Nitrile-tolerant Iridium-catalysed Hydrogen Isotope Exchange

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Isotopically labeled molecules are essential for assessing drug candidate ADMET profiles.
• Transition metal-catalyzed hydrogen isotope exchange (HIE) allows for late-stage deuterium or tritium labeling.
• Nitrile functionalities in molecules inhibit current HIE catalyst turnover, limiting method applicability.

Purpose of the Study:

• To develop novel HIE catalysts tolerant to nitrile functionalities.
• To establish an efficient method for labeling nitrile-containing molecules.

Main Methods:

• In silico solvent binding energy parameter approaches were used to design catalysts.
• Development of neutral iridium catalyst species with reduced binding affinity to nitriles.
• Utilizing ortho-directed C(sp2)-H activation with air- and moisture-stable Ir(COD)(NHC)Cl pre-catalysts under deuterium gas.

Main Results:

• Discovery of uniquely tolerant neutral iridium catalyst species.
• First effective nitrile-tolerant HIE methodology demonstrated.
• Successful labeling of molecules with various directing groups (heterocycles, ketones, amines) and bioactive compounds.
• High levels of isotopic labeling achieved under mild conditions.

Conclusions:

• The developed methodology overcomes the challenge of labeling nitrile-containing molecules via HIE.
• This advancement provides a powerful tool for drug discovery and development.
• The new catalysts and method offer broad applicability and efficiency in isotopic labeling.