Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics

Abstract

Fluorine-18 (t ½ ¼ 109.7 min) is the most commonly used isotope to prepare radiopharmaceuticals for molecular imaging by positron emission tomography (PET). Nucleophilic aromatic substitution reactions of suitably activated (electron-deficient) aromatic substrates with no-carrier-added [ 18 F]fluoride ion are routinely carried out in the synthesis of radiotracers in high specific activities. Despite extensive efforts to develop a general 18 F-labelling technique for non-activated arenes there is an urgent and unmet need to achieve this goal. Here we describe an effective solution that relies on the chemistry of spirocyclic hypervalent iodine(III) complexes, which serve as precursors for rapid, one-step regioselective radiofluorination with [ 18 F]fluoride. This methodology proves to be efficient for radiolabelling a diverse range of non-activated functionalized arenes and heteroarenes, including arene substrates bearing electron-donating groups, bulky ortho functionalities, benzylic substituents and meta-substituted electron-withdrawing groups. Polyfunctional molecules and a range of previously elusive 18 F-labelled building blocks, compounds and radiopharmaceuticals are synthesized.

Iodonium Ylide–Mediated Radiofluorination of 18F-FPEB and Validation for Human Use

“…A recent study by Coenen and coworkers demonstrated the satisfactory application of this method using Meldrum’s acid auxiliaries, but led to non-regiospecific labeling and formation of several byproducts (7). Concurrently, we explored the application of iodonium ylide precursors with barbituric acid and Meldrum’s acid auxiliaries for 18 F-labeling but also found yields to be sub-optimal (8). We discovered that spirocyclic iodonium(III) ylide precursors, in conjunction with systematic optimization of the reaction conditions, led to efficient, regiospecific, one-step radiosyntheses of non-activated aromatics with 18 F-fluoride (8).…”

Synthesis and Crystal Structures of Two New Oxaspirocyclic Compounds

“…In recent years, many efforts have been devoted to the preparation and characterization of spiro compounds due to diverse industrial and biomedical applications in medicine [1][2][3], catalysis [4], 18F-radiolabeling [5] and optical material [6][7][8]. The asymmetric characteristic of the molecules, owing to the chiral spiro carbon, is one of the important criteria of the biological activities.…”

In Vitro and in Vivo Evaluation of 11C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies

“…70–73, 75 The aryl iodide 12 could be oxidized in chloroform. 70 Without further purification, the resulted intermediate could couple the spirocyclic auxiliaries (SPIAd) 71 directly to afford the desired ylide precursor 17 . In specific, oxidant m CPBA (1.3 mmol, 77% max.…”