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No description available.

Cephalotaxine is a naturally occurring alkaloid which is the structural motif of a number of compounds which have shown promising anti-cancer properties. This fact together with its relatively complex pentacyclic structure, which incorporates an azaspirocycle annular to a benzazepine moiety, has resulted in its popularity as a synthetic target. The aim of this project was to synthesise the azaspirocycle of cephalotaxine using a Noyori annulation method involving the reaction of an enamine and an a,a' -dibromo ketone in the presence of Fe2{CO)9. In the first attempt the reaction of l-benzyl-2-methylenepyrrolidine (117) with methyl 2,4-dibromo-3-oxobutanoate (116) proved to be unsuccessful, the electron withdrawing ester functionality of methyl 2,4-dibromo-3-oxobutanoate (116) being unable to stabilise the intermediates formed during the reaction and thus resulting in its failure. Reaction of l-benzyl-2-methylenepyrrolidine (117) and 2,4-dibromo-3-pentanone (114) resulted in the formation of an azaspirocycle though in an extremely poor yield and the reaction was deemed inefficient for the synthesis of the cephalotaxine spirocycle. Finally, reaction of 2-(l-benzyl-2-pyrrolidinylidene)acetonitrile (129) and 2,4-dibromo-3-pentanone (114) resulted in the successful synthesis of a novel azaspirocycle. The product, l-benzyl-7,9-dimethyl-8-oxo-1-azaspiro[4.4]nonane-6-carbonitrile (130), contained four stereogenic centres and one of the diastereomers was successfully crystallised out. The X-ray structure in conjunction with NOESY NMR experiments showed the relative stereochemistry to be 5s', 6s', 7s', 9s'. Significant progress was made in the application of this methodology to the construction of the cephalotaxine pentacyclic skeleton with the synthesis of a novel lactam, 1-[2-(6-iodo-I,3-benzodioxol- 5-yl)ethyl]-2-pyrrolidinone, being achieved. In the course of this work a novel compound, 2-(6-Iodo-1 ,3-benzodioxol-5-yl)ethyl 4-methylbenzenesulfonate (98), was also synthesised and its X-ray structure revealed it to be conformationally interesting. As a result a conformation analysis study was carried out on this compound as well as 2-(6-Iodo-I,3-benzodioxol- 5-yl)ethyI 4-nitrobenzenesulfonate (15a). The Noyori annulation reaction was not implemented in the route to the basic pentacyclic structure of cephalotaxine due to time constraints, however synthesis of analogues of cephalotaxine and other alkaloids possessing azaspirocycles should now be possible based on the methodology developed in this project. / Thesis (M.Sc.)-University of Natal Pietermaritzburg, 2001.

Cylindricines A-K [1-11], lepadifonnine [12] and fasicularin [13] are tricyclic ascidian alkaloids exhibiting the perhydropyrrolo[2,1 :j]quinoline and perhydropyrido[2,1-j]quinoline ring systems. The structural features and biological activity of these alkaloids make them ideal targets for total synthesis. The first aim of this project was to construct the azabicycles [111] and [112] that resemble the spirocyclic core of these alkaloids. The synthesis began with the C ring intact and the attempted construction of the B ring using Diels-Alder methodology. A key step was the Eschenmoser coupling reaction between thiolactams [105] and [106] to give the vinylogous amides [107] and [108]. All attempts to convert the vinylogous amides to the corresponding dienes proved to be unsuccessful, due to the fact that the preferred site for deprotonation was ~ to nitrogen and not a to the carbonyl group. Due to time constraints we moved to our second aim, the enantioselective synthesis of the B and C rings offasicularin [13]. Significant progress was made towards our second goal. (5S)-5-Hydroxytetrahydro2(lH)pyridinone [127], which represents the C ring of fasicularin, was successfully synthesized in 5 steps from L-glutamic acid [113]. This lactam was O-protected with tertbutyldiphenylsilyl group to afford (5S)-5-tert-butyldiphenylsilyloxy-2-piperidinone [114]. Thionation of lactam [114] gave the thiolactam [160]. Conjugate addition of this thiolactam to methyl acrylate gave methyl 3-[(5S)-5- {[tert-butyl(diphenyl)silyl]oxy}-2-thioxotetrahydro1(2H)-pyridinyl ]propanoate [163], which underwent a Eschenmoser coupling reaction with bromoacetone to gIve methyl 3-[(5S)-5-{ [tert-butyl(diphenyl)-silyl]oxy} 2-[(£)-2oxopropylidine] tetrahydro-2(1H)-pyridinyl]propanoate [164]. Unfortunately conversion of [164] into the corresponding diene using KHMDS and TBSCI was unsuccessful. The reaction conditions caused the cleavage of the methyl acrylate protecting group on nitrogen, affording the secondary E-vinylogous amide [167]. This constituted an important serendipitous discovery - methyl acrylate can be used to protect the nitrogen atom of enaminones and can be removed by KHMDS to access secondary E-enaminones that are otherwise difficult to synthesise. Another route pursued was to introduce the hexyl chain in the A ring of fasicularin by means of an SN2 reaction between lactam [114] and mesylate [116]. The stereodefined (lR)1-(2-{[tert-butyl-(dimethyl)sily]oxy}ethyl)heptyl methanesulfonate [116] was successfully x synthesized in 5 steps from l-octyne [115]. Unfortunately the subsequent SN2 reaction with lactam [114] failed when we using t-BuOK and THF and time constraints prevented us from attempting this coupling reaction using alternative conditions. / Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2002.

