Graduation date: 1993

More than 30 members of the diverse amphidinolide family of biologically active macrolides have been isolated over last three decades. From this family, amphidinolides C and F stand among the most complex and densely functionalized affiliates. Recently, we have accomplished the first total synthesis of amphidinolide F. The all-carbon framework of amphidinolide C has been synthesized. During endeavor toward the total syntheses of amphidinolides F / C, we have uncovered a "hidden symmetry element" present in the northern and southern domains of amphidinolides F / C. The southern C₁-C₈ and northern C₁₈-C₂₅ tetrahydrofuran segments were derived from a common intermediate. A scalable silver-catalyzed isomerization / cyclization on propargyl-benzoate / diol furnished the common intermediate in multigram quantity. The common intermediate provided access to over half of carbon backbone of the macrocycle as well as majority of stereochemistry present in amphidinolides F / C. Two strategically different techniques have been developed for the C₉-C₁₁ diene preparation. A metal-catalyst free Weinreb amide-vinyl lithium coupling / methylenation sequence furnished the diene motif. Alternately, diastereoselective addition of a dienyl iodide derived 2-lithio-1,3-diene species to an α-oxy aldehyde installed the C₉-C₁₁ diene and secured the C₈ stereochemistry in single operation. The dienyl iodide was prepared via a regioselective hydrostannylation on an enyne. A challenging alkylation between an α-branched sulfone and an α-silyloxy iodide generated the all-carbon frameworks of amphidinolides F / C. An efficient oxidative desulfurization incorporated the carbonyl moiety at C₁₅. The protecting group on C₁₈ alcohol was found to have significant effect on the sulfone-iodide alkylation / oxidative desulfurization sequence. Installation of chelating ethoxyethyl ether on C₁₈ alcohol helped the successful incorporation of C₁₅ ketone and solved the deprotection problem in advanced stage of synthesis. A detailed analytical and computational study on proline sulfonamide-catalyzed aldol reactions has been performed. The pKa value of a proline sulfonamide catalyst was determined experimentally via NMR titration technique. Computational study revealed the origin of enhanced stereoselectivity by proline sulfonamide catalysts over parent proline. The non-classical hydrogen bonding interactions were found to be responsible for improved diastereoselectivity. / Graduation date: 2013

Herein is described our work towards the total synthesis of the marine natural product (±)-chartelline C and the potent antibiotic (-)-platensimycin. Part 1 relates the (±)-chartelline C project. The first chapter reviews (±)-chartelline C’s isolation, biogeneity, and previously reported studies relevant to the area. Chapter 2 tells of our contributions including the development of a convergent, regioselective assembly of an indole-imidazole compound en route to the natural product. Chapter 3 includes the experimental details of this work and the characterization of previously unreported compounds. Part 2 recounts the (-)-platensimycin research project. Chapter 4 discusses the importance of the natural product and the relevant previous research reported. Chapter 5 describes our efforts in this area, culminating in the stereoselective synthesis of an intermediate closely related to a known compound, which was converted to the natural product. Chapter 6 includes the experimental details of this work and the characterization of previously unreported compounds. / text

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

No description available.

The total synthesis of the biologically active, dextrorotatory enantiomer of 3-methyl-7(beta)-phenylacetamido-(DELTA)('3)-O-2-isocephem-4-carboxylic acid was accomplished. The key step involved the asymmetric cycloaddition of azidoacetyl chloride to the cinnamylidene Schiff base of protected D-threonine to generate the desired monocyclic cis (beta)-lactam diastereomer (9:1). The absolute configuration of the final product was confirmed by comparing its antimicrobial activity with that of the corresponding racemate. / The influence of (a) the (beta)-chiral center in the starting (alpha)-amino acid, (b) the bulk of the carboxylic acid and (c) the distribution of bulk throughout the imine on the stereochemical outcome of the reaction was studied. The absence of racemization during the cycloaddition was demonstrated by the use of deuterated precursors. The great potential of D-glucosamine derivatives as chiral templates in this reaction was clearly illustrated.

The syntheses of the cephalosporin analogs cis-N-(2'-hydroxyphenyl)-3-phenylacetamido-4-hydroxymethyl-2-azetidinone (37), cis-N-(2'-hydroxy-5'-nitrophenyl)-3-phenylacetamido-4-hydroxymethyl-2-azetidinone (59) and 7-(beta)-phenylacetamido-3'-hydroxybenzo{3,4}-0,2-isocephem (77) are described. Compounds 37 and 59 were devoid of antibacterial activity, while (beta)-lactam 77 showed weak activity against two micoorganisms. / Two new ring systems, 2-phenylcarbapenams 146 and 157 have been prepared. These are key intermediates in the syntheses of phosphonic acid carbapenam 148 and the carboxylic acid derivative 158, respectively. / The one carbon homologation of (beta)-trimethylsilyl-(alpha),(beta)-unsaturated esters with diazomethane was extended to the corresponding (beta)-trimethylsilyl or (beta)-t-butyldimethylsilyl aldehydes.

No description available.

Bibliography: leaves 181-187 / 187 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--Dept. of Organic Chemistry, University of Adelaide, 1986

No description available.