Synthetic progress toward Parvistemonine, Spiroxins A and B, and Generation of Palmarumycin Analogues
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.
Advisor:Dr. Kazunori Koide; Dr. Billy Day; Dr. Peter Wipf; Dr. Theodore Cohen
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:01/28/2009