Towards γ-Rubromycin: Model Studies, Development of a C3 Building Block, and Synthesis of 4′-Silyl-γ-rubromycin

The human telomerase inhibitor γ-rubromycin belongs to a class of natural products, which features a rare [5,6]-bisbenzannulated spiroketal core as its central structural motif. Also termed “aromatic spiroketals”, these scaffolds pose great challenges to total synthesis. The ideal approach through an acid-mediated spiroketalization event is demanding, since this transformation is susceptible to even slight electronic alterations on the polyaromatic ring system. Herein, we report our strategy towards this class of natural products, that led to the identification of an electronically well-balanced spiroketalization precursor and eventually culminated in the preparation of an unnatural 4′-silyl-substituted γ-rubromycin derivative in racemic form. In the course of this study, we additionally introduced a new type of γ-silylated allylic phosphonate reagents that served as valuable C3 building blocks to forge the spiroketalization precursor in a convergent manner.