Photoinduced Preparation Of Unnatural Amino Acids And Modification Of Peptides Based On Glycine

Peptides play a crucial role in living processes,such as cell proliferation and differentiation,immune defense,and tumor formation.However,the shortcomings of natural peptides such as short action time,lack of receptor selectivity,and inability to take orally,severely limit their development and application in the pharmaceutical field,by using modification of peptides with natural amino acid residues can greatly reduce or eliminate these shortcomings.Despite natural peptides continuing to be of great importance,modification of peptides by introduction of unnatural amino acids can significantly improve their activities and pharmacokinetics as compared to their natural counterparts.In the past few decades,transition metal catalyzed synthesis of unnatural amino acids has made great progress.However,heavy metal residues and harsh reaction conditions(especially high temperature)limit the application of such reactions in the late-stage modification of peptides or proteins.Therefore,it is urgent to develop a mild,green and economical alternative method to realize the synthesis of unnatural amino acids and the late-stage modification of peptides.Light energy is a very clean energy in nature.How to use this clean energy in the construction of unnatural amino acids has attracted extensive attention of chemists.With the rapid development of photoredox catalytic reaction,scientists began to introduce light energy into the synthesis of unnatural amino acids.Due to its mild reaction conditions and green economy,it has become a nonclassical reaction mode in the synthesis of unnatural amino acids,and the method of photocatalysis can also be directly applied to polypeptide and protein modification.Glycine is the basic skeleton ofα-amino acids.Direct functionalization of theα-C(sp~3)-H of glycine or a glycine residue in a peptide represents the most straightforward way for the synthesis of unnaturalα-amino acids.Therefore,this thesis will focus on exploring new strategies for synthesis of unnaturalα-amino acids based on glycine under photocatalysis and applying them to the late-stage modification of peptides.This paper mainly contains the following five chapters:The first chapter introduces the synthesis of unnatural amino acids under photoinduced,mainly including two parts:the synthesis methods of unnatural amino acids based on polar amino acids and the synthesis methods of unnatural amino acids based on non-polar amino acids.In the second chapter,we used the electron donor acceptor complex(EDA complex)formed between glycine derivative and Katritzky salts derived from fatty primary amines to excite under the irradiation of violet light at395-400 nm,and realized the metal free alkylation of glycine by intermolecular electron transfer.In the third chapter,on the basis of the second chapter,we realized copper catalyzed asymmetric C(sp~3)-H alkylation under visible light and synthesized a series of unnaturalα-amino acids.In this reaction,we introduced a quinolinyl group at the N-terminus of glycine,which formed a new bifunctional catalyst in situ with a chiral copper phosphorus complex to provide intermolecular charge transfer and stereocontrolment strategy stands at a previously unexplored intersection of asymmetric synthesis and would enable the development of other classes of enantioselective radical couplings.In the fourth chapter,on the basis of the method established in the third chapter,we reported the first example of photoinduced copper-catalyzed stereoselective C(sp~3)-H glycosylation.The mild reaction conditions are compatible with various carbohydrate substrates and are amenable to the synthesis of a wide variety of C-glycoamino acids and C-glycopeptidomimetics with good yields and excellent stereoselectivities.Given that the modification of peptides by introduction of carbohydrate moieties can significantly enhance the therapeutic behavior of peptide drugs,we anticipate that our protocol would have important impacts on the development of peptide drugs.In the fifth chapter,we summarize this paper and prospect the related research in this field.