Asymmetric alpha-amino acid or polypeptide derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of organic synthetic chemistry, in particular to an asymmetric alpha-amino acid or polypeptide derivative as well as a preparation method and application thereof. The preparation method comprises the following step: under the irradiation of a water-free and oxygen-free solvent and a light source, reacting an arylamine compound, an aldehyde compound and a formamide compound under the action of a photocatalyst and a chiral phosphoric acid catalyst to obtain the asymmetric alpha-amino acid or polypeptide derivative. The asymmetric alpha-amino acid or polypeptide derivative synthesized by the invention can be used as a precursor of the corresponding asymmetric alpha-amino acid or polypeptide derivative, and an effective synthesis way of the amino acid or polypeptide derivative is provided.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis chemistry, specifically to an asymmetric... α - Amino acids or polypeptide derivatives, their preparation methods, and applications. Background Technology

[0002] α Amino acids are fundamental building blocks of nature, forming the core structure of proteins and many other important biomolecules. Amino acids and their derivatives are also crucial in drug development, materials science, and asymmetric catalysis. Driven by advancements in screening technologies such as mRNA display, peptide-based therapies have proliferated, increasing the demand for structurally diverse amino acids with high stereoselectivity. Therefore, developing efficient, economical, and scalable methods for the synthesis of chiral amino acids is both important and urgent.

[0003] In 1850, Streker et al. used imine as a raw material and potassium cyanide as a nucleophile to attack the imine to generate an intermediate. α -Cyanoamine. This intermediate is hydrolyzed under high temperature and strong acid conditions to produce... α - Amino acids, this is the most classic synthesis. α The method for synthesizing amino acids has the disadvantage of requiring the use of the highly toxic substance potassium cyanide and demanding reaction conditions. In addition, there are many other methods for synthesizing amino acids, including dehydrogenated amino acids or... α Asymmetric hydrogenation of α-imino esters, electrophilic amination of enolates, alkylation of glycine derivatives via phase transfer catalysis, nucleophilic addition of α-imino esters, and asymmetric Ugi-type multicomponent reactions, etc.

[0004] In recent years, the synthesis of asymmetric amino acids based on free radical methods has shown great promise. Among various free radical species, carbamoyl radicals possess significant potential for asymmetric amino acid synthesis due to their nucleophilicity and the ability to directly form peptide bonds. However, strategies utilizing carbamoyl radicals typically rely on 4-substituted-1,4-dihydropyridine as a precursor, requiring multi-step synthesis and limiting the substrate range; while using formamide as a precursor for carbamoyl radicals requires the use of strong bases and chiral auxiliaries, restricting practical applications. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides an asymmetric... α - Amino acid or polypeptide derivatives, their preparation methods, and applications. Starting from readily available aldehydes, amines, and formamide substrates, optically active derivatives can be synthesized under visible light irradiation via a dual-catalytic system composed of chiral sodium phosphate and tetrabutylammonium decapentotungstate, without the need for substrate prefunctionalization. α-Aminoamide. The product obtained by this invention can be converted into free amino acids in two steps while maintaining high enantioselectivity.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: The first objective of this invention is to provide asymmetry. α A method for preparing amino acid or polypeptide derivatives, characterized by comprising the following steps: under anhydrous and oxygen-free solvent conditions and under light irradiation, using aromatic amine compounds, aldehyde compounds, and formamide compounds as reactants, and reacting them in the presence of a photocatalyst and a chiral phosphoric acid catalyst to obtain an asymmetric... α - Amino acids or polypeptide derivatives; the asymmetry α -The amino acid or polypeptide derivative has the following structure: ; Among them, R 1 It is one of 3-monosubstituted or unsubstituted phenyl, 4-monosubstituted or unsubstituted phenyl, or 3,4,5-trisubstituted or unsubstituted phenyl; the substituent of the 3-monosubstituted phenyl is fluorine, chlorine, bromine, methyl, methoxy, or phenoxy, R 1 The 4-monosubstituted phenyl group has substituents of fluorine, chlorine, bromine, methyl, methoxy, or p-methoxyphenoxy, R 1 The substituents of the 3,4,5-trisubstituted phenyl group are 3,4,5-trimethoxy, 3,4,5-trimethyl, 3,5-dimethyl-4-bromo, 3,5-dimethyl-4-methoxy, 4-methyl-3,5-dibromo or 3,5-dimethoxy-4-chloro.

[0007] R 2 It is one of the following: substituted or unsubstituted C1-C21 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted heterocyclic group; the alkyl substituent is chlorine, benzyloxy, phenyl, 4-isopropylphenyl, 4-tert-butylphenyl, or tert-butyldimethylsiloxy; the cycloalkyl substituent is fluorine; the heterocyclic group is 4-oxocyclohexane or 4-azacyclohexane, and the heterocyclic group substituent is tert-butoxycarbonyl.

[0008] R 3 It can be hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, aryl, amino acid residue or dipeptide residue; wherein the aryl group is phenyl, the amino acid residue is glycine methyl ester, glycine ethyl ester, valine methyl ester, leucine methyl ester or tertiary leucine methyl ester, and the dipeptide residue is glycine-phenylalanine methyl ester, glycine-valine methyl ester, glycine-tertiary leucine methyl ester, leucine-phenylalanine methyl ester or valine-phenylalanine methyl ester.

[0009] In a preferred embodiment of the present invention, R 2For substituted or unsubstituted C2-C18 alkyl, substituted or unsubstituted C4-C6 cycloalkyl; R 3 It is a C2-C7 alkyl or C3-C8 cycloalkyl.

