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CN-122010765-A - Asymmetric alpha-amino acid or polypeptide derivative and preparation method and application thereof

CN122010765ACN 122010765 ACN122010765 ACN 122010765ACN-122010765-A

Abstract

The invention relates to the technical field of organic synthetic chemistry, in particular to an asymmetric alpha-amino acid or polypeptide derivative, a preparation method and application thereof. The preparation method comprises reacting aromatic amine compound, aldehyde compound and formamide compound under the action of photocatalyst and chiral phosphoric acid catalyst under the irradiation of anhydrous anaerobic solvent and light source to obtain 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 provides an effective synthesis path of the amino acid or polypeptide derivative.

Inventors

  • GONG LIUZHU
  • HE ZHIYUAN
  • DING WEIWEI
  • HAN ZHIYONG
  • WANG WANYU

Assignees

  • 中国科学技术大学

Dates

Publication Date
20260512
Application Date
20260203

Claims (9)

  1. 1. A method for preparing an asymmetric α -amino acid or polypeptide derivative, comprising the steps of: Under the condition of anhydrous and anaerobic solvent, under the irradiation of a light source, aromatic amine compounds, aldehyde compounds and formamide compounds are used as reactants, and the reaction is carried out under the action of a photocatalyst and a chiral phosphoric acid catalyst to obtain an asymmetric alpha-amino acid or polypeptide derivative, wherein the asymmetric alpha-amino acid or polypeptide derivative has the following structure: ; Wherein R 1 is one of 3-monosubstituted or unsubstituted phenyl, 4-monosubstituted or unsubstituted phenyl, 3,4, 5-trisubstituted or unsubstituted phenyl, the substituent of 3-monosubstituted phenyl is fluorine, chlorine, bromine, methyl, methoxy or phenoxy, the substituent of 4-monosubstituted phenyl of R 1 is fluorine, chlorine, bromine, methyl, methoxy or p-methoxyphenoxy, the substituent of 3,4, 5-trisubstituted phenyl of R 1 is 3,4, 5-trimethoxy, 3,4, 5-trimethyl, 3, 5-dimethyl-4-bromine, 3, 5-dimethyl-4-methoxy, 4-methyl-3, 5-dibromo or 3, 5-dimethoxy-4-chlorine; r 2 is one of substituted or unsubstituted C1-C21 alkyl, substituted or unsubstituted C3-C6 cycloalkyl and substituted or unsubstituted heterocyclic group, wherein the substituent of the alkyl is chlorine, benzyloxy, phenyl, 4-isopropylphenyl, 4-tert-butylphenyl or tert-butyldimethylsiloxy, the substituent of the cycloalkyl is fluorine, the heterocyclic group is 4-oxo-cyclohexane or 4-azacyclohexane, and the substituent of the heterocyclic group is tert-butoxycarbonyl; R 3 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, aryl, amino acid residue or dipeptide residue, wherein aryl is phenyl, amino acid residue is glycine methyl ester, glycine ethyl ester, valine methyl ester, leucine methyl ester or tertiary leucine methyl ester, and 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. 2. The method for producing an asymmetric α -amino acid or polypeptide derivative according to claim 1, wherein R 2 is a substituted or unsubstituted C2-C18 alkyl group, a substituted or unsubstituted C4-C6 cycloalkyl group, and R 3 is a C2-C7 alkyl group or a C3-C8 cycloalkyl group.
  3. 3. The method for producing an asymmetric α -amino acid or polypeptide derivative according to claim 2, wherein R 2 is a substituted or unsubstituted C2-C15 alkyl group, a substituted or unsubstituted C5-C6 cycloalkyl group, and R 3 is a C3-C6 alkyl group or a C5-C8 cycloalkyl group.
  4. 4. A method of preparing an asymmetric α -amino acid or polypeptide derivative according to claim 3, wherein the asymmetric α -amino acid or polypeptide derivative has one of the following structures: 、 、 、 、 、 、 、 。
  5. 5. The preparation method of the asymmetric alpha-amino acid or polypeptide derivative according to claim 1, wherein the anhydrous anaerobic solvent is a mixed solvent of acetonitrile and dichloromethane, the volume ratio of acetonitrile to dichloromethane is 1:0.5-4, the molar ratio of arylamine compounds, aldehyde compounds to formamide compounds is 1-2:1-2.5:1, the reaction temperature is-78 ℃ to 40 ℃, the reaction time is 12h to 96h, the light source is an LED lamp, the wavelength is 390nm, and the power is 10W to 40W.
  6. 6. The method for preparing an asymmetric alpha-amino acid or polypeptide derivative according to claim 1, wherein the photocatalyst is tetrabutylammonium decatungstate, and the chemical structure of the photocatalyst is shown as formula (V): 。
  7. 7. the method for preparing an asymmetric α -amino acid or polypeptide derivative according to claim 1, wherein the chiral phosphoric acid catalyst has a structural formula shown in formula (VI): ; wherein M is sodium, potassium, cesium, magnesium or calcium, and R 4 is hydrogen, isopropyl or cyclopentyl.
  8. 8. An asymmetric α -amino acid or polypeptide derivative prepared by the method of any one of claims 1 to 7.
  9. 9. Use of an asymmetric α -amino acid or polypeptide derivative according to claim 8 for the preparation of an asymmetric α -amino acid or polypeptide derivative.

