Extending the Scope of the C -Functionalization of Cyclam via Copper(I)-Catalyzed Alkyne–Azide Cycloaddition to Bifunctional Chelators of Interest

Cédric Ollier, Alejandro Méndez-Ardoy, Fernando Ortega-Caballero, José L. Jiménez-Blanco, Nathalie Le Bris*, and Raphaël Tripier

J. Org. Chem. 2024, 89, 9, 5988–5999, doi: 10.1021/acs.joc.3c02854

Cyclam, known for its potent chelation properties, is explored for diverse applications through selective N-functionalization, offering versatile ligands for catalysis, medical research, and materials science. The challenges arising from N-alkylation, which could decrease the coordination properties, are addressed by introducing a robust C-functionalization method. The facile two-step synthesis proposed here involves the click chemistry-based C-functionalization of a hydroxyethyl cyclam derivative using Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC). Boc-protecting groups prevent undesired copper coordination, resulting in compounds with a wide range of functionalities. The optimized synthesis conditions enable C-functional cyclams to be obtained easily and advantageously, with high application potential in the previously cited fields. The methodology has been extended to trehalose-based Siamese twin amphiphiles, enabling efficient gene delivery applications.