Photoinduced Copper-Catalyzed Preparation Of Chiral Unnatural Aromatic Amino Acids

Artificial design and synthesis of unnatural amino acids not only broaden the range of amino acids used in medicine and reduce the difficulty of their preparation,but also the introduction of unnatural amino acids into peptide drugs can significantly improve their inherent defects,enhance pharmacological activity and reduce drug toxicity,which has important application value in the field of medicine.Unnatural aromatic amino acid fragments,especially phenylalanine analogues,are widely used in analgesic,antitumor,hypoglycemic,antibacterial and antiviral drugs.Therefore,it is of great significance to develop a synthesis method for unnatural aromatic amino acids with a wide range of substrates,high stereoselectivity,mild and stable reaction conditions.Photochemically driven free radical coupling reactions are favored for their mild reaction conditions,good chemical selectivity and excellent functional group tolerance,and are widely used in the synthesis and functional modification of complex active molecules.At present,most of the photoinduced synthesis strategies of unnatural aromatic amino acids are the construction of C-N bonds or the introduction of fluorine-containing functional groups,and there is a lack of general methods for the synthesis of unnatural aromatic amino acids with diverse structures.C-H activation is an important field in modern synthesis.The development of a general strategy for the synthesis of unnatural amino acids based on the activation of N-α-C-H bonds in the amino acid skeleton is of great significance for the synthesis of various unnatural amino acids.As the only non-chiral protein source amino acid,the N-αcarbon of glycine contains two C(sp~3)-H bonds.The stereoselective functionalization based on C(sp~3)-H bonds is the most convenient way to synthesize a variety of unnatural amino acids.At the same time,the introduction of aryl functional groups also provides an opportunity for the synthesis of unnatural aromatic amino acids.Based on this,the main objective of this thesis study was to establish a photo-induced copper-catalyzed benzylation of glycine C(sp~3)-H with high stereoselectivity and good yields and to prepare a series of chiral non-natural aromatic amino acids.The sequence of literature review and pre-experimentation,analysis and demonstration of research feasibility,screening of optimal reaction conditions using the controlled variable method,substrate extension and mechanistic studies was followed.A mild,green,substrate broadening and highly stereoselective method for the synthesis of unnatural aromatic amino acids was developed and a series of unnatural aromatic amino acids with various substituents were prepared.Furthermore,fine-tuning or simplifying the reaction conditions also enables the preparation of D-type and racemic unnatural aromatic amino acids.It provides a new method for the preparation of chiral unnatural aromatic amino acids and a new idea for peptide drug synthesis and protein labelling.