Operation Hot Sandwich: Incorporating pyrones in [4 + 2] cycloaddition reactions to prepare thermorubin
| dc.contributor.author | Kohanov, Zachary Aaron | en |
| dc.contributor.committeechair | Lowell, Andrew Nesemann | en |
| dc.contributor.committeemember | Tanko, James M. | en |
| dc.contributor.committeemember | Santos, Webster | en |
| dc.contributor.committeemember | Schulz, Michael | en |
| dc.contributor.department | Chemistry | en |
| dc.date.accessioned | 2025-03-11T08:00:22Z | en |
| dc.date.available | 2025-03-11T08:00:22Z | en |
| dc.date.issued | 2025-03-10 | en |
| dc.description.abstract | 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. | en |
| dc.description.abstractgeneral | Over the past few decades, the decline in effective ways to treat bacterial infections has become a serious threat to our survival as a species. Easily-treated infections are now becoming impossible to treat, requiring new solutions in the forms of new drugs or drug derivatives. Looking back into the literature, however, potential molecules may have already been discovered but may have been underdeveloped due to having undesirable properties. One such molecule is thermorubin, which shows high selectivity towards bacteria and high activity against a broad range of bacteria. Thermorubin is not water soluble, so part of this work would involve making thermorubin while also making small changes to it to make it more soluble in water. The synthetic construction of thermorubin has never been performed before. The route we would like to use would involve an annulation reaction, a chemical reaction that produces an aromatic ring, with a material that has not been reported in the literature. The structure of this material would also allow for the formation of unwanted side materials. After careful testing, the ideal conditions were developed for product formation, and twenty-one various pyrone esters and amides were applied in the reaction. This optimized reaction was also attempted in the pathway for thermorubin and proved successful, although the product could not be further modified. Due to this inability to be modified, the starting material was altered to already include these modifications before the annulation reaction. Further annulation proved successful, though continued work is required to finish the construction of thermorubin. The synthetic construction of thermorubin has never been performed before. The route we would like to use would involve an annulation reaction, a chemical reaction that produces an aromatic ring, with a material that has not been reported in the literature. The structure of this material would also allow for the formation of unwanted side materials. After careful testing, the ideal conditions were developed for product formation, and twenty-one various pyrone esters and amides were applied in the reaction. This optimized reaction was also attempted in the pathway for thermorubin and proved successful, although the product could not be further modified. Due to this inability to be modified, the starting material was altered to already include these modifications before the annulation reaction. Further annulation proved successful, though continued work is required to finish the construction of thermorubin. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:42554 | en |
| dc.identifier.uri | https://hdl.handle.net/10919/124842 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | antibiotic | en |
| dc.subject | thermorubin | en |
| dc.subject | total synthesis | en |
| dc.subject | [4 + 2] cycloaddition | en |
| dc.title | Operation Hot Sandwich: Incorporating pyrones in [4 + 2] cycloaddition reactions to prepare thermorubin | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Chemistry | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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