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 and Hirohisa Ohmiya ()
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Kenji Ota: Kyoto University
Kazunori Nagao: Kyoto University
Dai Hata: Research, Takeda Pharmaceutical Company Limited
Haruki Sugiyama: Institute for Molecular Science Myodaiji
Yasutomo Segawa: Institute for Molecular Science Myodaiji
Ryosuke Tokunoh: Research, Takeda Pharmaceutical Company Limited
Tomohiro Seki: Research, Takeda Pharmaceutical Company Limited
Naoya Miyamoto: Research, Takeda Pharmaceutical Company Limited
Yusuke Sasaki: Research, Takeda Pharmaceutical Company Limited
Hirohisa Ohmiya: Kyoto University

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42639-y

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