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

• Published in: RSC advances 2021-08, Vol.11 (44), p.27369-2738
• Main Authors: Suresh, R. Rama, Poe, Russell B, Lin, Baorui, Lv, Kexin, Campbell, Ryan G, Gao, Zhan-Guo, Liston, Theodore E, Toti, Kiran S, Jacobson, Kenneth A
• Format: Article
• Language: English
• Subjects: Adenine; Adenosine; Chemistry; Convergence; Functional groups; NMR; Nuclear magnetic resonance; Receptors; Ribose; Substitutes; Synthesis
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d1ra05096f

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.