[0010] In a preferred embodiment of the present invention, R 2 For substituted or unsubstituted C2-C15 alkyl groups, or substituted or unsubstituted C5-C6 cycloalkyl groups; R 3 It is a C3-C6 alkyl or a C5-C8 cycloalkyl.

[0011] In a preferred embodiment of the present invention, the asymmetry α -An amino acid or polypeptide derivative has one of the following structures: , , , , , , , .

[0012] In a preferred embodiment of the present invention, the anhydrous and oxygen-free solvent is a mixed solvent of acetonitrile and dichloromethane, with a volume ratio of acetonitrile to dichloromethane of 1:0.5~4; the molar ratio of aromatic amines, aldehydes, and formamides is 1~2:1~2.5:1; the reaction temperature is -78℃~40℃; the reaction time is 12h~96h; and the light source is an LED lamp with a wavelength of 390nm and a power of 10W~40W.

[0013] In a preferred embodiment of the present invention, the photocatalyst is tetrabutylamine decapentotungstate, whose chemical structure is shown in formula (V): .

[0014] In a preferred embodiment of the present invention, the chiral phosphoric acid catalyst has the structural formula shown in formula (VI): ; Where M is sodium, potassium, cesium, magnesium, or calcium, and R 4 It is hydrogen, isopropyl or cyclopentyl.

[0015] A second objective of this invention is to provide an asymmetric material prepared by the above-described method. α - Amino acids or polypeptide derivatives.

[0016] A third objective of this invention is to provide the aforementioned asymmetry. α -Amino acids or polypeptide derivatives in the preparation of asymmetric... α Applications in amino acids or polypeptide derivatives.

[0017] Compared with the prior art, the beneficial effects of the present invention are: This invention provides asymmetry α - A method for preparing amino acid or polypeptide derivatives, starting from readily available aldehydes, amines, and formamide substrates, without the need for substrate prefunctionalization, using a dual catalytic system composed of chiral sodium phosphate and tetrabutylammonium decapolytungstate under visible light irradiation, to synthesize optically active derivatives. α -Aminoamide. The reaction mechanism involves tetrabutylamine decapentotungstate being activated under light and reacting with formamide via a hydrogen atom transfer process to generate the corresponding amino carbonyl radical intermediate. The reactants aldehyde and aromatic amine react to generate the corresponding imine, which is then activated under a chiral phosphoric acid catalyst. The aforementioned amino carbonyl radical attacks the activated imine, which is then reduced by a photocatalyst to obtain the product. The anhydrous and oxygen-free solvent is a mixture of acetonitrile and dichloromethane. The product obtained using the method described in this invention can be converted into free amino acids in two steps while maintaining high enantioselectivity. The synthetic method of this invention can synthesize various useful and biologically significant structures, including β-branched structures, from corresponding formyl starting materials. α -Amino acid derivatives, α,β-diamino acid derivatives, glycosylated amino acids, deuterium and 15 N-labeled derivatives and peptides have broad applicability, providing a powerful platform for obtaining a variety of chiral scaffolds related to peptide science and medicinal chemistry. Attached Figure Description

[0018] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of product 1 in Example 1 of the present invention.

[0019] Figure 2 This is the carbon NMR spectrum of product 1 in Example 1 of the present invention.

[0020] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of product 2 in Example 2 of the present invention.

[0021] Figure 4 This is the carbon NMR spectrum of product 2 in Example 2 of the present invention.

[0022] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of product 3 in Example 3 of the present invention.

[0023] Figure 6 This is the carbon NMR spectrum of product 3 in Example 3 of the present invention.

[0024] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of product 4 in Example 4 of the present invention.

[0025] Figure 8 This is the carbon NMR spectrum of product 4 in Example 4 of the present invention.

[0026] Figure 9 This is the hydrogen nuclear magnetic resonance spectrum of product 5 in Example 5 of the present invention.

[0027] Figure 10 This is the carbon NMR spectrum of product 5 in Example 5 of the present invention.

[0028] Figure 11 This is the hydrogen nuclear magnetic resonance spectrum of product 6 in Example 6 of the present invention.

[0029] Figure 12 This is the carbon NMR spectrum of product 6 in Example 6 of the present invention.

[0030] Figure 13 This is the hydrogen nuclear magnetic resonance spectrum of product 7 in Example 7 of the present invention.

[0031] Figure 14 This is the carbon NMR spectrum of product 7 in Example 7 of the present invention.

[0032] Figure 15 This is the hydrogen nuclear magnetic resonance spectrum of product 8 in Example 8 of the present invention.

[0033] Figure 16 This is the carbon NMR spectrum of product 8 in Example 8 of the present invention.

[0034] Figure 17 The image shows the hydrogen nuclear magnetic resonance spectrum of product 6 in Application Example 1 of this invention.

[0035] Figure 18 This is a high-performance liquid chromatogram of product 1 in Example 1 of the present invention.

[0036] Figure 19 This is a high-performance liquid chromatogram of product 2 in Example 2 of the present invention.

[0037] Figure 20 This is a high-performance liquid chromatogram of product 3 in Example 3 of the present invention.

[0038] Figure 21 This is a high-performance liquid chromatogram of product 4 in Example 4 of the present invention.

[0039] Figure 22 This is a high-performance liquid chromatogram of product 5 in Example 5 of the present invention.

[0040] Figure 23 This is a high-performance liquid chromatogram of product 6 in Example 6 of the present invention.

