3 Hz, 2H), 6.94 - 6.89 (m, 1H), 6.85 (dd, J = 5.0, 1.4 Hz, 1H), 2.99 - 2.88 (m, 1H), 2.76 - 2.66 (m, 2H), 2.64 - 2.43 (m, 3H), 2.39 - 2.20 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 197.3, 175.4, 166.0 (d, J = 256.8 Hz), 140.1, 133.1 (d, J = 9.4 Hz, 2C), 130.6, 127.7, 125.9, 120.8, 115.8 (d, J = 21.7 Hz, 2C), 92.3, 39.7, 30.7, 28.0, 24.3 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.4 ppm. [α] D 20 = -21.0 (c = 0.1, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 254 nm, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min): t R (major) = 10.3 min, t R(minor)=11.2 min. HRMS(ESI): m / z calculated for C 17 H 16 FO3S + [M + H + : 319.0799, found: 319.0796.

[0088] Example 18: Preparation of Chiral Lactone Compound 3p

[0089]

[0090] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%), chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equivalent) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, cyclopentane 2h (350.5 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction end point was determined by thin layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. After combining the organic phases, they were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the asymmetric lactone product 3p (18.3 mg, 63% yield, 91% e.e.), which was a colorless oily liquid.

[0091] 1 H-NMR: (400 MHz, Chloroform-d) δ = 8.19 (dd, J = 9.0, 5.4 Hz, 2H), 7.14 (t, J = 8.6 Hz, 2H), 2.94 (ddd, J = 13.1, 9.5, 5.1 Hz, 1H), 2.64 - 2.41 (m, 2H), 2.32 - 2.10 (m, 3H), 1.89 - 1.69 (m, 3H), 1.64 - 1.37 (m, 4H), 1.17 - 0.96 (m, 2H) ppm. 1313C-NMR (101 MHz, Chloroform-d): δ = 197.6, 175.6, 165.8 (d, J = 256.5 Hz), 133.2 (d, J = 9.3 Hz, 2C), 130.7 (d, J = 3.1 Hz), 115.7 (d, J = 21.7 Hz, 2C), 93.1, 45.0, 35.7, 33.80, 33.75, 31.2, 28.1, 25.0, 24.7 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.9 ppm. [α] D 20 = -39.8 (c = 0.21, chloroform); The e.e. was determined by HPLC analysis (Chiralpak OD-H column, λ = 239 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 7.4 min, t R (minor) = 9.4 min. HRMS (ESI): m / z calculated for C 17 H 20 FO3 + [M + H + : 291.1391, found: 291.1392.

[0092] Example 19: Preparation of chiral lactone compound 3q

[0093]

[0094] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equivalent), and a magnetic stir bar. Subsequently, under nitrogen protection, cyclohexane 2i (421.0 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation with a 3W 455 nm blue light at 20 °C for 72 hours, and the reaction endpoint was determined by thin-layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3q (23.7 mg, 78% yield, 91% e.e.), which is a colorless oily liquid.

[0095] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.16 (dd, J = 8.9, 5.5 Hz, 2H), 7.14 (t, J = 8.6 Hz, 2H), 2.91 (ddd, J = 13.1, 9.5, 5.0 Hz, 1H), 2.66 - 2.41 (m, 2H), 2.22 (dt, J = 13.1, 9.1 Hz, 1H), 2.09 (dd, J = 14.4, 6.4 Hz, 1H), 1.94 (dd, J = 14.4, 5.6 Hz, 1H), 1.79 - 1.53 (m, 5H), 1.48 - 1.37 (m, 1H), 1.27 - 1.03 (m, 3H), 1.03 - 0.82 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 197.6, 175.6, 165.8 (d, J = 256.4 Hz), 133.1 (d, J = 9.3 Hz, 2C), 130.8 (d, J = 3.1 Hz), 115.8 (d, J = 21.7 Hz, 2C), 92.8, 46.3, 34.31, 34.27, 33.6, 31.5, 28.0, 26.1 (2C), 25.9 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.97 ppm. [α] D 20=-30.1 (c = 0.63, chloroform). The e.e. was determined by HPLC analysis (Chiralpak IB column, λ = 252 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major)=6.5 min, t R (minor)=7.5 min. HRMS (ESI): m / z calculated for C 18 H 22 FO3 + [M + H + : 305.1547, found: 305.1549.

