Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• such reactive preQ1 and (2,6-diamino-7-aminomethyl-7-deazapurine) DPQ1 ligands. The readily accessible key intermediates of preQ0 and DPQ0 (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 preQ0 and DPQ0 that allow for cleaner and faster access to preQ1 compared to existing routes and provide the

• -diaminopyrimidin-4(3H)-one to afford preQ0 (7), as originally reported by Townsend et al. [30]. The next step, namely the reduction of the nitrile moiety by hydrogenation is critical and notoriously difficult due to the low reactivity of this group in preQ0 [26]. We solved this problem by applying strongly acidic

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• residue in huimycin and to a 2-[4'-(4''-O-methyl-ß-ᴅ-glucopyranosyl)-6'-deoxy-α-ᴅ-glucopyranosyl] moiety in dapiramicin A [19][20]. In the biosynthetic pathway, the conversion of preQ0 into huimycin requires methylation of preQ0 and attachment of the N-acetylglucosamine moiety as final steps [18]. The

• natural sources. Earlier syntheses of preQ1, preQ0 and m6preQ0 The synthesis of preQ1 has been first described by Goto starting from 2-methylthio-6-methoxy-7-methyl-7-deazapurine and requiring more than ten steps [21]. More efficient was a procedure reported by Nishimura applying a Mannich reaction with

• following published procedures. Chloroacetonitrile and methyl formate gave 2-chloro-2-cyanoacetaldehyde which was then reacted with 2,6-diaminopyrimidin-4-one to provide preQ0 in good yields [31]. Protection of the exocyclic amino group using pivaloyl chloride was optimized from a published procedure [32

Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ₀)

• Sabin Llona-Minguez and
• Simon P. Mackay

Beilstein J. Org. Chem. 2014, 10, 1333–1338, doi:10.3762/bjoc.10.135

• & Biophysics, Karolinska Institutet, Stockholm, S-171 21, Sweden 10.3762/bjoc.10.135 Abstract A convergent and stereoselective synthesis of chiral cyclopentyl- and cyclohexylamine derivatives of nucleoside Q precursor (PreQ0) has been accomplished. This synthetic route allows for an efficient preparation of 4

• -substituted analogues with interesting three-dimensional character, including chiral cyclopentane-1,2-diol and -1,2,3-triol derivatives. This unusual substitution pattern provides a useful starting point for the discovery of novel bioactive molecules. Keywords: diol synthesis; nucleoside; PreQ0

• pharmacological profiles including antibacterial, antiviral and anticancer properties [2][3][4]. Nucleoside Q precursor (PreQ0) 1 is a common precursor in the biosynthesis of queuosine (Q, 2) and archaeosine (G+, 3), two hyper-modified nucleosides present in the tRNA of prokaryote/eukaryote and euryarchaeota