The formal total synThesis of the human telomerase inhibitor (±)-γ-rubromycin

Abstract

The formal synthesis of (±)-y-rubromycin 1 via Kita's pentacyclic spiroketal 165 is described. The correct balance of electronic effects within the eastern fragment was crucial in effecting previously unrealized acid-mediated spiroketalization step to provide access to the key densely functionalized CD-core. This involved the use of isocoumarin precursor 231 in which isocoumarin ring formation is delayed until after the key spiroketalization. A novel regioselective allyloxylation-Claisen rearrangement of 2-azido-l,4-naphthoquinone 216 was developed to provide access to the highly oxygenationed naphthalene fragment 243. This strategy was readily amenable for generation of regioisomeric naphthalene fragment 220. Fragment coupling of alkynol 243 and iodide 231 was achieved by a Sonogashira coupling reaction. Subsequent cyclization of ketone 225 took place under mild acidic conditions, thus providing a practical method for the synthesis of the challenging rubromycin family of natural products.