Process for the polyfluoraromatization modification of serine derivatives or serine-containing polypeptides

Abstract

The application discloses a method for polyfluorinated aromatic modification of serine derivatives or polypeptides containing serine, under the protection of inert gas and the driving of visible light, the serine derivatives or polypeptides containing serine or polypeptide derivatives, polyfluorinated aromatic compounds, photocatalysts, reaction solvents, Lewis acids, hydrogen transfer reagents and inorganic bases are mixed and reacted to obtain non-natural serine derivative or polypeptide modification products modified by polyfluorinated aromatic compounds. 3 The method has mild and green conditions, excellent functional group tolerance in the conversion process, excellent yield, high site selectivity, realizes the polyfluorinated aromatic modification of C(sp 3 )‑H bond in the polypeptide, has good diastereoselectivity, and can separate diastereoisomers through semi-preparative high performance liquid chromatography.

Description

Technical Field

[0001] This invention belongs to the field of amino acid and polypeptide modification, specifically relating to a method for polyfluorinated aromatization modification of serine derivatives or serine-containing polypeptides. Background Technology

[0002] Fluorinated amino acids and peptides are becoming increasingly popular tools in medicinal chemistry and protein engineering due to the following advantages:

[0003] (1) The spatial perturbation of fewer fluorine atoms allows fluorinated amino acids to be well tolerated by proteins.

[0004] (2) Increased hydrophobicity is beneficial to protein folding and stability;

[0005] (3) Stability and isotopes of fluorine 19 The abundance of F can be used for the localization and tracking of live cells;

[0006] (4) Polyfluorination is also a method to effectively change electrostatic properties in vitro and in vivo. Polyfluorinated arylation of amino acids and peptides can also enhance binding affinity through polar-π interactions, realize the co-assembly of binary systems to prepare supramolecular systems, and promote molecular recognition in protein-protein interactions.

[0007] Furthermore, compared to process modification of peptides, chemically selective and precise post-modification of existing peptides is a more efficient and direct method. It achieves diverse modifications of complex peptide molecules while avoiding the complex "from start to finish" synthetic process. Besides nucleophilic groups such as hydroxyl, thiol, amide, carboxyl, and amino groups, peptides also contain C(sp...) 2 -H bond and C(sp) 3 The α-H bond is also a very valuable modification site. Considering the unique reactivity of polyfluorinated aromatic compounds, it holds promise for application to the α-C(sp) hydroxyl group of serine side chain. 3 In polypeptide modification involving )-H bonds, but no such method has been reported to date.

[0008] Currently, most polyfluoroarylation modification methods for peptides are still limited to modifying nucleophilic residues of amino acids, such as the polyfluoroarylation of nucleophilic side chains of cysteine ​​(Cys), lysine (Lys), tyrosine (Tyr), and serine (Ser). Modification of the amino acid side chains in peptides can disrupt the side chain structure and affect the pharmacophore's function. Furthermore, most methods for synthesizing polyfluoroaryl non-natural amino acids require strong bases, metallic reagents, and high temperatures, which are highly detrimental to the preparation of the target compound and the preservation of the peptide molecule's activity.

[0009] Therefore, it is necessary to develop a method for inhibiting the C(sp) content commonly found in peptides under mild conditions. 3The method of modifying amino acids and peptides with polyfluoroaryl groups by )-H bonds can achieve polyfluoroaryl modification of amino acids and peptides while protecting the pharmacophores to the greatest extent, which has important application value. Summary of the Invention

[0010] Objective of the Invention: To address the shortcomings of existing technologies, this invention provides a method for polyfluorinated aromatization modification of serine derivatives or serine-containing peptides. This method modifies the polyfluorinated aromatization of C(sp) compounds commonly found in peptides under mild conditions. 3 The method of modifying polypeptides by polyfluoroarylization of the )-H bond can achieve the functionalization and modification of polypeptides by polyfluoroaryl groups, while protecting the pharmacophores to the greatest extent.

[0011] To address the aforementioned technical problems, this invention discloses a method for polyfluorinated aromatic modification of serine derivatives or serine-containing peptides. Under inert gas protection and visible light drive, a serine derivative or serine-containing peptide or peptide derivative, a polyfluorinated aromatic compound, a reaction solvent, a photocatalyst, a Lewis acid, a hydrogen transfer reagent, and an inorganic base are mixed and reacted to achieve visible light-driven reaction of the polyfluorinated aromatic compound with serine β-C(sp) in the serine derivative or serine-containing peptide or peptide derivative. 3 Selective polyfluorinated arylation modification of the )-H bond yields non-natural serine derivatives or peptide-modified products modified with polyfluorinated aromatic compounds.

[0012] The serine derivative has the following structure: Among them, R 1 R 2 Each can be independently acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, or hydrogen; R 3 It is any one of methoxy, ethoxy, and tert-butoxy;

[0013] The polyfluorinated aromatic compound has the following structure: Among them, R 4 It is an electron-deficient polyfluoroaromatic hydrocarbon containing at least one functional group selected from fluorine, chlorine, trifluoromethyl, cyano, pentafluorophenyl, ester or amide;

[0014] The N-terminus of the serine-containing polypeptide or polypeptide derivative is -NR. 5 R 6 The group has a C-terminus of -COR. 7 , where R 5 R 6 Each group can be independently acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, or hydrogen; R 7 It is methoxy, ethoxy, hydroxy, or amino. Preferably, the number of amino acids in the polypeptide or polypeptide derivative does not exceed 20.

[0015] Preferably, after the reaction is completed, the product is quenched, extracted, washed, dried, and concentrated under reduced pressure, and then purified by silica gel column chromatography or semi-preparative high-performance liquid chromatography to obtain a non-natural serine derivative or peptide-modified product modified with polyfluorinated aromatic compounds.

[0016] Specifically, the reaction solvent is dimethyl sulfoxide (DMSO) or a mixture of DMSO and an organic solvent, wherein the organic solvent is an organic solvent capable of dissolving fluoroaromatic compounds; the volume ratio of DMSO to the organic solvent is 4:1 to 10:1. Preferably, the reaction solvent is a mixture of DMSO and chlorobenzene, DMSO and acetonitrile, DMSO and ethyl acetate, DMSO and toluene, or DMSO and 1,2-dichloroethane. More preferably, the reaction solvent is a mixture of DMSO and chlorobenzene, with a mixing volume ratio of 6:1 to 8:1. A higher content of DMSO increases the solubility of the polypeptide, while polyfluoroaromatic compounds have better solubility in organic solvents. More preferably, when the reaction substrate is a serine derivative, the reaction solvent is a mixture of DMSO and chlorobenzene in a volume ratio of 6:1; when the reaction substrate is a serine-containing polypeptide or polypeptide derivative, the reaction solvent is a mixture of DMSO and chlorobenzene in a volume ratio of 8:1.

[0017] The photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, Ir[dF(CF3)ppy]2(dtbpy)PF6, Ir[dF(F)ppy]2(dtbpy)PF6, 4-CzTPN-Ph, or [Acr-Mes]. + (ClO4) - The Lewis acid is any one of zinc chloride, zinc bromide, cerium chloride, magnesium chloride, lanthanum chloride, aluminum chloride, scandium trifluoromethanesulfonate, indium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, and samarium trifluoromethanesulfonate; the hydrogen transfer reagent is a quinine ring or a 3-acetoxyquinine ring; the inorganic base is any one of lithium chloride, lithium bromide, lithium tetrafluoroborate, cesium fluoride, potassium phosphate, dipotassium hydrogen phosphate, cesium acetate, potassium acetate, sodium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and potassium trifluoroacetate.

