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(Professor Jo Michael, Professor Charles de Koning, Dr Andy Dinsmore, Dr Steve Pelly, Associate Professor Willem van Otterlo)
The current programme in organic synthesis at Wits is a team effort involving the four organic chemistry staff members. Each team member spearheads a research theme, although intellectual input into all themes is a shared responsibility. Resources and laboratories are shared, and post-graduate students are jointly supervised by two staff members. This approach has worked extremely well for us, since the strategy has ensured that the younger team members have the opportunity of working with students and implementing their own research ideas while being mentored by the more experienced team members. Co-authorship of research publications arising from the programme provides a tangible reward for the participants.
 Work in progress includes
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THEME 1: Synthetic routes to nitrogen heterocycles, and applications to alkaloid synthesis
(Theme leader and overall programme coordinator: Prof Jo Michael)_____________________________________________________________________
Bioactive heterocycles containing nitrogen are extremely well represented in nature, and also dominate the pharmaceuticals industry. The objective in this theme is to devise novel, efficient and stereochemically well defined routes to saturated nitrogen heterocycles in particular, and adapt the methods to the enantioselective synthesis of alkaloids, antibiotics and related biologically active targets. Methodological studies in this theme centre on the synthesis and reactivity of thiocarbonyl compounds, beta-acylated enamines ("enaminones" N-C=C-Z, where Z is a conjugated electron-withdrawing group, e.g. COR, CO2R) and related compounds (e.g. Z = CN, NO2, SO2Ar). The ambident nucleophilic and electrophilic characteristics of these key intermediates are subsequently exploited in the synthesis of monocyclic, bicyclic and polycyclic nitrogen-containing heterocycles, especially alkaloids. In general, the enaminone serves as a scaffold onto which additional rings can be elaborated by intramolecular and intermolecular annulation processes, including metal-assisted coupling reactions. Diastereoselective and enantioselective transformations of enaminones incorporated into cyclic systems are crucial components of the project. Specific projects currently under way or completed in the recent past include methodological developments for, and total synthesis of, indolizidine and quinolizidine alkaloids from animals (ants and amphibians) and plants (lupin alkaloids, phenanthroindolizidines, hydroxylated glycosidase inhibitors); antimalarial quinazoline alkaloids (febrifugine and analogues); antibacterial and anticancer antibiotics (quinolones, aziridinomitosens). A key reference describing the general philosophy and approach was published in 1999 (J.P. Michael, C.B. de Koning et al., Pure Appl. Chem., 1999, 71, 979-988). Many of the alkaloidal targets in this programme contain bridgehead nitrogen ("izidine" systems), and these were comprehensively reviewed in 2001 (J.P. Michael, in The Alkaloids, G. Cordell, ed., Academic Press, New York, 2001, Volume 55, pp 91-258). Professor Michael also produces an annual series of reviews on this topic, and also on the topic of quinoline, quinazoline and acridone alkaloids, for the Royal Society of Chemistry?s high-impact journal Natural Product Reports.
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THEME 2: Synthetic routes to aromatic and heteroaromatic systems, and applications to aromatic natural products
(Theme leader: Professor Charles de Koning)
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Many natural and synthetic aromatic compounds and their quinone analogues are broad-spectrum antibiotics, anticancer agents, antitubercular agents, or active against HIV. The question addressed in this theme is whether we can invent new methods for constructing and functionalising condensed aromatic, biaryl and polyaryl systems, and apply the methodology to the synthesis of selected natural product targets. The research embraces methodological studies on the de novo construction of aromatic and heteroaromatic rings by a novel light- and base-induced cyclisation, the synthesis of isochromanes and related oxygen heterocycles, the synthesis of quinones, palladium-mediated couplings for the synthesis of biaryls, and stereocontrol at benzylic positions via arene-chromiumtricarbonyl complexes. The methodology is exemplified by application to the total synthesis of relevant natural products and analogues. Current methodological investigations include further exemplification of the base- and light-induced synthesis of condensed aromatics, biaryl synthesis by palladium-mediated coupling, routes to isochromanes and stereocontrolled reactions of arene-chromium complexes. The specific targets under investigation to illustrate these methodologies include benzo-, naphtho-, furo-, pyridocarbazoles and the related bisindole carbazoles, and natural products containing these systems; isochromane-containing targets (e.g., cardinalins); and antibiotics related to the landomycinones. Stereoselective syntheses of models for these target systems by means of palladium- and chromium-mediated reactions are central to current investigations. The following comprehensive review on naphthalene synthesis is based in part on the team s research: C.B. de Koning, A.L. Rousseau and W.A.L. van Otterlo, Tetrahedron, 2003, 59, 7-36.
