Lee, Christopher Allen
(2005)
Synthesis and Studies Directed Toward Multidrug Resistance-Modulating Natural Products.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Studies directed toward the enantioselective preparation of dihydroagarofuran natural products are presented. The purpose of this project is to synthesize dihydroagarofuran natural products in order to study what structural features are required for inhibition of Phospho-glycoprotein (P-gp) induced multidrug resistance in this family of molecules. Once an optimal synthetic route is established, analogs can be synthesized to probe P-gp function at the molecular level. Three synthetic routes to the dihydroagarofuran family of natural products were investigated. Each synthesis utilized (R)-(-)-carvone, an inexpensive terpene available in high enantiomeric purity, as the sole source of chirality. Our studies have shown that the dihydroagarofuran tricyclic skeleton can be prepared in as few as eight steps from (R)-(-)-carvone. Each synthesis is substantially shorter than previously published routes to similar ring systems.In conjunction with our studies toward interesting multidrug resistance modulating natural products, a short and enantioselective route to the tetrahydropyran (THP) bryostatin B ring was developed. This new method utilizes a cyclic acetal to generate a reactive oxocarbenium ion, which was subsequently trapped with a tethered silyl enol ether. The resulting diastereoselective reaction gives exclusively 2,6-cis-tetrahydropyranone rings in excellent yield. Unlike previous routes to create oxocarbenium ions from acetals, our approach uses Ce(NO3)3 an exceptionally mild Lewis acid. Ce(NO3)3 is inexpensive, non-toxic, and easy to separate from reaction mixtures. The use of acetals as oxocarbenium ion precursors is an attractive method for complex molecule synthesis, since acetals can be constructed under extemely mild conditions. This new method can be easily extended to the enantioselective preparation of other complex THP ring containing macrolide natural products, such as (+) Phorboxazole A or (+) Leucascandrolide A.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Lee, Christopher Allen | calee@pitt.edu | CALEE | |
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| ETD Committee: |
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| Date: |
31 January 2005 |
| Date Type: |
Completion |
| Defense Date: |
25 October 2004 |
| Approval Date: |
31 January 2005 |
| Submission Date: |
26 October 2004 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| 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: |
Bryostatin; Dihydroagarofurans; MDR; Orbiculin A; P-gp; Celafolin A-1; tandem conjugate addition aldol |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-10262004-113523/, etd-10262004-113523 |
| Date Deposited: |
10 Nov 2011 20:03 |
| Last Modified: |
15 Nov 2016 13:50 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9516 |
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