Peptide Modification Through Pd-Catalyzed Site-selective C(sp~2)-H Olefination

Chemical modification of peptides can often improve their biological activities and pharmacokinetic properties.Therefore,the development of peptide site-selective modification methods is of great significance for the development of peptide drugs.In this thesis,the research focuses on the selective olefination of C(sp~2)-H of phenylalanine and tryptophan by Pd-catalysis mediated by peptide backbone,which is divided into the following two parts:1.The olefination and macrocyclization of the phenylalanine residue at?-C(sp~2)-H position has been developed.This method uses phenylalanine C-terminal amide bond as a directing group to coordinate with the metal palladium,to activate the adjacent C-H bond of phenylalanine.The olefination reaction is compatible with dipeptide substrates of different sequences.This new chemical tool can be applied to the conjugation of polypeptides.This method is also efficient in the synthesis of macrocyclic peptides of various sizes and sequences.Furthormore,our research shows that palladium-catalyzed macrocyclization of peptides is directional and follows the"N-to-C"direction.Combined with the previous N-terminal alanine?-C(sp~3)-H arylation method,we achieved one-pot synthesis of bicyclic peptides with high regioselectivity.2.A method for selective olefination and macrocyclization of C(sp~2)-H bonds at the C-2 and C-4 positions of tryptophan in peptides has been developed.First,the C-2site of tryptophan was selectively olefinated with the tryptophan C-terminal amide bond as a directing group.Olefination at the Trp(C-4)position was achieved by utilizing Tf as a directing group.This method is effective in the preparation of peptide macrocycles of various sizes and sequences with Trp-alkene crosslinks.This study provides the first examples of peptide macrocyclization through site-selective olefination of tryptophan at C-4 position.