Motherwell William Branks
Mis à jour le mardi 28 janvier 2014 à 14h22min
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Professor William B. Motherwell
"... Willie is a remarkably creative and eclectic organic chemist, whose broad and curiosity-driven research ranges from the invention of new reactions involving free radicals, radical ions, hydride transfers, metallocarbenoids, and transition metal complexes, to the exploration of molecular recognition and the design and synthesis of artificial enzymes. His impeccable, crystal-clear, and riveting lectures are legendary ; they have thrilled and inspired countless young — and not so young— organic chemists.
A Holder of a Carnegie Fellowship, Willie obtained his PhD at the University of Glasgow under Sir Ralph Raphael, before moving to the University of Stirling as an independent ICI Research Fellow. In 1975, he joined the group of Sir Derek Barton at Imperial College as a Schering-Plough Fellow. Two years later, he moved with Sir Derek to France and was appointed to the C.N.R.S, first as “Attaché de Recherches” then as “Chargé de Recherches”. In 1983, he returned to Imperial College as a Lecturer and was promoted to a Readership in 1991. In 1993 he moved to University College London as the first Alexander Williamson Professor of Chemistry, a Chair he occupied until his retirement in September 2012. He has remained an Emeritus Professor at University College.
Early in his career, Willie developed the chemistry of metallocarbenoids and demonstrated the possibility of generating alkenes and cyclopropanes from ketones and aldehydes, using, among others, a combination of metallic zinc and chlorotrimethylsilane. Remarkably, he is the sole author on the first paper describing this original chemistry. He also devised various ionic and organometallic cascade reactions involving sulfones, and cyclopropylidenes, as well as ingenious radical sequences leading for example to the stereoselective formation of spiro compounds and to hindered biaryls. He further described a spectacular photochemical oxidation of arenes with osmium tetroxide, which allows the synthesis of cyclitols from benzene derivatives in essentially one step. He has found methods allowing the synthesis of fluorinated derivatives of carbohydrates and steroids and studied various processes involving unusual hydride transfer steps. He made seminal contributions to the synthesis of natural products, the chemistry of thionitrites, molecular recognition, molecular imprints and artificial enzymes.
Willie’s research has been recognised by numerous prestigious awards, including the Corday-Morgan Medal and Prize, the Bader Award, and Tilden Medal and Lectureship, from the Royal Society of Chemistry. He was named Merck- Frosst Lecturer in 1994 and received in 2000 the Silver Medal of the Institut de Chimie des Substances Naturelles. He was elected Fellow of the Royal Society (FRS) in 2004 and Fellow of the Royal Society of Edinburgh (FRSE) in 2007.
As Editor of Tetrahedron Reports, Willie insured a constant flow of high quality reviews covering a broad variety of topics. The number of reports will reach 1000 this spring. A special virtual issue of Tetrahedron, containing all one thousand reports, will be created in his honor and made freely available to the scientific community.
Willie’s balanced views, perceptive comments, quick wit, equanimity, friendliness, and immense erudition, both within and outside of chemistry, have contributed much to the Tetrahedron Board discussions. It has indeed been a rare pleasure to work alongside him on the Board of Editors for Tetrahedron Publications. We shall miss him greatly."
Samir Z. Zard
Bordeaux and Palaiseau 2012
Scientific Resumé William B. Motherwell FRS, FRSE
Emeritus Professor of Chemistry, University College London. Christopher Ingold Laborarories, Department of Chemistry,
Short Biographical Sketch.
