Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first part of this thesis deals with the syntheses of ovalicin and its analogues. Ovalicin inhibits the endothelial cell proliferation. Apart from being anti-angiogenic it also exhibits antibiotic, antitumor, and immunosuppressive properties. Unlike other syntheses, we started with an acyclic compound, ethyl propiolate (1.66). Our flexible route towards the synthesis used intramolecular Heck cyclization reaction to construct an appropriately functionalized 3-methylene-6-(tert-butyldimethylsilyloxy)cyclohexene (1.63) from 1.66 in four steps. A number of synthetic analogues were synthesized via this strategy. Upon selective epoxidation and dihydroxylation of 1.63, a mixture of diols (3S*,4R*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.107) and (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.108) were obtained. Subsequent functional group transformations of diols 1.107 and 1.108 gave ketones (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan-4-one (1.112) and (3S*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan -4-one (1.117). Addition of vinyl lithium to the ketones followed by functional group transformation gave ovalicin analogues. Several intermediates were subjected to biological activity test for inhibition of growth of T. brucei. Our synthetic efforts towards the synthesis of ovalicin are discussed. The second part of my thesis deals with the synthesis of different tricyclic pyrone (TP) analogues which inhibit the aggregation of Aβ peptides. Alzhemier’s disease (AD) is caused by accumulation of fibrillar amyloid deposits in the AD brain. We synthesized a series of tricyclic pyrone derivatives and evaluated their counteraction on amyloid toxicity. TP analogue, (5aS,7S)-7-[(1R) and (1S)-2-(N3-adenyl)-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3 -b] [1] benzopyran (CP2) is nontoxic, small and permeable molecule prevents the death of human neuroblastoma MC65 cells that conditionally expressed SβC gene. We further found that CP2 ameliorates the toxicity and inhibits the formation of Aβ oligomeric complexes. Binding studies using surface plasma resonance and atomic force microscopy studies suggest that CP2 permeates into the cells and interacts with Aβ peptides and inhibits the Aβ oligomerization. To understand the mechanism of Aβ aggregation and toxicity, CP2 and its derivatives are synthesized to evaluate their action. The key intermediate in the synthesis of CP2 is (5aS*,7S*)-7-[(1R*) and (1S*)-2-bromo-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3-b][1] benzopyran (2.9), which in turn can be prepared from our previously reported method. Our aim is to synthesize a series of compounds and investigate the biological activities of different TP analogues.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / I. Ovalicin is a natural product isolated from the culture of fungus Pseudorotium ovalis Stolk, it selectively inhibit type 2 methionine amino-peptidase (MetAP 2), which related to many physiological activities such as angiogenesis. Total synthesis of [plus or minus] ovalicin, its C4(S*), C4(S*)C5(S*) stereo-isomers, and C5 regio-isomer were synthesized via an intramolecular Heck reaction of (Z)-3-(t-butyldimethyl silyloxy)-1-iodo-1,6-heptadiene utilizing a catalytic amount of palladium acetate. Subsequent epoxidation, dihydroxylation, methylation (or stereochemistry inversion before or after methylation) and oxidation led to a variety of ketones, key intermediates for synthesis of ovalicin and its analogues. Introduction of side-chain to ketones by lithium (Z)-6-methylhepta-2,5-dien-2-ide and following functional group transformation led to ovalicin and its analogues. Anti-trypanosomal activities of various ovalicin analogues and synthetic intermediates were evaluated. II. Bio-based polymers from vegetable oils are renewable and environment-friendly materials. Dihydroxylated, trihydroxylate, tetrahydroxylated and hexahydroxylated triglycerides, triamino and triisopropylamino glycerides were synthesized from model triglyceride glyceryl trioleoate. These monomers were cross-linked with 1, 4-phenylene diisocynate to make polyurethanes and polyureas. The physical properties of these polymers were examined by gel content and swelling value measurements, thermodynamic and viscoelastic properties were studied from TGA, DSC and DMA measurements. The structure-property relationship was discussed based on these measurements. III. Diacetylenic fatty acids were widely applied in material science to regulate alignment on surface and stabilize self-assembled nanomaterials. A novel synthetic method of diacetylenic fatty acids from vegetable oils was developed. Its self-assembling properties on alumina surface were measured and discussed.