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.