Synthetic Studies Towards the Telomerase Inhibitors the Griseorhodins

Abstract

Synthetic investigations towards the griseorhodin family of antibiotics are described. The griseorhodins are a subclass of the wider rubromycin family of natural products. These compounds exhibit a wide array of biological activity, notably, inhibition of human telomerase (griseorhodin C (2), IC50 = 5.87 μM). No total synthesis of the griseorhodins has been reported to date. Use of an acid-mediated spirocyclisation of isocoumarin-containing dihydroxyketone precursors to afford the spiroketal unit of structurally related compounds has been problematic due to the unforeseen electron-withdrawing properties of the isocoumarin moiety. The influence of the pendant functional groups of the isocoumarin have therefore been thoroughly investigated and the key structural requirements to effect a successful spirocyclisation step have been determined. The synthesis of the griseorhodin model spiroketal 413 was executed in 28 steps. Performing the spirocyclisation step on a ring-opened precursor of the isocoumarin lactone was found to be essential in order to effect a successful acid-mediated spirocyclisation. Despite the successful synthesis of 413, unfortunately all subsequent efforts to prepare fully oxygenated griseorhodins via common intermediate 472 were unsuccessful, due to the sensitivity of the extensively substituted naphthalene ring system and steric congestion at the benzylic position. The insights gained during these investigations will inform further synthetic endeavours to achieve a concise, flexible synthesis of these complex bioactive natural products.