Nonclassical NonlinearEffects (nc-NLEs) Provide MechanisticInsights in Asymmetric Catalytic Cascade Reactions

The observation of a nonlinear relationship between product enantiomeric excess and catalyst enantiopurity has become a key tool to probe catalyst active species and reaction mechanisms in asymmetric catalysis. While the phenomenon has primarily been attributed to the involvement of dimeric catalyst species either on or off the catalytic cycle, or to bimolecular reactions between two monomeric catalyst species, a growing body of evidence points to cases in complex reaction networks where the phenomenon cannot be explained by classical nonlinear effect (NLE) models involving higher-order catalyst species. We highlight examples of organocatalytic cascade reaction sequences setting multiple stereocenters where an observation of either a positive or a negative NLE is rationalized without invoking catalyst aggregation or dual-catalyst activation. A general model is developed here for nonclassical NLEs (nc-NLE) observed in parallel-consecutive catalytic networks involving intermediate products that disengage and then re-engage with the catalyst in a further catalytic cycle. These models may provide insights that cannot be understood by treating the system as a simple, single catalytic cycle. The mechanistic understanding afforded by studying these systems may help to inform catalyst and reaction design in reaction networks whose complexity begins to mimic metabolic systems in biology.