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Synthetic progress toward Parvistemonine, Spiroxins A and B, and Generation of Palmarumycin Analogues

Englund, Erika Elaine (2009) Synthetic progress toward Parvistemonine, Spiroxins A and B, and Generation of Palmarumycin Analogues. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Natural products can both challenge synthetic chemists and guide biologists. In this work, they prompted the extension of oxidative methodology to new systems, inspired the systematic modification of the palmarumycin scaffold to produce potent thioredoxin/thioredoxin reductase (Trx/TrxR) inhibitors, and demanded creative synthetic solutions to the structural challenges Mother Nature provided. The first pursuit was the total synthesis of parvistemonine, a pentacyclic azacycle isolated from Stemona plants. These plants have been used in Chinese folk medicine, and the isolated Stemona alkaloids possess therapeutic uses that range from antitussive to antiparasitic activity. The oxidative cyclization of tyrosine was incorporated into the syntheses of several natural products, and the extension of this methodology to homotyrosine for construction of the azacyclic core was investigated. Ultimately, the desired cyclization was not optimized to give synthetically viable yields, but the competing pathways and preferred reactivity was elucidated. In a separate project, a library of palmarumycin based prodrugs was synthesized. The bisnaphthospiroketal functionality, which is present in palmarumycin, is a lucrative scaffold that potently inhibits thioredoxin/thioredoxin reductase (Trx/TrxR). Some of the analogues suffered from low solubility, so various amino ester and sugar containing prodrugs were investigated. A prodrug library with improved solubility and greater plasma stability was successfully generated. One gram of the lead prodrug was needed for further biological testing, which would have been challenging with the first generation synthesis. An alternative synthesis was developed that afforded 1 g of the prodrug and decreased the total number of steps by half while significantly improving the overall yield. Finally, the total synthesis of spiroxins A and B was pursued. The spiroxins were isolated from an unidentified marine fungus and only spiroxin A was tested for biological activity. These highly oxygenated octacyclic compounds only differ in their degree of chlorination. A synthetic route was proposed that allowed access to both spiroxin A and B, and only diverged in the final chlorination step. Through a series of oxidations and reductions, this challenging core was accessed.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Englund, Erika
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf, Peterpwipf@pitt.eduPWIPF
Committee MemberDay, Billybday@pitt.eduBDAY
Committee MemberKoide, Kazunorikoide@pitt.eduKOIDE
Committee MemberCohen, Theodorecohen@pitt.eduCOHEN
Date: 28 January 2009
Date Type: Completion
Defense Date: 7 October 2008
Approval Date: 28 January 2009
Submission Date: 6 November 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Trx/TrxR; Palmarumycin; Spiroxins
Other ID:, etd-11062008-090058
Date Deposited: 10 Nov 2011 20:04
Last Modified: 15 Nov 2016 13:51


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