One‐Pot Synthesis of Nucleotides and Conjugates in Aqueous Medium

Abstract

Herein, we describe a one‐pot synthesis, in a mixture of water/acetonitrile, of nucleoside 5′‐polyphosphates and some derivatives starting from their corresponding nucleoside 5′‐monophosphates. Phosphorimidazolide intermediates are formed in the presence of imidazole and 2‐chloro‐1,3‐dimethylimidazolinium hexafluorophosphate. Under these mild conditions, nucleoside 5′‐di‐ and 5′‐triphosphates, dinucleoside 5′,5′‐polyphosphates, as well as some nucleotide analogues modified either on the nucleoside or on the phosphate moieties are obtained in moderate to high yields.

Synthetic Strategies for Dinucleotides Synthesis

“…While these methods involving phosphoromidazolides are straightforward and rapid, they all require dry conditions to prevent side-product formation and most often, use trialkylammonium salts. To avoid this drawback, our research group has recently developed a one-pot synthesis of dinucleotides, either in aqueous solution or mechanochemically, through the use of phosphorimidazolides intermediates [55,56]. These strategies will be detailed in Section 5 and are related to green chemistry approaches.…”

“…In 2017, our research group reported a one-pot synthesis, in water medium, of nucleoside 5 -polyphosphates and dinucleotides starting from the corresponding NMPs [55,56]. This method uses 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (DMP) and imidazole as coupling reagents to activate the NMP into their phosphorimidazolides.…”

“…The authors performed the coupling of a sugar-1-phosphate with a nucleotide in D2O, using 2chloro-1,3-dimethylimidazolinium chloride (DMC) and imidazole (Scheme 28). Based on 1 H and 31 P NMR spectroscopies, the reaction was shown to proceed via a 2-imidazolyl-1, 3 The main advantage of these reactions, which occur in D2O [85] or in H2O/CH3CN [55,56] instead of the usual organic solvents, is that the NMPs are used in their commercially available and watersoluble forms, i.e., sodium and potassium salts. This greatly simplifies the handling of the reaction.…”

“…This greatly simplifies the handling of the reaction. The main advantage of these reactions, which occur in D 2 O [85] or in H 2 O/CH 3 CN [55,56] instead of the usual organic solvents, is that the NMPs are used in their commercially available and water-soluble forms, i.e., sodium and potassium salts. This greatly simplifies the handling of the reaction.…”

“…In the course of our investigations on new strategies for phosphoanhydride bond formation, we also investigated the ball-milling technique [93]. To begin with, activation of UMP was performed according to the conditions previously reported in water medium (DMP/imidazole) [55,56], without adding any solvent in a vibratory ball-mill (vbm) at 30 Hz. A complete conversion to Up 2 U was obtained within 30 min, suggesting that UMP was activated to its phosphorimidazolide and reacted promptly with the remaining UMP to form the dimer.…”