A non-natural methionine and its synthesis method

Abstract

This invention relates to a non-natural methionine and its synthesis method, using inexpensive and readily available transition metals as catalysts. N Using arylglycine, styrene compounds, and disulfides as raw materials, a series of non-natural methionine compounds were obtained with high selectivity and high yield through a three-component reaction under mild conditions. The compounds prepared in this invention are multifunctional non-natural methionine derivatives, representing a novel class of natural methionine derivatives. They can be used in drug modification, biosensor fabrication, and other fields, possessing significant research and application value and providing new synthetic strategies for the preparation of novel peptide drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical intermediate synthesis technology, specifically relating to a non-natural methionine and its synthesis method. Background Technology

[0002] Non-natural amino acids are derivatives of natural amino acids, possessing diverse side chain groups and unique chemical properties. They are not encoded by the 64 genetic codes present in biological entities. They are characterized by strong site specificity, minimal disturbance to protein structure, high sensitivity, and flexible use, making them applicable in basic research, drug development, bioengineering, and other fields. They are widely used for detecting changes in protein structure, drug coupling, and biosensors.

[0003] Existing methods for synthesizing non-natural methionine suffer from numerous problems, including multiple synthetic steps, expensive catalysts, low yields, poor reaction selectivity, and complex post-processing, making it difficult to meet the requirements of cost control and quality stability for industrial production. For example, the Malins group developed a 5-step synthetic method (Org. Lett. 2023, 25, 3157-3162) for synthesizing non-natural methionine.

[0004]

[0005] How to construct non-natural methionine compounds in one step using green, simple, and mild reaction conditions has always been a research challenge in the field of organic synthesis. Summary of the Invention

[0006] To overcome the shortcomings of existing technologies, this invention provides a non-natural methionine and its synthesis method. This invention uses inexpensive and readily available transition metals (such as copper salts) as catalysts. N Using arylglycine, styrene compounds, and disulfides as raw materials, a series of non-natural methionine compounds were obtained with high selectivity and high yield through a three-component reaction under mild conditions. These compounds represent a novel class of natural methionine derivatives with significant research and application value, providing a new synthetic approach for the preparation of novel peptide drugs.

[0007] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows: A non-natural methionine, the structural formula of which is shown in Formula IV:

[0008] Wherein: R1 is one of alkyl or aryl; R2 is one of hydrogen, alkyl or aryl; X is one of nitrogen or oxygen; R3 is one of alkyl, amino acid or polypeptide; Ar1 ​​is one of substituted aryl; Ar2 is one of substituted aryl.

[0009] The substituted aryl group is a phenyl or naphthyl group with one or more alkyl, halogen, or alkoxy substituents attached to the aromatic ring.

[0010] This invention also provides a method for synthesizing the above-mentioned non-natural methionine, as shown in Formula I. N Using arylglycine, styrene compounds of Formula II, and disulfide of Formula III as raw materials, and adding them to an organic solvent, non-natural methionine of Formula IV is synthesized through a three-component tandem reaction in the presence of a transition metal catalyst;

[0011] Wherein: R1 is one of alkyl or aryl; R2 is one of hydrogen, alkyl or aryl; X is one of nitrogen or oxygen; R3 is one of alkyl, amino acid or polypeptide; Ar1 ​​is one of various substituted aryl groups; Ar2 is one of various substituted aryl groups.

[0012] The reaction equation is as follows:

[0013] Three-component tandem reaction: refers to a reaction mode in which three raw materials, N-arylglycine, styrene compounds, and disulfide, undergo sequential addition and coupling reactions in the same reaction system to generate the target product in one step without the need to separate intermediate products.

[0014] As a preferred option N The molar ratio of arylglycine, styrene compounds and disulfide is 1:0.8 to 10:0.8 to 5, preferably 1:1:1.