[0018] Preferably, the photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4-CzIPN); the Lewis acid is zinc trifluoromethanesulfonate; the hydrogen transfer reagent is quinine ring; and the inorganic base is sodium acetate.

[0019] The serine derivative is a serine derivative with both its N-terminus and C-terminus protected; the serine-containing polypeptide or polypeptide derivative is a polypeptide or polypeptide derivative with its N-terminus, C-terminus, and side chains protected or unprotected. The reaction concentration of the serine derivative or the serine-containing polypeptide or polypeptide derivative is 0.05 mol / L to 0.5 mol / L. Preferably, the concentration of the serine derivative is 0.2 mol / L, and the preferred concentration of the serine-containing polypeptide or polypeptide derivative is 0.05 mol / L.

[0020] Specifically, the light source used for the reaction is visible light with a wavelength of 390-430nm, the reaction time is 18-24h, and the reaction temperature is room temperature.

[0021] Preferably, the molar ratio of photocatalyst, Lewis acid, hydrogen transfer reagent, inorganic base to serine derivative or serine-containing polypeptide or polypeptide derivative is (0.005-0.1):(1-3):(0.5-1):(1-5):1, more preferably 0.005:1.5:0.5:3:1; the molar ratio of serine derivative or serine-containing polypeptide to polyfluorinated aromatic compound is 1:(1-20), preferably 1:5.

[0022] Furthermore, this invention also proposes another method for synthesizing non-natural serine from polyfluoroaromatic hydrocarbons based on the above-described modification method, comprising the following steps:

[0023] (1) Under the protection of inert gas and driven by visible light, serine derivatives, polyfluorinated aromatic compounds, reaction solvents, photocatalysts, Lewis acids, hydrogen transfer reagents and inorganic bases are mixed and reacted. After the reaction is completed, the mixture is quenched, extracted, washed, dried and concentrated under reduced pressure. Then, it is separated and purified by silica gel column chromatography to obtain non-natural serine derivatives modified with polyfluorinated aromatic compounds.

[0024] (2) The non-natural serine derivative modified with the polyfluorinated aromatic compound is subjected to a group removal reaction using an inorganic base or an inorganic acid. Specifically, when R 3 When the methyl or ethoxy group is present, it is removed by saponification in a reaction solvent using an inorganic base. After the reaction, the residue is quenched, pH adjusted, extracted, washed, dried, and concentrated under reduced pressure to obtain polyfluoroaromatic modified non-natural serine. 3 It is a tert-butoxy group, obtained by removing Boc in an organic solvent using a strong acid. After the reaction is complete, it is purified by rotary evaporation under reduced pressure and semi-preparative chromatography to obtain non-natural serine modified with polyfluorinated aromatic compounds.

[0025] The inorganic base is lithium hydroxide, and the reaction solvent is a mixture of tetrahydrofuran and water. Insufficient tetrahydrofuran is detrimental to the dissolution of non-natural serine derivatives modified with polyfluorinated aromatic compounds, while excessive tetrahydrofuran is detrimental to the mixing of the inorganic base and the raw materials. The ratio of tetrahydrofuran to water should be between 2:1 and 5:1, preferably 4:1.

[0026] The strong acid is trifluoroacetic acid, and the organic solvent is dichloromethane, with a volume ratio of 1:3 to 1:1, preferably 1:2.

[0027] Beneficial effects: Compared with the prior art, this application has the following advantages:

[0028] (1) The visible light-driven synthesis strategy is mild and green, and the functional groups are well tolerated during the transformation process.

[0029] (2) Using serine or protected or unprotected peptides containing serine as raw materials, which are inexpensive and readily available, non-natural serine or peptides containing various types of fluoroaromatics can be prepared; based on serine, direct and precise polyfluoroaryl modification with site selectivity of unprotected peptides can be achieved without the need for pre-preparation of non-natural amino acids and installation of activated functional groups; the conditions are mild and suitable for direct polyfluoroaryl modification of bioactive peptides.

[0030] (3) The developed method can be applied to the synthesis of various β-polyfluoroaryl non-natural serines and retains the functional group of serine side chain - hydroxyl group; the method can retain the pharmacophore of serine side chain when applied to the polyfluoroarylation modification of unprotected peptides.

[0031] (4) The method of this application has excellent yield, high site selectivity, good diastereoselectivity, and can separate diastereomers by semi-preparative high performance liquid chromatography. Attached Figure Description

[0032] Figures 1 to 3 The 1H, 1C, and fluorine spectra of 3aa are shown respectively.

[0033] Figure 4 This is a single crystal structure diagram of 3aa;

[0034] Figures 5 to 7 The 1H, 1C, and fluorine spectra of 3ba are shown respectively.

[0035] Figures 8 to 10 The 3ca fluorocarbon spectrum, carbon spectrum, and fluorine spectrum are shown below;

[0036] Figures 11 to 13 The 1H, 1C, and fluorine spectra of 3ab are shown respectively.

[0037] Figures 14 to 16 The images are the proton, carbon, and fluorine spectra at 3 ac, respectively.

[0038] Figures 17 to 19 The 1H, 1C, and fluorine spectra of 3ad are shown respectively.

[0039] Figure 20 This is a single crystal structure diagram of 3ad;

[0040] Figures 21 to 23 The 3ae spectra are the proton, carbon, and fluorine spectra, respectively.

[0041] Figures 24 to 26 The 1H, 1C, and fluorine spectra are for 3af.

[0042] Figures 27 to 29 The 1H, 1C, and fluorine spectra are for 3 ag, respectively.

[0043] Figures 30 to 32 The 3Ah spectral density (Hb), carbon spectral density (Cb), and fluorine spectral density (

[0044] Figure 33 This is a diagram of the single crystal structure of a 3Ah crystal.

[0045] Figures 34 to 36 The 1H, 1C, and fluorine spectra of 3ai are shown respectively.

[0046] Figures 37 to 39 The 1H, 1C, and fluorine spectra of 3aj are shown respectively.

[0047] Figures 40 to 42 The 1H, 1C, and fluorine spectra of 3ak are shown respectively.

[0048] Figures 43 to 45 The 1H, 1C, and fluorine spectra are for 3 da;

[0049] Figures 46 to 48 The 1H, 1C, and fluorine spectra are for 3ea, respectively.

[0050] Figures 49 to 51 These are the proton, carbon, and fluorine spectra of 3fa, respectively.

[0051] Figures 52 to 54 The 1H, 1C, and fluorine spectra of 3ga are shown respectively.

[0052] Figure 55 Results of 3ga HPLC purity analysis and low-resolution mass spectrometry;

[0053] Figure 56 HPLC purity analysis and low-resolution mass spectrometry results for 3ha;

[0054] Figure 57 HPLC purity analysis and low-resolution mass spectrometry results for 3ia;

[0055] Figure 58 HPLC purity analysis and low-resolution mass spectrometry results for 3ja;

[0056] Figure 59 Results of HPLC purity analysis and low-resolution mass spectrometry for 3 ka;

[0057] Figure 60 The results are HPLC purity analysis and low-resolution mass spectrometry analysis of 3la.

