Fluorination and hydrolytic stability of water-soluble platinum complexes with a borane-bridged diphosphoramidite ligand

Abstract

The high fluorophilicity of borane-containing ligands offers promise for accessing new metallodrug candidates capable of bifunctional [¹⁸F]-positron emission tomography (PET) imaging, but this requires water soluble and hydrolytically stable ligands that can be fluorinated under mild conditions. Toward this goal, here we report the synthesis and characterization of water-soluble Pt(II) complexes containing a triaminoborane-bridged diphosphoramidite ligand called ^MeOTBDPhos that can be fluorinated using simple fluoride salts. NMR and XRD studies show that (^MeOTBDPhos)PtCl₂ (1) dissolves in water with cooperative H–OH addition across the bridgehead N–B bond to form 1-H₂O. The B–OH bond in 1-H₂O undergoes rapid displacement with fluoride (<10 min) when treated with CsF in MeCN to form 1-HF. 1-HF can also be prepared in <10 min by addition of KF to 1 in the presence Kryptofix® 222 and (HNEt₃)Cl in MeCN. In addition to using fluoride salts, we show how mononuclear 1 can be fluorinated with HBF₄·Et₂O to form dinuclear [(^MeOTBDPhos-HF)Pt(μ-Cl)]₂(BF₄)₂ (4-HF). Comparative studies show that the B–F bond in 1-HF undergoes hydrolysis as soon as it is dissolved in water or saline, but the B–F bond persists for hours when the pH of the solution is lowered to pH ≤ 2. In contrast to 1-HF, the B–F bond in dinuclear 4-HF persists for days when dissolved in water, which may be attributed to slow, sacrificial release of fluoride from the BF₄⁻ anion. The results show how cooperative N–B reactivity on the ligand can be leveraged to rapidly fluorinate water-soluble ^MeOTBDPhos complexes under mild conditions and afford suggestions for how to enhance hydrolytic B–F stability, as required for use in biomedical applications.