[0015] Preferably, the transition metal catalyst is any one of cuprous iodide, cuprous chloride, cupric chloride, copper acetate, ferric chloride, nickel chloride, cobalt chloride, and palladium chloride. The transition metal catalyst is in contact with... N The mass ratio of -arylglycine to feed is 0.01 to 0.5:1, preferably 0.02 to 0.1:1.

[0016] Preferably, the organic solvent is ethyl acetate, dichloromethane, 1,2-dichloroethane, ethanol, acetonitrile, etc. N,N - Any one of dimethylformamide, tetrahydrofuran, and dimethyl sulfoxide, organic solvents and N The mass ratio of -arylglycine to feed is 10 to 150:1.

[0017] Preferably, the reaction temperature is 25–100℃, more preferably 60–85℃, and most preferably 80℃; the reaction time is 4–24 hours, more preferably 8–16 hours, and most preferably 12 hours.

[0018] Preferably, the N -Arylglycine compounds areN - Phenylacetic glycine ethyl ester, N -(4-methyl)-phenylglycine ethyl ester, N -(4-chloro)-phenylglycine ethyl ester, N -(3-methyl)-phenylglycine ethyl ester, N One of the following: (3-bromo)-phenylglycine ethyl ester, glycine dipeptide derivative, tryptophan dipeptide derivative, isoleucine dipeptide derivative, methionine dipeptide derivative, and glycine polypeptide derivative.

[0019] Preferably, the styrene compound is styrene, 4-methylstyrene, 4-chlorostyrene, 4-methoxystyrene, 3-methylstyrene, 3-fluorostyrene, 3-chlorostyrene, 3-methoxystyrene, 2-methoxystyrene, 2-chlorostyrene. α -Methylstyrene, α One of the phenylstyrene species.

[0020] Preferably, the disulfide is one of phenyl disulfide or alkyl disulfide.

[0021] Preferably, the diphenyl disulfide is one of diphenyl disulfide, p-toluene disulfide, p-fluorophenyl disulfide, p-methoxyphenyl disulfide, 3-methylphenyl disulfide, 2-fluorophenyl disulfide, and benzothiazole disulfide; the alkyl disulfide is one of dipropyl disulfide, diethyl disulfide, and dibutyl disulfide.

[0022] Preferably, the reaction includes a post-processing step: quenching the reaction by adding a saturated sodium bicarbonate aqueous solution, extracting with dichloromethane, drying, filtering, concentrating the organic layer, and purifying it by silica gel column chromatography to obtain the target product.

[0023] The beneficial effects of this invention are as follows: This invention is based on N Using arylglycine, styrene compounds, and disulfide as raw materials, non-natural methionine and its derivatives were obtained in high yield and with high selectivity (no two-component products or other three-component products were generated, i.e., a two-component product without the glycine fragment and a three-component product containing only the styrene and disulfide fragments) through a three-component tandem reaction under mild conditions. The obtained non-natural methionine is a novel methionine structure, a non-classical methionine structure containing multiple functional groups, providing a new synthetic approach for developing novel methionine-based peptide drugs. The products are multifunctional non-natural methionine derivatives, which can be used in drug modification, biosensor preparation, and other fields. The obtained non-natural methionine derivatives have potential applications in pharmaceuticals, chemicals, materials, and dyes. Attached Figure Description

[0024] Figure 1 The 1H NMR spectrum of the product from Example 1; Figure 2 The carbon NMR spectrum of the product of Example 1; Figure 3 The 1H NMR spectrum of the product from Example 2; Figure 4 The carbon NMR spectrum of the product in Example 2; Figure 5 The hydrogen NMR spectrum of the product of Example 13; Figure 6 The carbon NMR spectrum of the product of Example 13; Figure 7 The graphs show the spectral response of the products of Examples 1 (Case 1), 5 (Case 5), 7 (Case 7), and 10 (Case 10) to metal ions. Detailed Implementation

[0025] The technical solution of the present invention will be further described in detail below through embodiments. These embodiments are for illustrative purposes only and are not intended to limit the present invention. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0026] Unless otherwise specified, the experimental methods described in the embodiments are conventional methods; the percentages mentioned are all mass percentages unless otherwise specified; and the reagents and materials mentioned are all commercially available unless otherwise specified.

