Twisted Host–Guest Systems Exhibit Superamplification of Asymmetry via Coupled Strong Association and Helicity-Driven Cooperativity

Chiral host-guest systems are central to applications in chiral separation, chiral sensing, and asymmetric catalysis. Chiral interactions involving multiple guest molecules exhibit three key features: helicity-driven amplification of asymmetry (i.e., chiral amplification), strong cooperative binding, and extremely high selectivity. Coupling of amplification of asymmetry with the latter two features can lead to a phenomenon that surpasses conventional amplification of asymmetry, which we propose to term 'superamplification of asymmetry'. Despite its potential, no established theoretical framework exists. In this work, we developed three models: a general 1:2 twisted host-guest interaction model; the 1:n model assuming independent binding events at multiple sites; and a model assuming mutually exclusive binding. These models were applied to twisted macrocycles and triple-stranded metallohelicates, offering new insights into the amplification of asymmetry mechanisms. Superamplification of asymmetry unlocks powerful new strategies for chiral separation, asymmetric catalysis, and chiral sensing through highly cooperative molecular interactions.