Site-selective Functionalization Of Oligopeptides Via Pd-Catalyzed C-H Activation

Peptide and peptidomimics are attracting increasing attention in both the chemical and pharmaceutical communities as a rich source of drug candidates and biological tools.Compared with small molecular drugs,peptide drugs often show better medicine generation of nature,such as low toxicity,high targeting property and stronger pharmacological activity.However,peptide natural products also has certain limitation,such as poor cell penetrability,easy degradation,poor oral utilization.In order to improve its stability and biology activity,peptide often modified by chemical and biological methods.The main contents include two parts:The chapter I introduced palladium catalyzed C(sp~3)-H functionalization to implement the peptide N terminal C? arylation,which applied to build a series of C?-Ar crosslinking structure cyclic peptide via intramolecular reaction.We then evaluate the potential of C?-Ar cyclic peptide for biological application.This method has well application to different length and amino acid sequence of oligopeptides.Compared with the linear counterpart,cyclic peptide showed improved stability against proteolytic degradation in the aspect of biochemical.In the aspect of biological activity,we synthesis and demonstrated that the RGD cyclic peptide contain C?-Ar linkage exhibits significantly enhanced the integrin binding to U87MG cells.Finally,we applied this macrocyclization methodology to synthesis the key intermediate of natural product Celogentin C.The chapter ? introduced the N terminal sulfonamide oligopeptide oriented palladium catalytic C-H functionalization.1)We initially investigated the olefination of N-sulfonated oligopeptide.A series of benzosultam peptidomimics was sysnthesis by Pd(?)-catalyzed late-stage intermolecular cyclization.The reaction has well substrate compatibility and notable features of this strategy include:a)the N-sulfonated oligopeptide in subsrates act as internal direaction auxiliary and no external ligand is required.b)The reaction follows a unique Pd(?)-catalyzed sequential activation mechanism,in which the initial ortho-C(sp2)-H olefination of benzosulfonamides is followed by a second C(sp2)-H amination of the newly conjugated acrylate.c)The precursor compounds are easily prepared from widely avalilable sulfonal chlorides and N-terminal unprotected oligopeptide/pepeidomimics.2)While investigate the reaction beteen N-terminal sulfonated oligopeptide with the activated olefins,we obtained a series of palladium-oligopeptide complexes.Reductive reaction could be conducted while addition of 1,2-bis(diphenyl-phosphino)ethane(DPPE)to the palladium-oligopeptide complexes and benzodicyclic compound with new quaternary were obtained as well.3)Then we applied the N terminal oligopeptide oriented methodology to arylation.Preliminary realizes the aromatics ortho C(sp2)-H arylation.Moreover,while the aromatic ortho was occupied with methyl,the C(sp~3)-H arylation could be conducted in the optimization reaction condition.Next we further investigate the reaction.