title: Mechanistic Studies and Radiofluorination of Structurally Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides.
abstract: Synthesis of non-activated electron-rich and sterically hindered18F-arenes remains a major challenge due to limitations of existing radiofluorination methodologies. Herein, we report on our mechanistic investigations of spirocyclic iodonium(III) ylide precursors for arene radiofluorination, including their reactivity, selectivity, and stability with no-carrier-added [18F]fluoride. Benchmark calculations at the G2[ECP] level indicate that pseudorotation and reductive elimination at iodine(III) can be modeled well by appropriately selected dispersion-corrected density functional methods. Modeling of the reaction pathways show that fluoride-iodonium(III) adduct intermediates are strongly activated and highly regioselective for reductive elimination of the desired [18F]fluoroarenes (difference in barriers, ΔΔG‡> 25 kcal·mol-1). The advantage of spirocyclic auxiliaries is further supported by NMR spectroscopy studies, which bolster evidence for underlying decomposition processes which can be overcome for radiofluorination of iodonium(III) precursors. Using a novel adamantyl auxiliary, sterically hindered iodonium ylides have been developed to enable highly efficient radiofluorination of electron-rich arenes, including fragments of pharmaceutically relevant nitrogen-containing heterocycles and tertiary amines. Furthermore, this methodology has been applied for the syntheses of the radiopharmaceuticals 6-[18F]fluoro-meta-tyrosine ([18F]FMT, 11 ± 1% isolated radiochemical yield, non-decay-corrected (RCY, n.d.c.;n= 3), andmeta-[18F]fluorobenzylguanidine ([18F]mFBG, 14 ± 1% isolated RCY, n.d.c.,n= 3) which cannot be directly radiolabeled using conventional nucleophilic aromatic substitution with [18F]fluoride.
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, United States of America; Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts, 02114, United States of America.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Rotstein
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, United States of America.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, United States of America.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Liu
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, United States of America.
authors.forename: Jon
authors.initials: J
authors.lastname: Patteson
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, United States of America.
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Kwan
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, United States of America; Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts, 02114, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging & Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, United States of America; Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts, 02114, United States of America.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Liang