Investigations into the synthesis of a nucleotide dimer via mechanochemical phosphoramidite chemistry

Johnston, Christopher; Hardacre, Christopher; Migaud, Marie E.

doi:10.1098/rsos.201703

Cited by 8 publications

(11 citation statements)

References 26 publications

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“…For this specific reaction, better outcomes have been achieved with anhydrous MeCN than anhydrous DCM (Johnston et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

“…The second critical parameter for consideration is the volume and type of solvent within the milling vessel. When the reaction was attempted using solventless conditions (Johnston et al., 2021), only finely milled solids were observed in the milling vessel after completion of the milling reaction. This observation is due to poor mass transfer and contact between reactants and is thus indicative of poor reaction outcomes.…”

Section: Commentarymentioning

confidence: 99%

“…If high levels of 3 form in reactions A and B, it is not possible to conclude whether the reactions occurred during ball-milling or following addition of the deuterated solvent. If reaction A shows high levels of 3 but reaction B shows high levels of 5, this is indicative that the ball-milling step was essential for formation of 3 and the reaction did not occur as a result of the deuterated solvent (Johnston et al, 2021).…”

Section: Confirmation Of the Efficacy Of Mechanochemical Conditionsmentioning

confidence: 99%

“…Although mechanochemical reactions are rarely performed under a dry and/or inert atmosphere, mechanochemistry by ball‐milling has been reported to be useful for some reactions that would normally be performed under anhydrous conditions (Bowmaker & Hanna, 2009). Mechanochemical methodologies have recently been applied to nucleoside couplings by means of the phosphoramidite method (Johnston, Hardacre, & Migaud, 2021; Thorpe, O'Reilly, Friščić, & Damha, 2020). The protocol described below is based on our previously reported solvent‐assisted methodology (Johnston et al., 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Mechanochemical methodologies have recently been applied to nucleoside couplings by means of the phosphoramidite method (Johnston, Hardacre, & Migaud, 2021; Thorpe, O'Reilly, Friščić, & Damha, 2020). The protocol described below is based on our previously reported solvent‐assisted methodology (Johnston et al., 2021). Mechanochemistry presents substantial advantages to oligonucleotide synthesis as it offers a means to reduce hydrolysis of phosphoramidite reagents and thus allows for a reduction in the equivalents of reagents used.…”

Section: Introductionmentioning

confidence: 99%

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Solvent‐Assisted Mechanochemical Synthesis of a Nucleotide Dimer

Johnston

Migaud

2022

Current Protocols

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This article contains a synthetic protocol for solvent‐assisted mechanochemical synthesis of a nucleotide dimer. First, a dinucleoside phosphite is prepared by solvent‐assisted mechanochemistry via the phosphoramidite method. Second, the dinucleoside phosphite is oxidized to form the dinucleotide under mechanochemical conditions. Finally, the dinucleotide is purified by column chromatography. Support protocols are also provided for preparing the acidic salts that can be utilized for phosphoramidite couplings and for demonstrating that the reaction occurs under mechanochemical conditions rather than as a result of solvent added for analysis. Mechanochemistry as applied to synthesis of dinucleotides is a recent development and it is anticipated that the principles in this protocol will be widely applicable to a range of nucleoside and ribonucleoside monomers. The advantages of mechanochemistry over traditional solution‐phase chemistry are the simplicity of the procedure, improved hydrolytic stability, and elimination of the need to solubilize poorly soluble compounds. © 2022 Wiley Periodicals LLC. Basic Protocol: Solvent‐assisted mechanochemical synthesis of a nucleotide dimer Supplementary Protocol 1: Synthesis of N‐methylimidazolium triflate Supplementary Protocol 2: Synthesis of pyridinium trifluoroacetate Supplementary Protocol 3: Confirmation of the efficacy of mechanochemical conditions

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“…For this specific reaction, better outcomes have been achieved with anhydrous MeCN than anhydrous DCM (Johnston et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

Section: Commentarymentioning

confidence: 99%

Section: Confirmation Of the Efficacy Of Mechanochemical Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Solvent‐Assisted Mechanochemical Synthesis of a Nucleotide Dimer

Johnston

Migaud

2022

Current Protocols

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Ball‐Milling to Access Dinucleoside Polyphosphates and Analogues

Navarro,

Vasco,

Bantreil

et al. 2024

Adv Synth Catal

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Dinucleoside 5’,5’‐polyphosphates (NpnNs) play essential roles in various biological processes. Access to these high value‐added compounds, while avoiding the many drawbacks of solution phase synthesis, is a challenge that has been overcome thanks to mechanochemistry. A straightforward solid‐state synthesis based on activation of phosphate or pyrophosphate sodium salts to their diimidazolides, followed by coupling with commercially available nucleotides, under air conditions, gave symmetrical NpnNs. The scope ranged from Np3Ns to highly challenging Np6Ns. The methodology has also been implemented using medronic acid and imidodiphosphate to obtain NpnNs analogues, some of which are unprecedented.

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Mechanochemical Synthesis of Boroxine‐linked Covalent Organic Frameworks

Hamzehpoor,

Effaty,

Borchers

et al. 2024

Angewandte Chemie

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We report a rapid, room‐temperature mechanochemical synthesis of 2‐ and 3‐dimensional boroxine covalent organic frameworks (COFs), enabled by using trimethylboroxine as a dehydrating additive to overcome the hydrolytic sensitivity of boroxine‐based COFs. The resulting COFs display high porosity and crystallinity, with COF‐102 being the first example of a mechanochemically prepared 3D COF, exhibiting a surface area of ca. 2,500 m2 g–1. Mechanochemistry enabled a >20‐fold reduction in solvent use and ~100‐fold reduction in reaction time compared with solvothermal methods, providing target COFs quantitatively with no additional work‐up besides vacuum drying. Real‐time Raman spectroscopy permitted the first quantitative kinetic analysis of COF mechanosynthesis, while transferring the reaction design to Resonant Acoustic Mixing (RAM) enabled synthesis of multi‐gram amounts of the target COFs (tested up to 10 g).

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Investigations into the synthesis of a nucleotide dimer via mechanochemical phosphoramidite chemistry

Cited by 8 publications

References 26 publications

Solvent‐Assisted Mechanochemical Synthesis of a Nucleotide Dimer

Solvent‐Assisted Mechanochemical Synthesis of a Nucleotide Dimer

Ball‐Milling to Access Dinucleoside Polyphosphates and Analogues

Mechanochemical Synthesis of Boroxine‐linked Covalent Organic Frameworks

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