O5′,6-Methanocytidine — Synthesis, Conformational Properties and Deamination by Cytidine Deaminase

Abstract

Abstract The synthesis of O5′,6-methanocytidine (4), a pyrimidine nucleoside restricted to the anti conformation, is described. Molecular modeling studies suggest that 4 is more flexible than conventional cyclonucleosides because of its larger-than-usual bridging system and that it can exist in a number of low energy conformations where the glycosyl rotation angles (X) cover an ∼80° segment of the anti range. However, while both N-type (C2′-exo) and S-type (C3′-exo) sugar puckerings are possible, none of the low energy conformers adopt the C3′-endo or C2′-endo puckering modes generally seen for unconstrained nucleosides. The lowest energy conformer predicted for 4 (X = −152°, y = 73°, P = 206°) is similar to the X-ray structure of a related compound, namely 5-hydroxy-O5′,6 -methanouridine (12, X = −138°. Y = 63°, P = 200°). In solution, NMR evidence suggests an equilibrium between C2′-exo and C3′-exo puckerings for 4, and CD evidence suggests an average glycosyl rotation angle (X) of around −160°. O5′,6 -...