Palladium‐Mediated Arylation of Lysine in Unprotected Peptides

Abstract

A mild method for the arylation of lysine in an unprotected peptide is presented. In the presence of a preformed biarylphosphine‐supported palladium(II)–aryl complex and a weak base, lysine amino groups underwent C−N bond formation at room temperature. The process generally exhibited high selectivity for lysine over other amino acids containing nucleophilic side chains and was applicable to the conjugation of a variety of organic compounds, including complex drug molecules, with an array of peptides. Finally, this method was also successfully applied to the formation of cyclic peptides by macrocyclization.

Organometallic AlaM Reagents for Umpolung Peptide Diversification

“…Site-and chemoselective modification of proteins and peptides is becoming recognized as an important tool for probing structure-function relationship and accessing new therapeutic leads. [1][2][3][4] Significant advances have been made over the past decade to modify peptides using heteroatom conjugation with cysteine or lysine, [5][6][7][8][9][10] site specific C-H functionalization of aromatic rings in tryptophan, histidine, or phenylalanine, [11][12][13] radical functionalization, 14,15 and decarboxylative couplings of C-terminal amino acids or side chains functionalities in aspartic and glutamic acids. [16][17][18][19][20] In addition to the diversification strategies, 21 natural peptides with posttranslational modifications are gaining increasing importance due to their translational potential.…”

Aryl C(sp2)–X Coupling (X = C, N, O, Cl) and Facile Control of N-Mono- and N,N-Diarylation of Primary Alkylamines at a Pt(IV) Center

“… 15 In turn, to the best of our knowledge, no C(sp 2 )–N(hydrocarbyl) reductive coupling reactions of any isolable group 10 M(IV) amines complexes have been characterized so far. Considering the importance of metal-catalyzed and metal-mediated N-mono- and N,N-diarylation, especially in the synthesis of biologically active compounds, 16 , 17 we report here the preparation of aryl Pt(IV) complexes with a series of alkylamines, as well as experimental and computational characterization of their unusually facile aryl C(sp 2 )–N(Alk) reductive elimination reactivity. By merely changing the basicity of the system, selective and high-yielding mono- or diarylation of the coordinated amine can be achieved ( Scheme 1 c).…”

Late‐Stage Functionalization of Peptides and Cyclopeptides Using Organozinc Reagents

“…[1] Thepossibility of combinatorial modification of drug targets is essential for an efficient search of optimal properties like bioavailability,stability,and membrane permeability and to achieve improved structure-activity relationships. [3] Barluenga [4] and Davis [5] have demonstrated the utility of Suzuki-Miyaura cross-couplings for the modification of amino acids and small peptides.A sa na lternative to the Suzuki-Miyaura reaction, the Negishi cross-coupling involving organozinc reagents often requires milder reaction conditions and less sophisticated ligands. [3] Barluenga [4] and Davis [5] have demonstrated the utility of Suzuki-Miyaura cross-couplings for the modification of amino acids and small peptides.A sa na lternative to the Suzuki-Miyaura reaction, the Negishi cross-coupling involving organozinc reagents often requires milder reaction conditions and less sophisticated ligands.…”