[0027] Example 1

[0028] Will N Ethyl phenylglycine (179 mg, 1 mmol), styrene (104 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask, dissolved in ethyl acetate (20 g), and stirred at 80 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 g) was added to quench the reaction, followed by dichloromethane (20 g). After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 368 mg of a deep yellow liquid, with a yield of 94%. The 1H NMR spectrum of the product is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 As shown.

[0029] 1H NMR (400 MHz, Chloroform- d ) δ 7.38 (d, J = 7.6 Hz, 2H), 7.30 (dd, J = 9.0, 7.2 Hz, 5H), 7.22 (s, 1H), 7.19 (d, J = 9.7 Hz, 1H), 7.15 (dd, J =7.7, 5.4 Hz, 3H), 6.74 (dd, J = 17.2, 7.8 Hz, 3H), 4.77 (d, J = 3.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.53 – 3.44 (m, 2H), 3.33 (dd, J = 11.7, 4.0 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d δ 172.82,147.55, 138.47, 135.41, 130.31, 129.36, 129.06, 128.66, 128.37, 127.83,126.61, 118.99, 114.61, 61.28, 59.35, 47.35, 36.26, 14.22. HRMS-ESI: Theoretical Calculation C 24 H 25 NO2S[M+H] + 392.1679, measured value 392.1680.

[0030] Example 2

[0031] N-(4-methyl)phenylglycine ethyl ester (193 mg, 1 mmol), styrene (104 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask, dissolved in ethyl acetate (20 g), and stirred at 80 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 g) was added to quench the reaction, followed by the addition of dichloromethane (20 g). After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 365 mg of a deep yellow liquid, with a yield of 90%. The 1H NMR spectrum of the product is shown below. Figure 3 As shown, the carbon NMR spectrum is as follows: Figure 4 As shown.

[0032] 1 H NMR (400 MHz, Chloroform- d ) δ 7.25 – 7.17 (m, 7H), 7.13 – 7.08 (m,3H), 6.90 – 6.84 (m, 2H), 6.45 (dd, J = 8.5, 2.2 Hz, 2H), 4.33 (d, J = 6.6Hz, 1H), 3.84 (ddd, J = 7.0, 4.6, 2.4 Hz, 2H), 3.63 (dd, J = 13.1, 5.9 Hz,1H), 3.31 – 3.16 (m, 2H), 2.15 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H). 13 C NMR (101MHz, Chloroform- d δ 172.25, 144.16, 138.88, 136.05, 129.86, 129.58, 129.01, 128.53, 128.51, 128.02, 127.68, 126.27, 114.21, 61.46, 61.06, 48.32, 36.39, 20.45, 13.91. HRMS-ESI: Theoretical Calculation C 25 H 27 NO2S [M+H] + 406.1835, measured value 406.1839.

[0033] Example 3

[0034] Will N Ethyl 4-methoxy)phenylglycine (209 mg, 1 mmol), styrene (104 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask, dissolved in ethyl acetate (20 g), and stirred at 80 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 g) was added to quench the reaction, followed by the addition of dichloromethane (20 g). After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain a deep yellow liquid of 383 mg, with a yield of 91%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.34 – 7.29 (m, 2H), 7.22 (q, J = 7.4 Hz, 5H), 7.16 – 7.12 (m, 1H), 7.09 – 7.05 (m, 2H), 6.68 (d, J = 9.0Hz, 2H), 6.62 (d, J = 8.9 Hz, 2H), 4.62 – 4.53 (m, 1H), 3.99 (qd, J = 7.1,2.3 Hz, 2H), 3.66 (s, 3H), 3.48 (d, J = 3.5 Hz, 1H), 3.37 – 3.24 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d δ 173.12, 153.18, 141.58, 138.59, 135.47, 130.28, 129.04, 128.61, 128.36, 127.77, 126.57, 116.59, 114.77, 61.16, 60.85, 55.70, 47.25, 36.26, 14.22. HRMS-ESI: Theoretical Calculation C 25 H 27 NO3S [M+H] +422.1784, measured value 422.1789.

