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This thesis focuses on the use of unsaturated aldols as useful substrates in natural product synthesis. Two methodologies have been investigated for the asymmetric synthesis of highly substituted lactones containing multiple contiguous stereocentres from unsaturated aldol precursors. These lactones have potential application as building blocks for natural product synthesis. Firstly, synthetic applications of the retro aldol reaction are reviewed. The second chapter describes a novel methodology for the asymmetric synthesis of highly substituted δ-lactones from syn-aldol cyclopropanes iii. Mercury mediated cyclopropane ringopening of the methyl ester cyclopropanes iv followed by concomitant cyclisation produced organomercurial δ-lactones v, which subsequently undergo reductive demercuration in basic sodium borohydride to afford the highly substituted δ-lactones vi in good yield and excellent diastereoselectivity. The scope of this method was investigated with variation of the R1 and R2 groups. The synthetic utility of this process was also demonstrated with the synthesis of a series of (+)-Prelactone natural products. The third chapter decribes a method of preparing hydroxy-γ-butyrolactones (viii-x) containing multiple contiguous stereocentres in high yield with good diastereoselectivity. Upjohn dihydroxylation conditions using catalytic osmium tetroxide were employed to β-alkenyl-β- hydroxy-N-acyloxazolidin-2-ones vii with different alkene substitution patterns. This resulted in the formation of triols that underwent spontaneous intramolecular 5-exo-trig cyclisation reactions to afford hydroxy-γ-butyrolactones viii, ix or x depending on the substitution pattern of the alkene precursor.

Unsaturated fatty acids of known degree, position, and configuration of unsturation were esterified, and stereospecifically dihydroxylated at the double bond(s). cis-Hydroxylation was effected using Woodward's reagent (silver acetate/iodine/acetic acid), while trans-hydroxylation was effected using Fenton's reagent (hydrogen peroxide/ferrous sulfate/acetic acid). Diols derived from monounsaturated esters were recovered quantitatively, while tetraols derived from diunsaturates were lost, presumably during extensive washing. The stereospecifically dihydroxylated esters were analyzed by thin-layer chromatography on borate-impregnated silica gel plates, and by gas-liquid chromatography, on a nonpolar capillary column, as the trimethylsilyl, acetyl, n-butylboronyl, isopropylidene, and trifluoroacetyl derivatives. For each derivative, the erythro and threo diols were readily separable, and some resolution of positional isomers was observed. Thus, the cis/trans configuration, and in some instances, the position of unsaturation of the original monounsaturated fatty acid may be deduced. However, gas chromatography-mass spectrometry of appropriately derivatized diol esters is required for unambiguous determination of position of unsaturation in most cases. These reactions are simple, use readily available reagents, and require relatively little operator attention. Further, they do not require specialized apparatus, as do hydrogenation and ozonolysis, or potentially toxic chemicals, such as osmium tetroxide. This series of analyses was applied to the unsaturated non-hydroxylated fatty acids of Legionella species, which were shown to be monounsaturated and of the cis Δ9 family. Position of unsaturation was confirmed by gas chromatography-mass spectrometry.

Synthetic efforts toward fumonisin analog were described. These are accomplished via amino acid Schiff base methodology. These efforts can be divided three major phases. First, tandem reductive alkylation with DIBAL/TRIBAL and different types of organo-lithium or Grignard nucleophiles provided threo-amino alcohol with excellent stereoselecitivites (2-27:1). The reductive alkylation utilized most hydrocarbon nucleophiles, e.g. alkyl-, vinyl-, alkenyl-, phenyl-, and dienyl-, and afforded high selectivites unless donor solvents (e.g. THF and Et2O) were used. Second, syntheses of the protected threo-γ-amino-β-hydroxy aldehydes and their stereoselectivities were introduced. The reductive alkylated threo-amino allyl alcohol was transformed via Brown’s hydroboration/oxidation protocol with 9-BBN, followed by TEMPO oxidation to give the resultant aldehydes in reasonable yields. Then, TBDPS and Schiff base protected aldehyde was coupled with phenyl- and decyl Grignard reagents to obtain predominant 3,5-anti-diols (ca. 80:20 anti:syn), characterized by ¹³C NMR analysis of Rychnovsky’s 1,3-acetonide groups. Products can be useful analogues for fumonisin and 5-hydroxy-sphingosine due to their structural similarity. Third stage involved the synthesis of C₁₁-C₂₀ fragment analog of fumonisin. Chiral auxiliaries (e.g. Evans and Myers) were administrated for stereoselective methylation, Sharpless asymmetric dihydroxylation in the presence of (DHQ)2PHAL catalyst was performed to form 1,2- syn-diols, and the manipulation of protection/deprotection and Finklestein reaction furnished C₁₁-C₂₀ fragment analog of fumonisin.

