Examination of the scope of the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction as well as the development of a domino [Rh(CO)₂Cl]₂-catalyzed allylic alkylation/Pauson Khand reaction is described. A number of experiments were carried out in order to explore the novel regioselectivity in the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction, and the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction was found to give products resulting from attack of the nucleophile on the carbon bearing the leaving group in a highly regioselective fashion in most cases. Examination of allylic carbonate substrates containing similar substitution at each allylic site was carried out, and conditions that minimize equilibration of active intermediates were determined. Intramolecular [Rh(CO)₂Cl]₂-catalyzed allylic alkylation was accomplished to synthesize challenging eight-membered lactone ring systems. Nucleophile scope was explored with regards to the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction, and malonates, substituted malonates, aliphatic amines, and ortho-substituted phenols were all determined to be effective in the reaction. A domino [Rh(CO)₂Cl]₂-catalyzed allylic alkylation/Pauson-Khand reaction was developed which allows the rapid synthesis of bicyclopentenone products from simple, readily available starting materials. The first application of the Pauson-Khand reaction to the synthesis of azabridged bicyclic structures is also described. Various cis-2,6-disubstituted piperidines were cyclized to the corresponding azabridged bicyclopentenones is high yields often in high diastereoselectivities. The effect of ring size, nitrogen substituent, and remote functionality on the Pauson-Khand substrates was studied. The methodology developed was applied to the concise, enantioselective total synthesis of the antimalarial and anticancer indole alkaloid (-)-alstonerine. Pauson-Khand reaction of a readily available enyne synthesized in four steps from L-tryptophan provided a cyclopentenone in high yield as one diastereomer. Elaboration of the Pauson-Khand product required the development of a one pot conversion of a five-membered cyclic silyl enol ether to a sixmembered lactone and the mild acylation of a glycal.

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Master / Master of Philosophy

The natural alkaloid himbacine 1, first isolated in 1955 from Galbulimina baccata Bail, has attracted attention as a potential therapetic agent for Alzheimer's disease. It is proposed that a late stage in the biosynthesis of this compound may proceed via an iminium ion mediated Diels-Alder reaction (Scheme 1), which would yield the related alkaloid himgravine 2, which can be reduced to himbacine 1. Precident for the iminium ion mediated Diels-Alder reaction has been provided by a related oxonium ion mediated cycloaddition reaction (Scheme 2). Confirmation of the stereochemistry of the product of this reaction has been obtained by X-ray crystallography of the tricyclic alcohol. Studies towards the synthesis of the iminium ion have been undertaken. Piperidine sulfone has been synthesised in a 17% yield over 16 linear steps, and a synthesis of dihydrofuran has been investigated involving an enyne metathesis reaction. Additionally, methodology has been developed for a Julia coupling to join piperidine sulfone to dihydrofuran, and a Polonovski reaction for generation of the required iminium ion.

M.Sc. (Chemistry) / The aim of this study was to investigate alternative routes for the stereocontrolled synthesis of hydroxylated indolizidine, piperidine and pyrrolidine alkaloids, starting from monosaccharides as chiral building blocks. This study was not aimed at improving consisting routes - it was rather aimed at developing new routes towards the synthesis of these alkaloids. Mixed results were obtained in the investigation into alternative routes for the synthesis of the bicyclic poly hydroxylated indolizidine alkaloids, but a new and efficient stereospecific synthesis of polyhydroxylated piperidine- and pyrrolidine alkaloids were developed. The aims and results can be summarised in more detail as follows: a. Stereospecific synthesis of castanospermine. The synthesis of this medium sized nitrogen-containing bicyclic molecule was approached in a unique way. The utilization of bifunctional Wittig- and Wittig-Horner reagents containing nitrogen functionalities was considered promising for the aims of this study. By the usage of known reactions, e.g. Wittig, Wittig-Horner, Schiff-base and Aza-Wittig reactions, it was foreseen that these bifunctional reagents could be coupled in two concurrent steps to dicarbonyl compounds to form a nitrogen containing rings. Several nitrogen containing Wittig reagents were prepared. At the one end of these reagents a phosphonate or phosphine group furnished the phosphorus moiety while the other end of these reagents comprised the nitrogen moiety by reduction of a nitrile group or azide displacement of a leaving group. No coupling was obtained between these bifunctional reagents and a dicarbonyl compound derived from D-glucose and the influence of two functional groups in such close proximity in the Wittig reagent is being further investigated. Coupling was, however, achieved by the utilization of an alternative bifunctional reagent in which a Wittig-Horner reaction was used. The successful implementation of this unique methodology in the synthesis of medium size nitrogen containing ring is being further investigated.

No description available.

A general methodology for the synthesis of pyrrolizidine alkaloids has been developed. The two key steps in the sequence were the synthesis of the dienic azide system 1 and its regioisomer 2 by utilizing the vinylogous Reformatsky reaction, and the intramolecular additions of the azide moiety across the activated dienes with subsequent pyrolyses to provide the pyrrolizidines of type 3. This study broadened the scope of the vinylogous Reformatsky reaction to include the preparation of alkaloid synthons and introduced the heteroatom equivalent of the carbenoid [4+1] annulation as a method or alkaloid synthesis. [See docment for associated image] / M.S.

