Now, Haraldur G. Gudmundsson, Troels Skrydstrup and co-workers report a strategy for synthesizing multi-carbon labelled N-alkyl containing compounds in a single operation (pictured). In a three-chamber glassware system, three gases — namely 13C-labelled carbon monoxide, doubly 13C-labelled ethylene, and hydrogen — are produced via known chemistries, such as ruthenium-based ring-closing metathesis from solid precursors, and used for the synthesis of triple-13C-labelled propionaldehyde via a hydroformylation reaction catalysed by a rhodium catalyst. The [13C3]propionaldehyde can then be directly incorporated into a target of interest via reductive amination to generate multi-labelled N-propylated compounds. The approach was validated in the synthesis of several multi-13C-labelled pharmaceuticals. Late-stage isotope incorporation and derivatization of known pharmaceuticals was also demonstrated. Moreover, the researchers adapted their protocol to deuterium labelling. For this purpose, the H2/CO precursor was deuterated by hydrogen deuterium exchange in D2O and tetrahydrofuran. Following the established process, this led to the release of D2 gas instead of H2 and the corresponding generation of deuterated propionaldehyde. This variation also allows for the simultaneous incorporation of deuterium and carbon isotopes into target compounds.
Taken together, this work provides a rare example of the insertion of three 13C atoms in a single operation and is applicable to highly functionalized drugs. While the individual reactions performed were rather well established, their integration is interesting from a technological perspective and could prove valuable for drug development.
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