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.

Keywords: DNA; green chemistry; mechanochemistry; nucleoside; nucleotide.

Figure 1

Examples of equipment used to perform mechanochemistry on nucleoside and nucleotide substrates (not to scale). a) Mixer ball mill; b) mortar grinder; c) improvised attritor [19]. Figures a) and b) are reused with the permission of Retsch (https://www.retsch.com); c) is adapted with permission from [19], copyright 2006 American Chemical Society.

Figure 2

Ganciclovir.

Scheme 1

Nucleoside tritylation effected by hand grinding in a heated mortar and pestle.

Scheme 2

Persilylation of ribonucleoside hydroxy groups (and in situ acylation of cytidine) in a MBM.

Scheme 3

Nucleoside amine and carboxylic acid Boc protection using an improvised attritor-type mill.

Scheme 4

Nucleobase Boc protection via transient silylation using an improvised attritor-type mill.

Scheme 5

Chemoselective N-acylation of an aminonucleoside using LAG in a MBM.

Scheme 6

Azide–alkyne cycloaddition reactions performed in a copper vessel in a MBM.

Figure 3

a) Custom-machined copper vessel and zirconia balls used to perform CuAAC reactions (showing: upper half of vessel with PTFE insert (front), pristine ZrO₂ ball, used ZrO₂ ball and lower half of vessel showing deformation of the metal). b) Crude solid ball mill click reaction mixture after removal from copper vessel (left) and during extraction of pure product with DMSO (right).

Scheme 7

Thiolate displacement reactions of nucleoside derivatives in a MBM.

Scheme 8

Selenocyanate displacement reactions of nucleoside derivatives in a MBM.

Scheme 9

Nucleobase glycosidation reactions and subsequent deacetylation performed in a MBM.

Scheme 10

Regioselective phosphorylation of nicotinamide riboside in a MBM.

Scheme 11

Preparation of nucleoside phosphoramidites in a MBM using ionic liquid-stabilised chlorophosphoramidites (route A) or phosphorodiamidites (route B).

Scheme 12

Preparation of a nucleoside phosphite triester using LAG in a MBM.

Scheme 13

Internucleoside phosphate coupling linkages in a MBM.

Scheme 14

Preparation of ADPR analogues using in a MBM.

Scheme 15

Synthesis of pyrophosphorothiolate-linked dinucleoside cap analogues in a MBM to effect hydrolytic desilylation and phosphate coupling.

Figure 4

Early low temperature mechanised ball mill as described by Mudd et al. – adapted from reference [78].

Scheme 16

Co-crystal grinding of alkylated nucleobases in an amalgam mill (N.B. no frequency was recorded in the experimental description).

Figure 5

Materials used to prepare a smectic phase.

Figure 6

Structures of 5-fluorouracil (5FU) and nucleoside analogue prodrugs subject to mechanochemical co-crystal or polymorph transformation.

Scheme 17

Preparation of DNA-SWNT complex in a MBM.