Naoko Ichiishi

Late-stage [18F]fluorination: new solutions to old problems

The last 2-3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011.

Cu-Catalyzed Fluorination of Diaryliodonium Salts with KF

A mild Cu-catalyzed nucleophilic fluorination of unsymmetrical diaryliodonium salts with KF is described. This protocol preferentially fluorinates the smaller aromatic ligand on iodine(III). The reaction exhibits a broad substrate scope and proceeds with high chemoselectivity and functional group tolerance. DFT calculations implicate a Cu(I)/Cu(III) catalytic cycle.

Copper-Catalyzed [18F]Fluorination of (Mesityl)(aryl)iodonium Salts

A practical, rapid, and highly regioselective Cu-catalyzed radiofluorination of (mesityl)(aryl)iodonium salts is described. This protocol utilizes [18F]KF to access 18F-labeled electron-rich, -neutral, and -deficient aryl fluorides under a single set of mild conditions. This methodology is applied to the synthesis of protected versions of two important radiotracers: 4-[18F]fluorophenylalanine and 6-[18F]fluoroDOPA.

Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids

A copper-mediated radiofluorination of aryl- and vinylboronic acids with K18F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of [18F]FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors.

Palladium- and Nickel-Catalyzed Decarbonylative C–S Coupling to Convert Thioesters to Thioethers

This Letter describes the development of a catalytic decarbonylative C-S coupling reaction that transforms thioesters into thioethers. Both Pd- and Ni-based catalysts are developed and applied to the construction of diaryl, aryl alkyl, and heterocycle-containing thioethers.

Development of Customized [18F]Fluoride Elution Techniques for the Enhancement of Copper-Mediated Late-Stage Radiofluorination

In a relatively short period of time, transition metal-mediated radiofluorination reactions have changed the PET radiochemistry landscape. These reactions have enabled the radiofluorination of a wide range of substrates, facilitating access to radiopharmaceuticals that were challenging to synthesize using traditional fluorine-18 radiochemistry. However, the process of adapting these new reactions for automated radiopharmaceutical production has revealed limitations in fitting them into the confines of traditional radiochemistry systems. In particular, the presence of bases (e.g. K2CO3) and/or phase transfer catalysts (PTC) (e.g. kryptofix 2.2.2) associated with fluorine-18 preparation has been found to be detrimental to reaction yields. We hypothesized that these limitations could be addressed through the development of alternate techniques for preparing [18F]fluoride. This approach also opens the possibility that an eluent can be individually tailored to meet the specific needs of a metal-catalyzed reaction of interest. In this communication, we demonstrate that various solutions of copper salts, bases, and ancillary ligands can be utilized to elute [18F]fluoride from ion exchange cartridges. The new procedures are effective for fluorine-18 radiochemistry and, as proof of concept, have been used to optimize an otherwise base-sensitive copper-mediated radiofluorination reaction.

Pd-Catalyzed Decarbonylative Cross-Couplings of Aroyl Chlorides

This report describes a method for Pd-catalyzed decarbonylative cross-coupling that enables the conversion of carboxylic acid derivatives to biaryls, aryl amines, aryl ethers, aryl sulfides, aryl boronate esters, and trifluoromethylated arenes. The success of this transformation leverages the Pd0/Brettphos-catalyzed decarbonylative chlorination of aroyl chlorides, which can then participate in diverse cross-coupling reactions in situ using the same Pd catalyst.