Advances in Chiral Covalent Organic Frameworks for Enantiomer Separation: Synthesis, Applications, and Future Directions

Chiral drugs, characterized by their enantioselective biological activities and pharmacological effects, necessitate precise separation techniques to ensure therapeutic efficacy and safety. This review systematically summarizes the advancements in chiral separation technologies, with a focus on the application of chiral covalent organic frameworks (CCOFs) in chromatographic enantioseparation. Traditional methods such as crystallization, asymmetric synthesis, and chromatography-based approaches are discussed, highlighting their limitations in scalability, cost, and solvent compatibility. In contrast, CCOFs, emerging as a novel class of chiral stationary phases (CSPs), exhibit exceptional structural tunability, high porosity, and robust stability, enabling efficient enantiomer resolution across gas chromatography (GC), high-performance liquid chromatography (HPLC), and capillary electrochromatography (CEC). Key synthesis strategies for CCOFs—post-synthesis modification, chiral induction, and bottom-up assembly—are critically evaluated, alongside their performance in separating pharmaceuticals, amino acids, and agrochemicals. Recent breakthroughs, including β-cyclodextrin-functionalized COFs and camphorsulfonyl chloride-modified CCOFs, demonstrate superior separation efficiency and reproducibility. This review underscores the potential of CCOFs to address longstanding challenges in chiral separation while identifying future directions for optimizing their design and scalability in industrial applications.