[0058] Figure 61 HPLC purity analysis and low-resolution mass spectrometry results for 3 mA;

[0059] Figure 62 HPLC purity analysis and low-resolution mass spectrometry results for 3na;

[0060] Figure 63 HPLC purity analysis and low-resolution mass spectrometry results for 3oa;

[0061] Figure 64 HPLC purity analysis and low-resolution mass spectrometry results for 3 Pa;

[0062] Figure 65 The results are HPLC purity analysis and low-resolution mass spectrometry results for 3qa. Detailed Implementation

[0063] 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.

[0064] This application proposes a method for polyfluorinated aromatic modification of serine derivatives or serine-containing peptides. Using a serine derivative with protected N-terminus and C-terminus, or a serine-containing peptide molecule 1 with unprotected N-terminus, C-terminus, and side chains, as a starting material, and a polyfluorinated aromatic compound 2 as another starting material, under the combined action of a photocatalyst, a Lewis acid, a hydrogen transfer reagent, and an inorganic base, visible light-driven reaction is achieved between the polyfluorinated aromatic compound and the serine β-C(sp) group in molecule 1. 3 Selective polyfluorinated arylation modification reaction of )-H bond. After the reaction, the product was quenched, extracted, washed, dried and concentrated under reduced pressure, and then purified by silica gel column chromatography or semi-preparative high performance liquid chromatography to obtain non-natural serine derivatives or peptide-modified products modified with polyfluorinated aromatic compounds.

[0065] The general reaction formula is as follows:

[0066]

[0067] In this formula, AA represents amino acids, and the above general formula is not a limitation on the length of the polypeptide, but merely indicates the basic structure of the polypeptide. AA can be any amino acid independently, and R... 1 R 2Each group can be independently acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, or hydrogen, R 3 It is methoxy, ethoxy, or tert-butoxy. R 4 It is an electron-deficient polyfluoroaromatic hydrocarbon containing functional groups such as fluorine, chlorine, trifluoromethyl, cyano, pentafluorophenyl, ester, and amide. 5 R 6 Each group can be independently acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, or hydrogen, R 7 It can be methoxy, ethoxy, hydroxy, or amino.

[0068] The structure of raw material 1 involved in the following embodiments is as follows:

[0069]

[0070] The polyfluorinated aromatic compound 2 used in the examples has the following structure:

[0071]

[0072] The prepared structure is shown below:

[0073]

[0074]

[0075] Example 1: Synthesis of 3aa.

[0076] In a glove box, serine derivative 1a (0.2 mmol, 32.2 mg), 4-CzIPN (0.001 mmol, 0.8 mg), quinine ring (0.1 mmol, 11.1 mg), zinc trifluoromethanesulfonate (0.3 mmol, 109 mg), and sodium acetate (0.6 mmol, 49.2 mg) were added to a dried 10 mL quartz tube, along with dimethyl sulfoxide / chlorobenzene (6:1, 1 mL) and polyfluorinated aromatic compound 2a (186 mg, 1 mmol). The quartz tube was sealed and removed from the glove box. The reaction mixture was placed in a purple LED light reactor (24-W, 400-410 nm) and reacted for 18 hours. After the reaction was complete, the reaction mixture was quenched with 3 mL of H2O, then extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography with hexane / ethyl acetate (1:1) as the eluent to obtain the target product 3aa. Its structural characterization parameters are as follows:

[0077] The product was a white solid with a melting point of 92-95℃, a yield of 71% (46.6 mg), and a diastereomer ratio of 6.7:1. 1 (H NMR determination). Figures 1 to 3 The images show the proton, carbon, and fluorine spectra of 3aa, respectively. Figure 4 This is a single crystal structure diagram of 3aa.

[0078] HRMS(ESI)C 12 H 10 F5NNaO4[M+Na] + Theoretical value: 350.0422, measured value: 350.0418.

[0079] 1 H NMR(300MHz, CDCl3)δ7.03(brs,0.87H),6.81(brs,0.13H),5.53-5.49(m,0.88H),5.43(brs,0.12H),5.24 -5.22(m,0.12H),5.01(brs,0.12H),4.87-4.69(m,1.78H),3.80(s,0.46H),3.76(s,2.54H),2.00(s,3H).

[0080] 13 C NMR (75MHz, CDCl3) δ172.50,171.52,169.53,146.49,143.21,142.63,139.14,135. 78,113.61(t,J=14.3Hz),68.76,67.25,57.46,57.06,53.09,52.87,22.53,22.47.

[0081] 19 F NMR (282MHz, CDCl3) δ -142.52—-142.95 (m, 2F), -153.45—-153.96 (m, 1F), -161.89 (t, J=22.5Hz, 2F). Example 2 Synthesis of 3ba.

[0082] Using serine derivative 1b (0.2 mmol, 43.8 mg) and polyfluorinated aromatic compound 2a (186 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ba. Its structural characterization parameters are as follows: white solid, melting point 65-67 °C, yield 62% (47.7 mg), diastereomer ratio 5.7:1 (…). 1 (H NMR determination). Figures 5 to 7 The 1H, 1C, and fluorine spectra of 3ba are shown respectively.

[0083] HRMS(ESI)C 15 H 16 F5NNaO5[M+Na] +Theoretical value: 408.0841, measured value: 408.0838.

[0084] 1 H NMR(300MHz, CDCl3)δ5.58-5.50(m,2H),5.02-5.00(m,0.15H),4.83(brs,0 .15H),4.66-4.63(m,0.85H),3.80(s,3H),3.65(brs,0.85H),1.39(s,9H).

[0085] 13 C NMR (75MHz, CDCl3) δ169.57,156.92,155.80,146.67,143.45,142.55,139.23,1 36.00,113.70(d,J=17.3Hz),81.62,80.92,70.09,68.40,58.40,53.09,28.02.

[0086] 19 F NMR (282MHz, CDCl3) δ -142.43—-143.03 (m, 2F), -153.83—-154.15 (m, 1F), -161.83 (t, J = 19.7Hz, 2F). Example 3: Synthesis of 3ca

[0087] Using serine derivative 1c (0.2 mmol, 50.6 mg) and polyfluorinated aromatic compound 2a (186 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ca. Its structural characterization parameters are as follows: colorless oily liquid, yield 52% (43.7 mg), diastereomer ratio 2:1 (…). 1 (H NMR determination). Figures 8 to 10 The 3ca spectral density (HbA1c), carbon spectral density (CbA), and fluorine spectral density (FbA1c) are shown respectively.

[0088] HRMS(ESI)C 18 H 14 F5NNaO5[M+Na] + Theoretical value: 442.0684, measured value: 442.0682.

[0089] 1H NMR (300MHz, CDCl3) δ7.35-7.31(m,5H),5.89(d,J=9.0Hz,0.64H),5.67(d,J=9.0Hz,0.34H),5.53-5.42(m,1H),5.14-5. 00(m,2H),4.88-4.84(m,0.37H),4.73-4.69(m,0.62H),4.47(d,J=9.0Hz,0.32H),3.78(s,3H),3.64(d,J=9.0Hz,0.67H).

