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People in the Department |
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W. Russell BowmanProfessor of Organic ChemistryBSc Cape Town, PhD Alberta, CChem, FRSC. Telephone: +44(0)1509-222569 E-mail: W.R.Bowman@lboro.ac.uk Professor Russ Bowman is a graduate of the University of Cape Town, South Africa. After graduation he spent a year working for AE&CI, a joint company of ICI and Anglo-American, as a research officer before leaving for Canada. He carried out his PhD in the University of Alberta in Edmonton under the supervision of Professor William A Ayer, during which time he carried the first synthesis of the alkaloid lycopodine. He came to England in 1968 on a Leverhulme Overseas Visiting Fellowship to work on biosynthesis with Professor Gordon Kirby at the then new Loughborough University. He then moved to Warwick University on a further postdoctoral fellowship with Professor Sir John Cornforth (Nobel laureate) on the synthesis of vitamin B12. He returned to Loughborough University as a lecturer in organic chemistry in 1970. The research of Russ Bowman is centred on free radical chemistry for which he has an international reputation. The use of free radicals in organic chemistry has increased dramatically in recent years and now provides one of the central and exciting new methodologies for synthesis. Many novel and interesting reactions are being discovered and many are applied to carrying out important natural product syntheses. The research interests are split into three main areas but all are interlocking and overlap with each other.
Synthesis using Free Radical ReactionsSynthesis of bi- and Polycyclic- N-HeterocyclesNitrogen heterocycles are central to the pharmaceutical industry and much of our synthetic studies are aimed towards radical cyclisation with N-heteroarenes. The group is investigating two directions in these radical cyclisations: cyclisation onto different heteroarenes and the use of radical building blocks. The heteroarenes includes, indoles, pyrroles, pyrazoles, imidazoles and quinazolin-4-ones. The building blocks include w-phenylselanyl-alkyl (alkyl radicals), w-phenylselanylcarbonyl-alkyl (acyl radicals), w-phenylselanylimidoyl-alkyl (imidoyl radicals) and halogeno-arylalkyl (aryl radicals). An example is shown for the synthesis of withasomnine. These two tactics facilitate a wide range of compounds to be prepared thereby facilitating methods for generating libraries of compounds. To further the synthesis of libraries, solid-phase synthesis using radical reactions is also part of the studies. Synthesis of Heterocycles by Radical Cyclisation Iminyl Radical Intermediates in Domino ReactionsDomino cyclisations have been developed which involve cyclisation onto nitriles to yield iminyl radicals which in turn are cyclised onto alkenes or undergo rearrangement depending substituents. This domino cyclisation methodology has been applied to the synthesis of polycyclic nitrogen heteroarenes, in particular those with anticancer activity, e.g. luotonin and camptothecin (see synthesis of rings A-D of camptothecin below).
Radical Cyclisation onto Nitriles Imidoyl Radicals in New Synthetic MethodologyPresent studies are developing the use of imidoyl radicals in synthesis. The strategy facilitates a wide variety of amide starting materials which can be easily converted into imidoyl-selanides [PhSe–C(R)=N–] radical precursors. Amide starting materials allow complex moieties to be simply joined by amide coupling of carboxylic acids and amines to facilitate development of libraries of compounds. Standard radical methodology (e.g. Bu3SnH, Bu3GeH, TTMSS) to be used to abstract the phenylselanyl group (PhSe) to generate the imidoyl radicals. The imidoyl radicals can then be used in a number of radical cyclisation and domino reactions. The protocol has provided an excellent route to 2,3-disubsituted indoles and quinolines. The protocol has recently been adapted to a five step synthesis of the anti-cancer alkaloid ellipticine and related carbazole analogues as shown in the Scheme below. Synthesis of several other important anti-cancer and anti-HIV alkaloids are under study. Recent advances includes the generation of imidoyl radicals from imines (amine plus aldehyde) by H-abstraction using di-tert-butyl peroxide.
