Kaiqiang Zhang et al.

Link: https://www.nature.com/articles/s41467-024-54208-y

Published: 28 November 2024

Abstract

Constructing organic fluorophosphines, vital drug skeletons, through the direct fluorination of readily available alkyl phosphonates has been impeded due to the intrinsic low electrophilicity of P^V and the high bond energy of P═O bond. Here, alkyl phosphonates are electrophilically activated with triflic anhydride and N-heteroaromatic bases, enabling nucleophilic fluorination at room temperature to form fluorophosphines via reactive phosphine intermediates. This approach facilitates the late-stage (radio)fluorination of broad dialkyl and monoalkyl phosphonates. Monoalkyl phosphonates derived from targeted drugs, including cyclophosphamide, vortioxetine, and dihydrocholesterol, are effectively fluorinated, achieving notable yields of 47−71%. Radiofluorination of medically significant ¹⁸F-tracers and synthons are completed in radiochemical conversions (radio-TLC) of 51−88% and molar activities up to 251 ± 12 GBq/μmol (initial activity 11.2 GBq) within 10 min at room temperature. Utilizing a phosphonamidic fluoride building block (BFPA), [¹⁸F]BFPA-Flurpiridaz and [¹⁸F]BFPA-E[c(RGDyK)]₂ demonstrate high-contrast target imaging, excellent pharmacokinetics, and negligible defluorination.

[Author Profile]

Dr. Zijing Li is an Associate Professor at the School of Public Health, Xiamen University. Her research centers on ¹⁸F-labeling chemistry, functionalized fluorophosphine compounds and their diverse applications. Her team has made notable contributions to the field, with key findings published in prestigious journals, including Nature Communications (2019) and the Journal of the American Chemical Society (2024).