This thesis describes the development of chiral auxiliary based methodologies for the asymmetric synthesis of hydroxylated !-lactones and "-lactones containing multiple contiguous stereocentres. The first chapter introduces the concept of chirality and provides a general overview of the range of strategies available for the preparation of chiral molecules in enantiomerically pure forms. The second chapter critically reviews the range of synthetic methodology that is currently available for the asymmetric synthesis of chiral #-lactones that are either natural products or useful chiral building blocks for synthesis. The third chapter describes the development of novel methodology for the epoxidation/lactonisation of a range of $-vinyl-syn-aldols to directly afford !-lactones containing up to four contiguous stereocentres in high de. These reactions were shown to proceed via a mechanism whereby hydroxyl-directed diastereoselective epoxidation is followed by intramolecular attack of their !-acyl-oxazolidin-2- one fragment, to directly afford the desired chiral !-lactone. The ‘self-cleavage’ aspect of these reactions was exploited to enable this methodology to be transferred to polymer-support using an immobilised Evans’-oxazolidin-2-one for asymmetric synthesis. Chapter 4 describes the development of a complementary methodology for the asymmetric synthesis of this type of hydroxylated !-lactone based on a strategy involving dihydroxylation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols using catalytic amounts of osmium tetroxide. This methodology was developed as part of a reinvestigation of previously reported dihydroxylation reactions by Dias and coworkers, where we have clearly shown that the stereochemistry of thelactones reported in their paper have been incorrectly assigned. This diastereoselective dihydroxylation methodology has been successfully applied to the asymmetric synthesis of the natural product deoxyribonolactone. Finally, Chapter 5 describes the development of methodology for the asymmetric synthesis of chiral "-lactones containing four contiguous stereocentres of use as potential chiral building blocks for the synthesis of polyketide natural products. In this approach, cyclopropanation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols occurs under the sterodirecting effect of the $- hydroxyl group to afford cyclopropyl-aldols in very high de. These cyclopropyl-aldols are then ring opened in the presence of mercuric ions, with their N-acyl-oxazolidin-2-one fragment acting as an internal nucleophile, to afford highly functionalised alkyl-mercury species that may be subsequently reduced to afford their corresponding "-lactones in high de.

Doctor of Philosophy (PhD), Science / A concise stereo-selective synthesis of a protected form of APTO 1, an unusual amino acid component of microsclerodermin C 2, was undertaken. Sequential Sharpless Asymmetric Aminohydroxylation (AA) and Asymmetric Dihydroxylation (AD) reactions were used to introduce the chiral amino and hydroxyl groups. Specific directing groups were chosen to ensure high regio- and enantio-selectivity in these reactions. The target compound was reached in a linear reaction sequence of fourteen steps. The strategy was designed to generate common intermediates which could be used to access analogous amino acid fragments in other microsclerodermins. A protected form of AETD 3, from microsclerodermin E, was synthesised via a late-stage common intermediate. Initial studies into the modification of the sequence to allow access to AMPTD 4 and 10-methyl AMPTD 5 were made.

