In contrast to stable and natural abundant carbon‐12, the synthesis of organic molecules with carbon (radio)isotopes must be conceived and optimized in order to navigate through the hurdles of radiochemical requirements, such as high costs of the starting materials, harsh conditions and radioactive waste generation. In addition, it must initiate from the small cohort of available C‐labeled building blocks. For long time, multi‐step approaches have represented the sole available patterns. On the other side, the development of chemical reactions based on the reversible cleavage of C−C bonds might offer new opportunities and reshape retrosynthetic analysis in radiosynthesis. This review aims to provide a short survey on the recently emerged carbon isotope exchange technologies that provide effective opportunity for late‐stage labeling. At present, such strategies have relied on the use of primary and easily accessible radiolabeled C1‐building blocks, such as carbon dioxide, carbon monoxide and cyanides, while the activation principles have been based on thermal, photocatalytic, metal‐catalyzed and biocatalytic processes.
The need for carbon-labeled radiotracers is increasingly higher in drug discovery and development (carbon-14, β − , t 1/2 = 5730 years) as well as in positron emission tomography (PET) for in vivo molecular imaging applications (carbon-11, β + , t 1/2 = 20.4 min). However, the structural diversity of radiotracers is still systematically driven by the narrow available labeled sources and methodologies. In this context, the emergence of carbon dioxide radical anion chemistry might set forth potential unexplored opportunities. Based on a dynamic isotopic equilibration between formate salts and [ 13 C, 14 C, 11 C]CO 2 , C-labeled radical anion CO 2•− could be accessed under extremely mild conditions within seconds. This methodology was successfully applied to hydrocarboxylation and dicarboxylation reactions in late-stage carbon isotope labeling of pharmaceutically relevant compounds. The relevance of the method in applied radiochemistry was showcased by the whole-body PET biodistribution profile of [ 11 C]oxaprozin in mice.
Carbon isotope labeling is a useful technology for tracking the fate of organic compounds in the environment and in living organisms. In this context, the development of robust and general methodologies amenable to the direct functionalization of CO2 remains a significant task. In this communication, a de‐risking approach was developed to evaluate the robustness of the Staudinger aza‐Wittig sequence for carbon isotope labeling. This technology is based on [14C]CO2 screening that allowed to investigate the tolerance of the procedure with most representative heterocycles and functional groups found in FDA approved drugs.
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