Rhodium-catalyzed activation of c-h bonds for the preparation of novel amino acids

Abstract

The application discloses rhodium catalytic hydrogen activation for preparation of novel amino acids, and belongs to the technical field of organic synthesis. The method comprises the following steps: adding lysine derivative, disubstituted alkyne, pentamethylcyclopentadienyl rhodium catalyst, cesium acetate and anhydrous copper acetate into a reactor; stirring in a solvent; after the reaction is completed, removing the solvent by using a rotary evaporator to obtain a crude product; and separating the crude product by using a silica gel column chromatography to obtain a target compound. The synthesis method of the novel amino acid has the characteristics of scientific rationality, simple operation, high yield of the target compound, easy purification of the product, fluorescence activity and the like. The reaction equation is as follows.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to rhodium-catalyzed carbon-hydrogen activation for preparation of novel amino acids. BACKGROUND

[0002] Compared with small molecule drugs, polypeptide drugs have the advantage of specific binding with targets, and therefore, polypeptide therapy has been widely concerned by pharmaceutical companies and research institutions, and in the past decade, more and more polypeptide drugs have been approved for clinical trials. Compared with polypeptides from natural amino acids, polypeptides from unnatural amino acids have better biological and drug activity. Therefore, it is very important to develop a method for preparing unnatural amino acids, which can fine-tune the structure by selective modification of natural amino acids to change their physical and chemical and biological properties. Although traditional amino acid modification methods have made great progress, they often rely on pre-functionalized substrates and require lengthy synthesis steps. Developing a high-atom and step-economical method will not only make the selective modification of amino acids more direct and efficient, but also increase the complexity and diversity of amino acids for the development of new drugs. SUMMARY

[0003] The present application provides a method for preparing novel amino acids by rhodium-catalyzed carbon-hydrogen activation, which overcomes the shortcomings of the prior art and serves as a supplement to the existing synthetic methods of unnatural amino acids.

[0004] Technical solution: In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0005] Rhodium-catalyzed carbon-hydrogen activation is used for the preparation of novel amino acids, and the novel amino acids have the structure shown in formula I:

[0006]

[0007] The R substituent is selected from phenyl, p-methylphenyl, p-methoxyphenyl, p-trifluoromethylphenyl and n-propyl; and the method is characterized in that lysine derivatives, disubstituted alkynes, pentamethylcyclopentadienyl rhodium catalyst, cesium acetate and anhydrous copper acetate are added to a reactor. Stirring is performed in a solvent, and after the reaction is completed, a rotary evaporator is used to remove the solvent to obtain a crude product, and the crude product is separated by silica gel column chromatography to obtain the target compound. The chemical process is shown in reaction formula II:

[0008]

[0009] The molar ratio of the lysine derivatives, disubstituted alkynes, pentamethylcyclopentadienyl rhodium catalyst, cesium acetate and anhydrous copper acetate is 1:1.1:0.05:2:2. The solvent is 2-methyl-2-butanol, the reaction temperature is 120℃, and the reaction time is 24 hours.

[0010] The present application has the advantages that the synthesis method of the novel amino acid provided by the present application is scientific and reasonable, a new approach for synthesizing the novel amino acid is provided, the novel amino acid with various substituents is obtained through the method, the synthesis method is simple, the yield of the target product is high, the product is easy to purify, and the product has fluorescence activity. BRIEF DESCRIPTION OF DRAWINGS

[0011] Figure 1 Chemical reaction formula for preparing the novel amino acid;

[0012] Figure 2 NMR spectrum of the compound 3a prepared in Example 1;

[0013] Figure 3 NMR spectrum of the compound 3b prepared in Example 2;

[0014] Figure 4 NMR spectrum of the compound 3c prepared in Example 3;

[0015] Figure 5 is the emission spectrum result diagram of the compound 3c. DETAILED DESCRIPTION

[0016] The present application will be further described in detail below in combination with the drawings and specific examples.

[0017] In the following examples, the test methods are described, and if no special description is given, they are all conventional methods; the reagents and materials are commercially available, and if no special description is given, they are commercially available.