Synthesis of Indoles using Cyclisation of Imidoyl Radicals Pharmaceutical ChemistryThe development of new pharmaceuticals is of central importance for the improved health in modern society. The relevance of the research group's research is closely related to providing an input into this socially important connection. Most of the study of the group is aimed towards the development of new synthetic methods and the synthesis of biologically active pharmaceuticals or natural products. New methods of synthesis include novel amino acids, hormones (e.g. thyroxine), antibiotics (e.g. metronidazole) and anti-cancer anti-HIV agents (e.g, luotonin, ellipticine and camptothecin analogues). The mode of action of important drugs, especially amino acids, hormones (e.g. thyroxine), and preservatives (e.g. bronopol) have been part of the groups research. New methods for the synthesis of a wide range of biologically active compounds are being carried out using reactions proceeding via radical intermediates, e.g. bicylic nitrogen-heterocycles and polycyclic heteroarenes. The synthesis of withasomnine, the active constituent from Withania somnifera (Solanaceae), a well known Ayervudic herbal remedy, is shown in the Scheme below.
New non-toxic organogermanium reagents and protocols are being developed to replace the toxic triorganotin hydrides for the generation of radicals for synthesis of pharmaceuticals. The group is also involved in developing the use radical reactions using solid-phase synthesis and solid phase reagents, a major new area of interest to the pharmaceutical industry. Radical Mechanisms and StructureThe study of the novel mechanisms of radical reactions provides an area of unusual interest, but more importantly, is being used to develop new synthetic methods and industrial processes. We also have a key interest in Single Electron Transfer (SET) in organic chemistry which is now recognised as common in organic and biological reactions. New synthetic methods, mechanisms of action of biologically active molecules, and pharmaceutical processes which proceed by radical intermediates and/or SET are being studied. We have a particular interest in the mechanism of ‘oxidative’ cyclisation using tributyltin hydride as shown in the example for the synthesis for bicyclic imidazoles. The mechanism is a homolytic aromatic substitution but all aspects of the mechanism are not yet fully understood. The methodology is being applied to the synthesis of a range of biologically active natural products and pharmaceutical compounds.
Synthesis using Aromatic Homolytic Substitution – Recent Advances Radical Reactions for a Clean EnvironmentIn organic chemistry, a number of projects have environmental aims as the central rationale, particularly those which have potential industrial application. This area of research is generally titled 'clean technology', an area of increasing importance. New catalysts for a range of organic reactions are being investigated as a means of cutting down on reagents in order to minimise waste are underway. Organogermanium reagents: A combined organometallic/organic project, the development of new organometallic triorganogermanes (R3GeH) is being investigated for the catalytic generation of free radicals in place of the environmentally toxic tributyltin hydride. Triorganotin hydrides (R3SnH) are the main reagents of generating radicals in organic reactions but the application of many important synthetic methods to industrial reactions, especially in the pharmaceutical industry, is precluded by the toxicity of organotin compounds. The non toxic germanium compounds have not been used because of relatively high cost. These reagents have several crucial advantages over triorganotin hydrides: low toxicity, high stability and shelf-life and ease of work-up. Present studies are developing low cost synthetic methods towards triorganogermanium compounds and their use in catalytic amounts so as to minimise cost and pollution at the same time. The new reagents and protocols are being applied to most of the group’s synthetic work. The long term aim is to provide facile new and environmentally safe reagents for radical synthesis in the pharmaceutical industry. Recently we have developed a solid phase triorganogermanium hydride which is undergoing testing. Tributylgermanium Hydride as a Replacement for Tributyltin Hydride in Radical Reactions Waste minimisation. In industrial reactions the production of waste is a major problem even if the waste is relatively non toxic, e.g. organic solvents. A new trend in organic chemistry of cascade reactions, a process in which two or more synthetic steps are carried in 'one-pot' reactions, is leading the way on minimising solvent usage and waste production. For instance, the research group is studying the application of cascade radical cyclisation for the synthesis of biologically active nitrogen heterocycles, in particular, complex anti-cancer compounds. Solid-phase synthesis. The group has initiated research with the aim of using solid-phase resins for radical synthetic reactions as a method of minimising waste and purification. For instance, a solid-phase triorganogermanium reagent has been developed for carrying out radical reactions. Radical cyclisations onto heteroarenes on solid-phase continues to be of interest in the group.
Aromatic Homolytic Substitution using Solid Phase Synthesis |
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