[0035] Example 4

[0036] Will N Ethyl 4-chlorophenylglycine (213 mg, 1 mmol), styrene (104 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask and dissolved in ethyl acetate (20 g). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 20 g of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane (20 g) was then added, and the mixture was stirred thoroughly and allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 388 mg of a deep yellow liquid, with a yield of 91%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.33 – 7.29 (m, 2H), 7.20 (dq, J =19.3, 7.2 Hz, 8H), 7.03 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 4.65(d, J = 3.0 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.42 – 3.34 (m, 2H), 3.26 (dd, J = 10.2, 8.3 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d δ 172.60, 146.15, 138.24, 135.19, 130.39, 129.16, 129.09, 128.73, 128.28, 127.93, 126.74, 123.61, 115.79, 61.39, 59.31, 47.21, 36.23, 14.21. HRMS-ESI: Theoretical Calculation C 24 H 24 ClNO2S [M+H] +426.1289; Measured value 426.1290.

[0037] Example 5

[0038] Will N Ethyl 3-methyl)phenylglycine (193 mg, 1 mmol), styrene (104 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask and dissolved in ethyl acetate (20 g). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 20 g of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane (20 g) was then added, and the mixture was stirred thoroughly and allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 352 mg of a deep yellow liquid, with a yield of 87%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.32 – 7.28 (m, 2H), 7.24 – 7.14 (m,6H), 7.08 – 7.04 (m, 2H), 6.98 (td, J = 7.3, 1.4 Hz, 1H), 6.50 (d, J = 7.5Hz, 1H), 6.46 (d, J = 7.1 Hz, 2H), 4.68 (d, J = 3.5 Hz, 1H), 4.01 (q, J = 7.1Hz, 2H), 3.45 – 3.35 (m, 2H), 3.25 (dd, J = 11.8, 4.1 Hz, 1H), 2.17 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- dδ 172.87, 147.56, 139.17, 138.52, 135.50, 130.22, 129.23, 129.04, 128.63, 128.38, 127.80, 126.56, 119.88, 115.42, 111.55, 61.24, 59.29, 47.40, 36.23, 21.59, 14.23. HRMS-ESI: Theoretical calculation C 25 H 27 NO2S [M+H] + 406.1835, measured value 406.1845.

[0039] Example 6

[0040] Will N Ethyl 3-fluorophenylglycine (197 mg, 1 mmol), styrene (104 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask, dissolved in ethyl acetate (20 g), and stirred at 80 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 g) was added to quench the reaction, followed by the addition of dichloromethane (20 g). After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 360 mg of a deep yellow liquid, with a yield of 88%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.41 – 7.37 (m, 2H), 7.34 – 7.27(m, 5H), 7.25 – 7.21 (m, 1H), 7.14 – 7.11 (m, 2H), 7.10 – 7.05 (m, 1H), 6.48– 6.40 (m, 3H), 4.74 (d, J = 3.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.46 (dd, J = 5.6, 2.3 Hz, 2H), 3.36 – 3.29 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d ) δ 172.45, 163.94 (d, J = 243.6 Hz), 149.33 (d, J =10.4 Hz), 138.23, 135.21, 130.46, 130.38, 129.07, 128.50 (d, J = 44.0 Hz),128.29, 127.92, 126.73, 110.15 (d, J = 2.4 Hz), 105.41 (d, J = 21.4 Hz), 101.31 (d, J = 25.4 Hz), 61.40, 58.98, 47.29, 36.28, 14.18. 19 F NMR (376 MHz, Chloroform- d ) δ -112.48. HRMS-ESI: Theoretical calculation C 24 H 24 FNO2S [M+H] + 410.1585, measured value 410.1587.

