Nitrogen Arylation for Macrocyclization of Unprotected Peptides

Abstract

We describe an efficient and mild method for the synthesis of macrocyclic peptides via nitrogen arylation from unprotected precursors. Various electro-philes and lysine-based nucleophiles were investigated and showed high-yielding product formation, even for a macrocyclization scan with 14 variants. We found that nitrogen-linked aryl products were more stable to base and oxidation when compared to thiol arylated species, thereby highlighting the utility of this methodology. Finally, N-aryl macrocyclization was performed on a p53 peptide inhibitor of MDM2 and resulted in identification of a nanomolar binder with improved proteolytic stability and cell permeability.

Oxetane Grafts Installed Site‐Selectively on Native Disulfides to Enhance Protein Stability and Activity In Vivo

“…Considering natural residues, cysteine (Cys) has been the residue of choice for stapling through alkylation,3 arylation,4 cycloaddition,4b and disulfide forming reactions both at native5 or engineered6 Cys residues. More recently, nitrogen arylation has also been shown to be a useful strategy for macrocyclization of lysine residues on peptides 7. Otherwise, efficient macrocyclization of linear peptides through the formation of an oxadiazole has also been reported 8.…”

Palladium‐Mediated Arylation of Lysine in Unprotected Peptides

“…Recently, we have reported a lysine stapling strategy with highly electron deficient arenes that proceeds via S N Ar to form chemically and biologically stable constructs that addresses the aforementioned concerns. 27 …”

Palladium‐Mediated Arylation of Lysine in Unprotected Peptides

“…Recently, we have reported a lysine stapling strategy with highly electron deficient arenes that proceeds via S N Ar to form chemically and biologically stable constructs that addresses the aforementioned concerns. 27 In the presence of a stapling reagent derived from 1,2-bis(4-bromophenoxy)ethane, p53 peptide with an additional lysine residue underwent facile macrocyclization (Scheme 2). The protocol provided access to both [i, i+4] and [i, i+7] stapled products with comparable efficiencies.…”

“…The reaction allows for the formation of N-aryl conjugates, which are more stable than the corresponding S-aryl conjugates. 27 Furthermore, this protocol operates under mild conditions and is selective over most other nucleophilic amino acid residues. The success of this method stems from the use of the biarylphosphine ligands BrettPhos and t-BuBrettPhos in conjunction with the mildly basic sodium phenoxide.…”