A method for synthesizing unnatural amino acid derivatives and polypeptide compounds containing a piperidine ring by visible light-mediated decarboxylation of carboxylic acids

Abstract

The application discloses a synthesis method of a visible light-mediated carboxylic acid decarboxylation construction containing a piperidine ring non-natural amino acid derivative and a polypeptide compound, which comprises the following steps: placing reaction raw materials, N-protected dehydroalanine ester compounds and piperidine carboxylic acid compounds, in a reaction solvent, and using visible light to induce the reaction under the action of a photocatalyst and alkali to obtain the target product, the non-natural amino acid derivative and the polypeptide compound containing the piperidine ring. The application uses the green and clean visible light as an energy source to induce the reaction, meanwhile, the additional oxidant and the carboxylic acid pre-activation are avoided, the raw materials are simple and easy to obtain, and the yield of the target product is high. The synthesized target compound shows better antitumor activity than that of a control drug, 5-fluorouracil.

Description

Technical Field

[0002] This invention belongs to the field of amino acid and polypeptide synthesis technology, and relates to methods for synthesizing non-natural amino acids and polypeptide compounds. Specifically, it relates to a method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids. Background Technology

[0004] Peptides are widely present in living systems and are deeply involved in core biological processes such as cell proliferation, immune defense, and tumor evolution, serving as an important carrier bridging basic research and drug development. While peptides composed of natural amino acids exhibit high activity and strong targeting in vitro, their poor metabolic stability limits their in vivo activity and clinical application. Constructing non-natural amino acids and integrating them into the peptide backbone can significantly regulate the pharmacokinetic properties of peptides, compensate for the structural shortcomings of natural amino acids, and enhance their biological activity. Currently, non-natural amino acids have been used in several marketed drugs and drug candidates, such as the anti-novel coronavirus drug parvovirde (Commun. Chem. 2022, 5, 156), the anti-diabetic drug saxagliptin (J. Med. Chem. 2005, 48, 5025-5037), and the calcitonin gene-related peptide receptor antagonist candidate HTL22562 (J. Med. Chem. 2026, 69, 6337-6395).

[0005] Piperidine is a six-membered nitrogen-containing heterocycle, a key pharmacophore and molecular skeleton in medicinal chemistry, and the most prevalent nitrogen-containing heterocycle structure among approved small molecule drugs. The piperidine skeleton effectively expands the molecular chemical space, enhances the binding affinity of molecules to receptors, and improves the drug-likeness of candidate drugs. Currently, over one hundred piperidine-containing drugs have been approved for marketing worldwide, used in the treatment of diseases such as cancer (Eur. J. Med. Chem. 2018, 157, 480-502), central nervous system diseases (Nat. Commun. 2022, 13 (1), 2795), and infectious diseases (Eur. J. Med. Chem. 2026, 302, 118213).

[0006] Introducing piperidine rings into non-natural amino acids offers several advantages: first, it enhances the molecule's resistance to protease hydrolysis, prolongs its in vivo half-life, and optimizes pharmacokinetic properties; second, it imparts suitable basicity to the molecule, improving its water solubility; third, it strengthens hydrogen bonding between the molecule and biological targets, enhancing pharmacological activity; and fourth, it overcomes the structural limitations of natural amino acids, constructing novel peptide mimics. HTL22562 is a typical application case of piperidine amino acids in new drug development. In summary, developing efficient synthetic systems for piperidine-based non-natural amino acids and peptides is of great significance to research in medicinal chemistry and chemical biology.

[0007] High-performance piperidine-based total synthetic non-natural amino acid candidates have been developed (J. Med. Chem. 2005, 48, 5921-5931), but existing synthetic routes are lengthy and complex (J. Med. Chem. 2020, 63, 7906-7920), limiting the application of these compounds. Visible light photocatalysis, with its mild reaction conditions and high efficiency, has become an important technique for constructing non-natural amino acids. However, research on piperidine-based non-natural amino acids remains relatively limited.

[0008] Existing reports utilize pyridinium salts as free radical precursors to synthesize these compounds (Nat. Commun. 2021, 12, 6873). However, this method requires the amine raw material to be converted into pyridinium salt beforehand, and the reaction process also generates triphenylpyridine as a byproduct, resulting in poor atom economy. Therefore, there is an urgent need in this field to develop a photocatalytic synthesis method for non-natural amino acid derivatives and peptides containing piperidine rings that is readily available, versatile, atom-economical, and environmentally friendly, in order to overcome the shortcomings of existing technologies and promote the development of peptide drugs. Summary of the Invention

[0010] The technical problem solved by this invention is to provide a simple and low-cost method for synthesizing non-natural amino acid derivatives and peptides containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids. This method uses N-protected dehydroalanine esters and piperidine carboxylic acids as starting materials. Under the action of a photocatalyst and a base, visible light induces a reaction to obtain non-natural amino acid derivatives and peptides containing piperidine rings. The preparation process uses greener and cleaner visible light as an energy source, the raw materials are simple and readily available, and the yield of the target product is high.

[0011] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0012] A visible light-mediated decarboxylation method for constructing non-natural amino acid derivatives and peptides containing piperidine rings is disclosed. The specific synthetic steps are as follows: N-protected dehydroalanine ester compounds and piperidine carboxylic acid compounds, a catalyst, a base, and a reaction solvent are sequentially added to a reaction vessel. The target products, non-natural amino acid derivatives and peptides containing piperidine rings, are obtained by visible light-induced reaction. The structures of the N-protected dehydroalanine ester compounds are shown in Formula A, the piperidine carboxylic acid compounds in Formula B, and the non-natural amino acid derivatives and peptides containing piperidine rings in Formula C.

[0013] In Formulas A and C, PG is a Phth-protecting group or a Boc-protecting group, and AA is methanol, benzyl alcohol, or an amino acid residue selected from the ester or benzyl groups of L-leucine, L-phenylalanine, L-methionine, L-tert-leucine, D-valine, D-phenylglycine, glycine, β-alanine, or L-lysine; in Formula B, R is Boc, Cbz, acetyl, or a substituted acetyl group; in Formulas B and C, n is 0 or 1; and the catalyst is one or more of a non-metallic photocatalyst or a transition metal complex photocatalyst.

[0014] Further specifying, the compound shown in formula A is:

[0015] , , , , , , , , , , , , , , , ;

[0016] The compound shown in formula B is:

[0017] , , , , , , , , , ;

[0018] The compound shown in formula C is:

[0019] , , , , , , , , , , , , , , , , , , , , , , , , .

[0020] Further specified, the molar ratio of the N-protected dehydroalanine ester compound, piperidine carboxylic acid compound, catalyst and base is 1:1~3:0.01~0.1:1~3.

[0021] Further specified, the catalyst is selected from one or more of 4CzIPN, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Rhodamine B, Rhodamine 6G, or Eosin Y; preferably, the photocatalyst is 4CzIPN or Ir[dF(CF3)ppy]2(dtbbpy)PF6; more preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6; wherein the structural formulas of catalyst 4CzIPN or Ir[dF(CF3)ppy]2(dtbbpy)PF6 are as follows:

[0022] .

