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To pursue the important problem: the career of Raymond Lemieux.

Lemieux's work is proof that supporting basic science will result in important human and commercial benefits in the long-term

Under the series title, "Profiles, Pathways, and Dreams", with Jeffrey Seeman as editor, the American Chemical Society is publishing the autobiographies of 22 world famous chemists. About half of the volumes have appeared and I have read four of them and glanced through several more. All seem to be worthwhile reading, but most Canadians will find the autobiography of Raymond Lemieux, FCIC, entitled Explorations with Sugars: How Sweet It Was (122 pages ACS, Washington, D.C., 1990, cost US $24.95) the most interesting.

Lemieux was born to French-Canadian parents in northern Alberta. His mother died when he was seven years old, and he was brought up by his eldest sister Alice while his father worked as an itinerant carpenter in the foothills of the Rockies. He did well at school but his main preoccupation was hockey until the age of 19, when he realized that he would not be heavy enough to play in the NHL. In the meantime he had entered the University of Alberta and became hooked on chemistry. He writes: "A major consideration in choosing chemistry was that, in the absence of a graduate school, the university employed a number of second-year honors chemistry students as teaching assistants. This added income would be of crucial importance."

The legendary lectures of Reuben Sandin made him decide to become an organic chemist, and in 1943 he took the three-day train trip to Montreal to register for graduate studies at McGill under Clifford Purves. He worked on a topic related to the war effort, and presented a thesis on some reactions of cellulose that were not particularly engaging. "but the association with Clifford B. Purves put the final touch on my decision to seek a career in research, especially in... carbohydrate chemistry."

Carbohydrates were involved in living processes, the main reason for his interest in chemistry, and in discussions with Purves he had become fascinated with stereochemistry, and in particular with the still unsolved problem of the synthesis of sucrose.

In 1946 Lemieux accepted a post-doctoral fellowship with M.L. Wolfrom at Ohio State University, and started work on the newly-discovered antibiotic streptomycin, a pseudotrisaccharide. His work involved the Raney nickel desulfurization of thioacetals, and as a sideline he used this reaction to convert the thioacetal of N-acetyl-D-glucosamine to a product which on oxidation followed by hydrolysis gave L-alanine. This correlated the configurations of the L-amino acids with those of D-glyceraldehyde and the D-sugars, a most important discovery at that time.

One day in Wolfrom's office Lemieux overheard a heated argument between Wolfrom and his physical organic colleague, Wallace R. Brode, over the evidence for the relative configurations of the anomeric centres of carbohydrates. Thus began a life-long interest in this problem, which we shall follow below.

In 1947 Lemieux went to Saskatoon as lecturer at the University of Saskatchewan. A year later he married Jeanne, soon after she had obtained a PhD in infrared spectroscopy from Ohio State. The next year, he accepted a position as senior research officer at the Prairie Regional Laboratory of the National Research Council (NRC) in Saskatoon. He tells us, "My appointment had been to investigate the utilization of wheat starch, because of the large wheat surplus that then existed."

About a year after he had moved to NRC, the laboratory was visited by C.J. Mackenzie, the president. Lemieux was startled when Mackenzie took him aside and told him: "He appreciated my efforts with starch, but really I should feel free to do whatever I wished to do."

What Lemieux wished to do was to study the stereochemistry of reactions at anomeric centres. The time was ripe. In 1950 Barton had introduced the ideas of conformational analysis to explain stereochemical effects in reactions of cyclohexane derivatives and R.E. Reeves had independently developed similar ideas to explain some reactions of [alpha]-and B-pyranosides. Earlier, Winstein and Buckles (1942) had shown how a neighboring acetoxy group of the proper stereochemistry could accelerate nucleophilic displacements by what came to be known as "anchimeric assistance."

Lemieux applied these ideas in studies of the [SnCl.sub.4]-catalyzed acetate exchange reactions (using [sup.13]C-labelled acetate) at the anomeric centres of sugar acetates, and in 1954 published an article in Advances in Carbohydrate Chemistry reviewing these and other reactions. Nowadays most chemists would find this article unexceptional, but in 1954 it was a bombshell. Carbohydrate chemists up to that time had made very little use of the electronic theories that were transforming mainstream organic chemistry; from now on they could no longer ignore them.