[0090] 13 C NMR (75MHz, CDCl3) δ169.70,169.50,156.89,156.51,146.57,143.28,139.22,135.81,135.55,1 28.54,128.34,128.18,127.98,113.24,68.97,67.96,67.78,67.47,58.79,58.48,53.21,53.11.

[0091] 19 F NMR (282MHz, CDCl3) δ -142.32—-142.78 (m, 2F), -153.03—-153.47 (m, 1F), -161.23—-161.49 (m, 2F). Example 4, synthesis of 3ab.

[0092] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2b (150 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ab. Its structural characterization parameters are as follows: white solid, melting point 75-77 °C, yield 48% (28.1 mg), diastereomer ratio 19:1 (…). 1 (H NMR determination). Figures 11 to 13 The 1H, 1C, and fluorine spectra of 3ab are shown respectively.

[0093] HRMS(ESI)C 12 H 12 F3NNaO4[M+Na] + Theoretical value: 314.0611, measured value: 314.0607.

[0094] 1H NMR (300MHz, CDCl3) δ7.16-7.05(m,1H),6.86-6.80(m,1H),6.61(d,J=9.0Hz,0.9H),6.43(brs,0.04H),5.51- 5.50(m,0.97H),5.35(brs,0.03H),5.09(brs,0.05H),5.01-4.97(m,0.95H),3.80-3.75(m,4H),2.02(s,3H).

[0095] 13 C NMR (75MHz, CDCl3) δ170.92,169.85,157.56,154.22,146.86,145.55-145.36( m),117.72-116.66(m),111.23-110.89(m),67.90,58.37,57.08,52.83,22.78.

[0096] 19 F NMR (282MHz, CDCl3) δ-119.29 (d, J = 14.1Hz, 1F), -137.48 (d, J = 19.7Hz, 1F), -141.62 (dd, J = 5.6Hz, 14.1Hz, 1F).

[0097] Example 5: Synthesis of 3ac.

[0098] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2c (157 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ac. Its structural characterization parameters are as follows: white solid, melting point 64-67 °C, yield 60% (35.7 mg), diastereomer ratio 9:1 (…). 1 (H NMR determination). Figures 14 to 16 The 3ac spectral data are 1H, 1C, and 1F spectra, respectively.

[0099] HRMS(ESI)C 13 H 12 F₂N₂NaO₄[M+Na] + Theoretical value: 321.0657, measured value: 321.0655.

[0100] 1H NMR (300MHz, CDCl3) δ7.21(d,J=6.0Hz,2H),6.68(d,J=9.0Hz,0.9H),6.48(d,J=6.3Hz,0.1H),5.53(brs,1H ),5.10(brs,0.1H),5.00-4.96(m,0.9H),4.01(d,J=6.0Hz,1H),3.81(s,0.3H),3.76(s,2.7H),2.01(s,3H).

[0101] 13 C NMR (75MHz, CDCl3) δ171.10, 169.48, 162.44 (d, J = 9Hz), 159.09 (d, J = 9Hz), 121.95 (t ,J=15Hz),116.12,115.98,115.72,113.68(t,J=12Hz),67.95,56.90,53.03,22.80.

[0102] 19 F NMR(282MHz, CDCl3)δ-109.61,-109.87.

[0103] Example 6: Synthesis of 3ad

[0104] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2d (200 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ad. Its structural characterization parameters are: white solid, melting point 78-81 °C, yield 60% (35.7 mg), diastereomer ratio 9:1 (…). 1 (H NMR determination). Figures 17 to 19 The 3ad spectral data are the proton, carbon, and fluorine spectra, respectively. Figure 20 This is a single crystal structure diagram of 3ad.

[0105] HRMS(ESI)C 13 H 13 F5NO4[M+H] + Theoretical value: 342.0758, measured value: 342.0751.

[0106] 1H NMR (300MHz, CDCl3) δ7.18(d,J=9.0Hz,2H),6.58(d,J=9.0Hz,0.82H),6.44(d,J=12.0Hz,0.16H),5.63(t,J=6. 3Hz,0.1H),5.53(t,J=6.9Hz,0.9H),5.12(brs,0.1H),5.01(t,J=6.0Hz,0.9H),3.81-3.75(m,4H),2.03(s,3H).

[0107] 13 C NMR (75MHz, CDCl3) δ172.45, 171.07, 169.74, 169.51, 162.45 (d, J = 8.3Hz), 159.12 (d, J = 8.3Hz), 132.83-132. 38(m),124.19,119.92-119.48(m),109.69,109.29,69.66,67.73,58.08,56.97,53.21,52.96,22.84,22.75.

[0108] 19 F NMR (282MHz, CDCl3) δ-63.23—-63.26(m,3F),-110.34—-110.44(m,2F).

[0109] Example 7: Synthesis of 3ae.

[0110] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2e (232 mg, 1 mmol) as raw materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ae. Its structural characterization parameters are as follows: white solid, melting point 75-78 °C, yield 30% (22.4 mg), diastereomer ratio 19:1 (determined by high performance liquid chromatography, IA column separation, hexane / ethanol = 4 / 1). Figures 21 to 23 The 3ae spectra are the proton, carbon, and fluorine spectra, respectively.

[0111] HRMS(ESI)C 13 H 13 Cl2F3NO4[M+H] + Theoretical value: 374.0168, measured value: 374.0161.

[0112] 1H NMR (300MHz, CDCl3) δ7.57(s,2H),6.61(d,J=6.0Hz,1H),5.65(d,J=7.8Hz,1H),5.36(t,J=7.5Hz,1H),4.06(brs,1H),3.64(s,3H),2.09(s,3H).

[0113] 13 C NMR (75MHz, CDCl3) δ171.63,169.37,138.20,135.50,132.21,131.75,126.31,124.09,120.48,73.63,55.75,52.99,23.04.

[0114] 19 F NMR (282MHz, CDCl3) δ -63.15.

[0115] Example 8: Synthesis of 3af.

[0116] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2f (208 mg, 1 mmol) as raw materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3af. The three configurations of the product (A, B, and C) could be separated and purified by semi-preparative high-performance liquid chromatography. Its structural characterization parameters were: white solid, melting point 92-96 °C, yield 75% (52.4 mg), diastereomer ratio 4:1 (…). 1 (H NMR determination), A:B:C = 25:1:1. Figures 24 to 26 The 3af spectral data are the proton, carbon, and fluorine spectra, respectively.

[0117] HRMS(ESI)C 14 H 15 F3NO6[M+H] + Theoretical value: 350.0846, measured value: 350.0843.

[0118] 1 H NMR (300MHz, CDCl3) δ7.47-7.41(m,1H),6.60(d,J=6.0Hz,0.84H),6.45(d,J=6.0Hz,0.13H),5.53 (brs,1H),5.14-5.10(m,0.2H),5.03-4.98(m,0.8H),3.95(s,3H),3.86-3.77(m,4H),2.03(s,3H).

[0119] 13C NMR (75MHz, CDCl3) δ172.52,171.46,169.59,169.47,162.72,156.46,153.19,151.10,148.90-147.71(m),122.30( dd,J=12.7Hz,5.3Hz),119.77(d,J=9.0Hz,),113.05-112.64(m),69.47,67.83,57.68,56.89,53.16,52.95,22.65.

