Paired electrolysis has a limited reaction scope for organic synthesis because it is often not compatible with reactions involving short-lived intermediates. We addressed this limitation using alternating current electrolysis (ACE). Using trifluoromethylation of (hetero)­arenes as a model reaction, we showed that the yield was improved from 13% using paired electrolysis to 84% using ACE. We have also developed a theory for guiding the rational design of reaction parameters for future applications of ACE.

The Ir-catalyzed enantioselective fluorination of racemic, branched allylic trichloroacetimidates with Et3N·3HF is a mild and efficient route for selective incorporation of fluoride ion into allylic systems. We herein describe the asymmetric fluorination of racemic, secondary allylic electrophiles with Et3N·3HF using a chiral-diene-ligated Ir complex. The methodology enables the formation of acyclic fluorine-containing compounds in good yields with excellent levels of asymmetric induction and overcomes the limitations previously associated with the enantioselective construction of secondary allylic fluorides bearing α-linear substituents.

Asymmetric allylic fluorination has proven to be a robust and efficient methodology with potential applications for the development of pharmaceuticals and practical synthesis for 18F-radio­labeling. A combined computational (dispersion-corrected DFT) and experimental approach was taken to interrogate the mechanism of the diene-ligated, iridium-catalyzed regio- and enantio­selective allylic fluorination. Our group has shown that, in the presence of an iridium­(I) catalyst and nucleo­philic fluoride source (Et3N·3HF), allylic trichloro­acet­imidates undergo rapid fluoride substitution to generate allylic fluoride products with excellent levels of branched-to-linear ratios. Mechanistic studies reveal the crucial role of the trichloro­acet­imidate as a potent leaving group and ligand to enable conversion of racemic allylic trichloro­acet­imidates to the corresponding enantio­enriched allylic fluorides, via a dynamic kinetic asymmetric transformation (DYKAT), in the presence of the chiral bicyclo­[3.3.0]­octadiene-ligated iridium catalyst.

The ability to use racemic allylic trichloroacetimidates as competent electrophiles in a chiral bicyclo[3.3.0]­octadiene-ligated iridium-catalyzed asymmetric fluorination with Et3N·3HF is described. The methodology represents an effective route to prepare a wide variety of α-linear, α-branching, and β-heteroatom substituted allylic fluorides in good yields, excellent branched-to-linear ratios, and high levels of enantioselectivity. Additionally, the catalytic system is amendable to the fluorination of optically active allylic trichloroacetimidate substrates to afford the fluorinated products in good yields with exclusively branched selectivity. Excellent levels of catalyst-controlled diastereoselectivities using either (R,R) or (S,S)-bicyclo­[3.3.0]­octadiene ligand are observed. The synthetic utility of the fluorination process is illustrated in the asymmetric synthesis of 15-fluorinated prostaglandin and neuroprotective agent P7C3-A20.

Background: Radionuclides emitting Auger electrons (AEs) with low (0.02–50 keV) energy, short (0.0007–40 µm) range, and high (1–10 keV/µm) linear energy transfer may have an important role in the targeted radionuclide therapy of metastatic and disseminated disease. Erbium-165 is a pure AE-emitting radionuclide that is chemically matched to clinical therapeutic radionuclide 177Lu, making it a useful tool for fundamental studies on the biological effects of AEs. This work develops new biomedical cyclotron irradiation and radiochemical isolation methods to produce 165Er suitable for targeted radionuclide therapeutic studies and characterizes a new such agent targeting prostate-specific membrane antigen. Methods: Biomedical cyclotrons proton-irradiated spot-welded Ho(m) targets to produce 165Er, which was isolated via cation exchange chromatography (AG 50W-X8, 200–400 mesh, 20 mL) using alpha-hydroxyisobutyrate (70 mM, pH 4.7) followed by LN2 (20–50 µm, 1.3 mL) and bDGA (50–100 µm, 0.2 mL) extraction chromatography. The purified 165Er was radiolabeled with standard radiometal chelators and used to produce and characterize a new AE-emitting radiopharmaceutical, [165Er]PSMA-617. Results: Irradiation of 80–180 mg natHo targets with 40 µA of 11–12.5 MeV protons produced 165Er at 20–30 MBq·µA−1·h−1. The 4.9 ± 0.7 h radiochemical isolation yielded 165Er in 0.01 M HCl (400 µL) with decay-corrected (DC) yield of 64 ± 2% and a Ho/165Er separation factor of (2.8 ± 1.1) · 105. Radiolabeling experiments synthesized [165Er]PSMA-617 at DC molar activities of 37–130 GBq·µmol−1. Conclusions: A 2 h biomedical cyclotron irradiation and 5 h radiochemical separation produced GBq-scale 165Er suitable for producing radiopharmaceuticals at molar activities satisfactory for investigations of targeted radionuclide therapeutics. This will enable fundamental radiation biology experiments of pure AE-emitting therapeutic radiopharmaceuticals such as [165Er]PSMA-617, which will be used to understand the impact of AEs in PSMA-targeted radionuclide therapy of prostate cancer.