Multivariate approach of metal-chiral covalent organic frameworks for leaching-resistant asymmetric transfer hydrogenation

Abstract Achieving precise integration of chiral microenvironments and catalytic metals in covalent organic frameworks (COFs) remains a formidable challenge, often resulting in amorphous materials with poor stability and metal leaching. Here, we introduce a modular multivariate approach strategy coupled with post-synthetic metalation to engineer metal-chiral COFs (MCCOFs) with tunable crystallinity, porosity, and stereocontrol. Co-condensation of chiral Boc-protected diamines with variable achiral diamine ratios and tritopic aldehydes produced three crystalline frameworks (CCOFX-Boc, X = 0–2). Ruthenium metalation afforded CCOF2-Ru, which catalyzes asymmetric transfer hydrogenation of ketones with >99% yield, 97% ee, and a TOF of 1104 h −1 . The catalyst exhibits broad substrate tolerance, including pharmacologically relevant chroman-4-ols, and maintains ≥95% ee over 5 gram-scale cycles with minimal Ru leaching (0.1 wt%). This approach upgrades unstable binary COFs into robust MCCOFs, enhancing activity, enantioselectivity, and durability via optimized pore architecture. It establishes a versatile platform for leaching-resistant chiral catalysts, advancing sustainable enantiopure pharmaceutical synthesis.