Expanding the Organoiridium Catalyst Design Space Using Sulfur-Containing Bioisosteres

Although half-sandwich metal complexes are promising as intracellular catalysts, only a limited subset can promote transfer hydrogenative reduction of organic substrates in living systems. To expand the design space for biocompatible transfer hydrogenation catalyst discovery, a bioisostere-based approach was successfully employed. Starting from the parent [Cp*Ir( N -phenyl-2-pyridylamidate]Cl] complex ( Ir1; where Cp* = pentamethylcyclopentadienyl anion), the 2-pyridylamidate donor was replaced with either 2-pyridylthioamidate or 2-pyridyliminosulfide to furnish the corresponding N,S -chelated Ir2 / Ir3 or N,N -chelated Ir4, respectively. When the iridium complexes were tested in the presence of HCOONa and benzaldehyde in dimethyl sulfoxide/H 2 O (1:9), benzyl alcohol was obtained with the activity trend Ir1 > Ir4 > Ir3 . In contrast, the corresponding nonsulfur containing analogues Ir3 ′ and Ir4 ′ afforded only trace amounts of product. Although Ir3 and Ir4 are predicted to have low and moderate passive diffusability across lipid membranes, respectively, both display higher 50% inhibition concentrations relative to Ir1 in mammalian cells. Based on a combination of reactivity and biocompatibility factors, Ir4 was identified as the most promising candidate for future intracellular catalysis studies. Most importantly, this work demonstrates that modifying Ir complexes with bioisosteres is a powerful strategy for achieving structural diversity while retaining catalytic function, opening new avenues for metallodrug or biotechnology development.