[0120] 19 F NMR(282MHz, CDCl3)δ-114.22—-114.30(m,0.04F),-118.24—-118.48(m,1F),-120.41—-120.46(m,0.04F),-129.12—-129.22(m,0.04F),-1 35.13—-135.47(m,1F),-137.28—-137.34(m,0.04F),-138.28—-138. 45(m,1F),-139.26—-139.39(m,0.04F),-140.15—-140.28(m,0.04F).

[0121] Example 9: Synthesis of 3ag.

[0122] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2 g (168 mg, 1 mmol) as raw materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3 g. The A and B configurations of the product can be separated and purified by semi-preparative high-performance liquid chromatography. Its structural characterization parameters are: white solid, melting point 140-145 °C, yield 65% (40 mg), diastereomer ratio 9:1 (…). 1 (H NMR determination), A:B = 10:1. Figures 27 to 29 The 1H, 1C, and 1F spectra are for 3 ag of hydrogen, carbon, and fluorine, respectively.

[0123] HRMS(ESI)C 12 H 11 F4NNaO4[M+Na] + Theoretical value: 332.0516, measured value: 332.0514.

[0124] 1H NMR (300MHz, MeOD) δ7.35-7.23 (m, 1H), 5.43 (d, J = 6.0Hz, 0.9H), 5.34 (d, J = 6. 0Hz, 0.1H), 4.80 (d, J = 3.0Hz, 1H), 3.59 (s, 2.7H), 3.57 (s, 0.3H), 1.88 (s, 3H).

[0125] 13 C NMR(75MHz,MeOD)δ173.44,172.80,171.92,171.02,148.97,147.56,145.69,14 4.50, 121.46 (t, J = 14.3Hz), 106.93 (t, J = 23.3Hz), 67.75, 58.30, 56.90, 22.26.

[0126] 19 F NMR(282MHz,MeOD)δ-117.88—-117.99(m,0.1F),-135.04—-135.30(m,0.1F),-136.38—-136. 85(m,0.1F),-141.73--141.95(m,2F),-144.49--144.99(m,2F),-168.33--168.53(m,0.1F).

[0127] Example 10: Synthesis of 3ah.

[0128] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2h (334 mg, 1 mmol) as raw materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ah. The A and B configurations of the product can be separated and purified by semi-preparative high-performance liquid chromatography. Its structural characterization parameters are: white solid, melting point 145-150 °C, yield 77% (73.2 mg), diastereomer ratio 4:1 (…). 1 (H NMR determination), A:B = 12.5:1. Figures 30 to 32 The 3Ah spectral data are 1H, 1C, and 1F spectra, respectively. Figure 33 This is a diagram of the single crystal structure of a 3ah crystal.

[0129] HRMS(ESI)C 18 H 11 F9NO4[M+H] + Theoretical value: 476.0539, measured value: 476.0533.

[0130] 1H NMR (300MHz, CDCl3) δ6.82(d,J=6.0Hz,0.8H),6.65(d,J=6.0Hz,0.2H),5.62(d,J=3.0Hz,0.8H),5.52 (d,J=6.0Hz,0.2H),5.18-5.15(m,0.2H),5.05-4.99(m,0.8H),3.85(s,1H),3.78(s,3H),2.05(s,3H).

[0131] 13 C NMR (75MHz, CDCl3) δ173.00,171.52,169.51,169.21,146.25,145.59,142.90,142.22,139.57, 136.18,120.81-120.64(m),106.28,102.12,70.19,67.98,58.18,56.98,53.36,53.04,22.77.

[0132] 19 F NMR(282MHz, CDCl3)δ-117.29—-117.38(m,0.08F),-130.19—-130.33(m,0.08F),-131.51 —-131.62(m,0.08F),-137.22——-137.33(m,2F),137.61——-138.00(m,0.16F),-138.04——-13 8.26(m,2F),-141,82—-142.07(m,2F),-149.85—150.09(m,1F),-150.45—150.60(m,0.08 F),-160.35—-160.66(m,2F),-160.71—-160.89(m,0.16F),-162.28—-162.47(m,0.08F).

[0133] Example 11: Synthesis of 3ai.

[0134] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2i (202 mg, 1 mmol) as raw materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ai. Its structural characterization parameters are: white solid, melting point 120-124 °C, yield 65% (45 mg), diastereomer ratio 7:1 (…). 1 (H NMR determination), A:B:C = 2.5:1:1. Figures 34 to 36 The 1H, 1C, and 1F spectra of 3ai are shown respectively.

[0135] HRMS(ESI)C 12 H 10 ClF4NNaO4[M+Na] + Theoretical value: 366.0127, measured value: 366.0126.

[0136] 1 H NMR (400MHz, CDCl3) δ6.97 (d, J=8.0Hz, 0.88H), 6.73 (d, J=8.0Hz, 0.12H), 5.62-5.48 (m, 1H), 5. 27(brs,1H),5.06–5.03(m,0.15H),5.01–4.87(m,0.85H),3.81–3.76(m,3H),2.03-2.02(m,3H).

[0137] 13 C NMR (100MHz, CDCl3) δ171.74,169.52,169.48,169.45,169.35,159.04,152.99,150.51,149.0 9,146.49,146.09-145.89(m),145.56-145.18(m),143.61-143.43(m),142.89-142.69(m),122 .29,117.21(t,J=18.0Hz),116.40-116.06(m),113.73-113.55(m),112.33(t,J=18.0Hz),107 .60-107.19(m),71.08,69.32,67.59,57.70,57.10,57.01,56.37,53.22,52.99,29.68,22.58.

[0138] 19 F NMR (376MHz, CDCl3) δ-120.23 (d, J=9.4Hz, 0.4F), -132.06 (dd, J=5.3Hz, 15.8Hz, 0.3 F),-136.26—-136.57(m,0.3F),-137.23—-137.30(m,0.3F),-140.61(dd,J=7.5Hz,1 5.0Hz, 2F), -141.47—-141.55(m, 0.4F), -142.22(q, J=11.3Hz, 2F), -152.60—-153.41(m, 0.4F), -155.74—-156.04(m, 0.4F), -161.33—-161.50(m, 0.4F). Synthesis of Examples 12 and 3aj.

[0139] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2j (226 mg, 1 mmol) as raw materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3aj. Its structural characterization parameters are: white solid, melting point 136-139 °C, yield 67% (49 mg), diastereomer ratio 10:1 (…). 1 (H NMR determination), A:B:C = 25:1:1. Figures 37 to 39 The 1H, 1C, and 1F spectra of 3aj are shown respectively.

[0140] HRMS(ESI)C 14 H 14 F4NO6[M+H] + Theoretical value: 368.0752, measured value: 368.0759.

[0141] 1 H NMR(400MHz, CDCl3) δ6.74(d,J=8.0Hz,0.92H),6.56(d,J=5.2Hz,0.08H),5.56(d,J=4.0Hz,0.95H ),5.48(d,J=5.2Hz,0.05H),5.11-4.90(m,2H),3.98(s,3H),3.82-3.79(m,3H),2.07-2.05(m,3H).

