Hierarchical Porous Homochiral Metal‐Organic Frameworks for Enantiomeric Separation of Chiral Drugs

Abstract Homochiral metal‐organic frameworks (HMOFs) have been recently reported for applications in chiral separation. However, the development of hierarchical porous homochiral metal‐organic frameworks (HPHMOFs) for the separation of chiral drugs has been scarcely explored and still faces formidable challenges. Herein, a controlled water treatment (CWT) is created with intensive ultrasonic action to modulate the hydrolysis process of DUT‐5‐NH2, followed by post‐synthetic modification to develop a novel type of enantioselective HPHMOFs through the grafting of chiral amino acids and carboxymethyl‐β‐cyclodextrin (CM‐β‐CD). As‐obtained versatile HPHMOFs that can be used for selective adsorption resolution, solid‐phase extraction resolution, and even chromatographic column resolution exhibits favorable enantioselectivity for drug enantiomers while maintaining permanent stability and exceptional reusability. Remarkably, a combination of molecular dynamics simulation and quantum chemical calculation unveils the insights into the chiral recognition process closely related to weak interactions between HPHMOFs and drug enantiomers, revealing that the corresponding differences in mutual adsorption and interaction energies are consistent with their enantioselective resolution capacities. This is the first work on achieving enantiomeric separation of macromolecular chiral drugs (molecular weight exceeding 300 Daltons) by HPHMOFs and also lays the foundation for the resolution of other chiral molecules.