[0041] Figure 24 This is a high-performance liquid chromatogram of product 7 in Example 7 of the present invention.

[0042] Figure 25This is a high-performance liquid chromatogram of product 8 in Example 8 of the present invention. Detailed Implementation

[0043] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0044] It should be noted that the technical terms used in this invention are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of this invention. Unless otherwise specified, all raw materials, reagents, instruments and equipment used in the following embodiments of this invention can be purchased from the market or prepared by existing methods.

[0045] First, the present invention provides an asymmetric α A method for synthesizing amino acids or polypeptide derivatives, comprising the following steps: Under anhydrous and oxygen-free solvent conditions and under light irradiation, aromatic amines represented by formula (I), aldehydes represented by formula (II), and formamides represented by formula (III) were reacted in the presence of a photocatalyst and a chiral phosphoric acid catalyst to obtain an asymmetric... α - Amino acids or polypeptide derivatives, i.e., compounds represented by formula (IV).

[0046] The reaction route is shown below: .

[0047] It should be noted that the reaction mechanism is as follows: .

[0048] In this process, tetrabutylamine decatungstate is activated under light and reacts with formamide through a hydrogen atom transfer process to generate the corresponding amino carbonyl radical intermediate. The reactants aldehyde and aromatic amine react to generate the corresponding imine, which is then activated under the action of a chiral phosphoric acid catalyst. The above-mentioned amino carbonyl radical attacks the activated imine and is then reduced by a photocatalyst to obtain the product.

[0049] Preferably, the anhydrous and oxygen-free solvent is a mixture of acetonitrile and dichloromethane.

[0050] In asymmetry α In the structural formula of an amino acid or polypeptide derivative, R 1It is one of 3-monosubstituted or unsubstituted phenyl, 4-monosubstituted or unsubstituted phenyl, or 3,4,5-trisubstituted or unsubstituted phenyl; the substituent of the 3-monosubstituted phenyl is fluorine, chlorine, bromine, methyl, methoxy, or phenoxy, R 1 The 4-monosubstituted phenyl group has substituents of fluorine, chlorine, bromine, methyl, methoxy, or p-methoxyphenoxy, R 1 The substituents of the 3,4,5-trisubstituted phenyl group are 3,4,5-trimethoxy, 3,4,5-trimethyl, 3,5-dimethyl-4-bromo, 3,5-dimethyl-4-methoxy, 4-methyl-3,5-dibromo or 3,5-dimethoxy-4-chloro.

[0051] R 2 It is one of the following: substituted or unsubstituted C1-C21 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted heterocyclic group; the alkyl substituent is chlorine, benzyloxy, phenyl, 4-isopropylphenyl, 4-tert-butylphenyl, or tert-butyldimethylsiloxy; the cycloalkyl substituent is fluorine; the heterocyclic group is 4-oxocyclohexane or 4-azacyclohexane, and the heterocyclic group substituent is tert-butoxycarbonyl.

[0052] R 3 It can be hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, aryl, amino acid residue or dipeptide residue; wherein the aryl group is phenyl, the amino acid residue is glycine methyl ester, glycine ethyl ester, valine methyl ester, leucine methyl ester or tertiary leucine methyl ester, and the dipeptide residue is glycine-phenylalanine methyl ester, glycine-valine methyl ester, glycine-tertiary leucine methyl ester, leucine-phenylalanine methyl ester or valine-phenylalanine methyl ester.

[0053] Preferred, R 2 For substituted or unsubstituted C2-C18 alkyl, substituted or unsubstituted C4-C6 cycloalkyl; R 3 It is a C2-C7 alkyl or C3-C8 cycloalkyl.

[0054] More preferably, R 2 For substituted or unsubstituted C2-C15 alkyl groups, or substituted or unsubstituted C5-C6 cycloalkyl groups; R 3 It is a C3-C6 alkyl or a C5-C8 cycloalkyl.

[0055] In a specific embodiment of the present invention, when R 1 It is 3,4,5-trimethoxyphenyl, R 2 For cyclohexyl and R 3 When R is tert-butyl, it corresponds to compound 1; when R... 1 It is 3,4,5-trimethoxyphenyl, R 2 For cyclohexyl and R 3 When R is cyclohexyl, it corresponds to compound 2; when R1 3-Chlorophenyl, R 2 For cyclohexyl and R 3 When R is tert-butyl, it corresponds to compound 3; when R 1 It is 3,5-dimethyl-4-bromophenyl, R 2 For cyclohexyl and R 3 When R is 3,4-dimethoxyphenethyl, it corresponds to compound 4; when R 1 It is 3,5-dimethyl-4-bromophenyl, R 2 For cyclohexyl and R 3 When it is valine-phenylalanine methyl ester, it corresponds to compound 5; when R 1 p-Methoxyphenyl, R 2 For cyclohexyl and R 3 When R is tert-butyl, it corresponds to compound 6; when R 1 It is 3,4,5-trimethoxyphenyl, R 2 For propyl and R 3 When R is tert-butyl, it corresponds to compound 7; when R 1 It is 3,5-dimethyl-4-bromophenyl, R 2 It is N-tert-butoxycarbonyl-4-piperidinyl and R 3 When it is tert-butyl, it corresponds to compound 8.

[0056] The volume ratio of acetonitrile to dichloromethane in the mixed solvent is 1:0.5~4, preferably 1:2.

[0057] The light source is an LED lamp with a wavelength of 390nm and a power of 10W~40W.