Compounds containing the 2,3-dioxabicyclo[2.n.n] moiety, otherwise known as bicyclic endoperoxides, are a class of cyclic peroxides that are readily found in nature and can be utilized as important synthetic building blocks. The chemistry of endoperoxides has chiefly been concerned with the relative weakness of the peroxide bond, with comparatively little attention directed towards transformations of the alkene unit within these compounds. Therefore the focus of this thesis is on dihydroxylation of bicyclic endoperoxides and examination of their further utility. A broad range of 1,4-disubstituted-2,3-dioxabicyclo[2.2.2]oct-5-enes were synthesized featuring a variety of alkyl and aryl substituents. These compounds were subsequently dihydroxylated with osmium tetroxide to yield diols anti to the peroxide linkage, as single diastereomers, in excellent yields. Reduction of the peroxide bond afforded cyclohexane-1,2,3,4-tetraols of toxocarol relative stereochemistry in excellent yield; this configuration of hydroxyl groups is quite prevalent in nature. In order to demonstrate the synthetic scope of dihydroxylation of bicyclic endoperoxides followed by reduction of the peroxide linkage, tetraol formation from alkyl and aryl substituted diols was examined. It was confirmed that both alkyl and aryl substituents can be tolerated in the 1,4-positions. Dihydroxylation of endoperoxides containing H atoms at the 1,4-positions was also documented. The methodology of dihydroxylation followed by reduction of the peroxide linkage was employed to synthesize the reported natural product (1S,2R,3S,4R,5R)-2-methyl-5-(propan-2-yl)cyclohexane-1,2,3,4-tetrol in a short sequence from (R)-α-phellandrene. The 2,3-dioxabicyclo[2.2.2]octane-5,6-diols discussed above were also found to undergo an extremely clean rearrangement to yield 1,4-dicarbonyls and glycoaldehyde, a rearrangement not reported in the literature. The possible mechanism of this rearrangement was probed and is discussed in detail. The repercussions of diol orientation to product outcome were also investigated. Finally, the possibility of expanding the scope of synthetic application for this rearrangement, particularly the potential for synthesis of optically pure 1,4-dicarbonyls is discussed. Some preliminary results are reported. / Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2009

Doctor of Philosophy (PhD), Science / A concise stereo-selective synthesis of a protected form of APTO 1, an unusual amino acid component of microsclerodermin C 2, was undertaken. Sequential Sharpless Asymmetric Aminohydroxylation (AA) and Asymmetric Dihydroxylation (AD) reactions were used to introduce the chiral amino and hydroxyl groups. Specific directing groups were chosen to ensure high regio- and enantio-selectivity in these reactions. The target compound was reached in a linear reaction sequence of fourteen steps. The strategy was designed to generate common intermediates which could be used to access analogous amino acid fragments in other microsclerodermins. A protected form of AETD 3, from microsclerodermin E, was synthesised via a late-stage common intermediate. Initial studies into the modification of the sequence to allow access to AMPTD 4 and 10-methyl AMPTD 5 were made.

Au niveau industriel, l'accès aux acides azélaïque et pélargonique, composés à forte valeur ajoutée, est possible grâce à une réaction d'ozonolyse de l'acide oléïque. Cependant, cette méthode présente certains désavantages sur le plan écologique. Le but de cette étude a donc été de développer une méthode alternative à ce procédé industriel, visant à limiter autant que possible les impacts écologiques, directs ou indirects, lors de la synthèse des acides azélaïque et pélargonique. Nous avons ainsi montré qu'un clivage en deux étapes peut être préférable à un clivage oxydant en une étape. Notre procédé propose ainsi, dans un premier temps, une dihydroxylation de la double liaison d'acides gras par une méthode connue, laquelle est suivie par un clivage oxydant en présence d'hypochlorite de sodium. Ce nouveau procédé mis au point au sein du laboratoire présente l'avantage de ne nécessiter l'emploi ni de métaux de transition, ni de solvant organique. Nous avons par la suite étudié l'hypochlorite de sodium afin de déterminer son rôle et son mode d'action dans la réaction de clivage de diols vicinaux / Industrial production of two high added value compounds called pelargonic acid and azelaic acid is made possible by the ozonolysis reaction of oleic acid. However, this method has numerous disadvantages in term of ecological impact. In this dissertation, we present an alternative to the current industrial process in order to lower direct or indirect negative environmental impacts when synthetizing azelaic and pelargonic acids. At first we demonstrate that a two-step oxidative cleavage may be preferable to a one-step cleavage. Then we present in details a novel synthesis method which starts with the dihydroxylation of the fatty acids double bond using a well known method, followed by the oxidative cleavage in presence of sodium hypochlorite. One notes that this original fabrication process developed in our laboratory does not require to use transition metals nor organic solvents. As a complement to this work, we have subsequently studied the sodium hypochlorite to determine its role and operating mode in the vicinal diols cleavage reaction