Method for synthesizing chiral alpha-non-natural aromatic amino acid derivative under driving of visible light

Abstract

The invention belongs to the technical field of chemical synthesis, and relates to a method for synthesizing a chiral alpha-non-natural aromatic amino acid derivative under visible light driving. The preparation method comprises the following steps: carrying out in-situ matching on a compound 1 and a ligand under the action of a catalyst, and then continuously carrying out photocatalytic coupling reaction on the compound 1 and a compound 2 under the action of an additive to obtain a compound 3, namely the chiral alpha-non-natural aromatic amino acid derivative. Rich types of natural carboxylic acids exist in the nature, redox active ester derived from aromatic acetic acid is adopted as an aryl donor, a guarantee is provided for structural diversity synthesis of chiral alpha-non-natural aromatic amino acid, a non-natural amino acid compound library can be enriched to a great extent, and assistance is provided for development of polypeptide innovative drugs.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology and relates to a method for synthesizing chiral α-non-natural aromatic amino acid derivatives under visible light. Background Technology

[0002] Peptide drugs assembled from natural amino acids suffer from inherent drawbacks such as short half-life, poor enzymatic stability, and weak cell permeability. Introducing non-natural amino acid residues into the natural amino acid peptide sequence can significantly improve the drug activity of the peptide, including enhancing pharmacological activity and reducing drug toxicity. Therefore, non-natural amino acids play a crucial role in the medical field, especially chiral α-non-natural aromatic amino acids, which are structurally similar to phenylalanine, tyrosine, and tryptophan and are widely found in various drug molecules, such as melphalan, levodopa, levothyroxine, and cetrorexate. Therefore, the development of synthetic methods for chiral α-non-natural aromatic amino acids is an important research area in peptide drug development, providing crucial technical support for the development of innovative peptide drugs.

[0003] Due to the unique value of chiral α-non-natural aromatic amino acids, their synthetic methods have attracted considerable attention in recent years, particularly with the rapid development of photo-oxidation-reduction catalysis, which provides an effective route for modifying α-natural aromatic amino acid residues under mild conditions. For example, since 1989, a series of photoinduced functionalizations of tryptophan have been reported, including heteroarylation, fluoroalkylation, alkylation, phosphorylation, and amidation. Kimoto and Krska also disclosed the trifluoromethylation of tyrosine residues based on the radical pathway in 1992 and 2018, respectively. Furthermore, arylation and amination of tyrosine, and carbinylation and amination of phenylalanine, have further enriched the structural diversity of α-non-natural aromatic amino acids. However, these methods are all based on the modification of the aromatic structure of the corresponding α-natural aromatic amino acids, resulting in each method only synthesizing one class of chiral α-non-natural aromatic amino acids. Therefore, a universal method for synthesizing chiral α-non-natural aromatic amino acids is still urgently needed. As the basic structural backbone of all α-amino acids, glycine α-C(sp...) 3 Direct functionalization of the α-H bond is the most direct way to synthesize various α-non-natural amino acids. In recent years, photo-induced glycine modification has also emerged in large numbers, but there is still a lack of a general strategy for synthesizing chiral α-non-natural aromatic amino acids.

[0004] Therefore, it is necessary to develop a glycine α-C(sp)-based... 3 An enantioselective benzylation strategy for α-H bonds was employed to achieve the efficient synthesis of all types of chiral α-non-natural aromatic amino acids. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for synthesizing chiral α-non-natural aromatic amino acid derivatives under visible light driving, and to provide an enantioselective benzylation strategy based on glycine α-C(sp3)-H bond to achieve efficient synthesis of all types of chiral α-non-natural aromatic amino acids.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0007] This invention discloses a method for synthesizing chiral α-non-natural aromatic amino acid derivatives under visible light. Compound 1 is in situ coordinated with a ligand under the action of a catalyst, and then undergoes a photocatalytic coupling reaction with compound 2 under the action of an additive to obtain compound 3, which is a chiral α-non-natural aromatic amino acid derivative.

[0008]

[0009] The ligand is (S)-(+)-4,12-bis(diphenylphosphine)-[2.2]-p-cycloarane or (R)-(-)-4,12-bis(diphenylphosphine)-[2.2]-p-cycloarane;

[0010] When the ligand is (S)-(+)-4,12-bis(diphenylphosphine)-[2,2]-p-cycloarane, the structure of compound 3 is as follows:

[0011]

[0012] When the ligand is (R)-(-)-4,12-bis(diphenylphosphine)-[2,2]-p-cycloarane, the structure of compound 3 is as follows:

[0013]

[0014] in,

[0015] R' is

[0016] R is selected from C1-C6 alkoxy or C1-C6 alkylamino;

[0017] Ar is selected from substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups.

[0018] In some embodiments, preferably, the ligand is (S)-(+)-4,12-bis(diphenylphosphine)-[2,2]-p-cycloaramine.

[0019] In some embodiments, preferably

[0020] R is selected from C1-C6 alkoxy or C1-C6 alkylamino;

[0021] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indolyl; wherein the substitution is selected from any one or more identical or different groups selected from halogen, C1-C6 alkyl, phenyl, C1-C6 alkoxy, phenoxy, tert-butoxycarbonylamino and tert-butyldimethylsiloxy.

[0022] In some embodiments, more preferably

[0023] R is selected from C2-C4 alkoxy or C4 alkylamino;

[0024] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indolyl; wherein the substitution is selected from any one or more identical or different groups selected from F, Cl, Br, methyl, n-pentyl, phenyl, methoxy, phenoxy, tert-butoxycarbonylamino, and tert-butyldimethylsiloxy.

[0025] In some embodiments, more preferably

[0026] R is selected from ethoxy, tert-butoxy, or tert-butamino;

[0027] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indolyl; wherein the substitution is selected from any one or more identical or different groups selected from F, Cl, Br, methyl, n-pentyl, phenyl, methoxy, phenoxy, tert-butoxycarbonylamino, and tert-butyldimethylsiloxy.

[0028] In some embodiments, the catalyst is any one or a combination of several of cuprous bromide, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, and copper trifluoromethanesulfonate.

[0029] In some embodiments, preferably, the catalyst is copper trifluoromethanesulfonate.

[0030] In some embodiments, the additive is triethylenediamine.

[0031] In some embodiments, the molar ratio of compound 1 to catalyst is 1.0:(0.10 to 0.25); the molar ratio of catalyst to ligand is 1.0:(1.0 to 1.3).

[0032] In some embodiments, preferably, the molar ratio of compound 1 to catalyst is 1:0.2; and the molar ratio of catalyst to ligand is 1:1.1.

[0033] In some embodiments, compound 1 coordinates in situ with a ligand under the action of a catalyst, and the coordination is carried out under inert gas protection and at room temperature.

[0034] The solvent used in the in-situ coordination process is preferably any one or a combination of several of ethyl acetate, dichloromethane and acetone, and more preferably acetone. There are no special requirements for the amount of solvent used; it is sufficient to dissolve and disperse the raw materials evenly.

[0035] The inert gas is preferably argon.

[0036] Wherein, compound 1 coordinates with the ligand in situ under the action of a catalyst, and the time required is 30 to 60 minutes, preferably 40 minutes.

