Direct metal‐catalyzed tritiation of organic compounds

Abstract

The metal catalyzed tritium labelling of diverse biologically relevant compounds at PerkinElmer Health Sciences is described.

Hydrogen Isotope Exchange with Iridium(I) Complexes Supported by Phosphine‐Imidazolin‐2‐imine P,N Ligands

“…Thus, HIE is commonly employed to insert deuterium (D) atoms into pharmaceutical drug candidates for use as internal standards for mass spectrometry, for kinetic isotope studies, and for alteration of reaction pathways in total syntheses . Additionally, tritium (T) atoms can be incorporated by HIE labelling to provide radioactive tritium tracers, which are important drug discovery tools for, e.g., radioligand, protein, and covalent binding assays, for photoaffinity labelling and for ADME profiling of new drug candidates (ADME=absorption, distribution, metabolism and excretion). Homogeneous iridium catalysts have proved to be highly efficient for selective label introduction at the ortho ‐position,, next to a directing group, with commercial Crabtree's catalyst [(cod)Ir(PCy 3 )(py)]PF 6 , ( A , Figure ) and Kerr's catalysts [(cod)Ir(IMes)(PR 3 )]PF 6 ( B ) being the most prominent catalysts applied today.…”

Selective Ru(0)-Catalyzed Deuteration of Electron-Rich and Electron-Poor Nitrogen-Containing Heterocycles

“…Various methods for the incorporation of deuterium were reported previously, and the topic was recently reviewed . In addition, tritiated compounds are of increasing importance for radiolabeling of bioactive compounds in medicinal chemistry applications. , Hence, facile, fast, and efficient protocols for the deuteration and tritiation , of indole and pyridine derivatives are of great value. A novel method to conduct such transformations is reported in this contribution.…”

Tritium-labelled alkaloids: Synthesis and applications

“…Discovered 40 years ago in the bacteria Streptomyces staurosporeus , the bisindole staurosporine ( 6 ), first in a family of several unique alkaloids, generated immediate excitement because of its interesting pharmacology based on blockade of protein kinases. We reported the synthesis of [ 3 H]staurosporine by a direct tritium exchange using 5% palladium on barium sulfate . Our laboratories also prepared [methyl‐ 3 H]dimethylstaurosporine at high specific activity by methylation of staurosporine with [ 3 H]methyl iodide, and it exhibited potency comparable with staurosporine itself at the enzyme protein kinase C .…”

“…We reported the synthesis of [ 3 H]staurosporine by a direct tritium exchange using 5% palladium on barium sulfate. 24 Our laboratories also prepared [methyl-3 H]dimethylstaurosporine at high specific activity by methylation of staurosporine with [ 3 H]methyl iodide, and it exhibited potency comparable with staurosporine itself at the enzyme protein kinase C. 25 Furthermore, in collaboration with Cephalon medicinal chemists evaluating potentially new oncology agents, we tritiated several staurosporine structural analogues using sodium borotritide for their radiolabelling. 26,27 The ergot alkaloids arise as secondary metabolites resulting from fungal infection of grain crops, and they have been historically linked to both medieval St. Anthony's fire as well as the notorious 17th-century Salem Massachusetts Witch Trials.…”

“…Monocrotaline was tritium labelled by the biosynthetic incorporation of [ 3 H]putrescine, 124 and a similar strategy was used to prepare the pyrrolizidine alkaloid [ 3 H]jacobine. 125 Useful pyrrolizidine intermediate retronecine (24) was tritiated by reacting a methyl ester precursor with lithium aluminum tritide, and it was then taken on to prepare [ 3 H]indicine N-oxide for oncology research. 126 This same approach was also used to synthesize [ 3 H] disenecioyl retronecine.…”