This lesson was reinforced when Lemieux and Huber published the first chemical synthesis of sucrose, something which had defied the best efforts of carbohydrate chemists for decades. It is not possible to summarize in this article the theoretical interpretation given by Lemieux to the reactions of Brigl's anhydride (1,2-anhydro-3, 4,6-tri-O-acetyl-[alpha]-D-glucopyranose), making use of the recently-formulated Furst-Plattner rule.

Using Brigl's anhydride he synthesized not only sucrose but D-maltose and D-trehalose, disaccharides containing [alpha]-D-glucopyranoside units which also had previously defied synthesis.

The Ottawa years

In 1959, at the age of 34, Lemieux was invited to become chair of the department of chemistry and vice-dean of the faculty of science at the University of Ottawa, "in order to help the dean, Pierre Gendron, build the faculty in an |atmosphere of research'. The central plan was to build the university |backwards'.

"That is, we would start with a PhD program so that we could promise prospective teaching staff attractive opportunities for research with, at least for a few years, little teaching at the undergraduate level. We expected that as the stature of our staff grew, we would attract sufficient graduate students to serve as teaching assistants to properly handle undergraduate laboratory studies. Furthermore, we expected that as the stature of the faculty would grow, the enrollment in undergraduate courses would grow, and eventually the whole effort would become viable as a first-class university.

"My main responsibility was to build a world-class department of chemistry, and this mission became possible by attracting such outstanding chemists... as F.A.L. Anet, R.F. Bader, B. Belleau, B.E. Conway, R.R. Fraser, and K.J. Laidler..."

At a lecture at NRC soon after arriving in Ottawa, Lemieux heard Chris Reid, University of British Columbia, discuss the effect of steric interactions on the NMR chemical shifts of protons in fused aromatic systems. He wondered whether steric effects also would cause axial and equatorial hydrogen atoms of chair-shaped rings to have different chemical shifts.

Fortunately, W.G. Schneider and H.J. Bernstein of the NRC had started their investigations on the application of NMR to chemistry and offered the use of the NRC machine to Lemieux's graduate student, Rudolf Kullnig.

The NMR spectra of the sugar acetates showed that Lemieux's guess was right, and that an equatorially oriented hydrogen atom of a pyranoside generally gave rise to a signal at a lower field than did an otherwise identical hydrogen which was axial. More importantly, it was found that spin-spin coupling constants for vicinal hydrogens in anti-periplanar orientation were two to three times larger than those for vicinal hydrogens in a syn-clinal relationship. This was the first experimental evidence for what later became the Karplus equation relating vicinal coupling constants to torsion angles, and could be used to establish the configuration of chiral centres in organic molecules.

In particular, the uncertainties about configurations at anomeric centres which had caused the argument between Wolfrom and Brode were finally settled. Since that time the use of NMR in organic chemistry has become so habitual that it is described in every elementary textbook. It is easy to forget that Lemieux was the pioneer in this field.

Back to Edmonton

The growth of the faculty of pure and applied science and of the department of chemistry at Ottawa had laid heavy responsibilities on Lemieux, and had given him time for research but little for writing papers. In 1961 he accepted the offer of a professorship at the University of Alberta, lured by the prospect of more time for research and raising his growing family in Alberta. In Lemieux's own words, "It is said that I am pathologically Albertan, and this could well be the case."

It might have been expected that Lemieux would now devote himself entirely to these two abiding passions, his research and his family. But obviously he is a man with energy to burn. He has twice been chair of his department,

has served as president of The Cherrrical Institute of Canada, has founded three companies, has served on the editorial boards of many journals. and has given invited lectures all over the world. But here we shall consider only his chemistry.

He decided that the most important task for carbohydrate chemists was the development of improved methods for synthesizing [alpha]-glycosides. Soon he had developed the haloalkoxylation of glycals and the halide-ion catalyzed reaction of [alpha]-halides for this purpose. He also developed new methods using 2-oximino, 2-azido, and 2-phthalimido sugars to produce diand oligosaccharides containing 2-amino sugars.

