Denis Billen

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 alpha-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/pi interactions that cumulatively account for the unusual stereoselectivity.

A non-acidic sulfaphenazole analog demonstrating high intrinsic clearance and selectivity by canine CYP2C21.

In contrast to human CYP2C9, non-human CYP2C enzymes do not appear to preferentially bind and metabolize anionic drugs. Using analogs of sulfaphenazole, the effect of an acidic sulfonamide group on apparent affinity and turnover rates was characterized with canine CYP2C21. Blocking the sulfonamide with a methyl group increased the intrinsic clearance by CYP2C21 > 100-fold and decreased K(m). Furthermore, CYP2C21 demonstrated selectivity for formation of the benzylic hydroxylation product and a high estimated f(m,CYP) value. The findings suggest that canine CYP2C21, unlike human CYP2C9, does not derive ligand binding affinity from an anion binding interaction with sulfaphenazole analogs.