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.