A novel method for the preparation of 18F-labeled α-SCF3 carbonyl compounds
As fluorine-18 (18F) is the most commonly used radioisotope in positron emission tomography (PET), significant efforts have been devoted to the exploration of efficient methods for the incorporation of 18F into small and biological molecules. However, the studies on this 18F-radiochemistry have so far been mainly limited to [18F]fluorination and [18F]trifluoromethylation. Despite the fact that trifluoromethylthio group (CF3S) is a valuable functionality in medicinal chemistry and drug discovery, the installation of [18F]CF3S moiety has never been fully realized and thus represents a significant challenge. Recently a difluorocarbene-derived one-step [18F]trifluoromethylthiolation was discovered as one of the first examples for [18F]trifluoromethylthiolation despite the fact that significant accomplishments have been made for non-radioactive trifluoromethylthiolation. While the novelty and utility of difluorocarbene in the 18F-trifluoromethylthiolation have been demonstrated in this work, the characteristics of these radiofluorination reactions, including the underlying mechanism and interaction with transition metals, remain elusive and represent a major roadblock to further advance these reactions into the radiolabeling of SCF3-containing pharmaceuticals, for example, Cefazaflur.
Herein we report an unprecedented mechanistic observation of trifluoromethylthio formation among difluorocarbene, sulfur and fluoride, and the subsequent interactions between ensuing SCF3 anions and transition metals (Fig. 1). Supported by experimental and theoretical studies, this work overrides our putative and long-standing interpretation of trifluoromethylthio group formation from difluorocarbene, and leads us to discover a new class of trifluoromethylthiolation for α-bromo carbonyl compounds in the presence of copper complex. As proof of concept, we demonstrate a general and practical copper-mediated radiosynthesis of 18F-labeled SCF3 carbonyl compounds with broad substrate scope and functional group compatibility, which is otherwise hardly achievable from traditional methods.
Division of Nuclear Medicine and Molecular Imaging and Gordon Center for Medical Imaging,
Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, USA
An Unconventional Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of 18 F-Labeled α-SCF3 Carbonyl Compounds.
Zheng J, Cheng R, Lin JH, Yu DH, Ma L, Jia L, Zhang L, Wang L, Xiao JC, Liang SH
Angew Chem Int Ed Engl. 2017 Feb 14