The N-7 Regioisomer of 2-Chloro-2′-deoxyadenosine: Synthesis, Crystal Structure, Conformation, and Stability.

Abstract 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 ( ΔH f ). NOE experiments in (CD 3 ) 2 SO 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 9 H tautomer 8 . Likewise, removal of the 2-chloro substituent has little effect on the tautomerism.