Convergent synthesis of 2-thioether-substituted ( N )-methanocarba-adenosines as purine receptor agonists.

A linear route has been used to prepare ( N )-methanocarba-nucleoside derivatives, which serve as purine receptor ligands having a pre-established, receptor-preferred conformation. To introduce this rigid ribose substitute, a Mitsunobu reaction of a [3.1.0]bicyclohexane 5'-trityl intermediate 3 with a nucleobase is typically followed by functional group modifications. We herein report an efficient scalable convergent synthesis for 2-substituted ( N )-methanocarba-adenosines, which were demonstrated to bind to the A ₃ adenosine receptor. The adenine moiety was pre-functionalized with 2-thioethers and other groups before coupling to the bicyclic precursor (3) as a key step to facilitate a high yield Mitsunobu product. This new approach provided the ( N )-methanocarba-adenosines in moderate to good yield, which effectively increased the overall yield compared to a linear synthesis and conserved a key intermediate 3 (a product of nine sequential steps). The generality of this convergent synthesis, which is suitable as an optimized preclinical synthetic route, was demonstrated with various 2-thioether and 2-methoxy substituents.
Competing Interests: T. E. L. and R. B. P. are employees of Astrocyte Pharmaceuticals Inc. The other authors have no competing interest to declare.
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