William B. Motherwell completed his B.Sc and PhD Degrees from the University of Glasgow as a Carnegie Scholar in 1972, and was then awarded a prestigious ICI Fellowship to conduct independent research. In 1975, he moved to Imperial College London to work with Professor Sir Derek Barton as a Schering Plough Postdoctoral Fellow, and was then invited by Sir Derek to accompany him to L’Institut de Chimie des Substances Naturelles of the CNRS where he served for the next six years as Chargé de Recherche. He returned to Imperial College in 1983, first as lecturer and then Reader in Chemistry and, in 1993 was invited to become the first incumbent of the Alexander Williamson Chair of Chemistry at University College London. University College London is currently ranked as fourth in the list of world leading Universities.Throughout his career, he has received many awards, including the Corday Morgan and Tilden Medals of The Royal Society of Chemistry as well as the Bader Award, and was elected as a Fellow of the Royal Society (FRS) in 2005 and a Fellow of the Royal Society of Edinburgh (FRSE) in 2007. On the industrial scene he has acted for many years as a consultant to, inter alia, Glaxo-Smith Kline, Astra Zeneca, Quest International (now Givaudan), and also serves the international scientific community as a member of the Leverhulme Trust Advisory Panel and as an Editor and Member of the Executive Board of the Tetrahedron family of Journals Elsevier).Most recently, in 2008, he was invited to become the international member of the Conseil Scientifique de l’Institut de Chimie du CNRS, at a moment in time when strategic planning for the future is essential. He is fluent in French and since his time in France he has always maintained close links, being a regular visitor and lecturer, fluent in French, and enjoyed very stimulating scientific collaborations with the late Pierre Potier. As detailed below, he has an unusually vast range of interests and expertise within organic chemistry, having worked with many Natural Product families including steroids ,alkaloids, carbohydrates and terpenoids, and has been recognised for the invention of many new reactions involving unusual reactive intermediates including free radicals, organometallic chemistry including transition metal catalysis, and selective fluorination. Most recently, his interests have also encompassed molecular recognition and artificial enzymes.
The research effort within the group has, over the years, been primarily directed towards the invention and discovery of new synthetic reactions which respond to the formidable challenges posed by the fine chemicals and pharmaceutical industries. Within this framework however, a curiosity driven approach to fundamental science has always been adopted, and, for this reason, a deliberate policy of concentrating on those reactive intermediates which are traditionally avoided by synthetic organic chemists has been followed. The end result is a very diverse range of research programmes featuring themes involving transition metal catalysis, metallocarbenoids, electron transfer, and free radical chain reactions. This curiosity driven research philosophy has remained unchanged over the year in terms of the questions addressed, and has always attempted to follow the advice given by Sir Derek Barton (Prix Nobel) : “If, in the Academic world you know how to do a reaction, then you should not do it. You should only work on reactions that are potentially important, and you do not know how to do.” D.H.R.Barton in“Reason and Imagination. Reflections on Research in Organic Chemistry “. World Scientific Publishing Co.Pte.Ltd., Singapore, 1996.
The following research themes and case histories are not exhaustive and merely illustrative of this modus operandi and of some of the questions which have been addressed within the research group, with some selected publications from the list indicated in parenthesis.
Free Radical Chemistry.
Unlike their carbocationic and anionic counterparts, free radical reactions possess the inherent advantage of proceeding under neutral conditions and hence, essentially unencumbered by solvation and aggregation effects, can operate in highly hindered and polar molecular environments. The design of controlled free radical chain reactions, especially for carbon-carbon bond formation, has, in consequence been a focus of ongoing interest within the group, as demonstrated by : The stereospecific construction of bicyclic systems via a Tandem Cyclopropylcarbinyl Rearrangement-Cyclisation strategy, wherein an all carbon quaternary centre can be produced. The use of the beautiful samarium diiodide reducing agent introduced by Henri Kagan also provided additional possibilities for carbon carbon bond formation in this cascade reaction.
A novel route to the ubiquitous Biaryl unit and heterobiaryl congeners, involving Free radical Ipso substitution of suitably tethered arene sulphonates and sulphonamides was invented. As a consequence of the orthogonality of approach of the two aromatic rings in the formation of a spirocyclic intermediate, and in contrast to palladium mediated coupling reactions such as those developed by Heck and Suzuki, this approach proved to be especially effective when highly sterically hindered systems were prepared.
The free radical chemistry of thionitrite esters, and, in particular , their potential for release of biologically fundamental nitric oxide was explored in a series of papers in collaboration with the late Pierre Potier. Thus, the thionitrite derived from D-Glutathione was used as a molecular probe for a receptor site, and several new free radical chain reactions such as decarboxylative nitrosation and the rearrangements of allylic thionitrites were explored. Interest in the potential behaviour of thiyl radicals derived from biologically versatile dithiodiketopiperazines also stemmed from this research and culminated in the development of a facile route for their assembly as well as a demonstration that these compounds can block the interaction between hypoxia inducible factor-1alpha (HIF-1alpha) and P300 by a zinc ejection mechanism.
