Thesis (Ph.D.) - University of Queensland, 2003. / Includes bibliography.

Thesis (Ph. D.)--University of Wisconsin--Madison, 2007. / Includes bibliographical references (p. 179-185). Also available on the Internet.

Thesis (Ph.D.)--University of Wisconsin--Madison, 2007. / Includes bibliographical references (p. 196-206). Also available on the Internet.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Also available online.

Chapter 1 describes an introduction to the area of organocatalysis and delineates previous work within the Smith group on the use of isothioureas in asymmetric catalysis. Chapter 2 showcases a one-pot isothiourea-catalysed Michael addition-lactamisation using cheap and readily available starting materials (carboxylic acids) and easily prepared α,β-unsaturated ketimines via an ammonium enolate intermediate to give dihydropyridinones with high diastereo- and enantioselectivity (typically >90:10 dr, up to 99% ee). The resultant dihydropyridinones can be successfully derivatised into multiple products without erosion of stereointegrity. In chapter 3 the same concept has also been applied to the synthesis of planar molecules by using (phenylthio)acetic acid as a suiTable ammonium enolate precursor. Generation of an ammonium enolate using an achiral isothiourea (DHPB) and reaction with α,β-unsaturated trifluoromethyl ketones allows an isothiourea-mediated Michael addition / lactonisation / thiophenol elimination cascade reaction for the formation of 4,6-disubstituted and 3,4,6-trisubstituted 2-pyrones in good to excellent yields (61-99%). Notably this method allows low catalyst loadings of 1% to be used. The methodology has successfully been applied to the synthesis of a COX-2 inhibitor and a wide range of derivatisations has been performed, giving valuable aromatic and heteroaromatic products containing the trifluoromethyl motif. In chapter 4 a novel N- to C-sulfonyl migration of dihydropyridinones via photoisomerisation is investigated. The scope and limitations of this process is investigated and the process is shown to proceed without compromising the diastereo- or enantiomeric purity of the starting material, giving 5-sulfonyl products in good to excellent yields (67-95%). Mechanistic crossover has indicated that this migration includes an intermolecular step, while EPR studies provided evidence of its radical nature.

As part of a worldwide effort to develop efficient catalysts for use in organic chemistry and in the synthesis of highly valuable molecules, work performed during the course of my stay in St Andrews has focused on the design and synthesis of new group 11 metal complexes for their applications in catalysis. The aim of this work was to develop new, active and stable, easy to synthesise group 11 complexes and investigate their catalytic activity as well as to try to understand their mode of action. Two different types of complexes were explored in order to develop more active catalysts: the neutral N-Heterocyclic carbene metal complexes and the cationic derivatives. More than 20 new catalysts were developed and their reactivity studied in different catalytic reactions. New hydroxide and tert-butoxide copper(I) or silver(I) complexes were developed and compared to the common NHC metal systems. Overall, the neutral NHC-metal catalysts showed to be highly active in a broad range of applications: in the methylation of amines using CO₂ as a C1 source, in a multicomponent reaction (A³ coupling) and in dual catalysis (hydrophenoxylation). Additionally, mechanistic studies were undertaken to obtain a greater understanding of these transformations and to possibly lead to the design of new generations of catalyst. Regarding the cationic NHC metal complexes, a straightforward methodology was developed leading to a library of highly stable catalysts. Bis-NHC, mixed NHC/ phosphine as well as NHC/pyridine species were efficiently synthesised using thermal or microwave heating, in high purity and yields. In addition, the effect of the presence of two different or identical ligands on catalytic reactivity was investigated in the 3+2 cycloaddition and in the alkynylation of ketones. Insight into the catalytic cycle was obtained via mechanistic studies. These showcased the release of one ligand during the catalytic cycle and the crucial role of this ligand displacement in generating the catalytically relevant active species. The results highlight the importance of understanding the reactivity of catalyst in order to develop new and improved ones.

Ph.D. / The first part of the research described in this thesis involves the development of a new methodology for the synthesis of N-hydroxy pyrrolidines, starting from carbohydrates as building blocks. The products were identified as possible synthons for the stereocontrolled synthesis of isosteric analogues of polyhydroxylated indolizidine alkaloids. The consecutive reduction and cyclisation of selectively protected 5-0-mesyl hexose O-(tert-butyldiphenylsilyl) oximes to afford chiral N-hydroxy pyrrolidines is discussed. The mechanism involves a cascade of neighbouring group participation steps by the O-benzoyl protecting groups. This protocol gave rise to novel chiral N-hydroxy pyrrolidines in good overall yield. The choice of leaving group as well as a labile oxime protecting group proved to be of great import in the outcome of the cyclisation reactions. The second part of the research concerns the ongoing development in our laboratories of the synthesis of analogues of biologically active compounds. In this regard, we were interested in synthesising the aza analogues of f3-C-nucleosides and f3-C-glycosides. Our strategy involves the synthesis of a D-ribose derived chiral cyclic nitrone as the key synthon. A facile route towards cyclic nitrones was developed starting from suitably protected hemiacetals of Dribofuranose. Readily available tri-O-benzyl-D-ribofuranose was allowed to react with hydroxylamine hydrochloride to afford an acyclic oxime. Selective silylation followed by iodonation at C-5 (with inversion of configuration) furnished the cyclisation precursor. Anhydrous TBAF-mediated desilylation and subsequent intramolecular nucleophilic attack afforded a cyclic nitrone in excellent yield. Following the same protocol, 2,3-isopropylidene-5- 0-trityl-D-ribofuranose was converted into the corresponding nitrone. The 1,3-dipolar cycloaddition reaction of a nitrone to an alkene is an extremely powerful synthetic method for the creation of complex heterocyclic structures. The reaction of the Dribose derived nitrones with a,(3-unsaturated carbonyl compounds furnished the corresponding cycloadducts in good diastereomeric excess. The exo-product was isolated as the major isomer in each case. The reaction of a variety of carbon nucleophiles, including a Grignard reagent, with the nitrones led to the formation of interesting p-C-glycoside analogues. One of the carbohydrate nitrones was also converted into its thymine C-nucleoside analogue. This work clearly shows that the construction of chiral cyclic nitrones from D-ribose derivatives is an extremely efficient and simple procedure. The final part of the work described in this thesis involve the construction of CD-ring analogues of the natural metabolite, streptonigrin. The use of metalation and palladium catalysed cross-coupling reactions were investigated for the synthesis of highly functionalised biaryls. The synthesis and crystal structure determination of [3-(tert-butoxycarbonylamino)-4- pyridyl]-trimethyltin(IV) is discussed. The Stille cross-coupling reaction between an electron rich arylstannane and an electron poor aryl halide proved to be the most successful. The use of co-catalytic copper(I) had a dramatic effect on the overall yield and rate of this Stille crosscoupling reaction. This methodology would , in principle, allow the construction of the natural product and appropriate structural analogues.

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