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THEME 3: Mechanistic elucidation in bio(in)organic chemistry and methodological development of metallation chemistry
(Theme leader Dr Andy Dinsmore)
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An understanding of the mechanism of action of heterocyclic enzyme cofactors and their metal complexes requires the synthesis of these substances and analogues. The primary aim in this theme is to devise efficient routes to selected targets, especially routes involving novel metallation chemistry, in order to gain insights into processes such as electron transfer in enzyme cofactors. A major project entails the synthesis of model metal/ethene-1,2-dithiolate complexes capable of closely mimicking the molybdenum cofactor (essential to all life because of its role in the transfer of oxygen between biological substrates), as well as studies towards the total synthesis of the molybdenum cofactor itself. Another project, on the synthesis and metallation chemistry of pyrroles, is designed to produce novel coordination compounds for investigation as anticancer drugs. A more recent development entails the production and use of metal nanoparticles (especially gold nanoparticles), which catalyse the oxidative production of nanofibres from aniline.
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THEME 4: Approaches to small- and medium-sized ring systems by metal-mediated ring closing metathesis
(Theme leader: Associate Professor Willem van Otterlo)
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Metal-catalysed carbon-carbon bond formation is an important objective in organic chemistry, and a modern strategy for this task uses ruthenium carbene complexes to accomplish ene-ene and ene-yne bond metathesis. The focus of this theme is to use ring-closing metathesis (RCM) mediated by the Grubbs catalyst for the synthesis of small and medium sized ring systems that may also incorporate heteroatoms, thereby facilitating access to diverse cyclic molecular scaffolds such as naphthalenes and indenes, as well as a variety of 6-,7- and 8-membered unsaturated nitrogen, oxygen and sulfur heterocycles. Furthermore, the ruthenium-catalysed isomerization of O-and C-allyl groups to the corresponding O-and C-vinyl functional groups prior to RCM has also paved the way for the synthesis of a number of interesting benzo-fused compounds, More recent developments of RCM methodology entail its application to the synthesis of fullerene- and nanotube-containing polymers; and to the synthesis of novel nucleosides for biological testing. Finally, a new departure has seen the inception of a novel project on the synthesis of pancratistatin analogues as potential anticancer agents.
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THEME 5: Medicinal chemistry and molecular modelling
(Theme leader: Dr Steve Pelly)
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To be added.
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Post-graduate students in training (2010)
Gail Brankin (PhD) - Novel Nef reactions
Kathy Hadje Georgiou (MSc) - Aspects of medicinal chemistry
Myron Johnson (MSc) - Cationic lipids for use in gene therapy
Candice Langley (MSc) - Rational design and synthesis of inhibitors targeted at the malarial kinase - Plasmodium falciparum Protein Kinase 5
Tlabo Leboho (PhD) ? New methodology for the synthesis of heteroaromatic compounds
Siyanda Mthembu (PhD) ? Enaminones in the synthesis of alkaloids containing the 1-azabicyclo[5.3.0]decane core
Winston Nxumalo (PhD) ? The development of novel pterin chemistry leading to potential dihydrofolate reductase inhibitors
Justin Omolo (PhD) - Bioactive natural products from Tanzanian medicinal plants
Adushan Pillay (PhD) - Pyranonaphthoquinones
Stefania Scalzullo (PhD) - Synthesis of lamellarins and lamellarin analogues
Saleem Sultan (MSc) - Hydroxylated indolizidines from enaminone precursors
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