Dynamic Conformational Constraint-Enabled Palladium-Catalyzed Higher-Order Dipolar Cycloaddition

Manipulating remote acidic proton-tethered allylic carbonates with tunable frameworks into extended π-allyl palladium dipoles offers a robust entry to higher-order dipolar cycloaddition toward structurally diverse medium-sized rings/macrocycles valued in drug discovery, yet challenging due to compromised chemoselectivity in key intramolecular deprotonation arising from the conformational freedom of the dipole precursors. Herein, we propose an intramolecular hydrogen bond (IMHB)-mediated dynamic conformational constraint strategy that enables chemoselective intramolecular deprotonation and structural tunability of dipole precursors, as exemplified by chiral amino alcohol-based allylic carbonates with varied stereocenter substituents, functional groups, ring scaffolds, and chain lengths. Associated higher-order cycloaddition provides streamlined access to chiral 9- to 18-membered rings across wide chemical space. Molecular dynamics simulations and control experiments indicate that IMHB-induced dynamic pseudocyclic structures contribute to the high chemoselectivity of intramolecular deprotonation and broad tolerance in molecular architecture, in line with our initial hypothesis. Furthermore, the biological evaluation and mechanistic study reveal that a macrocyclic product exhibits potential anti-inflammatory activity.