Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

TY - UNPB

T1 - Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

AU - Willems, Lianne Irene

AU - Murphy, Lloyd

AU - Huxley, Kathryn

AU - Wilding, Ava

AU - Robinson, Cyane

AU - Foucart, Quentin Pierre Olivier

PY - 2023/1/27

Y1 - 2023/1/27

N2 - Phosphates are regularly incorporated into bioactive small molecules, for example in sugar-1-phosphate derivatives that are used for metabolic oligosaccharide engineering. To enable efficient cellular uptake, the phosphate groups are commonly masked with biolabile S-acyl-2-thioethyl (SATE) protecting groups that are removed once the molecule is inside the cell. Typically, SATE-protected monophosphates are synthesised through phosphoramidite chemistry, which suffers from issues with hazardous and unstable reagents and can give unreliable yields. Here, we report the development of an alternative approach that makes use of an easy to synthesise tri(2-bromoethyl)phosphotriester precursor, providing access to bis-SATE-protected mixed phosphotriesters in two steps. We demonstrate the viability of our strategy on tetrabenzylated glucose as a model monosaccharide, onto which a bis-SATE-protected phosphate is introduced at either the anomeric position or at C6. We also show compability with various protecting groups and further explore the scope and limitations of the approach on different substrates, including N-acetylhexosamines and amino acid derivatives.

AB - Phosphates are regularly incorporated into bioactive small molecules, for example in sugar-1-phosphate derivatives that are used for metabolic oligosaccharide engineering. To enable efficient cellular uptake, the phosphate groups are commonly masked with biolabile S-acyl-2-thioethyl (SATE) protecting groups that are removed once the molecule is inside the cell. Typically, SATE-protected monophosphates are synthesised through phosphoramidite chemistry, which suffers from issues with hazardous and unstable reagents and can give unreliable yields. Here, we report the development of an alternative approach that makes use of an easy to synthesise tri(2-bromoethyl)phosphotriester precursor, providing access to bis-SATE-protected mixed phosphotriesters in two steps. We demonstrate the viability of our strategy on tetrabenzylated glucose as a model monosaccharide, onto which a bis-SATE-protected phosphate is introduced at either the anomeric position or at C6. We also show compability with various protecting groups and further explore the scope and limitations of the approach on different substrates, including N-acetylhexosamines and amino acid derivatives.

U2 - 10.26434/chemrxiv-2023-l45n1

DO - 10.26434/chemrxiv-2023-l45n1

M3 - Preprint

BT - Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

PB - ChemRxiv

ER -