[0041] Example 7

[0042] N-phenylglycine ethyl ester (179 mg, 1 mmol), 4-methylstyrene (118 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask and dissolved in ethyl acetate (20 g). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 20 g of saturated sodium bicarbonate aqueous solution was added to quench the reaction. Dichloromethane (20 g) was added, and the mixture was stirred thoroughly and allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 365 mg of a deep yellow liquid, with a yield of 90%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.39 – 7.36 (m, 2H), 7.29 (d, J =1.1 Hz, 1H), 7.25 (d, J= 4.6 Hz, 1H), 7.23 – 7.17 (m, 2H), 7.16 – 7.12 (m,3H), 7.03 (d, J = 8.1 Hz, 2H), 6.78 – 6.73 (m, 1H), 6.73 – 6.69 (m, 2H), 4.74(d, J = 3.6 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.51 – 3.40 (m, 2H), 3.32 (dd, J = 12.0, 4.5 Hz, 1H), 2.33 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13 C NMR (101MHz, Chloroform- d δ 172.92, 147.60, 137.48, 135.54, 135.31, 130.22, 129.38, 129.34, 129.03, 128.20, 126.53, 118.91, 114.58, 61.23, 59.35, 46.95, 36.34, 21.16, 14.24. HRMS (ESI+): Theoretical calculation C 25 H 27 NO2S [M+H] + 406.1835, measured value 406.1839.

[0043] Example 8

[0044] N-phenylglycine ethyl ester (179 mg, 1 mmol), 3-bromostyrene (183 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask and dissolved in ethyl acetate (20 g). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 20 g of saturated sodium bicarbonate aqueous solution was added to quench the reaction. Dichloromethane (20 g) was then added, and the mixture was stirred thoroughly and allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 395 mg of a deep yellow liquid, with a yield of 84%. 1 H NMR (400 MHz, Chloroform- d) δ 7.44 – 7.36 (m, 3H), 7.32 – 7.27 (m,3H), 7.25 – 7.16 (m, 4H), 7.08 (dt, J = 7.7, 1.4 Hz, 1H), 6.81 – 6.73 (m,3H), 4.74 (d, J = 3.6 Hz, 1H), 4.11 (qd, J = 7.1, 1.0 Hz, 2H), 3.50 – 3.39(m, 2H), 3.29 (dd, J = 12.1, 4.7 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d δ 172.49, 147.38, 140.92, 135.08, 131.54, 130.89, 130.49, 130.11, 129.40, 129.11, 126.95, 126.81, 122.71, 119.23, 114.73, 61.48, 59.51, 47.28, 36.13, 14.22. HRMS-ESI: Theoretical Calculation C 24 H 24 BrNO2S [M+H] + 470.0784, measured value 470.0789.

[0045] Example 9

[0046] N-phenylglycine ethyl ester (179 mg, 1 mmol), 2-methylstyrene (118 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask and dissolved in ethyl acetate (20 g). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 20 g of saturated sodium bicarbonate aqueous solution was added to quench the reaction. Dichloromethane (20 g) was then added, and the mixture was stirred thoroughly and allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 324 mg of a deep yellow liquid, with a yield of 80%. 1 H NMR (400 MHz, Chloroform- d) δ 7.41 – 7.37 (m, 2H), 7.33 – 7.27 (m,3H), 7.23 – 7.13 (m, 6H), 6.80 – 6.76 (m, 1H), 6.75 – 6.72 (m, 2H), 4.74 (d, J = 4.5 Hz, 1H), 4.11 (dd, J = 10.8, 7.2 Hz, 1H), 4.00 (dd, J = 10.8, 7.1 Hz, 1H), 3.71 (dt, J = 8.8, 5.1 Hz, 1H), 3.48 (dd, J = 13.4, 8.7 Hz, 1H), 3.24(dd, J = 13.5, 5.6 Hz, 1H), 2.07 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d δ 173.13, 147.34, 137.15, 136.64, 135.44, 130.77, 130.47, 129.37, 129.04, 127.44, 127.31, 126.65, 126.22, 119.02, 114.59, 61.29, 58.93, 41.77, 37.47, 19.46, 14.02. HRMS (ESI+): Theoretical calculation C 25 H 27 NO2S [M+H] + 406.1835; Measured value 406.1849.

