Peptide late-stage C(sp³)–H arylation by native asparagine assistance without exogenous directing groups

Abstract

There is a strong demand for novel native peptide motifs for post-synthetic modifications of peptides without pre-installation and subsequent removal of directing group. Herein, we report an efficient method for...

Construction of Racemic and Enantiopure Biaryl Unnatural Amino Acid Derivatives via Pd(II)‐Catalyzed Arylation of Unactivated Csp3−H Bonds

“…In 2015, Yu, reported a single example of Pd‐catalyzed ligand‐enabled arylation of methylene C−H bond of L‐phenylalanine [12b] . Ackermann also reported two examples of arylation of methyl C−H bondin peptides using 4‐iodobiphenyl, [12c] but on a different theme of functionalization of peptides. We therefore found it is important to demonstrate the construction of various DL‐ and L‐ and D‐biaryl unnatural amino acid derivatives via the Pd(II)‐catalyzed, diastereoselective sp 3 C−H activation and arylation of various DL‐, L‐ and D‐amino acid derivatives with iodobiaryls, which will enrich the library of biaryl unnatural amino acid derivatives.…”

Post-Assembly Modification of Peptides by Ligand-Enabled β-C(sp3)–H Arylation of Alanine at the C-Terminus: Overcoming the Inhibition Effect of Peptide Bonds

“…In addition, Ackermann and Weng recently reported another strategy for β-C(sp 3 )−H arylation of N-terminal Ala, in which the proximal asparagine residue (Asp) was used as the directing group (Figure 1a). 8 Compared with N-terminal Ala, 9,10 C−H functionalization of C-terminal Ala has been rarely explored (Figure 1b). With 2-(methylthio)aniline as the auxiliary linked to the C-terminus, Kazmaier developed β-C(sp 3 )−H arylation of N-methyl alanine at the C-terminus of short peptides.…”

“…We were pleased to find that the reactivity was not reduced as the length of peptides increased. A wide range of MTEA-linked peptides including tetra-(4a− 4c), penta-(5a), hexa-( 6), hepta- (7), and decapeptides (8) were coupled with 4-iodotoluene successfully to give the Cterminal Ala C−H arylation products as the single products in 47−70% yield. In addition, MTA-linked pentapeptide under-Scheme 2.…”

“…In addition, direct functionalization of C­(sp 2 )–H bonds on aromatic side chains (of Trp, Phe, and His) has been extensively explored in the past decade . In contrast, peptide modification via C­(sp 3 )–H functionalization on aliphatic side chains has been far less investigated, and the existing methods were mainly limited to the functionalization of amino acid residues at the N-terminus. − Inspired by the work on monoprotected amino acid (MPAA) promoted C­(sp 3 )–H functionalization, Yu developed the first β-C­(sp 3 )–H arylation of Ala at the N-terminus of oligopeptides using the peptide backbone as the directing group (Figure a) . Later, Noisier and Albericio and Wang applied this directing strategy to the development of intramolecular β-C­(sp 3 )–H arylation of the N-terminal Ala for peptide stapling or the synthesis of bioactive macrocyclic peptides (Figure a).…”

“…Later, Noisier and Albericio and Wang applied this directing strategy to the development of intramolecular β-C­(sp 3 )–H arylation of the N-terminal Ala for peptide stapling or the synthesis of bioactive macrocyclic peptides (Figure a). In addition, Ackermann and Weng recently reported another strategy for β-C­(sp 3 )–H arylation of N-terminal Ala, in which the proximal asparagine residue (Asp) was used as the directing group (Figure a) . Compared with N-terminal Ala, , C–H functionalization of C-terminal Ala has been rarely explored (Figure b).…”