The selective introduction of one or more fluorine atoms into a molecule is a proven stratagem within the pharmaceutical industry as a consequence of the unique properties of this atom. Three very different topics within this specialist area have been studied.
Initial interest stemmed from the challenge to invent a new electrophilic fluorinating agents and led to the introduction of hypervalent iodoarene difluorides for this purpose. In the event, a very unusual electron transfer chain reaction was discovered in their reaction with electron rich dienamines and the term “ Pretense Electrophilic Fluorination” was coined. A subsequent study using Cephalosporins led to the observation of the affinity of hypervalent iodine for sulphur atoms and this, in turn, led to methods for the conversion of dithioketals into geminal difluoro compounds, xanthates into fluorides, and a concise method for the preparation of fluoroglycosides. Exploitation of Pummerer chemistry also proved to be very fruitful with such reagents.
The second challenge was to invent a new reagent for anionic trifluoromethylation which bypassed the problem posed by the ban on the use of chlorofluorocarbon compounds (CFC’s) in the Montreal protocol. The Trifluoromethylacetophenone-N,N-dimethyl- trimethylsilylamine adduct was readily prepared and proved to be a new shelf stable reagent for this purpose.
The desire to achieve regiospecific replacement of the anomeric oxygen atom in sugars by the difluoromethylene group as an isostereoelectronic mimic led to the introduction of exocyclic carbohydrate gemdifluoroenol ethers as versatile building blocks and the opportunity to invent new free radical chain reactions using this functional group then led to the first examples of difluoromethylene analogues of glycolipids,disaccharides, phosphates and O-serine glycopeptides, thereby emphasizing the power of free radical chemistry in polar environments.
Transition Metal Catalysed Reactions.
The power of transition metals as catalysts has dominated Organic Synthesis over the last forty years and is certainly one of the most aesthetically attractive and of potential use to industry. It has remained an ongoing focus for research within our group as exemplified by some of the following studies.
The enolate anion must be considered as a cornerstone of modern day synthesis and is invariably generated by deprotonation of a carbonyl compound. Consideration of the many limitations of this approach led us to the very simple idea that transition metal mediated isomerisation of a preformed lithium alkoxide of a suitably substituted allylic alcohol would provide a very attractive alternative which avoids the use of strong bases or preformed silyl enol ethers. This concept was reduced to practice in a series of papers which demonstrated that, by selection of appropriate Nickel or Rhodium catalysts, high levels of regio- and stereocontrol in enolate anion formation were possible. Moreover, problems such as aldehyde enolate generation or the stereocontrolled formation of tetrasubstituted enolate anions could also be solved.
The catalytic Photoinduced Charge Transfer Osmylation of Arenes was, and still is, the first and only chemical method to convert benzene directly into cis diol derivatives such as conduritols and inositol. Amusingly, this new reaction arose as a direct challenge from my long time friend Professor Steve Ley, who was, at that time engaged in using benzene diols produced from the microorganism Pseudomonas Putida, as a starting material. This reaction was then used in a very concise five step synthesis of Pinitol which featured stereocontrolled monobromopentahydoxylation of benzene as the very first step.
In terms of the construction of complex bicyclic systems, the group was also one of the earliest to recognize the inherent potential of using strained systems such as alkylidenecyclopropanes in the intramolecular variant, as well as tandem sequences such as a rhodium catalysed hydrosilylation-intramolecular Aldol reaction which was used in a formal enantioselective synthesis of Carbovir.
The design of new and more effective ligands is, of course, an essential element of transition metal catalysis. In this area, a longstanding collaborative effort with Dr.Andreas Danopoulos, currently the holder of a Gutenberg Chair in Strasbourg, has proven to be very successful, and culminated in the generation and use of several new N- Heterocyclic Pincer Carbene metal complexes.
Organometallic Chemistry-From Carbonyl Compounds to Organozinc Carbenoids.
