Engineered non-covalent π interactions as key elements for chiral recognition

Molecular recognition and self-assembly are often mediated by intermolecular forces involving aromatic pi-systems. Despite the ubiquity of such interactions in biological systems and in the design of functional materials, the elusive nature of aromatic pi interaction results in that they have been seldom used as a design element for promoting challenging chemical reactions. Described here is a well-engineered catalytic system into which non-covalent pi interactions are directly incorporated. Enabled by a lone pair-pi interaction and a pi-pi stacking interaction operating collectively, efficient chiral recognition is successfully achieved in the long-pursued dihydroxylation-based kinetic resolution. Density functional theory calculations shed light on the crucial role played by the lone pair-pi interaction between the carbonyl oxygen of the cinchona alkaloid ligand and the electron-deficient phthalazine pi moiety of the substrate in the stereoselectivity-determining transition states. This discovery serves as a proof-of-principle example showing how the weak non-covalent pi interactions, if ingeniously designed, could be a powerful guide in attaining highly enantioselective catalysis. Non-covalent pi interactions have been rarely used as a design element for promoting chemical reactions. Here the authors report a Sharpless asymmetric dihydroxylation (SAD)-based kinetic resolution in which a-priori-designed non-covalent forces play a central role in differentiating the enantiomeric substrates.

Automated summary

Non-covalent pi interactions play a central role in differentiating enantiomeric substrates in a Sharpless asymmetric dihydroxylation (SAD)-based kinetic resolution.