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

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...

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Autores principales: Ota, Kenji, Nagao, Kazunori, Hata, Dai, Sugiyama, Haruki, Segawa, Yasutomo, Tokunoh, Ryosuke, Seki, Tomohiro, Miyamoto, Naoya, Sasaki, Yusuke, Ohmiya, Hirohisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618202/
https://www.ncbi.nlm.nih.gov/pubmed/37907473
http://dx.doi.org/10.1038/s41467-023-42639-y
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author Ota, Kenji
Nagao, Kazunori
Hata, Dai
Sugiyama, Haruki
Segawa, Yasutomo
Tokunoh, Ryosuke
Seki, Tomohiro
Miyamoto, Naoya
Sasaki, Yusuke
Ohmiya, Hirohisa
author_facet Ota, Kenji
Nagao, Kazunori
Hata, Dai
Sugiyama, Haruki
Segawa, Yasutomo
Tokunoh, Ryosuke
Seki, Tomohiro
Miyamoto, Naoya
Sasaki, Yusuke
Ohmiya, Hirohisa
author_sort Ota, Kenji
collection PubMed
description 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.
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spelling pubmed-106182022023-11-02 Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions Ota, Kenji Nagao, Kazunori Hata, Dai Sugiyama, Haruki Segawa, Yasutomo Tokunoh, Ryosuke Seki, Tomohiro Miyamoto, Naoya Sasaki, Yusuke Ohmiya, Hirohisa Nat Commun Article 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. Nature Publishing Group UK 2023-10-31 /pmc/articles/PMC10618202/ /pubmed/37907473 http://dx.doi.org/10.1038/s41467-023-42639-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ota, Kenji
Nagao, Kazunori
Hata, Dai
Sugiyama, Haruki
Segawa, Yasutomo
Tokunoh, Ryosuke
Seki, Tomohiro
Miyamoto, Naoya
Sasaki, Yusuke
Ohmiya, Hirohisa
Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions
title Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions
title_full Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions
title_fullStr Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions
title_full_unstemmed Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions
title_short Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions
title_sort synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618202/
https://www.ncbi.nlm.nih.gov/pubmed/37907473
http://dx.doi.org/10.1038/s41467-023-42639-y
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