[0058] The photocatalyst is tetrabutylamine decapolytungstate (TBADT), as shown in formula (V).

[0059] The chiral phosphoric acid catalyst is shown in formula (VII).

[0060] The amount of the photocatalyst is 9 mol, and the amount of the chiral phosphoric acid catalyst is 20 mol.

[0061] The molar ratio of the aromatic amine compound, aldehyde compound, and formamide compound is 1~2:1~2.5:1. Preferably, the molar ratio is 2.5:2:1.

[0062] The reaction temperature is -78℃ to 40℃; the reaction time is 12h to 96h. Preferably, the temperature is -78℃ and the time is 48h.

[0063] Secondly, the present invention provides an asymmetric α - Amino acids or polypeptide derivatives.

[0064] Finally, the present invention provides an asymmetric α -Amino acids or polypeptide derivatives in the preparation of asymmetric... α Applications in amino acids or polypeptide derivatives.

[0065] The following specific examples will provide further explanation.

[0066] In this invention, the abbreviation for tetrabutylamine decatungstate is TBADT.

[0067] Example 1 an asymmetry α -The amino acid derivative, namely compound 1, has the following structural formula: .

[0068] The preparation method of compound 1 includes the following steps: In a dry 10 mL Schlenk reaction tube, 0.125 mmol of 3,4,5-trimethoxyaniline, 0.05 mmol of N-tert-butylformamide, 0.1 mmol of cyclohexylformaldehyde, 0.0045 mmol of TBADT, 0.01 mmol of chiral phosphoric acid catalyst (VII), 0.25 mL of acetonitrile, and 0.5 mL of dichloromethane were added. The reaction was carried out under anhydrous and oxygen-free conditions at -78 °C, irradiated with an LED lamp (390 nm, 40 W), for 48 h. Product 1 was obtained by column chromatography.

[0069] Product 1 was a white solid with a yield of 85%. The product was characterized by proton and carbon NMR spectroscopy, as follows: Figure 1 and Figure 2 As shown, the results are as follows, indicating that the structure of the product is the same as that shown in product 1. 1 H NMR (400 MHz, Chloroform- d ) δ 6.55 (s, 1H), 5.82 (s, 2H), 3.80 (s, 6H), 3.76 (s, 3H), 3.37 (d, J = 4.4Hz, 1H), 2.01 – 1.88 (m, 1H), 1.85 – 1.64 (m, 5H), 1.32 (s, 9H), 1.28 – 1.06(m, 5H). 13 C NMR (101 MHz, Chloroform- dThe product was characterized by high performance liquid chromatography (HPLC), as shown in the following values: δ 171.9, 154.0, 144.4, 131.0, 91.2, 66.0, 61.2, 56.0, 50.9, 41.2, 30.4, 28.8, 28.4, 26.4(26.44), 26.4(26.44), 26.3. Figure 18 As shown, the enantiomeric excess of the product was measured to be 96%.

[0070] Example 2 an asymmetry α -The amino acid derivative, namely compound 2, has the following structural formula: .

[0071] The preparation method of compound 2 includes the following steps: In a dry 10 mL Schlenk reaction tube, 0.125 mmol of 3,4,5-trimethoxyaniline, 0.05 mmol of N-cyclohexylformamide, 0.1 mmol of cyclohexylformaldehyde, 0.0045 mmol of TBADT, 0.01 mmol of chiral phosphoric acid catalyst (VII), 0.25 mL of acetonitrile, and 0.5 mL of dichloromethane were added. The reaction was carried out under anhydrous and oxygen-free conditions at -78 °C, irradiated with an LED lamp (390 nm, 40 W), for 48 h. Product 2 was obtained by column chromatography.

[0072] Product 2 was a white solid with a yield of 98%. The product was characterized by proton and carbon NMR spectroscopy, as shown below. Figure 3 and Figure 4 As shown in the figure, the results are as follows, indicating that the structure of the product is the same as that of product 2. 1 H NMR (400 MHz, Chloroform- d ) δ 6.62 (d, J = 8.7 Hz, 1H), 5.82 (s, 2H), 3.80 (m, 7H), 3.76 (s,3H), 3.49 (d, J = 4.1 Hz, 1H), 2.00 (td, J = 12.2, 3.7 Hz, 1H), 1.90 – 1.52 (m, 10H), 1.43 – 0.97 (m, 10H). 13 C NMR (101 MHz, Chloroform- dThe product was characterized by high performance liquid chromatography (HPLC), with the following values: δ 171.5, 154.0, 144.4, 131.1, 91.2, 65.4, 61.2, 56.1, 47.9, 33.4, 33.2, 30.5, 28.1, 26.4(26.42), 26.4(26.38), 26.3, 25.6, 25.0, 24.8. Figure 19 As shown, the enantiomeric excess of the product was measured to be 93%.

[0073] Example 3 an asymmetry α -The amino acid derivative, namely compound 3, has the following structural formula: .

[0074] The preparation method of compound 3 includes the following steps: In a dry 10 mL Schlenk reaction tube, 0.125 mmol of 3-chloroaniline, 0.05 mmol of N-tert-butylformamide, 0.1 mmol of cyclohexylformaldehyde, 0.0045 mmol of TBADT, 0.01 mmol of chiral phosphoric acid catalyst (VII), 0.25 mL of acetonitrile, and 0.5 mL of dichloromethane were added. The reaction was carried out under anhydrous and oxygen-free conditions at -78 °C, irradiated with an LED lamp (390 nm, 40 W), for 48 h. Product 3 was obtained by column chromatography.

