Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds

Lighting the way to drug labeling It is important during drug development to study how candidate compounds get absorbed and broken down biologically. One common technique for tracking a drug's fate is to label its molecular framework with heavier isotopes of hydrogen (either deuterium or tritium). Loh et al. developed a light-promoted protocol to install these labels on alkyl carbons adjacent to nitrogen. The technique relies on incorporation of the heavy isotope into a thiol from a convenient heavy water source through acid-base chemistry. Next, a photoredox catalyst strips a hydrogen atom equivalent from the carbon, and the thiol engages in radical chemistry to transfer the deuterium or tritium in its place. Science, this issue p. 1182 A light-promoted atom transfer protocol uses heavy water to isotopically label alkyl sites for drug metabolism studies. Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp3 carbon-hydrogen bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T2, providing access to high-specific-activity T2O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.