Described in this thesis is the development of a key Diels-Alder reaction for use in a total synthesis of the potently immunosuppressant marine alkaloid palau'amine. This study focuses on the originally proposed structure of palau'amine. The strategy utilizes a computationally designed thiohydantoin dienophile as the 2pi component and a thermally stable 2-silyloxy-5-(silyloxymethyl)cyclopentadiene as the 4pi component in the critical Diels-Alder reaction. Essential to the design and study of these partners was the use of computational density functional theory (DFT) predictions. / Four families of dienophiles---oxazolones, dehydroalanines, hydantoins and thiohydantoins---were investigated. The hydantoins and thiohydantoins react with cyclopentadiene with up to 13:1 exo-selectivity while the dehydroalanines are modestly selective and the oxazolones are unselective. The exo-selectivity of the hydantoin and thiohydantoin dienophiles is attributed to a novel stabilizing interaction whereby the lone pair of electrons on nitrogen interacts with a developing positive charge on the diene in the transition state. In terms of reactivity, the oxazolones are the superior dienophiles. The reactivity of the thiohydantoins is greater than that of analogous hydantoins and approaches that of the oxazolones. The bolstered reactivity of the thiohydantoins is attributed to the increased donation of the nitrogen lone-pair into the thiocarbonyl bond. This phenomenon was recognized first in DFT predictions and then proven experimentally. Synthetic access to the requisite beta-(chloromethylene)thiohydantoins necessitated the development of a reaction between dilithium diamides and thiophosgene. / 2-silyloxy-5-(silyloxymethyl)cyclopentadienes were studied experimentally and computationally and found to be much more stable than conventional 5-substituted cyclopentadienes towards thermal decomposition by 1,5 hydride shift. The new dienes undergo Diels-Alder reaction with oxazolone and thiohydantoin dienophiles with exoselectivities as high as 6:1 for nonchlorinated dienophiles. Fully functionalized chlorinated exo-cycloadducts were prepared with up to 1.5:1 selectivity and subjected to oxidative ring-opening to reveal the persubstituted core of palau'amine.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103369 |
| Date | January 2007 |
| Creators | Cernak, Timothy Andrew. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Chemistry.) |
| Rights | © Timothy Andrew Cernak, 2007 |
| Relation | alephsysno: 002668581, proquestno: AAINR38567, Theses scanned by UMI/ProQuest. |
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