Asymmetric Activation of Tropos Biphenolic Moieties by Isohexides: An Integrated Computational‐Experimental Approach

The asymmetric activation of conformationally dynamic ( tropos ) biaryls through covalent bond formation with stereochemically stable chiral subunits is a powerful strategy to induce a prevalent diastereomeric conformation on chiral ligands for asymmetric catalysis. This work presents an integrated computational‐experimental investigation into the capability of isohexides to induce a prevalent sense of twist on a tropos tetra‐arylic moiety derived from 2,2’‐dihydroxybiphenyl (BIPOL), connected to the isohexide scaffold by ester linkages, leading to the formation of macrocyclic architectures. The position of carboxylic acid groups on the tetra‐aryl moiety was crucial for the cyclization reaction: this parameter was investigated by density functional theory (DFT) calculations, which successfully predicted that meta‐substitution on the tetra‐aryl framework is thermodynamically optimal for the purpose. The stereodynamic characterization of the newly synthesized compounds, using variable‐temperature nuclear magnetic resonance (VT‐NMR) and electronic circular dichroism (ECD) spectroscopies, combined with time‐dependent DFT (TD‐DFT) simulations demonstrated that both the sense of twist of the tetra‐aryl moiety and the extent of its prevalence depend not only on the stereochemistry of the carbohydrate scaffold but also on the steric and electronic features of the 2,2’‐substituents on the tetra‐aryl moiety.