The N-7 regioisomer of 2-chloro-2'-deoxyadenosine: synthesis, crystal structure, conformation, and stability

Article abstract of DOI:10.1016/0008-6215(95)00168-S

The nucleoside 6-amino-2-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-purine 7 is readily accessible in two steps from 2,6-dichloropurine.The crystal structure of this unusual nucleoside reveals a bifurcated intramolecular hydrogen bond from the amino group to the O-5' with a weaker branch to the O-4' which imposes a syn glycosidic torsion angle: χ=67.0 deg.Semi-empirical calculations using AM1 parameters and optimisation of atomic co-ordinates derived from the crystal structure of 7 suggest that the molecule can adopt either anti or syn conformations with a slight preference for anti by 0.4 kcal mol^-1 in heat of formation (ΔH_f).NOE experiments in (CD3)2SO solution support the theoretical results indicating the presence of both syn and anti conformations and that the anti population is marginally favoured.The antileukaemic agent 2-chloro-2'-deoxyadenosine (6), the N-9 regioisomer of 7, was shown to be 9.6 kcal mol^-1 more stable than 7.The increased stability of 6 over 7 seems attributable mainly to the relative stability of the aglycon tautomers 8 and 9, the energy difference between thase being 6.7 kcal mol^-1 in favour of the 9H tautomer 8.Likewise, removal of the 2-chloro substituent has little effect on the tautomerism. Keywords: N-7 nucleoside; X-ray structure; semi-empirical; Conformation; NOE