Catalytic asymmetric synthesis of carbocyclic C-nucleosides

Access to carbocyclic C-nucleosides (CC-Ns) is currently restricted. The few methods available to make CC-Ns suffer from long syntheses and poor modularity, hindering the examination of potentially important chemical space. Here we report an approach to CC-Ns which uses an asymmetric Suzuki-Miyaura type reaction as the key C-C bond forming step. After coupling the densely functionalized racemic bicyclic allyl chloride and heterocyclic boronic acids, the trisubstituted cyclopentenyl core is elaborated to RNA analogues via a hydroborylation-homologation-oxidation sequence. We demonstrate that the approach can be used to produce a variety of enantiomerically enriched CC-Ns, including a carbocyclic derivative of Showdomycin. Carbocyclic nucleosides show a broad spectrum of antiviral activity with enhanced flexibility, lipophilicity and metabolic stability, however, synthetic access to carbocyclic C-nucleosides (CC-Ns) remains very challenging. Here, the authors use an asymmetric Suzuki-Miyaura coupling reaction as the key C-C bond forming step to produce a variety of enantiomerically enriched CC-Ns, including antiviral showdomycin.