6-Azauracil or 8-aza-7-deazaadenine nucleosides and oligonucleotides: the effect of 2′-fluoro substituents and nucleobase nitrogens on conformation and base pairing

Organic & Biomolecular Chemistry Pub Date: 2008-01-02 DOI: 10.1039/B715512C

Abstract

The stereoselective syntheses of 6-azauracil- and 8-aza-7-deazaadenine 2′-deoxy-2′-fluoro-β-D-arabinofuranosides 1c and 2c employing nucleobase anion glycosylation with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide 6 as the sugar component are described; the 6-azauracil 2′-deoxy-2′-fluoro-β-D-ribofuranoside 1d was prepared from 6-azauridine 8via the 2,2′-anhydro intermediate 9 and transformation of the sugar with DAST. Compounds show a preferred N-conformer population (100% N for 1c, 1d and 78% N for 2c) being rather different from nucleosides not containing the combination of a fluorine atom at the 2′-position and a nitrogen next to the glycosylation site. Oligonucleotides incorporating 1c and 2c were synthesized using the phosphoramidites 3b and 4. Although the N-conformation is favoured in the series of 6-azauracil- and 8-aza-7-deazaadenine 2′-deoxy-2′-fluoroarabinonucleosides only the pyrimidine compound 1c shows an unfavourable effect on duplex stability, while oligonucleotide duplexes containing the 8-aza-7-deazaadenine-2′-deoxy-2′-fluoroarabinonucleoside 2c were as stable as those incorporating dA or 8-aza-7-deaza-2′-deoxyadenosine 2a.

Graphical abstract: 6-Azauracil or 8-aza-7-deazaadenine nucleosides and oligonucleotides: the effect of 2′-fluoro substituents and nucleobase nitrogens on conformation and base pairing
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