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), mutually exclusive 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:<i>n</i> 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 sensing through highly cooperative molecular interactions.