Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges

Abstract

Carbon-14 ( 14 C) is a gold standard technology routinely utilized in pharmaceutical and agrochemical industries for tracking synthetic organic molecules and providing their metabolic and safety profiles. While the state of the art has been dominated for decades by traditional multistep synthetic approaches, the recent emergence of late-stage carbon isotope labeling has provided new avenues to rapidly access carbon-14-labeled biologically relevant compounds. In particular, the development of carbon isotope exchange has represented a fundamental paradigm change, opening the way to unexplored synthetic transformations. In this Perspective, we discuss the recent developments in the field with a critical assessment of the literature. We subsequently discuss research directions and future challenges within this rapidly evolving field.

Skeletal Metalation of Lactams through Carbonyl-to-Nickel Exchange Logic

“…Quantitative formation of starting lactams 6, 10 and 13 from the corresponding nickellacycles was established following addition of 1 atm CO(g), along with clean formation of (IPr)Ni(CO)3 as the sole nickel species. This finding unveiled a protocol to exchange the lactam carbonyl with exogenous CO(g) with potential applications in carbon isotope labelling, (44)(45)(46) highlighting a useful synthetic application of the organonickel reagents. Moreover, the reductive elimination of C(sp 3 )-N or C(sp 2 )-N bonds from the deinserted nickellacycles was also investigated, as it would provide a net CO deletion process for singleatom editing.…”

“…(47) The direct editing of the carbon framework could rapidly provide valuable, skeletally distinct derivatives for biological testing. In addition, the selective incorporation of a carbon isotope into a carbonyl group of azasteroids could provide useful new methods for their radiolabeling (44,46) and metabolism studies. (48) The use of stoichiometric metal in highly challenging reactions could also provide significantly improved outcomes, especially in drug discovery research where the successful first-pass reaction significantly outweighs reagent costs.…”

“…This result demonstrated a new strategy for late-stage carbon isotope exchange of the carbonyl group in aliphatic lactams, which might prove challenging to perform by established methods. (44,46) Metalation of azasteroid 20, the α, β-unsaturated variant of 19, occurred readily at RT affording the corresponding vinyl nickellacycle and treatment with 13 CO successfully afforded the labeled product 13 C-20 (fig. S28).…”

Rapid Access to Carbon-Isotope-Labeled Alkyl and Aryl Carboxylates Applying Palladacarboxylates

“…Often, staple synthetic techniques used in process or medicinal chemistry to access carboxylic acids and esters do not transfer to isotope labeling programs due to stringent limitations in efficiently incorporating the valuable radiolabel. The synthesis of isotopically labeled compounds differs from traditional organic synthesis due to (1) the scarcity of isotopically labeled reagents, (2) the high cost of these reagents, and (3) the production of dangerous radioactive waste, which therefore requires new synthetic routes to be devised . Radiochemists therefore aim to incorporate the radiolabel in high radiochemical yields at the latest stage possible in a synthetic route in order to minimize cost and hazardous waste.…”

“…The synthesis of isotopically labeled compounds differs from traditional organic synthesis due to (1) the scarcity of isotopically labeled reagents, (2) the high cost of these reagents, and (3) the production of dangerous radioactive waste, which therefore requires new synthetic routes to be devised. 3 Radiochemists therefore aim to incorporate the radiolabel in high radiochemical yields at the latest stage possible in a synthetic route in order to minimize cost and hazardous waste.…”