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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.

The stereoselective synthesis of urdamycinone B (17) was achieved in a 21% overall yield from C-glycosyl-naphthoquinone 197. The key reaction was the Diels-Alder cycloaddition reaction of 197 and siloxydiene (�)-117 promoted by a chiral Lewis acid derived from (S)-3,3�-diphenyl-1,1�-binaphthalene-2,2�-diol (291), BH₃.THF and acetic acid. An effective kinetic resolution of (�)-117 occurred. Four cycloadducts 199a-d were formed in a ratio between 84:8:2:6 and 70:9:2:19. Aromatisation of the mixture by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave 200a and 200b in 4:1 ratio. A sequence of reactions involving deacetylation, conversion of a phenyldimethylsilyl group into a hydroxyl group and photooxidation gave a 4:1 mixture of urdamycinone B (17) and its C-3 epimer (154). Separation of these products was achieved by high performance liquid chromatography (HPLC). The C-glycosyl donor, 1,3,4-tri-O-acetyl-2,6-dideoxy-D-glucopyranose (204), was synthesised from readily accessible tri-O-acetyl-D-glucal (237) using two approaches. The first involved a sequence of deacetylation, tosylation, lithium aluminium hydride (LiAlH₄) reduction and acetylation to give di-O-acetyl-6-deoxy-D-glucal (242). The triphenylphosphine hydrogen bromide (TPPHBr) catalysed addition of acetic acid to 242 gave 204 in overall yields ranging from 0 to 32%. The step involving the reduction of the tosylate intermediate was the cause of the variable yields. The alternative synthesis started with the TPPHBr catalysed addition of benzyl alcohol to 237. Subsequent deacetylation, tosylation and reduction with LiAlH₄ gave benzyl 2,6-dideoxy-D-glucopyranoside (250). Acetylation and hydrogenolytic debenzylation gave 3,4-di-O-acetyl-2,6-dideoxy-D-glucopyranose (247). Acetylation gave 204 in 40% overall yield. A third approach to 204 involved selective tosylation of methyl α-D-mannopyranoside (258) and subsequent treatment with 2,2-dimethoxypropane under acidic conditions to give acetonide 255. LiAlH₄ reduction of the tosylate gave methyl 6-deoxy-2,3-O-isopropylidene-α-D-mannopyranoside (256). Acidic hydrolysis of 256 and subsequent acetylation afforded 1,2,3,4-tetra-O-acetyl-6-deoxy-α-D-mannopyranoside (260). Treatment of 260 with hydrogen bromide in acetic acid and subsequent reductive elimination with a zinc-copper couple gave 242. The addition of acetic acid catalysed by TPPHBr afforded 204 in 18% overall yield. The final synthesis of 204 started with thiophenyl 2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside (269). A sequence of deacetylation, tosylation and LiAlH₄ reduction gave thiophenyl 2,3-O-isopropylidene-6-deoxy-α-D-mannopyranoside (274). The structure of 274 was confirmed from a single crystal X-ray diffraction study. Hydrolysis of the isopropylidene group of 274 and subsequent acetylation afforded thiophenyl 6-deoxy-2,3,4-tri-O-acetyl-α-D-mannopyrannoside (282). Treatment of 282 with iodine monobromide and subsequent reductive elimination with zinc-copper couple gave 242. The TPPHBr catalysed addition of acetic acid to 242 afforded 204 in 19% overall yield. Differentially protected C-glycosyl donor, 1,3-di-O-acetyl-4-O-benzyl-2,6-dideoxy-D-mannopyranose (265), was synthesised from 274. The benzylation of 274 gave thiophenyl 6-deoxy-2,3-O-isopropylidene-4-O-benzyl-α-D-mannopyranoside (276). Acidic hydrolysis followed by acetylation afforded thiophenyl 6-deoxy-1,2-di-O-acetyl-4-O-benzyl-α-D-mannopyranoside (278) which, upon bromination by iodine monobromide, gave thiophenyl 6-deoxy-1,2-di-O-acetyl-4-O-benzyl-α-D-mannopyranosyl bromide (279). The reductive elimination of 279 with zinc-copper couple gave 3-O-acetyl-4-O-benzyl-6-deoxy-D-glycal (264). The TPPHBr catalysed addition of acetic acid to 264 afforded 1,3-di-O-acetyl-4-O-benzyl-2,6-dideoxy-D-mannopyranose (265) in 16% overall yield from 274. The instabillity of bromide 279 affected the yield of 265. A C-glycosylation study of 2-naphthol 227 and 1,4-dimethoxy-5-hydroxynaphthalene (205) with 2-deoxy-glycosyl acetates was undertaken. Boron trifluoride diethyl etherate (BF₃.Et₂O) and scandium triflate [Sc(OTf)₃] proved effective promoters. For example, the glycosylation reaction of donor 265 and 227, promoted by 0.5 equivalents of Sc(OTf)₃, afforded C-glycoside 2-hydroxy-1-[3�-O-acetyl-4�-O-benzyl-2,6-dideoxy-β-D-manno-hexopyranosyl]-naphthalene (289) in 85% yield.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on February 13, 2008) Vita. Includes bibliographical references.