[0047] Example 10

[0048] N-phenylglycine ethyl ester (179 mg, 1 mmol), α1,2-methylstyrene (118 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask, dissolved in ethyl acetate (20 g), and stirred at 80 °C for 12 hours. After the reaction was complete, 20 g of saturated sodium bicarbonate aqueous solution was added to quench the reaction, followed by the addition of dichloromethane (20 g). After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 360 mg of a deep yellow liquid, with a yield of 89%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.40 – 7.26 (m, 12H), 7.25 – 7.10(m, 12H), 6.78 – 6.70 (m, 2H), 6.70 – 6.66 (m, 2H), 6.60 – 6.56 (m, 2H), 4.35(d, J = 9.2 Hz, 2H), 4.00 (t, J = 7.1 Hz, 2H), 3.81 – 3.69 (m, 4H), 3.58 (d, J = 12.3 Hz, 1H), 3.46 (d, J = 12.4 Hz, 1H), 1.68 (s, 3H), 1.66 (s, 3H), 1.08(t, J = 7.1 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d)δ 172.17, 172.07, 147.28, 147.08, 141.65, 141.18, 137.64, 137.50, 129.71,129.59, 129.40, 129.27, 128.90, 128.85, 128.29, 128.25, 127.28, 127.22,127.15, 126.09, 125.98, 119.04, 118.96, 114.43, 114.41, 65.88, 65.26, 61.04,60.80, 46.36, 45.96, 44.98, 44.35, 21.84, 19.69, 14.09, 13.69. HRMS (ESI+): Theoretical Calculation 25 H 27 NO2S[M+H] + 406.1835, measured value 406.1841.

[0049] Example 11

[0050] N-phenylglycine ethyl ester (179 mg, 1 mmol), styrene (104 mg, 1 mmol), di(4-methyl-phenyl)disulfide (246 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask and dissolved in ethyl acetate (20 g). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 g) was added to quench the reaction. Dichloromethane (20 g) was then added, and the mixture was stirred thoroughly and allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain a deep yellow liquid of 368 mg, with a yield of 91%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.34 – 7.28 (m, 5H), 7.19 –7.10 (m, 6H), 6.80 – 6.75 (m, 1H), 6.75 – 6.71 (m, 2H), 4.82 – 4.77 (m, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.49 – 3.41 (m, 2H), 3.31 – 3.24 (m, 1H), 2.34 (s,3H), 1.19 (t, J = 7.1 Hz, 3H).13 C NMR (101 MHz, Chloroform- d δ 172.90,147.58, 138.57, 136.90, 131.28, 129.83, 129.33, 128.60, 128.39, 127.75,118.92, 114.61, 61.22, 59.24, 47.34, 37.02, 21.10, 14.21. HRMS (ESI+): Theoretical calculation C 25 H 27 NO2S [M+H] + 406.1835, measured value 406.1844.

[0051] Example 12

[0052] N-phenylglycine ethyl ester (179 mg, 1 mmol), styrene (104 mg, 1 mmol), dipropyl disulfide (150 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask, dissolved in ethyl acetate (20 g), and stirred at 80 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 g) was added to quench the reaction, followed by the addition of dichloromethane (20 g). After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain a deep yellow liquid of 268 mg, with a yield of 75%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.35 – 7.29 (m, 3H), 7.20 – 7.15 (m,4H), 6.77 – 6.71 (m, 3H), 4.74 (d, J = 4.0 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.45 (ddd, J = 9.5, 5.6, 3.9 Hz, 1H), 3.11 (dd, J = 13.1, 9.4 Hz, 1H), 2.96(dd, J = 13.1, 5.6 Hz, 1H), 2.60 – 2.53 (m, 2H), 1.27 (d, J= 7.4 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d δ 173.06, 147.62, 138.82, 129.31, 128.60, 128.33, 127.73, 118.85, 114.51, 61.26, 59.37, 47.78, 33.80, 26.28, 14.79, 14.27. HRMS-ESI: Theoretical Calculation C 21 H 27 NO2S [M+H] + 358.1835, measured value 358.1836.

