Syntheses, Mechanism Insights, and Anti-Inflammatory Activities of Conformationally Defined [ <i>n</i> ]Metacyclophanes

Conformationally defined [n]metacyclophanes represent promising targets in drug discovery and materials science. However, the catalytic asymmetric syntheses of these atropisomers is challenging because of their conformational lability and high degrees of ring strain. This paper presents an ansa chain editing strategy for the atropo- and enantioselective synthesis of planar-chiral [n]metacyclophanes. This approach involves chiral phosphoric acid-catalyzed desymmetrization or (dynamic) kinetic resolution, affording [9]–[14]metacyclophanes in high yields and enantioselectivities. Racemization kinetic studies reveal that the conformational stability is governed by the ansa chain length, the size of the benzene ring substituent, and the atropisomerism of the tertiary amide. Computational studies indicate that C–H···O interactions and catalyst distortion in the transition states are key determinants of the absolute configuration in the final product. Furthermore, biological evaluations reveal promising anti-inflammatory activities for these macrocycles, which are attributed to the rebalancing of inflammatory homeostasis in macrophages within a lipopolysaccharide-induced model.