Chemo-enzymatic access to C-4 '-hydroxyl-tetrahydrofurano-spironucleosides

The demand to attain structural pre-organisation and recognition in potential antiviral agents has provoked spirocyclic restriction to be incorporated in nucleosides. With an aim to achieve pre-organization, C-4 '-hydroxyl-tetrahydrofurano-spironucleosides have been synthesised from the naive d-glucose via an intramolecular cyclisation route starting in over 10 steps. The process involves the Lipozyme (R) TL IM-mediated monoacetylation of the primary hydroxyl group of 4-C-hydroxymethyl-1,2,5,6-di-O-isopropylidene-beta-l-mannofuranose. The assessment for the selectivity of monoacylation in the dihydroxymannofuranose sugar derivative using various vinyl esters revealed that different acyl chain lengths did not affect the selectivity of lipase but led to an increase in the rate of reaction with increasing chain length. A hydroxytetrahydrofuran ring, which is a C-4 '-spirocycle on furano-nucleoside, was picked as the modification to furnish C4 '-exo, NE-conformational restriction in the nucleosides, which conclusively revealed that the bicyclic framework did not bind the sugar pucker to the anticipated N/S-conformation only.

Automated summary

The study introduced spirocyclic restriction into nucleosides to achieve structural pre-organisation, leading to the synthesis of C-4 '-hydroxyl-tetrahydrofurano-spironucleosides. Assessing the selectivity of monoacylation in the sugar derivative revealed that different acyl chain lengths could increase reaction rate without affecting enzyme selectivity. The modification of a hydroxytetrahydrofuran ring in furano-nucleosides demonstrated the ability to generate C4'-exo, NE-conformational restriction in nucleosides.