[0096] Example 20: Preparation of Chiral Lactone Compound 3r

[0097]

[0098] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%), chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, adamantane 2j (681.0 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 h, and the reaction end point was determined by TLC spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3r (22.8 mg, 64% yield, r.r = 4.5:1, 82% / 91% e.e.), which was a colorless oily liquid.

[0099] 11H-NMR: (400 MHz, Chloroform-d) δ = 8.16 (dd, J = 8.9, 5.5 Hz, 2H), 7.14 (t, J = 8.6 Hz, 2H), 2.90 (ddd, J = 13.1, 9.6, 5.1 Hz, 1H) [2.74 (ddd, J = 13.0, 9.5, 5.9 Hz, 1H)], 2.62 - 2.52 (m, 1H), 2.49 - 2.37 (m, 1H), 2.32 - 2.20 (m, 2H), 1.94 - 1.85 (m, 3H), 1.79 - 1.35 (m, 13H) ppm. Inside the brackets is the chemical shift of another regioisomer. 13 13C-NMR (101 MHz, Chloroform-d): δ (mixture of two regioisomers) = 198.4, 197.7, 175.7, 175.6, 165.7 (d, J = 256.3 Hz), 133.2 (d, J = 9.3 Hz), 133.1 (d, J = 9.3 Hz), 131.1 (d, J = 3.2 Hz), 115.8 (d, J = 21.7 Hz), 93.4, 92.8, 52.9, 43.3, 42.4, 39.6, 38.8, 37.9, 36.6, 34.2, 33.4, 33.1, 33.0, 31.6, 31.5, 31.2, 28.5, 28.1, 27.8, 27.5, 27.4 ppm. 19 19F NMR (376 MHz, CDCl3) δ (mixture of two regioisomers) = -103.9 (s), -104.2 (s) ppm. [α] D 20 = -11.1 (c = 0.33, chloroform); The e.e. was determined by HPLC analysis (Chiralpak OD-H column, λ = 254 nm, n-hexane / isopropanol = 97 / 3, flow rate = 1.0 mL / min): t R (major) = 9.3 min, t R (minor) = 10.6 min, for another regioisomer: t R (major) = 8.3 min, t R (minor) = 11.3 min. HRMS (ESI): m / z calculated for C22 H 26 FO3 + [M+H + :357.1860,found:357.1864.

[0100] Example 21: Preparation of Chiral Lactone Compound 3s

[0101]

[0102] At 25 °C under a nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a (22.2 mg, 0.1 mmol, 1.0 equiv) linked with α-β unsaturated ketone and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, 2,3-dimethylbutane 2k (431.0 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation with a 455 nm blue light lamp at 20 °C for 72 hours, and the end point of the reaction was determined by thin layer chromatography (TLC) spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3s (25.4 mg, 83% yield, 84% e.e.), which was a colorless oily liquid. 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.15 (dd, J = 8.8, 5.5 Hz, 2H), 7.13 (t, J = 8.7 Hz, 2H), 2.71 (ddd, J = 12.9, 9.5, 6.2 Hz, 1H), 2.65 - 2.53 (m, 1H), 2.50 - 2.39 (m, 1H), 2.42 (d, J = 16 Hz, 1H), 2.29 (ddd, J = 12.9, 9.4, 7.3 Hz, 1H), 1.98 (d, J = 14.6 Hz, 1H), 1.53 - 1.40 (m, 1H), 0.87 (s, 3H), 0.84 (s, 3H), 0.81 (d, J = 6.9 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H) ppm. 1313C-NMR(101MHz,Chloroform-d):δ=198.7,175.5,165.6(d,J=256.2Hz),133.2(d,J=9.3Hz,2C),131.2,115.7(d,J=21.7Hz,2C),93.3,46.8,38.4,35.9,34.5,27.8,25.8,24.9,17.4,17.3ppm. 19 19F NMR(376MHz,CDCl3)δ=-104.3ppm.[α] D 20 =-16.3(c=0.31,chloroform); The e.e. was determined by HPLC analysis(Chiralpak IG column,λ=255nm,n-hexane / isopropanol=95 / 5,flow rate=0.5mL / min):t R (minor)=17.7min,t R (major)=18.7min.HRMS(ESI):m / z calculated for C 18 H 24 FO3 + [M+H + :307.1704,found:307.1706.

