3-Bromopyrazolo[3,4-d]pyrimidine 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides: modified DNA constituents with an unusually rigid sugar N-conformation.
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-alpha-d-arabinofuranosyl bromide (5) furnished the protected N(1)-beta-d-nucleosides 7 (60%) and 8 (ca. 2%) along with the N(2)-beta-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-beta-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-beta-d-arabinofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4, 6-diamine] (78%). Both nucleosides form more than 98% N-conformer population (P(N) ca. 358 degrees and psi(m) ca. 37 degrees ) in aqueous solution. Single-crystal X-ray analysis of 1 showed that the sugar moiety displays also the N-conformation [P = 347.3 degrees and psi(m) = 34.4 degrees ] in the solid state. The remarkable rigid N-conformation of the pyrazolo[3,4-d]pyrimidine 2'-deoxy-2'-fluoro-beta-d-arabinonucleosides 1 and 2 observed in solution is different from that of the parent purine 2'-deoxy-2'-fluoro-beta-d-arabinonucleosides 3 and 4, which are in equilibrium showing almost equal distribution of the N/S-conformers.
He
Junlin
J
Laboratorium für Organische und Bioorganische Chemie, Institut für Chemie, Universität Osnabrück, Barbarastrasse 7, D-49069 Osnabrück, Germany.
Mikhailopulo
Igor
I
Seela
Frank
F
D001087:Arabinonucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D012996:Solutions
D001087:Arabinonucleosides; D011741:Pyrimidine Nucleosides; D012996:Solutions