Cu(II)-Mediated direct ¹⁸F-dehydrofluorination of phosphine oxides in high molar activity

Background: The ¹⁸F/¹⁹F-isotope exchange method employing P(V)-centered prosthetic groups demonstrates advantages in addressing mild one-step aqueous ¹⁸F-labeling of peptides and proteins. However, the molar activity (A_m) achieved through isotope exchange remains relatively low, unless employing a high initial activity of [¹⁸F]F^-. To overcome this drawback, our work introduces a novel approach through a Cu-mediated direct ¹⁸F-dehydrofluorination of phosphine oxides. This method leverages the straightforward separation of the ¹⁸F-labeled product from the phosphine oxide precursors, aiming to primarily increase A_m.

Results: Through a ¹⁹F-dehydrofluorination efficiency test, Cu(OAc)₂ was identified as the optimal oxidative metal salt, exhibiting a remarkable 100% conversion within one hour. Leveraging the straightforward separation of phosphine oxide precursors and phosphinic fluoride products, the A_m of an activated ester, [¹⁸F]4, sees an impressive nearly 15-fold increase compared to the ¹⁸F/¹⁹F-isotope exchange, with the same initial activity of [¹⁸F]F^-. Furthermore, this Cu(II)-mediated ¹⁸F-dehydrofluorination approach demonstrates tolerance up to 20% solvent water content, which enables the practical radiosynthesis of ¹⁸F-labeled water-soluble molecules under non-drying conditions.

Conclusions: The direct ¹⁸F-dehydrofluorination of phosphine oxide prosthetic groups has been successfully accomplished, achieving a high A_m via Cu(II)-mediated oxidative addition and reductive elimination.