Water-Dispersible Ruthenium Nanocatalyst for Carbonyl Reduction With D₂ or T₂ in Aqueous Media

The growing development of biologics as therapeutic agents urges the development of efficient catalytic methods enabling the direct incorporation of hydrogen isotopes from readily available and easy-to-handle isotopic sources in aqueous media. In this context, we report the synthesis and characterization of water-dispersible ruthenium nanoparticles stabilized by the commercially available phosphine ligand sSPhos, and their application as catalysts for carbonyl reduction reactions under low-pressure deuterium and tritium atmospheres. Using this nanocatalyst, a broad range of functionalized deuterated alcohols was successfully obtained in high isotopic enrichment from diverse aldehyde precursors, including a large cyclic peptide derivative (acetyl-cyclosporin A). Mechanistic investigations revealed that in some cases, deuterium incorporation proceeds through both hydrogen isotope exchange on the aldehyde starting material and the reductive deuteration pathway. To demonstrate the synthetic utility of this methodology for the regioselective labeling of complex molecules, a two-step sequence consisting of Bobbitt's salt-mediated oxidation of the alcohol followed by its reductive deuteration was successfully applied to the active pharmaceutical ingredient losartan and a peptide-derived cathepsin-cleavable linker widely used in antibody-drug conjugates. Together with the successful tritiation experiment, these results highlight the broad method potential for the challenging hydrogen isotope labeling of complex polar molecules and biologics.