[0023] Further specified, the alkali is one or more selected from LiOH·H2O, potassium hydroxide, sodium hydroxide, potassium carbonate, or potassium acetate; preferably, the alkali is LiOH·H2O.

[0024] Further specifying, the reaction solvent is an anhydrous DMF / H2O mixed solvent, wherein the volume ratio of anhydrous DMF to H2O is 50:1.

[0025] Further specifying, the visible light is blue light, and the light source of the blue light is a blue LED lamp with a wavelength of 450~480nm and a power of 5~10W.

[0026] Further, the reaction temperature is specified as 15-40℃ and the reaction time as 12-36 h.

[0027] Further, after the reaction was completed, water and saturated NaCl solution were added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate three times. The organic phases were combined and washed multiple times with water and saturated NaCl solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain the target compound, a non-natural amino acid derivative containing a piperidine ring, and a polypeptide compound.

[0028] The present invention describes a method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings via visible light-mediated decarboxylation of carboxylic acids. The synthetic route is as follows:

[0029]

[0030] In the formula, PG is a Phth-protecting group or a Boc-protecting group; AA is methanol, benzyl alcohol, or an amino acid residue, which may be selected from the ester group or benzyl group of L-leucine, L-phenylalanine, L-methionine, L-tert-leucine, D-valine, D-phenylglycine, glycine, β-alanine, or L-lysine; R is Boc, Cbz, acetyl, or a substituted acetyl group.

[0031] The application of the non-natural amino acid derivatives and polypeptide compounds containing piperidine rings described in this invention in the preparation of anticancer drugs.

[0032] Compared with existing technologies, this invention has the following advantages and beneficial effects: This invention does not require pre-activation of carboxylic acids or the addition of external oxidants. It uses dimethylformamide and water as reaction solvents and employs the photosensitizer Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a catalyst under visible light to synthesize the target product at room temperature. This method is simple and safe, with mild reaction conditions, inexpensive and readily available raw materials, and uses visible light as the light source, making it green and pollution-free. The catalyst is also relatively environmentally friendly. Furthermore, this invention achieves a high yield of the synthesized target product, exhibits good functional group tolerance, and has a wide substrate applicability. This method can be used for the later-stage modification of drugs and is expected to be applied in drug development. Detailed Implementation

[0034] The following examples further illustrate the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0035] Example 1

[0036] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL glass reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 30 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 37.1 mg of the target product. The target product was a white solid, and the yield of the target product was 89% based on 1a molar amount as 100%. The structural formula of the target product is as follows:

[0037]

[0038] The above-mentioned white solid was subjected to nuclear magnetic resonance spectroscopy analysis, and the data are as follows: 1 H NMR (600 MHz, CDCl3) δ7.89-7.84 (m, 2H), 7.78-7.73 (m, 2H), 4.95 (dd, J = 11.3, 4.4 Hz, 1H), 4.02(s, 2H), 3.71 (s, 3H), 2.58 (s, 2H), 2.35-2.27 (m, 1H), 2.12-2.02 (m, 1H),1.82 (d, J = 13.1 Hz, 1H), 1.56 (d, J = 13.1 Hz, 1H), 1.42 (s, 9H), 1.35-1.28(m, 1H), 1.22-1.04 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 170.1, 167.3, 154.9,134.43 131.9, 123.8, 79.4, 53.0, 49.7, 35.3, 33.0, 32.5, 30.9, 28.5. HRMS(ESI) m / z calcd. for C 22 H 28 N2NaO6 + [M + Na] + : 439.1840, found: 439.1844.

[0039] Example 2

[0040] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 1-Cbz-4-piperidincaric acid (2b, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL glass reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 31.7 mg of the target product. The target product was a white solid, and the yield of the target product was 70% based on 1a molar amount as 100%. The structural formula of the target product is as follows:

[0041]

[0042] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (600 MHz, CDCl3)δ 7.82-7.78 (m, 2H), 7.70-7.66 (m, 2H), 7.30-7.19 (m, 5H), 5.03 (s, 2H), 4.89(dd, J = 11.3, 4.4 Hz, 1H), 4.07 (s, 2H), 3.65 (s, 3H), 2.61 (s, 2H), 2.29-2.22 (m, 1H), 2.05-1.99 (m, 1H), 1.86-1.75 (m, 1H), 1.53 (s, 1H), 1.34-1.24(m, 1H), 1.17-1.02 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 170.0, 167.8, 155.3,134.4, 131.8, 128.5, 128.0, 127.9, 123.7, 67.0, 52.9, 49.6, 44.0, 43.9, 35.3,32.9. HRMS (ESI) m / z calcd. for C 25 H 26 N2NaO6 + [M + Na] + : 473.1683, found:473.1688.

[0043] Example 3

[0044] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 1-acetyl-4-piperidincaric acid (2c, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL glass reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 20.6 mg of the target product. The target product was a white solid, and the yield of the target product was 57% based on 1a molar amount as 100%, with an isomer ratio of 1:1. The structural formula of the target product is as follows:

[0045]

[0046] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (600 MHz, CDCl3)δ 7.88-7.84 (m, 2H), 7.77-7.74 (m, 2H), 4.93 (td, J = 10.9, 4.3 Hz, 1H), 4.59-4.49 (m, 1H), 3.79-3.72 (m, 1H), 3.71 (s, 3H), 2.96-2.88 (m, 1H), 2.46-2.39 (m, 1H), 2.34-2.27 (m, 1H), 2.10-2.05 (m, 1H), 2.05-2.02 (m, 3H), 1.94-1.85 (m, 1H), 1.68-1.59 (m, 1H), 1.45-1.36 (m, 1H), 1.24-1.05 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 169.9, 169.8, 168.8, 168.7, 167.7, 134.4, 131.7, 131.7,123.7, 52.9, 49.6, 49.5, 46.4, 46.3, 41.6, 41.4, 35.1, 33.0, 32.9, 32.9,32.1, 31.4, 30.6, 21.5. HRMS (ESI) m / z calcd. for C 19 H 22 N2NaO5 + [M + Na] + :381.1421, found: 381.1425.

[0047] Example 4

[0048] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 1-ethoxycarbonyl-4-piperidinecarboxylic acid (2d, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, water and saturated NaCl solution were added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 25.8 mg of the target product. The target product was a white solid, and the yield of the target product was 66% based on 1a molar amount as 100%. The structural formula of the target product is as follows:

[0049]

[0050] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1H NMR (600 MHz, CDCl3)δ 7.88-7.84 (m, 2H), 7.76-7.73 (m, 2H), 4.94 (dd, J = 11.4, 4.4 Hz, 1H), 4.08(q, J = 7.1 Hz, 3H), 3.71 (s, 3H), 2.67-2.57 (m, 2H), 2.34-2.27 (m, 1H),2.10-2.04 (m, 1H), 1.86-1.81 (m, 1H), 1.60-1.55 (m, 1H), 1.37-1.29 (m, 1H),1.24-1.06 (m, 6H). 13 C NMR (150 MHz, CDCl3) δ 170.0, 167.8, 155.6, 134.4,131.8, 123.7, 61.2, 52.9, 49.7, 43.9, 43.8, 35.3, 32.9, 32.4, 30.8, 14.8.HRMS (ESI) m / z calcd. for C 20 H 24 N2NaO6 + [M + Na] + : 411.1527, found: 411.1530.

