Development of the “phase separation” strategy: addressing dilution effects in macrocyclization

The “phase separation” strategy exploits aggregated solvent mixtures of poly(ethylene)glycol (PEG) solvents and hydrophilic organic solvents to control the effective molarity of substrates and catalysts in macrocyclization reactions. The slow diffusion of acyclic precursors from the PEG aggregate “phase” to the organic solvent/catalyst “phase” mimics the slow addition processes typically employed in the synthesis of macrocycles. With the aid of mechanistic studies, the strategy has been applied to copper-catalyzed Glaser–Hay couplings, copper-catalyzed azide–alkyne cycloadditions, copper-catalyzed azide-iodoalkyne cycloadditions, and ruthenium-catalyzed olefin metathesis processes. “Phase separation” has been used to form macrocycles of interest in aromachemicals, lipid-based macrocycles, bioactive natural products, macrocyclic peptides, and bioactive pharmaceuticals. The “phase separation” strategy has been proven to promote transition metal-catalyzed macrocyclization processes with increases in concentration up to three orders of magnitude larger than traditional methods like high dilution or pseudo high dilution/slow addition.