Description

Asymmetric alpha-amino acid or polypeptide derivative and preparation method and application thereof Technical Field The invention relates to the technical field of organic synthetic chemistry, in particular to an asymmetric alpha-amino acid or polypeptide derivative, a preparation method and application thereof. Background Alpha-amino acids are essential components in nature, constituting the core structure of proteins and many other important biomolecules. Amino acids and their derivatives are also important in the fields of drug development, material science and asymmetric catalysis. The proliferation of peptide-based therapies driven by advances in screening technologies such as mRNA display has increased the need for structurally diverse amino acids with high stereoselectivity. Therefore, the development of efficient, economical and expandable chiral amino acid synthesis methods is important and urgent. 1850, Streker et al used imine as a starting material and potassium cyanide as a nucleophile to attack the imine to form the intermediate α -cyanoamine. This intermediate hydrolyzes under conditions of high temperature and strong acid to form alpha-amino acids, which is the most classical method of synthesizing alpha-amino acids. The disadvantage is that the highly toxic substance potassium cyanide must be used and the reaction conditions are relatively severe. In addition, there are various methods for synthesizing amino acids, including asymmetric hydrogenation of dehydroamino acids or α -imino esters, electrophilic amination of enolates, alkylation of glycine derivatives by phase transfer catalysis, nucleophilic addition of α -imino esters, asymmetric Ugi-type multicomponent reactions, and the like. In recent years, the synthesis of asymmetric amino acids by radical-based methods has great development prospects. Among the various radical species, carbamoyl radicals have great potential for asymmetric amino acid synthesis due to their nucleophilicity and the property of potentially directly forming peptide bonds. However, strategies utilizing carbamoyl radicals generally rely on 4-substituted-1, 4-dihydropyridines as precursors, requiring multi-step syntheses and limited substrate ranges, while the use of strong bases and chiral auxiliary reagents for carbamoyl radical precursors limits practical applications. Disclosure of Invention In order to solve the problems, the invention provides an asymmetric alpha-amino acid or polypeptide derivative, and a preparation method and application thereof. Starting from easily available aldehyde, amine and formamide substrates, the optically active alpha-amino amide is synthesized under the irradiation of visible light through a double catalytic system consisting of chiral sodium phosphate and tetrabutylammonium decatungstate without the need of pre-functionalization of the substrates. The product obtained by the invention can be converted into free amino acid in two steps, and can keep high enantioselectivity. In order to achieve the above purpose, the invention adopts the following technical scheme: The first object of the invention is to provide a preparation method of an asymmetric alpha-amino acid or polypeptide derivative, which is characterized by comprising the following steps of reacting an arylamine compound, an aldehyde compound and a formamide compound serving as reactants under the irradiation of a light source in the absence of an oxygen solvent under the action of a photocatalyst and a chiral phosphoric acid catalyst to obtain the asymmetric alpha-amino acid or polypeptide derivative, wherein the asymmetric alpha-amino acid or polypeptide derivative has the following structure: ; Wherein R 1 is one of 3-monosubstituted or unsubstituted phenyl, 4-monosubstituted or unsubstituted phenyl and 3,4, 5-trisubstituted or unsubstituted phenyl, the substituent of the 3-monosubstituted phenyl is fluorine, chlorine, bromine, methyl, methoxy or phenoxy, the substituent of the 4-monosubstituted phenyl of R 1 is fluorine, chlorine, bromine, methyl, methoxy or p-methoxyphenoxy, and the substituent of the 3,4, 5-trisubstituted phenyl of R 1 is 3,4, 5-trimethoxy, 3,4, 5-trimethyl, 3, 5-dimethyl-4-bromine, 3, 5-dimethyl-4-methoxy, 4-methyl-3, 5-dibromo or 3, 5-dimethoxy-4-chlorine. R 2 is one of substituted or unsubstituted C1-C21 alkyl, substituted or unsubstituted C3-C6 cycloalkyl and substituted or unsubstituted heterocyclic group, the substituent of the alkyl is chlorine, benzyloxy, phenyl, 4-isopropylphenyl, 4-tert-butylphenyl or tert-butyldimethylsiloxy, the substituent of the cycloalkyl is fluorine, the heterocyclic group is 4-oxo-cyclohexane or 4-azacyclohexane, and the substituent of the heterocyclic group is tert-butoxycarbonyl. R 3 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, aryl, amino acid residue or dipeptide residue, wherein aryl is phenyl, amino acid residue is glycine methyl ester, glycine ethyl ester, valine methyl ester, leucine methyl ester or ter