An organometallic route to oligonucleotides containing phosphoroselenoate

Unlike the widespread use of phosphorothioates in nucleic acid chemistry, complementary research on phosphoroselenoates has been severely limited. Previous routes to DNA and RNA that contain phosphoroselenoates employ elemental Se and KSeCN as Se transfer agents, although these reagents suffer from low or unselective reactivity. The metastability of the P-Se bond demands soluble, selective Se transfer reagents. The organometallic reagent (iPrC₅H₄)₂TiSe₅ satisfies these criteria, as we demonstrate by the synthesis of phosphoroselenoate derivatives of mono- and oligonucleotides of DNA and a dinucleotide of RNA. The new general method is compatible with high-throughput phosphoramidate oligonucleotide synthesis, which allows for the preparation of site-specifically labeled oligonucleotides. A ³¹P NMR spectroscopy study shows that the phosphoroselenoate of (5′)-d(GGAATGTC_SeTGTCG)-(3′) selectively binds to soft Cd²⁺ ions but not Mg²⁺ ions.