[0053] Example 13

[0054] by N Using phenylglycine (10 mmol) and glycine methyl ester hydrochloride (11 mmol) as raw materials, and dicyclohexylcarbodiimide (DCC, 10 mmol) and N,N-dimethyl-4-aminopyridine (DMAP, 10 mmol) as catalysts, and dichloromethane (20 mL) as solvent, the reaction was carried out at room temperature for 12 hours to obtain glycine-glycine dipeptide derivatives.

[0055]

[0056] Glycine-glycine dipeptide derivative (222 mg, 1 mmol), styrene (104 mg, 1 mmol), diphenyl disulfide (218 mg, 1 mmol), and cuprous iodide (3.8 mg, 0.02 mmol) were added to a reaction flask and dissolved in ethyl acetate (20 g). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 g) was added to quench the reaction. Dichloromethane (20 g) was added, and the mixture was stirred thoroughly and allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:80) to obtain 326 mg of a deep yellow liquid, with a yield of 75% (dr 1:1). The 1H NMR spectrum of the product is shown below. Figure 5 As shown, the carbon NMR spectrum is as follows: Figure 6 As shown.

[0057] 1 H NMR (400 MHz, Chloroform- d) δ 7.40 – 7.27 (m, 12H), 7.25 – 7.15(m, 12H), 7.05 (t, J = 5.6 Hz, 1H), 6.91 (t, J = 5.6 Hz, 1H), 6.82 – 6.76 (m,2H), 6.63 – 6.56 (m, 4H), 4.41 (d, J = 5.5 Hz, 1H), 4.34 (d, J = 5.0 Hz, 1H),4.00 – 3.81 (m, 6H), 3.69 (d, J = 1.3 Hz, 6H), 3.48 (ddd, J = 13.3, 7.8, 6.7Hz, 2H), 3.39 (dt, J = 7.8, 3.9 Hz, 1H), 3.31 (dd, J = 13.3, 7.5 Hz, 1H). 13 CNMR (101 MHz, Chloroform- d ) δ 172.79, 171.58, 169.79, 146.53, 146.22, 138.54,138.14, 135.77, 135.55, 130.13, 129.62, 129.52, 129.44, 129.04, 129.00,128.86, 128.62, 128.44, 128.00, 127.93, 126.47, 126.31, 119.45, 119.33,114.12, 113.96, 61.50, 61.39, 52.34, 52.33, 48.13, 47.25, 41.12, 41.01, 36.49, 35.85. HRMS-ESI: Theoretical Calculation C 25 H 26 N₂O₃S [M+H] + 435.1737, measured value 435.1740.

[0058] Example 14 The obtained non-natural methionine compounds contain nitrogen-oxygen-sulfur polydentate ligands within their molecules, which can coordinate and bind to metal ions to achieve specific recognition.

[0059] First, prepare a 10 μM working solution for Example 1 (Case 1). Take nine clean cuvettes and accurately add 2 mL of the working solution to each cuvette. Then, add different metal ion solutions (metal ions include: Fe) to each cuvette. 3+ Al 3+ Ni 2+ Co 2+ Cu 2+ Cd 2+ , Mn 2+ Na + Zn 2+ The volume of ion solution added each time was controlled at 20 μL and the concentration at 5 mM, so that the final concentration of metal ions in each cuvette was 50 μM. After shaking all cuvettes, they were incubated at room temperature for 10 minutes. Then, the absorption spectrum and fluorescence emission spectrum of each solution at specific wavelengths were recorded sequentially using a UV-Vis spectrophotometer and a fluorescence spectrophotometer. The spectral response of the probe in the presence of each metal ion was compared. Similarly, the same operation was performed on Examples 5 (Case 5), 7 (Case 7), and 10 (Case 10). The spectral response results of the products of different examples to metal ions are as follows. Figure 7 As shown, experimental results indicate that this novel non-natural methionine compound can effectively identify Zn in the environment. 2+ ion.

