Post-Assembly Modification of Head-to-Tail Cyclic Peptides by Methionine-Directed β-C(sp³)–H Arylation

Abstract

Peptide modification by C(sp 3 )−H functionalization of internal residues remains a major challenge due to the inhibitory effect of peptide bonds. In this work, we developed a methionine-directed β-C(sp 3 )−H arylation method for internal alanine functionalization. By tuning the σ C−C bond rotation of internal Ala through head-to-tail cyclization, we overcame the inhibitory effect and functionalized a wide range of head-totail cyclic peptides with aryl iodides with excellent position selectivity.

Pd-catalyzed site-selective C(sp2)–H chalcogenation of amino acids and peptides using a picolinamide auxiliary

“…[12][13][14][15][16][17][18][19][20] Recently, metal-catalyzed C-H activation has emerged as a powerful synthetic methodology for various types of challenging chemical transformations including the structural modification of amino acids/peptides. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] Directing group (DG)-assisted metal-catalyzed C(sp 3 )-H bond functionalizations of amino acids and peptides have been well investigated, [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] in contrast to the poorly investigated C(sp 2 )-H activation on aromatic rings of aromatic amino acids and their peptides. [54][55][56][57]…”

“…12–20 Recently, metal-catalyzed C–H activation has emerged as a powerful synthetic methodology for various types of challenging chemical transformations including the structural modification of amino acids/peptides. 21–34 Directing group (DG)-assisted metal-catalyzed C(sp 3 )–H bond functionalizations of amino acids and peptides have been well investigated, 35–53 in contrast to the poorly investigated C(sp 2 )–H activation on aromatic rings of aromatic amino acids and their peptides. 54–59 However, the C–H functionalizations of phenylalanine and phenylglycine have shown significant progress.…”

Backbone-enabled modification of peptides with benzoquinone via palladium-catalyzed δ-C(sp2)–H functionalization

“…8 Several remarkable works on peptide decoration have been developed by Ackermann, 9 Yu, 10 Chen, 11 Shi, 12 and Wang, 13 among others. 14 Despite significant advancements, the limited availability of a reactive moiety within phenylalanine (Phe) has resulted in a scarcity of methods for late-stage C–H functionalization of Phe residues in peptides. 8 a…”

Postassembly Modification of Peptides by Histidine-Directed β-C(sp3)–H Arylation of Alanine at the Internal Positions: Overcoming the Inhibitory Effect of Peptide Bonds

“…Later, Chen 11 and our group 12 independently established Lmethionine (Met)-directed C−H functionalization approaches, leading to γand β-C(sp 3 )−H arylation of N-terminal residues. Although modification of medium-size head-to-tail cyclic peptides was also realized by our group, 12 C−H functionalization of internal Ala in linear peptides under the same conditions encountered low conversion of the starting material and poor yield of the product (<30%), probably due to the inhibitory effect of backbone amides through the formation of the N ∧ N ∧ S−Pd complex (Figure 1b, right bottom). 12 The L-histidine residue (His) exists in the active domains of many naturally occurring peptides and proteins, playing important roles in catalysis, 13 metal ion transportation, 14 and so on.…”