Straightforward Ball‐Milling Access to Dinucleoside 5′,5′‐Polyphosphates via Phosphorimidazolide Intermediates

Abstract

A solvent‐assisted mechanochemical approach to access symmetrical and mixed dinucleoside 5,5′‐polyphosphates is reported. Under ball‐milling conditions, nucleoside 5′‐monophosphates were quantitatively activated using 1,1′‐carbonyldiimidazole, forming their phosphorimidazolide derivatives. The addition of a nucleoside 5′‐mono‐, di‐ or triphosphate directly led to the formation of the corresponding dinucleotides. Benefits of the reported one‐pot method include the use of unprotected nucleotides in their sodium or acid form, activation by the eco‐friendly 1,1′‐carbonyldiimidazole, non‐dry conditions, short reaction time, high conversion rates, and easy setup and purification. This work offers new perspectives for the synthesis of nucleotide conjugates and analogues, combining the phosphorimidazolide approach and milling conditions.

The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

“…In this regards, mechanochemical milling is less affected by solvent conditions as bulk chemistry and thus it makes possible the synthesis of moisture sensitive compounds, without requiring inert atmosphere conditions necessary for their synthesis in solution. In this framework, mechanochemical approaches have been recently investigated for the straightforward synthesis of a wide range of biomolecules: amino acids [ 8 ], peptides [ 9 ], glycosides [ 10 ], nucleosides/nucleotides [ 11 ], and lipids [ 12 ]. Also, protein-based nano-bio-conjugates [ 13 ] have been prepared by ball milling, retaining the native properties of the proteins after mechanochemical synthesis.…”

Recent Advances in Mechanochemical Organic Synthesis

“…Among the reactions for the formation of other types of bonds which were not previously carried in ball milling conditions are C▬P bond by phosphonylation with MnOAc [63], O▬P phosphate nucleoside bond using CDI [64], S▬P bond via Arbuzov reaction [65], C▬B bond by borylation using Ir catalyst [66], and P▬S and P▬Se bond formation by milling of phosphines with S and Se [67]. A recent example of mechanochemical enantioselective reactions is the fluorination of aliphatic cyclic and acyclic β-keto esters using N-fluorobenzenesulfonimide with the aid of chiral oxazoline copper catalysts (Figure 15) [68].…”

Synthetic Strategies for Dinucleotides Synthesis

“…Although advantageous, this methodology requires the use of costly reagents, namely tetrazole and the phosphoromorpholidate substrate, the latter may be prepared beforehand in solution using conventional solution synthesis [45]. 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.…”

“…This activation step was applied successfully to several ribonucleotides and a 2′-deoxyribonucleotide (dTMP). 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.…”