A general route to β,β-carbocyclic sidechains in peptides: an aqueous metallaphotoredox approach driven by green light

Abstract

Amino acids with β,β-carbocyclic sidechains are valuable replacements for endogenous Val, Leu, and Ile, with therapeutic benefits. When placed into ordinary peptides, these annulated variants improve metabolic stability, cell permeability, and receptor affinity and selectivity. Yet, their appearance in modern peptide drugs is often limited to β,β-cyclopentyl- and β,β-cyclohexyl-rings, one reason being the limited availability of resin- and solution-compatible β,β-carbocyclic amino acids for direct coupling. More ‘exotic’ rings, i.e., those with different sizes, chemical compositions, and geometric preferences, could be superior, but finding and assessing their benefits calls for more general ways to incorporate and test them. Herein, we pioneer a modular route to convert a single unsaturated residue, known as β-sulfonyldehydroamino acid (ΔSulf), in a peptide into many unique β,β-carbocycles—cyclic, polycyclic, and heteroatom-containing—in two telescoped steps. First, an unprecedented photocatalyst, Pyronin Y, in an original combination with an organodiiodide, cobalt porphyrin catalyst, sacrificial amine, and green LEDs converts ΔSulf into a Δ-amino acid with a pendant iodide. Adding Zn/Cu couple then triggers an intramolecular and stereoselective Giese cyclization. We detail the mechanism of our procedure, highlighting the interplay between aqueous metallaphotoredox catalysis, halogen-atom abstraction, and ligand-controlled cyclization using spectroscopy, cyclic voltammetry, intermediate-trapping, and radical-clock experiments.