Chemical modification of nucleotides can improve the metabolic stability and target specificity of oligonucleotide therapeutics, and alkylphosphonates have been employed as charge-neutral replacements for naturally-occurring phosphodiester backbones in these compounds. However, at present, the alkyl moieties that can be attached to phosphorus atoms in these compounds are limited to methyl groups or primary/secondary alkyls, and such alkylphosphonate moieties can degrade during oligonucleotide synthesis. The present work demonstrates the tertiary alkylation of the phosphorus atoms of phosphites bearing two 2’-deoxynuclosides. This process utilizes a carbocation generated via a light-driven radical-polar crossover mechanism. This protocol provides tertiary alkylphosphonate structures that are difficult to synthesize using existing methods. The conversion of these species to oligonucleotides having charge-neutral alkylphosphonate linkages through a phosphoramidite-based approach was also confirmed in this study.

核苷酸的化学修饰可以提高寡核苷酸治疗的代谢稳定性和靶标特异性，并且烷基膦酸酯已被用作这些化合物中天然存在的磷酸二酯主链的电中性替代品。然而，目前，这些化合物中可连接至磷原子的烷基部分仅限于甲基或伯/仲烷基，并且此类烷基膦酸酯部分可在寡核苷酸合成过程中降解。目前的工作证明了带有两个 2'-脱氧核苷的亚磷酸酯的磷原子的三级烷基化。该过程利用通过光驱动的自由基-极性交叉机制产生的碳正离子。该方案提供了使用现有方法难以合成的叔烷基膦酸酯结构。本研究还证实了通过基于亚磷酰胺的方法将这些物质转化为具有电荷中性烷基膦酸酯键的寡核苷酸。