[0075] Product 3 was a white solid with a yield of 79%. The product was characterized by proton and carbon NMR spectroscopy, as follows: Figure 5 and Figure 6 As shown in the figure, the results are as follows, indicating that the structure of the product is the same as that shown in product 3. 1 H NMR (400 MHz, Chloroform- d ) δ 7.09 (t, J = 8.1 Hz, 1H), 6.74 (ddd, J = 7.9, 1.9, 0.9 Hz, 1H),6.60 (t, J = 2.1 Hz, 1H), 6.47 (ddd, J = 8.2, 2.4, 0.8 Hz, 1H), 6.35 (s, 1H), 4.00 (d, J = 4.1 Hz, 1H), 3.38 (t, J= 4.3 Hz, 1H), 2.01 – 1.90 (m, 1H), 1.84 –1.64 (m, 5H), 1.31 (s, 9H), 1.28 – 1.04 (m, 5H). 13 C NMR (101 MHz, Chloroform- d The product was characterized by high performance liquid chromatography (HPLC), with the following values: δ 171.2, 148.8, 135.2, 130.4, 118.9, 113.8, 111.9, 65.3, 51.1, 41.1, 30.4, 28.8, 28.3, 26.4, 26.3(26.33), 26.3(26.27). Figure 20 As shown, the enantiomeric excess of the product was measured to be 93%.

[0076] Example 4 an asymmetry α -The amino acid derivative, compound 4, has the following structural formula: .

[0077] The preparation method of compound 4 includes the following steps: In a dry 10 mL Schlenk reaction tube, 0.125 mmol of 4-bromo-3,5-dimethylaniline, 0.25 mmol of N-[2-(3,4-dimethoxyphenyl)ethyl]formamide, 0.1 mmol of cyclohexylformaldehyde, 0.0045 mmol of TBADT, 0.02 mmol of chiral phosphoric acid catalyst (VII), 0.25 mL of acetonitrile, and 0.5 mL of dichloromethane were added. The reaction was carried out under anhydrous and oxygen-free conditions at -78 °C, irradiated with an LED lamp (390 nm, 40 W), for 48 h. Product 4 was obtained by column chromatography.

[0078] Product 4 was a white solid with a yield of 64%. The product was characterized by proton and carbon NMR spectroscopy, as follows: Figure 7 and Figure 8 As shown in the figure, the results are as follows, indicating that the structure of the product is the same as that of product 4. 1 H NMR (500 MHz, Chloroform- d ) δ 6.73 (t, J = 5.8 Hz, 1H), 6.68 – 6.60 (m, 2H), 6.54 (dd, J= 8.1,1.9 Hz, 1H), 6.32 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.60 – 3.42 (m, 3H),2.83 – 2.59 (m, 2H), 2.32 (s, 6H), 2.00 – 1.53 (m, 6H), 1.35 – 0.97 (m, 5H). 13 C NMR (126 MHz, Chloroform- d The product was characterized by high performance liquid chromatography (HPLC), as shown in the following values: δ 172.4, 149.0, 147.7, 146.1, 139.1, 131.2, 120.8, 116.5, 113.6, 111.7, 111.1, 64.9, 56.0, 55.8, 41.1, 40.4, 35.6, 30.4, 28.0, 26.3(26.33), 26.3(26.28), 26.2, 24.1. Figure 21 As shown, the enantiomeric excess of the product was measured to be 83%.

[0079] Example 5 An asymmetric polypeptide derivative, namely compound 5, has the following structural formula: .

[0080] The preparation method of compound 5 includes the following steps: In a dry 10 mL Schlenk reaction tube, 0.125 mmol of 4-bromo-3,5-dimethylaniline, 0.25 mmol of N-formylvaline-phenylalanine methyl ester, 0.1 mmol of cyclohexylformaldehyde, 0.0045 mmol of TBADT, 0.02 mmol of chiral phosphoric acid catalyst (VII), 0.5 mL of acetonitrile, and 1.0 mL of dichloromethane were added. The reaction was carried out under anhydrous and oxygen-free conditions at -78 °C, irradiated with an LED lamp (390 nm, 40 W), for 96 h. Product 5 was obtained by column chromatography.

[0081] Product 5 was a white solid with a yield of 41%. The product was characterized by proton and carbon NMR spectroscopy, as follows: Figure 9 and Figure 10 As shown, the results are as follows, indicating that the structure of the product is the same as that shown in product 5. 1 H NMR (500 MHz, Chloroform- d ) δ 7.35 – 7.26 (m, 3H), 7.15 (d, J= 9.0 Hz, 1H), 7.07 (d, J = 6.6Hz, 2H), 6.36 (s, 2H), 6.16 (d, J = 7.8 Hz, 1H), 4.95 – 4.78 (m, 1H), 4.21 (dd, J = 9.0, 6.5 Hz, 1H), 3.83 (d, J = 3.8 Hz, 1H), 3.70 (s, 3H), 3.56 (t, J = 4.0 Hz,1H), 3.21 – 2.96 (m, 2H), 2.31 (s, 6H), 2.04 – 1.59 (m, 6H), 1.30 – 1.05 (m,7H), 0.83 (d, J = 6.8 Hz, 1H), 0.70 (d, J = 6.8 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 172.8, 171.6, 170.6, 145.8, 139.1, 135.6, 129.4, 128.8, 127.4, 116.6, 113.8, 77.4, 76.9, 64.7, 58.3, 53.2, 52.5, 41.3, 38.0, 31.0, 30.4, 28.2, 26.4, 26.2, 24.0, 19.2, 17.8. The product was characterized by high performance liquid chromatography, such as... Figure 22 As shown, the diastereomeric excess of the product was measured to be 90%.

