Methoden der C‐H‐Funktionalisierung für den Wasserstoffisotopenaustausch

Abstract

The varied applications of hydrogen isotopes (deuterium, D, and tritium, T) in the physical and life sciences demands a range of methods for their installation in an array of molecular architectures. In this review, we describe recent advances in synthetic C-H functionalization for hydrogen isotope exchange.

Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

“…In this Review,advances in the application of hydrogen isotopes in the life sciences are described. Compared to 13 Co r 14 Cl abelling,h ydrogen isotope labelling is typically easier,q uicker,a nd much less expensive. [6] On the other hand, it is more difficult to predict the metabolic stability of 2 H-or 3 H-labelled compounds.I nt he case of tritium, reduced tracer stability under biological conditions may result in the in vivo formation of highly toxic 3 H 2 O, which can be distributed throughout the whole body and thus makes radioactivity measurements and quantification more difficult.…”

“…These methods are highlighted in the related review "CÀHA ctivation and Functionalisation for Hydrogen Isotope Exchange". [13] labelled versus unlabelled analyte;and 4) the use for absolute quantification through internal standardization. Thel atter three applications are quite similar as the underlying principle is the generation of aMS-detectable mass shift relative to the unlabelled analyte.C onsequently,t hese applications are not restricted to deuterium alone as asimilar mass shift could also be achieved by employing other stable isotopes (e.g., 13 C, 15 N, or 18 O).…”

“…[13] labelled versus unlabelled analyte;and 4) the use for absolute quantification through internal standardization. Thel atter three applications are quite similar as the underlying principle is the generation of aMS-detectable mass shift relative to the unlabelled analyte.C onsequently,t hese applications are not restricted to deuterium alone as asimilar mass shift could also be achieved by employing other stable isotopes (e.g., 13 C, 15 N, or 18 O). Theq uestion whether to use deuterium or another stable isotope label often depends on commercial availability, costs,and the synthetic efforts needed for label introduction.…”

Palladium(II)‐Mediated C−H Tritiation of Complex Pharmaceuticals

“…Molecules labeled with tritium (T, 3 H, half-life:1 2.3 years) [1] are in perpetually high demand for the study of protein receptor-ligand interactions, [2,3] autoradiographic imaging of molecular interactions in biological tissue, [3,4] and the investigation of molecular absorption, distribution, metabolism and excretion (ADME). [5][6][7] To enable such applications quickly and with low cost, particularly in academic and industrial settings with rapid turnover cycles for evaluation of candidate pharmaceuticals and imaging tracers,direct C À Htritiation on the final molecule of interest is ad esired synthetic approach. [7][8][9][10][11] Thep referred source of tritium is tritium gas (T 2 ), because T 2 is the low cost synthetic precursor of other tritium building blocks,and is practical to handle on micromole scale with commercially available manifolds.F urthermore,T 2 is available in > 99 %i sotopic purity,w hich facilitates the synthesis of high specific activity compounds used in binding and autoradiography studies (> 15 Ci mmol À1 ,a pprox.…”

“…Predominant methods for C À Ht ritiation with T 2 employ transition metals that are reduced to low valency and/or form metal tritides by reaction with T 2 . [7][8][9][10] Iridium complexes such as Crabtreescatalyst, [Ir(COD)(PCy 3 )(py)]PF 6 ,are regarded as state of the art for aromatic H/T exchange ( Figure 1A), but have al imited scope of useful directing groups,a nd are poisoned by common coordinating groups in bioactive compounds that do not direct CÀHa ctivation, such as 4-pyridyl substituents. [9] Heterogeneous catalysts such as rhodium and palladium metal are generally limited to tritiation at activated N-heterocycle,b enzylic,a nd anomeric C À Hb onds in reactions with T 2 .…”