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

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: X = 67.0°. 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− in heat of formation (ΔHf). 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− 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 these being 6.7 kcal mol− in favour of the 9H tautomer 8. Likewise, removal of the 2-chloro substituent has little effect on the tautomerism.