published_or_final_version / Chemistry / Master / Master of Philosophy

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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.

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The natural alkaloid himbacine 1, first isolated in 1955 from Galbulimina baccata Bail, has attracted attention as a potential therapetic agent for Alzheimer's disease. It is proposed that a late stage in the biosynthesis of this compound may proceed via an iminium ion mediated Diels-Alder reaction (Scheme 1), which would yield the related alkaloid himgravine 2, which can be reduced to himbacine 1. Precident for the iminium ion mediated Diels-Alder reaction has been provided by a related oxonium ion mediated cycloaddition reaction (Scheme 2). Confirmation of the stereochemistry of the product of this reaction has been obtained by X-ray crystallography of the tricyclic alcohol. Studies towards the synthesis of the iminium ion have been undertaken. Piperidine sulfone has been synthesised in a 17% yield over 16 linear steps, and a synthesis of dihydrofuran has been investigated involving an enyne metathesis reaction. Additionally, methodology has been developed for a Julia coupling to join piperidine sulfone to dihydrofuran, and a Polonovski reaction for generation of the required iminium ion.