[0103] Example 22: Preparation of chiral lactone compound 3t

[0104]

[0105] At 25 °C and under a nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equivalent), and a magnetic stir bar. Subsequently, under nitrogen protection, tetrahydrofuran 2k (360.5 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation with a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction end point was determined by thin layer chromatography spotting; subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3t (12.9 mg, 44% yield, dr = 1:1, 88% / 89% e.e.), which was a colorless oily liquid.

[0106] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.23 - 8.02 (m, 2H), 7.20 - 7.06 (m, 2H), 4.17 - 3.98 (m, 1H), 3.73 - 3.51 (m, 2H), 3.02 - 2.89 (m, 0.5H) [2.11 (dd, J = 14.2, 3.3 Hz, 0.5H)], 2.74 - 2.36 (m, 4H), 2.33 - 2.24 (m, 1H), 2.07 - 1.95 (m, 1H), 1.93 - 1.74 (m, 2H), 1.53 - 1.40 (m, 1H) ppm. Inside the brackets is the chemical shift of another diastereomer. 13 13C-NMR (101 MHz, Chloroform-d): δ (mixture of two diastereomers) = 199.0, 197.0, 176.1, 175.7, 165.6 (d, J = 255.9 Hz), 165.5 (d, J = 255.3 Hz), 133.0 (d, J = 9.3 Hz), 132.9 (d, J = 9.2 Hz), 131.4 (d, J = 3.1 Hz), 130.7 (d, J = 3.3 Hz), 115.7 (d, J = 19.8 Hz), 115.4 (d, J = 19.7 Hz), 91.5, 91.2, 74.2, 74.0, 68.0, 67.3, 44.9, 43.9, 32.5, 31.8, 29.9, 28.1, 27.9, 25.3, 25.2 ppm. 1919F NMR (376 MHz, CDCl3) δ (mixture of two diastereomers) = -104.4 (s), -104.9 (s). [α] D 20 = -11.2 (c = 0.17, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IB column, λ = 254 nm, n - hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 10.5 min, t R (minor) = 12.7 min, for another diastereomer: t R (major) = 13.9 min, t R (minor) = 16.3 min. HRMS (ESI): m / z calculated for C 16 H 18 FO4 + [M + H + : 293.1184, found: 293.1187.

[0107] Example 23: Preparation of chiral lactone compound 3u

[0108]

[0109] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equivalent), and a magnetic stir bar. Subsequently, under nitrogen protection, 1,4-dioxane 2l (440.5 mg, 5 mmol, 50.0 equivalents), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equivalents), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction endpoint was determined by thin-layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3u (22.2 mg, 72% yield, dr = 1:1, 92% / 89% e.e.), which was a colorless oily liquid.

[0110] One isomer: 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.13 (dd, J = 9.0, 5.4 Hz, 2H), 7.13 (t, J = 8.6 Hz, 2H), 3.85 - 3.75 (m, 1H), 3.72 - 3.49 (m, 5H), 3.30 (dd, J = 11.5, 10.0 Hz, 1H), 3.01 - 2.89 (m, 1H), 2.69 - 2.38 (m, 3H), 2.17 (dd, J = 14.7, 9.0 Hz, 1H), 2.04 (dd, J = 14.8, 2.8 Hz, 1H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 196.8, 175.7, 165.7 (d, J = 256.4 Hz), 133.0 (d, J = 9.5 Hz, 2C), 130.6 (d, J = 3.1 Hz), 115.8 (d, J = 21.8 Hz, 2C), 90.4, 71.1, 70.7, 66.4, 66.2, 39.8, 30.6, 27.9 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -104.0 ppm. [α] D 20 = 39.2 (c = 0.17, chloroform); The e.e. was determined by HPLC analysis (Chiralpak OD-H column, λ = 248 nm, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min): t R(minor) = 18.0 min, t R (major) = 25.4 min. HRMS(ESI): m / z calculated for C 16 H 18 FO5 + [M + H + : 309.1133, found: 309.1135. Another isomer: 1 H-NMR: (400 MHz, Chloroform-d) δ = 8.07 (dd, J = 9.0, 5.5 Hz, 2H), 7.12 (t, J = 8.7 Hz, 2H), 3.94 - 3.81 (m, 1H), 3.78 - 3.59 (m, 3H), 3.57 - 3.44 (m, 2H), 3.29 (dd, J = 11.4, 9.8 Hz, 1H), 2.75 - 2.30 (m, 5H), 1.87 (dd, J = 14.4, 2.5 Hz, 1H) ppm. 13 C-NMR(101 MHz, Chloroform-d): δ = 199.0, 175.4, 165.5 (d, J = 255.6 Hz), 132.8 (d, J = 9.3 Hz, 2C), 131.4 (d, J = 3.2 Hz), 115.5 (d, J = 21.7 Hz, 2C), 90.4, 71.2, 70.5, 66.2, 66.1, 40.9, 33.2, 27.8 ppm. 19 F NMR(376 MHz, CDCl3) δ = -104.7 ppm. [α] D 20 = 24.1 (c = 0.11, chloroform); The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 266 nm, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min): t R (minor) = 16.7 min, t R (major) = 18.1 min. HRMS(ESI): m / z calculated for C 16 H 18 FO5 + [M + H + : 309.1133, found: 309.1134.

