Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions
Kenji Ota, Kazunori Nagao, Dai Hata, Haruki Sugiyama, Yasutomo Segawa, Ryosuke Tokunoh, Tomohiro Seki, Naoya Miyamoto, Yusuke Sasaki, Hirohisa Ohmiya
Abstract
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.