Part one: The formal total synthesis of dehydrogliotoxin and the first synthesis of an epidiselenodiketopiperazine and Part two: Towards the total synthesis of the tetrapetalones
| dc.contributor.author | McMahon, Travis Chandler, author | |
| dc.contributor.author | Wood, John L., advisor | |
| dc.contributor.author | Kennan, Alan J., committee member | |
| dc.contributor.author | Ferreira, Eric M., committee member | |
| dc.contributor.author | Bailey, Travis S., committee member | |
| dc.contributor.author | Crick, Dean C., committee member | |
| dc.date.accessioned | 2007-01-03T05:53:53Z | |
| dc.date.available | 2007-01-03T05:53:53Z | |
| dc.date.issued | 2013 | |
| dc.description.abstract | Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), affects approximately one third of the global population and is associated with nearly two million deaths annually. Although there are known cures for TB, current treatment plans suffer due to length, usually taking 6-9 months to complete. Additionally, developing countries lack the infrastructure and resources necessary to both efficiently diagnose and treat patients. Of particular concern are an increasing number of strains of TB that are becoming resistant to the current drug regimens, which has been a result of patients beginning, but not completing their treatment. In light of these facts it is clear there is a continuing need to develop simplified and shorter treatments for TB, and with the increasing prevalence of resistant strains, chemically unique targets should be investigated. As part of a collaborative effort with the Hung group at the Broad Institute, we identified two related epidithiodiketopiperazine (ETP) natural products, gliotoxin and dehydrogliotoxin, as potential candidates for exploration as anti-TB agents. We initially targeted a synthesis of dehydrogliotoxin, as it had also never been tested against MTB, whereas gliotoxin was known to be active. Additionally, as dehydrogliotoxin was the simpler of the two compounds, we believed it could be synthesized more rapidly and also be more amenable to derivatization to form structural analogs. The synthetic studies towards dehydrogliotoxin culminated in a formal total synthesis that featured a key two step amidation-intramolecular ring-closure. With access to dehydrogliotoxin we were able to test it against MTB and found its activity to be comparable to gliotoxin. We next turned our attention to the synthesis of structural analogs in hopes of identifying a compound that could potentially be used as an anti-TB therapeutic. In that regard, we targeted a compound wherein the disulfide region of the natural product was replaced with a diselenide. As an epidiselenodiketopiperazine (ESeP) had never been synthesized before, we initially explored the installation of this functional group in a model system. These synthetic efforts resulted in the synthesis of an ESeP, both from a simple diketopiperazine and directly from an ETP. Additionally, in these model systems, the ESeP exhibited comparable activity towards MTB as the ETP. Tetrapetalone A was isolated in 2003 by Hirota and coworkers from a culture filtrate of Streptomyces sp. USF-4727. The related compounds tetrapetalones B, C, and D were isolated from the same Streptomyces strain in 2004. We became interested in this family of natural products due to their interesting structural features and the synthetic challenge they present. Salient features of the tetrapetalones include a tetracyclic core containing a tetramic acid, a seven-membered ring possessing a trisubstituted double bond, a p-quinol, and a five-membered ring with a pendant β-rhodinose. Several strategies towards the synthesis of the tetrapetalones have been explored. In our initial approach we hoped to form the seven-membered ring of the natural product through nucleophilic attack of the aromatic ring onto a pendant palladium π-allyl species. While exploring this process, we found that the desired seven-membered product was not formed, instead we isolated a product containing a five-membered ring, the result of attack at the wrong position of the palladium π-allyl species. Attempts to bias the substrate towards formation of the desired seven-membered ring through a transannular palladium π-allyl approach proved unfruitful. Our current route features a Friedel-Crafts acylation to form the seven-membered ring containing the trisubstituted double bond. The precursor for this approach was built up rapidly from simple starting materials, and the desired Friedel-Crafts reaction proceeds smoothly. Furthermore, we have implemented a C-H oxidation protocol to install a synthetic handle, which can ultimately be converted to an alkyne that we envision can be transformed into the five-membered ring bearing the sugar moiety in order to finish the natural product. Concurrent to the approaches described above, we have also targeted the related natural product, ansaetherone, which was isolated from the same Streptomyces strain as the tetrapetalones and is proposed to be a biosynthetic precursor to the family. The ultimate goal in this approach was to develop a synthesis of ansaetherone and explore methods to convert it to one of the members of the tetrapetalones in a biomimetic fashion. Our proposed synthesis included a key tandem enyne-cross metathesis to form the eleven-membered ring present in the natural product. Although this synthesis is still in its infancy, we have accessed a compound that is a few synthetic steps away from the precursor to explore the key step. We are currently exploring an improved synthesis of this intermediate and ways to elaborate it to the natural product. | |
| dc.format.medium | born digital | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier | McMahon_colostate_0053A_11981.pdf | |
| dc.identifier.uri | http://hdl.handle.net/10217/80165 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation.ispartof | 2000-2019 | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.subject | total synthesis | |
| dc.subject | epidiselenodiketopiperazine | |
| dc.subject | tetrapetalone | |
| dc.subject | ansaetherone | |
| dc.subject | dehydrogliotoxin | |
| dc.title | Part one: The formal total synthesis of dehydrogliotoxin and the first synthesis of an epidiselenodiketopiperazine and Part two: Towards the total synthesis of the tetrapetalones | |
| dc.title.alternative | The formal total synthesis of dehydrogliotoxin and the first synthesis of an epidiselenodiketopiperazine | |
| dc.title.alternative | Towards the total synthesis of the tetrapetalones | |
| dc.type | Text | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Chemistry | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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