Convergent synthesis of 2-thioether-substituted ()-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. Enabling efficient synthesis of rigid methanocarba nucleotides and nucleosides as clinically promising purinergic receptor ligands.