3-Bromopyrazolo[3,4-d]pyrimidine 2‘-Deoxy-2‘-fluoro-β-d-arabinonucleosides: Modified DNA Constituents with an Unusually Rigid SugarN-Conformation

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Abstract
The nucleobase anion glycosylation of 3-bromo-4-isopropoxy-1H-pyrazolo[3,4-d]pyrimidin-6-amine (6) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-d-arabinofuranosyl bromide (5) furnished the protected N1-β-d-nucleosides 7 (60%) and 8 (ca. 2%) along with the N2-β-d-regioisomer 9 (9%). Debenzoylation of compounds 7 and 9 yielded the nucleosides 10 (81%) and 11 (76%). Compound 10 was transformed to the 2‘-deoxyguanosine derivative 1 [6-amino-3-bromo-1-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4-one] (85% yield) and the purine-2,6-diamine analogue 2 [3-bromo-1-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4, 6-diamine] (78%). Both nucleosides form more than 98% N-conformer population (PN ca. 358° and ψm ca. 37°) in aqueous solution. Single-crystal X-ray analysis of 1 showed that the sugar moiety displays also the N-conformation [P = 347.3° and ψm = 34.4°] in the solid state. The remarkable rigid N-conformation of the pyrazolo[3,4-d]pyrimidine 2‘-deoxy-2‘-fluoro-β-d-arabinonucleosides 1 and 2 observed in solution is different from that of the parent purine 2‘-deoxy-2‘-fluoro-β-d-arabinonucleosides 3 and 4, which are in equilibrium showing almost equal distribution of the N/S-conformers.

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