[0018] Example 1

[0019] A 10 mL pressure tube was added with lysine derivative 1a (0.1 mmol, 36.4 mg), diphenylacetylene 2a (0.11 mmol, 19.6 mg), pentamethylcyclopentadienyl rhodium catalyst (0.005 mmol, 3.1 mg), cesium acetate (0.2 mmol, 38.4 mg), anhydrous copper acetate (0.2 mmol, 36.3 mg) and 2-methyl-2-butanol (1 mL), and was stirred at 120°C, and the reaction time was 24 hours. After the reaction was completed, a rotary evaporator was used to remove the solvent to obtain a crude product, the crude product was separated by silica gel column chromatography (200-300 mesh silica gel) (petroleum ether / ethyl acetate = 2 / 1), and a rotary evaporator was used to remove the solvent to obtain the target product 3a, and the yield was 71%.

[0020]

[0021] Spectrum analysis data 3a

[0022] 1H NMR (400 MHz, CDC13) δ 8.57 (d, J = 8.1 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.26 - 7.20 (m, 4H), 7.19 - 7.13 (m, 5H), 7.07 (t, J = 6.5 Hz, 2H), 5.15 (d, J = 8.2 Hz, 1H), 4.17 (q, J = 7.2, 6.4 Hz, 1H), 3.97 - 3.82 (m, 2H), 3.71 (s, 3H), 1.65 - 1.60 (m, 2H), 1.45 (s, 9H), 1.32 - 1.26 (m, 2H), 1.24 - 1.15 (m, 2H). 13 C NMR (101 MHz, CDC13) δ 173.2, 162.3, 155.4, 141.0, 137.2, 136.5, 134.6, 132.1, 131.5, 130.3, 130.2, 128.3, 128.0, 127.9, 127.9, 127.9, 126.8, 126.7, 125.4, 125.1, 119.3, 79.8, 53.4, 52.2, 45.5, 31.8, 28.4, 28.3, 22.6.

[0023] Example 2

[0024] Using 2b instead of 2a in Example 1, and other conditions are the same as Example 1, the experimental results are shown in Table 1.

[0025]

[0026] Spectral analysis data 3b

[0027] 1 H NMR (400 MHz, CDC13) δ 8.55 (d, J = 7.7 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.14 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 16.7 Hz, 6H), 6.94 (t, J = 6.5 Hz, 2H), 5.14 (d, J = 8.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 1H), 3.86 (hept, J = 6.8 Hz, 2H), 3.71 (d, J = 1.6 Hz, 3H), 2.34 - 2.26 (m, 6H), 1.60 (t, J = 7.5 Hz, 2H), 1.48 - 1.42 (m, 9H), 1.37 - 1.28 (m, 2H), 1.20 (q, J = 7.8 Hz, 2H). 13CNMR (101 MHz, CDC13) δ 173.2, 162.3, 155.4, 141.0, 137.9, 137.4, 136.1, 133.5, 131.9, 131.7, 131.2, 130.0, 130.0, 128.6, 128.6, 128.6, 127.8, 126.4, 125.4, 125.0, 119.2, 79.7, 53.4, 52.1, 45.4, 31.8, 28.4, 28.3, 22.6, 21.3, 21.2.

[0028] Example 3

[0029] Example 1, except that 2c was used instead of 2a. The results are shown in Table 1. A certain amount of compound 3c was dissolved in dichloromethane to prepare a solution with a concentration of 2 x 10"4, and the emission spectrum was measured Figure 5 , indicating that the maximum emission wavelength of compound 3c was 443 nm.

[0030]

[0031] Spectrum analysis data 3c

[0032] 1 H NMR (400 MHz, CDC13) δ 8.56 (d, J = 7.9 Hz, 1H), 7.52 (dt, J = 19.4, 7.3 Hz, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 8.2 Hz, 2H), 6.97 (dd, J = 8.1, 4.7 Hz, 2H), 6.77 (t, J = 8.7 Hz, 4H), 5.15 (d, J = 8.2 Hz, 1H), 4.17 (q, J = 7.1 Hz, 1H), 3.89 (q, J = 7.9, 7.4 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.71 (s, 3H), 1.60 (t, J = 7.4 Hz, 2H), 1.45 (s, 9H), 1.38 - 1.29 (m, 2H), 1.20 (q, J = 7.6 Hz, 2H). 13 CNMR (101 MHz, CDC13) δ 173.3, 162.4, 159.1, 158.1, 155.4, 141.0, 137.6, 132.5, 132.0, 131.5, 131.4, 128.9, 127.8, 127.1, 126.5, 125.4, 125.1, 119.2, 113.4, 79.8, 55.1, 55.1, 53.4, 52.2, 45.4, 31.9, 28.4, 28.3, 22.7.

