Willems, Lianne Irene orcid.org/0000-0001-5411-1329, Murphy, Lloyd, Huxley, Kathryn et al. (3 more authors) (2023) Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor. Chemical Science. ISSN 2041-6539
Abstract
Robust methods for the synthesis of mixed phosphotriesters are essential to accelerate the development of novel phosphate-containing bioactive molecules. To enable efficient cellular uptake, phosphate groups are commonly masked with biolabile protecting groups, such as S-acyl-2-thioethyl (SATE) esters, that are removed once the molecule is inside the cell. Typically, bis-SATE-protected phosphates are synthesised through phosphoramidite chemistry. This approach, however, suffers from issues with hazardous reagents and can give unreliable yields, especially when applied to the synthesis of sugar-1-phosphate derivatives as tools for metabolic oligosaccharide engineering. Here, we report the development of an alternative approach that gives access to bis-SATE phosphotriesters in two steps from an easy to synthesise tri(2-bromoethyl)phosphotriester precursor. We demonstrate the viability of this strategy using glucose as a model substrate, onto which a bis-SATE-protected phosphate is introduced either at the anomeric position or at C6. We show compability with various protecting groups and further explore the scope and limitations of the methodology on different substrates, including N-acetylhexosamine and amino acid derivatives. The new approach facilitates the synthesis of bis-SATE-protected phosphoprobes and prodrugs and provides a platform that can boost further studies aimed at exploring the unique potential of sugar phosphates as research tools.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 The Author(s). |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number EUROPEAN COMMISSION 851448 |
Depositing User: | Pure (York) |
Date Deposited: | 26 Apr 2023 11:50 |
Last Modified: | 17 Dec 2024 00:25 |
Published Version: | https://doi.org/10.1039/D3SC00693J |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1039/D3SC00693J |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:198629 |
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Filename: d3sc00693j.pdf
Description: Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor
Licence: CC-BY-NC 2.5