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

Abstract

Molecular recognition and self-assembly are often mediated by intermolecular forces involving aromatic π-systems. Despite the ubiquity of such interactions in biological systems and in the design of functional materials, the elusive nature of aromatic π 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 π interactions are directly incorporated. Enabled by a lone pair-π interaction and a π-π 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-π interaction between the carbonyl oxygen of the cinchona alkaloid ligand and the electron-deficient phthalazine π 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 π interactions, if ingeniously designed, could be a powerful guide in attaining highly enantioselective catalysis.

Scissor-like Face to Face π–π Stacking: A Surprising Preference Induced by the Isocyano Group in the Self-Assembled Dimer of Phenyl Isocyanide

“…With the surging interest in controlling molecular aggregations, , noncovalent interactions (NCIs) have been regarded as driving forces in defining and ruling organizations that lead to a wide variety of conformational architectures and thereafter govern the dynamic processes occurring within superstructures. , In particular, π–π stacking between aromatic rings are common motifs in biomolecular structures and also help understand the binding mechanism between the DNA and proteins, , stereoselective organic reactivity, catalyst design, and the stabilization of supramolecular complexes …”

“…W ith the surging interest in controlling molecular aggregations, 1,2 noncovalent interactions (NCIs) have been regarded as driving forces in defining and ruling organizations that lead to a wide variety of conformational architectures and thereafter govern the dynamic processes occurring within superstructures. 3,4 In particular, π−π stacking between aromatic rings are common motifs in biomolecular structures and also help understand the binding mechanism between the DNA and proteins, 5,6 stereoselective organic reactivity, 7 catalyst design, 8 and the stabilization of supramolecular complexes. 9 Despite its frequent occurrence, picturing the nature of the π−π stacking remains challenging, since it is defined by a subtle balance between competing energetic contributions and is generally contaminated by other types of NCIs (e.g., hydrogen bonds (HBs), 10 halogen bonds 11 ).…”

Asymmetric Dihydroxylation-Based Kinetic Resolution of Allylic Amides Enabled by Noncovalent π-Interactions

“…5 As shown in Figure 1a, we recently designed an effective bifunctional "N−π" catalysis mode to solve this persistent challenge. 6 This requires a πdonor (in red) at C9 in the cinchona alkaloid and a π-acceptor (in blue) close to the stereocenter in the racemic substrates, which enables a desirable noncovalent π-interaction that includes the substrate's stereocenter into the corresponding catalyst−substrate interacting framework and subsequently renders a successful chiral recognition process. 6 After extensive screening of matching π-components, we surprisingly found that the use of an electron-rich carbonyl group in the cinchona alkaloid ligand and an electron-deficient phthalazine moiety in the substrate helps to realize AD-based kinetic resolutions.…”

“…6 This requires a πdonor (in red) at C9 in the cinchona alkaloid and a π-acceptor (in blue) close to the stereocenter in the racemic substrates, which enables a desirable noncovalent π-interaction that includes the substrate's stereocenter into the corresponding catalyst−substrate interacting framework and subsequently renders a successful chiral recognition process. 6 After extensive screening of matching π-components, we surprisingly found that the use of an electron-rich carbonyl group in the cinchona alkaloid ligand and an electron-deficient phthalazine moiety in the substrate helps to realize AD-based kinetic resolutions. Density functional theory (DFT) calculations proved that a lone pair−π interaction between the carbonyl oxygen of the ligand and the π-auxiliary of the substrate played a key role in the stereoselectivity-determining transition states; besides this crucial NCI, synergistic cooperation of a π−π interaction between the quinoline moiety of the ligand and the trimethoxyphenyl group of the substrate is also present (Figure 1b).…”

“…6 As a more recently discovered type of NCIs, lone pair−π interactions have been found to play important functions in biological systems; 7 nevertheless, they have rarely been utilized for stereocontrol in organic reactions. 6,8 Furthermore, inspired by the success of the cinchona alkaloid with Weinreb-type carbamate that allows racemic allylic ethers with the phthalazine π-moiety to be resolved with the selectivity factor (s) of 34 (Figure 1b), 6 we envisioned that AD-based kinetic resolutions of allylic amides would be highly possible if the above-mentioned two π-components in ligands and substrates are switched. That means, as shown in Figure 1c, a similar and conducive lone-pair π-interaction could be constructed by incorporating an amide carbonyl in the substrate and an electron-deficient phthalazine π-moiety in the ligand.…”