[0051] Example 5

[0052] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 1-Boc-4-piperidinic acid (2e, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 11.8 mg of the target product. The target product was a colorless oil, and the yield of the target product was 27% based on 1a molar amount as 100%. The structural formula of the target product is as follows:

[0053]

[0054] The above-mentioned colorless oily substance was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows:1 H NMR (600 MHz, CDCl3) δ 7.89-7.85 (m, 2H), 7.77-7.73 (m, 2H), 4.80 (t, J = 7.8, 1H), 4.04(s, 2H), 3.72 (s, 3H), 2.63 (s, 2H), 2.26 (q, J = 8.1 Hz, 2H), 1.65-1.59 (m, 2H), 1.42 (s, 9H), 1.41-1.36 (m, 1H), 1.33-1.26 (m, 1H), 1.20-1.13 (m, 1H), 1.10-1.00 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 169.9, 167.8, 134.4, 131.9,123.7, 79.4, 52.9, 52.4, 35.7, 33.1, 32.3, 32.0, 28.6, 26.1. HRMS (ESI) m / zcalcd. for C 23 H 30 N2NaO6 + [M + Na] + : 453.1996, found: 453.2002.

[0055] Example 6

[0056] 2-(bis(tert-butyloxycarbonyl)amino)benzyl acrylate (1b, 0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 34.6 mg of the target product. The target product was a colorless oil, and the yield of the target product was 61% based on 1b molar amount as 100%. The structural formula of the target product is as follows:

[0057]

[0058] The above-mentioned colorless oily substance was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.19-5.09 (m, 2H), 4.98 (dd, J = 9.5, 5.0 Hz, 1H), 4.06 (s, 2H), 2.65 (q, J = 12.9 Hz, 2H), 2.08-1.99 (m, 1H), 1.90-1.81(m, 1H), 1.81-1.74 (m, 1H), 1.64-1.55 (m, 1H), 1.46-1.41 (m, 28H), 1.22-1.01(m, 2H). 13 C NMR (150 MHz, CDCl3) δ 171.0, 155.0, 152.4, 135.8, 128.6, 128.3,128.1, 83.3, 79.4, 67.0, 56.0, 36.5, 33.2, 32.7, 31.7, 28.6, 28.0. HRMS (ESI)m / z calcd. for C 30 H 46 N2NaO8 + [M + Na] + : 585.3146, found: 585.3137.

[0059] Example 7

[0060] To a 10 mL reaction tube equipped with a magnetic stir bar, 1c (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially. The reaction was stirred at room temperature for 24 h under a blue LED lamp at a wavelength of 475 nm. After the reaction was complete, a saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 35.8 mg of the target product. The target product was a white solid with a dr value of 1.5:1. Based on 1c molar amount as 100%, the yield of the target product was 67%. The structural formula of the target product is as follows:

[0061]

[0062] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 11H NMR (600 MHz, CDCl3)δ 7.89-7.85 (m, 2H), 7.77-7.74 (m, 2H), 6.56 (dd, J = 8.2, 5.1 Hz, 1H), 4.96-4.92 (m, 1H), 4.63-4.56 (m, 1H), 4.03 (s, 2H), 3.69-3.65 (m, 3H), 2.57 (s, 2H), 2.37-2.30 (m, 1H), 2.04-1.96 (m, 1H), 1.81-1.75 (m, 1H), 1.65-1.58 (m, 3H), 1.55-1.50 (m, 1H), 1.42 (s, 9H), 1.34-1.28 (m, 1H), 1.20-1.07 (m, 2H), 0.91-0.88 (m, 6H). 13 13C NMR (150 MHz, CDCl3) δ 173.3, 173.2, 168.8, 168.2, 168.2, 154.9, 134.6, 131.7, 123.9, 79.5, 52.5, 52.2, 52.2, 51.2, 51.1, 41.6, 41.6, 35.6, 35.5, 33.2, 33.2, 32.4, 31.2, 28.6, 25.0, 25.0, 22.9, 22.8, 22.1, 22.0. HRMS (ESI) m / z calcd. for C 28 H 39 N3NaO7 + [M + Na] + : 552.2680, found: 552.2682.

[0063] Example 8

[0064] To a 10 mL reaction tube equipped with a magnetic stir bar, 1d (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially. The reaction was stirred at room temperature for 24 h under a blue LED lamp at a wavelength of 475 nm. After the reaction was complete, a saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 39.2 mg of the target product. The target product was a white solid with a dr value of 1:1. Based on the 1d molar amount as 100%, the yield of the target product was 69%. The structural formula of the target product is as follows:

[0065]

[0066] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (600 MHz, CDCl3)δ 7.87-7.82 (m, 2H), 7.78-7.74 (m, 2H), 7.11-7.06 (m, 3H), 7.03-6.99 (m, 2H), 6.58 (dd, J = 86.2, 7.7 Hz, 1H), 4.90-4.80 (m, 2H), 4.00 (s, 2H), 3.72-3.68(m, 3H), 3.18-3.11 (m, 1H), 3.07-3.01 (m, 1H), 2.55 (s, 2H), 2.33-2.17 (m,1H), 1.97-1.85 (m, 1H), 1.74-1.66 (m, 1H), 1.61-1.56 (m, 1H), 1.41 (s, 9H), 1.32-1.25 (m, 1H), 1.16-1.00 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 171.7, 171.7,168.7, 168.5, 168.1, 168.0, 154.8, 135.7, 135.6, 134.5, 134.5, 131.6, 131.6,129.3, 129.2, 128.6, 128.5, 127.2, 127.1, 123.8, 123.8, 79.4, 79.4, 53.4,53.4, 52.5, 52.5, 52.4, 51.9, 37.7, 37.5, 35.4, 35.2, 33.1, 33.0, 32.2, 31.2,31.1, 28.5. HRMS (ESI) m / z calcd. for C 31 H 37 N3NaO7 + [M + Na] + : 586.2524, found:586.2526.

