Enantiopurity‐Dependent Peptide Coacervates and Asymmetric Organocatalysis

ABSTRACT Membraneless compartmentalization via liquid–liquid phase separation (LLPS) has emerged as a powerful strategy to organize biochemical reactions. Recently, peptide‐based coacervates demonstrated the potential to function as microreactors by enhancing reaction kinetics through increased local concentrations and altered microenvironments. Here, we introduce an O‐methylated diphenylalanine‐based tripeptide ^LLL PFF‐OCH ₃ containing an N‐terminal proline, designed to undergo LLPS, and simultaneously function as an enantioselective organocatalyst. Comprehensive characterization via confocal microscopy, fluorescence recovery after photobleaching (FRAP), micro‐Raman and attenuated total reflection infrared (ATR‐IR) spectroscopy, diffusion‐surface plasmon resonance ( D ‐SPR), and molecular dynamics (MD) simulations revealed the formation of stable liquid droplets. In contrast, a racemic mixture of ^LLL PFF‐OCH ₃ and ^DDD PFF‐OCH ₃ failed to form liquid droplets and instead formed a solid precipitate, unveiling a critical role of enantiopurity in LLPS. Proof‐of‐concept catalytic studies proved enantioselective organocatalytic activity of the ^LLL PFF‐OCH ₃ liquid coacervates. Beyond catalysis these results may have broader implications in understanding prebiotic chemistry and neurodegeneration.