It has been argued that “New Reactions can arise by Conception, Misconception and Accident”. Our first step in this area was, in fact, a misconception which revealed nevertheless that treatment of a carbonyl compound under very mild conditions with zinc and chlorotrimethylsilane led to generation of an organozinc carbenoid which subsequently evolved via C-H insertion to generate an olefin by Direct Deoxygenation. With this information in hand, it was then possible to invent a range of new, and valuable reactions including dicarbonyl coupling and inter and intramolecular variants of a simple cyclopropanation reaction.The early history of these discoveries is related in a personal account in a special issue of the Journal of Organometallic Chemistry dedicated to Jean Normant. Subsequent studies led to the discovery that congeneric acetals and ketals could also be used in the generation of organozinc carbenoids for direct deoxygenation, but by a different mechanism, and this ,in turn led to the selection of orthoformates as substrates for a practical alkoxycyclopropanation reaction which avoids the problematic use of Fischer Carbenoids. Amino- and amidocyclopropanation sequences have now been developed in response to interactions with Astra Zeneca in view of the importance of these units to the pharmaceutical industry as well as chiral variants based on oxazolidinones. The intramolecular variant has also been studied and shown to lead to highly strained tricyclic systems with unusual stereochemistry. Such cyclopropanation reactions, which avoid the use of explosive diazo compounds or highly toxic gem dihalo precursors are especially valuable because of the mild reaction conditions and the ready availability of carbonyl compounds.
The Use of Microreactors for High Throughput Synthesis.
The laboratory of the future will certainly use microreactors and high throughput flow technology to streamline and achieve efficiency in Organic Synthesis. In collaboration with Professor Asterios Gavrillidis in University College London Chemical Engineering Department, Microreactors and flow systems have been introduced within the group and ongoing work on the important problem of conducting ozonolysis safely on an industrial scale is under current investigation.
Non Covalent Interactions.
The essence of molecular recognition, whether it be in a designed organocatalyst, or in Nature’s enzymes, can only be fully understood if quantifiable measurements of non covalent interactions can be made, especially as a function of solvent. For this reason, in a more recent research programme, a conformational balance, based on a dibenzobicyclo[3 2 2 ] nonane framework has been designed to probe non-covalent arene functional group interactions. This has not only allowed detailed measurements of such phenomena as π facial intramolecular hydrogen bonding to be measured, but also provided very valuable insight into the essentially solvophobic behaviour of a fluorine atom or the particular affinity of a sulfur atom for an aromatic ring as opposed to an oxygen atom. Such results are of considerable interest to computational chemists, and molecular modellers, particularly in the pharmaceutical industry.
“Millipede” Artificial Enzymes.
A programme to explore cooperativity effects in Nature’s enzymes and hence to provide the Organic chemist with a molecular toolkit for the construction of artificial enzyme like catalysts has been initiated. In essence, the simplest approach of regarding an enzyme as a molecule with “hands to hold” (receptor site ), “teeth to bite” (catalytically active groups) and the flexibility to place the hands to the mouth has been taken. The receptor site can be quantified in terms of binding by measuring the affinity of a transition state mimic for a range of dipeptides using an NMR method based on Le Chatelier’s Principle. Chains containing catalytically active groups, as well as chains containing the receptor site are then attached to a polymeric backbone to create the artificial Millipede Enzymes which contain all of the essential requirements for catalytic activity. Using ester hydrolysis as a prototypical reaction for study, and a phosphonate estyer as a transition state mimic, it was possible to prepare catalytically active polymers whose rate enhancement was considerably grater than other approaches such as molecular imprinting. This system also allowed demonstration of competitive inhibition when both the ester and the phosphonate were present.
The foregoing overview has hopefully highlighted the fact that, within the research group, many different areas of organic chemistry have been tackled, even although, each of them could have become a lifetime study for many organic chemists in terms of becoming an expert. As every bench chemist knows however, curiosity driven research in which fundamental and difficult questions are asked, is only possible because our level of understanding of the subject is such that there is no substitute for experimentation. Within the last twenty years, enormous advances have been made in organic chemistry, and even more exciting opportunities exist in the future for Organic Synthesis and for designed molecules. In our own experience, the abilities of the Organic Chemist not only to prepare molecules, but also to design their properties for a particular function, convinces us that most of the useful Chemistry remains to be discovered.