[0060] The non-natural methionine derivatives obtained in the embodiments of this invention have potential applications in the fields of pharmaceuticals, chemicals, materials, and dyes.

[0061] Finally, it should be noted that the above examples are merely some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments and many variations are possible. All variations that can be directly derived or conceived by those skilled in the art from the disclosure of the present invention should be considered within the scope of protection of the present invention.

Claims

1. A non-natural methionine, characterized in that, The structural formula is shown in Formula IV: Wherein: R1 is one of alkyl or aryl; R2 is one of hydrogen, alkyl or aryl; X is one of nitrogen or oxygen; R3 is one of alkyl, amino acid or polypeptide; Ar1 ​​is one of substituted aryl; Ar2 is one of substituted aryl.

2. A method for synthesizing the non-natural methionine according to claim 1, characterized in that, Using N-arylglycine (Formula I), styrene compounds (Formula II), and disulfide (Formula III) as raw materials, and adding them to an organic solvent, non-natural methionine (Formula IV) is synthesized through a three-component tandem reaction in the presence of a transition metal catalyst. 。 3. The synthesis method according to claim 2, characterized in that, The molar ratio of N-arylglycine, styrene compounds, and disulfide is 1:0.8–10:0.8–5.

4. The synthesis method according to claim 2, characterized in that, The transition metal catalyst is one of cuprous iodide, cuprous chloride, cupric chloride, copper acetate, ferric chloride, nickel chloride, cobalt chloride, and palladium chloride; the mass ratio of the transition metal catalyst to N-arylglycine is 0.01 to 0.5:

1.

5. The synthesis method according to claim 2, characterized in that, The organic solvent is one of ethyl acetate, dichloromethane, 1,2-dichloroethane, ethanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, and dimethyl sulfoxide; the mass ratio of the organic solvent to N-arylglycine is 10-150:

1.

6. The synthesis method according to claim 2, characterized in that, The reaction temperature is 25–100℃, and the reaction time is 4–24 hours.

7. The synthesis method according to claim 2, characterized in that, The N-arylglycine is one of N-phenylglycine ethyl ester, N-(4-methyl)-phenylglycine ethyl ester, N-(4-chloro)-phenylglycine ethyl ester, N-(3-methyl)-phenylglycine ethyl ester, N-(3-bromo)-phenylglycine ethyl ester, glycine dipeptide derivative, tryptophan dipeptide derivative, isoleucine dipeptide derivative, methionine dipeptide derivative, and glycine polypeptide derivative.

8. The synthesis method according to claim 2, characterized in that, The styrene compounds are one of styrene, 4-methylstyrene, 4-chlorostyrene, 4-methoxystyrene, 3-methylstyrene, 3-fluorostyrene, 3-chlorostyrene, 3-methoxystyrene, 2-methoxystyrene, 2-chlorostyrene, α-methylstyrene, and α-phenylstyrene.

9. The synthesis method according to claim 2, characterized in that, The disulfide is a phenyl disulfide or an alkyl disulfide; the phenyl disulfide is one of diphenyl disulfide, p-toluene disulfide, p-fluorophenyl disulfide, p-methoxyphenyl disulfide, 3-methylphenyl disulfide, 2-fluorophenyl disulfide, and benzothiazole disulfide; the alkyl disulfide is one of dipropyl disulfide, diethyl disulfide, and dibutyl disulfide.

10. The synthesis method according to claim 2, characterized in that, After the reaction is complete, a post-processing step is also included: saturated sodium bicarbonate aqueous solution is added to the reaction system to quench the reaction, dichloromethane is added for extraction, the organic layer is dried, filtered, concentrated, and then purified by silica gel column chromatography to obtain the target product.

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