Accessing Diverse C(sp3)-Rich Cyclophane Linkers in Macrocyclic Peptides via Nickel-Mediated Deaminative Macrocyclic Arylation

Abstract Within macrocyclic peptides of both natural products and pharmaceutical targets, aryl rings play a crucial role in linker structure, and C(sp3)-rich cyclophane linkers can imbue beneficial physicochemical properties. Yet, methods to deliver C(sp3)-rich cyclophane linkers remain limited, restricting the types of carbon-rich linkers that can be efficiently investigated in medicinal chemistry campaigns. Herein, we describe the development of a nickel-mediated deaminative macrocyclic arylation that uses amino acid monomers compatible with solid-phase peptide synthesis workflows, accommodates a wide range of peptide functionalities, and can access broad macrocycle architectures including those of a natural alkaloid derivative and polycyclic peptides.