[0037] In some embodiments, the molar ratio of compound 1 to additive is 1.0:(0.2 to 1.0); the molar ratio of compound 1 to compound 2 is 1.0:(1.0 to 2.0).

[0038] In some embodiments, preferably, the molar ratio of compound 1 to the additive is 1:0.5; and the molar ratio of compound 1 to compound 2 is 1.0:1.5.

[0039] In some embodiments, the wavelength of the light in the photocatalytic coupling reaction is 400 nm to 530 nm; the luminous intensity of the light source is 7.5 W to 45 W.

[0040] In some embodiments, preferably, the wavelength of light in the photocatalytic coupling reaction is 445 nm to 455 nm.

[0041] In some embodiments, preferably, the light source has a luminous intensity of 15W.

[0042] In some embodiments, the photocatalytic coupling reaction is carried out under inert gas protection at room temperature.

[0043] The solvent used in the photocatalytic coupling reaction is preferably any one or a combination of several of ethyl acetate, dichloromethane and acetone, and more preferably acetone. There are no special requirements for the amount of solvent used; it is sufficient to dissolve and disperse the raw materials evenly.

[0044] The inert gas is preferably argon.

[0045] The photocatalytic coupling reaction has a reaction time of 12 to 48 hours, preferably 36 hours.

[0046] Furthermore, the chiral α-non-natural aromatic amino acid derivative (compound 3) prepared above can be further derivatized to prepare chiral α-non-natural aromatic amino acid raw materials. Specific derivatization methods can refer to existing techniques (Visible Light Induced Cu-Catalyzed Asymmetric C(sp3)-H Alkylation, J. Am. Chem. Soc. 2021, 143, 12777-12783), or can be carried out according to the following steps:

[0047]

[0048] Compound 3 undergoes a first reaction in the presence of cerium ammonium nitrate, followed by a coupling reaction with fluorenyl chloroformate in the presence of a base to give compound 5;

[0049] in,

[0050] R' is

[0051] R is selected from C1-C6 alkoxy or C1-C6 alkylamino;

[0052] Ar is selected from substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups.

[0053] In some embodiments, the molar ratio of compound 3 to cerium ammonium nitrate is 1:3 to 8, preferably 1:6; the first reaction is carried out at a temperature of -10°C to 10°C for 1 to 4 hours, preferably 2 hours.

[0054] The solvent used in the first reaction is preferably a mixture of water and acetonitrile in any proportion, more preferably a water-acetonitrile volume ratio of (1-5):2, and even more preferably 5:2. There are no special requirements for the amount of solvent used; it is sufficient to dissolve and disperse the raw materials evenly.

[0055] In some embodiments, the base is preferably triethylamine; the molar ratio of compound 3 to the base and chloroformate-9-fluorenylmethyl ester is 1.0:(1.0-2.0):(1.0-2.0), preferably 1.0:1.25:1.25.

[0056] The coupling reaction is carried out at room temperature for 1 to 4 hours, preferably 2 hours.

[0057] The solvent used in the coupling reaction is preferably dichloromethane. There are no special requirements for the amount of solvent used; it is sufficient to dissolve and disperse the raw materials evenly.

[0058] Beneficial effects:

[0059] (1) This invention provides a novel and universal strategy for synthesizing chiral α-non-natural aromatic amino acids. By establishing a new method, it enables the efficient construction of all types of chiral α-non-natural aromatic amino acids, perfectly avoiding the defect that traditional synthesis methods can only synthesize one type of chiral α-non-natural aromatic amino acid.

[0060] (2) There are a wide variety of natural carboxylic acids in nature. This invention uses redox active esters derived from aromatic acetic acid as aryl donors, which provides a guarantee for the structural diversity synthesis of chiral α-non-natural aromatic amino acids. This can greatly enrich the non-natural amino acid compound library and help the development of innovative peptide drugs.

[0061] (3) The improvement over existing technologies is that the present invention breaks through the limitation of previous technologies that could only synthesize one type of chiral α-non-natural aromatic amino acid. Starting from glycine, the most basic structural skeleton of amino acids, the invention creatively develops C(sp... 3 An enantioselective functionalization modification method for α-H bonds was developed, establishing a general synthetic strategy for the efficient synthesis of chiral α-non-natural aromatic amino acids.

[0062] (4) The raw material sources for synthesizing chiral α-non-natural aromatic amino acids in this invention are more extensive and the product structure is more abundant, providing a continuous and rich source of compounds for exploring innovative peptide drugs.

[0063] (5) Compared with the inventor's earlier research results (Visible Light Induced Cu-Catalyzed Asymmetric C(sp3)-H Alkylation, J.Am.Chem.Soc.2021,143,12777-12783), in the prior art, the reaction of cycloarane using ligand (S)-(+)-4,12-bis(diphenylphosphine)-[2.2]- cannot proceed smoothly; and when other ligands are used to catalyze the synthesis of the isomer of compound 3dy of the present invention, the ee value of the product is only 71%, and the optical purity is low; while in this application, when ligand (S)-(+)-4,12-bis(diphenylphosphine)-[2.2]- is used to catalyze the synthesis of compound 3dy of cycloarane, the ee value is as high as 95%. Attached Figure Description

[0064] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0065] Figure 1This is the 1H NMR spectrum of compound 3aa.

[0066] Figure 2 This is the carbon NMR spectrum of compound 3aa.

[0067] Figure 3 This is the 1H NMR spectrum of compound 5aa.

[0068] Figure 4 This is the carbon NMR spectrum of compound 5aa. Detailed Implementation

[0069] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0070] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0071] All compound structures in this invention were drawn using KingDraw.

[0072] 1. Reagents

[0073] The specific compound structural formulas of glycine derivative 1 used in the embodiments of the present invention are shown in Table 1.

[0074] Table 1

[0075]

[0076] The specific compound structures of the aromatic acetic acid-derived redox active ester 2 used in the embodiments of the present invention are shown in Table 2.

[0077] Table 2

[0078]

[0079]

[0080]

[0081] The specific compound structures of the ligands used in the embodiments of this invention are shown in Table 3.

[0082] Table 3

[0083]

[0084] Example 1: Synthesis of 3aa

[0085] In a 20 mL dry reaction flask equipped with a stir bar, glycine derivative 1a (0.2 mmol, 57.6 mg), copper trifluoromethanesulfonate (0.04 mmol, 14.4 mg), and (S)-(+)-4,12-bis(diphenylphosphine)-[2,2]-p-cycloarane (0.044 mmol, 25.6 mg) were added sequentially. After purging the reaction flask with air and replacing it with argon, 2 mL of acetone was added via syringe and the mixture was stirred at room temperature for 40 minutes. Subsequently, aromatic acetic acid-derived redox reactive ester 2a (0.3 mmol, 84.3 mg) and triethylenediamine (0.1 mmol, 11.2 mg) were dissolved in 4 mL of acetone and added to the reaction flask via syringe. The reaction flask was then transferred to a blue light reactor (445–455 nm, 15 W) and irradiated at room temperature for 36 hours. After the reaction was complete, the product was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The purified product was then obtained by silica gel column chromatography with hexane / ethyl acetate as the eluent, yielding the target product 3aa. The structure and characterization data of compound 3aa are as follows:

[0086] Yellow liquid, yield 77% (58.2 mg), ee value 93% (HPLC, Chiralpak IA-H column separation, n-hexane / isopropanol = 20 / 1). The 1H NMR spectrum of compound 3aa is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 As shown:

[0087] HRMS(ESI):C 23 H 27 N₂O₃[M+H] + Theoretical value: 379.2015, measured value: 379.2013.

