Mechanochemical Synthesis of Short DNA Fragments |
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Authors: | James D Thorpe Dr Daniel O'Reilly Prof Tomislav Friščić Prof Masad J Damha |
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Institution: | 1. Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, H3A 0B8 Canada
These authors contributed equally to this work.;2. Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, H3A 0B8 Canada |
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Abstract: | We demonstrate the first mechanochemical synthesis of DNA fragments by ball milling, enabling the synthesis of oligomers of controllable sequence and length using multi-step, one-pot reactions, without bulk solvent or the need to isolate intermediates. Mechanochemistry allowed for coupling of phosphoramidite monomers to the 5′-hydroxyl group of nucleosides, iodine/water oxidation of the resulting phosphite triester linkage, and removal of the 5′-dimethoxytrityl (DMTr) protecting group in situ in good yields (up to 60 % over three steps) to produce DNA dimers in a one-pot manner. H-Phosphonate chemistry under milling conditions enabled coupling and protection of the H-phosphonate linkage, as well as removal of the 5′-DMTr protecting group in situ, enabling a one-pot process with good yields (up to 65 % over three steps, or ca. 87 % per step). Sulfurization of the internucleotide linkage was possible using elemental sulfur (S8) or sulfur transfer reagents, yielding the target DNA phosphorothioate dimers in good yield (up to 80 % over two steps). This work opens the door to creation of solvent-free synthesis methodologies for DNA and RNA therapeutics. |
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Keywords: | DNA green chemistry H-phosphonate mechanochemistry phosphoramidite |
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