Site-Selective Modification of α-Amino Acids and Oligopeptides via Native Amine-Directed γ-C(sp³)-H Arylation

Abstract

Site-selective modification of chemically and biologically valuable α-amino acids and peptides is of great importance for biochemical study and pharmaceutical development. Few methods based on remote C(sp 3 )-H functionalization of aliphatic side-chains of peptides has been disclosed in recent years. In this report, we developed a novel approach for γ-C(sp 3 )-H and γ-/δ-C(sp 2 )-H arylation of α-amino acids with αhydrogen by native amine-directed C−H functionalization and further realized the γ-C(sp 3 )-H arylation of N-terminally unprotected peptides.

Postassembly Modifications of Peptides via Metal-Catalyzed C–H Functionalization

“…Rodrıguez et al 150 Yuan et al 154 Mondal et al 156 Tang et al 139 Zhan et al 155 Hernando et al 151 Zhan et al 152 Li et al 153 Scheme 11 | (a-e) Pd-catalyzed directed C-H functionalization of Val, Ile, Leu, and Pro in peptides. N-terminal Ala with meta-iodinated Phe was carried out in an intramolecular fashion to construct peptide macrocycles under slightly modified conditions (see 39).…”

“…In 2019, Yuan et al 154 demonstrated the free NH 2 group of αAA could serve as an endogenous DG for Pd-catalyzed γ methyl C-H arylation of single Val, Ile, and Tle substrates with aryl iodides under the optimized conditions of 10 mol % of Pd(OAc) 2 , AgOAc, 0.8 equiv of TfOH in the mixed solvents of HFIP/acetic acid (AcOH); 6∶1) at 100°C. Moreover, the N-terminal Tle group in short peptides could be modified on the γ methyl position to give a mixture of mono-and di-arylated products in good combined yield (see 50).…”

Transient imine directing groups for the C–H functionalisation of aldehydes, ketones and amines: an update 2018–2020

“…In a follow up paper, Yao developed a directing group free approach using aryl iodides (Scheme 25b). 75 The amine scope included complex oligopeptide substrates possessing many competing coordination sites for palladium. Triflic acid was identified as an effective additive for this transformation, both its high acidity and ligand effect being proposed to improve the reaction.…”

Peptide Modification via N-Terminal-Residue-Directed γ-C(sp3)–H Arylation

“…Carretero, Shi, and Chen reported γ- or δ-C­(sp 3 )–H functionalization of N-terminal Val, Ile, and Tle by installation of bidentate auxiliaries to the N-terminus, while Kazmaier and Chen developed β-C­(sp 3 )–H arylation of C-terminal Pro and Ala using C-linked bidentate auxiliaries as directing groups (Scheme a). Without auxiliaries, native amino and carboxyl groups at the N- and C-termini were also utilized as directing groups, which promoted γ-C­(sp 3 )–H arylation of N- or C-terminal Tle of short peptides, respectively (Scheme a). In addition, Weng and Ackermann reported β-C­(sp 3 )–H arylation of N-terminal Ala promoted by the side-chain amide group of asparagine (Scheme b) .…”

“…In order to solve this problem, steric effects, acidic conditions (solvents or additives), and special bidentate ligands were investigated to promote the conversion from bis­(amine)–metal complexes to more active mono­(amine)–metal complexes. As in our recent report on native-amine-directed γ-C­(sp 3 )–H functionalization of oligopeptides, both the steric factor (R 1 = t Bu) and acidic environment were crucial for reaction efficiency and position selectivity. The reaction was proposed to proceed by acid-promoted decomposition of bis­(amine)–Pd complex A to afford mono­(amine)–Pd complex B in the presence of TfOH.…”