Bronsted Acid Catalysis-Controlling the Competition between Monomeric versus Dimeric Reaction Pathways Enhances Stereoselectivities

Chiral phosphoric acids (CPA) have become a privileged catalyst type in organocatalysis, but the selection of the optimum catalyst is still challenging. So far hidden competing reaction pathways may limit the maximum stereoselectivities and the potential of prediction models. In CPA-catalyzed transfer hydrogenation of imines, we identified for many systems two reaction pathways with inverse stereoselectivity, featuring as active catalyst either one CPA or a hydrogen bond bridged dimer. NMR measurements and DFT calculations revealed the dimeric intermediate and a stronger substrate activation via cooperativity. Both pathways are separable: Low temperatures and high catalysts loadings favor the dimeric pathway (ee up to -98 %), while low temperatures with reduced catalyst loading favor the monomeric pathway and give significantly enhanced ee (92-99 % ee; prior 68-86 % at higher temperatures). Thus, a broad impact is expected on CPA catalysis regarding reaction optimization and prediction.

Automated summary

Chiral phosphoric acids (CPA) have been widely used as catalysts in organocatalysis, but the selection of the optimal catalyst is still a challenge. This study identified two reaction pathways with inverse stereoselectivities in the CPA-catalyzed transfer hydrogenation of imines, involving either a single CPA or a hydrogen bond bridged dimer as the active catalyst. Through NMR measurements and DFT calculations, it was revealed that the dimeric pathway had stronger substrate activation via cooperativity. The temperature and catalyst loading could be adjusted to favor either pathway and enhance the enantiomeric excess (ee) of the product. This research is expected to have a significant impact on the optimization and prediction of CPA catalysis.