The objective of the research described in the first part of this thesis involves the application of carbon monoxide and transition metals in key steps of a synthetic route to lavendamycin, an antic cancer compound, and its analogues. Lavendamycin is a pentacyclic compound that possesses a quinoline-5,8-quinone AB ring linked to a b- carboline CED ring. The development of general routes to the synthetic equivalents of the lavendamycin AB quinoline system together with a linker atom, quinoline -2- carboxaldehydes, as well as to the lavendamycin DE indole ring system, namely tryptophan derivatives, was addressed. The Pictet-Spengler cyclisation approach towards lavendamycin involves the reaction between quinoline-2-carboxaldehyde and tryptophan methyl ester to furnish the pentacyclic precursor of the methyl ester of lavendamycin. This synthetic approach requires the availability of quinoline-2-carboxaldehydes, previously prepared by the oxidation of 2-methylquinolines with toxic selenium dioxide. A general strategy towards the synthesis of the AB ring moiety utilising a pre-formed ring system such as commercially available 8-hydroxyquinoline has been successfully developed. It involved the high pressure palladium catalysed formylation of 2-bromo or other suitable 2-substituted quinoline derivatives under syngas (1:1 CO:H2). The preparation of the required 2-substituted quinoline derivative involved the methylation of the 8-hydroxylgroup followed by N-oxidation and then a rearrangement step. In both the Pictet-Spengler and Bischler-Napieralski synthetic approaches to lavendamycin, the CDE ring moiety is introduced using tryptophan methyl ester as building block. The application of this approach to the synthesis of lavendamycin analogues with a substituted D-ring required the availability of substituted tryptophan methyl esters. A general strategy towards the tryptophan derivatives starting with a Wittig reaction between a suitable 2-nitrobenzaldehyde precursor and 1,3-dioxolan-2- yl-methyltriphenylphosphonium bromide, followed by a two-stage, one -pot rhodium catalysed hydroformylation/reduction reaction, has been successfully developed. This methodology yielded ten different possible tryptophan precursors in moderate to good yields. The second part of the research described in this thesis included the identification of factors effecting the rate and regioselectivity of palladium catalysed methoxycarbonylation of a-olefins. The results showed that fast reactions under polar conditions give mainly linear esters. However, reactions under less polar conditions are slower, yielding mainly branched esters. Detailed analysis of the results suggest the operation of a so-called “cationic” mechanism (involving cationic palladium intermediates) in the formation of mainly linear esters, but the operation of a so-called “neutral” mechanism (involving neutral palladium intermediates) in the formation of mainly branched esters. The nature of the phosphine ligands was found to play a significant, but secondary role in determining regioselectivity of methoxycarbonylation. Another objective was the optimisation of the palladium catalysed hydroformylation of a-olefins. An evaluation of the efficiency of the palladium catalysed hydroformylation process required a comparison with the hydroformylation processes based on cobalt and rhodium. Variation of ligands (diphosphines of the type R2P(CH2)nPR2), solvents, acids, etc. had a dramatic effect on the products and the rate of the reaction. In the presence of trifluoroacetic acid 1-pentene is converted to C-6 aldehydes, while in the presence of trifluoromethanesulfonic acid 1-pentene is converted to C-11 ketones. Corresponding results were obtained with 1-octene as substrate. The palladium catalysts were found to also effect isomerisation of the a- olefin into internal olefins, but isomerisation was not a rate limiting process with respect to the hydroformylation reaction. Palladium catalysed isomerisation reactions occurred at a slower rate than the corresponding cobalt catalysed isomerisation process. However, with rhodium no isomerisation occurred. The comparison between cobalt, rhodium and palladium showed that rhodium is the best catalyst for the hydroformylation of a-olefins. The pressures and temperatures required for this process are much lower than that required for palladium and cobalt. The ligand used is triphenylphosphine, which is relatively inexpensive and non-toxic,in contrast with the more expensive ligands required for the cobalt and palladium hydroformylation processes. The use of palladium opens up the unique possibility of converting a-olefins into “dimeric” ketones, which show promise as precursors for the new class of geminidetergents. / Prof. C.W. Holzapfel
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uj/uj:6983 |
| Date | 09 May 2008 |
| Creators | Ferreira, Alta Carina |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
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