[0082] Example 6 an asymmetry α -The amino acid derivative, compound 6, has the following structural formula: .

[0083] The preparation method of compound 6 includes the following steps: In a dry 10 mL Schlenk reaction tube, 0.125 mmol of 4-methoxyaniline, 0.05 mmol of N-tert-butylformamide, 0.1 mmol of cyclohexylformaldehyde, 0.0045 mmol of TBADT, 0.01 mmol of chiral phosphoric acid catalyst (VII), 0.25 mL of acetonitrile, and 0.5 mL of dichloromethane were added. The reaction was carried out under anhydrous and oxygen-free conditions at -78 °C, irradiated with an LED lamp (390 nm, 40 W), for 48 h. Product 6 was obtained by column chromatography.

[0084] Product 6 was a white solid with a yield of 95%. The product was characterized by proton and carbon NMR spectroscopy, as follows: Figure 11 and Figure 12 As shown, the results are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.81 – 6.74 (m, 2H), 6.71 (s, 1H), 6.60 – 6.52 (m, 2H), 3.74 (s, 3H), 3.65 (s, 1H), 3.30 (d, J = 4.2 Hz,1H), 2.01 – 1.91 (m, 1H), 1.83 – 1.62 (m, 5H), 1.30 (s, 9H), 1.28 – 1.09 (m,5H). 13 C NMR (101 MHz, Chloroform- d The values ​​of δ 172.1, 153.1, 141.8, 115.0, 114.9, 66.6, 55.8, 50.8, 41.2, 30.5, 28.8, 28.2, 26.4 (26.45), 26.4 (26.39), and 26.3 indicate that the structure of this product is as shown in product 6. The product was characterized by high-performance liquid chromatography (HPLC), as shown in... Figure 23 As shown, the enantiomeric excess of the product was measured to be 83%.

[0085] Example 7 an asymmetry α -The amino acid derivative, namely compound 7, has the following structural formula: .

[0086] The preparation method of compound 7 includes the following steps: In a dry 10 mL Schlenk reaction tube, 0.125 mmol of 4-methoxyaniline, 0.05 mmol of N-tert-butylformamide, 0.1 mmol of butyraldehyde, 0.0045 mmol of TBADT, 0.01 mmol of chiral phosphoric acid catalyst (VII), 0.25 mL of acetonitrile, and 0.5 mL of dichloromethane were added. The reaction was carried out under anhydrous and oxygen-free conditions at -78 °C, irradiated with an LED lamp (390 nm, 40 W), for 48 h. Product 7 was obtained by column chromatography.

[0087] Product 7 was a colorless liquid with a yield of 95%. The product was characterized by proton and carbon NMR spectroscopy, as follows: Figure 13 and Figure 14 As shown, the results are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.57 (s, 1H), 5.82 (s,2H), 3.79 (s, 6H), 3.76 (s, 3H), 3.49 (dd, J = 8.1, 4.5 Hz, 1H), 1.96 – 1.82(m, 1H), 1.75 – 1.61 (m, 1H), 1.55 – 1.37 (m, 2H), 1.31 (s, 9H), 0.96 (t, J =7.3 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d The values ​​of δ (172.8, 154.0, 144.0, 131.0, 91.2, 61.2, 61.0, 56.0, 50.8, 35.9, 28.7, 19.4, 14.0) indicate that the structure of this product is as shown in product 7. The product was characterized by high-performance liquid chromatography (HPLC), as shown in... Figure 24 As shown, the enantiomeric excess of the product was measured to be 92%.

[0088] Example 8 an asymmetry α -The amino acid derivative, compound 8, has the following structural formula: .

[0089] The preparation method of compound 8 includes the following steps: In a dry 10 mL Schlenk reaction tube, 0.125 mmol of 3,5-dimethyl-4-bromoaniline, 0.25 mmol of N-tert-butylformamide, 0.1 mmol of butyraldehyde, 0.0045 mmol of TBADT, 0.02 mmol of chiral phosphoric acid catalyst (VII), 0.25 mL of acetonitrile, and 0.5 mL of dichloromethane were added. The reaction was carried out under anhydrous and oxygen-free conditions at -78 °C, irradiated with an LED lamp (390 nm, 40 W), for 48 h. Product 8 was obtained by column chromatography.

[0090] Product 8 was a white solid with a yield of 88%. The product was characterized by proton and carbon NMR spectroscopy, as follows: Figure 13 and Figure 14 As shown, the results are as follows: 1 H NMR (400 MHz, Chloroform- d) δ 6.48 (s, 1H), 6.35 (s,2H), 3.87 – 3.64 (m, 1H), 3.42 (t, J = 4.0 Hz, 1H), 2.69 (d, J = 12.6 Hz, 2H), 2.32 (s, 6H), 2.14 (ddq, J = 12.1, 7.7, 4.0 Hz, 1H), 1.67 – 1.56 (m, 2H), 1.46(s, 9H), 1.44 – 1.34 (m, 2H), 1.31 (s, 9H), 1.29 – 1.21 (m, 2H). 13 C NMR (101MHz, Chloroform- d The values ​​of δ 171.0, 154.8, 145.9, 139.2, 116.8, 113.9, 79.8, 64.6, 51.2, 39.4, 28.7, 28.6, and 24.1 indicate that the structure of this product is as shown in product 8. The product was characterized by high-performance liquid chromatography (HPLC), as shown in... Figure 25 As shown, the enantiomeric excess of the product was measured to be 95%.