[0111] Example 24: Preparation of chiral lactone compound 3v

[0112]

[0113] Under the conditions of 25 °C and a nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube. * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equiv), and a magnetic stir bar. Subsequently, under nitrogen protection, 4-chloroanisole 2m (713.0 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation with a 3W 455 nm blue light lamp at 20 °C for 72 h, and the reaction endpoint was determined by thin-layer chromatography (TLC). Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3v (15.6 mg, 43% yield, 91% e.e.), which was a yellow oily liquid.

[0114] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.13 (dd, J = 9.0, 5.4 Hz, 2H), 7.21 - 7.05 (m, 4H), 6.57 (d, J = 9.0 Hz, 2H), 4.18 - 4.00 (m, 2H), 2.87 (ddd, J = 12.9, 8.8, 5.7 Hz, 1H), 2.75 (ddd, J = 14.6, 8.0, 5.3 Hz, 1H), 2.66 - 2.35 (m, 4H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 197.3, 175.2, 165.8 (d, J = 256.6 Hz), 156.4, 133.0 (d, J = 9.3 Hz, 2C), 130.7 (d, J = 3.1 Hz), 129.3 (2C), 126.2, 115.7 (d, J = 21.8 Hz, 2C), 115.4 (2C), 90.6, 62.9, 38.4, 31.9, 27.8 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.8 ppm. [α] D 20= 20.3 (c = 0.17, chloroform); The e.e. was determined by HPLC analysis (Chiralpak OD-H column, λ = 282 nm, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min): t R (major) = 17.8 min, t R (minor) = 20.8 min. HRMS (ESI): m / z calculated for C 19 H 17 ClFO4 + [M + H + : 363.0794, found: 363.0795.

[0115] Example 25: Preparation of Chiral Lactone Compound 3w

[0116]

[0117] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%), chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, isopentyl acetate 2n (651.0 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixture. The reaction was carried out under irradiation of a 455 nm blue light lamp at 20 °C for 72 h, and the reaction end point was determined by TLC spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3w (18.2 mg, 52% yield, 80% e.e.), which was a colorless oily liquid.

[0118] 11H-NMR: (400 MHz, Chloroform-d) δ = 8.14 (dd, J = 9.0, 5.4 Hz, 2H), 7.14 (dd, J = 9.0, 8.3 Hz, 2H), 4.07 (t, J = 7.4 Hz, 2H), 2.72 - 2.40 (m, 4H), 2.28 (ddd, J = 12.3, 9.1, 7.0 Hz, 1H), 2.07 - 1.94 (m, 1H), 2.02 (s, 3H), 1.70 - 1.58 (m, 2H), 0.96 (d, J = 5.1 Hz, 6H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 198.7, 175.3, 171.1, 165.7 (d, J = 256.4 Hz), 133.2 (d, J = 9.4 Hz, 2C), 131.1 (d, J = 3.2 Hz), 115.9 (d, J = 21.7 Hz, 2C), 92.7, 61.2, 49.8, 41.5, 34.7, 33.2, 28.4, 28.0, 27.6, 21.1 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.9 ppm. [α] D 20 = -4.7 (c = 0.23, chloroform). The e.e. was determined by HPLC analysis (Chiralpak IA column, λ = 279 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 15.7 min, t R (minor) = 16.8 min. HRMS (ESI): m / z calculated for C 19 H 23 FNaO5 + [M + H + : 373.1422, found: 373.1426.

