Approaches to a conformationally restricted, methylene-tethered adenosine

The preparation of key intermediates in the synthesis of new conformationally restricted methylene tethered adenosine nucleosides is reported. To access 11, our target nucleoside, the novel carbaxaldehyde intermediate 14 is expected to undergo an intramolecular aldol-like condensation in acid or base, connecting the C8-methyl to the C5`-aldehyde. The low steric hindrance of methylene tether restriction of 11 is designed to retain all molecular recognition binding sites and keep the preferred anti conformation while restricting the rotation about the glycosidic and C4`-C5` bonds. This motif of restricted nucleoside is expected to be useful as an enzyme probe for adenosine deaminase (ADA) and for further exploring the conformational requirements of other binding sites.