Delineating Origins of Stereocontrol in Asymmetric Pd-Catalyzed α-Hydroxylation of 1,3-Ketoesters

Systematic studies of reaction conditions and subsequent
optimization led to the identification of important parameters for
stereoselectivity in the asymmetric α-hydroxylation reaction
of 1,3-ketoesters. Enantioselectivities of up to 98% can be achieved
for cyclic substrates and 88% for acyclic ketoesters. Subsequently,
the combination of cyclic/acyclic ketoester, catalyst, and oxidant
was found to have a profound effect on reaction rates and turnover-limiting
steps. The stereochemistry of the reaction contradicts that observed
for other similar electrophilic substitution reactions. This was rationalized
by transition-state modeling, which revealed a number of cooperative
weak interactions between oxidant, ligand, and counterion, together
with C−H/π interactions that cumulatively account for
the unusual stereoselectivity.