[0119] Example 26: Preparation of Chiral Lactone Compound 3x

[0120]

[0121] At 25 °C under a nitrogen atmosphere, copper (I) trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L were added to a dry 10 mL Schlenk reaction tube *(3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a (22.2 mg, 0.1 mmol, 1.0 equiv) linked with α-β unsaturated ketone, and a magnetic stir bar. Subsequently, under nitrogen protection, dichloromethane 2o (424.5 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv), and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation with a 3W 455 nm blue light lamp at 20 °C for 72 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the asymmetric lactone product 3x (20.4 mg, 67% yield, 83% e.e.), which was a yellow oily liquid.

[0122] 1 1H-NMR: (400 MHz, Chloroform-d) δ = 8.10 (dd, J = 9.0, 5.4 Hz, 2H), 7.15 (t, J = 8.6 Hz, 2H), 5.94 (dd, J = 8.2, 4.8 Hz, 1H), 3.38 (dd, J = 15.0, 8.2 Hz, 1H), 2.88 (dd, J = 15.0, 4.8 Hz, 1H), 2.77 - 2.57 (m, 2H), 2.55 - 2.41 (m, 2H) ppm. 13 13C-NMR (101 MHz, Chloroform-d): δ = 197.4, 174.5, 165.9 (d, J = 257.1 Hz), 133.1 (d, J = 9.4 Hz, 2C), 130.6 (d, J = 3.2 Hz), 116.0 (d, J = 21.7 Hz, 2C), 89.6, 67.5, 51.3, 32.7, 27.3 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.1 ppm. [α] D 20 = 27.6 (c = 0.23, chloroform); The e.e. was determined by HPLC analysis (Chiralpak OD-H column, λ = 266 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 19.3 min, t R(minor) = 21.8 min. HRMS(ESI): m / z calculated for C 13 H 12 C l2 FO3 + [M + H + : 305.0142, found: 305.0146.

[0123] Example 27: Preparation of Chiral Lactone Compound 3y

[0124]

[0125] Under 25 °C and nitrogen atmosphere, copper trifluoromethanesulfonate (1.5 mg, 0.004 mmol, 4 mol%) and chiral oxazoline ligand L * (3.1 mg, 0.006 mmol, 6 mol%), carboxylic acid 1a linked with α-β unsaturated ketone (22.2 mg, 0.1 mmol, 1.0 equiv) and a magnetic stir bar were added to a dry 10 mL Schlenk reaction tube. Subsequently, under nitrogen protection, chloroform 2p (597.0 mg, 5 mmol, 50.0 equiv), di-tert-butyl peroxide (58.5 mg, 0.4 mmol, 4.0 equiv) and 3.0 mL of 3,5-difluorochlorobenzene were added to the mixed system. The reaction was carried out under irradiation of a 455 nm blue light lamp at 20 °C for 72 hours, and the reaction end point was determined by thin layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the asymmetric lactone product 3y (23.1 mg, 68% yield, 75% e.e.), which was a colorless oily liquid.

[0126] 1 H-NMR: (400 MHz, Chloroform-d) δ = 8.17 (dd, J = 9.0, 5.4 Hz, 2H), 7.15 (t, J = 8.6 Hz, 2H), 4.06 (d, J = 15.3 Hz, 1H), 3.38 (d, J = 15.4 Hz, 1H), 2.72 - 2.59 (m, 2H), 2.58 - 2.46 (m, 2H) ppm. 1313C-NMR (101 MHz, Chloroform-d): δ = 197.5, 174.3, 165.9 (d, J = 257.0 Hz), 133.4 (d, J = 9.5 Hz, 2C), 130.7 (d, J = 3.1 Hz), 115.9 (d, J = 21.9 Hz, 2C), 94.0, 89.7, 59.6, 33.4, 27.1 ppm. 19 19F NMR (376 MHz, CDCl3) δ = -103.3 ppm. [α] D 20 = 1.9 (c = 0.28, chloroform). The e.e. was determined by HPLC analysis (Chiralpak OD-H column, λ = 276 nm, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min): t R (major) = 17.0 min, t R (minor) = 18.0 min. HRMS (ESI): m / z calculated for C 13 H 11 Cl3FO3 + [M + H + : 338.9752, found: 338.9755。