These important practical developments emerged in the course of prolonged studies, described in detail in Lemieux's book, to understand the mechanisms of reactions at anomeric centres.

Lemieux also continued studies of the anomeric effect, a term which he introduced in 1958 to describe the effect responsible for an electronegative substituent such as chlorine or acetoxyl at an anomeric centre preferring an axial to an equatorial orientation. He later suggested that the effect works in the opposite direction (the reverse anomeric effect for an electropositive substituent at the anomeric centre, as might be expected if it is electrostatic in origin.

Later yet, he introduced the notion of the exoanomeric effect, which determines the favored conformation about the glycosyl-alkoxyl oxygen bond of an [alpha]- or [beta]-alkyl glycoside. As would be expected if the effect is determined by electrostatic interactions, the conformational equilibria are solvent-dependent.

In 1980 Lemieux introduced the HSEA (hard-sphere-exo-anomeric effect) method for calculating the conformational preferences of oligosaccharide chains. Hard-sphere calculations had already been used to calculate the conformations of peptides; HSEA worked well to give the conformations of oligosaccharides, as judged by X-ray studies of oligosaccharide molecules in the solid crystal and NMR studies of the molecules in DMSO-[d.sub.6] solution.

This was a historic moment. Oligo- and polysaccharides together with proteins and nucleic acids comprise the majority of large molecules making up the machinery of the living cell. In 1954 Pauling received the Nobel Prize for work which culminated in the [alpha]-helical structure for proteins, and in 1962 Watson and Crick had received the same prize for the double-helix structure of DNA. These discoveries triggered off the rise of the new science of molecular biology. However, while it was now realized that proteins and nucleic acids had three dimensional structures determined by the interplay of intramolecular hydrogen bonding and hydrophobic and van der Waals forces, and that these structures could be correlated with the biological functions of the molecules, the same could not yet be done for oligosaccharides.

Indeed, most chemists at this time probably regarded oligosaccharides in solution as having no more structure than a loose chain of beads. And yet immunologists since the 40s and earlier had known that oligosaccharides attached to cell walls played a crucial role in molecular recognition exemplified in the immune response to bacteria, the rejection reaction of foreign blood cells or other tissues, and much else.

Lemieux's HSEA calculations showed that oligosaccharides also had well-defined three-dimensional structures. Furthermore, this structure had hydrophilic ("wet") and hydrophobic ("oily") surfaces which could bind to corresponding "wet" and "oily" surfaces of complementary molecules by hydrogen and hydrophobic bonding to account for the recognition of one molecule by another.

In fact, as Lemieux pointed out in a lecture at the University of Montreal in 1984, it should be possible to construct a non-carbohydrate molecule with the proper spatial disposition of wet and oily surfaces to mimic the antigenic prop erties of the blood group substances, but (to my knowledge) so far this has not been done.

The challenge of immunology

These theories could be tested immediately, because Lemieux already in the mid-70s had taken up the enormous challenge of entering the field of immunology. He writes: "By the 1970s, a good number of structures of complex carbohydrates important to medical science were known, and the specific noncovalent binding of these by both lectins [a special type of protein] and antibodies had been impressively demonstrated. By this time we were well armed for the engagement, because of our long preoccupations with conformational analysis and synthesis of oligosaccharides.

"A major problem was to find in Canada funding adequate to support the highly work intensive synthetic efforts. It was also necessary to establish collaborations with the researchers required to assess the worth of the products to medical science.

"The financial problem was eventually solved by a generous grant from the Medical Research Council of Canada. This success came after an application to the National Research Council of Canada had failed, purportedly because of its biomedical content... Bureaucracy at its best!... Because of this experience, I have little confidence in the current concepts for the formal organization of so-called centres of excellence...

"I suggest that the support of individuals, rather than organizations, is the superior way of supporting multi-disciplinary efforts.

"The problem of finding support for such activities seems to arise mainly because the peer committees of the granting agencies have expertise largely limited to one discipline and have a vested interest in keeping money within that discipline."

