Annulation methods toward the total synthesis of thermorubin: Construction of the AB and BCD ring systems

02 June 2025, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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 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 four-electron synthon suitable for annulation with two-electron Michael acceptors within the core tetracycle—an unusual planar aromatic system. An activated form of this symmetric intermediate enabled annulation with a 6-carboxy pyrone as well as traditional alpha-beta-unsaturated ketones. Beyond advancing the total synthesis of thermorubin, these strategies offer broader utility for constructing other complex heterocycles.

Keywords

Thermorubin
Total Synthesis
Antibiotic
Natural Product
Annulation

Supplementary materials

Title
Description
Actions
Title
Supporting Information
Description
1H and 13C NMR spectra
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.