9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin

As part of a comprehensive study of N-unsubstituted bispidines, the novel 9,9-difluorobispidine (D) has been synthesized. The compound crystallizes from pentane below 0 °C in the ordered-crystalline phase D-II and undergoes at 0-30 °C a stepwise endothermic phase transition to a dynamically disordered crystalline phase D-I; melting occurs at 227 °C. Single crystalline D-II has been subjected to X-ray structure analysis, revealing association of the molecules to form chains. Reaction of (1,5-hexadiene)PtCl₂ with D affords {C₇H₁₀F₂(NH)₂}PtCl₂ (D1), which can be converted by conventional routes to {C₇H₁₀F₂(NH)₂}Pt(cbdca)·5H₂O (D2) and {C₇H₁₀F₂(NH)₂}Pt(C₂O₄) (D3). Compound D1 crystallizes solvent-free from water and is isomorphous to the solvent-free parent bispidine analogue (A1). The pentahydrate D2 is isomorphous to the bispidine and 9-oxabispidine homologues (A2 and C2), as shown by X-ray structure analyses. An increased polarity of the bispidine skeleton as a consequence of the high electronegativity of fluorine is seen as the reason for low cytotoxic potency of D1-D3.