[0091] Application Example 1 an asymmetry α -Amino acid, namely compound 9, has the following structural formula: .

[0092] The synthetic route of compound 9 is shown below: .

[0093] The preparation method of compound 9 includes the following steps: In a 25 mL flask, 0.1 mmol of compound 1, acetonitrile (volume ratio 1:1), and water were added. Then, 200 µL of 3 mol / L hydrochloric acid and 0.1 mmol of trichloroisocyanuric acid were slowly added. The reaction mixture was stirred at room temperature for 12 h, and then the solvent was removed by evaporation. The residue was dissolved in 2 mL of deionized water and extracted three times with dichloromethane. After removing the solvent by evaporation, 2 mL of methanol was added to the residue, and the mixture was filtered to remove sparingly soluble inorganic substances. After removing the solvent again by evaporation, 1 mL of 6 mol / L hydrochloric acid was added to the residue, and the resulting solution was stirred at 100 °C for 12 h. The final reaction mixture was washed with deionized water and saturated sodium carbonate solution after removing the solvent, and then acidified with hydrochloric acid. The residue was dissolved in methanol, filtered to remove sparingly soluble substances, and the solvent was removed by evaporation to obtain the final product, compound 9.

[0094] Compound 9 was a white solid in 95% yield. The product was analyzed by proton NMR spectroscopy, as shown in... Figure 11 As shown in the figure, the results are as follows, indicating that the structure of the product is the same as that shown in product 6. 1 H NMR (500 MHz, Methanol-) d 4) δ 3.87 –3.77 (m, 1H), 2.02 – 1.64 (m, 6H), 1.38 – 1.11 (m, 5H). The product was characterized by high performance liquid chromatography, and the enantiomeric excess was found to be 91%.

[0095] Application Example 2 an asymmetry α The synthetic pathway of amino acids, i.e., compound 9, is shown below: .

[0096] The preparation method of compound 9 includes the following steps: In a 25 mL flask, 0.15 mmol of compound 2, acetonitrile, and water (volume ratio 1:1) were added. Then, 300 µL of 3 mol / L hydrochloric acid and 0.15 mmol of trichloroisocyanuric acid were slowly added. The reaction mixture was stirred at room temperature for 12 h, and then the solvent was removed by evaporation. The residue was dissolved in 2 mL of deionized water and extracted three times with dichloromethane. After removing the solvent by evaporation, 2 mL of methanol was added to the residue, and the mixture was filtered to remove sparingly soluble inorganic substances. After removing the solvent again by evaporation, 1.5 mL of 6 mol / L hydrochloric acid was added to the residue, and the resulting solution was stirred at 100 °C for 12 h. After removing the solvent from the final reaction mixture, the yield was determined by NMR, yielding compound 9 in a 40% yield.

[0097] Application Example 3 an asymmetry α The synthetic pathway of amino acids, i.e., compound 9, is shown below: .

[0098] The preparation method of compound 9 includes the following steps: In a 25 mL flask, 0.15 mmol of compound 3, acetonitrile, and water (volume ratio 1:1) were added. Then, 300 µL of 3 mol / L hydrochloric acid and 0.15 mmol of trichloroisocyanuric acid were slowly added. The reaction mixture was stirred at room temperature for 12 h, and then the solvent was removed by evaporation. The residue was dissolved in 2 mL of deionized water and extracted three times with dichloromethane. After removing the solvent by evaporation, 2 mL of methanol was added to the residue, and the mixture was filtered to remove sparingly soluble inorganic substances. After removing the solvent again by evaporation, 1.5 mL of 6 mol / L hydrochloric acid was added to the residue, and the resulting solution was stirred at 100 °C for 12 h. After removing the solvent from the final reaction mixture, the yield was determined by NMR, yielding compound 9 in a 34% yield.

[0099] Application Example 4 an asymmetry α The synthetic pathway of amino acids, i.e., compound 9, is shown below: .

[0100] The preparation method of compound 9 includes the following steps: In a 25 mL flask, 0.1 mmol of compound 4, acetonitrile (1:1 v / v), and water were added. Then, 200 µL of 3 mol / L hydrochloric acid and 0.1 mmol of trichloroisocyanuric acid were slowly added. The reaction mixture was stirred at room temperature for 12 h, and then the solvent was removed by evaporation. The residue was dissolved in 2 mL of deionized water and extracted three times with dichloromethane. After removing the solvent by evaporation, 2 mL of methanol was added to the residue, and the mixture was filtered to remove sparingly soluble inorganic substances. After removing the solvent again by evaporation, 1 mL of 6 mol / L hydrochloric acid was added to the residue, and the resulting solution was stirred at 100 °C for 12 h. After removing the solvent from the final reaction mixture, the yield was determined by NMR, yielding compound 9 in 49% of the sample.

[0101] Application Example 5 A polypeptide derivative, namely compound 10, has the following structural formula: .

[0102] The synthetic route of compound 10 is as follows: .