[0088] 1 H NMR (300MHz, CDCl3) δ8.77(d,J=3.9Hz,1H),8.47(d,J=8.4Hz,1H),7.37(q,J=4.2Hz,1H),7.30-7.22(m,5H),6.71(d,J=8.1Hz ,1H),6.58(d,J=8.4Hz,1H),6.33(d,J=8.7Hz,1H),4.36(dd,J=14.4,7.5Hz,1H),3.90(s,3H),3.30-3.17(m,2H),1.28(s,9H). 13C NMR (75MHz, CDCl3) δ172.40,147.79,146.17,139.01,137.57,137.18,130.58,129.45 ,128.26,126.62,121.11,120.58,105.21,105.11,81.26,58.93,55.80,38.91,27.84.

[0089] Example 2: Synthesis of 3aa'

[0090] The preparation method was the same as in Example 1, except that the ligand (S)-(+)-4,12-bis(diphenylphosphine)-[2,2]-p-cycloarane was replaced with (R)-(-)-4,12-bis(diphenylphosphine)-[2,2]-p-cycloarane, finally yielding the target product 3aa'. The structure and characterization data of compound 3aa' are as follows:

[0091] Yellow liquid, yield 75% (56.9 mg), ee value -92% (HPLC, Chiralpak IA-H column separation, n-hexane / isopropanol = 20 / 1).

[0092] HRMS(ESI):C 23 H 27 N₂O₃[M+H] + Theoretical value: 379.2015, measured value: 379.2013.

[0093] 1 H NMR (300MHz, CDCl3) δ8.77(d,J=3.9Hz,1H),8.47(d,J=8.4Hz,1H),7.37(q,J=4.2Hz,1H),7.30-7.22(m,5H),6.71(d,J=8.1Hz ,1H),6.58(d,J=8.4Hz,1H),6.33(d,J=8.7Hz,1H),4.36(dd,J=14.4,7.5Hz,1H),3.90(s,3H),3.30-3.17(m,2H),1.28(s,9H). 13 C NMR (75MHz, CDCl3) δ172.40,147.79,146.17,139.01,137.57,137.18,130.58,129.45 ,128.26,126.62,121.11,120.58,105.21,105.11,81.26,58.93,55.80,38.91,27.84.

[0094] Example 3: Synthesis of 3ab

[0095] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2b, and copper trifluoromethanesulfonate is replaced with cuprous bromide. Using glycine derivative 1a and aromatic acetic acid-derived redox active ester 2b as raw materials, and cuprous bromide as a catalyst, the target product 3ab is finally obtained. The structure and characterization data of compound 3ab are as follows:

[0096] Yellow liquid, yield 84% (66.6 mg), ee value 93% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0097] HRMS(ESI):C 23 H 26 FN2O3[M+H] + Theoretical value: 397.1921, measured value: 397.1913.

[0098] 1 H NMR (300MHz, CDCl3) δ8.78-8.77(m,1H),8.48(d,J=8.4Hz,1H),7.38(q,J=4.2Hz,1H),7.25(t,J=5.4Hz,2H),6.97(t,J=8.7Hz,2H),6. 71(d,J=8.4Hz,1H),6.57(d,J=8.4Hz,1H),6.32(d,J=7.8Hz,1H),4.36-4.32(m,1H),3.91(s,3H),3.21(d,J=6.3Hz,2H),1.30(s,9H). 13 C NMR (75MHz, CDCl3) δ172.23,147.86,146.28,139.01,137.45,132.89,132.85,130.99,130.89 ,130.66,121.15,120.65,115.21,114.93,105.26,105.09,81.46,58.92,55.83,37.93,27.89. 19 F NMR (564.67MHz, CDCl3) δ116.51.

[0099] Example 4: Synthesis of 3ac

[0100] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2c, and copper trifluoromethanesulfonate is replaced with copper hexafluorophosphate tetraacetonitrile. Using glycine derivative 1a and aromatic acetic acid-derived redox active ester 2c as raw materials, and copper hexafluorophosphate tetraacetonitrile as a catalyst, the target product 3ac is finally obtained. The structure and characterization data of compound 3ac are as follows:

[0101] Yellow liquid, yield 78% (64.4 mg), ee value 91% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0102] HRMS(ESI):C 23 H 26 ClN2O3[M+H] + Theoretical value: 413.1626, measured value: 413.1620.

[0103] 1 H NMR (300MHz, CDCl3) δ8.80-8.79(m,1H),8.47(d,J=8.4Hz,1H),7.39-7.32(m,3H),7.18-7.15(m,2H),6.71(d ,J=8.1Hz,1H),6.61(d,J=8.4Hz,1H),6.36(s,1H),4.52(s,1H),3.90(s,3H),3.46-3.24(m,2H),1.27(s,9H). 13 C NMR (75MHz, CDCl3) δ172.39,147.81,146.24,139.01,137.57,135.28,134.38,131.80,130.64 ,129.43,128.15,126.69,121.11,120.59,105.44,105.17,81.35,57.19,55.84,37.26,27.83.

[0104] Example 5: Synthesis of 3ad

[0105] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2d, and copper trifluoromethanesulfonate is replaced with copper tetrafluoroborate tetraacetonitrile. Using glycine derivative 1a and aromatic acetic acid-derived redox active ester 2d as raw materials, and copper tetrafluoroborate tetraacetonitrile as a catalyst, the target product 3ad is finally obtained. The structure and characterization data of compound 3ad are as follows:

[0106] Yellow liquid, yield 69% (56.9 mg), ee value 94% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0107] HRMS(ESI):C 23 H 26 ClN2O3[M+H] + Theoretical value: 413.1626, measured value: 413.1618.

[0108] 1 H NMR (300MHz, CDCl3) δ8.79(d,J=4.2Hz,1H),8.49(d,J=8.4Hz,1H),7.39(q,J=4.2Hz,1H),7.28(s,1H),7.19(dd,J=10.5,6.0Hz,3H),6 .73(d,J=8.4Hz,1H),6.59(d,J=8.4Hz,1H),6.33(d,J=5.1Hz,1H),4.36(d,J=5.4Hz,1H),3.92(s,3H),3.27-3.14(m,2H),1.31(s,9H). 13 C NMR (75MHz, CDCl3) δ172.02,147.91,146.36,139.22,137.32,134.00,130.67,129.63,129 .54,127.72,126.85,121.18,120.68,105.38,105.08,81.65,58.69,55.84,38.36,27.89.

[0109] Example 6: Synthesis of 3ae

[0110] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2e, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2e are used as raw materials to finally obtain the target product 3ae. The structure and characterization data of compound 3ae are as follows:

[0111] Yellow liquid, yield 79% (65.1 mg), ee value 91% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0112] HRMS(ESI):C 23 H 26 ClN2O3[M+H] + Theoretical value: 413.1626, measured value: 413.1627.

