Operation Hot Sandwich: Incorporating pyrones in [4 + 2] cycloaddition reactions to prepare thermorubin

The current increase in antibiotic resistance is of growing concern to the global community. Once easily-treated infections now require last-resort antibiotics with further application only encouraging the eventual buildup of resistance. New drugs are required to fight these infections, specifically with novel mechanisms of action that bacteria have no resistance for. Generally, these drugs will have different scaffolds, contributing to their different mechanisms of action. The literature contains a vast number of antimicrobial metabolites that are understudied but could serve as potential leads for future drugs. One such metabolite is thermorubin, a molecule with a unique scaffold and bacteriostatic mechanism of action. It shows promising sub micromolar activity against both Gram-positive and negative bacteria but suffers from poor oral bioavailability. Difficulties in obtaining this material have led to our development of a total synthetic strategy including a new method for incorporating pyrone moieties into aromatic systems. Based off the Hauser annulation, these conditions were successfully used to insert 15 different pyrones esters and amides into an aromatic system as a dieneophile or a 2-electron component. Modification of the electron-donor, the 4 -electron sulfoxide diene, was also attempted and proved to be somewhat effective. After attempts to use single sulfoxide cycloaddition products failed to propagate, a new donor substrate needed to be created: a symmetrical intermediate already containing both phenyl sulfoxide functionalities. This material was tested and proved successful with further optimization needed to complete the total synthesis of thermorubin.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2025

Author dc:creator

• Kohanov, Zachary Aaron

Chair dc:contributor.committeechair

• Lowell, Andrew Nesemann

Committee members dc:contributor.committeemember

• Tanko, James M.
• Santos, Webster
• Schulz, Michael

• antibiotic
• thermorubin
• total synthesis
• [4 + 2] cycloaddition

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:42554

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/124842