[0142] 13 C NMR(100MHz, CDCl3)171.66,169.25,159.92,145.87(dd,J=5.0Hz,10.0Hz),143.41-143.29(m),12 1.63(t,J=14.0Hz),112.37(t,J=16.0Hz),70.09,68.05,58.10,56.87,53.33,53.12,22.69,22.6.

[0143] 19F NMR (376MHz, CDCl3) δ-117.23—-117.26(m,0.04F),-130.06—-130.13(m,0. 03F),-131.00—-131.09(m,0.03F),-139.15—-139.23(m,2F),-140.91—-140 .95(m,0.04F),-141.78(s,0.08F),-142.04—-142.12(m,2F),-143.67—-14 3.76(m,0.02F),-162.12—-162.16(m,0.06F),-162.71—-162.79(m,0.03F).

[0144] Example 13: Synthesis of 3ak.

[0145] Using serine derivative 1a (0.2 mmol, 32.2 mg) and polyfluorinated aromatic compound 2k (301 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1, finally yielding the target product 3ak. The A and B configurations of the product were separated and purified by semi-preparative high-performance liquid chromatography. Its structural characterization parameters were: white solid, melting point 146-150 °C, yield 60% (53 mg), diastereomer ratio 10:1 (…). 1 (H NMR determination), A:B = 10:1. Figures 40 to 42 The images show the proton, carbon, and fluorine spectra of 3ak, respectively.

[0146] HRMS(ESI)C 20 H 18 F4N2NaO5[M+Na] + Theoretical value: 465.1046, measured value: 465.1038.

[0147] 1 H NMR (400MHz, MeOD) δ7.36-7.27(m,5H),5.57-5.48(m,0.85H),5.35-5.30(m,0.15H),5.03(d,J=8.0Hz,0.1 5H), 4.90 (d, J = 4.0Hz, 0.85H), 4.75 (s, 2H), 3.77 (s, 0.5H), 3.71 (s, 2.5H), 1.96 (s, 2.5H), 1.79 (s, 0.5H).

[0148] 13C NMR(100MHz,MeOD)172.09,171.50,170.30,169.42,159.34,158.95,145.83-145.70(m),144.21,143.41-143.22(m),141.89-141.75(m),13 7.71,137.61,128.28,127.19,127.12,121.08(t,J=15.0Hz),116.28( t,J=20.0Hz),66.51,65.76,56.81,55.50,51.67,51.53,43.25,20.86.

[0149] 19 F NMR (376MHz, MeOD) δ-121.29—-121.54(m,0.1F),-134.30—-134.79(m,0.06F),-137.69—-138. 18(m,0.06F),-143.11--143.67(m,2F),-145.06--145.20(m,2F),-166.91--167.05(m,0.1F).

[0150] Example 14: Synthesis of 3da.

[0151] Using serine derivative 1d (0.2 mmol, 72.4 mg) and polyfluorinated aromatic compound 2a (186 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1. The eluent was n-hexane / ethyl acetate (1:2), and the target product 3da was finally obtained. Its structural characterization parameters were: white solid, melting point 95-98 °C, yield 65% (68.7 mg), diastereomer ratio 3:1 (…). 1 (H NMR determination). Figures 43 to 45 The 3da spectral data are the proton, carbon, and fluorine spectra, respectively.

[0152] HRMS(ESI)C 21 H 25 F5N2NaO8[M+Na] + Theoretical value: 551.1423, measured value: 551.1416.

[0153] 1H NMR (300MHz, CDCl3) δ7.60(d,J=7.8Hz,0.25H),7.46(d,J=7.5Hz,0.75H),5.85(d,J=8.4Hz,0.75H),5.68-5.60(m,1H),5.20-5.08(m,0.5H),4. 68-4.52(m,2.77H),3.78(s,0.75H),3.75(s,2.25H),3.68(s,3H),2.48 -2.39(m,2H),2.28-2.17(m,1H),2.08-1.96(m,1H),1.39-1.28(m,9H).

[0154] 13 C NMR (75MHz, CDCl3) δ 173.45, 173.19, 172.61, 171.72, 170.39, 169.29, 155.94, 155.23, 146.69, 143.38, 139.10, 135.86 (d, J = 12.8Hz), 127. 70,113.58(d,J=14.3Hz),80.79,80.36,67.58,66.70,58.71,56.92,5 2.84,52.60,52.20,51.86,29.97,29.84,27.93,27.77,26.99,26.54.

[0155] 19 F NMR (282MHz, CDCl3) δ -141.09—-141.94 (m, 2F), -154.68—-154.91 (m, 1F), -162.02—-162.87 (m, 2F). Example 15, Synthesis of 3ea.

[0156] Using serine derivative 1e (0.2 mmol, 93.0 mg) and polyfluorinated aromatic compound 2a (186 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1. The eluent was n-hexane / ethyl acetate (1:2), and the target product 3ea was finally obtained. Its structural characterization parameters are as follows: white solid, melting point 89-93 °C, yield 60% (75.6 mg), diastereomer ratio 3:1 (…). 1 (H NMR determination). Figures 46 to 48 The 1H, 1C, and 1F spectra are for 3ea.

[0157] HRMS(ESI)C 29 H 35 F5N3O7[M+H] + Theoretical value: 632.2389, measured value: 632.2383.

[0158] 1 H NMR (300MHz, CDCl3) δ8.05(d,J=7.8Hz,0.75H),7.85(d,J=7.8Hz,0.25H),7.24-7.17(m,5.75H),6.91(d,J=8.4Hz,0.25H),5.49-5.21(m,2H),5. 14-4.85(m,2H),4.53-4.27(m,2H),3.75(s,0.75H),3.68(s,2.25H),3.1 2-2.99(m,2H),2.08-2.04(m,1H),1.36-1.33(m,9H),0.97-0.84(m,6H).

[0159] 13 C NMR (75MHz, CDCl3) δ172.51,172.04,169.98,169.47,155.73,146.69,143.38,139.10,136.63,136.27,135.75,129.28,129.20,128.7 0,128.56,127.01,126.83,113.62,80.75,80.32,67.10,66.57,58.82,58.26,57.08,55.86,52.72,37.48,31.05,28.11,18.96,18.31.

[0160] 19 F NMR (282MHz, CDCl3) δ -141.52—-142.10 (m, 2F), -153.76—-154.38 (m, 1F), -161.76—-162.26 (m, 2F). Example 16, Synthesis of 3fa.

[0161] Using serine derivative 1f (0.2 mmol, 97.9 mg) and polyfluorinated aromatic compound 2a (186 mg, 1 mmol) as starting materials, the reaction was carried out according to the method and material amounts in Example 1. The eluent was n-hexane / ethyl acetate (1:2), and the target product 3fa was finally obtained. Its structural characterization parameters are as follows: white solid, melting point 85-98 °C, yield 57% (75 mg), diastereomer ratio 2:1 (…). 1 (H NMR determination). Figures 49 to 51 The 3fa spectra are the proton, carbon, and fluorine spectra, respectively.

[0162] HRMS(ESI)C 29 H 42 F5N3NaO8[M+Na]+ Theoretical value: 678.2784, measured value: 678.2789.

