Catalyst or Catalyst System? Nonlinear Behaviour and the Limits of Mechanistic Understanding in Proline-Based Asymmetric Catalysis.

Asymmetric catalysis has expanded the range of chiral products readily accessible through increasingly efficient synthetic catalysts. The development of these catalysts often starts with a result obtained by systematic screening of known privileged chiral structures and is based on the assumption that the active species would be an isolated monomolecular species. Here, we have studied the activity of three proline-derived ligands that differ in minor chemical modifications. In the zinc-catalysed alkylation of benzaldehyde, we found that they exhibit completely different systems-level behaviours, characterized by multiple aggregation levels that are catalytically active simultaneously. Notably, we were able to establish the possibility of at least trimeric active species in equilibrium with less aggregated active species. These results were obtained through a combination of nonlinear effect studies and other related studies such as product ee versus catalyst loading and temperature as well as in situ NMR studies. Simulations using a mathematical model have confirmed the possibility of such systems-level behaviour. This indicates that the chiral structure alone does not necessarily correlate with systems-level behaviour that could alter the outcome of a given catalytic reaction.