Burrows, James
(2022)
Synthetic Studies Toward Epidithiodiketopiperazine MPC1001 and 2-Pralidoxime Analogs. An Exploration in Birch Reduction, Oxidation, and N-Alkylation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The first chapter presented in this dissertation describes the efforts toward the total synthesis of MPC1001. Three separate synthetic routes are discussed. Additionally, experiments with assorted additives led to a proposed radical degradation mechanism involving a biaryl triazene intermediate. A Birch reduction was uncovered during the synthetic studies that did not require liquid ammonia, allowing quick optimization to a mole-scale Birch alkylation. Then, oxidation conditions compatible with sterically-congested alcohols were found that granted studies into the following aldol condensations. Additionally, an intramolecular aza-Wacker reaction of an enamide was investigated. The second chapter describes an easy-to-use Birch reduction borne out of the total synthesis effort. After selecting a suitable internal standard, the reduction was optimized for both electron-poor and electron-rich systems. The substrate scope of the reduction was then investigated, with over 36 substrates being compatible. The structure-reactivity relationship with the amine ligand allowed a change in the selectivity from electron-poor arenes to electron-rich arenes. Also, the method was shown to be compatible with an organocuprate-mediated Michael addition with an electrophile that was previously incompatible with the Birch reduction. Finally, kinetic studies were completed that investigated the reduction mechanism, leading to the postulation of more active roles for both the solvent and the proton donor than previously suggested. The third chapter describes the synthesis of both bicyclic and sterically-congested reactivators of phosphylated acetylcholinesterase. Their synthesis necessitated a slight change in both the synthetic route and the purification protocol, allowing the reproducible and robust synthesis of analogs in the hypothesis-driven library. Although all analogs synthesized were not more potent than the already approved treatment, two analogs were shown to be more broadly active against assorted organophosphorus nerve agents than the approved treatment.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
13 August 2022 |
| Date Type: |
Publication |
| Defense Date: |
4 March 2022 |
| Approval Date: |
4 December 2024 |
| Submission Date: |
6 April 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
936 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Birch reduction, dissolving metal reduction, aza-wacker reaction, wacker oxidation, pralidoxime, MPC1001, epipolythiodiketopiperazine, total synthesis, methodology, medicinal chemistry, epidithiodiketopiperazine, aldol condensation, oxidation |
| Date Deposited: |
04 Dec 2024 16:55 |
| Last Modified: |
04 Dec 2024 18:07 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42388 |
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