Divergence of catalytic systems in the zinc-catalysed alkylation of benzaldehyde mediated by chiral proline-based ligands

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 assumes that the active species would be an isolated monomolecular species. Here we report the study of three proline-derived ligands, diphenyl-N-methyl-prolinol, diphenylprolinol and 5-(hydroxydiphenylmethyl)-2-pyrrolidinone, in the zinc-catalysed alkylation of benzaldehyde. The three ligands exhibit different system-level behaviour, characterized by multiple levels of aggregation that may be catalytically active simultaneously. While diphenyl-N-methyl-prolinol behaves as expected from a mechanistic point of view, diphenylprolinol shows enantiodivergence during the reaction due to an asymmetric autoinduction process. With 5-(hydroxydiphenylmethyl)-2-pyrrolidinone, we were able to establish the possibility of at least trimeric active species in equilibrium with less aggregated active species. Simulations using a mathematical model confirm the possibility of such systems-level behaviour. Parallel study of the three systems reveals three distinct system-level behaviours that are central to the efficiency of the catalytic reaction. Three closely related proline-based ligands give rise to different catalytic systems in asymmetric dialkylzinc addition reactions. Mechanistic studies reveal that monomeric, dimeric and product–catalyst complexes and aggregates larger than dimers are all catalytically active.