[0113] 1 H NMR (300MHz, CDCl3) δ8.78-8.77(m,1H),8.48(d,J=8.4Hz,1H),7.38(q,J=4.2Hz,1H),7.25-7.20(m,4H),6.71(d,J=8.4Hz ,1H),6.56(d,J=8.4Hz,1H),6.32(d,J=8.1Hz,1H),4.34(d,J=6.9Hz,1H),3.91(s,3H),3.20(d,J=6.6Hz,2H),1.31(s,9H). 13 CNMR (75MHz, CDCl3) δ172.10,147.88,146.31,139.01,137.39,135.70,132.49,130.83 ,130.66,128.38,121.16,120.66,105.27,105.08,81.56,58.74,55.83,38.03,27.90.

[0114] Example 7: Synthesis of 3af

[0115] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2f, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2f are used as raw materials to finally obtain the target product 3af. The structure and characterization data of compound 3af are as follows:

[0116] Yellow liquid, yield 82% (74.8 mg), ee value 93% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0117] HRMS(ESI):C 23 H 26 BrN2O3[M+H] + Theoretical value: 457.1121, measured value: 457.1115.

[0118] 1H NMR (300MHz, CDCl3) δ8.78(d,J=3.9Hz,1H),8.48(d,J=8.1Hz,1H),7.41-7.37(m,3H),7.16(d,J=7.8Hz,2H),6.72(d,J=8.4H z,1H),6.56(d,J=8.4Hz,1H),6.31(d,J=7.8Hz,1H),4.34(d,J=6.3Hz,1H),3.92(s,3H),3.19(d,J=6.6Hz,2H),1.31(s,9H). 13 CNMR(75MHz, CDCl3)δ172.07,147.88,146.31,139.01,137.37,136.22,131.34,131.22 ,130.67,121.16,120.67,120.58,105.27,105.08,81.59,58.67,55.84,38.09,27.91.

[0119] Example 8: Synthesis of 3ag

[0120] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2g, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2g are used as raw materials to finally obtain the target product 3ag. The structure and characterization data of compound 3ag are as follows:

[0121] Yellow liquid, yield 86% (67.5 mg), ee value 94% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0122] HRMS(ESI):C 24 H 29 N₂O₃[M+H] + Theoretical value: 393.2172, measured value: 393.2168.

[0123] 1H NMR (300MHz, CDCl3) δ8.77(d,J=3.9Hz,1H),8.47(d,J=8.4Hz,1H),7.36(q,J=4.2Hz,1H),7.18(d,J=7.8Hz,2H),7.09(d,J=7.8Hz,2H),6.71(d, J=8.4Hz,1H),6.57(d,J=8.4Hz,1H),6.31(d,J=8.1Hz,1H),4.33(q,J=6.9Hz,1H),3.90(s,3H),3.20(d,J=6.9Hz,2H),2.31(s,3H),1.30(s,9H). 13 C NMR (75MHz, CDCl3) δ172.50,147.77,146.13,139.02,137.65,136.10,134.05,130.58,12 9.30,128.96,121.12,120.57,105.22,105.17,81.22,59.04,55.83,38.43,27.88,21.04.

[0124] Example 9: Synthesis of 3ah

[0125] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2h, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2h are used as raw materials to finally obtain the target product 3ah. The structure and characterization data of compound 3ah are as follows:

[0126] White solid, melting point 41-42℃, yield 79% (70.8 mg), ee value 94% (high performance liquid chromatography, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0127] HRMS(ESI):C 28 H 37 N₂O₃[M+H] + Theoretical value: 449.2798, Measured value: 449.2798.

[0128] 1H NMR (300MHz, CDCl3) δ8.77(d,J=3.9Hz,1H),8.47(d,J=8.1Hz,1H),7.37(q,J=4 .2Hz,1H),7.21(d,J=7.8Hz,2H),7.09(d,J=7.5Hz,2H),6.71(d,J=8.4Hz,1H),6 .57(d,J=8.1Hz,1H),6.32(s,1H),4.33(s,1H),3.90(s,3H),3.27-3.13(m,2H) ,2.56(t,J=7.5Hz,2H),1.63-1.54(m,2H),1.28(s,13H),0.88(t,J=6.3Hz,3H). 13 CNMR (75MHz, CDCl3) δ172.56,147.78,146.15,141.21,139.02,137.66,134.30,130.59,129.31,128.33, 121.12,120.57,105.24,105.16,81.18,59.04,55.82,38.61,35.50,31.41,31.20,27.86,22.52,14.01.

[0129] Example 10: Synthesis of 3ai

[0130] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2i, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2i are used as raw materials to finally obtain the target product 3ai. The structure and characterization data of compound 3ai are as follows:

[0131] Yellow liquid, yield 73% (66.3 mg), ee value 95% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0132] HRMS(ESI):C 29 H 31 N₂O₃[M+H] + Theoretical value: 455.2328, measured value: 455.2325.

[0133] 1H NMR (300MHz, CDCl3) δ8.79-8.78(m,1H),8.48(d,J=8.4Hz,1H),7.55(dd,J=15.9,8.4Hz,4H),7.44-7.30(m,6H),6.72(d,J=8.4H z,1H),6.60(d,J=8.4Hz,1H),6.37(d,J=8.1Hz,1H),4.40(dd,J=13.5,7.2Hz,1H),3.90(s,3H),3.34-3.22(m,2H),1.30(s,9H). 13 C NMR (75MHz, CDCl3) δ172.40,147.84,146.23,140.98,139.53,139.04,137.57,136.33,130.63,129 .89,128.69,127.08,126.99,121.15,120.62,105.29,105.14,81.39,58.93,55.83,38.52,27.90.

[0134] Example 11: Synthesis of 3aj

[0135] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2j, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2j are used as raw materials to finally obtain the target product 3aj. The structure and characterization data of compound 3aj are as follows:

[0136] Yellow liquid, yield 64% (52.3 mg), ee value 93% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0137] HRMS(ESI):C 24 H 29 N₂O₄[M+H] + Theoretical value: 409.2121, measured value: 409.2117.

[0138] 1H NMR (300MHz, CDCl3) δ8.78-8.76(m,1H),8.47(d,J=8.4Hz,1H),7.36(q,J=4.2Hz,1H),7.21(d,J=8.1Hz,2H),6.82(d,J=8.1Hz,2H),6.71(d,J=8.4 Hz,1H),6.57(d,J=8.4Hz,1H),6.31(d,J=9.0Hz,1H),4.32(dd,J=15.3,7 .2Hz,1H),3.90(s,3H),3.76(s,3H),3.18(d,J=6.6Hz,2H),1.30(s,9H). 13 C NMR (75MHz, CDCl3) δ172.51,158.38,147.79,146.14,139.01,137.63,130.59,130.44,12 9.21,121.12,120.58,113.70,105.22,105.16,81.23,59.09,55.82,55.20,37.96,27.90.

[0139] Example 12: Synthesis of 3ak

[0140] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2k, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2k are used as raw materials to finally obtain the target product 3ak. The structure and characterization data of compound 3ak are as follows:

[0141] Yellow liquid, yield 74% (69.6 mg), ee value 93% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0142] HRMS(ESI):C 29 H 31 N₂O₄[M+H] + Theoretical value: 471.2278, measured value: 471.2280.

