Cyclic Tetrathiobisphosphonate Analogues as Selective Zinc-Ion Chelators

Recently we described the synthesis and features of tetrathiobisphosphonate including its ‘soft-base’ character as compared to bisphosphonate. To expand the chelation potential of the tetrathiobisphosphonate scaffold we synthesized novel crown-ethers containing tetrathiobisphosphonate unit, 2-6, and evaluated their Zn²⁺ vs. Mg²⁺ chelating potential, and their chemical stability. Analogues 2-6 were obtained upon treating methylene-bis(1,3,2-dithiaphospholane-2-sulfide), 1, with various diols in the presence of DBU under reflux in CHCl₃. Compound 1 was prepared from bis-methylene(phosphonicdichloride) treated with 1,2-ethanedithiol and 10 mol% AlCl₃ in CHBr₃. We explored Zn²⁺ vs. Mg²⁺-coordination by analogues 2, 4 and 5, by ¹H- and ³¹P-NMR monitored Zn²⁺/Mg²⁺-titrations. Zn²⁺ binding to analogues 2, 4 and 5, was manifested by a shift of signals (Δδ up to ~3 ppm in ³¹P-NMR). However, no shift of the signals was observed upon Mg²⁺-titration, indicating selectivity of analogues 2-5 to Zn²⁺ ions. ¹H-NMR monitored Zn²⁺-titrations of compound 4 showed no shift of the ether methylene protons, indicating a lack of coordination to the oxygen atoms in the ring. UV-monitored Zn²⁺-titration of compound 5 indicated an increasing shoulder at ~220 nm, typical of zinc thiolate ligation. Both compounds 2 (7-membered ring) and 4 (13-membered ring) were found to be highly stable to air-oxidation, for at least four weeks.  Compound 2 was found to be stable under pD 1.5 for at least four weeks, while, compound 4, decomposed with half-life of 42 h under the same conditions. In summary, the novel cyclic tetrathiobisphosphonate analogues 2-6 proved to be selective Zn²⁺-chelators. Among them compound 2 proved to be exceptionally stable.