Kassick, Andrew Jonathan
(2005)
CATALYTIC, ASYMMETRIC ACYL HALIDE-ALDEHYDE CYCLOCONDENSATIONS IN COMPLEX MOLECULE SYNTHESIS AND APPLICATION TO THE INSTALLATION OF QUATERNARY CARBON STEREOCENTERS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The synthetic utility of recently developed catalytic, asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions has been successfully demonstrated in complex molecule total synthesis. Extensive use of the enantiomerically enriched beta-lactone products of AAC methodology has led to the enantioselective total synthesis of the potent microtubule-stabilizing agent, (-)-laulimalide (1). Additional highlights of the synthesis include a diastereoselective aldol reaction that united major fragments 85 and 86 and a remarkably high-yielding modified Yamaguchi macrolactonization. Novel methodology was also developed to effect both the one-pot interconversion of beta-lactones to dihydropyranones and the Lewis acid-mediated addition of allenylstannane reagents to glycal acetates. Asymmetric AAC reactions have also been instrumental in recent studies toward the total synthesis of the cytotoxic marine natural product, amphidinolide B1 (133). By exploiting AAC methodology, several key stereochemical relationships present in major fragments 171 and 172 were established. A highly enantioselective installation of the C16 tertiary carbinol stereocenter was acheived through the application of Mukaiyama's Sn(IV)-allylation protocol, and a rapid synthesis of sulfone subunit 174 was realized from commercially available gamma-butyrolactone. Regioselective beta-lactone ring opening by phosphonate anions was also documented. The enantiomerically enriched beta-lactone products of AAC methodology have also been demonstrated to serve as useful templates for the installation of asymmetric quaternary carbon stereocenters. Treatment of beta-lactones with NaHMDS in the presence of an in situ electrophile at low temperature resulted in enolization and subsequent alkylation to afford to afford trans-3,4-disubstituted lactones in moderate to good yield with good levels of diastereoselectivity. Resubjecting the monoalkylated products to the reaction conditions and a different electrophile resulted in the efficient production of 3,3-disubstituted-beta-lactones in high yield with high trans-diastereoselectivity. A more efficient route to 3,3-disubstituted beta-lactones was realized starting from the cis-3,4-disubstituted beta-lactones products of the recently developed second generation AAC reaction. Asymmetric quaternary carbon formation was accomplished in two steps affording the desired 3,3-disubstituted-beta-lactones in high yield with excellent diastereoselectivity.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Kassick, Andrew Jonathan | aj316@pitt.edu | AJ316 | |
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| ETD Committee: |
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| Date: |
31 January 2005 |
| Date Type: |
Completion |
| Defense Date: |
1 November 2004 |
| Approval Date: |
31 January 2005 |
| Submission Date: |
29 November 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: |
amphidinolide; laulimalide |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-11292004-210347/, etd-11292004-210347 |
| Date Deposited: |
10 Nov 2011 20:06 |
| Last Modified: |
15 Nov 2016 13:52 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9843 |
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