Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(iii) ylides

Abstract

Synthesis of non-activated electron-rich and sterically hindered 18F-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), and meta-[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.

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib

“…It is therefore not surprising that fluordenitration was not fruitful in our hands by manual or microfluidic approaches. Fortunately, our iodonium ylide-based radiochemistry293031 proved to be the most effective method for preparation of the 18 F isotopologue of ( R )-1 (Fig. 5), resulting in a 14% uncorrected RCY, relative to starting [ 18 F]fluoride (compared to the 1% RCY by microfluidic fluorodenitration39), and in a radiochemical purity of >97%.…”

A Facile Radiolabeling of [18F]FDPA via Spirocyclic Iodonium Ylides: Preliminary PET Imaging Studies in Preclinical Models of Neuroinflammation

“…60% conversion. The intermediate was used without further purification in the subsequent coupling reactions with spirocyclic auxiliaries (SPI5 and SPIAd) 29 to afford SCIDY precursors 13 (22%, two steps from 11 ) and 14 (34%, two steps from 11 ), respectively.…”

“…26–29 These bench-stable precursors provide efficient, regiospecific and direct radiolabeling via [ 18 F]fluoride, demonstrating a broad substrate scope for non-activated and/or sterically-hindered (hetero)arenes. The operation is simple, metal-free and suitable for routine and automated production.…”

Synthesis of [18F]Fluoroarenes by Nucleophilic Radiofluorination of N‐Arylsydnones

“…[12] Alternatively, spirocyclic iodonium ylides have demonstrated regioselective 18 F-fluorination with a broad substrate scope. [13] Recently, a concerted S N Ar reaction was reported to enable 18 F-deoxyfluorination of phenols via uronium intermediates. [14] However, competing formation of volatile [ 18 F]fluoromethane, [15] regioisomeric mixtures of 18 F-labeled products, [8a] challenging precursor preparation or requirement for expensive reagents can be limiting for these methods.…”