[0143] 1H NMR (300MHz, CDCl3) δ8.76-8.74(m,1H),8.47(d,J=8.7Hz,1H),7.37(q,J=4.2 Hz,1H),7.28-7.22(m,3H),7.06(t,J=6Hz,2H),6.95(d,J=8.7Hz,3H),6.87(d ,J=7.8Hz,1H),6.70(d,J=8.4Hz,1H),6.54(d,J=8.4Hz,1H),6.33(d,J=7.2Hz ,1H),4.34(d,J=6.6Hz,1H),3.91(s,3H),3.20(d,J=6.6Hz,2H),1.31(s,9H). 13 C NMR (75MHz, CDCl3) δ172.24,157.18,157.07,147.81,146.20,139.23,138.99,137.52,130.60,129.62,129.56 ,124.46,123.04,121.13,120.61,120.02,118.73,117.22,105.19,105.12,81.44,58.81,55.84,38.76,27.91.

[0144] Example 13: Synthesis of 3al

[0145] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2l, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2l are used as raw materials to finally obtain the target product 3al. The structure and characterization data of compound 3al are as follows:

[0146] Yellow liquid, yield 84% (82.9 mg), ee value 97% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane / isopropanol = 9 / 1).

[0147] HRMS(ESI):C 28 H 36 N3O5[M+H] + Theoretical value: 494.2629, measured value: 494.2642.

[0148] 1H NMR (300MHz, CDCl3) δ8.76(d,J=3.9Hz,1H),8.46(d,J=8.4Hz,1H),7.35(q,J=4.2Hz,1H),7.27(d,J=8.4Hz,2H),7.19(d,J=8.1Hz,2H),6.7 1(d,J=8.1Hz,1H),6.57(d,J=7.8Hz,2H),6.32(s,1H),4.31(d,J=5.7Hz,1H),3.89(s,3H),3.17(d,J=6.6Hz,2H),1.49(S,9H),1.31(s,9H). 13 C NMR (75MHz, CDCl3) δ172.37,152.69,147.74,146.08,138.94,137.52,136.94,131.61,130.53,12 9.90,121.06,120.54,118.30,105.17,105.12,81.27,80.25,58.91,55.76,38.04,28.27,27.87.

[0149] Example 14: Synthesis of 3am

[0150] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2m, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2m are used as raw materials to finally obtain the target product 3am. The structure and characterization data of compound 3am are as follows:

[0151] Yellow solid, melting point 119-120℃, yield 75% (64.2 mg), ee value 93% (high performance liquid chromatography, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0152] HRMS(ESI):C 27 H 29 N₂O₃[M+H] + Theoretical value: 429.2172, measured value: 429.2170.

[0153] 1H NMR (300MHz, CDCl3) δ8.77-8.76(m,1H),8.47(d,J=8.4Hz,1H),7.77(dd,J=15.6,8.1Hz,4H),7.45-7.41(m,3H),7.39-7.34(m,1H),6.7 1(d,J=8.4Hz,1H),6.62(d,J=8.4Hz,1H),6.39(d,J=6.6Hz,1H),4.47(d,J=6.0Hz,1H),3.89(s,3H),3.40(d,J=6.6Hz,2H),1.25(s,9H). 13 C NMR (75MHz, CDCl3) δ172.40,147.82,146.22,139.04,137.56,134.73,133.40,132.34,130.61,128.07,127.86 ,127.73,127.57,127.53,125.88,125.38,121.14,120.61,105.34,105.14,81.35,58.96,55.82,38.99,27.85.

[0154] Example 15: Synthesis of 3an

[0155] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2n, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2n are used as raw materials to finally obtain the target product 3an. The structure and characterization data of compound 3an are as follows:

[0156] Yellow liquid, yield 85% (65.3 mg), ee value 94% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0157] HRMS(ESI):C 21 H 25 N₂O₃S[M+H] + Theoretical value: 385.1580, measured value: 385.1576.

[0158] 1H NMR (300MHz, CDCl3) δ8.78(d,J=3.9Hz,1H),8.48(d,J=8.4Hz,1H),7.38(q,J=4.2Hz,1H),7.25-7.23(m,1H),7.11(S,1H),7.05(d,J=4. 8Hz,1H),6.72(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),6.35(s,1H),4.35(d,J=5.4Hz,1H),3.91(s,3H),3.34-3.22(m,2H),1.32(s,9H). 13 C NMR (75MHz, CDCl3) δ172.37,147.84,146.20,139.01,137.55,137.28,130.63,128.73 ,125.28,122.50,121.15,120.63,105.19,105.15,81.35,58.26,55.84,33.24,27.87.

[0159] Example 16: Synthesis of 3ao

[0160] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2o, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2o are used as raw materials to finally obtain the target product 3ao. The structure and characterization data of compound 3ao are as follows:

[0161] Yellow liquid, yield 70% (60.0 mg), ee value 95% (high performance liquid chromatography, Chiralpak AD-H column separation, n-hexane / isopropanol = 2 / 1).

[0162] HRMS(ESI):C 26 H 28 N3O3[M+H] + Theoretical value: 430.2124, measured value: 430.2118.

[0163] 1H NMR (300MHz, CDCl3) δ8.87(d,J=3.9Hz,1H),8.77(d,J=3.9Hz,1H),8.48(d,J=8.4Hz,1H),8.06-8.03(m,2H),7.69(d,J=8.1Hz,2H),7.41-7.34(m,2H ),6.72(d,J=8.1Hz,1H),6.62(d,J=8.1Hz,1H),6.39(d,J=9.3Hz,1H),4.4 9(dd,J=14.7,7.8Hz,1H),3.91(s,3H),3.43(d,J=6.6Hz,2H),1.26(s,9H). 13 C NMR (75MHz, CDCl3) δ172.17,150.00,147.86,147.38,146.33,139.03,137.39,135.71,135.66,131.41 ,130.65,129.31,128.10,127.89,121.13,120.65,105.41,105.05,81.55,58.79,55.80,38.68,27.85.

[0164] Example 17: Synthesis of 3ap

[0165] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2p. Using glycine derivative 1a and aromatic acetic acid-derived redox active ester 2p as raw materials, the target product 3ap is finally obtained. The structure and characterization data of 3ap are as follows:

[0166] Yellow solid, melting point 60-61℃, yield 77% (64.5 mg), ee value 94% (high performance liquid chromatography, Chiralpak AD-H column separation, n-hexane / isopropanol = 2 / 1).

[0167] HRMS(ESI):C 25 H 28 N3O3[M+H] + Theoretical value: 418.2124, measured value: 418.2119.

[0168] 1H NMR (300MHz, CDCl3) δ8.74(d,J=3.9Hz,1H),8.46(d,J=8.4Hz,1H),8.19(s,1H),7.68(d,J=7.2Hz,1H),7.34(q,J=4.2Hz,1H),7.28(d,J=7.8Hz,1H) ,7.17-7.07(m,3H),6.70(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),6.40(s ,1H),4.46(t,J=5.4Hz,1H),3.89(s,3H),3.47-3.34(m,2H),1.26(s,9H). 13 C NMR (75MHz, CDCl3) δ173.02,147.72,146.07,138.96,137.83,136.06,130.63,127.60,123.01,121 .80,121.12,120.56,119.18,118.83,111.13,111.07,105.25,81.13,58.08,55.83,28.54,27.82.

