An innovative synthesis of the antiviral Vidarabine through the dual use of flow chemistry and biocatalysis

Nucleoside analogues are synthetic, chemically modified compounds that have been developed to mimic their physiological counterparts and act as antimetabolites, thus impairing cellular division and viral replication. Despite the dramatic progress in nucleoside chemistry to date, the preparation of nucleosides by conventional synthetic methods still suffers from low stereoselectivity, multi-step procedures and modest total yields. In this context, we focused our attention on a biocatalysed approach, developing a continuous flow process for the sustainable, efficient and scalable preparation and purification of nucleoside analogues (e.g., Vidarabine) [1]. The use of immobilised biocatalysts in continuous flow reactors, in fact, can help to overcome some of the constraints of batch protocols, such as long reaction times, scalability and productivity. Uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) were selected to perform a bi-enzymatic transglycosylation reaction (Scheme 1) [2]. Both enzymes were efficiently co-immobilised in flow and reaction parameters were optimised. Furthermore, an in-line purification step was added to isolate the pure product.