Syntheses, Mechanism Insights, and Anti-Inflammatory Activities of Conformationally Defined [n]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.