[0169] Example 18: Synthesis of 3aq

[0170] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2q. Using glycine derivative 1a and aromatic acetic acid-derived redox active ester 2q as raw materials, the target product 3aq is finally obtained. The structure and characterization data of compound 3aq are as follows:

[0171] Yellow liquid, yield 54% (46.5 mg), ee value 95% (high performance liquid chromatography, Chiralpak AD-H column separation, n-hexane / isopropanol = 2 / 1).

[0172] HRMS(ESI):C 26 H 30 N3O3[M+H] + Theoretical value: 432.2281, measured value: 432.2279.

[0173] 1H NMR(300MHz, CDCl3)δ8.74(d,J=3.9Hz,1H),8.45(d,J=8.4Hz,1H),8.05(s,1H), 7.53(d,J=7.8Hz,1H),7.33(q,J=4.2Hz,1H),7.10(s,1H),7.03(t,J=7.2Hz,1H), 6.94(d,J=6.9Hz,1H),6.69(d,J=8.4Hz,1H),6.57(d,J=8.4Hz,1H),6.40(s,1H), 4.46(t,J=6.3Hz,1H),3.88(s,3H),3.48-3.33(m,2H),2.34(s,3H),1.26(s,9H). 13 C NMR (75MHz, CDCl3) δ173.06,147.69,146.03,138.95,137.84,135.64,130.59,127.10,122.75,122.31,12 1.10,120.53,120.25,119.38,116.50,111.57,105.26,105.21,81.12,58.10,55.82,28.66,27.86,16.46.

[0174] Example 19: Synthesis of 3ar

[0175] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2r. Using glycine derivative 1a and aromatic acetic acid-derived redox active ester 2r as raw materials, the target product 3ar is finally obtained. The structure and characterization data of compound 3ar are as follows:

[0176] Yellow liquid, yield 75% (65.5 mg), ee value 95% (high performance liquid chromatography, Chiralpak AD-H column separation, n-hexane / isopropanol = 2 / 1).

[0177] HRMS(ESI):C 25 H 27 FN3O4[M+H] + Theoretical value: 436.2030, measured value: 436.2024.

[0178] 1H NMR (300MHz, CDCl3) δ8.72(d,J=3.9Hz,1H),8.47-8.43(m,2H),7.35-7.24(m,2H),7.10-7.06(m,2H),6.83(d,J=9.0Hz,1H),6 .71(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),6.40(s,1H),4.44(t,J=6.3Hz,1H),3.89(s,3H),3.41-3.27(m,2H),1.29(s,9H). 13 CNMR(75MHz, CDCl3)δ172.97,147.76,146.20,138.92,137.61,132.54,130.71,127.90,127.77,125.00,121.14,120.60 ,111.79,111.66,110.89,110.83,110.18,109.83,105.31,105.20,103.78,103.47,81.41,57.90,55.80,28.31,27.84. 19 F NMR (564.67MHz, CDCl3) δ125.04.

[0179] Example 20: Synthesis of 3as

[0180] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2s, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2s are used as raw materials to finally obtain the target product 3as. The structure and characterization data of compound 3as are as follows:

[0181] Yellow solid, melting point 209-210℃, yield 64% (58.0 mg), ee value 95% (high performance liquid chromatography, Chiralpak IC-H column separation, n-hexane / ethanol = 2 / 1).

[0182] HRMS(ESI):C 25 H 27 ClN3O3[M+H] + Theoretical value: 452.1735, measured value: 452.1724.

[0183] 1H NMR (300MHz, CDCl3) δ8.76(d,J=4.2Hz,1H),8.46(d,J=8.4Hz,1H),8.41(s,1H),7.34(q,J=4.2Hz,1H),7.13(q,J=7.8Hz,1H),7.08-6.9 7(m,3H),6.67(d,J=8.4Hz,1H),6.57(d,J=8.4Hz,1H),6.34(s,1H),4.58(t,J=6.6Hz,1H),3.87(s,3H),3.69-3.49(m,2H),1.28(s,9H). 13 C NMR (75MHz, CDCl3) δ173.42,147.70,146.09,138.91,137.95,137.69,130.69,126.10,124.82,124.16 ,122.31,121.09,120.53,120.36,111.62,109.99,105.56,105.30,80.96,59.10,55.83,30.15,27.86.

[0184] Example 21: Synthesis of 3at

[0185] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2t, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2t are used as raw materials to finally obtain the target product 3at. The structure and characterization data of compound 3at are as follows:

[0186] Yellow solid, melting point 71-72℃, yield 52% (46.5 mg), ee value 96% (high performance liquid chromatography, Chiralpak AD-H column separation, n-hexane / isopropanol = 2 / 1).

[0187] HRMS(ESI):C 25 H 27 ClN3O3[M+H] + Theoretical value: 452.1735, measured value: 452.1724.

[0188] 1H NMR (300MHz, CDCl3) δ8.74(d,J=3.9Hz,1H),8.46(d,J=8.4Hz,1H),8.41(s,1H),7.53(d,J=8.4Hz,1H),7.34(q,J=4.2Hz,1H),7.24(s,1H), 7.13(s,2H),6.71(d,J=8.4Hz,1H),6.57(d,J=8.4Hz,1H),6.41(s,1H),4.44(t,J=6.0Hz,1H),3.89(s,3H),3.43-3.29(m,2H),1.29(s,9H). 13 C NMR (75MHz, CDCl3) δ172.99,147.82,146.26,138.92,137.61,136.34,130.73,127.58,126.11,123.82 ,121.15,120.64,119.77,119.55,111.01,110.83,105.35,105.17,81.43,58.03,55.81,28.24,27.87.

[0189] Example 22: Synthesis of 3au

[0190] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2u. Using glycine derivative 1a and aromatic acetic acid-derived redox active ester 2u as raw materials, the target product 3au is finally obtained. The structure and characterization data of compound 3au are as follows:

[0191] Yellow solid, melting point 151–152 °C, yield 77% (64.3 mg), ee value 93% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 2 / 1).

[0192] HRMS(ESI):C 26 H 28 N3O3[M+H] + Theoretical value: 418.2124, measured value: 418.2117.

[0193] 1H NMR (300MHz, CDCl3) δ8.95(s,1H),8.84(d,J=3.9Hz,1H),8.52(d,J=8.4Hz,1H),7.54(d,J=7.2Hz,1H),7.41(q,J=4.2Hz,1H),7.23(d,J=7 .5Hz,1H),7.11-7.02(m,2H),6.68(q,J=8.1Hz,2H),6.47(s,1H),6.36(s,1H),4.42(s,1H),3.91(s,3H),3.46-3.28(m,2H),1.35(s,9H). 13 C NMR (75MHz, CDCl3) δ172.04,148.17,146.97,139.44,137.30,136.29,135.27,130.94,128.20,121.17 ,121.14,120.78,119.84,119.39,110.68,107.13,104.98,101.42,81.99,58.46,55.79,31.41,27.88.

