Peptide Modification Methods Based On Serine And Its Derivative

Chemistry-driven biomacromolecule modification is of paramount importance in the field of chemical biology,including proteins,nucleic acid,glycans and lipids.The modification of peptide or protein is one of the research focuses in the field of bioorganic,pharmaceutical chemistry and synthetic chemistry.Peptide or protein modification is generally divided into process modification and post modification,the chemical selective precise post modification of existing polypeptide is a more efficient and direct modification strategy than process modification.The post modification strategy of polypeptide or protein is manily based on the modification of proteinogenic amino acid residues,most of which take advantage of the nucleophilic properties of proteinogenic amino acid side chains,such as cysteine,lysine,histidine,etc.Owing to the pKa>13,the nucleophilicity of serine is significantly weaker than the above amino acids.Therefore,serine is rarely used as the site of peptide or protein modification.Furthermore,the abundance of serine on the protein surface as high as 7.9%,it can be seen that serine is very common and important.One of the most common methods is the conversion of serine to dehydroalanine.Dehydroalanine with unique olefin motifs have been extensively investigated as electrophilic acceptors for addition reactions and coupling reactions.In conclution,it is of greatly practical significance to explore the late modification methods of polypeptide based on serine and its derivative dehydroalanine.The renaissance of visible-light photoredox catalysis has led to a paradigm shift in organic synthesis during the past decade.It offers a green and sustainable approach to generate radical species by harnessing the power of light energy.In fact,these photocatalytic methodologies often exhibit high selectivity/reactivity,mild condition,fast kinetics,and good functional group tolerance.Thus,photochemical strategy has recently emerged as an ideal tool to modify peptide at the late stage.This paper focuses on the synthesis of unnatural amino acids and the chemical modification methods of peptides.With serine as the core,this paper studied the peptide modification methods of serine and its derivative,dehydroalanine.Firstly,the chemical modification methods of peptides based on serine and its derivative dehydroalanine are outlined.Then,we discovered that ionic compounds promoted the homolytic cleavage of the pyridinium C-N bond by exploiting the energy of visible-light.This finding was successfully applied in deaminative hydroalkylation of a series of alkenes including naturally occurring dehydroalanine,and the protocol provided an efficient way to prepareβ-alkyl substituted unnatural amino acids under mild and photocatalyst-free conditions.Importantly,by using this protocol,the deaminative cyclization of peptide backbone N-terminal was realized,it provides another effective way for cyclization of polypeptide except for amide bond and disulfide bond.Then we designed and synthesized glycosyl thianthrenium salts as a new glycosylation reagent,it provided a novel opportunity to generate glycosyl radicals at the C5 position of pentoses or the C6position of hexoses.Under visible-light irradiation,the C(sp~3)-S cleavage of glycosyl thianthrenium salt was successfully applied in the hydroglycosylation of a variety of Michael acceptors including dehydroalanine.The reaction provides an efficient toolkit to synthesizeβ-glycosyl substituted unnatural amino acids as well as the late-stage C-saccharide modification of peptides.Finaly,we combined Lewis acid(LA),photoredox catalyst(PC)and hydrogen transfer reagent(quinuclidine)to activate the serine hydroxylα-C(sp~3)-H bond,and coupled with polyfluoroarenes.A series ofβ-polyfluoroarene substituded unnatural amino acids was prepared,and the precisely polyfluoroarylated modification of serine residues in the polypeptide sequence was achieved under mild conditions.It provides a new scheme for the late modification of polypeptide.Through the above work,we have developed novel peptide modification methods based on serine and its derivative dehydroalanine,with mild conditions and good functional group compatibility,which provides a new strategy for peptide and protein modification,and it is a useful tool for the design of peptide drugs.