Preparation of 4-Halobenzoate-Containing Phosphane-Based Building Blocks for Labeling Reactions Using the Traceless Staudinger Ligation

Abstract

Functionalized phosphane-containing key building blocks were synthesized that are suitable for the labeling of biologically active molecules by the traceless Staudinger ligation. Thus, a 2-(diphenylphosphanyl)phenyl 4-stannylbenzoate building block was converted into the 4-iodobenzoate by the introduction of iodine. The traceless Staudinger ligation was used to introduce the resulting 4-iodobenzoate moiety into selected molecules of pharmacological interest. Furthermore, the labeling procedure was used to insert the 4-iodobenzoate moiety into a peptide on solid support. Finally, a convenient recovery procedure of the key phosphane building block 2-(diphenylphosphanyl)phenol from 2-(diphenylphosphoryl)phenol was evaluated.

Strategic Evaluation of the Traceless Staudinger Ligation for Radiolabeling with the Tricarbonyl Core

“…All the bond lengths and angles are within their expected ranges. As expected, the average C-P-C angle in 3b is significantly smaller (102.2 • ) than the ideal tetrahedral angle, whereas in 3c the bonding angles around the phosphorous have an average of 109.4 • with larger C-P-B and smaller C-P-C angles [24,25].…”

“…Azide-functionalized target molecules and label-containing phosphanes with benzoate moiety are required for the direct variant of the traceless Staudinger ligation (first line in Scheme 1). Two ways were elaborated in the past describing the functionalization of phosphanol 2b or the preparation of functionalized 2-iodophenyl esters from 2a followed by introduction of the phosphane residue [24,25]. Moreover, the dipicolylamine moiety, which is used as a chelating unit for the tricarbonyl core, was mandatory to connect to phosphanol skeleton by a benzoate linker.…”

Recent progress using the Staudinger ligation for radiolabeling applications

“…Later in 2015, Mamat et al presented a synthesis procedure starting from trimethylstannyl precursor 38, which was borane protected prior to the reaction with elemental iodine. 57 Next, elemental iodine was introduced leading to borane-protected 39 without any side reactions like oxidation or other degradation. Finally, the BH 3 group of 39 was removed to obtain phosphane 6d using methanol at 60°C (Scheme 14).…”

Structural and Kinetic Considerations for the Application of the Traceless Staudinger Ligation to Future 18F Radiolabeling Using XRD and 19F NMR

“…This is in accordance with the behavior of the compound 1 in solution. A broad band at 3227 cm −1 and a sharp band at 3515 cm -1 was found in the IR spectrum of compound 1 [23], indicating an intramolecular hydrogen bond and the occurrence of free OH group, respectively [46]. Additionally, data obtained from the 1 H NMR spectrum of 1 at a concentration of 72.33 mM show a broad signal for the proton of the OH group at δ = 6.07 ppm.…”

“…Therefore, the traceless variant of the Staudinger ligation [6][7][8] independently developed by Raines et al [9] and Bertozzi et al [10] is employed for several applications in chemistry, biochemistry, and (radio)pharmacy. The connection of proteins [11,12], peptides, and peptide fragments [9,13], the glycosylation [14] of amino acids and peptides [15,16], the preparation of large-sized lactams [17,18], the functionalization of polymers [19], and the introduction of radiolabels [20][21][22][23] as well as fluorescence dyes [24][25][26] makes this reaction widely applicable. Both the chemical modification of the biological active molecule and the preparation of the labeling building block are also quite facile.…”