Thesis submitted in fulfilment of the requirements for the Degree of Masters of Technology: Organic Chemistry, Durban University of Technology, 2011. / One of the greatest medical challenges facing mankind is the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) which has now become a major epidemic with more than 40 million people infected worldwide. Of equal concern is its implication in high mortality and the onset of a number of opportunist mycobacterial infections, principally tuberculosis. In spite of the discovery of some relatively effective antiretroviral (ARV) drugs such as Azido Thymidine (AZT), Nevirapine (NVP) and Efavirenz (EFV), its’ application as either a single or combinational form causes side effects by harming the bone marrow. Drug resistance is a key cause of failure for treatment of HIV infection. Hence greater interdisciplinary efforts, involving both natural and social sciences, are needed urgently to combat this HIV/AIDS pandemic. Heterocyclic nitrogen based compounds, obtained from either natural sources or synthesis are adequately documented to have increased biological activity against several diseases. Recently a study of drugs containing the naphthyridine scaffold has acquired increasing attention because of its potential against HIV/AIDS. Generally, naphthyridines demonstrate good potency in both the enzyme and cellular systems and this prompted our interest in the synthesis of naphthyridine derivatives from simple and readily available starting compounds. Furthermore we wanted to form an intermediate quinolone moiety since it has good biological potential. In this study we report the synthesis of three naphthyridine derivatives, i.e. 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2- methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine from easily available chemicals such as aniline, ortho-toludine, para-toluidine and ethyl benzoylacetate via a five step reaction scheme using either conventional reflux, microwave irradiation or both methodologies. It was found that microwave irradiation was several folds faster than conventional reflux methodology and the yield of the product was higher. The first step of the reaction scheme is a simple condensation reaction: three acrylate derivatives, viz. ethyl-3-aniline-3-phenyl acrylate, ethyl-3-phenyl-3-(ortho-tolylamino) acrylate and ethyl-3-phenyl-3-(para-tolylamino) acrylate were synthesized by refluxing ethyl benzoylacetate in an acidified ethanolic solution with aniline, ortho-toluidine and paratoluidine respectively for three hours; the yields were 95, 87.5 and 80 % respectively. Page v In the second step, thermal cyclisation was achieved for the synthesis of three quinoline derivatives, viz. 2-phenylquinoline-4(1H)-one, 8-methyl-2-phenylquinoline-4(1H)-one and 6- methyl-2-phenylquinoline-4(1H)-one from their respective acrylates under microwave irradiation for 5 minutes at 180 °C and 250 watts; the yields were 92, 84 and 80 % respectively. In the third step of the reaction, synthesis of 4-chloro-2-phenylquinoline, 4- chloro-8-methyl- 2-phenylquinoline and 4- chloro-6-methyl-2-phenylquinoline was achieved from a mixture of POCl3 and their respective quinolines via microwave irradiation for 3 minutes at 75 °C and 150 watts and via conventional reflux for 5 hours. It was found that under microwave irradiation, the reaction occurred nearly 100 fold faster but the % yield of the product was marginally higher. The fourth step of the reaction resulted in the formation of three schiff’s base, viz. 4-(Nphenyl)- 2-phenyl-4-aminoquinoline, 8-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline and 6-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline from their respective quinolines via microwave irradiation for 20 minutes at 180 °C and 180 watts and via conventional reflux for 2 hours. It was found that under microwave irradiation, the reaction occurred nearly 6 fold faster and the % yield of the product was over 10 % higher. The final step of the reaction was achieved by a Vilsmeir Haack reaction and in situ base catalyzed thermal cyclisation: 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6- phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine were synthesized from their respective schiffs base via microwave irradiation for 20 minutes at 75 °C at 120 watts and via conventional reflux for 21 hours. It was found that under microwave irradiation, the reaction occurred over 60 fold faster and the % yield of the product was over 20 % higher.The outline for the five step synthesis of the three naphthyridines is presented graphically below: Page vi Key: (a) R1= H; R2=H (b) R1 = H; R2 = CH3 (c) R1 = CH3; R2 =H Reaction Conditions: 1) conc.HCl, EtOH, 3hrs, 50 °C; 2) conc. HCl, hand stirring 10 min; 3) 180 °C, MWI, 250 watts, 5 min; 4) POCl₃, MWI, 75 °C, 150 watts, 2 min; 5) POCl₃, 100 oC, 5 hrs; 6) aniline, t-BuOH, MWI, 180 °C, 180 watts, 20 min; 7) aniline, t-BuOH, 80 °C, 3 hrs; 8) DMF, POCl₃, MWI, 75 °C,120 watts 20 minute; 9) DMF, POCl3, 100 oC, 21 hrs.

Graduation date: 1993

The diastereoselective formal syntheses of the corynanthe alkaloid hirsutine and oxindole alkaloid rhynchophylline are described. The general approach features the use of ring-closing metathesis (RCM) to construct an [alpha],[beta]-unsaturated lactam, which is subjected to 1,4-addition. The lithium enolate of ethyl-1,3-dithiolane-2-carboxylate was identified as the optimal nucleophile in these systems. A key feature of this approach is that the stereochemical outcome of the 1,4-addition can be effectively controlled by appropriately sequencing the indole Boc-protection step to give either the C(3)-H/C(15)-H cis or C(3)-H/C(15)-H trans stereochemical relationship. As a result, we have developed a unified approach to both the "normal" and "pseudo" corynanthe alkaloids. This finding was highlighted through the synthesis of the complete carbon skeleton of the archetypal normal corynanthe alkaloid dihydrocorynantheol. An efficient synthesis of the tricyclic spiroindolinone ABC-fragment of the marine alkaloid citrinadin A has been achieved. The synthesis relies on a novel asymmetric oxidative rearrangement of an indole to an oxindole using a chiral auxiliary on the indole nitrogen to achieve facial selectivity. The transformation proceeds via the epoxidation of the indole C(2),C(3) double bond using DMDO, followed by a silica gelmediated 1,2-epoxide rearrangement. Using this tactic, the spirooxindole of citrinadin A, which contains two adjacent quaternary centers, was formed in high yield and excellent diastereoselectivity. Efforts toward the fragment coupling of the tricyclic spiroindolinone with a 2,4,6-trisubstituted piperidine coupling partner are described. / text