Site-Selective Arylation And Macrocyclization Of Peptides Via Pd-catalyzed C-H Activation

Peptides and peptidomimetics are rich sources of bioactive compounds.Peptide drugs have attracted attention in medicinal research owing to their high biological activity and target specificity.However,several intrinsic disadvantages limit their application in clinical drugs,such as poor cell permeability and low stability to proteases.Chemical modification of peptides are often effective strategies to solve these problems.This thesis focuses on the functionalization of peptides and is composed of three chapters:In the first part,a late-stage C-H activation method to arylate the benzyl C(sp~3)-H of the N-terminal arylsulfonamide in peptidomimetics was developed.The peptide backbone amides act as directing elements for Pd catalyst.This protocol displays good substrate scope in terms of both arylation reagents and peptide substrates.Furthermore,this chemistry can also be utilized to synthesize peptide-peptide and peptide-amino acid conjugates.In the second part,we developed a site-selective method for the arylation of the C(sp~2)-H of the N-terminal arylformamide group of the peptide.This strategy exhibits broad substrate scope and can be utilized to synthesize peptide conjugates with various bioactive molecules.In addition,this method can be applied to the preparation of peptide macrocycles with aryl-aryl crosslinkers,which provided a new strategy for the synthesis of biaryl cyclic peptides.In the third part,we aimed to synthesize peptides containing a thioaldehyde structure through the photocleavable reaction of alkynyl phenylacyl modified cysteine and study their further reactions.Related experiments are in progress currently.