A Convergent Total Synthesis of the Telomerase Inhibitor (±)‐γ‐Rubromycin

Abstract

The total synthesis of the human telomerase inhibitor γ-rubromycin in its racemic form was accomplished in 3.8 % overall yield. The key feature of this synthesis is an efficient acid-catalyzed spiroketalization for the construction of the spiroketal core. The required electronically well-balanced spiroketal precursor was obtained by the convergent assembly of a naphthyl-substituted aldehyde, an α-methoxyallyl-γ-silyl-substituted phosphonate as the central C3 building block, and a highly functionalized aryl Grignard reagent. Another key feature is the late-stage construction of the isocoumarin moiety and a simultaneous protodesilylation furnishing the known methyl aryl ether protected precursor of γ-rubromycin.

Designed Spiroketal Protein Modulation

“…To enable an expedient testing of our binding hypothesis, we elected for a racemic synthesis of (±)‐ 1 , with a view to separating the enantiomeric spiroketals by chiral HPLC at a later stage. In reported syntheses of [6,5]‐ and [6,6]‐bisbenzannulated spiroketals, the spiroketal core is frequently formed under thermodynamically driven conditions through a dehydrative ring cyclisation. Our synthesis of (±)‐ 1 was based on work by Brimble and co‐workers on analogous [6,6]‐bisbenzannulated spiroketals and is described in Scheme .…”

Designed Spiroketal Protein Modulation

“…To enable an expedient testing of our binding hypothesis, we elected for a racemic synthesis of (±)‐ 1 , with a view to separating the enantiomeric spiroketals by chiral HPLC at a later stage. In reported syntheses of [6,5]‐ and [6,6]‐bisbenzannulated spiroketals, the spiroketal core is frequently formed under thermodynamically driven conditions through a dehydrative ring cyclisation. Our synthesis of (±)‐ 1 was based on work by Brimble and co‐workers on analogous [6,6]‐bisbenzannulated spiroketals and is described in Scheme .…”

Peer Review #2 of "Computational development of rubromycin-based lead compounds for HIV-1 reverse transcriptase inhibition (v0.1)"

“…γ-rubromycin was later shown to be an inhibitor of human telomerase (Ueno et al, 2000), fueling interest in its use as an anti-cancer agent. The development of less toxic variants of these lead compounds has long been prevented due to the difficulty of their laboratory synthesis, but several synthetic routes to these interesting molecules have recently become available (Akai et al, 2007;Rathwell et al, 2009;Wu, Mercado, & Pettus, 2011;Wilsdorf & Reissig, 2014), enabling the evaluation of many simpler derivatives as candidates for the inhibition of telomerase (Yuen et al, 2013). As far as we could ascertain, no derivatives of γrubromycin with substitution patterns as complex as those observed in the natural molecule have yet been synthesized.…”