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

Abstract

Postassembly modification of peptides via C(sp 3 )−H functionalization on aliphatic side chains provides a straightforward approach to access functionalized peptides as therapeutics. However, C(sp 3 )−H functionalization of C-terminal residues remains underdeveloped due to the inhibition effect of secondary amides in the backbone. Herein, we report a ligand-enabled, bidentate auxiliaryassisted β-C(sp 3 )−H arylation method, which is well tolerant of secondary amides. A wide range of peptides (tri-to dodecapeptides) underwent position-specific modification of alanine at the Cterminus.Letter pubs.acs.org/OrgLett

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

“…In comparison, direct functionalization of the inert but ubiquitous C­(sp 3 )–H bonds on the aliphatic side-chains has been less investigated . Pioneered by the early work of Corey, Yu, and Carretero, C­(sp 3 )–H functionalization of aliphatic side-chains of residues at the N- or C-termini had been well developed in the past decade (Figure a, left). , However, modification on aliphatic side-chains of internal residues remains underdeveloped (Figure a, right) . The main obstacles to this challenge are the lack of powerful directing groups to control the regioselectivity of C–H functionalization, and the existence of a sea of coordinating groups (particularly the backbone amide groups), which dramatically decrease the activity of transition metal catalysts…”

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

“…Compared with the traditional approaches by solid-phase peptide synthesis (SPPS) with unnatural amino acids as starting materials, site-selective post-assembly peptide modification represents an alternative, more efficient route to access modified peptides. The majority of the existing methods for peptide modification included the transformations of nucleophilic functional groups and the C­(sp 2 )–H functionalization of aromatic side chains. , Although dozens of reports of the direct functionalization of inert C­(sp 3 )–H bonds on the aliphatic side chains of peptides have also been disclosed in recent years, these methods were mainly restricted to the modification of residues at the N- or C-termini assisted by exogenous auxiliaries − or enabled by endogenous directing groups. − So far, only two protocols could be applied to C­(sp 3 )–H functionalization of internal residues (Figure a). One was the triazole-directed β-C­(sp 3 )–H arylation of internal Ala in triazole-embedded peptidomimetics developed by Ackermann .…”

Macrocyclization of bioactive peptides with internal thiazole motifs via palladium-catalyzed C–H olefination

“…[30][31][32] Two general strategies have been employed to achieve site-selective modification of the d-C(sp 2 )-H bonds of these three residues (Fig. 1B): (a) the installation of an external directing group at the terminal amino acids or on the N-atom of Trp residues; 18,19,21,22,[33][34][35][36][37] (b) the use of the peptide backbone amides or amide surrogates as either N,N-bidentate endogenous ligand. [38][39][40] The utilization of exogeneous directing groups takes advantage of the rich chemistry that has been developed for C-H activation of small molecule substrates with high efficiency.…”