[0067] Example 9

[0068] To a 10 mL reaction tube equipped with a magnetic stir bar, 1e (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H₂O (0.25 mmol), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (0.01 mmol), and anhydrous DMF / H₂O (1.0 mL, 50:1) were added sequentially. The reaction was stirred at room temperature for 24 h under a blue LED lamp at a wavelength of 475 nm. After the reaction was complete, a saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 36.4 mg of the target product. The target product was a yellow solid with a dr ratio of 1.8:1. Based on 1e molar amount as 100%, the yield of the target product was 66%. The structural formula of the target product is as follows:

[0069]

[0070] The above-mentioned yellow solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1¹H NMR (400 MHz, CDCl₃)δ 7.91-7.85 (m, 2H), 7.79-7.74 (m, 2H), 6.91 (dd, J = 30.0, 7.6 Hz, 1H), 4.95(dd, J = 10.8, 5.1 Hz, 1H), 4.73-4.65 (m, 1H), 4.04 (s, 2H), 3.75-3.70 (m,3H), 2.64-2.52 (m, 2H), 2.50-2.44 (m, 2H), 2.39-2.27 (m, 1H), 2.20-2.11 (m,1H), 2.09-1.94 (m, 5H), 1.80 (d, J = 12.9 Hz, 1H), 1.65-1.58 (m, 1H), 1.43(s, 9H), 1.35-1.28 (m, 1H), 1.22-1.05 (m, 2H). 13 ¹³C NMR (100 MHz, CDCl₃) δ172.2, 172.1, 168.9, 168.9, 168.2, 168.1, 154.9, 134.6, 134.6, 131.7, 123.9,79.5, 52.7, 52.2, 52.1, 52.1, 51.9, 35.5, 35.4, 33.2, 32.4, 31.2, 30.1, 30.1,28.6, 15.6, 15.6. HRMS (ESI) m / z calcd. for C 27 H 37 N₃NaO₇S + [M + Na] + : 570.2244, found: 570.2249.

[0071] Example 10

[0072] To a 10 mL reaction tube equipped with a magnetic stir bar, 1f (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially. The reaction was stirred at room temperature for 24 h under a blue LED lamp at a wavelength of 475 nm. After the reaction was complete, a saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 17.7 mg of the target product. The target product was a white solid with a dr value of 1.5:1. Based on 1f molar amount as 100%, the yield of the target product was 33%. The structural formula of the target product is as follows:

[0073]

[0074] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.92-7.86 (m, 2H), 7.80-7.74 (m, 2H), 6.74 (d, J = 9.2 Hz, 1H), 4.99-4.92(m, 1H), 4.42 (dd, J = 17.7, 9.1 Hz, 1H), 4.04 (s, 2H), 3.71-3.66 (m, 3H), 2.58 (d, J = 13.4 Hz, 2H), 2.42-2.29 (m, 1H), 2.08-1.92 (m, 1H), 1.83-1.74(m, 1H), 1.68-1.59 (m, 2H), 1.43 (d, J = 1.5 Hz, 9H), 1.20-1.06 (m, 2H), 0.95(d, J = 2.1 Hz, 9H). 13C NMR (150 MHz, CDCl3) δ 171.9, 171.9, 168.9, 168.3,168.3, 154.9, 134.7, 134.6, 131.7, 131.6, 124.0, 123.9, 79.5, 60.7, HRMS (ESI) m / z calcd. for C 28 H 39 N3NaO7 + [M + Na] + :552.2680, found: 552.2685.

[0075] Example 11

[0076] 1 g (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 20.3 mg of the target product. The target product was a white solid with a dr value of 1:1. Based on 1 g molar amount as 100%, the yield of the target product was 39%. The structural formula of the target product is as follows:

[0077]

[0078] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1¹H NMR (400 MHz, CDCl₃)δ 7.92-7.86 (m, 2H), 7.80-7.74 (m, 2H), 6.67 (dd, J = 12.3, 8.5 Hz, 1H), 4.99-4.93 (m, 1H), 4.57-4.49 (m, 1H), 4.05 (s, 2H), 3.72-3.69 (m, 3H), 2.58 (d, J = 13.1 Hz, 2H), 2.41-2.30 (m, 1H), 2.22-2.13 (m, 1H), 2.08-1.95 (m, 1H), 1.79 (d, J = 5.2 Hz, 1H), 1.64 (d, J = 13.4 Hz, 2H), 1.43 (s, 9H), 1.12 (dd, J = 12.1, 4.1 Hz, 1H), 0.94-0.86 (m, 7H). 13 ¹³C NMR (150 MHz, CDCl₃) δ 172.3, 172.3, 169.0, 168.3, 168.3, 154.9, 134.7, 134.6, 131.7, 131.7, 124.0, 123.9, 79.5, 57.6, 57.5, 52.5, 52.4, 52.4, 35.8, 35.6, 33.3, 33.2, 32.4, 31.5, 31.3, 31.2, 29.8, 28.6, 19.1, 19.1, 17.9, 17.8. HRMS (ESI) m / z calcd. for C 27 H 37 N₃NaO₇ + [M + Na] + : 538.2524, found: 538.2528.

[0079] Example 12

[0080] To a 10 mL reaction tube equipped with a magnetic stir bar, 0.1 mmol of 1 h solution, 0.2 mmol of 1-Boc-4-piperidinic acid (2a), 0.25 mmol of LiOH·H₂O, 0.01 mmol of Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, and 1.0 mL of anhydrous DMF / H₂O (50:1) were added sequentially. The reaction was stirred at room temperature for 24 h under a blue LED lamp with a wavelength of 475 nm. After the reaction was completed, a saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 21.2 mg of the target product. The target product was a white solid with a dr ratio of 1:1. Based on the 1 h molar amount as 100%, the yield of the target product was 38%. The structural formula of the target product is as follows:

[0081]

[0082] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (600 MHz, CDCl3)δ 7.89-7.85 (m, 2H), 7.77-7.73 (m, 2H), 7.36-7.28 (m, 6H), 5.52 (dd, J = 6.9,2.2 Hz, 1H), 4.98-4.94 (m, 1H), 4.02 (s, 2H), 3.69 (s, 3H), 2.56 (s, 2H),2.38-2.31 (m, 1H), 2.06-1.96 (m, 1H), 1.80-1.71 (m, 1H), 1.61 (dt, J = 13.1,2.8 Hz, 1H), 1.42 (s, 9H), 1.32-1.26 (m, 1H), 1.20-1.05 (m, 2H). 13C NMR (150MHz, CDCl3) δ 171.2, 171.1, 168.5, 168.4, 168.3, 168.2, 154.8, 136.2, 136.1,134.6, 134.6, 131.7, 131.6, 129.1, 129.1, 128.7, 128.7, 127.4, 127.3, 123.9,123.9, 79.4, 56.9, 56.9, 53.0, 53.0, 52.3, 52.1, 35.6, 35.5, 33.2, 33.2,32.3, 31.2, 28.5. HRMS (ESI) m / z calcd. for C 30 H 35 N3NaO7 + [M + Na] + : 572.2367, found: 572.2370.

[0083] Example 13

[0084] To a 10 mL reaction tube equipped with a magnetic stir bar, 1i (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially. The reaction was stirred at room temperature for 24 h under a blue LED lamp at a wavelength of 475 nm. After the reaction was complete, a saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 12.5 mg of the target product. The target product was a colorless oil, and the yield was 26% based on 1i molar amount as 100%. The structural formula of the target product is as follows:

[0085]

[0086] The above-mentioned colorless oily substance was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1H NMR (600 MHz, CDCl3) δ 7.90-7.86 (m, 2H), 7.79-7.75 (m, 2H), 6.71 (t, J = 5.1 Hz, 1H), 4.97(dd, J = 10.8, 5.4 Hz, 1H), 4.09-3.99 (m, 4H), 3.73 (s, 3H), 2.59 (s, 2H),2.38-2.31 (m, 1H), 2.06-2.00 (m, 1H), 1.79 (dt, J = 13.1, 3.0 Hz, 1H), 1.65-1.61 (m, 1H), 1.43 (s, 9H), 1.35-1.29 (m, 1H), 1.21–1.08 (m, 2H). 13 C NMR (150MHz, CDCl3) δ 170.1, 169.3, 168.3, 154.9, 134.7, 131.7, 123.9, 79.5, 52.6,52.2, 41.6, 35.6, 33.2, 32.4, 31.2, 28.6. HRMS (ESI) m / z calcd. forC 24 H 31 N3NaO7 + [M + Na] + : 496.2054, found: 496.2057.

