Issue 45, 2023

Internucleotidic bond formation using H-phosphonamidate derivatives and acidic activators

Abstract

We previously developed a synthesis method for oligodeoxynucleotides using H-phosphonamidate derivatives as monomers. In this synthesis method, H-phosphonamidate monomers having a heterocyclic amino group as a leaving group reacts with an alcohol to form an internucleotidic H-phosphonate diester in pyridine without any additives upon heating. In this study, H-phosphonamidate reacted to form an internucleotidic linkage in the presence of acidic activators at room temperature. This finding is the first example of the activation of an amino group of an H-phosphonamidate derivative in the presence of acidic activators. In addition, the condensation reaction with acidic activators was accelerated with the use of pyridine as a solvent. Moreover, heterocyclic amino groups that have an electronegative atom, such as S and O, effectively served as a leaving group of the H-phosphonamidate monomer. From the results, we hypothesized that the tautomerization to the phosphite-form of the H-phosphonamidate monomer is an important step of the condensation reaction using acidic activators, and such process is accelerated when using pyridine as the solvent and heterocyclic amino groups as the leaving groups of the H-phosphonamidate monomer. Molecular orbital calculations also support our hypothesis. We optimized the condensation reaction conditions and synthesized dinucleoside phosphorothioate derivatives bearing all nucleobases.

Graphical abstract: Internucleotidic bond formation using H-phosphonamidate derivatives and acidic activators

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Article information

Article type
Paper
Submitted
12 Sep 2023
Accepted
21 Oct 2023
First published
30 Oct 2023
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2023,13, 31674-31686

Internucleotidic bond formation using H-phosphonamidate derivatives and acidic activators

T. Tsurusaki, K. Sato and T. Wada, RSC Adv., 2023, 13, 31674 DOI: 10.1039/D3RA06193K

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