Pepsin-Functionalized Covalent Organic Framework Chiral Membrane Assembly via a Vacuum-Assisted Process for Chiral Separation

Chiral covalent organic framework (CCOF) membranes provide a promising direction for the large-scale preparation of optically pure drugs. Unfortunately, the limited types of chiral selectors make it difficult to help balance the contradiction between enantioselectivity and permeability in the field of CCOF membranes. To address the above challenge, pepsin with high stereoselectivity and good hydrophilicity was integrated into CCOF membrane manufacturing. The predictability of enzyme–drug interactions helped us screen potential targets and explored the chiral recognition mechanisms. Ionic liquid (IL)-mediated catalytic synthesis of achiral COF (Tp-Deth COF) was used to enhance the stability of pepsin in the membrane separation processes. A mild and convenient vacuum-assisted process further promoted efficient integration of Pepsin@Tp-Deth COF and the membrane. As predicted, the membrane achieved rapid (2 h) enantioselective separation of various chiral drugs such as propranolol, mandelic acid, and naproxen (e.e.% up to 30.8%) under the optimal preparation process and application conditions. Meanwhile, the ideal permeability (up to 115 × 10^–6 mol·cm^–2·h^–1) was superior to most CCOF membranes. This work emphasized the advantages of biomolecules in balancing the contradictions in the field of CCOF membranes and provided a paradigm for the design of high-performance chiral membranes.