Arabinose Conformations of 9-β -ᴅ-Arabinofuranosyladenine (ARA-A) Analogues Modified at the 2',3' or 5' Positions

Abstract

The solution conformations of 9-β-ᴅ-arabinofuranosyladenine analogues modified at the 2′,3′ or 5′ positions are derived from the HRNMR spectra and the longitudinal relaxation rates of the protons. The compounds studied are: 9-β-ᴅ-arabinofuranosyladenine and its 2′-amino-2′-deoxy, 2′-chloro-2′-deoxy, 2′-azido-2/-deoxy, 3′-amino-3′-deoxy, 3′-bromo-3′-deoxy, 3′-chloro-3′- deoxy, 3′-fluoro-3′-deoxy, 3r-azido-3′-deoxy, 2,,3,-diamino-2′,3′-dideoxy, 2′,5′-diamino-2′,5′-di- deoxy and 2′,5′-diazido-2′,5′-dideoxy analogues. It is derived from the data that the conforma­tional equilibria of the furanoside rings can be described by the two state N ⇔ 5 model of Altona and Sundaralingam. The emphasis in this work is to study systematically the influence of the different chemical modifications upon the conformational equilibria of the nucleosides. For the arabinosides it is found that substitution of the hydroxyl groups at C2′ or C3′ by other atoms or groups always stabilizes the N conformation oi the araoinose ring. The only exception is fluorine, where S is stabilized. The preference for the N state is correlated with an increasing population of the g+ rotamer of the exocyclic 5′-CH2OD group. From the relaxation study of 2′-chloro-2′-deoxy- arabinofuranosyladenine the position of the syn ⇔ anti equilibrium of the base was estimated to be predominantly anti. Thus a preference for the anti-N-g+ conformation was derived for the arabinosides excluding an intramolecular hydrogen bond between the 2′ and 5′ hydroxyl groups that was found in the solid state. The stabilization of the N conformer in the modified compounds can be qualitatively explained by steric effects.