PART I. The preparation of (-)-ibogamine (1) in fourteen steps from benzoquinone and in 10% overall yield is a powerful illustration of the value of the asymmetric Diels-Alder reaction as a starting point in a multistep synthesis. All four cycloadducts, 70, 77, 84 and 96, obtained with the (S)-BINOL-TiCl��� complex were found to have the same absolute configuration. Furthermore, they are in the same enantiomeric series that Mikami observed with 1,4-naphthoquinone using the same catalyst, lending confidence to future stereochemical predictions that may be made with this system. PART II. Three different routes for the synthesis of the hexahydroisoquinoline 98 met obstacles which defeated our approach to koumine. The Diels-Alder reaction of cyclic 1-azadienes 102 and 108 was abandoned due to the lack of reactivity of the dienes. An anionic oxy-Cope rearrangement of the azabicyclo[2.2.2]octane system caused mainly decomposition of the starting materials. Finally, an intramolecular [2+2] photocycloaddition generated "crossed", "straight" and hydroisoquinoline products in varying ratios, depending on the substituent pattern of the substrate, but this approach was not synthetically useful. The results from this last study may be valuable for predicting the regiochemical outcome of certain intramolecular photocycloadditions. / Graduation date: 2003

Graduation date: 1998

Organolithiums are key reagents and intermediates in organic synthesis. An exciting and growing field is the use of organolithiums in enantioselective synthesis. The often complex nature of these compounds makes their implementation towards the synthesis of natural products or pharmaceutical targets a challenging yet rewarding endeavour. The ability of organolithiums to form carbon-carbon bonds in a stereoselective and predictable way is vital to their success in organic synthesis.<p> The first chapter in this thesis summarizes the current mechanistic understanding of asymmetric carbon-carbon bond formation adjacent to nitrogen. A brief literature review is presented to illustrate the different ways in which a stereoselective lithiation/substitution reaction at carbon can occur. A review of the application of dipole-stabilized carbanions a to nitrogen used in the stereoselective synthesis of natural products is presented.<p> The second chapter in this thesis describes a study of the use of N-Boc-3-pyrroline, and related compounds, as molecular scaffolds for the stereoselective synthesis of functionalized five-membered ring containing alkaloids. The asymmetric alkylation of N-Boc-3-pyrroline is possible for simple alkyl halides but only modest enantioselectivity can be obtained using chiral lithium amides or s-butyl lithium/(-)-sparteine as bases. More promising was the enantioselective alkylation of a protected 3-pyrroline building block 116. The assignment for the stereochemistry of the alkylated product from 116 and benzaldehyde was achieved by NMR techniques and conformational analysis. The work done on the synthesis of enantiomerically pure castanospermine analogs is also presented.

Organolithiums are key reagents and intermediates in organic synthesis. An exciting and growing field is the use of organolithiums in enantioselective synthesis. The often complex nature of these compounds makes their implementation towards the synthesis of natural products or pharmaceutical targets a challenging yet rewarding endeavour. The ability of organolithiums to form carbon-carbon bonds in a stereoselective and predictable way is vital to their success in organic synthesis.<p> The first chapter in this thesis summarizes the current mechanistic understanding of asymmetric carbon-carbon bond formation adjacent to nitrogen. A brief literature review is presented to illustrate the different ways in which a stereoselective lithiation/substitution reaction at carbon can occur. A review of the application of dipole-stabilized carbanions a to nitrogen used in the stereoselective synthesis of natural products is presented.<p> The second chapter in this thesis describes a study of the use of N-Boc-3-pyrroline, and related compounds, as molecular scaffolds for the stereoselective synthesis of functionalized five-membered ring containing alkaloids. The asymmetric alkylation of N-Boc-3-pyrroline is possible for simple alkyl halides but only modest enantioselectivity can be obtained using chiral lithium amides or s-butyl lithium/(-)-sparteine as bases. More promising was the enantioselective alkylation of a protected 3-pyrroline building block 116. The assignment for the stereochemistry of the alkylated product from 116 and benzaldehyde was achieved by NMR techniques and conformational analysis. The work done on the synthesis of enantiomerically pure castanospermine analogs is also presented.

Part1: Application of electrooxidation reaction toward the synthesis of atropine allcaloids and synthesis of cocaine alkaloids. Part2: Application of electroreduction reaction toward the synthesis of yohimbine alkaloids.

Marine sponges produce a series of complex polycyclic diamine alkaloids which appear to have a common biogenesis from simple bis-pyridine macrocycles. These structurally novel secondary metabolites are presumably biosynthetically produced by the controlled ionic coupling of macrocyclic 3-alkyl piperidines leading to 3,4??-linked bis-piperidines (ii). Included among these diamine marine alkaloids is haliclonacyclamine C (i) which serves as our synthetic target. Chapter I in this thesis provides background information describing biological activity and proposed biosynthetic pathways to these important diamine marine alkaloids. Chapter II details progress towards the total synthesis of haliclonacyclamine C. The focus of Chapter II will be on our successful construction of the 3,4??-linked bispiperidine central core (ii) highlighted by the use of palladium-mediated C-C bond forming processes. The stereoselective hydrogenation of a coupled product will also be discussed.