Lemieux started collaborating with Elvin A. Kabat, Columbia University. Kabat had started as a carbohydrate chemist, and had become a world leader in the general area of immuno-chemistry, especially in the structure of the blood group oligosaccharides. Lemieux notes: "Melding our chemistry with immunology presented a serious problem because my chemistry students were not particularly enchanted with the idea of learning some immunology. Although I did not feel that we could become experts in this immense and highly developed field, I did expect that the development of some immunochemistry at home would be a necessary step toward eventual, significant collaborations in medical science."

This step was taken with David Bundle, who had worked in a bio-chemical environment for some years and who entered the field of immunochemistry with enthusiasm. Together they learned how to join oligosaccharides by a linking arm to soluble proteins to produce soluble artificial antigens and to insoluble solids to produce immunoadsorbents. This has led to important developments in molecular biology, and the possibility of better carbohydrate vaccines for a wide variety of diseases. It has also led to illuminating studies on the binding of trisaccharides to monoclonal antibodies, which in turn have led to Lemieux's, hydrated polar gate theory" for specific molecular recognition. He adds: "...All the binding reactions that we have examined involve the acceptance by the combining site [of the protein] of a cluster of hydroxyl groups presented by the oligosaccharide (the polar key). . .

"Complexation occurs as the key polar groups are so disposed that they can establish a strong (well-directed) polar interaction with polar groups of the so-called gate of the combining site. Thus the water molecules are displaced with perhaps some [entropic] stabilization of the system. However, it is expected that the main driving force for complex formation likely occurs when the adjacent complementary nonpolar surfaces come together."

This expectation was still at the base of his working hypothesis when he undertook to write the autobiography.

The main source of Lemieux's continuing preoccupation with molecular association was the fact that, somehow, strongly hydrophilic structures such as a simple sugar could be essentially extracted by a lectin or antibody from extremely dilute (less than millimolar) aqueous solutions.

Indeed, Lemieux now believes that the main driving force for the association of an oligosaccharide with a protein results from the decrease in exposure to water not only of hydrophobic surfaces but also of mosaics of complementary amphiphilic structural units that are presented by the contracting surfaces of both the oligosaccharide and the protein. Such interactions may be the source of most associations of biological molecules.

After "retirement"

Lemieux wrote the autobiographical sketch of his research while convalescing from a difficult bout with cancer. During this period, 1985-87, the probing of the combining sites of antibodies and lectins continued under the guidance of his senior research associate, Dr. Ulrike Spohr.

As mentioned in his book, Dr. Louis Delbaere and his associates in Saskatoon labored on the crystal structure of the lectin GS-IV and its complex with [Le.sup.b]-OMe. As expected from earlier probing experiments, only about half of the [Le.sup.b]-OMe tetrasaccharide comes into contact with the lectin.

Most interesting was that five of the 10 hydroxyl groups remained in contact with the aqueous phase. Indeed, it was found that O-methylation of these

hydroxyl groups had little effect on the extent of binding. Furthermore, all of these five hydroxyl groups could be deoxygenated with little change in the free energy of binding.

Of major interest was the discovery that such a small change in structure as a monodeoxygenation could cause differential changes in enthalpy of up to 7 kcal/mole which, however, were virtually compensated by the differential change in entropy. This finding was particularly exciting, since enthalpy-entropy compensation was first encountered in a biological system by Ray Lemieux's dear friend, Bernard Belleau, in 1968 and attributed on the basis of circumstantial evidence to changes in hydration phenomena.

Lemieux's direct evidence for this unique property of water appears unequivocal and comprises what he believes is the source of his most important idea; namely, the formation of importantly perturbed layers of water over polyamphiphilic surfaces.

The finding provides a rational explanation as to why hydrophilic surfaces may associate in aqueous solution which Lemieux and his collaboration, Helmut Beierbeck, have found to be justified by Monte Carlo simulations of the hydration of carbohydrate and protein polyamphiphilic surfaces.

Lemieux is particularly excited by his notion that the heat transfers that result from the reorganization of water molecules in the course of molecular recognitions are the source of the energy required for nerve impulses, such as taste and odor, which rely on molecular complementarity.

