Synthetic studies on the bis-guanidinium toxin zetekitoxin AB
Abstract/Contents
- Abstract
- Zetekitoxin AB (ZTX) is a bis-guanidinium toxin isolated from the skin of the Panamanian golden frog, Atelopus zeteki. The structure of this molecule has only recently been elucidated, and these studies have revealed ZTX to be structurally related to the marine toxins (+)-saxitoxin and (+)-gonyautoxin 3. Two key structural features distinguish ZTX from other bis-guanidinium toxins - a bridging lactam containing a 3,4-disubstituted isoxazolidine, and an N-hydroxycarbamate substituent on the five-membered guanidine. Synthetic efforts were undertaken to construct this complex natural product. Synthesis of the tricyclic core of ZTX was initially accomplished according to a previously described route to (+)-gonyautoxin 3. Key improvements to this route include the use of biphasic reactions conditions for the coupling of L-serine methyl ester with pyrrole-1-carboxylic acid chloride, and the identification of the 2,2,2-trichloroethoxycarbonyl (Troc) group as a suitable guanidine protecting group. These advances have increased material throughput and enabled exploration of a variety of novel chemistries for advancement of material toward ZTX. As part of these studies, a novel N, S-acetal [2,3]-sigmatropic rearrangement was identified. Subsequent elaboration of the resultant allylic alcohol has led to the synthesis of a novel C10-substituted analogue of saxitoxin. A second strategy for access to ZTX the use of a trialkylsilyl-substituted pyrrole starting material in a selective, intramolecular iminium ion cyclization reaction. The bicyclic product afforded from this reaction positions the trialkylsilyl group at the desired C11 position for further elaboration to the tertiary alcohol moiety found in the natural product. Advancement of the bicyclic product to a silyl-substituted allylic alcohol was accomplished using an N, S-acetal [2,3]-sigmatropic rearrangement. Oxidation of this material yielded an alpha-hydroxy ketone as a result of a directed epoxidation-Brook rearrangement reaction sequence. Cerium(III)-mediated addition of a methyl anion to this C11-ketone has provided a proof-of-principle for establishing the requisite C11 tertiary alcohol. Accordingly, synthesis of the bridging lactam of ZTX can be accomplished through nucleophilic addition of an isoxazoline-derived enolate to the C11 ketone. This strategy for the assembly of ZTX has laid the foundation for future construction of this challenging toxin, and lessons learned along the way may also aid in synthesis of novel bis-guanidinium toxin analogues.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Merit, Jeffrey Eric |
|---|---|
| Associated with | Stanford University, Department of Chemistry. |
| Primary advisor | Du Bois, Justin |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Trost, Barry M |
| Thesis advisor | Wender, Paul A |
| Advisor | Trost, Barry M |
| Advisor | Wender, Paul A |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Jeffrey Eric Merit. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Jeffrey Eric Merit
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