Diastereomeric Configuration Modulates Liquid–Liquid Phase Separation and Catalysis in Minimalist Dipeptide Coacervates

ABSTRACT Although coacervates formed via liquid–liquid phase separation (LLPS) of small molecules are widely recognized as plausible protocell models relevant to the origin of life, how the stereochemistry of small molecules influences LLPS remains largely unexplored. Here we report a set of minimalist dipeptide stereoisomers composed of l ‐proline ( L P ) or d ‐proline ( D P ), and l ‐naphthylalanine ( L Nal ), or d ‐naphthylalanine ( D Nal ), in which chirality modulates the propensity for LLPS under identical aqueous conditions. Specifically, L P D Nal and D P L Nal independently undergo LLPS to form coacervates that selectively accumulate diverse guest molecules and act as efficient crucibles, markedly accelerating stereoselective reactions. By contrast, the remaining stereoisomers, L P L Nal and D P D Nal , preferentially access a competing crystallization pathway. Single‐crystal x‐ray diffraction and all‐atom molecular dynamics simulations reveal that this divergence originates from stereochemistry‐dependent variations in intermolecular hydrogen‐bonding patterns and aromatic stacking. Together, these findings establish diastereomeric configuration‐modulated LLPS in a minimalist molecular system and demonstrate how molecular stereochemistry can directly regulate protocell‐like compartmentalization.