[0087] Example 14

[0088] 1j (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 20.8 mg of the target product. The target product was a colorless oil, and the yield of the target product was 42% based on 1j molar amount as 100%. The structural formula of the target product is as follows:

[0089]

[0090] The above-mentioned colorless oily substance was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.89-7.83 (m, 2H), 7.77-7.71 (m, 2H), 6.70 (t, J = 6.1 Hz, 1H), 4.86(dd, J = 11.0, 5.0 Hz, 1H), 4.01 (s, 2H), 3.62 (s, 3H), 3.57-3.51 (m, 1H), 3.47-3.40 (m, 1H), 2.61-2.46 (m, 4H), 2.31-2.23 (m, 1H), 1.99-1.92 (m, 1H), 1.81-1.74 (m, 1H), 1.61-1.55 (m, 1H), 1.41 (s, 9H), 1.31-1.24 (m, 1H), 1.19-1.04 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 173.1, 168.9, 168.1, 154.8, 134.5,131.7, 123.8, 79.4, 51.9, 51.8, 35.4, 35.3, 33.5, 33.1, 32.4, 31.1, 28.5.HRMS (ESI) m / z calcd. for C 25 H 33 N3NaO7 + [M + Na] + : 510.2211, found: 510.2213.

[0091] Example 15

[0092] 1kJ (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 33.6 mg of the target product. The target product was a white solid with a dr value of 1:1. Based on 1kJ molar amount as 100%, the yield of the target product was 52%. The structural formula of the target product is as follows:

[0093]

[0094] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.88-7.82 (m, 2H), 7.80-7.74 (m, 2H), 7.37-7.26 (m, 5H), 7.10-7.01 (m, 3H), 6.96-6.90 (m, 2H), 6.68-6.50 (m, 1H), 5.20-5.07 (m, 2H), 4.91-4.83 (m, 2H),4.01 (s, 2H), 3.20-3.11 (m, 1H), 3.10-3.02 (m, 1H), 2.55 (q, J = 12.1, 11.6Hz, 2H), 2.34-2.17 (m, 1H), 1.97-1.82 (m, 1H), 1.73-1.67 (m, 1H), 1.59 (d, J= 13.3 Hz, 2H), 1.43 (s, 9H), 1.16-1.01 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ171.2, 171.1, 168.7, 168.6, 168.2, 168.1, 154.9, 135.6, 135.5, 135.1, 135.1,134.6, 134.6, 131.7, 131.7, 129.4, 129.4, 128.8, 128.8, 128.7, 128.7, 128.6,128.5, 127.2, 127.1, 123.9, 123.9, 79.5, 67.5, 67.5, 53.5, 53.4, 52.5, 52.1,37.7, 37.6, 35.5, 35.3, 33.2, 33.1, 32.3, 31.2, 31.1, 29.8, 28.6. HRMS (ESI)m / z calcd. for C 37 H 41 N3NaO7 + [M + Na] + : 662.2837, found: 662.2840.

[0095] Example 16

[0096] 1 L (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 30.6 mg of the target product. The target product was a pale yellow oil with a dr value of 1.5:1. Based on 1 L molar amount as 100%, the yield of the target product was 40%. The structural formula of the target product is as follows:

[0097]

[0098] The above-mentioned pale yellow oily substance was analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The data are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.87-7.82 (m, 2H), 7.72-7.67 (m, 2H), 7.37-7.27 (m, 11H), 6.77-6.61(m, 1H), 5.20-5.04 (m, 5H), 5.00 (q, J = 6.2 Hz, 1H), 4.96-4.91 (m, 1H), 4.66-4.59 (m, 1H), 4.03 (s, 2H), 3.15-3.07 (m, 2H), 2.56 (s, 2H), 2.35-2.25(m, 1H), 2.07-1.99 (m, 1H), 1.94-1.72 (m, 3H), 1.71-1.54 (m, 3H), 1.49-1.45(m, 2H), 1.43 (d, J = 3.4 Hz, 9H), 1.42-1.39 (m, 1H). 13C NMR (150 MHz, CDCl3)δ 172.0, 168.8, 168.7, 168.3, 168.2, 156.6, 156.6, 154.9, 136.8, 135.2,135.2, 134.6, 134.6, 131.6, 131.6, 129.6, 128.8, 128.8, 128.7, 128.7, 128.7,128.6, 128.5, 128.4, 128.2, 128.2, 79.5, 79.5, 67.5, 67.4, 66.7, 66.7, 52.5,52.4, 52.0,51.8,40.7,40.6,39.0,35.6,35.5,33.14,33.11,31.9,31.8,29.8,29.3,29.3,28.6,22.2,22.1. HRMS (ESI) m / z calcd. for C 42 H 50 N4NaO9 + [M+ Na] + : 777.3470, found: 777.3468.

[0099] Example 17

[0100] 1 M (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 21.5 mg of the target product. The target product was a pale yellow oil with a dr value of 1:1. Based on 1 M molar amount as 100%, the yield of the target product was 35%. The structural formula of the target product is as follows:

[0101]

[0102] The above-mentioned pale yellow oily substance was analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The data are as follows: 11H NMR (400 MHz, CDCl3) δ 7.89-7.82 (m, 2H), 7.78-7.73 (m, 2H), 7.36-7.32 (m, 5H), 7.10 (d, J= 7.1 Hz, 1H), 6.95 (t, J = 5.2 Hz, 1H), 5.51 (d, J = 7.0 Hz, 1H), 4.92 (dd, J = 10.8, 5.0 Hz, 1H), 4.10-3.95 (m, 3H), 3.85 (dd, J = 16.9, 5.0 Hz, 1H), 3.70 (d, J = 5.2 Hz, 1H), 3.67 (s, 3H), 2.63-2.49 (m, 2H), 2.30-2.21 (m, 1H), 2.05-1.96 (m, 1H), 1.78 (d, J = 12.8 Hz, 1H), 1.67 (dd, J = 10.9, 7.3 Hz, 2H), 1.57 (d, J = 12.4 Hz, 1H), 1.43 (s, 9H). 13 13C NMR (150 MHz, CDCl3) δ 171.1, 169.5, 168.2, 168.1, 154.9, 136.0, 134.6, 131.7, 129.2, 128.8, 127.5, 123.9, 79.5, 56.7, 53.0, 51.6, 43.3, 35.6, 33.1, 31.1, 28.6. HRMS (ESI) m / z calcd. for C 32 H 38 N4NaO8 + [M + Na] + : 629.2582, found: 629.2585.