[0194] Example 23: Synthesis of 3av

[0195] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2v, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2v are used as raw materials to finally obtain the target product 3av. The structure and characterization data of compound 3av are as follows:

[0196] Yellow liquid, yield 81% (94.7 mg), ee value 96% (high performance liquid chromatography, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0197] HRMS(ESI):C 29 H 40 BrN2O4Si[M+H] + Theoretical value: 587.1934, measured value: 587.1924.

[0198] 1H NMR (300MHz, CDCl3) δ8.79-8.77(m,1H),8.48(d,J=8.4Hz,1H),7.44(s,1H), 7.37(q,J=4.2Hz,1H),7.08(d,J=8.4Hz,1H),6.78(d,J=8.4Hz,1H),6.71(d, J=8.1Hz,1H),6.58(d,J=8.4Hz,1H),6.33(d,J=5.7Hz,1H),4.32(d,J=6.0Hz ,1H),3.90(s,3H),3.20-3.07(m,2H),1.31(s,9H),1.03(s,9H),0.22(s,6H). 13 C NMR (75MHz, CDCl3) δ172.15,151.28,147.84,146.23,138.99,137.36,134.18,131.34,130.59,129.33,1 21.10,120.60,119.96,114.94,105.31,105.03,81.49,58.80,55.77,37.55,27.89,25.70,18.29,-4.29.

[0199] Example 24: Synthesis of 3aw

[0200] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2w, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2w are used as raw materials to finally obtain the target product 3aw. The structure and characterization data of compound 3aw are as follows:

[0201] Yellow liquid, yield 87% (110.4 mg), ee value 93% (HPLC, Chiralpak IA-H column separation, n-hexane / isopropanol = 40 / 1).

[0202] HRMS(ESI):C 35 H 55 N₂O₅Si₂[M+H] + Theoretical value: 639.3643, measured value: 639.3639.

[0203] 1H NMR (300MHz, CDCl3) δ8.77(d,J=3.6Hz,1H),8.48(d,J=8.4Hz,1H),7.38(q,J=4.2Hz,1H),6.82(s,1H),6.77(s,2H),6.72(d,J=8.4Hz,1H),6.57( d,J=8.1Hz,1H),6.35(s,1H),4.30(s,1H),3.92(s,3H),3.15(d,J=6.6H z,2H),1.33(s,9H),1.00(s,9H),0.97(s,9H),0.20(s,6H),0.16(s,6H). 13 C NMR (75MHz, CDCl3) δ172.61,147.68,146.49,146.06,145.56,138.98,137.70,130.51,130.32,122.38,121.07,120.81 ,120.53,105.13,105.03,81.17,59.01,55.79,38.34,27.90,25.94,25.88,18.42,18.32,-4.13,-4.16,-4.21,-4.22.

[0204] Example 25: Synthesis of 3ax

[0205] The preparation method is the same as in Example 1, except that compound 2a is replaced with compound 2w, and glycine derivative 1a and aromatic acetic acid-derived redox active ester 2w are used as raw materials to finally obtain the target product 3ax. The structure and characterization data of compound 3ax are as follows:

[0206] Yellow liquid, yield 74% (84.6 mg), ee value 93% (HPLC, Chiralpak AD-H column separation, n-hexane / isopropanol = 20 / 1).

[0207] HRMS(ESI):C 31 H 45 N₂O₆Si[M+H] + Theoretical value: 569.3041, measured value: 569.3042.

[0208] 1H NMR (300MHz, CDCl3) δ8.74-8.73(m,1H),8.46(d,J=8.4Hz,1H),7.35(q,J=4.2Hz,1H),6.70(d,J=8.1Hz,1H),6.56(d,J=8.4Hz,1H),6. 46(s,2H),6.38(s,1H),4.34(t,J=6.0Hz,1H),3.89(s,3H),3.72(s,6H),3.18(d,J=6.3Hz,2H),1.32(s,9H),1.00(s,9H),0.11(s,6H). 13 C NMR (75MHz, CDCl3) δ172.39,151.28,147.65,146.02,138.94,137.50,132.99,130.54,129.31,121. 04,120.53,106.58,105.13,105.09,81.11,58.60,55.72,55.57,38.76,27.87,25.75,18.63,-4.75.

[0209] Example 26: Synthesis of 3bg

[0210] The preparation method is the same as in Example 1, except that compound 1a is replaced with compound 1b and compound 2a is replaced with compound 2g. Using glycine derivative 1b and aromatic acetic acid-derived redox active ester 2g as raw materials, the target product 3bg is finally obtained. The structure and characterization data of compound 3bg are as follows:

[0211] Yellow liquid, yield 84% (61.2 mg), ee value 80% (high performance liquid chromatography, Chiralpak IC-H column separation, n-hexane / ethanol = 8 / 1).

[0212] HRMS(ESI):C 22 H 25 N₂O₃[M+H] + Theoretical value: 365.1859, measured value: 365.1852.

[0213] 1H NMR (300MHz, CDCl3) δ8.77-8.76(m,1H),8.46(d,J=8.4Hz,1H),7.36(q,J=4.2Hz ,1H),7.16(d,J=7.5Hz,2H),7.09(d,J=7.8Hz,2H),6.69(d,J=8.4Hz,1H),6.55(d ,J=8.1Hz,1H),6.32(d,J=4.5Hz,1H),4.42(d,J=5.4Hz,1H),4.09(dd,J=13.8,7. 2Hz, 2H), 3.88 (s, 3H), 3.23 (d, J = 6.6Hz, 2H), 2.30 (s, 3H), 1.11 (t, J = 7.2Hz, 3H). 13 CNMR (75MHz, CDCl3) δ173.34,147.78,146.20,138.90,137.34,136.21,133.72,13 0.58,129.09,121.08,120.59,105.06,60.76,58.56,55.72,38.46,21.00,14.06.

[0214] Example 27: Synthesis of 3cg

[0215] The preparation method is the same as in Example 1, except that compound 1a is replaced with compound 1c and compound 2a is replaced with compound 2g. Using glycine derivative 1c and aromatic acetic acid-derived redox active ester 2g as raw materials, the target product 3cg is finally obtained. The structure and characterization data of compound 3cg are as follows:

[0216] Yellow liquid, yield 68% (53.6 mg), ee value 94% (HPLC, Chiralpak IA-H column separation, n-hexane / isopropanol = 9 / 1).

[0217] HRMS(ESI):C 24 H 30 N3O2[M+H] + Theoretical value: 392.2332, measured value: 392.2329.

[0218] 1H NMR (300MHz, CDCl3) δ8.74(d,J=4.2Hz,1H),8.48(d,J=8.4Hz,1H),7.38(q,J=4.2Hz,1H),7.24(d,J=7.5Hz,2H),7.10(d,J=7.8Hz,2H),6.78(s,1H) ,6.70(d,J=8.4Hz,1H),6.52(d,J=8.1Hz,1H),6.16(s,1H),3.91(s,3H), 3.84(dd,J=8.1,4.2Hz,1H),3.35-3.11(m,2H),2.28(s,3H),1.29(s,9H). 13 C NMR (75MHz, CDCl3) δ172.34,147.96,146.90,138.89,137.56,136.26,134.08,130.86,12 9.23,129.18,120.81,120.68,106.60,104.81,62.13,55.71,50.63,38.65,28.49,21.02.

