Synthetic studies on the potent voltage-gated sodium ion channel agonist batrachotoxin
Abstract/Contents
- Abstract
- Batrachotoxin (BTX) is a complex steroidal alkaloid that causes depolarization and persistent activation of voltage-gated sodium ion channels (Nav). These channels are large transmembrane proteins that are responsible for the rapid transmission of electrical impulses in neuronal cells. Much remains unknown about the structure and function of these integral proteins as well as the origins of the complex array of responses that batrachotoxin elicits when applied to Navs. Structure-function analysis has been limited due to the paucity of the natural product, whose primary source is endangered Colombian poison dart frogs, and the small number of available congeners and semi-synthetic analogues. Synthetic efforts were undertaken to construct batrachotoxin in a modular, convergent fashion that would facilitate access to both the natural product and analogs thereof. Construction of the C/D/E ring system was first targeted based on pharmacological data indicating that variations in this portion of the molecule dramatically reduced activity. A synthetic plan was successfully executed that capitalized on the latent symmetry of the D ring in order to maximize convergency. Key steps include a novel Mannich reaction, intramolecular C-ring closure from an unusual bis-acetal, and formation of the unique homomorpholine ring structure through intramolecular reductive amination or SN2 displacement. A furan moiety was purposefully introduced as a B-ring surrogate for use in subsequent Diels-Alder reactions with the goal of generating both BTX and novel A/B-ring analogs. Intermolecular benzyne-furan Diels-Alder reactions provided access to the pentacyclic ring system of BTX. When efforts to introduce the C19 angular methyl group through dearomatization processes proved unfruitful, a revised synthetic strategy was explored. Cyclohexallene, cyclohexyne, and cyclopropene dienophiles were found to undergo furan Diels-Alder reactions to furnish steroidal core structures. Together with the successful use of benzyne, these results demonstrate that highly-strained dienophiles can serve effectively in intermolecular Diels-Alder reactions with structurally advanced diene derivatives. Through these studies, CsF was found to be a uniquely effective promoter for in situ generation of strained dienophiles, which reacted in most cases to give high yields of the desired cycloadducts. Strategies outlined in this thesis toward the synthesis of batrachotoxin lay the foundation for the construction of both the natural product and other highly oxidized steroidal compounds. De novo chemical synthesis has enabled preparation of C/D/E ring BTX analogs, unique molecular probes that are now being used to elucidate the structure of the batrachotoxin binding site in voltage-gated sodium ion channels and to explore the remarkable effect of this natural product on channel function.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2012 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Devlin, Abigail Sloan |
|---|---|
| Associated with | Stanford University, Department of Chemistry |
| Primary advisor | Du Bois, Justin |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Kool, Eric T |
| Thesis advisor | Wender, Paul A |
| Advisor | Kool, Eric T |
| Advisor | Wender, Paul A |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Abigail Sloan Devlin. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2012. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2012 by Abigail Sloan Devlin
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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