Mechanochemistry of nucleosides, nucleotides and related materials

Abstract

The application of mechanical force to induce the formation and cleavage of covalent bonds is a rapidly developing field within organic chemistry which has particular value in reducing or eliminating solvent usage, enhancing reaction rates and also in enabling the preparation of products which are otherwise inaccessible under solution-phase conditions. Mechanochemistry has also found recent attention in materials chemistry and API formulation during which rearrangement of non-covalent interactions give rise to functional products. However, this has been known to nucleic acids science almost since its inception in the late nineteenth century when Miescher exploited grinding to facilitate disaggregation of DNA from tightly bound proteins through selective denaturation of the latter. Despite the wide application of ball milling to amino acid chemistry, there have been limited reports of mechanochemical transformations involving nucleoside or nucleotide substrates on preparative scales. A survey of these reactions is provided, the majority of which have used a mixer ball mill and display an almost universal requirement for liquid to be present within the grinding vessel. Mechanochemistry of charged nucleotide substrates, in particular, provides considerable benefits both in terms of efficiency (reducing total processing times from weeks to hours) and by minimising exposure to aqueous conditions, access to previously elusive materials. In the absence of large quantities of solvent and heating, side-reactions can be reduced or eliminated. The central contribution of mechanochemistry (and specifically, ball milling) to the isolation of biologically active materials derived from nuclei by grinding will also be outlined. Finally non-covalent associative processes involving nucleic acids and related materials using mechanochemistry will be described: specifically, solid solutions, cocrystals, polymorph transitions, carbon nanotube dissolution and inclusion complex formation.

Prebiotic Sugar Formation Under Nonaqueous Conditions and Mechanochemical Acceleration

“…In this respect, only a scarce number of mechanochemical approaches [31,32] have been identified so far that plausibly demonstrate the formation of biologically relevant molecules when only grinding or milling of dry substrates is used to trigger reactivity. Such examples include the synthesis of α-amino acid derivatives [33,34] and modification of nucleosides and nucleotides [35]. Sources for mechanochemical energy considered are lithospheric activities such as weathering, erosion, diagenetic processes and meteoritic impacts on Earth.…”

Synthetic Strategies for Dinucleotides Synthesis

“…Moreover, protecting groups on the nucleotide are not required and no carbonation of ribonucleotides are observed, in contrast to the use of CDI. Alternatively, mechanochemistry has emerged in the field of nucleosides and, to a lesser extent, nucleotides [86]. This technique enables solid/solid reactions through mechanical grinding under solvent-free conditions [87][88][89][90][91].…”

Solid-phase synthesis and structural characterisation of phosphoroselenolate-modified DNA: a backbone analogue which does not impose conformational bias and facilitates SAD X-ray crystallography

“…5 0 -Deoxythymidine-5 0 -selenocyanate has been prepared on small scales in solution over 24 hours 59 or using liquid assisted grinding over 9-11 hours. 60,61 In order to prepare this material more efficiently, we therefore examined the application of microwaves which has been reported to enhance the rate of Sselective alkylation of the thiocyanate anion. 62 In the presence of excess potassium selenocyanate, clean transformation of 5 0tosylthymidine (1) into the corresponding 5 0 -selenocyanate (2) was observed within 90 minutes following irradiation (20 W, 100 C) of the stirred reaction mixture in acetonitrile (Scheme 1).…”