[0219] Example 28: Synthesis of 3dy

[0220] The preparation method is the same as in Example 1, except that compound 1a is replaced with compound 1d and compound 2a is replaced with compound 2y. Using glycine derivative 1d and aromatic acetic acid-derived redox active ester 2y as raw materials, the target product 3dy is finally obtained. The structure and characterization data of compound 3dy are as follows:

[0221] White liquid, yield 53% (50.8 mg), ee value 95% (high performance liquid chromatography, Chiralpak IA-H column separation, n-hexane / isopropanol = 9 / 1).

[0222] HRMS(ESI):C 28 H 39 N₂O₃Si[M+H] + Theoretical value: 479.2724, measured value: 479.2718.

[0223] 1H NMR (300MHz, CDCl3) δ8.73(d,J=3.9Hz,1H),8.03(d,J=8.1Hz,1H),7.37-7.30(m,2H),7.15(d,J=7.8Hz,2H),7.07(d,J=8.4Hz,1H) ,6.77-6.71(m,3H),6.64(d,J=7.8Hz,1H),4.36(dd,J=14.4,7.5Hz,1H),3.25-3.13(m,2H),1.32(s,9H),0.97(s,9H),0.17(s,6H). 13 C NMR (75MHz, CDCl3) δ172.13,154.42,147.12,143.40,138.36,135.77,130.45,129.65,128.5 8,127.37,121.38,119.95,114.78,105.40,81.47,58.32,38.00,27.89,25.67,18.19,-4.47.

[0224] Example 29: Synthesis of 5aa

[0225]

[0226] The derivatization method for compound 3aa can be found in existing technology (Visible Light Induced Cu-Catalyzed Asymmetric C(sp3)-H Alkylation, J.Am.Chem.Soc.2021,143,12777-12783), and the specific method is as follows:

[0227] Compound 3aa (0.2 mmol, 75.8 mg) and cerium ammonium nitrate (1.2 mmol, 657.8 mg) were dissolved in a water / acetonitrile mixture (5:2, 2.5 mL) and stirred at 0°C for 2 hours. After the reaction was complete, the pH of the mixture was adjusted to alkaline with saturated sodium carbonate solution. After extraction with dichloromethane, washing with saturated brine, and drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain the chiral α-non-natural aromatic amino acid ester intermediate 4aa. Intermediate 4aa was dissolved in 5 mL of dichloromethane, and 9-fluorenyl chloroformate (0.25 mmol, 64.7 mg) was added. The temperature was lowered to 0°C, and then triethylamine (0.25 mmol, 0.04 mL) was slowly added dropwise. Five minutes after the addition of triethylamine was completed, the reaction temperature was raised to room temperature and stirred for another 2 hours. After the reaction was complete, 25 mL of dichloromethane was added, and the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was then purified by silica gel column chromatography with hexane / ethyl acetate as the eluent to give the target product 5aa, a colorless liquid with a yield of 78% (69.1 mg) and an ee value of 92% (HPLC, Chiralpak IA-H column separation, hexane / isopropanol = 92 / 8-88.5 / 11.5). The 1H NMR spectrum of compound 5aa is shown below. Figure 3 The carbon NMR spectrum is shown below. Figure 4 The characterization data of compound 5aa are as follows:

[0228] HRMS(ESI):C 28 H 29 NNaO4[M+Na] + Theoretical value: 466.1989, Measured value: 466.1989.

[0229] 1 H NMR (600MHz, CDCl3) δ7.76(d,J=7.6Hz,2H),7.57(t,J=7.5Hz,2H),7.40(t,J=7.5Hz,2H),7.33–7.24(m,5H),7.15(d,J=7.3Hz,2H),5.30(d,J=8.1 Hz,1H),4.55(q,J=6.3Hz,1H),4.43(dd,J=10.7,7.2Hz,1H),4.32(dd,J=10.6,7.1Hz,1H),4.21(t,J=7.2Hz,1H),3.12–3.06(m,2H),1.41(s,9H). 13C NMR (151MHz, CDCl3) δ170.55,155.49,143.87,143.79,141.27,136.04,129.53,128.37,127.6 6,127.01,126.95,125.15,125.06,119.95,119.93,82.37,66.86,55.07,47.15,38.39,27.94.

[0230] This invention provides a method for synthesizing chiral α-non-natural aromatic amino acid derivatives under visible light-driven conditions. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for synthesizing chiral α-non-natural aromatic amino acid derivatives under visible light-driven conditions, characterized in that, Compound 1 coordinates with a ligand in situ under the action of a catalyst, and then undergoes a photocatalytic coupling reaction with compound 2 under the action of an additive to obtain compound 3, which is a chiral α-non-natural aromatic amino acid derivative. The ligand is (S)-(+)-4,12-bis(diphenylphosphine)-[2.2]-p-cycloarane or (R)-(-)-4,12-bis(diphenylphosphine)-[2.2]-p-cycloarane; When the ligand is (S)-(+)-4,12-bis(diphenylphosphine)-[2,2]-p-cycloarane, the structure of compound 3 is as follows: When the ligand is (R)-(-)-4,12-bis(diphenylphosphine)-[2,2]-p-cycloarane, the structure of compound 3 is as follows: in, R' is R is selected from C1-C6 alkoxy or C1-C6 alkylamino; Ar is selected from substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups.

2. The method according to claim 1, characterized in that, R is selected from C1-C6 alkoxy or C1-C6 alkylamino; Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indolyl; wherein the substitution is selected from any one or more identical or different groups selected from halogen, C1-C6 alkyl, phenyl, C1-C6 alkoxy, phenoxy, tert-butoxycarbonylamino and tert-butyldimethylsiloxy.

3. The method according to claim 1, characterized in that, R is selected from C2-C4 alkoxy or C4 alkylamino; Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indolyl; wherein the substitution is selected from any one or more identical or different groups selected from F, Cl, Br, methyl, n-pentyl, phenyl, methoxy, phenoxy, tert-butoxycarbonylamino, and tert-butyldimethylsiloxy.

4. The method according to claim 1, characterized in that, The catalyst is any one or a combination of several of the following: cuprous bromide, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, and copper trifluoromethanesulfonate.

5. The method according to claim 1, characterized in that, The additive mentioned is triethylenediamine.

6. The method according to claim 1, characterized in that, The molar ratio of compound 1 to catalyst is 1.0:(0.10-0.25); the molar ratio of catalyst to ligand is 1.0:(1.0-1.3).

7. The method according to claim 1, characterized in that, Compound 1 undergoes in-situ coordination with a ligand under the action of a catalyst, and the coordination is carried out under inert gas protection and at room temperature.

8. The method according to claim 1, characterized in that, The molar ratio of compound 1 to additive is 1.0:(0.2-1.0); the molar ratio of compound 1 to compound 2 is 1.0:(1.0-2.0).

9. The method according to claim 1, characterized in that, The photocatalytic coupling reaction uses light with a wavelength of 400 nm to 530 nm and a light source with an luminous intensity of 7.5 W to 45 W.

10. The method according to claim 1, characterized in that, The photocatalytic coupling reaction is carried out under inert gas protection at room temperature.

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