THE N-7 REGIOISOMER OF 2-CHLORO-2'-DEOXYADENOSINE - SYNTHESIS, CRYSTAL-STRUCTURE, CONFORMATION, AND STABILITY

The nucleoside amino-2-chloro-7-(2-deoxy-beta-D-erythro-7H-purine 7 is readily accessible in two steps from 2,6-dichloropurine. The crystal structure of this unusual nucleoside reveals a bifurcated intramolecul ar 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: chi=67.0 de grees. Semi-empirical calculations using AM1 parameters and optimisati on of atomic co-ordinates derived from the crystal structure of 7 sugg est 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 (Delta H-f). NOE experiments in (CD3)(2)SO solution support the theore tical results indicating the presence of both syn and anti conformatio ns and that the anti population is marginally favoured. The antileukae mic agent 2-chloro-2'-deoxyadenosine (6), the N-9 regioisomer of 7, wa s shown to be 9.6 kcal mol(-1) more stable than 7. The increased stabi lity of 6 over 7 seems attributable mainly to the relative stability o f the aglycon tautomers 8 and 9, the energy difference between these b eing 6.7 kcal mol(-1) in favour of the 9 H tautomer 8. Likewise, remov al of the 2-chloro substituent has little effect on the tautomerism.