[0033] Example 4

[0034] Using 2d instead of 2a in Example 1, and otherwise as in Example 1, the experimental results are shown in Table 1.

[0035]

[0036] Spectral analysis data 3d

[0037] 1 H NMR (400 MHz, CDC13) δ 7.78 (d, J = 7.6 Hz, 1H), 7.57 (q, J = 7.8, 6.1 Hz, 2H), 7.50 (d, J = 7.3 Hz, 1H), 7.44 (q, J = 7.4, 6.7 Hz, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.16 (t, J = 9.8 Hz, 1H), 6.95 - 6.73 (m, 1H), [6.30 (s), 5.77 (s), 1H], 5.12 (dd, J = 23.1, 8.3 Hz, 1H), 4.30 (s, 1H), 3.75 (d, J = 3.7 Hz, 3H), 3.47 (q, J = 6.7 Hz, 1H), 1.67 (dq, J = 14.0, 7.5 Hz, 2H), 1.42 (d, J = 11.2 Hz, 13H). Mixture of rotamer (1.6:1). 13 C NMR (101 MHz, CDC13) δ 173.3, 173.1, 169.9, 167.7, 155.6, 142.9, 142.9, 142.7, 142.3, 139.3, 138.2, 137.7, 137.0, 136.5, 134.7, 133.2, 131.4, 131.2, 131.0, 129.1, 128.5, 128.3, 126.9, 126.0, 125.0, 124.2, 124.0, 53.2, 52.9, 52.4, 52.3, 39.6, 39.4, 32.7, 32.5, 29.7, 29.1, 28.3, 28.3, 22.6, 22.6. Mixture of rotamer.

[0038] Example 5

[0039] Using 2e instead of 2a in Example 1, and otherwise as in Example 1, the experimental results are shown in Table 1.

[0040]

[0041] Spectral analysis data 3e

[0042] 1 H NMR (400 MHz, CDC13) δ 8.47 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 4.0 Hz, 2H), 7.47 - 7.39 (m, 1H), 5.30 (d, J = 8.2 Hz, 1H), 4.30 (q, J = 6.9 Hz, 1H), 4.12 (t, J = 7.6 Hz, 2H), 3.75 (d, J = 1.8 Hz, 3H), 2.70 (q, J = 8.8 Hz, 4H), 1.97 - 1.73 (m, 4H), 1.63 (q, J = 8.0 Hz, 4H), 1.46 (d, J = 1.8 Hz, 11H), 1.13 - 1.06 (m, 6H). 13 C NMR (101 MHz, CDC13) δ 173.2, 162.5, 155.5, 139.3, 136.6, 132.0, 128.3, 125.6, 124.9, 122.6, 114.2, 79.8, 53.4, 52.2, 43.6, 32.2, 31.4, 29.9, 28.9, 28.3, 23.6, 23.4, 22.8, 14.5, 14.3.

[0043] Table 1

[0044]

Claims

1. A method for preparing amino acids using rhodium-catalyzed hydrocarbon activation, wherein the amino acids have the structure shown in Formula I: The R substituent is selected from phenyl, p-methylphenyl, p-methoxyphenyl, p-trifluoromethylphenyl, and n-propyl; characterized in that, Lysine derivative, disubstituted alkyne, [RhCp*Cl2]2 catalyst, cesium acetate, and anhydrous copper acetate were added to the reactor. The mixture was stirred in the solvent. After the reaction was completed, the solvent was removed using a rotary evaporator to obtain the crude product. The crude product was then separated by silica gel column chromatography to obtain the target compound. The chemical process is shown in reaction formula II: .

2. According to the preparation method of claim 1, the molar ratio of the lysine derivative, disubstituted alkyne, [RhCp*Cl2]2 catalyst, cesium acetate, and anhydrous copper acetate is 1:1.1:0.05:2:2.

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