Stereoselective syntheses of (-)-Batrachotoxin, (+)-Batrachotoxin, and related structural analogues
Abstract/Contents
- Abstract
- (--)-Batrachotoxin (BTX), a poisonous constituent of the Colombian poison dart frog, is distinguished among small molecule natural products as one of the most lethal. The stereochemically rich, highly oxidized steroidal architecture of BTX, which underlies its unique function as an agonist of voltage-gated sodium ion channels (NaVs), presents a complex, contemporary challenge in synthetic chemistry. Our interest in elucidating the molecular details of BTX binding to NaV and its influence on channel gating has motivated efforts to synthesize this unique natural product. Ultimately, we discovered that a C8−C14 bond connection united A/B- and D-ring steroid building blocks and facilitated a stereoselective synthesis of BTX. This route is highlighted by a n-Bu3SnH-mediated radical cyclization cascade, a strategy that has enabled expedient access to the steroidal core of the toxin. In this reaction, assembly of the central C-ring occurs with concomitant installation of the C13 quaternary center, a latent C18 aldehyde for homomorpholine ring construction, and an allyl stannane that can be oxidatively manipulated to the desired C11 alcohol. Additional highlights of this work include a novel CuCl2 and O2-mediated allylic stannane oxidation reaction, acid-catalyzed Curtius rearrangement, Stille cross-coupling reaction, and stereoselective 8-electron reduction of an oxidized precursor to batrachotoxinin A. Optimization of a final-step esterification of batrachotoxinin A has enabled preparation of ~4 mg of BTX, or 2.5% of the available world supply. The studies presented in this thesis lay the foundation for future experiments aimed at resolving questions regarding the differential activity of BTX analogues, which will likely reveal unique molecular insights into NaV function.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Logan, Matthew Michael |
|---|---|
| Associated with | Stanford University, Department of Chemistry. |
| Primary advisor | Du Bois, Justin |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Chen, James |
| Thesis advisor | Wender, Paul A |
| Advisor | Chen, James |
| Advisor | Wender, Paul A |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Matthew Michael Logan. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Matthew Michael Logan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...