[0103] Example 18

[0104] To a 10 mL reaction tube equipped with a magnetic stir bar, 1n (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially. The reaction was stirred at room temperature for 24 h under a blue LED lamp at a wavelength of 475 nm. After the reaction was complete, a saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 23.3 mg of the target product. The target product was a pale yellow oil with a dr ratio of 1:1. Based on 1n molar amount as 100%, the yield of the target product was 37%. The structural formula of the target product is as follows:

[0105]

[0106] The above-mentioned pale yellow oily substance was analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.90-7.85 (m, 2H), 7.78-7.74 (m, 2H), 7.37-7.33 (m, 5H), 7.12 (d, J= 7.2 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 5.50 (d, J = 7.1 Hz, 1H), 4.94 (dd,J = 10.7, 5.2 Hz, 1H), 4.58-4.54 (m, 1H), 4.03 (s, 2H), 3.73-3.69 (m, 1H), 3.67 (d, J = 3.4 Hz, 3H), 2.31-2.19 (m, 2H), 2.08-1.97 (m, 2H), 1.80 (d, J =13.0 Hz, 2H), 1.60 (d, J = 13.0 Hz, 2H), 1.47 (d, J = 12.3 Hz, 3H), 1.43 (s,9H). 13C NMR (150 MHz, CDCl3) δ 171.4, 171.2, 169.1, 168.3, 154.9, 136.0,134.6, 131.8, 129.2, 128.8, 127.4, 124.0, 79.5, 56.8, 53.0, 51.9, 49.1, 35.7,33.1, 29.8, 28.6, 28.6, 17.9. HRMS (ESI) m / z calcd. for C 33 H 40 N4NaO8 + [M + Na] + :643.2738, found: 643.2743.

[0107] Example 19

[0108] To a 10 mL reaction tube equipped with a magnetic stir bar, 1O (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially. The reaction was stirred at room temperature for 24 h under a blue LED lamp at a wavelength of 475 nm. After the reaction was complete, a saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 25.6 mg of the target product. The target product was a white solid with a dr value of 1:1. Based on 1O moles as 100%, the yield of the target product was 38%. The structural formula of the target product is as follows:

[0109]

[0110] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1¹H NMR (400 MHz, CDCl₃)δ 7.89-7.83 (m, 2H), 7.78-7.72 (m, 2H), 7.35-7.29 (m, 5H), 6.90 (t, J = 7.4Hz, 1H), 6.83 (dd, J = 9.0, 2.6 Hz, 1H), 5.47 (dd, J = 19.8, 6.9 Hz, 1H),5.00-4.92 (m, 1H), 4.36-4.27 (m, 1H), 4.02 (s, 2H), 3.70-3.61 (m, 3H), 2.65-2.49 (m, 2H), 2.42-2.26 (m, 1H), 2.10-1.87 (m, 1H), 1.82-1.73 (m, 1H), 1.60(d, J = 12.9 Hz, 1H), 1.42 (s, 9H), 1.21-1.06 (m, 2H), 0.98-0.92 (m, 1H),0.87 (s, 9H). 13 ¹³C NMR (150 MHz, CDCl₃) δ 170.9, 170.9, 169.6, 169.6, 169.0,168.8, 168.3, 168.2, 154.9, 136.4, 136.4, 134.6, 134.5, 131.7, 131.7, 129.1,129.0, 128.7, 128.7, 127.5, 127.5, 123.9, 123.9, 79.5, 79.4, 60.9, 60.6,56.8, 56.7, 53.0, 52.9, 52.4, 52.3, 35.7, 35.5, 35.3, 35.1, 33.2, 32.4, 31.2,31.1, 28.6, 26.7, 26.6. HRMS (ESI) m / z calcd. for C 36 H 46 N₄NaO₈ + [M + Na] + : 685.3208, found: 685.3211.

[0111] Example 20

[0112] 1p (0.1 mmol), 1-Boc-4-piperidinic acid (2a, 0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic flux. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 22.7 mg of the target product. The target product was a white solid with a dr value of 1.2:1. Based on 1p molar amount as 100%, the yield of the target product was 33%. The structural formula of the target product is as follows:

[0113]

[0114] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.88-7.81 (m, 2H), 7.81-7.75 (m, 2H), 7.20-7.18 (m, 2H), 7.16-6.96 (m, 3H), 6.74-6.50 (m, 1H), 6.21 (d, J = 8.0 Hz, 1H), 4.90-4.83 (m, 1H), 4.68-4.59 (m,1H), 4.54-4.43 (m, 1H), 4.01 (s, 2H), 3.68 (d, J = 15.9 Hz, 3H), 3.21-3.10(m, 1H), 3.08-2.96 (m, 1H), 2.61-2.48 (m, 2H), 2.29-2.08 (m, 1H), 1.99-1.83(m, 1H), 1.77-1.64 (m, 2H), 1.61-1.44 (m, 5H), 1.43 (d, J = 1.9 Hz, 9H), 0.88(d, J = 6.3 Hz, 3H), 0.83 (t, J = 6.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ172.8, 172.8, 170.3, 170.2, 167.0, 168.9, 168.1, 168.1, 154.9, 136.5, 136.2,134.7, 134.6, 131.6, 131.6, 129.4, 129.4, 128.8, 128.6, 127.2, 127.1, 123.9,79.5, 54.7, 54.2, 52.4, 52.4, 52.0, 52.0, 51.1, 51.1, 41.3, 41.2, 37.6, 37.5,35.5, 35.4, 33.2, 33.0, 28.6, 24.9, 24.8, 23.0, 22.8, 21.9. HRMS (ESI) m / zcalcd. for C 37 H 48 N4NaO8 + [M + Na] + : 699.3364, found: 699.3365.

[0115] Example 21

[0116] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 2f (0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 41.2 mg of the target product. The target product was a white solid with a dr value of 1:1. Based on 1a molar amount as 100%, the yield of the target product was 81%. The structural formula of the target product is as follows:

[0117]

[0118] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1¹H NMR (400 MHz, CDCl₃)δ 7.88-7.81 (m, 2H), 7.77-7.71 (m, 2H), 7.14-7.00 (m, 4H), 4.97-4.53 (m, 2H), 3.87-3.75 (m, 2H), 3.73-3.66 (m, 3H), 2.84-2.01 (m, 6H), 1.91-1.72 (m, 3H), 1.65-1.44 (m, 1H), 1.42-1.36 (m, 3H), 1.20-0.81 (m, 8H). 13 ¹³C NMR (150 MHz, CDCl₃) δ 172.2, 171.9, 170.0, 169.9, 167.8, 140.2, 140.1, 140.1, 139.8, 139.7, 139.3, 134.4, 134.4, 131.8, 131.8 129.7, 129.7, 129.6, 129.6, 127.1, 127.1, 127.0, 123.8 , 53.0, 52.9, 52.9, 49.7, 49.6, 49.5, 45.7, 45.6, 45.52, 45.45, 45.1, 43.2, 43.1, 42.9, 42.8, 42.4, 42.2, 42.1, 42.0, 35.2, 35.1, 33.0, 32.9, 32.9, 32.4, 32.1, 32.1, 31.3, 30.7, 30.4, 30.4, 30.3, 30.3, 22.5, 22.5, 22.4, 22.4, 20.8. HRMS (ESI) m / z calcd. for C 30 H 36 N₂NaO₅ + [M + Na] + : 527.2516, found: 527.2520.

