Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds

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Science  01 Dec 2017:
Vol. 358, Issue 6367, pp. 1182-1187
DOI: 10.1126/science.aap9674

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


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.

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