Innovative Cyclic Nucleotides - Nucleoside 2',3'-Seven Membered Cyclic Diphosphonate Derivatives. Theoretical Feasibility, Synthesis, and Properties.

Abstract

7-membered cyclic nucleotides have remained unknown despite the natural abundance of their 5- and 6-membered counterparts. Here, we report the first synthesis of 2',3'-cyclic nucleosides (tetrathio)diphosphonate (2',3'-cNTDPs) by a rapid one-step, regioselective, and protection-free reaction of U, A, C, I, and G, with methylene-bis(1,3,2-dithia-phospholane-2-sulfide) (DTPS). The reaction proceeds instantaneously, even at -35 °C, resulting in the quantitative conversion of methylene-bis-DTPS. Density functional theory (DFT) calculations of ∆Gr confirm the synthetic feasibility and regioselectivity, attributing the efficiency to strain release in DTPS rings and entropic gain from thiirane elimination. The resulting 2',3'-cNTDPs exhibited remarkable hydrolytic stability and greater solution structural rigidity than free nucleosides.