It is on this note that Lemieux ended his career in research. He had hoped to continue for a few more years, primarily to further examine the role of water in biological associations since the Monte Carlo simulations clearly suggest water provides the main driving force for all biological associations. However, Lemieux could not gain the necessary financial support from NSERC for this basic research. His terminating grant was for two years at the level required for the support of only one research associate. The interdisciplinary effort required at least three associates. A crash program was therefore organized with advanced credits from the department of chemistry to allow one final year with a full team.

As if pre-ordained, the Pharmaceutical Manufacturers Association of Canada awarded Lemieux its gold medal in 1992 and a $50.000 prize for his research. This bonanza, together with funds from research contracts that Lemieux had squirreled away in a special account for a rainy day, allowed a second year and an orderly retirement from active research.

The University of Alberta will continue to provide him an office and clerical help for the preparation of manuscripts for publication. Actually, Lemieux has adjusted well to this situation and looks forward to more time with his wife on golf links and mountain trails.

His best hope is to remain in sufficiently good health to learn what the next several years will bring to the subject of molecular recognition.

What are the lessons?

The account above is skimpy and popular (without the benefit of a single structural formula) describing almost 50 years of chemical research. Students who make the effort to read Lemieux's book will learn a great deal about stereochemistry, reaction mechanisms, NMR, hydrogen-bonding, and much else. More importantly, they will glimpse the way in which a creative mind operates.

On the first page of his account Lemieux says that he decided on an academic career because he could do the research "in which discoveries made along the way prove more important than the initial goals for the research program... The trend of scientists behaving more like surveyors than explorers has been reinforced by the politicization in the guise of government granting agencies.

His book lets us see how this has worked in his own case. He has always tried to deepen his theoretical understanding of what he was doing, and often the unanticipated result has been the discovery of a new method for making oligosaccharides. This in turn allowed him to enter the field of immunology equipped to do things impossible for others in this field.

But we should not underestimate the formidable psychological barrier to entering a new field. Most organic chemists know of stars in their field who confide that while their skill in molecular acrobatics gives them great satisfaction in dazzling their audience of other organic chemists, the truly important scientific challenges of today are in molecular biology and next year... five years from now... sometime, they will apply their skills in this field. We wait, and nothing happens. Lemieux said nothing, but did it. He has never been afraid to tackle the truly important problems wherever he finds them, provided he thinks he has the skiDs to conquer them.

For this author, perhaps the most important lesson of Lemieux's account is in the realm of science policy. The funding of university scientists by NRC in the days of E.W.R. Steacie was determined only by the intrinsic scientific interest of their work, as judged by fellow scientists, and not by hypothetical considerations of usefulness to industry. This was the policy, until recently, carried on by NSERC. It worked well, as shown by the fact that for a long time Lemieux was amongst the most generously funded organic chemists in Canada.

On the other hand, Lemieux believes it crucially important that it be well recognized that the support for basic research that he received from NSERC, although generous in the light of the budgets it had received from the Government of Canada, would have been completely inadequate for the support of competitive involvement toward leadership in his field.

It was the strong support for research provided by the Government of Alberta that made the difference, both by way of grants to the University of Alberta and the establishment of the Alberta Heritage Foundation for Medical Research. Lemieux was always worried that the provinces might relegate their responsibilities for the support of basic research in universities to the central government.

His concern was that centralization would inevitably lead to further politicization of the funds available for research which, Lemieux believes, has already caused great waste of opportunity. He is concerned that funding for excellence has lost priority to funding for political ends and the current support appears directed more toward ineffectual make-work projects than to the intrinsic value of improved knowledge.

The support of Lemieux's research has not only produced outstanding research but the expertise thus gained was used successfully both in his own and other people's companies to develop products for the market. Regrettably, none of this gets more than sketchy mention in his book. But in any case it seems likely that the progression from an intense interest in the mechanisms of reactions at anomeric centres to an equally intense interest in the mechanisms of the reactions of bacteria, vaccines and the receptors on cell membranes of the immune system could not have been programmed by a bureaucrat in Ottawa.

C.J. Mackenzie and E.W.R. Steacie were right: for pure science, the best policy is the least policy. Identify the best scientists, give them money, and let them do what they want, and practical applications may come afterwards.
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Title Annotation:chemist
Author:Edward, John T.
Publication:Canadian Chemical News
Date:Apr 1, 1994
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