[0103] The method for preparing compound 10 includes the following steps: In a 25 mL flask, 0.05 mmol of compound 5, acetonitrile (1:1 v / v), and water were added. Then, 100 µL of 3 mol / L hydrochloric acid and 0.05 mmol of trichloroisocyanuric acid were slowly added. The reaction mixture was stirred at room temperature for 12 h, and then the solvent was removed by evaporation. The residue was dissolved in 2 mL of deionized water and extracted three times with dichloromethane. After removing the solvent by evaporation, 2 mL of methanol was added to the residue, and the mixture was filtered to remove sparingly soluble inorganic substances. After removing the solvent again by evaporation, 1 mL of 6 mol / L hydrochloric acid was added to the residue, and the resulting solution was stirred at 100 °C for 12 h. After removing the solvent from the final reaction mixture, the yield was determined by NMR, yielding compound 10 in 93% yield.

[0104] It should be noted that when numerical ranges are involved in this invention, it should be understood that both endpoints of each numerical range, as well as any value between the two endpoints, can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described here to avoid redundancy. Although preferred embodiments of this invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended scope of protection is intended to be interpreted as including the preferred embodiments and all changes and modifications falling within the scope of this invention.

[0105] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of protection of this invention and its equivalents, this invention also intends to include these modifications and variations.

Claims

1. An asymmetry α A method for preparing amino acids or polypeptide derivatives, characterized in that, Includes the following steps: Under anhydrous and oxygen-free solvent conditions and under light irradiation, aromatic amines, aldehydes, and formamides were reacted in the presence of a photocatalyst and a chiral phosphoric acid catalyst to produce an asymmetric... α - Amino acids or polypeptide derivatives; the asymmetry α -The amino acid or polypeptide derivative has the following structure: ； Among them, R 1 It is one of 3-monosubstituted or unsubstituted phenyl, 4-monosubstituted or unsubstituted phenyl, or 3,4,5-trisubstituted or unsubstituted phenyl; the substituent of the 3-monosubstituted phenyl is fluorine, chlorine, bromine, methyl, methoxy, or phenoxy, R 1 The 4-monosubstituted phenyl group has substituents of fluorine, chlorine, bromine, methyl, methoxy, or p-methoxyphenoxy, R 1 The substituents of the 3,4,5-trisubstituted phenyl group are 3,4,5-trimethoxy, 3,4,5-trimethyl, 3,5-dimethyl-4-bromo, 3,5-dimethyl-4-methoxy, 4-methyl-3,5-dibromo or 3,5-dimethoxy-4-chloro. R 2 It is one of the following: substituted or unsubstituted C1-C21 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted heterocyclic group; the substituent of the alkyl group is chlorine, benzyloxy, phenyl, 4-isopropylphenyl, 4-tert-butylphenyl or tert-butyldimethylsiloxy; the substituent of the cycloalkyl group is fluorine; the heterocyclic group is 4-oxocyclohexane or 4-azacyclohexane, and the substituent of the heterocyclic group is tert-butoxycarbonyl; R 3 It can be hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, aryl, amino acid residue or dipeptide residue; wherein the aryl group is phenyl, the amino acid residue is glycine methyl ester, glycine ethyl ester, valine methyl ester, leucine methyl ester or tertiary leucine methyl ester, and the dipeptide residue is glycine-phenylalanine methyl ester, glycine-valine methyl ester, glycine-tertiary leucine methyl ester, leucine-phenylalanine methyl ester or valine-phenylalanine methyl ester.

2. The asymmetry according to claim 1 α A method for preparing amino acids or polypeptide derivatives, characterized in that, R 2 For substituted or unsubstituted C2-C18 alkyl groups, or substituted or unsubstituted C4-C6 cycloalkyl groups; R 3 It is a C2-C7 alkyl or C3-C8 cycloalkyl.

3. The asymmetry according to claim 2 α A method for preparing amino acids or polypeptide derivatives, characterized in that, R 2 For substituted or unsubstituted C2-C15 alkyl groups, or substituted or unsubstituted C5-C6 cycloalkyl groups; R 3 It is a C3-C6 alkyl or a C5-C8 cycloalkyl.

4. The asymmetry according to claim 3 α A method for preparing amino acids or polypeptide derivatives, characterized in that, The asymmetry α -An amino acid or polypeptide derivative has one of the following structures: 、 、 、 、 、 、 、 。 5. The asymmetry according to claim 1 α A method for preparing amino acids or polypeptide derivatives, characterized in that, The anhydrous and oxygen-free solvent is a mixture of acetonitrile and dichloromethane, with a volume ratio of acetonitrile to dichloromethane of 1:0.5~4; the molar ratio of aromatic amines, aldehydes, and formamides is 1~2:1~2.5:1; the reaction temperature is -78℃~40℃; the reaction time is 12h~96h; and the light source is an LED lamp with a wavelength of 390nm and a power of 10W~40W.

6. The asymmetry according to claim 1 α A method for preparing amino acids or polypeptide derivatives, characterized in that, The photocatalyst is tetrabutylamine decapolytungstate, and its chemical structure is shown in formula (V): 。 7. The asymmetry according to claim 1 α A method for preparing amino acids or polypeptide derivatives, characterized in that, The structural formula of the chiral phosphoric acid catalyst is shown in Formula (VI): ； Where M is sodium, potassium, cesium, magnesium, or calcium, and R 4 It is hydrogen, isopropyl or cyclopentyl.

8. An asymmetry α -An amino acid or polypeptide derivative, characterized in that, It is prepared by the method described in any one of claims 1 to 7.

9. An asymmetry as described in claim 8 α -Amino acids or polypeptide derivatives in the preparation of asymmetric... α Applications in amino acids or polypeptide derivatives.

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