[0163] 1 H NMR (300MHz, CDCl3) δ7.37(d,J=6.0Hz,0.7H),7.27(d,J=9.0Hz,0.3H),6.93(d,J=9.0Hz, 0.3H),6.79(d,J=9.0Hz,0.7H),5.64-5.54(m,1H),5.15-5.08(m,1H),4.96(brs,1H),4.6 9-4.51(m,1H),4.41(d,J=9.0Hz,0.7H),4.30(d,J=6.0Hz,0.3H),4.21-4.14(m,1.5H),3. 71-3.68(m,3.5H),1.64-1.56(m,3H),1.42(s,9H),1.16-1.10(m,12H),0.94-0.83(m,6H).

[0164] 13 C NMR (75MHz, CDCl3) δ173.35,173.06,171.86,171.39,169.72,168.06,15 4.90,154.42,145.90,142.50,141.82,138.13,135.09,112.24,79.36,79 .08,73.58,73.39,66.18,66.06,65.82,58.04,57.11,56.28,54.79,52.4 6,51.96,51.43,40.64,40.46,27.30,23.83,23.72,22.10,20.84,19.94.

[0165] 19 F NMR (282MHz, CDCl3) δ -140.48—-141.69 (m, 2F), -154.33—-154.84 (m, 1F), -161.56—-162.54 (m, 2F). Example 17, Synthesis of 3ga.

[0166] In a glove box, 1 g (0.02 mmol, 7.2 mg) of a short peptide containing serine, 0.001 mmol (0.8 mg) of 4-CzIPN, 0.01 mmol (1 mg) of quinine ring, 0.06 mmol (21.8 mg) of zinc trifluoromethanesulfonate, and 0.12 mmol (9.8 mg) of sodium acetate were added to a dried 10 mL quartz tube, along with dimethyl sulfoxide / chlorobenzene (8:1, 0.4 mL) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol). The quartz tube was sealed and removed from the glove box. The reaction mixture was placed in a purple LED photoreactor (24-W, 400-410 nm) and reacted for 24 hours. After the reaction was complete, the reaction mixture was quenched with 1.5 mL of H₂O / acetonitrile (3:1) and 1 mL of dichloromethane. Finally, the aqueous phase was purified by semi-preparative high-performance liquid chromatography to obtain the target product 3ga. The HPLC yield was 72%, with a diastereomer ratio of 1:1 (determined by high performance liquid chromatography, C18 column, H2O / acetonitrile). Figures 52-54 The 1H, 1C, and fluorine spectra of 3ga are shown. HPLC purity analysis and low-resolution mass spectrometry results are as follows. Figure 55 As shown.

[0167] HRMS(ESI)C 20 H 27 F5N5O6[M+H] + Theoretical value: 528.1876, measured value: 528.1890.

[0168] 1 H NMR (300MHz, MeOD) δ8.38 (dd, J = 27Hz, 6.0Hz, 1H), 5.51 (d, J = 5.7Hz, 1H), 4.41-4.36 (m, 2H), 3.72 (s, 2H), 2.93 (t, J = 6.0Hz, 2H), 1.84-1.29 (m, 11H).

[0169] 13 C NMR(150MHz,MeOD)δ173.81,172.00,170.47,165.91,145.87,144.24,141.36,139.68,138.20(t,J=15Hz),13 6.55(t,J=12Hz),114.89(t,J=15Hz),66.37,56.93,53.06,49.08,40.04,38.99,31.17,26.71,21.98,16.56.

[0170] 19F NMR (282MHz, MeOD) δ-140.02—-140.12 (m, 2F), -154.51 (t, J=19.7Hz, 1F), -161.30—-161.48 (m, 2F).

[0171] Example 18: Synthesis of 3ha.

[0172] Using serine derivative 1h (0.02 mmol, 8.5 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3ha. The HPLC yield was 32%, and the diastereomer ratio was 1:2.8 (determined by high-performance liquid chromatography, C18 column, H2O / acetonitrile). HPLC purity analysis and low-resolution mass spectrometry results are as follows... Figure 56 As shown.

[0173] HRMS(ESI)C 24 H 25 F5N5O7[M+H] + Theoretical value: 590.1668, measured value: 590.1662.

[0174] Example 19, Synthesis of 3ia.

[0175] Using serine derivative 1i (0.02 mmol, 9 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3ia. The HPLC yield was 64%, and the diastereomer ratio could not be confirmed. HPLC purity analysis and low-resolution mass spectrometry results are as follows. Figure 57 As shown.

[0176] HRMS(ESI)C 26 H 30 F5N6O6[M+H] + Theoretical value: 617.2141, measured value: 617.2134.

[0177] Example 20: Synthesis of 3ja.

[0178] Using serine derivative 1j (0.02 mmol, 9.3 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3ja. The HPLC yield was 26%, and the diastereomer ratio could not be confirmed. HPLC purity analysis and low-resolution mass spectrometry results are as follows. Figure 58 As shown.

[0179] HRMS(ESI)C 26H 32 F5N8O5[M+H] + Theoretical value: 631.2410, measured value: 631.2394.

[0180] Example 21, Synthesis of 3ka.

[0181] Using serine derivative 1k (0.02 mmol, 7.6 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17, yielding the target product 3ka. The HPLC yield was 64%, and the diastereomer ratio could not be confirmed. HPLC purity analysis and low-resolution mass spectrometry results are as follows. Figure 59 As shown.

[0182] HRMS(ESI)C 23 H 24 F5N4O6[M+H] + Theoretical value: 547.1610, measured value: 547.1604.

[0183] Example 22, Synthesis of 3la.

[0184] Using serine derivative 1l (0.02 mmol, 6.9 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3la. The HPLC yield was 95%, but the diastereomer ratio could not be confirmed. HPLC purity analysis and low-resolution mass spectrometry results are as follows: Figure 60 As shown.

[0185] HRMS(ESI)C 18 H 21 F5N5O7[M+H] + Theoretical value: 514.1356, measured value: 514.1352.

[0186] Example 23: Synthesis of 3ma.

[0187] Using serine derivative 1m (0.02 mmol, 12.8 mg) and polyfluorinated aromatic compound 1m (0.02 mmol, 12.8 mg) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3mA. The HPLC yield was 18%, and the diastereomer ratio could not be confirmed. HPLC purity analysis and low-resolution mass spectrometry results are as follows: Figure 61 As shown.

[0188] HRMS(ESI)C 34 H 42 F5N6O 11 [M+H]+ Theoretical value: 805.2832, measured value: 805.2802.

[0189] Example 24: Synthesis of 3na.

[0190] Using serine derivative 1n (0.02 mmol, 15.5 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3na. The HPLC yield was 32%, with a diastereomer ratio of 1:1 (determined by high-performance liquid chromatography, C18 column, H2O / acetonitrile). HPLC purity analysis and low-resolution mass spectrometry results are as follows... Figure 62 As shown.

[0191] HRMS(ESI)C 41 H 55 F5N 11 O9[M+H] + Theoretical value: 940.4058, measured value: 940.4079.

[0192] Example 25: Synthesis of 3oa.

[0193] Using serine derivative 1o (0.02 mmol, 15.4 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3oa. The HPLC yield was 47%, and the diastereomer ratio was 1:4.5 (determined by high-performance liquid chromatography, C18 column, H2O / acetonitrile). HPLC purity analysis and low-resolution mass spectrometry results are as follows... Figure 63 As shown.

