Synthesis of electrophile-tethered preQ analogs for covalent attachment to preQ RNA.

The preQ cIass-I riboswitch aptamer can utilize 7-aminomethyl-7-deazaguanine (preQ) ligands that are equipped with an electrophilic handle for the covalent attachment of the ligand to the RNA. The simplicity of the underlying design of irreversibly bound ligand-RNA complexes has provided a new impetus in the fields of covalent RNA labeling and RNA drugging. Here, we present short and robust synthetic routes for such reactive preQ and (2,6-diamino-7-aminomethyl-7-deazapurine) DPQ ligands. The readily accessible key intermediates of preQ and DPQ (both bearing a nitrile moiety instead of the aminomethyl group) were reduced to the corresponding 7-formyl-7-deazapurine counterparts. These readily undergo reductive amination to form the hydroxyalkyl handles, which were further converted to the haloalkyl or mesyloxyalkyl-modified target compounds. In addition, we report hydrogenation conditions for preQ and DPQ that allow for cleaner and faster access to preQ compared to existing routes and provide the novel compound DPQ.