Nickel-mediated deaminative arylation builds sp3-rich cyclophane linkers in macrocyclic peptides
- A nickel-mediated deaminative macrocyclic arylation was developed to install carbon-rich (sp3-heavy) cyclophane linkers into macrocyclic peptides, addressing a gap in available linker chemistry.
- It relies on amino acid building blocks that fit standard solid-phase peptide synthesis workflows.
- The reaction tolerates a broad range of peptide functional groups and reaches diverse macrocycle architectures, including a natural alkaloid derivative and polycyclic peptides.
💡 Points Based on the abstract
Most of our macrocycle linkers are flat aryl or amide-heavy, which is exactly what hurts permeability and solubility. An sp3-rich cyclophane tether occupies a genuinely different shape space, and building it from SPPS-compatible amino acids means a library is actually feasible. The open question: does the linker rigidity preorganize the binding conformation, or just add lipophilicity?