No description available.

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.

No description available.

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.

No description available.

This thesis describes the first total synthesis of ancistrotanzanine A, a member of the naphthylisoquinoline class of natural products. In Chapter 1 the synthetic challenges presented by the naphthylisoquinoline alkaloids are discussed and strategies that have been adopted in previous syntheses of naphthylisoquinoline alkaloids overviewed. Chapter 2 describes the preparation of the key 5,3'-biaryl linkage via the Pinhey-Barton reaction. Studies into forming the linkage atropselectively were investigated using chiral hydrobenzoin acetal auxiliaries. This was found to have limited success with an atropisomeric ratio of 65:35 obtained. Changing the base from the achiral pyridine to the chiral brucine was also investigated and found to give no enhancement in the diastereoselectivity. From the results presented in Chapter 2, it was concluded that hydrobenzoin acetal auxiliaries were not appropriate for the diastereoselective synthesis of the key biaryl linkage of ancistrotanzanine A. As the chiral acetal strategy outlined in Chapter 2 failed to yield an atropselective process, efforts were re-focused on a new approach to the naphthylisoquinolines. In Chapter 3, an overview of all the methods available for the synthesis of chiral 3,4-dihydroisoquinolines is provided. From this, it was decided to apply the alkylation of o-tolylnitriles with chiral sulfinimines, as originally developed by Davis, to the synthesis of naphthylisoquinolines. Synthesis of the o-tolylnitrile lead reagent was readily achieved, but it was found that the amount of lead tetraacetate had to be carefully controlled to avoid side-reactions in the Pinhey-Barton reaction. After careful optimisation, the key 5,3'-biaryl linkage was prepared in high yield. Application of the Davis methodology to the MOM protected biaryl failed, with no reaction resulting. After much experimentation, it was established that the reaction was very sensitive to steric hindrance. A successful reaction was finally achieved by changing the base to lithium diethylamide. However, it was found the diastereoselection of the alkylation was quite low when p-tolyl sulfinimine was used. The use of the t-butane sulfinimine meant that the diastereoselection was significantly improved, with a ratio of 85:15 being obtained. After 3 more steps, the total synthesis was completed and ancistrotanzanine A was obtained, as a 1:1 mixture of atropisomers. Efforts to separate the atropisomers formed failed and even the use of chiral HPLC failed to resolve the material. To complete the Chapter, two analogues of ancistrotanzanine A were prepared – the tetrahydroisoquinoline and the methoxy ether. Chapter 4 summarises the above results and discusses the future potential of this research. / Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2010

The Lycopodiaceae is an ancient and cosmopolitan family of fern allies that include an estimated 35 Huperzia species occurring throughout the South-East Asian and Australian region. Thirteen species naturally occur in Australia and are found mainly in the tropical rainforests of far north Queensland. Over the past decade, there has been renewed interest in Huperzia and their respective Huperzine alkaloid concentrations following the discovery of Huperzine A (HupA) and Huperzine B (HupB) alkaloids in H. serrata (Thunb. ex Murray) Trevis. Both alkaloids are of pharmaceutical interest since they are highly selective and potent reversible inhibitors of acetylcholine esterase. Huperzine alkaloid concentrations of Australasian Huperzia have not been well documented, and no prior studies have been undertaken to investigate the amenability of Australasian Huperzia to alternative propagation techniques such as axenic culture. / This research presents an extensive screen of 16 Australasian Huperzia species to investigate their Huperzine alkaloid concentrations. HupA (0.032 to 1.012 mg g-1 DW) was detected in ten out of the sixteen Huperzia species examined, while HupB (0.008 to 0.339 mg g-1 DW) was detected in eight. From this extensive study, H. elmeri (Herter) Holub was observed as the species with the greatest potential to yield high Huperzine-containing individuals. In addition, the screen established that Australasian Huperzia generally contain higher HupA levels than H. serrata, the main source of commercial HupA, which on average only contains 0.082 mg g-1 DW HupA. The fractionation and spectrometric analysis of alkaloids as part of the screen led to the discovery of three Huperzine alkaloids co-occurring within the same plant: HupA, HupB and Huperzine C, isolated from an individual of an Australian H. carinata (Desv. Ex Poir.) Trevis. / The potential of establishing axenic cultures of Australasian Huperzia was also investigated in this research. Actively growing axenic cultures of H. carinata, H. squarrosa (C.Forster) Trevisan, H. phlegmaria (L.) Rothm. and H. phlegmarioidies (Gaudich.) Rothm., together with callus and cell suspension cultures of H. carinata and H. phlegmaria, were successfully established. The results suggest that culturing in total darkness is essential to allow for optimal callus and cell suspension growth. In addition, this study also investigated the possibilities of germinating various Huperzia spores, by both symbiotic and asymbiotic means. Germination of H. squarrosa spores was achieved by both symbiotic and asymbiotic means, and was only observed in cultures which were kept in the dark, implying that there is a form of photo-inhibition mechanism preventing spores from germinating when they are exposed to light. Beneficial effects of various types of spore treatments prior to sowing, in terms of increased spore germination was also observed. / In conclusion, the results presented suggest that Australasian Huperzia are indeed a potentially valuable resource for Huperzine alkaloids. The investigations into the conditions required for the successful introduction and maintenance of Australasian Huperzia in axenic culture has also further extended our understanding of these plants, and their amenability towards axenic culture conditions as a means of alternative propagation.

Thesis (Ph. D.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains xvi, 108 p. : ill. Includes abstract. Includes bibliographical references (p. 98-108).

Thesis (Ph. D.)--University of Texas Southwestern Medical Center at Dallas, 2008. / Vita. Includes bibliographical references (p. 25-28,39-40,87-89,191-192,247-248).

Thesis--Catholic University of America. / At head of title: The Catholic University of America.