[0119] Example 22

[0120] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 2 g (0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 37.1 mg of the target product. The target product was a white solid with a dr value of 1:1. Based on 1a molar amount as 100%, the yield of the target product was 65%. The structural formula of the target product is as follows:

[0121]

[0122] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (400 MHz, CDCl3)δ 8.04-8.00 (m, 1H), 7.90-7.84 (m, 3H), 7.78-7.73 (m, 2H), 7.55 (t, J = 7.4Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 7.4Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.17 (d, J = 3.4 Hz, 2H), 4.97-4.88 (m,1H), 4.59 (t, J = 14.8 Hz, 1H), 3.87 (t, J = 13.9 Hz, 1H), 3.72 (s, 3H), 3.70(d, J = 5.7 Hz, 2H), 2.96-2.86 (m, 1H), 2.53-2.44 (m, 1H), 2.35-2.25 (m, 1H), 2.10-2.02 (m, 1H), 1.88 (t, J = 13.6 Hz, 1H), 1.63 (t, J = 14.5 Hz, 1H), 1.45-1.34 (m, 1H), 1.22-0.97 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 190.9, 170.0,169.9, 169.1, 169.0, 167.82, 167.81, 160.4, 140.6, 140.5, 136.1, 136.0,135.7, 134.5, 132.9, 131.9, 131.8, 129.7, 129.6, 129.4, 129.2, 127.9, 125.3,125.2, 123.8, 121.3, 73.8, 53.0, 49.7, 46.3, 46.1, 42.1, 42.0, 39.9, 39.8,35.2, 35.1, 33.0, 33.0, 33.0, 32.2, 31.4, 30.6. HRMS (ESI) m / z calcd. forC 33 H 30 N2NaO7 + [M + Na] + : 589.1945, found: 589.1947.

[0123] Example 23

[0124] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 2h (0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 33.4 mg of the target product. The target product was a pale yellow oil with a dr value of 1:1. Based on 1a molar amount as 100%, the yield of the target product was 57%. The structural formula of the target product is as follows:

[0125]

[0126] The above-mentioned pale yellow oily substance was analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The data are as follows: 1¹H NMR (400 MHz, CDCl₃) δ 7.90-7.85 (m, 2H), 7.79-7.73 (m, 2H), 5.38-5.29 (m, 2H), 4.99-4.91 (m, 1H), 4.63-4.52 (m, 1H), 3.86-3.75 (m, 1H), 3.72 (s, 3H), 2.94-2.84 (m, 1H), 2.47-2.38 (m, 1H), 2.37-2.24 (m, 3H), 2.13-2.04 (m, 1H), 2.02-1.85 (m, 5H), 1.77-1.50 (m, 4H), 1.27 (d, J = 14.9 Hz, 22H), 0.86 (t, J = 6.7 Hz, 3H). 13 ¹³C NMR (150 MHz, CDCl₃) δ 171.6, 171.6, 170.0, 170.0, 167.8, 134.5 , 131.9, 130.1, 129.9, 123.8, 53.0, 49.70, 49.65, 45.8, 45.7, 41.8, 41.6, 35.3, 33.6, 33.6, 33.2, 33.2, 33.1, 32.7, 32.7, 32.3, 32.0, 31.7, 30.7, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 27.3, 27.3, 25.6, 25.5, 22.8, 14.2. HRMS (ESI) m / z calcd. for C 35 H 52 N₂NaO₅ + [M + Na] + 603.3768, found: 603.3767.

[0127] Example 24

[0128] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 2i (0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 34.2 mg of the target product. The target product was a white solid with a dr value of 1:1. Based on 1a molar amount as 100%, the yield of the target product was 55%. The structural formula of the target product is as follows:

[0129]

[0130] The above-mentioned white solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.91-7.85 (m, 2H), 7.80-7.75 (m, 2H), 7.33-7.16 (m, 5H), 7.11-7.06 (m, 1H), 6.50-6.36 (m, 1H), 5.20-5.06 (m, 1H), 4.93-4.78 (m, 1H), 4.50 (t, J = 15.4Hz, 1H), 3.73 (dd, J = 7.2, 2.1 Hz, 3H), 3.71-3.52 (m, 1H), 3.06-2.71 (m,3H), 2.44-2.32 (m, 1H), 2.31-2.19 (m, 1H), 2.18-1.95 (m, 2H), 1.94-1.83 (m,3H), 1.82-1.72 (m, 3H), 1.65-1.52 (m, 1H), 1.50-1.36 (m, 3H), 1.16-0.93 (m,4H), 0.87-0.83 (m, 6H). 13C NMR (150 MHz, CDCl3) δ 175.5, 169.9, 169.9, 169.9,169.8, 169.8, 169.8, 169.5, 169.5, 167.8, 167.8, 167.8, 136.5, 136.4, 136.3,136.3, 134.5, 131.9, 131.8, 131.8, 129.9, 129.9, 129.7, 129.6, 128.8, 128.7,128.4, 128.4, 127.2, 127.1, 127.0, 123.8, 53.0, 49.7, 49.6, 49.6, 49.2, 49.2, 45.9, 45.8, 45.7, 45.7, 45.4, 45.4, 43.4, 43.4, 42.3, 42.3, 42.2, 42.1, 40.1, 40.1, 39.9, 39.6, 35.1, 35.0, 35.0, 33.0, 33.0, 32.9, 32.9, 32.7, 32.6, 32.0, 32.0, 31.8, 31.5, 30.5, 30.5, 30.3, 29.9, 29.9, 29.6, 29.2, 29.1, 29.0, 19.9,19.9. HRMS (ESI) m / z calcd. for C 36 H 45 N3NaO6 + [M + Na] + : 638.3201, found:638.3203.

[0131] Example 25

[0132] 2-(1,3-dioxoisoindoline-2-yl)methyl acrylate (1a, 0.1 mmol), 2j (0.2 mmol), LiOH·H2O (0.25 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.01 mmol), and anhydrous DMF / H2O (1.0 mL, 50:1) were added sequentially to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction was stirred at room temperature for 24 h under blue LED light irradiation at a wavelength of 475 nm. After the reaction was completed, saturated NaCl aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 15.1 mg of the target product. The target product was a pale yellow oil, and the yield of the target product was 27% based on 1a molar amount as 100%. The structural formula of the target product is as follows:

[0133]

[0134] The above-mentioned pale yellow oily substance was analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.92-7.85 (m, 2H), 7.80-7.75 (m, 2H), 6.97 (d, J = 7.4 Hz, 1H), 6.62(d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 4.94 (dd, 2.29 (s, 3H), 2.14 (s, 3H), 2.09-2.01 (m, 1H), 1.89 (d, J= 12.9 Hz, 1H), 1.79-1.72 (m, 4H), 1.64 (d, J = 13.2 Hz, 1H), 1.44-1.34 (m,1H), 1.27 (s, 6H), 1.23-1.06 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 175.2, 170.0,167.9, 157.0, 136.6, 134.5, 131.9, 130.4, 123.8, 123.6, 120.8, 112.0, 68.0,53.0, 49.7, 42.5, 37.6, 35.2, 33.2, 32.9, 31.3, 27.2, 25.4, 21.5, 16.0. HRMS(ESI) m / z calcd. for C 32 H 40 N2NaO6 + [M + Na] + : 571.2779, found: 571.2766.

