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Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions

Author

Listed:
  • Kenji Ota

    (Kyoto University)

  • Kazunori Nagao

    (Kyoto University)

  • Dai Hata

    (Research, Takeda Pharmaceutical Company Limited)

  • Haruki Sugiyama

    (Institute for Molecular Science Myodaiji
    Comprehensive Research Organization for Science and Society Neutron Industrial Application Promotion Center
    SOKENDAI, Myodaiji)

  • Yasutomo Segawa

    (Institute for Molecular Science Myodaiji
    SOKENDAI, 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
    JST, PRESTO, 4-1-8 Honcho)

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.

Suggested Citation

  • Kenji Ota & Kazunori Nagao & Dai Hata & Haruki Sugiyama & Yasutomo Segawa & Ryosuke Tokunoh & Tomohiro Seki & Naoya Miyamoto & Yusuke Sasaki & Hirohisa Ohmiya, 2023. "Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42639-y
    DOI: 10.1038/s41467-023-42639-y
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    References listed on IDEAS

    as
    1. Taiga Kodo & Kazunori Nagao & Hirohisa Ohmiya, 2022. "Organophotoredox-catalyzed semipinacol rearrangement via radical-polar crossover," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    2. Jinbao Xiang & Ming Shang & Yu Kawamata & Helena Lundberg & Solomon H. Reisberg & Miao Chen & Pavel Mykhailiuk & Gregory Beutner & Michael R. Collins & Alyn Davies & Matthew Bel & Gary M. Gallego & Ji, 2019. "Hindered dialkyl ether synthesis with electrogenerated carbocations," Nature, Nature, vol. 573(7774), pages 398-402, September.
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