[0194] HRMS(ESI)C 38 H 61 F5N 13 O9[M+H] + Theoretical value: 938.4629, measured value: 938.4603.

[0195] Example 26: Synthesis of 3pa.

[0196] Using serine derivative 1p (0.02 mmol, 21.2 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3pa. The HPLC yield was 42%, with a diastereomer ratio of 1:1 (determined by high-performance liquid chromatography, C18 column, H2O / acetonitrile). HPLC purity analysis and low-resolution mass spectrometry results are as follows... Figure 64 As shown.

[0197] HRMS(ESI)C 56 H 73 F5N 15 O 11 [M+H] + Theoretical value: 1226.5528, measured value: 1226.5489.

[0198] Example 27, Synthesis of 3qa.

[0199] Using serine derivative 1q (0.02 mmol, 28.6 mg) and polyfluorinated aromatic compound 2a (37.2 mg, 0.2 mmol) as starting materials, the remaining steps and material amounts were the same as in Example 17 to obtain the target product 3qa. The HPLC yield was 16%, and the diastereomer ratio was 1:1 (determined by high-performance liquid chromatography, C18 column, H2O / acetonitrile). HPLC purity analysis and low-resolution mass spectrometry results are as follows... Figure 65 As shown.

[0200] HRMS(ESI)C 73 H 101 F5N 18 O 15 S[M+2H] 2+ Theoretical value: 798.3668, measured value: 798.3634.

[0201] Example 28, Synthesis of 4aa

[0202] 3aa (0.14 mmol, 45.6 mg) was added to a 10 mL round-bottom flask, followed by a 4:1 mixture of tetrahydrofuran and water (1.2 mL) and lithium hydroxide (3.7 mg, 1.1 equiv). The reaction mixture was stirred at room temperature for 2 hours. The reaction was checked for completeness by TLC, and tetrahydrofuran was removed by rotary evaporation under reduced pressure. The pH was then adjusted to 2-3 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure to obtain 4aa of non-natural serine modified with polyfluoroalkyl compounds.

[0203] Following the same method, 4ba and 4ah can be obtained by saponification of 3ba and 3ah respectively.

Claims

1. A method for polyfluorinated aromatization modification of serine derivatives or serine-containing polypeptides, characterized in that, Under inert gas protection and visible light drive, a serine derivative or a serine-containing polypeptide or polypeptide derivative, a polyfluorinated aromatic compound, a photocatalyst, a Lewis acid, a hydrogen transfer reagent, an inorganic base, and a reaction solvent are mixed and reacted to obtain a non-natural serine derivative or polypeptide-modified product modified with a polyfluorinated aromatic compound, wherein the serine derivative has the following structure: , Among them, R 1 R 2 It is acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, or hydrogen; R 3 It is any one of methoxy, ethoxy, and tert-butoxy; The polyfluorinated aromatic compound has the following structure: , where R 4 The polyfluoroaromatic compound is an electron-deficient polyfluoroaromatic hydrocarbon containing at least one functional group selected from fluorine, chlorine, trifluoromethyl, cyano, and pentafluorophenyl, or the polyfluoroaromatic compound has any of the following structural formulas: 、 、 ； The serine-containing polypeptide or polypeptide derivative is any one of the following structural formulas: 、 、 、 、、 、 、 、 、 、 、 、 、 、 ； The photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4-CzIPN); the Lewis acid is zinc trifluoromethanesulfonate; and the hydrogen transfer reagent is a quinine ring. The light source used for the reaction was visible light with a wavelength of 390-430 nm, the reaction time was 18-24 h, and the reaction temperature was room temperature.

2. The method according to claim 1, characterized in that, After the reaction is completed, the product is quenched, extracted, washed, dried and concentrated under reduced pressure, and then purified by silica gel column chromatography or semi-preparative high performance liquid chromatography to obtain non-natural serine derivatives or peptide-modified products modified with polyfluorinated aromatic compounds.

3. The method according to claim 1, characterized in that, The reaction solvent for serine derivatives is dimethyl sulfoxide or a mixture of dimethyl sulfoxide and an organic solvent, wherein the organic solvent is an organic solvent capable of dissolving fluoroaromatic compounds; the volume ratio of dimethyl sulfoxide to organic solvent is 4:1-10:

1.

4. The method according to claim 1, characterized in that... The inorganic base is any one of lithium chloride, lithium bromide, lithium tetrafluoroborate, cesium fluoride, potassium phosphate, dipotassium hydrogen phosphate, cesium acetate, potassium acetate, sodium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and potassium trifluoroacetate.

5. The method according to claim 1, characterized in that, The reaction concentration of serine derivatives, serine-containing peptides, or peptide derivatives is 0.05 mol / L to 0.5 mol / L.

6. The method according to claim 1, characterized in that, The molar ratio of photocatalyst, Lewis acid, hydrogen transfer reagent, inorganic base to serine derivative or serine-containing polypeptide or polypeptide derivative is (0.005~0.1):(1~3):(0.5~1):(1~5):1; the molar ratio of the serine derivative or serine-containing polypeptide to polyfluorinated aromatic compound is 1:(1~20).

7. A method for synthesizing non-natural serine modified with polyfluoroaromatic compounds, characterized in that, The steps include the following: (1) Under inert gas protection and visible light drive, a serine derivative, a polyfluorinated aromatic compound, a reaction solvent, a photocatalyst, a Lewis acid, a hydrogen transfer reagent, and an inorganic base are mixed and reacted. After the reaction is completed, the mixture is quenched, extracted, washed, dried, and concentrated under reduced pressure. Then, it is purified by silica gel column chromatography or semi-preparative high-performance liquid chromatography to obtain a non-natural serine derivative modified with a polyfluorinated aromatic compound. The serine derivative has the following structure: , where R 1 R 2 It is acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, or hydrogen; R 3 It is any one of methoxy, ethoxy, and tert-butoxy; The polyfluorinated aromatic compound has the following structure: , where R 4 The polyfluoroaromatic compound is an electron-deficient polyfluoroaromatic hydrocarbon containing at least one functional group selected from fluorine, chlorine, trifluoromethyl, cyano, and pentafluorophenyl, or the polyfluoroaromatic compound has any of the following structural formulas: 、 、 ； The photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4-CzIPN); the Lewis acid is zinc trifluoromethanesulfonate; the hydrogen transfer reagent is quinine ring; the light source used for the reaction is visible light with a wavelength of 390-430 nm; the reaction time is 18-24 h; and the reaction temperature is room temperature. (2) Remove R from the non-natural serine derivative modified with the polyfluorinated aromatic compound. 3 Following the group, non-natural serine modified with polyfluoroaromatic compounds is obtained, when R 3 When R is methoxy or ethoxy, it is removed by saponification in a reaction solvent using an inorganic base. 3 When it is tert-butoxy, it is obtained by removing Boc in an organic solvent using a strong acid.

8. The method according to claim 7, characterized in that, The inorganic base is lithium hydroxide, the reaction solvent is a mixture of tetrahydrofuran and water; the strong acid is trifluoroacetic acid, and the organic solvent is dichloromethane.

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