A Dual-Catalysis Anion-Binding Approach to the Kinetic Resolution of Amines: Insights into the Mechanism via a Combined Experimental and Computational Study

Racemic benzylic
amines undergo kinetic resolution via benzoylation
with benzoic anhydride in the presence of a dual catalyst system consisting
of a readily available amide-thiourea catalyst and 4-dimethylaminopyridine
(DMAP). An evaluation of various experimental parameters was performed
in order to derive a more detailed understanding of what renders this
process selective. The catalyst’s aggregation behavior and
anion-binding ability were evaluated in regard to their relevance
for the catalytic process. Alternate scenarios, such as catalyst deprotonation
or the in situ formation of a neutral chiral acylating reagent were
ruled out. Detailed computational studies at the M06/6-31G­(d,p) level
of theory including solvent modeling utilizing a polarized continuum
model provide additional insights into the nature of the ion pair
and reveal a range of important secondary interactions that are responsible
for efficient enantiodiscrimination.