Claims

1. Application of a chiral oxazoline ligand in a copper-catalyzed asymmetric radical reaction, characterized in that: Using carboxylic acid 1 of α,β-unsaturated ketone and hydrocarbon compound 2 as starting materials, copper trifluoromethanesulfonate as a metal catalyst, bulky chiral oxazoline reagent Box-L* as a ligand, and peroxide as an oxidant, under the irradiation of blue light, through a tandem reaction of radical addition / intramolecular asymmetric cyclization, the chiral lactone product 3 is obtained after separation and purification; the reaction route is as follows: ， Wherein: * represents a chiral carbon atom; Ar is an aromatic ring, a substituted aromatic ring or an aromatic heterocycle; R 1 、R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, halogen, ester group, acyl group, C 1-4 alkyl or oxyalkyl; R 6 、R 7 、R 8 are each independently selected from hydrogen, halogen, benzyl, cycloalkyl, oxyalkyl; The structure of the bulky chiral oxazoline reagent Box-L* is as follows: ， In the formula: R is independently selected from hydrogen, or the following substituted or unsubstituted groups: C 1-10 alkyl, benzyl, C 3-10 cycloalkyl or C 6-20 aryl, and R' is independently selected from hydrogen, or the following substituted or unsubstituted groups: C 1-10 alkyl, benzyl, or silyl.

2. The application according to claim 1, wherein It includes the following steps: Under a nitrogen atmosphere, add copper trifluoromethanesulfonate metal catalyst, bulky chiral oxazoline reagent Box-L*, carboxylic acid 1 connected with α,β-unsaturated ketone and a magnetic stir bar into the reaction flask. Subsequently, under nitrogen protection, add hydrocarbon compound 2, peroxide and an organic solvent into the mixed system, and react at 10-60 °C for 4-72 hours under blue light irradiation. Determine the end point of the reaction by thin layer chromatography spotting. Then dilute the reaction system with ethyl acetate and extract with water. Extract the aqueous phase with ethyl acetate. Combine the organic phases, dry with anhydrous sodium sulfate and concentrate under reduced pressure. Then separate the chiral lactone product 3 by column chromatography.

3. The application according to claim 2, characterized in that: The peroxide is selected from di-tert-butyl peroxide, benzoyl peroxide, lauroyl peroxide, 2,5-bis(tert-butyl)-2,5-dimethylhexane, N-fluorodibenzenesulfonamide, tert-butyl peroxybenzoate, dicumyl peroxide, 1,4-di-tert-butylperoxyisopropylbenzene, tert-butyl cumyl peroxide or di-tert-butyl peroxide isopropylbenzene.

4. The application according to claim 2, characterized in that: The molar ratio of copper trifluoromethanesulfonate metal catalyst to carboxylic acid 1 connected with α,β-unsaturated ketone is 0.002:1 - 0.5:1; the molar ratio of bulky chiral oxazoline reagent Box-L* to carboxylic acid 1 connected with α,β-unsaturated ketone is 0.002:1 - 0.5:1; the molar equivalent ratio of carboxylic acid 1 connected with α,β-unsaturated ketone to hydrocarbon compound 2 is 1:5 - 1:100; the molar ratio of carboxylic acid 1 connected with α,β-unsaturated ketone to peroxide is 1:1 - 1:

5.

5. The application according to claim 4, characterized in that: The molar ratio of copper trifluoromethanesulfonate metal catalyst to bulky chiral oxazoline reagent Box-L* is 1:1 - 1:

4.

6. The application according to claim 2, characterized in that: The wavelength range of the blue light is 415 - 495 nm.

7. The application according to claim 2, characterized in that: The organic solvent is selected from 1,4-dioxane, dichloromethane, dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, acetone, 1,2-dichloroethane, acetonitrile, benzene, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, trifluorotoluene, xylene, mesitylene, 1,2-dichlorobenzene, 1,2-difluorobenzene, 1,3-difluorobenzene, 1,4-difluorobenzene, 1,3,5-trifluorobenzene, 2,4-difluorochlorobenzene, 3,5-difluorochlorobenzene, 1-chloro-4-fluorobenzene, 1,2,4-trifluorobenzene, 1,2,3-trifluorobenzene, 1,2,4,5-tetrafluorobenzene, 1,2,3,5-tetrafluorobenzene, 1,2,3,4-tetrafluorobenzene, hexafluorobenzene or cyclohexane.

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