Synthetic studies on the bis-guanidinium toxins 11-saxitoxinethanoic acid and zetekitoxin AB
Abstract/Contents
- Abstract
- Zetekitoxin AB (ZTX) is a potent neurotoxin isolated from the endangered Panamanian golden frog, Atelopus zeteki. The tricyclic, bis-guanidinium core of ZTX is common to other toxins such as (+)-saxitoxin (STX) and 11-saxitoxinethanoic acid (11-SEA), but ZTX and 11-SEA are the only known congeners with a C11-alkyl substituent. An unusual guanidinium N, O-acetal and a bridging macrolactam structure composed of a 3,4-disubstituted isoxazolidine render ZTX considerably more complex than all other members in this family of natural products. Efforts to synthesize ZTX and 11-SEA from a common hydroxyketone intermediate were undertaken. A tricyclic core bearing a C11-ketone moiety was accessed through a previously described route utilizing a C11-silylated pyrrole. The development of chemistry to elaborate the hydroxyketone culminated in the successful total synthesis of 11-SEA. Key steps in the preparation of this toxin include an oxidative annulation of an N-guanidyl pyrrole to form a five-membered cyclic guanidine and a base-catalyzed redox isomerization reaction. The challenges in applying the hydroxyketone intermediate towards the synthesis of ZTX have resulted in the design and implementation of a new synthetic route towards this complex natural product. The use of a formylpyrrole starting material enables the selective installation of an iodide at the desired C11 position. A diastereoselective Mannich cyclization reaction installs the requisite C13 carboxylic acid and generates a key bicyclic intermediate; from this material, the tricyclic guanidinium core is formed through oxidative dearomatization of the pyrrole ring. The identification of cross-coupling conditions to install a suitable heterocyclic group at C11, followed by macrolactam formation with the C13 carboxylic acid should ultimately lead to the assembly of ZTX.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Tang, Doris Tsz Yan |
|---|---|
| Degree supervisor | Du Bois, Justin |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Burns, Noah |
| Thesis advisor | Wender, Paul A |
| Degree committee member | Burns, Noah |
| Degree committee member | Wender, Paul A |
| Associated with | Stanford University, Department of Chemistry. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Doris Tsz Yan Tang. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Doris Tsz Yan Tang
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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