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

Abstract

SummaryA 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.

Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers

“…To incorporate 4-substituents with more than one hydroxyl group in the cyclopentane ring as in the putative IKKα selective inhibitor NAM, 17 we prepared the diol 30 and triol 31 . 31 The synthesis of 30 began with bromination 32 of cyclopentene 32 to produce the unstable halide 33 , which was immediately treated with N , N -dibenzylamine. The resulting allylic amine 34 underwent syn -dihydroxylation to afford the diol 35 ( 33 ) with excellent diastereoselectivity, which was then protected as the dibenzoate 36 .…”

“…Compounds 23 – 29 were prepared from commercially available amines using the procedure detailed in Scheme . To incorporate 4-substituents with more than one hydroxyl group in the cyclopentane ring as in the putative IKKα selective inhibitor NAM, we prepared the diol 30 and triol 31 . The synthesis of 30 began with bromination of cyclopentene 32 to produce the unstable halide 33 , which was immediately treated with N , N -dibenzylamine.…”

“…Chromatographic purification (Biotage SP4, 50g cartridge, solvent system: MeOH/CHCl 3 ; gradient 0% 4CV, 0−15% 14CV, 15% 4CV) yielded 30 (33 mg, 42%) as a white solid. 1 2-Amino-4-((1R,2S,3R,4S)-2,3,4-trihydroxycyclopentylamino)-7Hpyrrolo [2,3-d]pyrimidine-5-carbonitrile (31). 5 (70 mg, 0.25 mmol), 42 (146 mg, 0.30 mmol), and Et 3 N (0.08 mL, 61 mg, 0.60 mmol) were suspended in n-BuOH (4 mL) and refluxed for 16 h. After cooling to room temperature, EtOH (4 mL) and KOH (3 pellets) were added and the reaction mixture was heated at 80 °C for 20 h. The mixture was neutralized using 6 M HCl and subsequently concentrated in vacuo.…”

Synthesis and Anti‐HIV Activity of Guanine Modified Fluorinated Acyclic Nucleoside Phosphonate Derivatives

“…[19] Formylation of 15 with methyl formate resulted in the formation of the unstable chloroaldehyde 16, which was immediately used in the next step without further purification to afford the cyclocondensation product 17. [19] Formylation of 15 with methyl formate resulted in the formation of the unstable chloroaldehyde 16, which was immediately used in the next step without further purification to afford the cyclocondensation product 17.…”

“…The heterocyclic building block 19 was available in four steps from chloroacetonitrile 15 according to a literature procedure (Scheme 3). [19] Formylation of 15 with methyl formate resulted in the formation of the unstable chloroaldehyde 16, which was immediately used in the next step without further purification to afford the cyclocondensation product 17. Then, the exocyclic amino group of compound 17 was protected using pivaloyl chloride, while the subsequent chlorination was accomplished with POCl 3 in the presence of a phase transfer catalyst to give the desired chlorointermediate 19.…”