[0135] Example 26

[0136] In vitro antitumor activity assay

[0137] method:

[0138] The in vitro anti-Ramos cell proliferation assay used the CellTiter-Glo (Promega, USA) assay method. After diluting the Ramos cell suspension to an appropriate concentration with culture medium, 95 µL was added to a 96-well plate. 5 µL of different concentrations of the target compound were added, and the plate was incubated at 37 °C with 5% CO2 for 72 hours. The plate was then removed and allowed to reach room temperature before assaying. 20 µL of CellTiter-Glo reagent was added to each well, and the mixture was shaken for 2 minutes to induce cell lysis. The cells were incubated at room temperature for 10 minutes to stabilize the fluorescence signal. Fluorescence intensity was recorded using a multi-mode microplate reader. Cell viability was calculated based on the formula and the fluorescence intensity of the blank control group, and the IC50 of the target compound was then calculated. 50 .

[0139] In vitro anti-HeLa or A549 cell proliferation assays were performed using the Cell Counting Kit-8 (CCK8, DOJINDO, Japan) method. HeLa or A549 cells were diluted to appropriate concentrations using culture medium, and 100 µL was added to each well of a 96-well plate. Cells were incubated at 37°C. o Incubate overnight at 37 °C and 5% CO2. After adding different concentrations of the target compound, incubate the plate at 37 °C and 5% CO2 for 72 hours. Add 10 µL of CCK8 reagent to each well and incubate at 37 °C for 2 hours. Record the absorbance at 450 nM and 630 nM using a multi-plate reader, and then calculate the IC50 of the target compound. 50 .

[0140] Table 1. In vitro antitumor activity of representative compounds

[0141] Example 15 0.9 ± 0.1 1.6 ± 0.2 0.3 ± 0.1 Example 18 2.1 ± 0.3 3.6 ± 0.4 5.9 ± 0.6 Example 20 1.2 ± 0.2 2.1 ± 0.1 0.6 ± 0.1 Example 22 0.8 ± 0.1 0.4 ± 0.1 1.6 ± 0.3 Example 25 3.5 ± 0.4 4.2 ± 0.2 2.5 ± 0.4 5-FU 4.8 ± 0.7 6.4 ± 0.8 7.3 ± 1.1

[0142] Examples 15, 18, 20, 22, and 25 all exhibited strong antitumor activity. The anti-human B-cell lymphoma (Ramos), cervical cancer (HeLa), and lung cancer (A549) activities of these compounds were significantly superior to the positive control drug 5-fluorouracil (5-FU), indicating that our method has significant application prospects in the field of antitumor drug development.

[0143] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are only illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from the scope of the principles of the present invention, and all such changes and modifications fall within the protection scope of the present invention.

Claims

1. A method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings via visible light-mediated decarboxylation of carboxylic acids, characterized in that... The specific synthesis steps are as follows: N-protected dehydroalanine ester compounds, piperidine carboxylic acid compounds, catalysts, bases, and reaction solvents are sequentially added to a reaction vessel. The target products, non-natural amino acid derivatives and polypeptide compounds containing piperidine rings, are obtained using a visible light-induced reaction. The structures of the N-protected dehydroalanine ester compounds are shown in Formula A, the piperidine carboxylic acid compounds in Formula B, and the non-natural amino acid derivatives and polypeptide compounds containing piperidine rings in Formula C. In Formulas A and C, PG is a Phth-protecting group or a Boc-protecting group, and AA is methanol, benzyl alcohol, or an amino acid residue selected from the ester or benzyl groups of L-leucine, L-phenylalanine, L-methionine, L-tert-leucine, D-valine, D-phenylglycine, glycine, β-alanine, or L-lysine; in Formula B, R is Boc, Cbz, acetyl, or a substituted acetyl group; in Formulas B and C, n is 0 or 1; and the catalyst is one or more of a non-metallic photocatalyst or a transition metal complex photocatalyst.

2. The method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids according to claim 1, characterized in that: The compound shown in Formula A is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； The compound shown in formula B is: 、 、 、 、 、 、 、 、 、 ； The compound shown in formula C is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. The method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids according to claim 1, characterized in that: The molar ratio of the N-protected dehydroalanine ester compound, piperidine carboxylic acid compound, catalyst, and base is 1:1~3:0.01~0.1:1~3; the reaction solvent is anhydrous DMF / H2O mixed solvent, wherein the volume ratio of anhydrous DMF to H2O is 50:

1.

4. The method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids according to claim 1, characterized in that: The catalyst is selected from one or more of 4CzIPN, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Rhodamine B, Rhodamine 6G, or Eosin Y, wherein the structural formulas of catalysts 4CzIPN and Ir[dF(CF3)ppy]2(dtbbpy)PF6 are as follows: 。 5. The method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids according to claim 1, characterized in that: The alkali is one or more of LiOH·H2O, potassium hydroxide, sodium hydroxide, potassium carbonate, or potassium acetate.

6. The method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids according to claim 1, characterized in that: The visible light is blue light, and the light source is a blue LED lamp with a wavelength of 450~480 nm and a power of 5~10 W.

7. The method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids according to claim 1, characterized in that: The reaction temperature is 15~40℃ and the reaction time is 12~36 h.

8. The method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids according to claim 1, characterized in that: After the reaction was completed, water and saturated NaCl solution were added to the reaction solution to quench the reaction, and then the solution was extracted three times with ethyl acetate. The organic phases were combined and washed multiple times with water and saturated NaCl solution, dried with anhydrous sodium sulfate, and separated by column chromatography to obtain the target compound, a non-natural amino acid derivative containing a piperidine ring, and a polypeptide compound.

9. The method for synthesizing non-natural amino acid derivatives and polypeptide compounds containing piperidine rings by visible light-mediated decarboxylation of carboxylic acids according to claim 1, characterized in that... The synthetic route is as follows: In the formula, PG is a Phth-protecting group or a Boc-protecting group; AA is methanol, benzyl alcohol, or an amino acid residue, which may be selected from the ester group or benzyl group of L-leucine, L-phenylalanine, L-methionine, L-tert-leucine, D-valine, D-phenylglycine, glycine, β-alanine, or L-lysine; R is Boc, Cbz, acetyl, or a substituted acetyl group.

10. The use of non-natural amino acid derivatives and polypeptide compounds containing piperidine rings synthesized by the method according to any one of claims 1 to 9 in the preparation of anticancer drugs.

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