Annulation Methods toward the Total Synthesis of Thermorubin: Construction of the AB and BCD Ring Systems.

New antibiotics are desperately needed to fight the growing threat of antimicrobial resistance. Thermorubin, a forgotten natural product, is one such candidate, as it binds to a novel site on the ribosome and uniquely disrupts both elongation and termination during protein synthesis. In this study, we report the synthesis of the AB and BCD ring portions of thermorubin in a 10% yield over six steps and an 8.9% yield over seven steps, respectively. The key disconnection for both systems involved identification of a symmetric nucleophilic donor synthon suitable for annulation with Michael acceptors within the core tetracycle─an unusual planar aromatic system. An activated form of this symmetric intermediate enabled a formal [4 + 2] cycloaddition with a 6-carboxy pyrone as well as traditional α-β-unsaturated ketones. Beyond advancing the total synthesis of thermorubin, these strategies offer broader utility for the construction of other complex heterocycles.